BENZIMIDZOLYL NEUROPEPTIDE Y RECEPTOR ANTAGONISTS

ANTAGONISTES BENZIMIDAZOLYLES DU RECEPTEUR DU NEUROPEPTIDE Y

English Abstract

This invention provides a series of substituted benzimidazoles which are
useful in treating or preventing a condition associated with an excess of
neuropeptide Y. This invention also provides methods employing these
substituted benzimidazoles as well as pharmaceutical formulations which
comprise as an active ingredient one or more of these compounds.

French Abstract

L'invention concerne une série de benzimidazoles substitués qui sont utiles dans le traitement ou la prévention d'un état associé à un excès de neuropeptides Y. L'invention concerne également des procédés mettant en application ces benzimidazoles substitués, ainsi que des formulations pharmaceutiques comprenant un ou plusieurs de ces composés en tant que principe actif.

Claims

-356-

We Claim:

1. A method of treating or preventing a physiological
disorder associated with an excess of neuropeptide Y, which method
comprises administering to a mammal in need of said treatment an
effective amount of a compound of the formula


Image


wherein:

R1 is phenyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl(C1-C6
alkylenyl)-, phenyl(C1-C6 alkoxy), phenoxy(C1-C6
alkylenyl)-, phenyl(C1-C6 alkoxy)-(C1-C6 alkylenyl)-,
naphtyl, naphthyl(C1-C6 alkylenyl)-, naphtyl(C1-C6
alkoxy), naphthyloxy(C1-C6 alkylenyl)-, or naphthyl(C1-C6
alkoxy)-(C1-C6 alkylenyl)-,

any one of which phenyl, C3-C8 cycloalkyl, phenoxy,
naphthyl, or naphthyloxy moieties may be substituted
with one or groups selected from the group consisting
of halo, trifluoromethyl, C1-C6 alkyl, C2-C7 alkenyl,
C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6
alkylamino, heterocyclic, unsaturated heterocyclic,
C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl,
phenoxy, phenyl(C1-C6 alkylenyl)-, phenyl(C1-C6
alkoxy)-, benzoyl, phenyl(C2-C7 alkanoyl)-, and
phenyl(C2-C7 alkanoyloxy)-;

- 357 -

R2 is C1-C12 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C7 alkanoyl,
C1-C6 alkoxy, heterocyclic(C1-C6 alkylenyl)-, C3-C8
cycloalkyl, C3-C8 cycloalkenyl, unsaturated
heterocyclic(C1-C6 alkylenyl)-, heterocyclic(C1-C6 alkoxy)-,
unsaturated heterocyclic(C1-C6 alkoxy)-, phenyl,
phenyl(C1-C6 alkylenyl)-, naphthyl, naphthyl(C1-C6
alkylenyl)-, phenoxy(C1-C6 alkylenyl)-, naphthyloxy(C1-C6
alkylenyl)-, benzoyl(C1-C6 alkylenyl)-, C2-C7 alkenyl, C2-C7
carbamoyl, C2-C7 amido, C1-C6 alkoxycarbonyl-, or C1-C6
haloalkyl,
any one of which C1-C12 alkyl, phenyl, naphthyl,
phenoxy, naphthyloxy, benzoyl, C3-C8 cycloalkyl,
C3-C8 cycloalkenyl, heterocyclic(C1-C6 alkoxy)-,
unsaturated heterocyclic(C1-C6 alkoxy)-, heterocyclic,
or unsaturated heterocyclic moieties may be
substituted with one or more groups selected from the
group consisting of C1-C6 alkyl, C1-C6 alkoxy, phenyl,
naphthyl, phenyl(C1-C6 alkylenyl)-, naphthyl(C1-C6
alkylenyl)-, halo, trifluoromethyl, C2-C7 alkenyl,
C2-C7 alkynyl, C1-C6 alkoxy, heterocyclic,
unsaturated heterocyclic, heterocyclic(C1-C6
alkylenyl)-, unsaturated heterocyclic(C1-C6
alkylenyl)-, heterocyclic(C1-C6 alkoxy), unsaturated
heterocyclic(C1-C6 alkoxy)-, C3-C8 cycloalkyl, C3-C8
cycloalkenyl, C2-C7 alkanoyl, C2-C7 alkanoyloxy,
C1-C6 alkylamino, C1-C6 alkylthio, C1-C6 haloalkyl,
amino, nitro, and hydroxy,
or R2 may also be -(CH2)n-NR7R8, where,

n is 0 to 10, and

R7 and R8 are independently hydrogen, C1-C6 alkyl, C2-C7
alkanoyl, C1-C6 alkoxy, heterocyclic(C1-C6 alkylenyl)-,


- 358 -

unsaturated heterocyclic(C1-C6 alkylenyl)-, phenyl,
phenyl(C1-C6 alkylenyl)-, naphthyl, naphthyl(C1-C6
alkylenyl)-, phenoxy(C1-C6 alkylenyl)-,
nalphthyloxy(C1-C6 alkylenyl)-, benzoyl(C1-C6
alkylenyl)-, heterocyclic(C1-C6 alkoxy)-, unsaturated
heterocyclic(C1-C6 alkoxy)-, C1-C6 haloalkyl, C2-C7
alkenyl, C2-C7 alkynyl, C3-C8 cycloalkenyl, or C3-C8
cycloalkyl,

any one of which phenyl, naphthyl, phenoxy,
naphthyloxy, C3-C8 cycloalkyl, benzoyl,
heterocyclic, unsaturated heterocyclic,
heterocyclic(C1-C6 alkoxy)-, or unsaturated
heterocyclic(C1-C6 alkoxy)- moieties may be
substituted with one or more groups selected
from the group consisting of C1-C6 alkyl, C1-C6
alkoxy, halo, trifluoromethyl, alkoxy, C3-C8
cycloalkyl, C3-C8 cycloalkenyl, heterocyclic,
unsaturated heterocyclic, heterocyclic(C1-C6
alkylenyl)-, unsaturated heterocyclic(Cl-C6
alkylenyl)-, heterocyclic(C1-C6 alkoxy)-,
unsaturated heterocyclic(C1-C6 alkoxy)-, C2-C7
alkanoyl, C2-C7 AlkAnoyloxy, C1-C6 alkylamino,
C1-C6 alkylthio, C2-C7 alkenyl, C2-C7 alkynyl,
C1-C6 haloalkyl, amino, nitro, and hydroxy;

and

R3, R4, R6, and R6 are independently hydrogen, halo, C1-C6 alkyl,
C1-C6 alkoxy, C2-C7 alkenyl, C2-C7 alkynyl, C2-C7 alkanoyl,
C2-C7 alkanoyloxy, C1-C6 alkylamino, C1-C6 alkylthio,
benzoyl, phenoxy, phenyl(C1-C6 alkylenyl)-, C3-C8
cycloalkyl, C3-C8 cycloalkenyl, phenyl(C1-C6 alkoxy)-,
phenyl(C1-C6 alkyleneamino)-, phenyl(C1-C6
alkyleneamino)-, phenyl(C2-C7 alkanoyl)-, phenyl(C2-C7



- 359-

alkanoyloxy)-, heterocyclic, unsaturated heterocyclic,
heterocyclic(C1-C6 alkylenyl)-, heterocyclic(C1-C6 alkoxy)-,
unsaturated heterocyclic(C1-C6 alkylenyl)-, unsaturated
heterocyclic(C1-C6 alkoxy)-, amino, nitro, hydroxy,
trifluoromethyl, or-(CH2)n-NR7R8;
or a pharmaceutically acceptable salt or solvate thereof.
2. A compound of the formula


Image


wherein:

R1 is phenyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl(C1-C6
alkylenyl)-, phenyl(C1-C6 alkoxy), phenoxy(C1-C6
alkylenyl)-, phenyl(C1-C6 alkoxy)-(C1-C6 alkylenyl)-,
naphthyl, naphthyl(C1-C6 alkylenyl)-, naphthyl(C1-C6
alkoxy), naphthyloxy(C1-C6 alkylenyl)-, or naphthyl(C1-C6
alkoxy)-(C1-C6 alkylenyl)-,

any one of which phenyl, C3-C8 cycloalkyl, phenoxy,
naphthyl, or naphthyloxy moieties may be substituted
with one or groups selected from the group consisting
of halo, trifluoromethyl, C1-C6 alkyl, C2-C7 alkenyl,
C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6
alkylamino, heterocyclic, unsaturated heterocyclic,
C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl,
phenoxy, phenyl(C1-C6 alkylenyl)-, phenyl(C1-C6
alkoxy)-, benzoyl, phenyl(C2-C7 Alk~noyl)-, and
phenyl(C2-C7 alkanoyloxy)-;


- 360-

R2 is C1-C12 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C7 alkanoyl,
C1-C6 alkoxy, heterocyclic(C1-C6 alkylenyl)-, C3-C8
cycloalkyl, C3-C8 cycloalkenyl, unsaturated
heterocyclic(C1-C6 alkylenyl)-, heterocyclic(C1-C6 alkoxy)-,
unsaturated heterocyclic(C1-C6 alkoxy)-, phenyl,
phenyl(C1-C6 alkylenyl)-, naphthyl, naphthyl(C1-C6
alkylenyl)-, phenoxy(C1-C6 alkylenyl)-, naphthyloxy(C1-C6
alkylenyl)-, benzoyl(C1-C6 alkylenyl)-, C2-C7 alkenyl, C2-C7
carbamoyl, C2-C7 amido, C1-C6 alkoxycarbonyl-, or C1-C6
haloalkyl,
any one of which C1-C12 alkyl, phenyl, naphtnyl,
phenoxy, naphthyloxy, benzoyl, C3-C8 cycloalkyl,
C3-C8 cycloalkenyl, heterocyclic(C1-C6 alkoxy)-,
unsaturated heterocyclic(C1-C6 alkoxy)-, heterocyclic,
or unsaturated heterocyclic moieties may be
substituted with one or more groups selected from the
group consisting of C1-C6 alkyl, C1-C6 alkoxy, phenyl,
naphthyl, phenyl(C1-C6 alkylenyl)-, naphthyl(C1-C6
alkylenyl)-, halo, trifluoromethyl, C2-C7 alkenyl,
C2-C7 alkynyl, C1-C6 alkoxy, heterocyclic,
unsaturated heterocyclic, heterocyclic(C1-C6
alkylenyl)-, unsaturated heterocyclic(C1-C6
alkylenyl)-, heterocyclic(C1-C6 alkoxy)-, unsaturated
heterocyclic(C1-C6 alkoxy)-, C3-C8 cycloalkyl, C3-C8
cycloalkenyl, C2-C7 alkanoyl, C2-C7 alkanoyloxy,
C1-C6 alkylamino, C1-C6 alkylthio, C1-C6 haloalkyl,
amino, nitro, and hydroxy,
or R2 may also be -(CH2)n-NR7R8, where,

n is 0 to 10, and

R7 and R8 are independent1y hydrogen, C1-C6 alkyl, C2-C7
alkanoyl, C1-C6 alkoxy, heterocyclic(C1-C6 alkylenyl)-,


- 361-

unsaturated heterocyclic(C1-C6 alkylenyl)-, phenyl,
phenyl(C1-C6 alkylenyl)-, naphthyl, naphthyl(C1-C6
alkylenyl)-, phenoxy(C1-C6 alkylenyl)-,
naphthyloxy(C1-C6 alkylenyl)-, benzoyl(C1-C6
alkylenyl)-, heterocyclic(C1-C6 alkoxy)-, unsaturated
heterocyclic(C1-C6 alkoxy)-, C1-C6 haloalkyl, C2-C7
alkenyl, C2-C7 alkynyl, C3-C8 cycloalkenyl, or C3-C8
cycloalkyl,

any one of which phenyl, naphthyl, phenoxy,
naphthyloxy, C3-C8 cycloalkyl, benzoyl,
heterocyclic, unsaturated heterocyclic,
heterocyclic(C1-C6 alkoxy)-, or unsaturated
heterocyclic(C1-C6 alkoxy)- moieties may be
substituted with one or more groups selected
from the group consisting of C1-C6 alkyl, C1-C6
alkoxy, halo, trifluoromethyl, alkoxy, C3-C8
cycloalkyl, C3-C8 cycloalkenyl, heterocyclic,
unsaturated heterocyclic, heterocyclic(C1-C6
alkylenyl)-, unsaturated heterocyclic(C1-C6
alkylenyl)-, heterocyclic(C1-C6 alkoxy)-,
unsaturated heterocyclic(C1-C6 alkoxy)-, C2-C7
alkylenyl, C2-C7 alkanoyloxy, C1-C6 alkylamino,
C1-C6 alkylthio, C2-C7 alkenyl, C2-C7 alkynyl,
C1-C6 haloalkyl, amino, nitro, and hydroxy;

and

R3, R4, R5, and R6 are independently hydrogen, halo, C1-C6 alkyl,
C1-C6 alkoxy, C2-C7 alkenyl, C2-C7 alkynyl, C2-C7 alkanoyl,
C2-C7 alkanoyloxy, C1-C6 alkylamino, C1-C6 alkylthio,
benzoyl, phenoxy, phenyl(C1-C6 alkylenyl)-, C3-C8
cycloalkyl, C3-C8 cycloalkenyl, phenyl(C1-C6 alkoxy)-,
phenyl(C1-C6 alkylaneamino)-, phenyl(C1-C6
alkyleneamino)-, phenyl(C2-C7 alkanoyl)-, phenyl(C2-C7



- 362-

alkanoyloxy)-, heterocyclic, unsaturated heterocyclic,
heterocyclic(C1-C6 alkylenyl)-, heterocyclic(C1-C6 alkoxy)-,
unsaturated heterocyclic(C1-C6 alkylenyl)-, unsaturated
heterocyclic(C1-C6 alkoxy)-, amino, nitro, hydroxy,
trifluoromethyl, or-(CH2)n-NR7R8;

or a salt or solvate thereof.

3. A pharmaceutical formulation comprising a
compound of the formula



Image


wherein:

R1 is phenyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl(C1-C6
alkylenyl)-, phenyl(C1-C6 alkoxy), phenoxy(C1-C6
alkylenyl)-, phenyl(C1-C6 alkoxy)-(C1-C6 alkylenyl)-,
naphthyl, naphthyl(C1-C6 alkylenyl)-, naphthyl(C1-C6
alkoxy), naphthyloxy(C1-C6 alkylenyl)-, or naphthyl(C1-C6
alkoxy)-(C1-C6 alkylenyl)-,

any one of which phenyl, C3-C8 cycloalkyl, phenoxy,
naphthyl, or naphthyloxy moieties may be substituted
with one or groups selected from the group consisting
of halo, trifluoromethyl, C1-C6 alkyl, C2-C7 alkenyl,
C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6
alkylamino, heterocyclic, unsaturated heterocyclic,
C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl,
phenoxy, phenyl(C1-C6 alkylenyl)-, phenyl(C1-C6




- 363 -

alkoxy)-, benzoyl, phenyl(C2-C7 alkanoyl)-, and
phenyl(C2-C7 alkanoyloxy)-;

R2 is C1-C12 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C7 alkanoyl,
C1-C6 alkoxy, heterocyclic(C1-C6 alkylenyl)-, C3-C8
cycloalkyl, C3-C8 cycloalkenyl, unsaturated
heterocyclic(C1-C6 alkylenyl)-, heterocyclic(C1-C6 alkoxy)-,
unsaturated heterocyclic(C1-C6 alkoxy)-, phenyl,
phenyl(C1-C6 alkylenyl)-, naphthyl, naphthyl(C1-C6
alkylenyl)-, phenoxy(C1-C6 alkylenyl)-, naphthyloxy(C1-C6
alkylenyl)-, benzoyl(C1-C6 alkylenyl)-, C2-C7 alkenyl, C2-C7
carbamoyl, C2-C7 amido, C2-C6 alkoxycarbonyl-, or C1-C6
haloalkyl,

any one of which C1-C12 alkyl, phenyl, naphthyl,
phenoxy, naphthyloxy, benzoyl, C3-C8 cycloalkyl,
C3-C8 cycloalkenyl, heterocyclic(C1-C6 alkoxy)-,
unsaturated heterocyclic(C1-C6 alkoxy)-, heterocyclic,
or unsaturated heterocyclic moieties may be
substituted with one or more groups selected from the
group consisting of C1-C6 alkyl, C1-C6 alkoxy, phenyl,
naphthyl, phenyl(C1-C6 alkylenyl)-, naphthyl(C1-C6
alkylenyl)-, halo, trifluoromethyl, C2-C7 alkenyl,
C2-C7 alkynyl, C1-C6 alkoxy, heterocyclic,
unsaturated heterocyclic, heterocyclic(C1-C6
alkylenyl)-, unsaturated heterocyclic(C1-C6
alkylenyl)-, heterocyclic(C1-C6 alkoxy)-, unsaturated
heterocyclic(C1-C6 alkoxy)-, C3-c8 cycloalkyl, C3-C8
cycloalkenyl, C2-C7 alkanoyl, C2-C7 alkanoyloxy,
C1-C6 alkylamino, C1-C6 alkylthio, C1-C6 haloalkyl,
amino, nitro, and hydroxy,
or R2 may also be -(CH2)n-NR7R8, where,
n is 0 to 10, and


- 364-

R7 and R8 are independently hydrogen, C1-C6 alkyl, C2-C7
alkalnoyl, C1-C6 alkoxy, heterocyclic(C1-C6 alkylenyl)-,
unsaturated heterocyclic(C1-C6 alkylenyl)-, phenyl,
phenyl(C1-C6 alkylenyl)-, naphthyl, naphthyl(C1-C6
alkylenyl)-, phenoxy(C1-C6 alkylenyl)-,
naphthyloxy(C1-C6 alkylenyl)-, benzoyl(C1-C6
alkylenyl)-, heterocyclic(C1-C6 alkoxy)-, unsaturated
heterocyclic(C1-C6 alkoxy)-, C1-C6 haloalkyl, C2-C7
alkenyl, C2-C7 alkynyl, C3-C8 cycloalkenyl, or C3-C8
cycloalkyl,

any one of which phenyl, naphthyl, phenoxy,
naphthyloxy, C3-C8 cycloalkyl, benzoyl,
heterocyclic, unsaturated heterocyclic,
heterocyclic(C1-C6 alkoxy)-, or unsaturated
heterocyclic(C1-C6 alkoxy)- moieties may be
substituted with one or more groups selected
from the group consisting of C1-C6 alkyl, C1-C6
alkoxy, halo, trifluoromethyl, alkoxy, C3-C8
cycloalkyl, C3-C8 cycloalkenyl, heterocyclic,
unsaturated heterocyclic, heterocyclic(C1-C6
alkylenyl)-, unsaturated heterocyclic(C1-C6
alkylenyl)-, heterocyclic(C1-C6 alkoxy)-,
unsaturated heterocyclic(C1-C6 alkoxy)-, C2-C7
alkanoyl, C2-C7 alkanoyloxy, C1-C6 alkyliamino,
C1-C6 alkylthio, C2-C7 alkenyl, C2-C7 alkynyl,
C1-C6 haloalkyl, amino, nitro, and hydroxy;

and
R3, R4, R5, and R6 are independently hydrogen, halo, C1-C6 alkyl,
C1-C6 alkoxy, C2-C7 alkenyl, C2-C7 alkynyl, C2-C7 alkanoyl,
C2-C7 alkanoyloxy, C1-C6 alkylamino, C1-C6 alkylthio,
benzoyl, phenoxy, phenyl(C1-C6 alkylenyl)-, C3-C8
cycloalkyl, C3-C8 cycloalkenyl, phenyl(C1-C6 alkoxy)-,





- 365 -

phenyl(C1-C6 alkyleneamino)-, phenyl(C1-C6
alkyleneamino)-, phenyl(C2-C7 alkanoyl)-, phenyl(C2-C7
alkalnoyloxy)-, heterocyclic, unsaturated heterocyclic,
heterocyclic(C1-C6 alkylenyl)-, heterocyclic(C1-C6 alkoxy)-,
unsaturated heterocyclic(C1-C6 alkylenyl)-, unsaturated
heterocyclic(C1-C6 alkoxy)-, amino, nitro, hydroxy,
trifluoromethyl, or-(CH2)n-NR7R8;

or a pharmaceutically acceptable salt or solvate thereof, in combination
with one or more pharmaceutically acceptable carriers, excipients, or
diluents therefor.

Description

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W O 97/25041 PCT~US97/00511


BEN5~1MI~ZOLYLNEURO~ EYRE~;~l~RAl~TAGONl~IS

Neuropeptide Y i~ a peptide present in the central and
5 peripheral nervous systems. The peptide co-e~sts with noradrenaline
in many neurons and acts as a neulo~ldn~ el per se or
synergistically together with noradrenaline. Neuropeptide Y-
cont~ining fibers are numerous around arteries in the heart, but are
also found around the arteries in the respiratory tract, the
10 gastrointestinal tract, and the genitourinary tract. Neuropeptide Y is
also present in the cerebrurn v~ith effects on blood pressure, feeding, and
the release of different hormones. Alterations in central concentrations
of neuropeptide Y have been imrlic~ted in the etiology of psyr.hi~t.ric
disorders.
Neuropeptide Y was discovered, isolated and sec~uenced in
1982 from porcine brain as part of a general screening protocol to
discover carboxy-terminal amidated peptides and was named
neuropeptide Y due to its isolation from neural tissue and the presence
of tyrosine as both the amino and carboxy terminal amino acid.
2 0 Neuropeptide Y is a member of the pancreatic family of peptides and
shares si~nific~nt sequence homology with pancreatic polypeptide and
peptide YY.
Neuropeptide Y and the other members of its family of
peptides all feature a tertiary structure consisting of an N-terminal
polyproline helix and an ~mphirhilic a-helix, connected with a ,13-turn,
creating a hairpin-like loop, which is sometimes referred to as the
pancreatic polypeptide (PP) fold. The helices are kept together by
h~ vl hobic interactions. The amidated C-termin~l end projects away
from the hairpin loop.
3~ Subsequent to its discovery neuropeptide Y was ~ntitied as
being the most abllnl1~nt peptide in the central nervous system with
widespread distribution including the corte~, brainstem, hippocampus,
q . hypot~hl~m~ , amygdala, and t.h~l~qrnus as well as being present in the
peripheral nervous system in symr~thetic neurons and adrenal
" 3 5 chrom~ffin cells.

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Neuropeptide Y seems to fulfill the main criteria for a role
as a neurulldnsmitter, as it is stored in synaptic granules, is released
upon electrical nerve stimlllAtion, and acts at specific receptors. It is
clear that neuropeptide Y is an important messenger in its own right,
probably in the brain, where neuropeptide Y potently inhibits the activity
of adenylate cyclase and induces an increase in the intracellular levels
of calcium. Central injection of neuropeptide Y results in blood
pressure changes, increased feeding, increased fat storage, elevated
blood sugar and insulin, decreased locomotor activity, reduced body
10 temperature, and catalepsy.
Neuropeptide Y (as well as its ~h~mic~sl relat*es) acts upon
membrane receptors that are dependent on guanyl-nucleotide hin-lin~
proteins, known as G protein-coupled receptors. G proteins are a family
of memhrane proteins that become activated only after hin-linE
15 gll~nosine triphosphate. Activated G proteins in turn activate an
~mpli~er enzyme on the inner face of a mçmhrane; the enzyme then
converts precursor molecules into second messengers.
Neuropeptide Y appears to interact with a family of closely
related receptors. These reGe~lols are generally rl~s~sifiefl into several
20 subtypes based upon the ability of different tissues and receptors to bind
different frslEment~ of neuropeptide Y and other members of the PP
f~rnily of peptides. The Y1 receptor subtype appears to be the major
vascular neuropeptide Y receptor. The Y2 receptor subtypes can also
occur postjunctionally on vAsctll~r smooth muscle. The as-yet-
25 llni.~ol~ted Y3 receptor subtype appears to be neuropeptide Y-specific,
not hintling peptide YY. This receptor is likely to be present in the
adrenal tissues, medulla, heart, and brain stem, ~mon~ other areas.
[For a review of neuropeptide Y and neuropeptide Y receptors, see. e.~.,
C. Wahlestedt and D. Reis, ~nnual Review of Ph~rmacolo~y and
30 Toxicolo~y, 33:309-352 ~1993); D. Gehlert and P. ~ir~kin~l, Current
Ph~rm~ceutical Desi1Jn,1:29~;-304(1995)].
In view of the wide number of clinical m~ lies associated
with an excess of neuropeptide Y, the development of neuropeptide Y ~
receptor antagonists will serve to control these clinical conditions. The
35 earliest such receptor antagonists, such as Patent Cooperation Treaty
Patent Publication WO 91/08223, pllhli~hell dune 13, 1991, and Patent

CA 02242579 1998-07-08

W O 97t25041 PCTrUS97/00511


Cooperation Treaty Patent Publication WO 94/00486, pllhli~hed January
6, 1994, were peptide del;vaLives. These antagonists are of limited
h~ ceutical utility ~hecause of their metabolic instability.
This invention provides a class of potent non-peptide
5 neuropeptide Y receptor antagonists. By virtue of their non-peptide
nature, the compounds of the present i~lvel~ion do not suffer from the
shortcoming~, in terms of metabolic instability, of known peptide-based
neuropeptide Y receptor antagonists.
This invention encomr~es methods for the tre~trn~nt or
10 l.level~tion of a physiological disorder associated with an excess of
neuropeptide Y, which method co~ ises ~mini~tering to a m~mm~ql
in need of said tre~tment an effect*e amount of a compound of Formula
I




R5 ~ \ ~ R

R6 R2
I




wherein-
RliS phenyl, C3-Cg cycloalkyl, C3-Cg cyclos~lkenyl, phenyl(Cl-C6
alkylenyl)-, phenyl(Cl-C6 alkoxy3, phenoxy(Cl-C6
alkylenyl)-, phenyl(Cl-C6 alkoxy)-(C1-C6 alkylenyl)-,
nFIphthyl~ n~rhthyl(C1-C6 alkylenyl)-, naphthyl(Cl-C6
alkoxy), naphthyloxy(Cl-C6 alkylenyl)-, or n~phthyl~Cl-C6
alkoxy)-(C1-C6 alkylenyl)-,

any one of which phenyl, C3-Cg cycloalkyl, phenoxy,
n~phthyl, or n~phthyloxy moieties may be subs~i~u~ed
with one or groups selected from the group consisting
3 0 of halo, trifluoromethyl, Cl-C6 alkyl, C2-C7 alkenyl,
C2-C7 alkynyl, Cl-C6 alkoxy, Cl-C6 alkylthio, Cl-C6

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W O 97/25041 PCTnUS97/OO511


alkyl~qmino, heterocyclic, unsaturated heterocyclic,
C3-Cg cycloalkyl, C3-Cg cyclo~lkenyl, phenyl,
phçno~y, phenyl(Cl-C6 alkylenyl)-, phenyl(Cl-C6
alko~y)-, benzoyl, phenyl(C2-C7 alk~qnQyl)-, and
phenyl(C2-C7 ~lk~noyloxy)-;

R2 is Cl-Cl2 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C7 ~lk~noyl,
Cl-C6 alkoxy, heterocyclic(Cl-C6 alkylenyl)-, C3-Cg
cycloalkyl, C3-Cg cycloalkenyl, lm~tllrated
heterocyclic(Cl-C6 alkylenyl)-, heterocyclic(Cl-C6 alko~y)-,
unsaturated heterocyclic(C1-C6 alkoxy)-, phenyl,
phenyl(C1-C6 alkylenyl)-, n~pht~yl,n~rht.~yl(C1-C6
alkylenyl)-, phenr~y(C1-C6 alkylenyl)-, n~pht~yloxy(Cl-C6
alkylenyl)-, benzoyl(Cl-C6 alkylenyl)-, C2-C7 alkenyl, C2-C7
carbPmoyl, C2-C7 amido, Cl-C6 alkolLyca,bonyl-, or Cl-C6
haloalkyl,
any one of which Cl-C12 alkyl, phenyl, naphthyl,
ph~no~y, n~pht~yloxy, benzoyl, C3-Cg cycloalkyl,
C3-Cg cycloalkenyl, heterocyclic(Cl-C6 alkoxy)-,
u~saturated heterocyclic(Cl-C6 alkoxy)-, heterocyclic,
or lln~tllrated heterocyclic moieties may be
substituted with one or more groups selected firom the
group con~i~t;n~ of Cl-C6 alkyl, Cl-C6 alkoxy, phenyl,
nslrh~yl, phenyl(Cl-C6 alkylenyl)-, n~phthyl(Cl-C6
a~ylenyl)-, halo, trifluoromethyl, C2-C7 alkenyl,
C2-C7 alkynyl, C1-C6 alkoxy, heterocyclic,
lln~atllrated heterocyclic, heterocyclic(Cl-C6
alkylenyl)-, lln~t~lrated heterocyclic(Cl-C6
alkylenyl)-, heterocyclic(C1-C6 alkoxy)-, unsaturated
heterocyclic(Cl-C6 alkoxy)-, C3-Cg cycloalkyl, C3-Cg
cyr.loAlk~nyl, C2-C7 ~lk~nnyl, C2-C7 f~lk~noyloxy,
Cl-C6 alkyl~mino, Cl-C6 alkylthio, Cl-C6 haloalkyl,
amino, nitro, and hyd~O~y~
or R2 may also be -(CH2)n-NR7R8, where,

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nisOtolO,and

R7 and R8 are indepen(l~ntly hydrogen, Cl-C6 alkyl, C2-C7
~ 5 ~lkAntlyl, Cl-C6 alkogy, heterocyclic(Cl-C6 alkylenyl)-,nn~t~lrated heterocyclic(Cl-C6 alkylenyl)-, phenyl,
phenyl(C1-C6 ~kylenyl)-, n~rht~yl, nApht.~yl(Cl-C6
alkylenyl)-, rh~nr~y(C1-C6 alkylenyl)-,
n~I~ht.hyloxy(Cl-C6 alkylenyl)-, benzoyl(Cl-C6
Ikylenyl)-, heterocyclic(Cl-C6 alkoxy)-, lm~tllrated
heterocyclic(Cl-C6 ~lkoxy)-, Cl-C6 h~lo~lkyl, C2-C7
alkenyl, C2-C7 ~kynyl, C3-Cg cycloAlk~nyl, or C3-Cg
cycloalkyl,

any one of which phenyl, nApht.hyl, phenogy,
naphthyloxy, C3-Cg cycloalkyl, benzoyl,
heterocyclic, llnfiAtllrated heterocyclic,
heterocyclic(Cl-C6 alkoxy)-, or lm~Atllrated
heterocyclic(Cl-C6 alkoxy)- moieties may be
substituted with one or more groups selected
from the group consisting of Cl-~6 alkyl, Cl-C6
alkoxy, halo, trifluoromethyl, alkoxy, C3-Cg
cycloalkyl, C3-Cg cycloalkenyl, heterocyclic,
lln~Atllrated heterocyclic, heterocyclic(Cl-C6
alkylenyl)-, lln~at.lrated heterocyclic(Cl-C6
alkylenyl)-, heterocyclic((: l-C6 alkoxy)-,
~n~Atnrated heterocyclictCl-C6 alkogy)-, C2-C7
~lk~n~yl, C2-C7 Alk~noylogy, Cl-c6 alkylAmino,
C1-C6 alkylthio, C2-C7 alkenyl, C2-C7 alkynyl,
Cl-C6 hAloAlkyl, amino, nitro, and hydlv~y,

and

R3, R4, R5, and R6 are indepenclen~ly hydrogen, halo, Cl-C6 alkyl,
3 5 Cl-C6 alkoxy, C2-C7 alkenyl, C2-C7 alkynyl, C2-C7 Alk~qn(~yl~
C2-C7 ~lk~noyloxy, Cl-C6 alkylArnino, Cl-C6 alkylthio,

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benzoyl, phqrlo~y, phenyl(Cl-C6 alkylenyl)-, C3-C8
cycloalkyl, C3-Cg cycloalkenyl, phenyl(cl-c6 alkoxy)-,
phenyl(C1-C6 alkyl~ne~mino)-, phenyl(C1-C6
alkylenq~mino)-, phenyl(c2-c7 ~lk~noyl)-, phenyl(c2-c7
~qlk~noyloxy)-~ heterocyclic, lln.~tllrated heterocyclic,
heterocyclic(Cl-C6 alkylenyl)-, heterocyclic(C1-C6 alko~y)-,
unsaturated heterocyclic(Cl-C6 alkylenyl)-, unsaturated
heterocyclic(Cl-C6 alkoxy)-, amino, nitro, hyL~ y,
tri~uoromethyl, ~o-(cH2)n-NR7R8~ or-(cH2)n-NR7R8;

or a pharmaceutically acceptable salt or solvate thereo~

This invention also çncolnpasses, in additional
embo-liment~, the novel compounds of Formula I, and the salts and
15 solvates thereof, as well as pharmaceutical formulations co~ ising a
compound of Formula I, or a pharmaceutically acceptable salt or solvate
thereof, in cnmhins~tion with one or more pharmaceutically acceptable
carriers, excipients, or diluents therefor.
The current invention concerns the discovery that a select
20 group of substituted bçn~i7ni.1~7:0les, those of Formula I, are useful as
neuropeptide Y receptor antagonists.
The terms and abbreviations used in the instant ~ mples
have their normal me~nin~ unless otherwise ~lesign~ed. For example
"~C" refers to degrees Celsius; aN" refers to normal or normality;
25 "mmol" refers to millimole or millimnles; "g" refers to gram or grams;
aml~ me~n~ milliliter or milliliters; "M" refers to molar or molarity;
"MS~ refers to mass spectrometry; aIRJJ refers to infrared spectroscopy;
and "NMR" refers to nuclear m:~Fnetic resonance ~pectroscopy.
As used herein, the term "Cl-Cl2 alkyl" refers to straight or
3 o branched, monovalent, saturated aliphatic chains of 1 to 12 carbon
atoms and includes, but is not limited to, methyl, ethyl, propyl,
iso~ro~yl, butyl, isobutyl, t-butylL, pentyl, isopentyl, and hexyl. The term
"Cl-C12 alkyl" includes within its flqfinition the terms "Cl-C6 alkyl" and
"C1-C4 alkyl".

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"C2-C7 s~lk~n()yloxyn represents a straight or branched alkyl
chain having from one to six carbon atoms attached to a carbonyl moiety
joined through an o~y~en atom. Typical C2-C7 ~lk~noyloxy groups
include acetoxy, propanoyloxy, isopropanoyloxy, butanoyloxy,
5 t-butanoyloxy, pentanoyloxy, hexanoyloxy, 3-methylp~nt~nnyloxy and the
like.
"C3-Cg cycloalkyl" represents a saturated hydrocarbon ring
structure cont~ining from three to eight carbon atoms. Typical C3-Cg
cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl,
10 cycloheptyl, and the like.
The term ~carbamoyl" as employed herein refers to a group
of the structure -NH-C(O)-. The term aC2-C7 carbamoyl" as employed
herein refers to a group of the structure (Cl-C6 alkyl)-NH-C(O~-
"Halo" represents chloro, fluoro, bromo or iodo.
The term "C1-C6 h~lo~lkyl" refers to a straight or branched,
monovalent, saturated ~ h~t.ic chains of 1 to 6 carbon atoms
substituted with one or more halo groups.
"Cl-Clo alkylthio" represents a straight or br~nl~he~ alkyl
chain having from one to ten carbon atoms ~tt~lh~fl to a sulfur atom.
Typical Cl-Clo ~lkylthio groups include methylthio, ethylthio,
yl~l~io, iso~lo~ylthio, butylthio and the like. The term "Cl-Clo
alkylthio" includes within its rl~finition the term "C1-C6 alkylthio" and
aC1-C3 alkylthio".
"C1-Cl2 alkylenyl" refers to a straight or branched, divalent,
saturated aliphatic chains of 1 to 12 carbon atoms and includes, but is
not limited to, methylenyl, ethylenyl, propylenyl, iso~lo~ylenyl,
butylenyl, isobutylenyl, t-butylenyl, pentylenyl, isopentylenyl, hexylenyl,
octylenyl, 3-methyloctylenyl, decylenyl. The term "Cl-C6 alkylenyl" is
encomr~.~sed within the term aCl-C~2 alkylenyl".
"C1-Clo alkyl~mino" represents a group of the formula
-NH(Cl-Clo alkyl)
wherein a chain having from one to ten carbon atoms is ~tt~ ed to an
- amino group. Typical Cl-C4 alkyl~mino groups include methyl~mino,
ethyl~mino, propyl~minn, iso~ yl~minn, butylamino, sec-butyl~minn
3 5 and the like.

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The term "C2-Clo alkenyl" as used herein represents a
straight or branched, monovalent, unsaturated aliphatic chain having s
from two to ten carbon atoms. Typical C2-Clo alkenyl groups include
ethenyl (also known as vinyl), 1-methylethenyl, 1-methyl-1-propenyl,
1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 1-propenyl, 2-propenyl,
2-butenyl, 2-pentenyl, and the like.
The term ''C2-Clo alkynyln as used herein represents a
straight or branched, monovalent, unsaturated aliphatic chain having
firom two to ten carbon atoms with at least one triple bond. Typical
C2-Clo alkynyl groups include ethynyl, 1-methylethenyl, 1-~lo~yl~y
1-butynyl, 1-hexynyl, 2-~ yllyl~ 2-butynyl, 2-pentynyl, and the like.
~C3-Cg cyclo~lk~nyl~ represents a hydrocarbon ring
structure cont~ining from three to eight carbon atoms and having at
least one double bond within that ring, which is unsubstituted or
substituted with 1, 2 or 3 substituents indepen~n~ly selected from halo,
halo(Cl-C4 alkyl), Cl-C4 alkyl, Cl-C4 alkoxy, carboxy, Cl-C4
alko,~y~;albonyl, carbamoyl, N-(Cl-C4 alkyl)carbamoyl, amino, Cl-C4
alkyl~mino, di(Cl-C4 alkyl)amino or ~(CH2)a-l~Y where a is 1, 2, 3 or 4
and RY is hy~ y~ Cl-C4 alkoxy, carboxy, Cl-C4 alk~yc~ll)onyl, amino,
carbamoyl, Cl-C4 alkylamino or di(Cl-C4 alkyl)amino.
"Cl-C6 alkylzlmino" represents a straight or br~n-hefl
alkyl~m;no chain having from one to six carbon atoms ~tt~ched to an
amino group. Typical Cl-C6 alkyl-amino groups include methyl~mino,
ethyl~minc-, propyl~mino, iso~lv~yl~mino, butyl~mino, sec-butylamino
and the like. "Cl-C6 alkylamino~ ~ncomrasses within this term "Cl-C4
alkyl~m;no~.
~Cl-C6 alkoxy~ represents a straight or br~nohe~ alkyl
chain having from one to six carbon atoms attached to an o~y~ell atom.
Typical Cl-C6 alkoxy groups include methoxy, ethoxy, propoxy,
3 o isopropoxy, butoxy, t-butoxy, pentoxy and the like. The term ~Cl-C6
alkoxy" includes within its definition the term ~Cl-C3 alkoxy".
"C2-C7 alkanoyl~ represents a straight or branched alkyl
chain having from one to six carbon atoms iqtt~hed to a carbonyl
moiety. Typical C2-C7 ~lks~nf~yl groups include ethanoyl, propanoyl,

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isopropanoyl, butanoyl, t-butanoyl, pentP~noyl~ he~noyl,
3-methylpent~noyl and the like.
"C1-C6 alkoxycarbonyl" represents a straight or branched
alkoxy chain having from one to six carbon atoms 2st~ hed to a carbonyl
5 moiety. Typical Cl-C6 alkoxycarbonyl groups include metho~yc~l~onyl,
etho~y~ onyl, propo~y~bonyl, isopropo~yca.bonyl, buto~ycalbonyl,
t-but~yc~Lbonyl and the like.
"C3-Cg cycloalkyl" represents a saturated hydrocarbon ring
structure cont~inin~ from three to eight carbon atoms. Typical C3-Cg
îO cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl,
cycloheptyl, and the like.
In those substitl~*ons employing nAphthyl, naphthyloxy,
n~I~ht.~nyl, or the like groups, the n~I ht.l~yl moiety may be attached at
the one, two, or three position.
The term "heterocycle" represents an unsubstituted or
substituted stable ~;- to 7-mPmhered monocyclic or 7- to 10-membered
bicyclic heterocyclic ring which is saturated and which consists o~
carbon atoms and from one to three heteroatoms selected from the group
consisting of nitrogen, oxygen or sulfur, and wherein the nitrogen and
20 sulfur hetero~t~m~ may optionally be oxidized, and the nitrogen
heteroatom may optionally be quaternized and including a bicyclic group
in wh;ch any of the above-.lefinetl heterocyclic rings is fused to a b~n~ene
ring. The heterocyclic ring may be ~tt~ch~d at any heteroatom or carbon
atom which affords a stable structure. The hetero-cycle is unsubstituted
25 or substituted with 1, 2 or 3 subs+itllen+~ indep~n~ently selected from
halo, halo(Cl-C4)-alkyl, Cl-C4 alkyl, Cl-C4 alkoxy, calbo~y, Cl-C4 alkoxy-
carbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl, amino, C1-C4
alkyl~mino, di(C1-C4)alkyl~mino or -(CH2)a-Rd where a is 1, 2, 3 or 4;
and Rd is hyJ~o~y, Cl-C4 alkoxy, carboxy, Cl-C4 alkoxycarbonyl, amino,
3 ~ carbamoyl, C1-C4 alkylAmino or di(C1-C4)alkyl~mino.
The term "llns~tllrated heterocycle" represents an
unsubstituted or substituted stable ~i- to 7-membered monocyclic or 7- to
10-membered bicyclic heterocyclic ring which has one or more double
bonds and which consists of carbon atoms and from one to three
3 5 heteroatoms selected from the group consisting of nitrogen, oxygen or
sulfur, and wherein the nitrogen and sulfur heteroatoms may optionally

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- 10-
be oxidized, and the nitrogen heteroatom may optionally be quarternized
and including a bicyclic group in which any of the above-defined
heterocyclic rings is fused to a bçn7ene ring. The lln.~Atllrated
heterocyclic ring may be Att~-~he-l at any heteroatom or carbon atom
5 which affords a stable structure. The l1n~A~ a~ed heterocycle is
unsubstituted or sul)~ u~ed with 1, 2 or 3 substitllen~ indepentl~ntly
selected from halo, Cl-C6 haloalkyl, Cl-C4 alkyl, Cl-C4 alkoxy, carboxy,
Cl-C4 alko~yc&ll,onyl, carbamoyl, N-(Cl-C4)alkylcarbamoyl, amino, Cl-
C4 alkylAmin-~, di(Cl-C4)alkylAmino or -(CH2)a-Re where a is 1, 2, 3 or 4;
10 and Re is hyd~oxy, Cl-C4 alkoxy, carboxy, Cl-C4 A~kokyc~llbonyl, Amino,
carbamoyl, Cl-C4 alkylArnino or di(Cl-C4)alkylAmino.
h'.~Amrles of such heterocycles and unsaturated
heterocycles include piperidinyl, piperazinyl, azepinyl, pyrrolyl, 4-
piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl,
15 imitlA7olinyl, imidazolidinyl, pyridyl, pyrazinyl, ~yl~idinyl,
pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl,
morpholinyl, thiazolyl, t~i~7O1i~inyl~ isothiazolyl, quinl1rli~inyl,
isothiA7oli(1inyl, indolyl, qninolinyl~ isoqninolinyl, ben7imidazolyl,
thiAAiA70lyl, ben;~o~yl~lyl, benzothiA7olyl, ben7o~7olyl, furyl,
20 tetrahy~orulyl, tetrahyJlo~ylal-yl, thienyl, benzothienyl,
thiAmorpholinyl, thiAmorpholinyl-sulfoxide, thiamorpholinylsul~one,
o~A~ olyl, triazolyl, tetr~ydroqllinolinyl~ tetrahydrisoquinolinyl, 4,~-
dihydrofhi~7Qlyl, 3-methylimi~A7olyl, 3-met~o~cy~y~;dyl, 4
chloroqllinolinyl, 4-aminothiA7.olyl, 8-methylqninolinyl, 6-
25 chloroqlfino~Alinyl, 3-etLyl~y..dyl, 6-methoxyben7.imidazolyl, 4-
hydiol~yrulyl,
4-methylisoqllinolinyl, 6~8-dibromoqllinolinyl~ 4,8-dimethyl-nArht~yl, 2-
methyl-1,2,3,4-tetrahydroisoqllinolinyl,
N-methyl-qllinolin-2-yl, 2-t-butoxycarbonyl-1,2,3,4-isoqllinolin-7-yl and
3 o the like.
The te~n "amino-protecting group" as used in the
sper~ificAt;on refers to substituents of the amino group commnnly
employed to block or protect the mino ~unctionality while reacting other
functional groups on the compound. h'~Arnrles of such
35 amino-protecting groups include for_yl, trityl, ph~l~Alimi~lo,
trichloroacetyl, chloroacetyl, br--moAcetyl, iodoacetyl, and urethane-type

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blocking groups such as benzylo~ycall)onyl, 4-phenylbenzylo~y~ ~bonyl,
2-methylbenzylo~y~ onyl, 4-methoxybenzylo~ycdl l)onyl,
4-fluorobenzylo~y.,all,onyl, 4-chlorobenzylu~y~all,onyl,
3-chlorobenzylo~y~l)onyl, 2-chlorobenzylokyc~hlJonyl,
5 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzylo~ycall,onyl,
3-bromobenzyloxycarbonyl, ~nitrobenzylo~y~allJonyl,
4-cyanobenzylo~yc~bonyl, t-buto~yca~lJonyl,
l,l-rliph~nyleth-l-ylo~ycall,onyl, l,~ phenyllJlo~-l-ylo~ycall)on
2-phellyl~ -2-ylo~y~l~onyl, 2-(p-toluyl)-prop-2-ylo~y. all~onyl,
10 cyclopentanyloxycarbonyl, l-methylcyclopentanyloxycarbonyl,
cycl~hç~nylogycarbonyl, 1-methylcyr.lohe~nylo~yca~l~onyl,
2-methylcyclohe~nylu~yc~bonyl, 2-(4-toluylsulfonyl)-etho~y~;~lJonyl,
2-(methylsulfonyl)ethoxycarbonyl,
2-(triphenylphosphimo)-ethoxycarbonyl, fluorenylmethoxy-carbonyl
15 ("FMOC~), 2-(trimethylsilyl)etho~y~ onyl, allylo~y.a.l,onyl,
1-(trimethylsilylmethyl)prûp- 1-enylo~yca~ bonyl,
~;-benzisoxalylmethoxycarbonyl, 4-acetoxybenzylo~ycalbonyl,
2,2,2-trichloroetho~y~l)onyl, 2-ethynyl-2-propo~y~all)onyl,
cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl,
2 o isobornylo,~y~all,onyl, 1-piperidylo~yca,bonyl and the like;
benzoylmethylsulfonyl group, 2-nitrophenylsulfenyl, diphenylphosphin
o~ide and like amino-proteC~in~ groups. The species of
~mino-protecting group employed is usually not critical so long as the
derivatized amino group is stable to the condition of subsequent
25 re~ction~ on other positions of the intermediate molecule and can be
selectively removed at the a~ ol~l;ate point without di~. u~ g the
r.qm~in~er of the molecule inr.lll~inE any other amino-protecting
groups. r~felled amino-protec~inF groups are trityl, t-butu~yca~l)onyl
(BoC), allylo~y. all,onyl and benzyloxycarbonyl. Further e~mrles of
3 0 groups 1 erellad to by the above terms are described by E. ~ m,
"Protective Groups in Organic Chemist~, (J.G.W. McOmie, ed., 1973),
at Chapter 2; and T.W. Greene and P.G.M. Wuts, PROTECTIVE GROUPS
IN ORGANI~ SYNTHESIS, (1991), at Chapter 7.
The term "carboxy-protect.in~ group" as used in the
3 5 specification refers to substituents of the carboxy group commonly
employed to block or protect the carboxy functionality while re~ctinF

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other functional groups on the compound. F~Amrles of such
carboxy-protecting groups include methyl, p-nitrobenzyl,
p-methylbenzyl, p-methoxy-benzyl, 3,4-dimethoxybenzyl,
2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl,
s p~nt~methylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl,
4,4'-dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, t-butyl,
t-amyl, trityl, 4-metho~y~ yl, 4,4'-dimetho~yl~;~yl,
4,4',4"-trimethoxy~rityl, 2-phenylprop-2-yl, trimethylsilyl,
t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl,
10 2-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl,
4-nitrobenzylsulfonylethyl, allyl, I~.innzlmyl,
1-(trimethylsilylmethyl)prop-1-en-3-yl and like moieties. rle~e. led
carboxy-protecting groups are allyl, benzyl and t-butyl. Further
mples of these groups are found in E. ~lAm, sul?ra, at Chapter 5,
15 and T.W. Greene, ~, supra, at Chapter 5.
The term "hydroxy-protecting groups" as used herein refers
to substitents of the hy~l~o~y group comm- nly employed to block or
protect the hy~l~ol~y functionAlity while reActin~ other fi~nct;onAl groups
on the compound. ~.~rAmples of such hy~ol~y-protecting groups include
20 methoxymethyl, benzyloxymethyl, methoxyethoxymethyl,
2-(trimethylsilyl)ethoxymethyl, methylf lti orn ethyl, 2,2-dichloro- 1,1-
difluoroethyl, tetrahyd~ yl~nyl, phçn~cyl, cyclc,~ ylmethyl, allyl, Cl-
C6 alkyl, 2,6-dimethylbenzyl, o-nitrobenzyl, 4-picolyl, dimethylsilyl,
t-butyldimethylsilyl, levlllin~qte, pivaloate, benzoate, ~limet~ylsulfonate,
25 dimethylphosphinyl, isol)ul,y.ate, a~ nt~slte and tetrahyLo~ylallyl.
Further ç~mples of these groups may be found in T. W. Greene and
P.G.M. Wuts, PROTECTrVE GROUPS IN OR~A~C SY1NTHESIS,(1991) at
Chapter 3.
The compounds of the present invention may have one or
3 o more asymmetric centers. As a consequence of these chiral centers,
those compounds of the present invention occur as r~c~m~tes, mixtures
of çns~ntiomers and as individual enS~ntinmers~ as well as diastereomers
and mixtures of diastereomers. All asymmetric forms, individual
isomers and combinations thereof, are within the scope of the present
3 s invention.

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- 13-
The terms "R" and "S" are used herein as commoIlly used
in organic ~hemi~try to denote specific configuration of a chiral center.
The term "R" (rectus) refers to that configuration of a chiral center with
a clockwise rel~t.ion~hip of group priorities ~highest to second lowest)
5 when viewed along the bond t~,v~d the lowest priority group. The term
''S~ (sinister) refers to that configuration of a chiral center with a
counterclockwise rçl~*orl.~hip of group priolities thighest to second
lowest) when viewed along the bond toward the lowest priority group.
The priority of groups is based upon their ~t~mic number (in order of
10 decreasing atom-ic number). A partial list of priorities and a discussion
of stereoche_istry iB cont~in~rl in NOMENCLATURE OF ORGANIC
COMPOUNDS: PRINCIPLES AND PRACTICE, (J.H. Fletcher, et al., eds.,
1974) at pages 103-12(?.
In ~iti~n to the (R)-(S) system, the older D-L system may
15 also be used in this docnment to denote absolute configuration,
especially with reference to amino acids. In this system a Fischer
projection formula is oriented so that the nlmnber 1 carbon of the main
chain is at the top. The prefix ''D~iS used to represent the absolute
configuration of the isomer in which the functional (determining) group
2 o is on the right side of the carbon atom at the chiral center and "L~, that of
the isomer in which it is on the left.
In order to preferentially prepare one optical isomer over its
enantiomer, the skilled practitioner can proceed by one of two routes.
The practitioner may first prepare the ...iX(..,e of en~ntiomers and then
25 separate the two en~ntiomers. A comml7I ly employed method for the
resolution of the r~cem;c ,~;x~ e (or l~ ule of en~n*omçrs) into the
individual çn~nti~mLers is to first convert the enantiomers to
diastereomers by way of ~l....llg a salt with an optically active salt or
base. These diastereomers can then be separated using differential
30 solubility, fractional cryst~ tion, chromatography, or ~ike methods.
Further details regarding resolution of enantiomeric ~i~ es can be
found in J. Jacques, et al., ENANTIOMERS, RACEMATES, AND
RESOLUTIONS, (1991).
In addition to the srhçmes described above, the practitioner
3 5 of this i~lvel~ion may also choose an ~n~n1;Qspecific protocol for the
preparation of the compounds of Formula I. Such a protocol employs a

CA 02242579 1998-07-08

W O 97~5041 PCT~US97/00~11

- 14-
synthetic reaction ~esi~n which m~int~in.q the chiral center present in
the starting material in a desired orient~tion These reaction s-hemes
usually produce compounds in which greater than 9~; percent of the title
product is the desired enantiomer.
As noted sul~ra, this invention includes methods employing
the pharmaceutically acceptable salts of the compounds defined by
Formula I as well as salts of the compounds of Formula II. A
compound of this invention can possess a sufficiently acidic, a
sufficiently basic, or both functional groups, and accoldillgly react with
10 any of a number of organic and inorganic bases, and inorganic and
org~nic acids, to form a pharmaceutically acceptable salt.
The term "pharmaceutically acceptable salt~ as used
herein, refers to salts of the compounds of the above forrn~ which are
subst~n~i~lly non-toxic to living org~ni~mq. Typical pharmaceutically
15 acceptable salts include those salts prepared by reaction of the
compounds of the present invention with a pharmaceutically acceptable
mineral or org~n;c acid or an organic or inorganic base. Such salts are
known as acid addition and base addition salts.
Acids commnnly employed to form acid addition salts are
20 inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic
acid, sulfuric acid, phosphoric acid, and the like, and organic acids
such as p-toluenesulfonic, methanesulfonic acid, oxalic acid,
p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,
benzoic acid, acetic acid, and the like. ~mples of such
2~ pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate,
sulfite, bisulfite, phosphate, monohydrogenphosphate,
dihydrogenphosphate, metaphosphate, pyrophosphate, chlonde,
bromide, iodide, acetate, propionate, rlec7lno~te, caprylate, acrylate,
formate, hydrochloride, dihydrochloride, isobutyrate, caproate,
30 heptanoate, propiolate, oxalate, m~lon~te, s~ cin~te, suberate, seh~c~te,
fumarate, maleate, butyne-1,4-dioate, hexglle-1,6-~io~te, benzoate,
chlorobenzoate, methylhen7o~te, hyJru2~yban~o~te~ methoxybenzoate,
phthalate, sulfonate, xylenesnlfon~qte, phenylacetate, phenyl~ ionate,
phenylbutyrate, citrate, lactate, ~-hy~o~yl~u~yl~lte~ glycolate, ta~ e,
35 methanesulfonate, propanesnlfor~S~te, n~phth~lene-1-~ulfonate~
napththalene-2-slllfon~te, m~n-lel~ta and the like. Preferred

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pharmaceutically acceptable acid addition salts are those formed with
mineral acids such as hydrochloric acid and hydrobromic acid, and
those formed with organic acids such as maleic acid and
methanesulfonic acid.
Base addition ~alts include those derived from inorganic
bases, such as ~qmmt nium or alkali or ~lk~line earth metal hydroxides,
carbonates, bicarbonates, and the like. Such bases useful in preparing
the salts of this invention thus include sodium hydroxide, potassium
hydro~ide, ~mmorium hydroxide, potassium carbonate, sodium
carbonate, sodium bicarbonate, potassium bicarbonate, calcillm
hydroxide, calcium carbonate, and the like. The potassium and sodium
salt forms are particularly ~ efelled.
It should be recognized that the particular counterion
forming a part of any salt of this invention is usually not of a critical
nature, 80 long as the salt as a whole is pharmacologically acceptable
and as long as the counterion does not contribute llnflesired qualities to
the salt as a whole.
This invention further ~nComrA~ses methods employing
the pharmaceutically acceptable solvates of the compounds of Formula
I. Many of the compounds of Formula I can combine with solvents such
as water, met~Anol, etl~nol and acetonitrile to form pharmaceutically
acceptable solvates such as the correspon-ling hydrate, met~Anol~e,
ethanolate and acetonitrilate.
This invention also çncomI-asses the pharmaceutically
acceptable prodrugs of the compounds of Fo~mula I. A prodrug is a
drug which has been çhemic~lly modified and may be biologically
inactive at its site of Actinn, but which may be degraded or modified by
one or more enzymatic or other ;n vivo processes to the parent hio~ctive
form This prodrug should have a different pharmacokinetic profile
3 o than the parent, enabling easier absorption across the mucosal
epithelium, better salt formation or solubility, or il~ oved syste~uc
stability (an increase in plA~mA half-life, for ~Ample).
- Typically, such rh~mic~l mor~ificAt.ions include:
1) ester or amide del;va~ives which may be cleaved by
3 5 esterases or lipases;

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- 16-
2) peptides which may be recognized by specific or
nonspecific proteases; or
3) derivatives that accumulate at a site of action through
memhrane selection of a prodrug form or a modified prodrug form;
or any comhin~tion of 1 to 3, $upra. ConventioTI~l procedures for the
selection and preparation of suitable prodrug del;v~,ives are described,
for ~mple, in H, Bllnrlg~s-rd, DESIGN OF PRODRUGS, (198~).
The compounds of the present invention are deliv2llives of
ben7imi~ ole which are named and numbered accol lillg to the RING
INDEX, The American Chemical Society, as follows.
~>

The ~efel~ed methods of this invention employ those
compounds of Formula I wherein.
a) R1 is phenyl, n~pht.hyl, phenyl(C1-C6 alkylenyl)-,
naphthyl(Cl-C6 alkylenyl)-, phenyl(Cl-C6 alkoxy)-, n~ph+l~yl(cl-c6
alkoxy)-, phenoxy(C1-C6 alkylenyl)-, n~pht~yloxy(C1-C6 alkylenyl)-, or
substituted de~;v~ives thereof;
b) R2 is phenyl, heterocyclic, lln.e$~t~lrated heterocyclic,
phenyl(Cl-C6 alkylenyl)-, n~ph~llyl(Cl-C6 alkylenyl)-, phenyl(Cl-C6
alkoxy)-, heterocyclic(Cl-C6 alkylenyl)-, lln~t.lrated heterocyclic(Cl-C6
alkylenyl)-, heterocyclic(Cl-C6 alko~y)-, unsaturated heterocyclic(Cl-C6
alkoxy)-, -(CH2)n-NR7R8, or substituted deliv~ives thereof;
c) R3, R4, R5, and R6, are indepçn~enfly hydrogen, chloro,
fluoro, bromo, C1-C6 alkyl, trifluoromethyl, Cl-c6 alkoxy, benzoyl, C2-C7
~lk~noyl, phenyl(Cl-C6 alkylenyl)-, phenyl(Cl-C6 alkoxy)-, or
-(CH2)n-NR7R8, or substituted del;v~lives thereof; and
d) at least one of R3, R4, R5, and R6 is not hydrogen.
3 0 The preferred compounds of this invention are those
compounds which are employed in the preferred methods of this
invention.

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- 17-
In the s~ientific literature deliva~ives of b~n~irnidazole are
already known to possess different biological activities, such as
analgesic and ~ntiinfl~nmsltoly activity (Japan Kokai 7~,126,682; United
States Patent 4,92~,853), gastric antise. let~l y activity OEuropean Patent
p~lhlic~tiQn 246,126), ~nhhi~minic activity (United States Patents
4,200,641 and 5,182,280), dop~rninergic and andrenergic activity (United
States Patent 4,92~,8~4), bronchodilatory activity, growth promotion
(United States Pate~t 4,960,783), tachykinin receptor antagonist (United
States Patent Application 08/235,401, filed April 29, 1994), and inhihitor of
10 ~-~myloid peptide production (United ~tates Patent Applic~ion
08/23~,400, f;led ApIil 29, 1994).
The compounds of Formula I can be prepared by processes
known in the liteld~e. ~ee~ e.~., G.W.H. Cheeseman and R.F.
Cook~on, THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS, (A.
15 Weissberger, et al., eds. 1979).

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- 18-
Syntllefii.~ of the Ben~imitlAznle Nucleus
R
R ~XNHHCl MeONa ,~N

NHo NC~ N~


Cl

Syn~e~i~ of the N-l Substituted Ben7.imidazoles

(Scheme I)

R R
Br CH2)30H J ~ ~ O~r
N~OAr 2. Br2/PPh3 >




R R
r\~ N r\~ N
~N~OAr HNR2 ~ N~OAr
K2CO3
>




Br R2N

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- 19-
Synt~esi~ of the N-1 Substituted Ben~imirl~7:oles

(Scheme II)

R R
N Br(CH2)3NR2 ~
~OAr ~ ~OAr
H ~>

R2N

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-20-
Another m e~n.~ of preparing the compounds of Formula I
i8 by cy(~ stio~ of an aL)~ .iately substituted o-phenylene~ min~
such as the one depicted in Formula II

R3 H
R4

R5~NHR2
R6
II

in a solvent or solvent mi~t.lre. It is generally ~lerelled ~hat the solvent
or solvent l.n~uLe be heated, lJie~e~ably to the boiling point of the
solvent. Suitable solvents include eth~nol, isopropanol, ~ 1 acetic
acid, ben7ene, toluene, chloroben7ene, glycol, ethylene glycol, dimethyl
ether, diethyl ether, dimethylform~ni~le~ chloroform, ethyl acetate, and
the like. It is generally l~lefelfed to add a con~n~ on agent such as
phosphorous oxychloride, thionyl chloride, p-toluenesulfonic acid,
hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid,
phosphorous pentoxide, methanesulfonyl hydroxide, meth~nçsulfonyl
chloride, and the like. The cyc~ tion re~ct.ion may also optionally be
performed in the presence of a base such as sodium hydro~ide, sodium
mesylate, or potassium tert-butylate.
In those compounds in which R2 is phenyl a d~livaliv~ of N-
phenyl-o-phenylenerli~mine was used as the starting material for the
cyc3ization re~ction The examples in~ provide sufficient guidance in
the preparation of those compounds of Formula I wherein all of R3, R4,
R5, and R6 are hydrogen.
Those compounds of Formula I wherein at least one of R3,
R4, R5, and R6 is not hydrogen, can be prepared by methods t~llght. in the
litela~ule. For ç~mIlle, the compounds of this invention wherein
phenyl portion of the b~n~imidazole is substituted with C2-C7 ~lk~noyl
can be prepared from the a~ .;ate keto o-phenylene~ nin~ of the
3 0 formula

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-21-

~n~2

(C1-C6 alkyl)--C~NH2

by methods known in the b~n7imitlA~ole art such as the procedures
described in U.S. Patent 4,401,817, issued August 30, 1983, the entire
5 cont,~nts of which are herein incorporated by reference. The method of
preparation involves the Ammonolysis and reduction of a 4-halo-3-
nitrophenyl ketone which is prepared by the Friedel-Crafts reaction of
either a 4-halo-3-nitrobenzoyl chloride with an 2~ ;ate hydrocarbon
or a halobenzene with an a~l lol liate acid chloride followed by aromAtic
10 nitration.
Alternatively, the keto bçn~imi~ ole re~ct~nts can be
Jal ad from acetanilide by a Friedel-~rafts acylation with the
~. ol~,iate derivative of C2-C7 AlkAnoic acid. The resulting 4-keto
acet~nili~le is nitrated to give a 2-nitro-4-ketoacet~nili~le. The acet~nilit1e
15 is hydrolyzed to give a 2-nitro-4-ketoAniline, which can then be
catalytically hydrogenated to yield a 4-keto-o-phenylene~iAminç which
can then be ring closed to provide the ~ or 6-substituted ben7imi~ ole.
Those compounds of Formula III wherein phenyl portion of
the b~n~imirlA7:0le is substituted with alkyl or alkylenyl may be prepared
2 0 by meAn~ of a Friedel-Crafts alkylation with the a~ ;ate deriv2li ive of
the sub~ ulillg moiety using standard procedures, usually employing
an alkyl halide or an olefin in the presence of a catalyst such as
aluinu_ chloride, alllminllm bromide or another Lewis acid.
An alternative strategy for preparing those compounds of
25 FnrrnlllA I wherein R~ is Cl-C6 alkoxy, R7R8N-(Cl-C6 alkoxy)-, or
heterocyclic-(C~ 6 alkoxy)-, or a substituted del;v~ive thereof, involves
first reAct.in~ a 3-nitro-4-a_inophennl with an acyl halide in the
presence of a base

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-- 22--


E~OJ~( base ~¦~NO~

Rl,C~o

to get substitution of the primary amine as well as substitution of the
hydroxy group, the ester moiety serving as a hyLo~y-protecting group
5 for subsequent re~qc~;on~. In the next step of this syn+~esi~ the nitro
group is then reduced to an amino group, usually by catalytic
hydrogenation.


o,¢~ H2, Pd/C ~,

Rl~ ~0 Rl_C~o
The primary amine of the above compound is then
substituted, usually using an aldehyde, such as benzaldehyde or a
substituted der lva~ive thereof, followed by hydrog~n~tiPn, if necessary.
In an alternative embodiment, those compounds of Formula I in which
15 R2 is alkyl or substituted alkyl may be produced by alkylation of an
aromatic amine with alkyl halide or tosylate, or the like, in the presence
of a suitable base, such as t~ialkyl~mine, potassium carbonate, 1,8-
hicyclo[~i.4.0]undec-7-ene (DBU), and the like.

,~N ,R

NH2 H2, Pd/C I NEI
2 o 1,C~O Rl,C~O R2

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-- 23--
Cyclization of this substituted phenylene~i~mine is then performed as
described supra, followed by cleavage of the ester group protecting the
hy~o~y group at the 6-position of the ban~imirl~ole. Suitable
cyclization catalysts include phosphorous oxychloride, thionyl chloride,
5 phosphorous pento~ide, phosphorous p~nt~hloride, and other like
strong dehydrating agents.

~ 2 NaOH ,~CN\>--R
l'C~~ R2 R2




10 A preferred method of cleaving this ester is by incubation of the
intermediate in a basic solution, such as lN sodium hydroxide, or a
weaker base such as potassium carbonate. The hydroxy group at the 6-
position is then substituted using an alkyl or aryl halide, resulting in a
compound of Formula I.


HO~CNR>--Rl alkyl or alyl halide J~CRN\>--R

The skilled artisan understands that compounds of
Formula I ~ubstitlltetl at the ~-position of the b~n7imidazole can be
20 prepared as described above by employing 3-amino-4-nitrophenol as the
starting material instead of the 3-nitro-4-aminoph~nol shown supra.
Those compounds of Formula I wherein R2 is alkyl or
substituted alkyl may alternatively be prepared by the direct alkylation of
a benzirnidazole wherein the nitrogen at the 1-position is substituted
2 5 with a hydrogen. This type of alkylation is usually performed by the
re~ction of the bçn~imitl~ 31e vwith an alkyl halide in the presence of a
strong base, such as sodium hydride. This reaction is usually
performed in a polar aprotic solvent, such as N,N-dimethylform~mi-le,

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-24-
dimethyl sulfoxide, dimethylacet~mi~, he~methylphosphoric
triamide, and the like.

The following ~.~Ample~ filr~her illustrate the compounds of
5 the present invention and the methods for their synthesifi. The
mples are not inten~e(1 to be l;..~;l.;..~ to the scope of the invention in
any respect, and should not be so construed. All exp~r-mçnts were run
under a positive pressure of dry nitrogen or argon. All solvents and
reagents were purchased from commercial sources and used as
0 received, unless otherwise indicated. Dry tetrahy~l,o~ (THF) was
obtained by distillAt.ion from sodiu_ or sodium benzophenon.q ketyl prior
to use.
Proton nllr.le~r ms~gn~tic resonance (lH NMR) spectra were
obtained on a GE QE-300 spectrometer at 300.15 MHz, a Bruker AM-600
spectrometer at 600 MHz, or a Bruker AC-200P spectrometer at 200 M HZ.
(Unless ~e~ign~ted otherwise, the term "NMR" as employed herein
refers to proton nuclear Tn~gn~tic reson~nce.) Free atom bombardment
mass spectroscopy (FAB) was performed on a VG ZAB-2SE instrllmen~
Field desorption mass spectroscopy (E'DMS) was performed using either
a VG 70SE or a Varian MAT 731 instrllm-ont
Optical rotations were measured with a Perkin-Elmer 241
polarimeter. Chromatographic separation on a Waters Prep 500 LC was
generally carried out using a linear gradient of the solvents in-lic~terl in
the text unless otherwise specified.
The reactions were generally monitored for completion
using thin layer chromatography (TLC). Thin layer chromatography
was performed using E. Merck Kieselgel 60 F2s4 plates, ~i cm x 10 cm,
0.25 mm thi~ kness. Spots were detected using a comhin~tion of W and
~.hemiç~l detection (plates dipped in a ceric ammonium molybdate
3 0 solution [75 g of ~mmonium molybdate and 4 g of ce. i~ (IV) sulfate in
~001 of 10% aqueous sulfuric acid~ and then he~te~l on a hot plate).
Preparative centrifugal thin layer chromatography was performed on a
Harrison Model 7924A Chromatotron using Analtech silica gel GF
rotors.
3 5 Cation exchange chromatography was performed with
Dowex(~) 50X8-100 ion e~rh~nge resin. Aniorl e~rrh~nFe

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chromatography was performed with Bio-Rad AG~) l-X8 ~nion-
e~çh~n~e resin (acetate form col~vel~ed to h~oxide form). Elash
chromatography was performed a~ described by Still, .et al., Journal of
Or~nic Chemistry,43:2923(1~78).
Optical rotations are reported at the sodium-D-line (3~4
nm) ~.lçment7~1 analyses for carbon, hydrogen, and nitrogen were
determined on a Control Eq7lipmçnt Corporation 440 ~,lçmçnt~l
Analyzer. Melting points were determined in open glass c~pill~ries on
a Thomas Hoover ç~p;ll~ry melting point apparatus or a Buchi melting
10 point apparatus, and are uncoll~c~ed.

General Procedure for B~n~imidazole Synthesis


R~ MeOH G~ NH2 HCl
NH2 NHa-HCl


NH2 HCl Cl~ ~o ,~} Cl

NH2 HCl MeONa /MeOH H

To a 0.4 M solution of the optionally substituted 1,2-
flis~minQben7:en~ in methanol, anhydrous hydrogen chloride gas was
bubbled until saturation. The solution was permitted to cool to room
tempe.d~,ule. The precipitate was collected, dried and then used in the
2 o next step.
A solution of 4-chloroI7heno~ynitrile (1.05 eq) in dry
methanol (0.3 M) was treated with sodium methl)~i.1e (1.05 eq). The
e was stirred at room tempeldLu~e. The mi~+nre was treated
with the dihydrochloride salt of the ~i~mine (1.0 eqL) and stirred at room
2 5 tempeld~ul e for about one hour. In most of the cases the precipitate was
observed upon addition. The crude cyrstals were washed with diethyl
ether and dried in vacuo.

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-26-
VVhne ~liAminotoluene was treated with 4-
chlorophen-)xyl~iL,;le there was no pre~.ipit~te observed immediately.
The reaction ~ e was condensed under vacuum. The crude
brownish solid was dissolved in ethyl acetate. The resulting solution
5 was washed with water, then brine, and then dried over sodium sulfate.
The solvents were then removed in vacuo to produce brown crystals with
a good yield.

Pre~ar~tion 1
Preparation of 2-benzylb~n7imitl~7.01e



~ NH2 S HCl(g) ~ ~

A 1 M solution of benzyl cyanide in anhydrous methanol
was treated with hydrogen chloride gas at 0~C for about thirty _inutes.
The ~ e was stirred for two hours at 0~C and then a 1 M solution of
minobenzene was added and the resulting solution was stirred at
0~C. The progress of the reaction was monitored by thin layer
20 chromatography. The reaction ~ e was then poured into water.
The unreacted nitrile was extracted with ethyl acetate. The aqueous
layer was neutralized with 1 N sodium hyd~ ide. The organic firaction
was extracted with ethyl acetate and conllan.~ed. The desired title
product was recryst~lli7:ed from meth~nol/water.

Pre~aration 2

Preparation of 2-(4-chlorophenyl)ben ~i mi dazole




;

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~ ~ MeOH 0~C ~ ~ Cl

The title compound was prepared essent.i~lly as described
in Preparation 1 except that an eq7limok7r amo7lnt of 4-
cblorobenzonitrile was employed instead of the benzyl cyanide employed
5 therein.

Preparatio l 3

Preparation of 2-(4-chlorobenzyl)ben~imidazole

2 < HCl (g) ~ N


Cl HN
The title compo7lnd was prepared essentially as described
in Preparation 1 except that an eqnimol~r amount of 4-cnlorobenzyl
cyanide was employed instead of the benzyl cyanide employed therein.

Prep,7ration 4
Preparation of 2-(benzylogymethyl)-7-hydlo~y7l)~n~imidazole


~ NH2 ~ NaHCO3 r ~o ~ H

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A ~ u~e of the 2,3~ min~phenol (6 g, 40.3 mmol, 1 eq)
and benzyloxyacetic acid (5.6 g, 48.3 ~nol, 1.2 eq) in 40 ml of a 10%
aqueous solution of sodium bicarbonate was stirred and re~u~ed at
140~C for one hour. The ..-;xl ..e was allowed to cool down to room
5 temperature. Ethyl acetate was poured into the ...; xl-.. e. The organic
fraction was extracted with ethyl acetate, washed with water, and then
dried over sodiu_ sulfate. The solvents were removed in vacuo. The
crude product was further purified by flash chromatography to yield 6.87
grams (67% yield) of the desired title product.
The following interrne~ tes were prepared essentially as
described above.

PreDaration 5
Preparation of 6-methyl-2-(4-chlorophenoxymethyl)beI~7imidazole


H3C ~ ~ O ~
H




2 o :~ and NMR were consistent with the desired title product. FDMS 272
(M~).

Preparation 6

25 Preparation of 2-(4-chloropheI o~ymethyl)ben7.imidazole

Cl

N

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-29-
IR and NMR were consistent with the desired tit~le product. FDMS 2~8
(M+).

Prepar~1ion 7




Preparation of 2 -(4-chlorophenoxymethyl )-7-nitrob~n ~i mi dazole



~ N ~ O
02M H

10 IR and NMR were consistent with the desired title product. FDMS 303
(M+).

Prep~ration 8

15 Preparation of 2-(4-chlorophenl)~ymethyl)-6-methoxyb~n~imidazole


H3CO ~ ~ O ~ Cl
H

IR and NMR were consistent with the desired title product. FDMS 288
20 (M+).

Pre~aration 9

Preparation of 2-(4-chloropheno~ymethyl)-6,7-dimethylben~imidazole

H3C ~ ~ Cl

.~ N
H3C H

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-3~-

NME~ was consistent with the desired title product.

Pre;Daration 10




Preparation of 2-(4-chlorophenoxymethyl)-7-methylbçn7.imidazole

~ ~ Cl
M




H3C H

10 NMR was consistent with the desired title product.

Preparation 11

Preparation of 2-(4-chloroph~no~ymethyl)-6-
15 methoxycarbonylben7:imidazole



H3C' ~ N ~ O Cl

1.9 grams (67% yield).
Preparation 12

Preparation of 2-(4-chlorophenn~ymethyl)-7-hydroxybçn~imidazole

~ ~ Cl
N




HO H

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W O 97/25041 PCT~US97/00511

NMR was consistent with the desired title product. Yield ~.3 grams
(91%).

Pre~aration 13

Preparation of 2-benzylben~ ole



H ~

10 NMR was consistent with the desired title product. Yield 1.26 grams
(14%).

Preparation 14

15 Preparation of 2-(3-chloropheno~rmethyl)berl~imidazole


O~C 1
N

NMR was consistent with the desired title product. Yield 1.~ grams
2 o (>99%).

Preparation 15

Preparation of 2-(2-chlorophenoxymethyl)ben~imidazole


N Cl

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NMR was consistent with the desired title product. Yield 1.36 grams
(gl%).

Preparation 16

Preparation of 2-(4-chlorophenyl)ben ~i mi dazole


~ ~ Cl

Prel?aration 17

Preparation of 2-(4-chlorobenzyl)ben~imid~ole

~ ~ Cl

H
NMR was consistent with the desired title product.

Pre~aration 18
Preparation of 2-(phenoxymethyl)ben~imidazole


~ 0~

25 NMR was consistent with the desired title product. Yield 1.06 grams
(65%).
Prel~aration 19

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-33-

Preparation of 2-(3,5-dichlorophenoxy~ethyl)ben~imi-1~7O1e

Cl


O~C 1
H




IR and NMR were consistent wi~h the desired t;tle product. Yield 0.28
grams (>99%). FDMS 292 (M+).
Analysis for Cl4HloCl2N20:
Theory: C, 57.36; H, 3.44; N, 9.56.
~ound: C, ~i7.46; H, 3.48; N, 9.41.

Preparation 20

Preparation of 2-(3,5-dichlorophenoxymethyl)-7-methylben7:imidazole



O~C 1
~3C H

IR and NMR were consistent with the desired title product. Yield 0.448
grams (75~). FDMS 306 (M+).
20 Analysis for ClsHl2Cl2N2O:
Theory: C, 58.65; H, 3.94; N, 9.12.
Found: C, 58.45; H, 3.95; N, 9.18.

Pre~aration 21
Preparation of 2-(3,5-dichlorophenoxy_ethyl)-7-hy~l~ o~yl)~n ~imi~ ole

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-34-



HO N

IR and NMR were consistent with the desired title product. Yield 0.46
graIns (78~). FDMS 308 (M+).
5 Analysis for C~ ocl2N2o2:
Theory: C, 54.39; H, 3.26; N, 9.06.
Fouund: C, 54.26; H, 3.22; N, 8.99.

Pre~aration 22
Preparation of 2-[4-(t~ ol-2-yl)phenogymethyl]-b~n~imidazole



~ 0~

15 NMR was con.~ tent with the desired title product. Yield 2.7 grams
(>99%).

Preparation 23
2 o Preparation of 2-[3-chlorophenoxymethyl]-7-methylben ~mi dazole

Cl
~0~ ~
H3C H

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-35-
NMR was consistent with the desired title product.

Pre~aratio~ 24

5 Preparation of 2-[3-chloropheno~ymethyl3-7-hydroxyberl7imidazole

Cl
N




HO H

NMR was consistent with the desired title product. Yield 1.5 gr~ms
10 (>99%).

Prel~aration 25

Preparation of 2-[1,6-dichloroI)heno~ymethyl]b~n~iTnidazole
Cl


H Cl
IR and NMR were consistent with the desired title product. Yield 0.27
grAlns (~99%). FDMS 292 (M+).
20 Analysis for Cl4EloCl2N2O:

Theory: C, 57.36; H, 3.44; N, 9.50.
Found: C, 57.50; H, 3.43; N, 9.54.

r~ ; on 26
Preparation of 2-~l~6-dichlorophenoxymethyl~-7-methylben~iTn~ ol e

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- 36-
~ Cl


H3C H Cl

IR and NMR were consistent with the desired title product. Yield 0.5
grams (94%). FDMS 306 (M+).
5 Analysis for ClsHl2Cl2N2O:
Theory: C,58.65; H,3.94; N, 9.12.
Found: C,58.36; H,3.92; N, 9.32.

Preparation 27
Preparation of 2-[1,6-dichlorophenoxymethyl]-7-hy~o~ylJ~n7imidazole

~ Cl


HO H Cl

15 IR and NMR were consistent with the desired title product. ~leld 0.52
grams (88%). FDMS 308 (M~).
Analysis for Cl4HloCl2N202:
Theory: C,64.39; H,3.26; N, 9.06.
Found: C,54.51; H,3.22; N, 9.22.
Prel~aration 28

Preparation of 2-~3-trifluoromethylpheno~ymethyl]-bçn7.imi~7ole


~ ~ G ~ CF3
N




H

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- 37-
N~ was consistent with the desired ti~e product. Yield 0.62 grams
(ss~).

Pre}; arati--n 29

Preparation of 2-[3-trifluoromethylphenoxymethyl]-7-
methylbe~ 7imi dazole



H3C H CF3

NMR was consistent with the desired title product.

Prep~ration 30

15 Preparation of 2-[4-chlorophenoxymethyl] -6-chloroben 7.imi dazole


Cl ~ ~ C
N

NMR and IR were consistent with the desired title product. Yield 8.20
20 grams (>99%). FDMS 292 (M~).

Preparation 31

Preparation of 2-[4-chloropheno~ymethyl]-~,6-dichloroben~imidazole


X~ ~

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-38-

NMR and IR were consistent with the desired title product. Yield 9.20
grams (>99%). FDMS 328 (M+).

Preparation ~

Preparation of 2-~4-chlorophPno~ymethyl]-5,6-dimethylbçn7.imi~ ole


E~ OJ~

NMR and IR were consistent with the desired title product. Yield 4,4
grams (52%). FDMS 286 (M+).

Preparation 33
Preparation of 2-[4-chlLoropheno~rymethyl~-4,5,6,7-
tetramethylben 7.imi dazole


H3C ~ ~ O
N




CH3 H

NMR was consi~tent with the desired title structure. Yield 0.~ grams
(38%).

Prel; aration 33
Preparation of 2-[4-chlorophenoxymethyl]-6-(t-butyl)ben7im~ 7~ole

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-39-


H3C ~ ~ Cl
CH3 H

NMR was consistent with the desired title product. Yield 1.5 gra~
(40%).




Preparation 34
Preparation of 2-~,4-dichloropheno~ymethyl]bçn7.imidazole

~ ~ Cl


H Cl
IR and NMR were consistent with the desired title product. Yield 6.7
grams (96%). FDMS 292 (M+).
Analysis for C ~ oC12N20:
Theory: C, 57.36; H, 3.44; N, 9.56.
~ound: C, 57.11; H, 3.64; N, 9.31.

Preparatinn 35

2 o Preparation of 2-l[2,4-dichloropheno~rymethyl]-5,6-dichloroben7imidazole



Cl ~ ~ Cl
N cl

..
Nl~R and IR were consistent with the desired title product. Yield 3.2
2s grams (91%).

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-40-
Prer~ration 36

Preparation of (3'R) ethyl 2-(piperidin-3-yl)acetate

~ ~ ~~" CH3
~NJ
H
Ethyl-3-pyridylacetate (lOOg, 0.606 mol~ was dissolved in
ethanol (1.8 liters), treated with 5% rhodium on all~mina (100 g) and
hydrogenated at 60~C and 60 psi hydrogen gas overnight. The catalyst
10 was removed by fi~tration and the solvent evaporated to give a brown
liquid (101.4 g, 98%). The brown liquid was dissolved in ethyl acetate (600
ml) and treated with L-(+)-m~n-lelic acid in warm ethyl acetate (600 ml).
After cooling in the refrigerator for four hours, the solid was collected
and the cryst~ ion fluid reserved for processing to the other
15 enantiomer, infra. The solid was again recrystallized from ethyl acetate
(1.5~;-1.6 liters, overnight at ambient tempe~a~u~e) to give the desired title
product as white needles. ~leld: 81.6, 41%.
O.R. (EtOH) ~589 nm = +44.9~, ~365 nm = +173.73~. mp 118-119~C.

Pren~ration 37

Preparation of (3'S) ethyl 2-(pipendin-3-yl)acetate

~ O~_ " CH3
J
N

The cryst~ ;on fluid from Preparation 36, su;~ra, was
evaporated to give a dark oil (100.3 g). This was dissolved in a cold
solllt;on of potassium carbonate (52 g, 0.377 mol) in water (250 1) and
extracted with ethyl acetate ~5 x 150 ml). The extracts were comhiner~
3 o and dried over m~nesium sulfate. The solvents were removed in vacuo

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-41-
to give a dark liquid (40.2~i g3. The dark liquid was treat,ed wit~ a warm
solution of D-(-)-mslntlelic acid (36 g) in ethyl acetate (650 ml) and cooled
at a_bient tempe~ s overnight. The crystals were recrystallized
twice more from ethyl acetate (1.2 liters and 1.1 liters, respectively) to
give ~he desired title product as white needles. Yield: 48.7 g, 24.9%.
O.R. OEtOH) ~589 nm = -43.14~, ~365 nm = -164.31~. mp 115.5-117~C.

Chiral ~n~ l Methof~

Cold a~ueous potassium carbonate (0.15 g in 10 ml of water)
was treated with 0.3 g ofthe m~nrle.lic acid salt and the ~;xl~..e was
extracted with ethyl acetate (3 x ~ ml). The comhined extracts were dried
over m~nesium sulfate and the solvents were removed in vacuo. The
residue was dissolved in diethyl ether (10 ml~ and treated with S-(-)-a-
methylbenzylisocyanate (0.121). After 2.5 hours, the re~ction was
treated wtih 1 N hydrochloric acid (2 ml). The ether was separated and
then washed seqllenti~lly with brine, a saturated aqueous sodium
bicarbonate solution, and brine. The organic fiaction was dried over
m,q~nesium sulfate and the solvents were removed hy evaporation. The
residue was analyzed on a CHIRA(~EL OJTM high perform~nce liquid
chromatography colulnn (4.6 x 250 mm), eluting with ~% et~l~nnl in
he~nes at a flow rate of 2.~ ml/minllte. The slower component comes
from the l-(+)-m~n~lelic acid salt and the faster from the d-(-)-m~n-lelic
acid salt. ~lPLC analysis of the final crys~ tion products of both
enantiomers show less than three percent of the opposite enantiomer.

Preparation 38

Preparation of (3'R) ethyl 2-[N-(t-butl ~yca~l~onyl)piperidin-3-yl]acetate
~ ~ O~_ " C~3
J
Boc

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-42-
(3'R)-Ethyl-2-(piperidin-3-yl)acetate (10.9 g, 34 mmol) as
prepared in Preparation 36 was dissolved in 60 ml of a 125b sodium
carbonate in water solution and the resulting solution was extracted
with chloroform. The extracts were dried and the solvents removed by
evaporation. The residue was suspended in diethyl ether, filtered, and
evaporated to give the free base (5.36 g). The liq~ud was dissolved in
ether (50 ml) and treated L-)~wise with di-t-butyldicarbonate (7.9 g) in
ether (10 ml). After stir~ing overnight, the solution was cooled in an ice
water bath and treated Lv~wise with saturated aqueous citric acid
(25 ml). The aqueous fraction was extracted with diethyl ether. The
organic fractions were con~hine.l, washed with water, a saturated
sodium bicarbonate solution, and then brine, and then dried over
m~gnesium sulfate. The solvents were removed in vacuo to give the
desired title product was a clear liquid. NMR was consistent with
proposed title structure.

Preparation 39

Preparation of (3'S) ethyl 2-[N-(t-butoxycarbonyl)piperidin-3-yl]acetate
~ O~_ " CH3
~ J
N
Boc

(3'S)-Ethyl-2-(piperidin-3-yl)acetate (48.6 g, 1~iO m mol), as
plelJaled in Preparation 37, was treated with a solution of potassium
carbonate (30 g, 0.217 mol) in water (220 ml) and the resulting solution
was extracted with chloroform (3 x 100 ml). The extracts were dried over
sodium sulfate and the solvents were removed in vacuo. The residue
was mixed with diethyl ether (200 ml) and filtered to remove some
suspended solids. Evaporation of the e~er gave a L~lowl.-sh liquid (2~ g,
3 0 Theory = 25.7 g). The residue was dissolved in diethyl ether (200 ml),
cooled in an ice water bath, and a solution of di-t-butyldicarbonate (31.8
g, 0.146 mol) in ether (25 ml) was added d~ wise with stiITing. Cooling

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was removed and reaction was stirred overnight. The solution was gain
cooled ;n ice water and a solution of saturated aqueous citric acid (100
ml) was added dL~-vise. The organics were washed with brine, a
saturated aqueous sodium bicarbonate solution, the brine, and then
5 dried over sodium sulfate. The solvents were removed in vacuo to give
the desired title product as a clear liquid (38.6 g, >99%). NMR was
consistent with desired title structure.

Preparation 40
Preparation of (RS) ethyl 3-[pyrid-3-yl]prop-2-enoate
o




O CH3


A solution of ethylphosphinoacetate (98.6 g, 0.44 mol) in dry
tetrahy~o~u.dll (1200 ml) was treated with 60% sodillm hydride (17.5 g,
0.44 mol). The ~l ule was stirred at room temperature for two hours
and was then cooled down to 0~C. To this ~..i x 1-. . e 3-pyridine
carboxaldehyde (38.9 g, 0.36 mol) was added and the resulting reaction
20 ~ e was stirred for 1'2 hours while warming to room temperature.
The progress of the reaction was monitored by thin layer
chromatography.
Water (1000 ml) was added to the reaction ..~;xl ..e. The
organic fraction was extracted with ethyl acetate (3 x 1000 ml). The
organic fr~ction~ were comhined, washed with water (2 x 1000 ml), brine
(1 x 1000 ml), and the dried over sodium sulfate. The solvents were
removed in vacuo to yield 62.~; grams (97%) of the desired title product.

Preparation 41
Preparation of (RS) ethyl 3-[piperidin-3-yl}propionoate
L

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-44-
o




~CH3


A solution of (RS3 ethyl-1-[pyrid-3-yl]prop-1-enoate (60 g, 0.34
mol) in ethanol (600 ml) was treated with ~;% rhodil~m on alumina
5 powder (17.2 g). The ....~ e was placed under a hydrogen atmosphere
(5~ psi) for five hours at 60~C. The reaction was stopped by removing the
hydrogen and the reaciton ~uLe was filtered through a layer of
CELITETM. The residue was washed with hot ethanol. The filtrate was
concentrated and purified by flash chrom~tography to provide 39.6
10 grams (63%) of the desired title product.
lR, NMR, and IR were consistent with the proposed title structure.

Preparation 42

15 Preparation of (3'S) ethyl 3-[piperidin-3-yl]propionoate m~n~lic acid salt
o




~'~ ~ o CH3

H ~mandelic acid

A solution of (RS) ethyl 3-[piperidin-3-ylJpropionoate (62.0 g,
2 o 281 mmol) in hot ethyl acetate (300 ml3 was added to the hot solution of R-(-) m~nrlçlic acid (42.7 g, 281 mmol). The resulting mixture was then
f;ltered and ~he clear solution was left at room temperature overnight.
The newly formed white crystals of the salt were filtered from the
solution. These crystals were recryst~lli7:e-1 twice by dissolution in hot
2 5 ethyl acetate (300 ml3 and letting it cool dwon to room temperature each
time. The final pure crystals were dried to yield 33.1 grams (70%).
NMR and IR were consistent with the desired title product. The
conformAtion about the chiral center was con~ ned by X-ray
crystallography.

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Prep~ration 43

Preparation of (3'R3 ethyl 3-[piperidin-3-yl]propionoate m~n~lelic acid
5 salt
o




C~ ~ CH3

N .mandelic acid

The title compound was prepared essentially as described
10 in Preparation 42, su~ra, except that S-(+) m~nfle.lic acid was employed
instead of the R-(-) m~nrlalic acid employed therein.
NMR and IR were consistent with the desired title product.

Prel~aration 44
Preparation of (3'S) ethyl 3-[piperidin-3-yl]propionoate
o




~ O ~ CH3


2 o A susr.qn~ion of (3'S) ethyl 3-[piperidin-3-yl3propiono~te
rn~n~elic add salt (33.1 g, 98 mmol) in ethyl acetate (500 ml) was treated
with a 30% aqueous solution of potassium carbonate until all the organic
layer was clear. The mixture was poured into a separatory funnel and
the organic fraction was extracted with ethyl acetate (3 x 300 ml). The
combined organic fraction was washed with water (2 x 300 ml), then
brine (1 x 300 ml), and then dried over sodium sulfate. The solvents
were removed in vacuo to yield an oily product in nearly 100% yield.
NMR and IR were consistent with the desired title product.

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-46-
Preparation ~6

Preparation of (3':~) ethyl 3-~piperidin-3-yl]propionoate

o
~ ~ O ~ C~3


The title compound was prepared essentially as described
in Preparation 44, sl~pra, except that (3'R) ethyl 3-[piperidin-3-
yl]propionoate mandelic acid ~alt was employed instead of the (3'S) ethyl
10 3-[piperidin-3-yl]propionoate mandelic acid salt therein.
NMR and IR were consistent with the desired title product.

Pre~aration 46

15 Preparation of (3'S) ethyl 3-[1-(t-buto~ycalL)onyl)piperidin-3-
ylJpropionoate
o




O CH3

BoC

A solution of(3'S) ethyl 3-~piperidin-3-yl]propionoate (12.5 g,
67.5 mmol) in tetrahydrofuran:water (2:1, 33~:168 ml) was treated with
potas~ium carbonate (14 g, 101 mmol) and di-tert-butyl dicarbonate (17.7
g, 81 mmol). The reaction ~ e was stirred at room temperature for
five hours. The ~ e was then poured into water (200 ml). The
organic fraction was extracted with ethyl acetate (3 x 200 ml). The
organic fractions were comhined, washed with water (2 x 2001) and
then brine (1 x 200 ml~, and then dlied over sodium sulfate. The solvents

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-47-
were removed in vacuo and the title product was fur~er purified by
~ash chromatography. Yield: 19.1 grams (99.2%).
NMR and IR were consistent with the desired title product.

Preparation 47

Preparation of(3'R) e1~hyl 3-~1-(t-buto~y~alluonyl)piperidin-3-
yl]propionoate
o




O CH3

J

BoC
The title product was prepared e~.~ent.i~lly as described in
Preparation 46, supra. except that an eqllimol~r amount of (3'R) ethyl 3-
[piperidin-3-yl}propionoate was employed instead of the (3'S) ethyl 3-
~piperidin-3-yl]propionoate employed therein.

Preparation 48

Preparation of (3'S) 3-[1-(t-buto~y~a~bonyl)piperidin-3-yl]propanol

OH


BoC

A solution of (3'S) ethyl 3-cl-(t-buto~yca~bonyl)piperidin-3-
yl]propi~no~te (17.1 g, 60 m m ol) in dry diethyl acetate (600 ml) was cooled
to 0~C. Lithium alu~num hydride powder (2.5 g, 65 ~ol) was
gradually added to the ~ e. The resulting mi~tllre was stirred at
0~C and slowly warmed to room tempe. al~LL e within two hours. The
reaciton was stopped by the slow addition of water (200 ml) and 15%

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aqueous sodium hydroxide (60 ml). The organic fraction was extracted
with diethyl e~her (3 x 300 ml). The comhined layer was washed with
water (2 x 20Q ml) and then brine (1 x 200 ml) and then dried over sodium
sulfate. The solvents were removed in vacuo to provide 13.2 grams (90%
5 yield) of the title product.
NMR and IR were consistent with the desired title product.

Preparation 49

10 Preparation of (3'S) 3-[1-(t-buto~y~aLl,onyl)piperidin-3-yl]propanol
Q "' OH

BoC

The title product was prepared essentially as described in
15 Preparation 48, supra, except that an eqllimol~r amount of (3'S) ethyl 3-
[1-(t-butoxycarbonyl)piperidin-3-yl~propionoate was employed instead of
the (3'R) ethyl 3-[1-(t-buto~y~albonyl)piperidin-3-yl]propionoate employed
therein.

Preparation ~;0

Preparation of ~3'S) 3-[1-(t-buto~ycall~onyl)piperidin-3-yl~propane
bromide

. ~ Br

BoC
To a cold (0~C) solution of tnphenylphosphine (19.96 g, 76
mmol) in anhydrous methylene cbloride ~110 ml) was added bromine
L~JlJwise until the solution turned pale yellow. A few crystals of

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-49-
triphenylphosphine were added to the ~--i x 1,.. ~ e to bring the color back to
white. To this .~.;x~ e was added a suspension of (3'S) 3-[1-(t-
buto~ycall~onyl)piperidin-3-yl]propanol (13.2 g, 54.4 mmol) and py~idine
(8.0 g, 76 mmol) in dry methylene chloride (110 ml). The resulting
5 l.~ ,~e was stirred for f;ve hours while warming to room t~mperature.
The reaction was stopped by s~ nE water (2001). The
organic fraction was extracted with methylene chloride (3 x 200 ml).
The comhined organic layer was washed with water (2 x 200 ml), then
brine (1 x 100 ~), and then dried over sodium sulfate. The solvents
10 were removed in vacuo to provide a light brownish crude product, which
was further purified by flash chrom~tography to yield 11.6 grams (70%)
of the desired title product.
NMR and IR were consistent with the title product.

Pre~ration ~;1

Preparation of (3'R) 3-[ l-(t-buto~y cal bonyl)piperidin-3-yl~propane
bromide

~ ~' ~ Br

BoC
The title product was prepared eRs~n~i~lly as desclibed in
Preparation ~0, supra~ except that an eql1imol~r amount of (3'R) 3-[1-(t-
buto~ycall)onyl)pipelidin-3-yl]propanol was employed instead of the (3'S)
25 3-[1-(t-buto~y~ onyl)piperidin-3-yl]propanol employed therein.

(~Teneral ~rocedure for PreI~arin~ Cnn~ounds of the Formula

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-60-



DMF N C


HO
A solution of ben7.imidazole (1.0 g, 3.9 mmol, 1.0 eq~ in
anhydrous N,N-dime~ylform~mi-le (10 ml) was treated with 60%
disperson of ~odium hydride (0.163 g, 4.1 mmol, 1.05 eq). The re~(~ion
5 mixture was stirred at room temperature for about thirty minutes.
Bromopropanol (0.6 g, 4.3 mmol, 1.1 eq) was added to the ..~;xI-..e and
the resulting ..~ix~,...e was stirred at 70~C for five hours. The progress of
the reaction was monitored by thin layer chrnm~to~raphy.
The reaction mixture was poured into water (20 ml). The
10 organic fraction was extracted wtih diethyl ether (3 x 60 ml). The
organic fractions were comhined, washed with water (2 x 20 ml), and
then brine (1 x 20 ml), and then dried over sodium sulfate. The solvents
were removed in vacuo to yield a white solid as a crude product. No
further purification was pelrol...ed on this product.
The following e~mples were prepared essan*~lly as
described above in the general procedure.

?le 1
Preparation of 2-[4-chlorophano~ymethyl]-1-(3-
hydro~y~l o~yl )ban ~i mi dazole


0


HO

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-51-

NMR was consistent with the desired title structure.

~ nn~l~ 2

Preparation of 2-[4-~hloropheno~ymethyl]-1-(3-llyLo~y~lo~yl~-5-
chlorob~n 7i mi ~ ~ 701e


0


HO
NMR was consistent with the desired title structure.
?le 3

Preparation of 2-[4-chloropheno~ymethyl]-1-(3-hydl o~y~. 01JY1)-~6
dichlorob~n7.irnidazole


C l~N~ o~ C 1


HO

20 NMR was consistent with the desired title structure.
,. ,
F~"~ le 4

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~62-
Preparation of 2-[4-c7 lorophenoxymethyl]-1-(3-hyd~o~y~lo~yl)-6,6-
dimethylben ~imi~ole


H3C ~ N ~ ~ ~ Cl


HO
NMR was consistent with the desired title structure.
T~le 5
Preparation of 2-[4-chloropheno~ymethyl]-1-(3-1lyd~ o~y~l o~yl)-4-
_ethylben7.imi~ole
CH3


N ~ ~


HO

15 NMR was consistent with the desired title structure.

(~eneral Procedure for Pre7~aration of Com1?ol7nds of the Formula

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-~3-
R R

\ ~ N ~ Cl Br2/PPh3 f \ ~ N
O ~ pyr dine ~ ~ O ~ Cl


EO Br
To a solution of triphenylphosphine (1.62 g, ~.8 mmol, L5
eq) in dry ~ hl~romethane (101) at 0~C was added l~lo~le solution
until it was pale yellow. To the resulting ,..ix~,... e as added additional
5 triphçnylphosphine until the solution was white. To this mi~tnre was
then added the hydroxyalkyl-substituted ben~imidazole (1.2 g, 3.9 m m ol,
1.5 eq) and pyridine (0.~ 1, 5.8 m m ol, 1.5 eq) in dIy dichloromethane.
The resulting ~ ula was stirred at 0~(~ and then warmed to room
tempe.d~ule at which temperature it was m~int~ined for about six
10 hours. The progress of the re~ction was m~ oled by thin layer
chromatography .
White prel irit~te was removed by filtration, washed with
dichloromethane, and dried in vacuo to provide the crude product.

The following compounds were prepared essentially as
described above.

~,x~ le 6

2 0 Preparation of 2-[4-chlorophenoxymethyl]-1-(3-brom l3. o~yl)-
ben~imi~ 0le


C~ 0
N

Br

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NMR and IR were consistent with the desired title structure. FDMS 380
(M+).

F~m~le 7

Preparation of 2-[4-chlorophenoxymethyl]- 1-(3-bromo~l o~yl)-5-
chlorobçn 7:i mitl~ole


~ ~ ~ Cl


Br
NMR was consistent with the desired title structure.

~ nnle 8
Preparation of 2-~4-chloroph~no~ymethyl~-1-(3-bromopro~yl)-5,6-
dichloroben 7:imi dazole

Cl

Cl ~ ~ O ~ Cl
N




NMR was consistent with the desired title structure.

~ple 9

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Preparation of 2-[4-chloroph~no~rymethyl]-1-(3-bromo~. o~yl)-5,6-
dimethylbçn ~imi dazole


H ] ~--0~ C 1


Br
NMR was consistent with the desired title structure.
~.~ml?le 10

Preparation of 2-[4-chloroph en o~ymethyl]- 1-(3-bromo~l o~yl)-4-
~ethylben7imi.1~7 ole


0


Br

15 NMR was consistent with the desired title structure. FDMS 393 (M~).

(~T~neral Procedure for PreI)aration of Corr~ollnds of the Formula

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WO 97/2s04l PCT~US97/OQ511

-5~-
R R

f\~N /=\ Clhydrochloride f\s~N
N ~ O ~ K2C03 ~ ~ ~ ~ Cl
~ DMF, 70~C N

Br M
C>
A sollltion of the ben~imi~ole (100 mg,0.26 mmol, 1.0 eq)
in anhydrous N~N-~imethylform~mi~le t2 ml) was treated with
potassium carbonate (90 mg, 0.65 mmol, 2.5 eq) and piperidine
hydrochloride (35 m g, 0.29 mn ol, 1.1 eq). The ~ ule was stirred at
70~C for about five hours. The resulting ~ ule was poured into water
. The org~nic fraction was extracted with diethyl ether (3 x 10 ml).
The comhined ether layers were washed with water (3 x 5 ml), then
brine, and then dried over sodium sulfate. The solvents were removed
in vacuo to yield an oily crude product. The desired title product was
then further purified by flash chromatography.

The following compounds were prepared es~enti~lly as
described above.
n~le 11

Preparation of 2-(4-chloropheno~ymethyl)-1-[3-(piperidin-1-
yl~l opyl]ben~imifl~7:ole


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-57-
~ ~ Cl




IR and NMR were consistent with the desired title product. FDMS 384
(M+).
Analysis for C22H26ClN30:
Theory: C, 68.83; H, 6.83; N, 10.94.
Found: C, 68.21; H, 6.90; N, 10.98.
e 12

Preparation of 2-(4-chloropll~no~ymethyl)-1-[3-(piperidin-1-
yl)~. olJyl]ben~imidazole
~ ~ Cl




IR and NMR were consistent with the desired title product. FDMS 384
(M+).
Analysis for C22H26ClN30:

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- 58-
Theory: C, 68.83; H, 6.83; N, 1û.94.
Found: C, 68.21; H, 6.90; N, 10.98.

ml~le 13

Preparation of 5-chloro-2-(4-chloroph~no~ymethyl)-1-[3-(piperidin-1-
yl)~lopyl]ben7.imidazole

Cl ~ ~ Cl




IR and NMR were consistent with the desired title product. FDMS 418
(M+)-

F.~m,l~le 14
Preparation of 5,6-dichloro-2-(4-chlorophenn~ymethyl)-1-[3-(piperidin-1-
yl)~lo~yl~bçn7.imidazole

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_~9_


Cl ~ ~ O



f ~



IR and NMR were consistent with the desired ti~le product. FDMS 452
(M+).




~n~le 15

Preparation of 2-(4-chlorophenoxymethyl)-5,6-dimethyl-1-[3-(piperidin-1-
yl)propyl]ban 7i mi dazole

H ~ ~ Cl




O

~le 16

Preparation of 2-(4-chlorophenoxymethyl3-4-methyl-1-[3-(piperidin-1-
Y1)L~1O~Y1]b~n7im; dazole

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- 60-
C~3
Q ~ Cl




IR and NMR were consistent with the desired title product. FDMS 397
(M+).




F.~mnle 17

Preparation of 2-(4-chlorophenoxymethyl)-5,6-dichloro-1-[3-~morpholin-
l-yl)~. o~yl]ben7imidazole
C ~ ~ O ~ Cl

~'
~ N ~


IR and NMR were consistent with the desired title product. FDMS 453,
454 (M+).
~m~le 18

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-61-
Preparation of 2-(4-chlorophenoxy~nethyl )-5 -chloro- 1- ~3-(morpholin- 1-
Y1)L~ Y1]b~n7; midazole

Cl ~ ~ Cl
~1


~ N ~




IR and NMR were consistent with the desired ti1~1e product. FDMS 419,
420 (M+).
m~le 19
Preparation of 2-(4-chloropheno~ymethyl~-1-[3-(morpholin-1-
yl)~lo~yl]b~n ~imi~ ole

Cl




N ~

J

IR and NMR were consistent with the desired title product. FDMS 385,
386 (M+).

CA 02242579 1998-07-08
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-62-
le 20

Preparation of 2-(4-chloroph~no~ymethyl)-1-[3-(piperazin-1-
yl)propyl3ben7.imi~ ole




Cl




N ~


~le 21

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-(piperazin-1-
yl)~l ol~yl]bçn 7.imi~ ole

~ ~ Cl

~,
N




5 IR and NMR were consistent with the desired t~tle product. FDMS 512
(M+).

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- 63-

rnrle 22

Preparation of 2-~4-chlorophenoxymethyl)-4-methyl-1-[3-[4-(pyrimidin-2-
5 yl)piperazin-1-yl]propyl]ben7.;midazole



~N~--




N ~ M


IR and NMR were consistent with the desired title product. FDMS 476.2
10 (M+).

ml?le 22

Preparation of 2-(4-chloroph~n()~ymethyl)-4-methyl-1-[3-[4-(pyrid-2-
yl~piperazin-l-yl]~ yl]ben7,imi~1~7.01e

CA 02242579 1998-07-08
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- 64-
CH3
Cl




~ N

N


IR and Nl~R were consistent with the desired title product. FDMS 475.2
(M+).




m~le 23
Preparation of 2-(4-chloroph çn o7~ymethyl)- 1-[3-~4-(N,N-
dimethyl~mino)piperidin-l-yl]~l0l,~13bçn7.imi~ole
~ ~ Cl

~,


H3C'' CH3

:
CA 02242579 1998-07-08

WO 97/25041 PCT/US97/00511


?le 24

Preparation of 2-(4-chlorophen~ymethyl)-5,6-dichloro-1-[3-[4-(N,N-
dimethy~mino)piperidin-l-yl]~l o~yl]bçn7imidazole


Cl~ ~ Cl
N




H3 C~ --CH3

IR and NMR were consistent with the desired title product. FDMS 49~.2
(M+).
Fx,~ 1e 25

Preparation of 2-(4-chloroph~no~ymethyl)-5-chloro-1-[3-[4-(N,N-
dimethylamino)piperidin-l-yl]~lo,~yl]ben7.imidazole


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- 66-
Cl ~ ~ Cl




H3C'' CH3

IR and NMR were consistent with the desired ti~le product. FDMS 495.2
(M~).




F,~ ple 26

Preparation of 2-(4-chloroph~no~ymethyl)-5,6-dimethyl-1-[3-[4-(N,N-
dimethyl~nnino)piperidin-1-yl]~,o~yl]ben7.imidazole

H3 ~ ~ Cl
~1




,,N
H3C CH3
IR and NMR were consistent with the desired title product. FDMS 455.4
(M~).

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-67-

~ rnl?le ~7

Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-[3-[4-(N,N-
5 dimethyl~minn)piperidin-l-yl]~. o~yl]ben~imidazole

~ ~ Cl
~1




~ N

IR and NMR were consistent with the desired title product. FDMS 441
lû ~M+).

?le 27

Preparation of 2-(4-chlorophçn o~ymethyl)-4-methyl- 1-[3-[4-(piperidin- 1-
15 yl)piperidin-1-yl]propyl]benzimidazole

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W O 97/25041 PCTAUS97/00511

- 68-
CH3


0
N




~.~

IR and NMR were consistent with the desired title product. FDMS 481
(M+).




(~eneral Procedure for Pre~arin~ Com~ounds of the Followin~
Formulae

R ~ ~ R ~ N



~) n and ~) n

N~ APG ~ N~
APG
10 where n is 0, 1, or 2, and APG is an amino protecting group.

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- 69-

R~ J~Cl ~N~O
N




H NaH
+ DMF, 80~C

Br~ ~ N~
N 3OC
BoC
A solution of the l-unsubstituted ben7imidazole (0.77 mmol,
1.0 eq) in anhydlous N,N-dimethylformamide (3 ml) was treated with a
60% disperson of sodium hydride (33 mg, 0.80 mmol, 1.~5 eq). The
5 mixture was stirred at room temperature for thirty minutes under a
stream of nitrogen. To this ~i~ e was added [1-(t-
buto~Ly~;aIl)onyl)piperidin-3-yl]l,lvlJyl bromide (260 mg, 0.85 mmol, 1.1 eq)
and the resulting ..,;x4.~e was stirred at 80~C for about three hours.
The progress of the reaction was monitored by thin layer
1 0 chromatography.
The reaction l~.iX~ e was then poured into water (10 ml3.
The org~nic fraction was extracted with diethyl ether (3 x 15 ml). The
organic fr~ on~ were comhine~, washed with water (2 x 10 ml), brine (1
x 10 ml), and then dried over sodium sulfate. The solvents were
15 removed in vacuo, leaving a light brown crude material which was
further purified by flash chromatography to yield the desired title
product as a white cryst~lline solid in 70-100% yield.

~mnle 28
Preparation of 2-(4-chloroph~nr ~ymethyl)-1-[3-[1-(t-
butoxycarbonyl)piperidin-2-yl]~ Jyl]bçn~ 01e

CA 02242579 1998-07-08

W O 97~S041 PCT~US97/00511

- 70-


0


, BoC


IR and NMR were consistent with the desired title product. FDMS 483,
484 (M+).
Analysis for C27H34ClN303:
Theory: C, 67.00; H, 7.08; N, 8.60.
Found: C, 66.g3; H, 7.09; N, 8.43.

F~ l

Preparation of 2-(4-chloroph~no~ymethyl)-5-methoxy-1-[3-[1-(t-
butoxycarbonyl)piperidin-2-yl]propyl]ben~imir~ 01e and 2-(4-
c~lorophenoxymethyl)-6-methoxy-1-[3-[1-(t-butoxycarbonyl)piperidin-2-
yl]~l ol~yl~bçn 7.imi(1~ole


H3C~ ~ ~ o



~ , BoC

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IR and NMR were consistent with the desired title products. FDMS 513,
~14 (M+).
Analysis for C2gH30ClN3O4:
Theory: C, 6~.42; H, 7.06; N, 8.17.
Found: C, 65.12; H, 6.96; N, 8.29.
m,l7le 30

Preparation of 2-(4-chloroph~no~y~nethyl)-4,5-dimethyl-1-[3-~1-(t-
10 butogycarbonyl)piperidin-2-yl]lJlol~yl]b~n~imidazole and 2-(4-
chlororheno~ymethyl)-6,7-dimethyl-1-[3-[1-(t-buto~yca. l~onyl)piperidin-2-
yl]~ yl~ben7imi~ ole

H3C ~ ~ Cl


< H3C

~ ~ BoC ~ , BoC


IR and NMR were consistent with the desired title products. FDMS 511,
512 (M~).
Analysis for C29H3gClN3O3:
Theory: C, 68.02; H, 7.48; N, 8.20.
Found: C, 68.32; H, 7.54; N, 8.36.
m~le 3 1

Preparation of 2-(4-chloroph~no~ymethyl)-5-methyl- 1-[3-[1-(~-
2 5 butoxycarbonyl)piperidin-2-yl]lJl o~yl]ben7.imi dazole and 2-(4-


CA 02242579 1998-07-08
W O 97/25041 PCT~US97/00511
- 72-
cl310roI-h~no~y_ethyl)-6-methyl-1-[3-[1-(t-butoxycarbonyl)piperidin-2-
yl]propyUben 7.imidazole

H3C~/ ~ Cl




~ ~ BoC




IR and NMR were consistent with the desired title products. FDMS 497,
498 (M+). 3:2 mixture of the 6-methyl isomer to the 6-methyl isomer.
Analysis for C2gH36ClN3O3:
Theory: C, 67.62; H, 7.28; N, 8.44.
Found: C, 68.37; H, 7.40; N, 8.60.
h',~m,l~le 31

Preparation of 2-(4-chloroph~nc~rymethyl)-4-methyl 1 [3 [1-(t-
butoxycarbonyl)piperidin-2-yl]propyl]ben~imidazole



~0


, BoC
N

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W O 97/25041 PCT~US97/00511


IR and NMR were consistent with the desired title product. FDMS 497,
498 (M+).
Analysis for C2gH36C~lN3O3:
Theory: C, 67.52; H, 7.29; N, 8.44.
Found: C, 67.14; H, 7.65; N, 8.85.
le 32

0 Preparation of 2-(4-chloropheno~rymethyl)-5-benzoyl-1-[3-~1-(t-
butoxycarbonyl)piperidin-2-yl]~l o~yl]bçn~;midazole
o




Cl




N~ BoC
V




15 IR and NMR were consistent with the desired title product. FDMS ~87,
588 (M+).

~le 33

Preparation of 2-(4-chlorophenoxymethyl)-5,6-dichloro-1-[3-[1-(t-
butoxycarbonyl)piperidin-2-yl]~L o~yuben~imitlsl7ole

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W O 97/25041 PCT~US97/00511

-74-

IR and NMR were consistent with the desired title product. FDMS 497,
498 (M+).
Analysis for C2gH36ClN3O3:
Theory: C, 67.52; H, 7.29; N, 8.44.
Found: C, 67.14; H, 7.65; N, 8.85.

~ m~le 32

10 Preparation of 2-(4-chlorophenn~ymethyl)-5-benzoyl-1-[3-[1-(t-
butoxycarbonyl)piperidin-2-yl]~, vl~yl]bçn7:imidazole
o




Cl




N~ BoC


15 IR and NMR were consistent with the desired title product. FDMS 587,
~88 (M+).

~m~le 33

Preparation of 2-(4-chloropheno~ymethyl)-5,6-dichloro-1-[3-[~-(t-
butoxycarbonyl)piperidin-2-yl]l~.o~yl]ben7imifl~ole

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-75-

~ C~ ~ N ~ Cl




, BoC
~ N


IR and NMR were consistent with the desired title product FDMS 687,
~88 (M+).




F',~m~l~le 34

Preparation of 2-(2,4-dichlorophenoxymethyl)-1-[3-[1-(t-
butoxycarbonyl)piperidin-2-yl]~i o~yl]b~n ~:i mi dazole



~N~


~N~ BoC


NMR was consistent with the desired title product.

h'.~ le 36

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W O 97/2SQ41 PCT~US97/00511

- 76-

Preparation of 2-(2,4-dichlorophenoxymethyl)-5,6-dichloro-1-[3-~ t-
butoxycarbonyl)piperidin-2-yl],~ yl]ben~iTnidazole


Cl~N~-- J~




NMR and IR were consistent with the desired title product. FDMS 587
(M+).
Analysi~ for C27H3lCl4N303:
Theory: C, 55.21; H, 5.32; N, 7.15.
Found: C, ~6.19; H, 5.69; N, 7.44.

F.~ le 36

Preparation of 2-(4-chloro~h~noxyInethyl)-5-methyl-1-[3-[1-(t-
15 buto~y~;alllonyl)piperidin-3-yl]~. o~yl]benzimidazole and 2-(4-
chloroph~no~ymethyl)-6-methyl-1-[3-[1-(t-butoxycarbonyl)piperidin-3-
yl]pl o~yl3ben ~i mi dazole




,

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-77-

H3C ~ ~ Cl



S and

C' ~
N~ ~ N~
BoC BoC
NMR and IR were consistent with the desired title products. FDMS 497,
498 (M+).
Analysis for C2gH36ClN303:
Theory: C, 67.52; H, 7.28; N, 8.44.
Found: C, 67.58; H, 7.42; N, 8.52.

~"~ le 37

0 Preparation of 2-~4-chloroph en o~ymethyl)-5-methoxy- 1-[3-[1-(t-
butoxycarbonyl)piperidin-3-yl3propyl~ben7imi~ ole and 2-(4-
chlorophenoxymethyl)-6-methoxy-1-[3-[1-(t-buto~y~al bonyl)piperidin-3-
yl]~. o~yl]b~n7.imi~1~7.ole

H3C ~ ~ Cl ~ Cl

N N

and S


~ N~ ~ M~
BoC BoC

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- 78-

NMR and IR were consistent with the desired title products. FDMS 513,
514 (M+).
Analysis for C2gH36ClN3O4:
Theory: C, 65.42; H, 7.06; N, 8.17.
Found: C, 65.18; H, 7.22; N, 7.94.

~le 38

Preparation of 2-(4-chlorophenoxymethyl)-4,5-dimethyl-1-[3-[1-(t-

10 butoxycarbonyl)piperidin-3-yl],~lul~yl]benzimidazole

H3 ~ ~ Cl




N~
BoC
NMR and IR were consistent with the desired title product. FDMS ~11,
512 (M+).
le 39

Preparation of 2-~4-chloroph~no~ymethyl)-4-methyl-1-[3-[1-(t-
butoxycarbonyl)piperidin-3-yl]~l v~yl~ben~irni(l~ole


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W O 97/25041 PCTnUS97/00511
- 79-

CH3
C1

N




N~
BoC

NMR and IR were consistent with the desired title product. FDMS 497,
498 (M+~.




~ m~ple 39a

Preparation of 2-(4-chloropheno~rymethyl)-4-methyl-1-[5-[1-~t-
buto~ bonyl)piperidin-3-yl3pentyl]b~n 7:i mi~ 701 e

CH3


0



~BoC


NMR was consistent with the desired tit~e product.

CA 02242579 1998-07-08
W O 97/25041 PCTAUS97/00511

F"r~m~le 40

Preparation of 2-(4-chloroph~.nl)xy ,ethyl)-~;-benzoyl-1-[3-[1-(t-
butoxycarbonyl)piperidin-3-ylJ~ l]ben7:imidazole
~o
Cl




N~
BoC

NMR and IR were consistent with the desired ti~le product. FDMS 497,
498 (M+).
F"~ ?le 41

Preparation of 2-(4-chlorophenoxymethyl)-6,6-dichloro-1-[3-~1-(t-
butoxycarbonyl)piperidin-3-yl]~ ylJbens:imi~ ole


Cl ~ ~ Cl
N



N~
BoC

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-81-

NMR and m were consistent with the desired title product. FDMS 552.5,
654.6 (M+).

m.~rle 42

Preparation of 2-(4-chloroph~n..~ymethyl)-5-chloro-1-[3-[1-(t-
butoxycarbonyl)piperidin-3-yl3propyl]ber-~imifi~7.ole

Cl ~ ~ Cl


N



N~
BoC
NMR and IR were consistent with the desired title product. FDMS 518
(M+).

F'.~n~le 43

Preparation of 2-~4-chloroph~no~ymethyl)-5,6-dimethyl-1-[3-~1-(t-
butoxycarbonyl)piperidin-3-yl]yio~yl]ben~imidazole

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-82-


H3C ~ ~ O




N~
BoC

NMR and IR were consistent with the desired title product. FDMS 512.4
(M+).
m~?le 44

Preparation of 2-(2,4-dichlorophenoxylllethyl)-1-[3-~1-(t-
butoxycarbonyl)piperidin-3-yl]l~lo~yl]ben7.imifl~ole


0




N~
BoC

NMR and IR were consistent with the desired title product. FDMS 517,
~18 C~
Analysis for C27H33C12N303:
Theory: C, 62.58; H, 6.41; N, 8.10.
Found: C, 62.54; H, 6.39; N, 8.20.

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-83-

~"~ le 45

Preparation of 2-(2~4-dic-hlorophenn~ymethy~ 6-~lirhloro-l-c3-[l-(t
butu~ycalbonyl)piperidin-3-yl]~ yl]ben7~ 7.0le



Cl ~ N



M~
BoC

NMR and IR were consistent wit-h- the desired title product. FDMS 587
10 (M+).

~"~le 46

Preparation of 2-(4-ch~orophçno~ymethyl)-4,5-dimethyl-1-[3-[1-(t-

15 butoxycarbonyl)piperidin-4-yl]~ro~yl~ben7.imidazole

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W O 97/25041 PCT~US97/00511
-84-

Cl

M




BoC

~ le 47

5 Preparation of 2-(4-chlorophenosrymethyl)-1-[3-[1-(t-
butoxycarbonyl)piperidin-4-yl]~l o~yl]b~n~imidazole

Cl

N




BoC

10 NMR and IR were consistent with the desired title product. FDMS 484
{M+).

F.~ le 48

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W o 97/25041 pcTnJs97/oos

-86-

Preparation of 2-(4-chlorophenoxymethyl)-4,5,6,7-tetr~met~yl- 1-[3-[1-(t-
butoxycarbonyl)piperidin-4-yl]~ yl]ben7.imi(~s~7.01e


H3 ~ ~ ~
CH3




BoC

~n~le 49

Preparation of 2-(4-chlorophenoxymethyl)-5-methogycarbonyl-1-[3-[1-(t-
butoxycarbonyl)piperidin-4-yl]~ yl]ben7imidazole and 2-(4-

10 chlorophenoxymethyl)-6-metho~ycall)onyl-1-[3-[1-(t-
butoxycarbonyl)piperidin-4-yl]~l o~yl]b~n7:irnidazole

H3C\ ~


--oJ~' ~OJ~


and


BoC

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-86-

NMR and IR were consistent with the desired title products. FDMS 541
(M+).
Analysis for C2gH36ClN30s:
Theory: C, 64.26; H, 6.69; N, 7.75.
Found: C, 64.07; H, 6.63; N, 7.96.

F,~m,l?le 50

Preparation of 2-(4-chloropheno~rymethyl)-4-methyl- 1-[3-[1-(t-
10 butoxycarbonyl)piperidin-4-yl]~ yl]ben7imi-1~7ole

CH3


N




BoC

NMR and IR were consistent with the desired title product. FDMS 497,
15 498 (M+).

F,~ml?le 50a

Preparation of 2-(4-chloropheno~ymethyl)-4-met-h-yl-l-[5-[l-(t
20 butoxyca~bonyl)piperidin-4-yl]pentyl]ben7.imi/1~7ole

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-87-

CH3
~ ~ Cl




N
BoC

NMR was consistent with the desired title product.

~ ?le 51

Preparation of 2-(4-chlorophçno~ymethyl)-4-(t-butyl)-1-[3-[1-(t-
buto~yca,l,onyl)piperidin-4-yl]propyl]ben7imidazole and 2-(4-
chloropheno~ymethyl)-7-(t-butyl)-1-[3-{1-(t-buto,~y~ lJonyl)piperidin-4-
10 yl]~io~yl]bçn7.imifl~q7.01e

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H3C\ ~CH3
C- CH3
Cl ~ ~ Cl


< H3C / C\ <
H3C CH3
and <


BoC BoC

NMR and IR were consistent with the desired title products. FDMS ~39,
540 (M+).

~ le 52

Preparation of 2-(4-chloroph~n o~ymethyl)-4-methyl- 1-~4-[ l-(t-
butoxycarbonyl)piperidin-4-yl]butyl]ben 7.imi ~ ol e

~ ~ Cl
-




BoC

CA 02242579 1998-07-08

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-89-

NMR and IR were consistent with the desired title product. FDMS 511
(M+).
!




le 53
~,
Preparation of 2-(4-chloroI heno~yme1~hyl)-6,6-dimethyl-1 [4-[1 (t
butol~yc~ bonyl)pipe~idin-4-ylJbutyl]ben Y.i mi ~ ol e

rl ~ ~ Cl




BoC

NMR and IR were consistent with the desired title product. FDMS 526
(M+).
rnl?le 54
Preparation of 2-(4-chloropheno~yme~hyl)-4,~-dimethyl-1-[4-[1-(t-
buto~ycall)onyl)piperidin-4-yl]butyl]bçn~imi~ ole amd 2-(4-
chloroph~nl ~ynnethyl)-6,7-dimethyl-1-[4-[1-(t-butokyca~l~onyl)piperidin-4-
yl]butyl]b~n7.imi~ ole


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W O 97/25041 PCT~US97/00511


H3 ~ ~ O ~ Cl H3C ~ O ~ Cl


N ~ N

< and



BoC BoC
NMR and IR were consistent with the desired title products.

~ le ~




Preparation of 2-benzyl-1-[3-[1-(t-buto~yc~bonyl)piperidin-3-
yl}~ o~yl~b~n7imidazole

N

N
<




BoC

NMR and IR were consistent with the desired title product. FDMS 433
(M~).

le ~6


CA 02242579 1998-07-08

W O 97~5041 PCT~US97/00511


Preparation of Z-(4-chlorophenyl)-1-[3-[1-(t-buto,~y~all,onyl)piperidin-3-
yl]~lo~l]ben 7imli~Sl 7:ole



N~' C 1


N~
BoC




NMR and IR were consistent with the desired title product. FDMS 453
(M+).
Analysis for C26H32ClN302:
Theory: C, 68.78; H, 7.10; N, 9.25.
10 . Found: C, 68.56; H, 7.03; N, 9.54.

?le ~7

Preparation of 2-(2-chlorophen~ ~ymethyl)-1-[3-[1-(t-
1~ bu~,o~ycall~onyl)piperidin-3-yl]~lo~yl]ben7:imidazole


N
Cl


N~
BoC

CA 02242579 1998-07-08
W O 97/25041 PCTnJS97/O0511


NMR and IR were consistent with the desired title product. FDMS 483
(M+).
Analysis for C27H34ClN303: '
Theory: C, 67.00; H, 7.08; N, 8.08.
Found: C, 67.25; H, 7.27; N, 8.81.

F.~s~rru?le 58

Preparation of 2-(3-chloropheno~ymethyl)-1-[3-Cl-(t-
10 butoxycarbonyl)piperidin-3-yl]l~l v~yl]ben~imidazole


N ~ ~



N~
BoC

NMR and IR were consistent with the desired title product. FDMS 483
15 (M+).

~le 59

Preparation of 2-(4-chlorobenzyl)-1-[3-[1-(t-buto~y-,~bonyl)piperidin-3-
20 yl]~lo~yl3b~n~.imi(1~ole

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W O 97~5041 PCTnUS97/00511

-93-

N Cl




N~
BoC

NMR ana IR were consistent with the desired title product. FDMS 467
(M+).
Analysis for C27H34ClN302:
Theory: C, 69.30; H, 7.32; N, 9.98.
Found: C, 69.54; H, 7.49; N, 9.08.

F,~rAm~I?le 60

Preparation of 2-(ph~no~rymethyl)-1-[3-[1-(t-buto~yL:~13onyl)piperidin-3-
yl]~l o~yl]b~n ~imidazole

N

N



N~
BoC

NMR and IR were consistent with the desired f;itle product. FDMS 449
(M+).

CA 02242579 l998-07-08
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Analysis for C27H3sN3O3:
Theory: C, 72.13; H, 7.85; N, 9.35.
Found: C, 71.85; H, 7.81; N, 9.25.
le 61
Preparation of 2-(3,5-r~i~hlorophenoxymethyl)-1-[3-[1-(t-
butoxycarbonyl)piperidin-3-yl]~ yl]ben7:imi~7.ole


~,~ , 0




~ N~
BoC
NMR and IR were consistent with the desired title product. FDMS 517
(M+).
Analysis for C27H33Cl2N3O3:
Theory: C, 62.65; H, 6.41; N,8.10.
Found: C, 62.33; H, 6.35; N,8.12.

~n~le 62

Preparation of 2-[4-(4,5-dihydrot~ ol-2-yl)pheno~rymethyl]-1-[3-[1-(t-
butoxycarbonyl)piperidin-3-yl]~l o~yl]be~imi~ole

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W O 97/25041 PCT~US97/OOSII

-95-
.,

~3 ~ o~N~




N~
BoC

NMR and IR were consistent with the desired ti~le product. FDMS 534
(M+).
5 Analysis ~or C30H3gN4O3S:
Theory: C, 67.38; H, 7.16; N, 10.48.
Found: C, 66.78; H, 7.0~; N, 10.00.

~ u?le 63
1~
Preparation of 2-(2,6-dichloropheno:~ymethyl)-1-[3-[1-(t-
butoxycarbonyl)piperidin-3-yl]~ v~l]ben~imidazole


N




BoC

NMR and IR were con~istent with the desired title product. FDMS ~;17
(M+).

CA 02242579 l998-07-08

W O 97/25041 PCTnJS97/00511

- 96-

Analysis for C27H33Cl2N303:
Theory: C, 62.55; H, 6.41; N, 8.10.
Found: C, 62.76; H, 6.44; N, 8.33.

m,~l-? 64

Preparation of 2-(3-trifluoromethylpher - ~rymethy~ -[3-~l-(t
butoxycarbonyl)piperidin-3-yl]p~ o~yl]ben ~imi dazole


~~



~ N~
BoC
NMR and IR were consistent with the desired title product. FDMS 517
(M+).
Analysis for C~gH34F3N3O3:
Theory: C, 64.98; H, 6.42; N, 8.12.
Found: C, 64.89; H, 6.48; N, 8.31.

?le 65

Preparation of 2-(4-chloroph~no~Fymethyl)-4-methyl-1-(3-
phenylpropyl)ben~imidazole

CA 02242579 1998-07-08

W O 97/2~041 PCTAUS97/00511

- 97-
-




~ ~Cl
'13




NMR and IR were consistent with the desired title product. FDM~3 390
(M+).
5 Analysis for C24H23clN2o:
Theory: C, 73.74; H, 5.93; N, 7.17.
Found: C, 73.87; H, ~;.99; N, 7.27.

~"~,~le 66

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-~3-
cyclohe~yl~, o E,yl )ben 7i Tll~i dazole

H3


N ~ C




NMR and IR were consi~tent with the desired title product. FDMS 390
(M+).

CA 02242579 1998-07-08
W O 97/25041 PCT~US97/00511


?le 67

Preparation of 2-~4-chlororhPno~ymethyl)-4-methyl-1-[3-(pyrid-3-
5 yl)~lo~l]ban~imi~ le and 2-(4-chloroTheno~ymethyl)-7-methyl-1-[3-
(pyrid-3-yl),~ yl]ben7~ 7.ole
CH3


N Cl ~ N ~ ~ Cl

/ and
~ N ~ N

NMR and IR were consistent with the desired title products.
10Analysis for C23H22ClN30:
Theory: C, 70.49; H, 5.66; N, 10.72.
Found: C, 70.20; H, 5.76; N, 10.50.

G~n~ral Procedure for Removal of the t-Buto~ycall)onyl Protect.in~
15 ¢~Trour~


R ~ N ~ ~ Cl ~ N ~ ~ Cl

trifluoroacetic acid S
dichloromethane

~ NH ~TFA
BoC

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511

_ 99_
-
To the amino-protected b~n7.imi~1S.sole was added a 1:1
e of trifluoroacetic acid in dichloromethane. The resulting
e was stirred at room tempe~a~ule for about one hour. The
progress of the reaction was monitored by thin layer chromatography.
5 The solvents were removed in vacuo and the residue was l,l~ ted with
diethyl ether (3 x 10 ml) and dried under vAclllln to yield white
crystalline hydroscopic ~olids.

~le 68

Preparation of 2-(4-chloropheno~ymethyl)-1-[3-(piperidin-3-
yl)~lo~yl]ben7.imi~A7ole trifluoro~cet~t~ salt


N ~ -Cl
~NH
~ ~TFA

NMR and IR were consistent with the desired title product. FDMS 383,
384 (M+).

le 69
Preparation of 2-(4-chloropheno~rymethyl)-5-metho2~y-1-[3-(piperidin-3-
yl)~ yl]ben7imirlA~ole trifluoroacetate salt

CA 02242579 1998-07-08
W O 97~5041 PCT~US97/00511

- 100-



N

~NH
~ ~TFA

NMR and IR were consistent with the desired title product. FDMS 413,
414 (M+).
5 Analysis for C23H2gClN3O3:
Theory: C, 66.87; H, 5.54; N, 7.96.
Found: C, 55.93; H, 5.31; N, 8.01.

u?le 70

Preparation of 2-(4-chloroI~heno~ymethyl)-4,5-dimethyl-1-r3-(piperidin-3-
yl)~lol3yl]ben7:imi~ole trifluoro~cet~te salt

H3C ~ H3


N ~ Cl


~NH
~ ~TFA

NMR and IR were consistent with the desired title product. FDM~ 411,
412 (M+).

CA 02242579 1998-07-08

W O 97/25041 PCTAUS97/00511

- 101-
le 71

Preparation of 2-(4-chlorophenoxymethyl)-~-methyl-1-[3-(piperidin-3-
yl)~ yl]b~n7imidazole trifluoroacetate salt and 2~(4-
5 chlorophenoxymethyl)-6-~ethyl-1-r3-(piperidin-3-
yl)~lo~yl]ben7imidazole trifluoroacetate salt



H3C ~ ~ O ~ N ~ Cl

~ and
~NH ~NH
~ ~TFA ~ ~TF~

NMR and IR were consistent with the desired title products. FDMS 397
lo (M+).
A~alysis for C23H28ClN30:
Theory: C, 58.65; H, 5.54; N, 7.96.
Found: C, ~8.26; H, 6.~6; N, 9.17.

F',~on~le 72

Preparation of 2-(4-chlorophP.no~ymethyl)-4-methyl-1-[3-(piperidin-2-
yl)~l~o~yl]bçn7.imidazole tlifluoroS.~etote salt

CA 02242579 1998-07-08
W O 97/25041 PCT~US97/00511
- 102-



C~~~CI


~N
~ ~TFA

NMR and IR were consistent with the desired title product. FDMS 397,
398 (M+).

~le 72a

Preparation of 2-(4-chlorophçno~ymethyl)-4-methyl-1-r~-(piperidin-3-
yl)pentyl3be~imi~ ole
CH3


~ ~ Cl
H




NMR and IR were consistent with the desired title product. FDMS 427
(M+).

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511
- 103-
-
Analysis for C2sH32ClN30:
Theory: C, 60.05; H, 6.16; N, 7.78.
Found: C, 59.75; H, 6.11; N, 7.78.

F"r~ le 73

Preparation of 2-(4-chlorophenoxy_ethyl)-~-benzoyl-1-[3-(piperidin-2-
yl)~ yl]ben7imidazole trifluoroacetate salt
~,

~Cl


~27,N~
l J ~TFA

NMR and IR were consi~tent with the desired title product. FDMS 487,
488 (M+).

~ ml~le 74

Preparation of 2-(4-chlorophenoxy~..ethyl~-~,6-dichloro-1-[3-(piperidin-3-
yl)~lo~yl]ben 7.i mi dazole trifluoroacetate salt

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511
- 104-



C ~ ~ ~ ~ Cl


~NH
~ ~TFA

NMR and IR were consistent with the desired title product. FDMS 451,
452 (M+).

nu?le 76

Preparation of 2-(2,4-dichlorophenoxymethyl)-5,6-dichloro-1-[3-
(piperidin-2-yl)~lo~yl]ben 7.imi~ 70le trifluoroacetate salt
Cl



11
~ N ~
~TFA

NMR and IR were consistent with the desired title product. FDMS 487
(M+).
~,~m~ e 76

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511

-105-

Preparation of 2-(2,4-dichloropheno~ymethyl)-1-~3-(piperidin-2-
yl)~lo~yl]b~n~:imidazole trifluoroacetate salt


Cl

H
~27,N~
~TFA




NMR and IR were consistent with the desired title product. FDMS 418
(M+).

71e 78
Preparation of 2-(4-chloropheno~ymethyl)-~;-methoxy-1-[3-(piperidin-3-
yl)~l o~yl]b~n 7 i mi dazole




t,
NMR and IR were consistent with the desired title product. FDMS 413
(M+).

~ u?le 79

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511
- 106-

Preparation of 2-(4-chlorophenoxymethyl)-6-methoxy-1-~3-(piperidin-3-
yl)propyl]bçn ~irnirl~ole


H3CO ~ N ~ ~ ~ Cl



~ NH

I \ J
NMR and IR were con.~i~t~nt, with the desired title product. FDMS 413
(M+).

F~nlr)le 80

Preparation of 2-(4-chlorophenoxymethyl)-4,5-dimethyl-1-[3-(piperidin-3-
yl)propyl]ben ~imidazole

H3C ~ H3


N ~ Cl


~ NH

~
NMR and IR were consistent with the desired title product. FDMS 411,
412 (M+).

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/OOSll
- 107-
,.
~le 81

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-(piperidin-3-
yl)~io~yl]ben7.imi~ ole and 2-(4-chloroph~no~ymethyl)-7-methyl-1-~3-
5 (piperidin-3-yl)propyl]ben~imi~ ole

H3


N ~ O ~ H3C ~ Cl

and
~J ~NH
~J
NMR and IR were consistent with the desired title products. FDMS 397,
3g8 ~M+).

h'.~nu?l.e 8~

Preparation of 2-(4-chlorophen o~rymethyl)-~i-benzoyl- 1-[3-(piperidin-3-
yl~propyl]bçn ~:;mi dazole
~,

N ~ Cl

~NH
~J

CA 02242579 1998-07-08

W O 97/25041 PCTAUS97/0051

- 108-

NM~ and IR were consistent with the desired title product. FDMS 487,
488 (M+)

li',~ le 83

Preparation of 2-(4-chlorophenoxymethyl)-6,6-dichloro-1-[3-(piperidin-3-
yl)propyl]ben7.imidazole
C1

Cl ~ ~ o ~ Cl



_ ' NH
\J
NMR and IR were consistent with the desired title product. FDMS 4~;2.2
(M+).

F.~mJ le 84

Preparation of 2-(4-chlorophenoxymethyl)-6-chloro-1-[3-(piperidin-3-
yl) ~l o ~yl]b~n ~i rni dazole

CA 02242579 1998-07-08

WO 97/25041 PCT/US97/00511

- 109-

Cl~s~


~ ~~Cl




NMR and IR were consistent with the desired title product. FDMS 418.2
(M+).




ml~le 8~

Preparation of 2-(4-chloroph~no~rymethyl)-~,6-dimethyl-1-[3-(piperidin-3-
yl)~lo~yl~ben7imi~ 0le
H3C~
>g\

H3C~N~ ~--Cl


~GNH


NMR and IR were consistent with the desired title product. FDMS 418.2
(M+).
~rr~le 86
.

CA 02242579 1998-07-08

W O 97/25041 PCTnJS97/00511

- 110-

Preparation of 2-(2,4-dichloroph~no~rymethyl)-1-[3-(piperidin-3-
yl)~l o~yl3bçn7imirl~701e


N ~ Cl


NH


NMR and IR were consistent with the desired title product. FDMS 417,
418 (M+).
Analysis for C22H2sCl2N30:
Theory: C, 53.14; H, 4.92; N, 7.89.
Found: C, 63.02; H, 4.74; N, 7.59.

~"~ 87

Preparation of 2-(2,4-dichlorophenoxymethyl)-5,6-dichloro-1-[3-
15 (piperidin-3-yl)~. o~yl]ben7.imidazole

Cl ~ N
Cl~ ~~Cl



~ NH
~J ;

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511
- 111-

NMR and IR were consistent with the desired title product. FDMS 487
(M+).
n~le 88




Preparation of 2-(4-chloroph en o~ymethyl)-4,5-dimethyl- 1-[3-(piperidin-4-
yl )1~, o ~yl]b ~.n 7:; mi dazole

H3C ~


N ~ Cl



~ NH

NMR and IR were consistent with the desired title product. FDMS 411
(M+).

h~ n~E?le 89
Preparation of 2-(4-chloroph~no~y~ethyl)-1-[3-(piperidin-4-
yl)~ro~yl]ben ~imi~7.ole

N

N ~ Cl



~ NH

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511
- 112-

NMR and IR were consistent with the desired title product. FDMS 383 ;
(M+).
Analysis for C22E26ClN30:
Theory: C, 57.89; H, 5.46; N, 8.44.
Found: C, 57.06; H, 5.44; N, 8.31.
m,l~le 90

Preparation of 2-(4-chloropheno~yn ethyl)-4,5,6,7-tetramethyl-1-[3-
(piperidin-4-yl)~l opyl]ben 7i miri~7.ole

H3C ~ H3

H3C ~ O ~ Cl



~ NH

NMR and IR were consistent with the propsoed title structure.

~,~slmnle 91

Preparation of 2-(4-chloropheno~ymethyl)-5-methoxycarbonyl-1-[3-
(piperidin-4-yl)propyl]b~n7imidazole and 2-(4-chlorophenoxymethylL)-6-
methoxycarbonyl-1-[3-(piperidin-4-yl)~l~Juyl]benzimidazole

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511

- 113-



H3C o ~ ~ N Cl


NH

NH
NMR and IR were consistent with the desired title products. FDMS 541
(M+).
Analysis for C24H2gClN30:
Theory: C, 66.17; H, 5.26; N, 7.50.
Found: C, 55.91; H, 5.32; N, 7.68.

F,~mnle 92

Preparation of 2-(4-chlorop~ano~ymethyl)-4-methyl~ 3-(piperidin-4-
yl)~l o~l]ben 7.irnidazole

H3


N ~ Cl



NH

5 IR and NMR were consistent with the desired title structure. FDMS 397
(Mt).

CA 02242579 1998-07-08

W O 97/Z5041 PCT~US97/00511
-114-

F.~ ?le 92a

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[5-(piperidin-4-
5 yl)pentyl]ben7imil1~701e
H3


N ~ Cl




N

IR and NMR were consistent with ~he desired title structure. FDMS 426
10 (M+).
Analysis for C2~H32ClN30:
Theory: C, 60.06; H, 6.16; N, 7.78.
Found: C, 60.30; H, 6.19; N, 7.65.

~mlI7le 93

Preparation of 2-(4-chlorophenoxymethyl)-4-(t-butyl)-1-r3-(piperidin-4-
yl)propyl]b~n 7.imi dazole and 2-(4-chlorophenoxymethyl~-7-(t-butyl)- 1-[3-
(piperidin-4-yl)propyl]ben7.imi(1~ole


CA 02242579 1998-07-08

W O 97/25041 PCTAUS97/00511

- 1~-
-
C'- CH3


N ~ Cl


H3C~ Cl



~NH
IR and NMR were consistent with the desired title structures. FDMS
439 (M+).

~z3m~rle 94

Preparation of 2-(4-chloroph ~.n o~rymethyl)-4-methyl- 1-[4-(piperidin-4-
yl)butyl]ben~imidazole

H3


N ~ Cl




H

CA 02242579 1998-07-08

W O 97/25041 PCTnUS97/W511
- 116-

IR and NMR were consistent with the desired title structure. FDMS 411
(M+).
F,~m~I?le 95




Preparation of 2-(4-chlorophenoxymethyl)-l ;,6-dimethyl- 1-[4-(piperidin-4-
yl)butyl]ben7imitl~0le
H3C

H3C ~ ~ ~ Cl




1~
IR and NMR were consistent with the desired title structure. FDMS 425
(M+ ).
m,~?le 96
~5
Preparation of 2-(4-chlorophPno~ymethyl)-4,5-dimethyl-1-~4-(piperidin-4-
yl)butyl]ben7.imidazole and 2-(4-chlorophenoxymethyl)-6,7--limethyl-1-~4-
(piperidin-4-yl)butyl]ben ~i mi dazole

CA 02242s79 l998-07-08

W O 97/25041 PCTAUS97/00511

-117-

H3C ~ CH3


M ~ Cl

and H3C ~ ~ Cl


H



IR and NMR were consistent with the desired title struetures. FDMS
425 (M+).

F,~nu~le 97

Preparation of 2-benzyl-1-[3-(piperidin-3-yl)propyl]b~n7:imi~ ol~


N




IR and NMR were consistent with the desired title structure. FDMS 344
(M+).

CA 02242579 1998-07-08

W O 97/25041 PCTAJS97/00511

- 118-

F',~m~l?le 98

Preparation of 2-(4-chlorophenyl)-1-[3-(piperidin-3-
yl)~l o~3yl]b~n 7.imidazole




N ~
<> Cl


M

IR and NMR were consistent with the desired title structure. FDMS 354
(M+).
~.~z~m~le 99

Preparation of 2-(2-ch~orophenoxymethyl)-1-[3-(piperidin-3-
yl)~l ol~yl3ben 7imidazole


N




N

IR and NMR were consistent with the desired title structure. FDMS 384
~M+).

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511

- 119-

F~m,~le 100

Preparation of 2-(3-chloroph en o~ymethyl)- 1-r3 -(piperidin-3-
5 yl)propyl]b~n7imi~A7ole


~N~\/




HN

IR and NMR were consistent with the desired title structure. FDMS 384
10 (~+).

F,~Anu~le 101

Preparation of 2-(4-chlorobenzyl)-1-[3-~piperidin-3-
15 yl)~lo~yl]ben7imidazole

N ~ Cl

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511
- 120-

IR and NMR were consistent with the desired title structure. FDMS 368
(M+).

le 102




Preparation of 2-(pheno~rymethyl)-1-[3-(piperidin-3-
yl)~ yl]bF~n~imi-1~7.ole
Q ~




IR and NMR were consi~tent with the desired title structure. FDMS 349
(M+).
Analysis for C22H27N3O:
Theory: C, 62.19; H~ 6.09; N, 9.07.
Found: C, 61.08; H, 6.01; N, 9.01.

m}?le 103

Preparation of 2-(3,6-dichlorophenoxymethyl)-1-[3-(piperidin-3-
2 0 yl)propyl]b~n7:imidazole

CA 02242579 1998-07-08

W O 97/25041 PCT/US97/00511

- 121-

N ~ C




H

IR and NMR were consistent with the desired title structure. FDMS 417
(M+).
5 Analysis for C22H2sCl2N3O:
Theory: C, 54.14; H, 4.92; N, 7.89.
Found: C, 54.06; H, 4.87; N, 7.82.

F,~ ?le 104

Preparation of 2-[4-(4,~;-diLyd~otl-i~7Ql-2-yl)~hen( ~ymethyl]-1-[3-
(piperidin-3-yl)propyl]bçn ~i mi ~ ol e

N
~ N ~ ~ /sN




IR and NMR were consistent with the desired title structure. FDMS 436
~M~).

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511
- 1~2-

~,~Am~le 106

Preparation of 2-(2,6-dichlorophenoxymethyl)-1-[3-(piperidin-3-
yl)~s o~yl]ben7:imidazole




~~




HN

IR and NMR were consistent with the desired title structure. FDMS 420
~M+)-
~A rr~,~l ~ 106

Preparation of 2-(3-~rifluoromethylphenoxymethyl)-1-[3-(piperidin-3-
yl),~ yl]b~n7~imidazole


~~~




H

IR and NMR were consistent with the desired title structure. FDMS 418
~M+).

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511
- 123-

Analysis for C23H26F3N30:
,~ Theory: C, ~6.60; H, ~.12; N, 7.91.
Found: C, 55.49; H, 5.03; N, 7.64.
,,

F,~ 1?le 107

Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-[4-[3-(piperidin-1-
yl)propylamino]-3-methylbutyl~ben7:imidazole


~ \>~ 0~

CH3

N
" ~

~rru?le 108

Preparation of 2-(4-chlorophçno~ymethyl)-4-methyl-1-[4-amino-3-
methylbutyl]b~n 7imi dazole

Cl


CH3

NH2
~.~ le 109

CA 02242579 1998-07-08

W O 97/25041 PCTnJS97/00511
- 124-

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[4-dimethylAminQ
3-methylbutyl]ben7:imi dazole


\>~ ~~

CH3

N(CH3)2




mple 110

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl- 1-[4-(1,2,3 ,4-
tetrahydroisoquinolin-2-yl)-3-methylbutyl]benzimidazole



~ H3
~b

F,~mple 111

15 Preparation of 2-(4-chlorophenoxymethyl~-4-methyl-1-[3-[2-[2-(piperidin-
1-yl)ethyl~piperidin-1-yl~carbonyl~butyl]b~n~irnidazole

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511

_ ~ _
.;
Cl


_~ 3
0~1~
o




mJ?le 112

Preparation o~ 2-(4-chlorophenoxymethyl)-4-methyl-1-{4-[2-[2-(piperidin-
l-yl)ethyl]piperidin-l-yl]-3-methylbutyl~bçn7im;dazole



~ H3
1~



.. O

m~ple 113

Preparation of 2-(4-chlorop~eno~ymethyl)-4-methyl-1-~4-[(1,2,3,4-
tetrahydronaphth-1-yl)amino~-3-methylbutyl}bçn7.imidazole

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511

- 126-

Cl


CH3
Y~


n~le 114

Preparation of 2-(4-chlorophçno~rymethyl)-4-methyl-1-l3-[3-~(2-
methylpiperidin-1-yl)propylz~minl ]carbonyl~-3-
methylpropyl}b~n 7:i mi dazole



~ CH3
0~



~ CH3
?le 115

Preparation of 2-(4-chlorophenoxymethyl~-4-methyl-1-~4-[3-(2-
15 methylpiperidin- 1-yl ~ ylamino] -3-methylbutyl}bçn ~i mi dazole

CA 02242579 1998-07-08

W O 97/Z5041 PCTnUS97/00511

- 127-




H3




CH3

F,~le 116

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[1-(3-
ethoxycarbonylbutyl)piperidin-3-yl]~lo~yl}ben7,imidazole

Cl


N ~

~ ~ O~_ " CH3

~0
le 1 17

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[1-(3-
ethoxycarbonyl4-phenylbutyl)piperidin-3-yl]~ v~yl}ben7.imidazole


CA 02242579 1998-07-08

W O 97~5041 PCT~US97/00511




N

~ N O~_,,CH3
o




Anlple 118

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[1-(2-
ethoxycarbonyl-4-phenylbutyl)piperidin-3-yl]propyl~b~n7:imidazole

~ ~ Cl

~ ;
o




O~

H3C

0 ~Am~le ~19

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[1-(3-
carbo2~ylJu~yl~piperidin-3-yl]propyl~ben7imidazole
;

CA 02242579 1998-07-08

WO 97/25041 PCT/US97/00511

- lL29-


r ~C \>~OJ~

N

CH3

C ~
OH
rn;ble 120

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[4-[2-~2-~piperidin-
l-yl)ethyl]piperidin-l-yl3-3-methyl]butyl]ben~imidazole


\>~~~
N
\_~H3



C~

~ ~le 121

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(3-phenyl-3-
carboxyl,ro~yl)piperidin-3-yl]~,o~yl]benzimidazole
.

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W O 97/25041 PCT~US97/00511
- 130-


\>~~~




HO O
rr~le 122

Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-[3-[1-(4-phenyl-3-
carboxybutyl)piperidin-3-yl]propyl]ben7.;mi-1~7ole




HO ~

h~mnle 123

Preparation of 2-(4-chlorophenoxy_ethyl)-4-methyl-1-t3-[1-(3-
benzoylbutyl)piperidin-3-yl]~ yl]ben7imidazole

CA 02242579 1998-07-08

W O 97t25041 PCTAUS97/00511
- 131-
Cl

N


N

H3C

m~le 124

Preparation of 2-~4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(3-benzoyl-3-
phenylpropyl)piperidin-3-yl]~ro~yl]ben7imidazole


~ >/~




~n~le 12~

Preparation of 2-(4-chloropheno:~ymethyl)-4-methyl-1-[3-r1-(3-benzoyl-3-
phenylpropyl)piperidin-3-yl]propyl]be~imi dazole

CA 02242579 1998-07-08

WO 97/25041 PCT/US97/00511

- 132-

,C1




~le 126

Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-[3-[1-(3-benzoyl-3-
ben;~yl~l o~yl)piperidin-3-yl]~l o~yl]ben 7.imi dazole

~3~C 1




N




~ ~le 127

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511
-133-

Preparation of 2-(4-chlorophenoxymethy1)-4-methyl-1-C3-[1-[4-(piperidin-
1-yl)-3-methylbutyl]piperidin-3-yl]~l o IJyl]ben ~imi dazole

~ ~ Cl




CJ~
CH3




~ml?le 128

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[4-(piperidin-
1-yl)-3-phenylbutyl]piperidin-3-yl]~ yl3ben ~imi dazole




~ N



rnnle 130

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511
- 134-

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[4-(piperidin-
l-yl)-3-benzylbutyl]piperidin-3-yl~lo~l]be~imidazole

~ ~ Cl




GN ~N



F,~ml?le 131

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(3-
ethoxycarbonyl-4-phenylbutyl)piperidin-3-yl]~l o~yl]ben7imitl~7:ole
Cl

N ~
~,
8 J
H3C ~ O N
~13 ..

CA 02242579 1998-07-08

W O 97/25041 PCT/US97/00511
- 13~;-
le 132

Preparation of 2-(4-chlorophe~o~ymethyl)-4-methyl-l-c3-[l-(3-carboxy-4
phenylbutyl)piperidin-4-yl]~l opyl]b~n7.i midazole




~\y~ 0




HO ~ N




mple 133

Preparation of 2-~4-chlorophenoxymethyl)-4-methyl-lL-[3-[1-[3-~piperidin-
1-ylcarbonyl)-4-phenylbutyl]piperidin-4-yl]~ ~ o~yl]be~ 7i mi dazole

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/005tl
- 136-

CH3 ~ Cl


M ~ ~


C~ '
~13




F.~ny?le 134

5Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-[3-[1-[3-(piperidin-
l-ylmethyl)-4-phenylbutyl3piperidin-4-yl]~ yl]b~n7:imidazole

CH3 ~ Cl
~~~
N ~



C N
'3 :

13F~nl~le 135

CA 02242579 1998-07-08

W O 97/25041 PCTnUS97/00511
- 137-
..
Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-[3-C1-L3-
(ethoxycarbonyl)butyl]piperidin-4-yl~propyl]benzimidazole

Cl




H3C
CH3
m~;?le 136

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-L1-r3-
(ethoxycarbonyl~propyl]piperidin-4-yl]propyl]b~n 7:imi dazole


~''~
1o




\~ N ~ o~ CH3

F!~mnle 137

Preparation of 2-(4-chlorophenoxymethyl3-4-methyl-1-[3-~1-[3-
(carboxy)butyl]piperidin-4-yl]~ o~yl]ben7:imidazole

CA 02242579 l998-07-08

W O 97/25041 PCT~US97/00511

- 138-




CH3

~m~le 138

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(3-
carbo2~yl,. o~yl)piperidin-4-yl]l3l ol~yl~b~n7imidazole

CH3 ~ Cl


~ N ~




h~ m~I?le 139

Preparation of 2-~4-chloro~heno~ymethyl)-4-methyl-1-[3-[1-[3-(piperid~n-
l-ylcarbonyl)butyl]piperidin-4-yl] ~l o~yl]ben 7.imidazole

CA 02242579 1998-07-08

W O 97/25041 PCTAJS97/00511

- 139-
;c


& \>~~~



Cll~

mnle 140

5Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-L1-[3-(piperidin-
1-ylcarbonyl)propyl]piperidin-4-yl]~ ol~yl]b~n 7i mi dazole

~ ~ Cl

~ O



10h~ rn~le 141

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[3-methyl-4-
(piperidin- 1-yl )butyl3piperidin-4-yl]~l vllyl~ben ~i rni dazole

CA 02242579 1998-07-08

W O 97/25041 PC~US97/00511
- 140-


~C \>~'0
N ~



CH3

m~le 142

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl- 1-L3-[l-[4-(piperidin
l-yl)butyl]piperidin-4-yl]propyl]benzimidazole




h~mrlle 143

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-
(ethoxycarbonyl~piperidin-4-yl]~ vlJyl]b~n~imidazole

CA 02242579 l998-07-08

W O 97/25041 PCT/US97/00511

-141-

Cl




N ~ O~_" CH3

F.~m~le 144

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[3-
(aminocarbonyl)l,l o~yl]piperidin-4-yl]propyl]-ben 7imi dazole



~~ O
J'--NH2

F,~ml;le 145

Preparation of 2-(4-chloroph~no~ylllethyl)-4-methyl-1-~3-~4-[3-
~benzyl~mino)~ yl]piperidin-l-yl]propyl]-bqn7:;mi~ 01e

CA 02242579 1998-07-08

W O 97/25041
PCT~US97/00511
- 142-

Cl




N

m,l7le 146

Preparation of 2-~4-chlorophenoxymethyl)-4-methyl-1-[3-[4-r2-
[(benzylamino)carbonyl]ethyl]piperidin-l-yl]propyl]-b~n7imidazole




N~ N~C3


lo ~m~le 147

Preparation of 2-(4-chloroph~n o~ymethyl)-4-methyl- 1-~3-~4-[2-[(4-
methoxybenzylamino)carbonyl]ethyl]piperidin-1-yl]~ yl]-
bçn7imi~1~701e


CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511
- 143-

Cl

N ~
\_~ f H3

H


?le 147

Preparation of 2-(4-ch~oropheno~ymethyl)-4-methyl-1-[3-[4-[2-
(benzyloxycarbonyl~mino)ethyl]piperidin- 1 -yl]propyl]-ber- 7:irni dazole

C




H

0 F:~nn~le 148

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[4-~4-
phenylpiperidin-l-yl)butyl]ben~;midazole

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511
- 144-



N


N



:F"~ ?le 149

Preparation of 2-(4-chloroI~h~no~ymethyl)-4-methyl-1-[3-methyl-4-~4-
phenyl-4-(acetamidomethyl)piperidin- 1-yl]butyl]ben ~i m; dazole


>~ o


CH3


N ~ HN CH3


~ le 160

Preparation of 2-(4-chloroph~no~ymethyl)-4-methyl-1-[3-[4-
(propyl~minocarbonylethyl)piperidin-1-yl]propyl3b~n7imidazole

CA 02242579 l998-07-08

W O 97/25041 PCTnJS97/OOSll
- 146-

Cl

M~ O

N ~ ~ CH3

n~ple 151

Preparal;ion of 2-(4-chloropheno~ymethyl)-4-methyl-1-[3-~3-(piperidin-1-
yl)propy~mino]~. o~yl]b~n7.imidazole

CH3

\~ 0
N




N

h',~mple 152

Preparation of 2-(4-chloroIlheno~ymethyl)-4-methyl-1-[3-(4-
phenylpiperidin-1-yl)propyl]ben7imidazole


\~ 0

_ 15 N ~ N
F.~mple 1~;3

Preparation of 2-(4-chlorophenQ~rymethyl)-4-methyl-1-[4-phenyl-4-(4-
20 phenyl-4-methyl~nninocarbonylpiperidin-1-yl)butyl]ben7imidazole

CA 02242579 1998-07-08

WO 97/25041 PCT/US97/00511

- 146-

CH, ~ C l

N

N
,CH3
~3

F,~m;l?le 1~;4




Preparation of 2-(4-chlorophenoxymethyl)-4-methyl- 1-[3-[3-~piperidin- 1-
yl)propyl~mino]propyl]ben7.imidazole


\~ 0

N ~N

~mnle 15~;

Preparation of 2-(4-ch~oropheno~ymethyl)-4-methyl-1-[3-(4-
benzylpiperidin-l-yl)~lo~yl]b~n7imi(1~7.01e
CH ~ ,~ C l


~ N~ ~3

CA 02242579 l998-07-08

W O 97/25041 PCTAJS97/00511
- 147-

F,~r~m,ple 1~6

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[N-benzoyl-N-[3-
(piperdin-l-yl)plopyl]~mino]propyl}ben7imidazole



\~ ~~
N ~ N

6~

F,~n~le 157

Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-{3-[4-
(ethoxycarbonylethyl~piperidin-l-yl]l,l.,pyl}b~n7.imi~7Qle
Cl


N ~ ~ CH3

~,~ ?le 158

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-l3-~4-hydroxy-4-
benzylpiperidin-l-yl]~ro~yl}ben7.imidazole

CA 02242579 1998-07-08

W O 97/25041 PCT/US97/00511




OH
N


l~a~ple 1~;9

Preparation of 2-(4-chlorophen-)~ymethyl)-4-methyl-1-{4-(1,2,3,4-
tetrahydroisoqllin-~lin-l-yl)butyl}ben7.imi~7.01e

~ ~ Cl


~3

h~ m,ple 160

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-{4-(4-propoxy-4-
phenylpiperidin-1-yl)pentyl~b~,n7imidazole



& \~~~
N ~ CH3

N ~
~ - CH3


~

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511

-149-

F,~ le 161

Preparation of 2-(4-chloroph çn o~ymethyl)-4-methyl- 1- ~3-[N-benzyl-N-(3-
piperidin-1-ylpropyl)amino]propyl}ben~imidazole

CH3 ~ Cl




F.~m~le 162

Preparation of 2-(4-chloropheno~ymethyl3-4-methyl-1-{3-[N-
(benzyloxycarbonylmethyl)-N-(3-piperidin-1-
ylpropyl)amino]propyl}ben zimi dazole

CH3 ~ Cl
~0~
o
f




- ~3

F~n~le 163

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511
- 1~0-

Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-{3-methyl-4-[4-
phenyl-4-(etho~ycal llonyl)piperidin- 1-yl]butyl}b~n ~imi dazole

N ~ ~


H3C N ~ ~ CH3




mI?le 164

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[(1,2,3,4-
tetrahydronaphth-1-yl)amino]~ yl}ben~imidazole


~

N



mple 165

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-
(benzyl~mino)propyl~benzimidazole

CA 02242579 1998-07-08

W O 97~5041 PCT~US97/00511

,;~ - 151-

C l


H


?le 166

Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-[3-[4-(piperidin-1-
ylcarbonylethyl)piperidin-l-yl]propyl]ben~imi~ ole



~
N ~ N
/ /

F,~ml?le 167

Preparation of 2-(4-chloroph~nQ~ymethyl)-4-methyl-1-[3-(piperidin-1-
yl)~l o~l]b~n 7 i mi dazole


~C >~ o

N

F,~mnle 168

CA 02242579 1998-07-08

W O 97/2S041 PCT~US97/00511
-152-

Preparation of 2-(4-chloropherloxymethyl)-4-methyl-1-[3-(4-phenyl-
1,2,~16-tetrahydl o~ylldin-l-yl~propyl]ben~imidazole

~C ~ ~


N

~ e 169

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-r3-(4-phenyl-4-
etho~ycall,onylpiperidin-l-yl)propyl]ban7.imitl~7Qle
CH3 ~ Cl
~C \>~~~


N ~ ~ CH3
/~


n~;~le 170

Preparation of 2-(4-chlorophenoxymethyl3-1-[2-(4-
dimethylaminopiperidin- 1-yl)ethyl]ben 7imi dazole

CA 02242579 l998-07-08

W O 97~5041 PCT~US97/00511
- 153-



~C >~ ~
~ ~N

N(CH3)2

.~An~l~ 171

5 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-~3-
hydroxypropyl)ben 7i mi dazole

Cl


N ~

OH

~,~Am~le 172

Preparation of 2-(4-chlorophenc.~ymethyl)-4-methyl-1-(3-
cyanopropyl)ben 7.i mi~l A 7ole

Cl


. N ~

- 15 CN
mp 112~. NMR, IR and W were consistent with the desired title
structure. FDMS 339 (M+).

CA 02242579 1998-07-08

WO 97n5041 PCTnJS97/00511
- ~54-

Analysis calculated for ClgHlgClN3O:
Theory: C, 67.16; H, 5.34; N, 12.37.
Found: C, 66.95; H, 5.26; N, 12.16.

e 173

Preparation of 2-(4-chlorophen o~ymethyl)-4-methyl- 1-(3-
azidopropyl)ben~imidazole


\>~~~
N


M~
0 N
mp 68~. NMR, IR and W were consistent w;th the desired title
structure. FDMS 355 (M+).
Analysis calculated for Cl8Hl8N5~3:
Theory: C, 60.76; H, ~.10; N, 19.68.
Found: C, 61.00; H, 5.13; N, 19.70.
h'"~le 174

Preparation of 2-(4-chlorophçno~ymethyl)-4-methyl-1-~3-[N-methyl-N-(7-
dimethyl~minoheptyl)amino]propyl]ben~imidazole

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511


Cl


N ~
\
\ N ~ 3
H3C CH3

nu?le 175

Preparation of 2-(4-chloroph~nn~ymethyl3-4-methyl-1-[3-[4-(2-
phenylethyl)piperazin- l-yl]propyl]b.3n 7:i mi dazole


~C \>~o
N

M
~ M
~'

lQ ~.~m;~;?le 176

Preparation of 2-(4-chlorophçno~ymethyl)-4-methyl-1-[3-[(4-
cyclohexylpiperazin- l-yl~acetoxy]propyl]bçn~ilnidazole
..

CA 02242579 1998-07-08

WO 97/2S041 PCT~US97/00511

- 156-



N ~

o~o
~ \ ~
~ N ~

NMR was consistent with the the desired title structure.
FAB e~act _ass calculated for C30H40ClN4O3:
Theory: ~39.2803
Found: ~39.2789

u?le 177

10 Preparation of (RS) 2-(4-chlorophenoxyethyl)-4-methyl-1-[3-(pyrrolidin-3-
yloxy)~ vpyl]ben7.imidazole.
CH3

/~N
~ ~ ~~0~

0~ .



15 NMR was consistent with the desired title structure. FDMS 399 (M+).

CA 02242579 1998-07-08

W O 97/25041 PCT/US97/OO511
-1~7-

FAB exact mass calculated for ~22H27clN3o2:
Theory: 400.1792
Found: 400.1805
..
F',~m~le 178

Preparation of 2-(4-ch~loropheno~ymethyl)-4-methyl-1-[3-~1-[3-~1-
benzoyl)propyl]piperidin-4-yl]~l o~yl]ben ~i mi dazole

/~N


~-Cl



10 ~
NMR, IR and UV were consistent with the desired title structure.
FDMS 544 (M~.
Analysis calculated for C33~I38ClN302:
Theory: C, 72.84; H, 7.04; N, 7.72.
Found: C, 72.58; H, 7.22: N, 7.72.
rnr)le 179

2 0 r~ dtion of 2-~4-chloropheno~ymethyl)-4-methyl-1-~3-~[4-2-
phenylethyl)piperazin- 1-yl]carbonyl]butyl]ben 7 i mi dazole

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/Q0511

-158-



N ~
CH3

o~ N N

mple 180

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-methyl-4-~4-(2-
phenylethyl)piperazin- 1 -yl]butyl]ben 7:imi dazole



~C ~
CH3

N N
\
lo ~,~mnle 181

Preparation of 2-(4-chloroph~no~ymethyl)-4-methyl-1-C3-(1-
benzylpiperidin-4-yl)propyl]benzimidazole

CA 02242579 1998-07-08

W O 97/25041 PCTfUS97/00511

- ~,59-

~ ~ Cl

~ N



N

~,~m ~ e 182

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(2-
phenylethyl)piperidin-4-yl]~lv,uyl~ben7imidazole


>~ o




F.~m~le 183

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-~3-[1-(3-
lphenylpropyl)piperidin-4-yl]~lo~yl]bçn7.imidazole

CA 02242579 l998-07-08

W O 97/25041 PCTAUS97/00511


Cl

N



M

MP 59~. NMR was consistent with the desired title structure.
FDMS 515 (M+).
5 Analysis calculated for C32H3gClN30:
Theory: C, 74.47; H, 7.42; N, 8.14.
Found: C, 74.20; H, 7.23; N, 8.17.

~ ,m~le 184

Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-[3-[1-
(benzoylmethyl)piperidin-4-yl]propyl]b~n 7.i mi dazole




~ o



NMR and IR were consistent with the desired title structure.
Analysis calculated for C31H34C~N302:

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511
- 161-
.i
Theory:C, 72.1~; H, 6.64; N, 8.14.
Found: C, 72.35; H, 6.61; N, 8.34.
,
?le 185




Preparation of 2-(4-chloroph~no~ymethyl)-4-methyl-1-[3-[1-(2-
benzoylethyl)piperidin-4-yl]propyl]b~n ~i mi dazole
~Cl




--~N> ~3

NMR was consistent with the desired title structure.
~AB exact mass calculated for C32H37ClN302:
Theory: 530.2574
Found: 530.2584
h'.~m~;?le 186

Preparation of 2-(4-chlorophenr~y_ethyl)-4-methyl-1-[3-[1-(3-hyd~o,.y-3-
phenylpropyl)piperidin-4-yl]~. olJyl]ben~imidazole


CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511
- 1~2-



N



N

OH

NMR was consistent with the desired title s~ructure.
FAB exact mass calculated for C32E3sclN3o2:
Theory: ~32.2731
Found: 532.2738

F,~-~m~le 187

Preparation of 2-(4-chloropheno~ymethyl~-4-methyl-1-[2-
formylethyl]bçn7.;m;dazole

Cl



CHO

F.~m,~le 188

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-(prop-1-en-3-
yl)ben~im; dazole

CA 02242579 1998-07-08

W O 97/25041 PCTAUS97/00511

- 163-


r ~ \ ~ O
N ~
CH2

~ m~le 189

Preparation of 2-(4-chlorophçno~ymethyl)-7-methyl-1-(prop-1-en-3-
yl)bçn~imi~ole

~ Cl
~r ~~~
\~~ N~
CH3 \~ CH2

~ mr)le 190

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[4-phenyl-4-
acetamidomethyl)piperidin-1-yl]propyl]ben~imidazole

& J~,Cl


~ CH3



m~?le 191

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511

- 164-

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-(4-
aminobutyl)b~.n7.imidazole

CH3 ~ Cl


N ~
~nH2




~ m~le 192

Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-[3-(piperidin-1-
y~)propyl)b~n7.imidazole
Cl



N ~

~,~r~m.I~le 193

15 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[[2-
(phenylethylcarbamoyl)ethyl]piperidin-1-yl]propyl]ben~irni dazole

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511
-165-


\>~0~


H
.~ ~ N


rnl?le 194

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[[N-[3-
(piperidin-l-yl)~ol~yl]-N-2-phenylethyl]amino]~lo~yl]berl~im;~ ole




"
~ N ~ N


~ ~le 195

Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-[3-[N-[3-(piperidin-
l-yl)~l o~yl]-N-(2-phenylethyl)amino]propyl]bçn7.irn;dazole

CA 02242579 l998-07-08

W O 97/25041 PCTAUS97/00511
- 166-


\>~~~
N ~

N ~ N


~n~ple 196

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[N-(2-
phenylethyl)amino~propyl]b~n7:irni dazole


\>~~~
N

HN


~ n~le 197

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-(1,2,3,4-
tetrahydroisoquinolin-l-yl)~ yl]ben7:imidazole

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511

- 167-
i,



~,
N



F~ nple 198

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-(4-
phenylpiperazin-l-yl)propyl]ben~imirl~ole


~C \>~0
N
b




h',~n~le 199

Preparation of 2-(4-c~lorophenoxymethyl)-4-methyl-1-~3-[N-[3-(piperidin-
l-yl)propyl]-N-(biphenylacetyl)amino]propyl]ben7:innidazole

CA 02242579 1998-07-08

W O 97/25041
PCT~US97/00511

- 168-


\>~~~



N
O


Tr~le 200

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl- 1-[3-tN-[3-(piperidin-
l-yl)propyl]-N-(hirhenylacetyl~arnino3~ yl3ben7imidazole

Cl



H3C ~ N ~ N
o




~rr~le 201

Preparation of 2-(4-chloroI heno~ymethyl)-4-methyl-1-[3-(4-
etho~yc~l~onylpiperidin-l-yl)propyl]ber-7:imi~ ole

CA 02242579 1998-07-08

W O 97/25041 PCTnJS97/00511

-169-

Cl

N ~
\_~

, ~ O~_ " CH3

F,~ ?le 202

5 Preparation of 2-(4-chlorophenoxymethyl~-4-methyl-1-(3-
aminopropyl)b~n s~ i dazole

Cl



NH2

F~ le 203

Preparation of 2-(4-clhlorophenoxymethyl)-4-methyl-1-(4-
hy dl O~YIJ uLyl)ben 7.i mi dazole


1~ '>'' ~
c N ~


OH
F,~ le 204

CA 02242579 1998-07-08

W O 97/25041 PCTrUS97/00511

-170-

Preparation of 2-(4-chloroph~no~rymethyl)-5-[2-(piperidin-1-
yl)ethylcarbamoyl]-1-[3-(piperidin-4-yl~ol yl]ben~imidazole


~ N ~ ~ ~ Cl



~ NH

~ml?le 205

Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-(3-
0 bromopropyl )ben ~:i m i dazole




Br

h~m~le 206
Preparation of 2-(4-chlorophenoxymethyl )-4-methyl- 1-[3 -
(ethoxycarbonyl~propyl]ben7:imi dazole

CA 02242579 l998-07-08

W O 97/25041 PCT~US97/00~11

- 171-



N ~



~ CH3
m~l~le 207

5 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-(3-
hydro~Ly~l o~yl)ben7.imidazole

Cl

N ~

OH

F',x~n~le 208

Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-{3-[N-ethyl-N-(3-
piperidin-1-ylpropyl)amino]propyl}b.o.n7.imidazole


., ~ ~ O


H3C

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/00511

-172-
m~le 209

Preparation of 2-(4-chloroph~no~ymethyl)-4-methyl-1-{3-[N-acetyl-N-(3-
piperidin-1-ylpropyl)amino~propyl}b~n~im;dazole




Cl




H3C

m~ le ~10

Preparation of 2-(4-chlorophçno~rymethyl)-4-methyl-1-{3-[N-
(benzoylmethyl)-N-(3-piperidin-1-ylpropyl)amino]propyl}ben~imidazole



~ ~ N ~ - N ~




~"r~rr~le ~11

Preparation of 2-(4-chlorophçno~rymethyl)-4-methyl~ 3-~N-
(benzylo~y~a. bonylmethyl)-N-(3-piperidin- 1-
ylpropyl)amino]plo~yl~berl~imi~ ole


CA 02242579 l998-07-08

WO 97/25041 PCT/US97/OOSll

- 173-


N ~Cl
o_~~ N~>
o




~3

F/~mI?le 212

Preparation of 2-(4-chloroph~no~ymethyl)-4-methyl-1-{3-[4-
benzoylpiperidin-l-yl]l,lo~yl}ber~7.imirl~Qle

,Cl


.


0 F,~ml;?le 212A

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[2-(piperidin-1-
ylethyl)piperid~n- 1-yl]propyl}ben 7.imi ~ ole

..

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-174-



N


C7

F.~m;l?le 213

S Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-{3-[4-
~propylcarbamoylethyl)piperidin-1-yl]propyl}ben7imidazole



~ H
N ~ N CH3

~ ml-le 214

Preparation of 2-(4-chlorophen()~rymethyl)-4-methyl-1-{3-[4-[2-
(phenylethylcarbamoyl)ethyl]piperidin-1-yl~io~yl}be~7~imidazole

CH3 ~ Cl

~ >~ o

N N3~,N O

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~ n~le 215

Preparation of 2-(4-cl~lorophenoxymethyl)-4-methyl-1-(4-methyl~minO 3
5 methylbutyl)b~n7.imidazole



CH3

NH
CH3

~ le 216

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-(4-methyl~minn-3-
benzylbutyl)benzimidazole

Cl

N

NH
CH3

mJr~le 217

Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-r4-(piperidin-1-yl)-
2 0 3-methylbutyl]bçn~irnidazole

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N ~
CH3

N


~ e 218

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-~4-(piperidin-1-yl)-
3-benzylbutyl]ban~:irnidazole




h~r~ le 219

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[3-~(piperidin-1-
yl)amino]carbonyl]-3-methylpropyl]ber-7.imidazole

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- 177-

Cl


- ~ ~3

M



le 220

Preparation of 2-(4-chloroph~no~ymethyl)-4-methyl-1-[3-[3-[(piperidin-1-
yl)amino~carbonyl~-3-benzylpropyl]ben~imidazole




N ~



F',~ ?Ie 221

Preparation of 2-(4-nitrophenoxymethyl)-4-methyl-1-[3-[1-(t-
butoxycarbonyl)piperidin-3-yU~lo~yl]be~imidazole

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N ~


N- BoC

NMR and IR were consistent with the desired title product. FDMS 508
(M+).
5 Analysis for C2gH36N4Os:
Theory: (~, 66.12; H, 7.13; N, 11.01.
Found: C, 6~.86; H, 7.09; N, 10.98.

~ le 222
1~
Preparation of 2-(4-~rninoph~n o~ymethyl)-4-me~hyl- 1-~3-[1-(t-
butoxycarbonyl)piperidin-3-yl]propyl]ben~imidazole


~~~


~ ~N--BoC

A mi sFtl1re of 2-(4-nitrophenoxymethyl)-4-methyl-1-[3-[1-(t-
butoxycarbonyl)piperidin-3-yl]propyl]ben~imidazole (396 mg, 0.78 mmol)
and 10% palladium on activated carbon (400 mg) in 10 ml of ethanol was
stirred under a hydrogen atmosphere at room temperature. After two
20 hours, the re~ction mixture was filtered through a CELITETM cake. The

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-179-

filtrate was cnn~len~ed on a rotoevaporator to yield 310 mg (83%) of the
desired title product.
NMR and IR were consistent with the desired title product. FDMS 478
(M+).
Analysis for C2gH3gN4O3:
Theory: C, 70.26; H, 8.00; N, 11.70.
Found: C, 70.00; H, 7.97; N, 11.60.

~m~le 223

Preparation of 2-r4-(t-buto~ycall)ony1~qmino)phenoxymethyl~-4-methyl-1-
[3-[1-(t-butoxycarbonyl)piperidin-3-yl],L,~o,~yl3bçn~imidazole


~ \~ OJ~ N BoC

~,
~ N--BoC

A solution of 2-(4-aminophenoxymethyl)-4-methyl-1-r3-[1-(t-
buto~yca~lJonyl)piperidin-3-yl]lJ o~yl]b~n7.imi~ole (160 mg, 0.33 m m ol,
1.0 eq.) in a 1~ e of anhydrous tetrahydrofuran and water (2 ml
total) was treated wtih pot~.c.cillm carbonate (56 mg, 0.4 m m ol, 1.2 eq.)
and di-t-butyl dicarbonate (90 mg, 0.4 mmol, 1.2 eq.). The mixture was
stirred at room temperature for two hours. Water (10 ml) was added to
the mi~Lu~ e. The organic fraction was extracted with ethyl acetate (3 x
~- 10 ml). The combined organic fraction was washed with water (10 ml),
brine (1 x 101), and then dried over sodium sulfate. The solvents were
removed in vacuo. The title product was further purified by flash
chromatography. Yield: 190 mg (>99%).
,.
Preparation 52

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- 180-

Preparation of a-benzyl-~-butyrol~ctone (3-benzyl-3,4-dihydrofuran-2-
one)




~ ~0
O
To a solution of diiso~lo~ylamine tl5.18 g, 0.15 mol) in dry
tetrahydrofuran (200 ml) at -78~C under a nitrogen atmosphere, n-
butyllithium (1.6 M in he~nes, 94 ml, 0.15 mol) was added d~ wise.
10 After twenty rninlltes of stirring at -78~C, ~-butyrolactone (12.91 g, 0.15
mol) was added d~ wise, such that the reaction temperature was
m~;nt~ined below -70~C. After twenty minutes of stirring at -78~C, a
u e of benzyl bromide (25.66 g, 0.15 mol) and
he~methylphosphoramide (26.85 g, 0.15 mol) was added dropwise to the
15 reaction mixture. The re~ctior~ ule was then permitted to warm to -
30~C and stirred at this temperature for two hours.
The reaction mixture was partitioned between a saturated
ammonium chloride solution (500 ml) and diethyl ether (600 ml). The
organic fraction was dried over potassium car~onate and the solvents
20 were removed in vacuo to yield 36.13 grams of the desired intermerii~tes
as a dark yellow oil.
The crude material was further purified by flash silica gel
chromatography eluting with a solvent gradient be~innin~ at 19:1
hç~nes/ethyl acetate and enllin~ with 3:1 hexanes/ethyl acetate. The
25 fractions cont~ining desired product were combined and concentrated
under reduced pressure to yield 20.1 grams (76%) as a pale yellow oil.
IR and NMR were consistent with the proposed title structure.
FDMS 177 (M+1)
Analysis for CllHl202:

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181-

Theory: C, 74.98; H, 6.86.
Found: C, 74.76; H, 6.73.

Preparation 53




Preparation of ethyl 2-benzyl-4-bromob~ no~te
~3

Br, ~O~CH3


In absolute ethanol (78 ml), a-benzyl-~-butyrolactone (14 g,
80 mmol) was added and then saturated for thirty minutes with gaseous
hydrogen bromide, m~int.~ining the temperature below 50~C. The
reaction was then heated to 45~C and stirred a~ this temperature for 16
hours. The solution was concentrated under reduced pressure and the
15 resulting oil was taksn into ethyl acetate (500 ml), washed once with
water, and then dried over magnesinm sulfate. The solvents were
removed in vacuo to yield 15.13 grams of tan oil.
The crude ...; xl. . . e was further purified by flask silica gel
chromatography, eluting with a gradient solvent of hexanes to a 1:1
mixture of h~ne.~/methylene chloride. The fractions c~nt~ining the
desired intermediate were comhined and concentrated under reduced
pressure to yield 13.47 grams (67%~.
IR and NMR were consistent with the proposed title structure.
FDMS 286.1 (M+1)
Analysis for C13H17O2Br:
Theory: C, 54.75; H, 6.01.
Found: C, 54.99; H, 6.02.

Pre~aration 54


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Preparation of ethyl 2-methyl-4-bromobllt~no~te
CH3
Br ~O~CH3

In absolute ethanol (78 ml), a-methyl-y-butyrolactone (8 g, 8
mmol) was added and then saturated for t~irty minutes with gaseous
hydrogen bromide, m~int~ining the temperature below ~0~~. The
reaction was then h~te-l to 4~~C and stirred at this temperature for 16
hours. The solution was concentrated under reduced pressure and the
10 resulting oil was taken into ethyl acetate (500 ml), washed once with
water, and then dried over magnesium sulfate. The solvents were
removed in vacuo.
The crude ..~ u~e was further purified by flask silica gel
chromatography, eluting with a gradient solvent of hç~r~n~s to a 1:1
15 ~ e of h~nes/methylene chloride. The fractions cont~in;ng the
desired intermediate were cornhin~d and concentrated under reduced
pressure to yield 7.1 grams (44%).
IR and NMR were consistent with the proposed title structure.
FDMS 208, 209, 210~0 Analysis for C7H13O2Br:
Theory: C, 40.21; H, 6.27.
Found: C, 39.24; H, 6.19.

Prel?aration 5
Preparation of ~RS) ethyl 2-phenyl-4-chlorobllt~no~te



Cl~O~CH3

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To a solution of diiso~lo~yl~mine (23 1, 0.16 mol) in dry
tetrahydrofuran (100 ml) at -78~C, under a nitrogen atmosphere, was
added dLop~vise n-butyllithium (100 ml of a 1.6 M solution, 160 mmol).
After stirring for thirty minutes at -78~C, ethyl phenylacetate ~25 g, 0.15
mol) in dry tetrahyd~ or~n (172 ml) was added dropwise to the reaction
.,~;xI.-.e. The resulting ~ e was perm7tted to warm to -30~C. After
stirring for fifteen minlltes at -30~C, N,N'-dimetllyl~lol~ylene urea (18
ml, 0.15 mol) in dry tetrahyLo~uLan (30 ml) was added L~l~wise and the
resulting mi~ e was stirred for ten minlltes.
The reaction ...i~ e was added via cannula under
nitrogen atmosphere into a flask cont5~in;ng 1-bromo-2-chloroethane (63
ml, 0.7~ mol~ in diethyl ether (200 ml) at -15~C. This re~c~ n ...;Y~ule
was then stirred at -15~C for three hours. The reaction mixture was
15 partitioned between a saturated ~mm()nium chloride in water solution
(~;00 ml) and diethyl ether (1 L). The organic fraction was dried over
potassium carbonate and the solvents were removed in vacuo to yield
41.37 grams of oil.
The crude material was further purified by ~ash solica gel
20 chromatography, eluting with a solvent gradient of hç~nes to 1:1
h~nes:methylene chloride. Fractions cont~;nin~ the desired title
product were comhined and concentrated under reduced pressure to
yield 1~.û grams (44%) as a clear oil.
NMR was consistent with the proposed title structure.
FDMS 226.1 (M+)
Analysis for C12H1sO2Cl:
Theory: C, 63.~;8; H, 6.67.
Found: C, 63.29; H, 6.80.

3 0 Pre~aration 56
,,
Preparation of 4-(cyclohexyl)piperidine and 4-phenylpiperidine
;

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- 1~4-



¢~ and

N

3-Phenylpyridine (25 g, 0.16 mol) was placed in ethanol (470
~1) along with rhodium (5% on alllmin~, 5.0 g) and was subjected to
5 hydrogenation at room tempeld~u~e for four hours at 60 psi. The
resulting solution was then filtered, and the resulting oil was taken into
ethyl acetate (500 ml), washed with water, and then dired over
potassium carbonate. The solvents were removed in vacuo to yield 24.41
gr~ms of a tan oil. The ....~ .e of compounds was further purifed by
lo flash chromatography, eluting with methanol. The fractions cont~ining
the desired title intermediates were cornhined and concentrated in vacuo
to yield 22.41 grams (86%) of a clear oil.
NMR and FDMS were consistent with the proposed title structures.

Preparation 57

Preparation of 4-(cyclohexylmethyl)piperidine and 4-benzylpiperidine



and

N
H H
3-Benzylpyridine (5 g, 0.029 mol) was placed in ethanol (145
ml) along with rhodium (5% on aluminaJ 0.125 g) and was subjected to

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- 185-

hydrogenation at room temp~rature for four hours at 60 psi. The
resulting solution was then filtered, and the resulting oil was taken into
ethyl acetate (~00 ml), washed with water, and then dired over
potassium carbonate. The solvents were removed in vacuo to yield 4.71
5 grams of a tan oil. The ~lule of compounds was further purifed by
flash chromatography, eluting with methanol. The fractions cont~ining
the desired title intermediates were c mhined and concentrated in vacuo
to yield 3.64 gr~rns (71%) of a clear oil.
NMR and FDMS were consistent with the proposed title structures.
ml;~le 224

Preparation of l-r3-(ethoxycarbonyl)butyl~-2-~(4-chlorophenoxy)methyl]-4-
methylbçn 7imi dazole
Cl




>--CH3
O=~

CH3

A sodillm hydride solution (60~o in oil, 810 mg, 20.3 mmol)
was washed with he~n~s (2 x 50 ml) and then diluted with N,N-
20 dimethylformamide (100 ml) At room temperature, under a nitrogenatmosphere, 2-[t4-chlorophenoxy)methyl]-4-methylben7imidazole (5 g,
18.3 mmol) was then added in one portion. The resulting mixture was
then stirred at room tempe~dl,ul~ for thirty minlltes, and then 3-
(etho~yc~bonyl)butyl bromide (4.25 g, 20.3 mmol) in N,N-


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- ~86-

dimethylform~mi-le (10 ml) was added dropwise. Upon compl~tion of
this addition, the reaction ~ ula was stirred for about six hours at a
temperature of 70-80~C. The reaction mixture was then cooled to room
temperature, poured into water (500 ml), and then extracted with ethyl
5 acetate (500 ml). The organic fraction was washed once with water (500
ml) and then dried over potassium car~onate. The solvents were
removed in vacuo, yielding 8.01 grams of a dark oil. The crude material
was further purified by flash silica gel chromatography, eluting with a
gradient solvent of methylene chloride to 3:1 methylene chloride:ethyl
10 acetate. The fractions col t,$~inin~ the desired title product were
comhineA and cnncP-ntrated in vacuo to yield 7.21 grams (98%) of a
viscous yellow oil.
NMR and IR were consistent with the proposed title structure.
FDMS 401 (M+)
Analysis for C22H2sN2O3Cl:
Theory: C, 65.91; H, 6.29; N, 6.99.
Found: C, 66.13; H, 6.50; N, 7.11.

n U?l e 225
Preparation of 1-[3-(ethoxycarbonyl3-4-phenylbutyl]-2-[(4-
chlorophenoxy)methyl]-4-methylben7imidazole

~cN ~3'
o




<O

CH3

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A sodium hydride solution (60% in oil, 810 mg, 20.3 mmol)
was washed with h~nes (2 x ~0 ml) and then diluted with N,N-
dimethylform~mi~e (100 ml). At room temperature, under a nitrogen
5 atmosphere, 2-[(4-chlorophenoxy)methyl]-4-methylb.qn~imidazole (~.0 g,
18.3 mmol) was then added in one portion. The resulting mi~tllre was
then stirred at room temperature for thirty minutes, and then 3-
(etho2~yc~ bony~)-4-phenylbutyl bromide (5.7g g, 20.3 mmol) in N,N-
dimethylformamide (10 ml) was added dropwise. Upon completion of
10 this addition, the reaction ~Lu~ was stirred for about six hours at a
temperature of 70-80~C. The reaction ~u~e was then cooled to room
temperature, poured into water (500 ml), and then extracted with ethyl
acetate (500 ml). The organic fraction was washed once with water (500
ml) and then dried over potassium carbonate. The solvents were
removed in vacuo, yielding 10.28 grams of a dark oil. The crude
material was further purified by flash silica gel chromatography,
eluting with a gradient solvent of methylene chloride to 9:1 methylene
chloride:ethyl acetate. The fractions cont~inin~ the desired title product
were cornhined and concentrated in vacuo to yield 8.08 grams (93%) of a
2 o viscous yellow oil.
NMR and IR were consistent with the proposed title structure.
FDMS 476, 477 (M+)
Analysis for C2gH2gN2O3Cl:
Theory: C, 70.50; H, 6.13; N, ~.87.
Found: C, 67.~6; H, 6.22; N, 6.37.

F'x~mple 226

Preparation of 1-~3-(ethoxycarbonyl)~i~)L)yl]-2-[(4-chlorophenoxy)methyl]-
3 o 4-methylbçn~:imirl~7 ole

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-188-



N




CH3

A sodium hydride solution (60% in oil, 325 mg, 8.1 mmol)
was washed with h~nes (2 x 50 ml) and then diluted with N,N-
dimethylform~ (100 ml). At room temperature, under a nitrogen
atmosphere, 2-[(4-chlorophenoxy)methyl]-4-methylbçn~imidazole (2.0 g,
7.3 mmol) was then added in one portion. The resulting ll~i~ule was
then stirred at room temperature for thirty minutes, and then 3-
(etho~yca~l,onyl)~o~yl bromide (1.58 g, 8.1 mmol) in N,N-
0 dimethylform~ 1e (10 ml) was added d~o~wise. Upon completion of
this addition, the reaction mixture was stirred for about six hours at a
tempela~ule of 70-80~C. The reaction ~ uie was then cooled to room
temperature, poured into water (500 ml), and then extracted with ethyl
acetate (500 ml). The organic fraction was washed once with water (500
15 ml) and then dried over potassium carbonate. The solvents were
removed in vacuo, yielding 3.16 grams of a semi-solid material. The
crude material was further purified by flash silica gel chromatography,
eluting with a gradient solvent of methylene chloride to 1:1 methylene
chloride:ethyl acetate. The fractions cont~inin~ the desired title product
20 were combined and conc~ntrated in vacuo to yield 2.21 grams (78%) of a
viscous yellow oil.
mp 78.~-80~C
NMR was consistent with the proposed title structure.
FDMS 386 (M+)

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- 189-

Analysis for C2lH23N203Cl:
Theory: C, 65.20; H, 5.99; N, 7.24.
Found: C, 64.97; H, 6.05; N, 7.23.

F',~z~m~ 7

Preparation of 1-(3-carbo~ybu~yl)-2-~(4-chlorophenogy)methyl]-4-
methylben7.imil1~701e
~ CEI3




O=~
OH
To a ~i2~ e of tetrahydrofuran (42 ml), methanol (14 ml),
and water (14 ml), were added 1-~3-(ethoxycarbonyl)butyl]-2-[(4-
chlorophenoxy)methyl3-4-methylb~n~imidazole (1.3 g, 3.2 mmol) and
15 lithium ll~o~de (403 mg, 3 eq.~. The resulting mi~tllre was stirred
overnight at room temperature and was then concentrated in vacuo to
yield a white solid. This residue was taken into 250 ml of a 3:1
bllt~nol toluene solution. The organic fraction was washed once with
200 ml of water and then dried over m~gnefiillm sulfate. The solvents
2 o were removed in vacuo to yield 1.22 grams of tan solid, which was
further purified by f~ash chromatography, eluting with a gradient
solvent of 19:1 ethyl acetate:methanol to 9:1 ethyl acetate:meth~n-ll. The
fractions cont~ining the desired material were combined and
concentrated under reduced pressure to yield 1.12 grams (94%) of the
25 desired title product as a white solid.
mp 149-161~C
NMR and IR were consistent with the proposed title structure.

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- 190-

FDMS 373 (M+)
Analysis for C2oH21N2O3CI:
Theory: C, 64.43; H, ~.68; N, 7.51.
Found: C, 64.62; H, 5.91; N, 7.26.




~"~m~le 228

Preparation of 1-(4-phenyl-3-carbo~ybu~yl~-2-[(4-chlorophenoxy)methyl]-
4-methylb~,n 7:i mi dazole




'/r- O
OH

To a ~ L~ll e of tetrahydrofuran (84 ml), meth~nol (28 ml),
and water (28 ml), were added 1-[3-(ethoxycarbonyl)-4-phenylbutyl]-2-[(4-
chlorophen--~y)methyl]-4-methylbenzimidazole (3.05 g, 6.4 mmol) and
lithium lly~oxide (788 mg, 3 eq.). The resulting ~.~ixl,...e was stirred
overnight at room temperature and was then conc~ntrated in vacuo to
yield a white solid. This residue was taken into 2~0 ml of a 3:1
bllt~nr~l toluene solution. The organic fraction was washed once vwith
2 o 200 ml of water and then dried over magnesill~n sulfate. The solvents
were removed in vacuo to yield 4.17 grams of tan solid, which was
further purified by flash chromatography, eluting with a gradient
solvent of 19:1 ethyl acetate:methanol to 9:1 ethyl acetate:methanol. The
fractions cont~ining the desired material were combined and ~'
concentrated under reduced pressure to yield 2.71 grams (94~o) of the
desired title product as a white solid.
mp 190-191.~;~C

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- 191-
.,
NMR and IR were consistent with the proposed title structure.
FDMS 448 (M+)
Analysis for C26H2sN2O3Cl:
Theory: C, 6g.~6; H, 5.61; N, 6.24.
Found: (:, 69.77; H, 5.68; N, 6.46.
ny le 2~9

Preparation of 1-(3-carbo~y~ yl)-2-~(4-chlorophenoxy)methyl]-4-
methylbe~7imi~7.01e



~, ~ \Y'~~

0~
0~

To a ~ ul e of tetrahy~L oîu~ dll (72 ml), methanol ~24 ml),
and water (24 ml), were added 1-[3-(ethoxycarbonyl)~lo~y~]-2-[~4-
chlorophenoxy)methyl3-4-methylben7.imitl~7O1e (2.0 g, ~.2 mmol) and
lithium hydroxide (642 mg, 3 eq.). The resulting ...; x 1. . . e was stirred
overnight at room temperature and was then concentrated in vacuo to
yield a white solid. This residue was taken into 2~0 ml of a 3-1
butanol:toluene solution. The org~nic fraction was washed once with
200 ml of water and then dried over m~gn~.qium sulfate. The solvents
~ were removed in vacuo to yield 1.~6 gr~m.q of tan solid, which was
further purified by flash chromatography, eluting with a gradient
solvent of 19:1 ethyl acetate:methanol to 9:1 ethyl acetate:met.h~nol The
fractions cont~ining the desired material were combined and
concentrated under reduced pressure to yield 1.31 grams (70%~ of the
desired title product as a white solid.

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- lg2-

NMR was consistent with the proposed title structure.
FDMS 3~9 (M+)
Analysis for ClgH1gN2O3Cl:
Theory: C, 63.60; H, 5.34; N, 7.81.
Found: C, 63.32; H, 6.26; N, 7.82.

le 230

Preparation of 1-[3-~N-methylcarbamoyl)butyl]-2-~(4-
10 chlorophenoxy)methyl]-4-methylben~im~ ole




~CH3

NH
H3C/

In methylamine (40% in water, 20 ml), 1-[3-
15 (etho~ycall/onyl)butyl]-2-[(4-chlorophenoxy)methyl]-4-
methylbqn~imidazole (1.60 g, 3.7 m mol) was placed. To this ,..ixl l.e 10
ml of methanol were added, to enh~nce solubility. The resulting
mi~t lre was stirred at room tempel~ule for about 64 hours, after
which time the reaction ~ ule was concentrated in vacuo. The
2 o residue was taken up in 200 ml of methylene chloride. The organic
fraction was washed once with 200 ml of water. The organic fraction
was dried over potassium carbonate and the solvents were removed in
vacuo to yield 1.61 grams of a dark oil. The crude material was further
purified by flash silica gel chrornatography, eluting with a gradient of
25 methylene chloride to a 1:1 methylene chloride:ethyl acetate ~i~ e.

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- 193-

The fractions cont~inin~ the desired material were comhined and
concentrated under reduced pressure to yield ~10 mg(36%) of the desired
title product as a white solid.
mp 167.6-168.5~C
NMR and IR were consistent with the proposed title structure.
FDMS 386 (M+)
Analysis for C21H24N3O2Cl:
Theory: C, 65.36; H, 6.27; N, 10.89.
Found: C, 65.10; H, 6.46; N, 10.96.
~ n~le 231

Preparation of 1-[3-(N-methylcarbamoyl)-4-phenylbutyl]-2-[(4-
chlorophenoxy)methyl]-4-methylben7imidazole



0~

H3C

In methyl~mine (40% in water, 10 ml), 1-[3-
(ethoxycarbonyl)-4-phenylbutyl]-2-~(4-chloroI~h~n o~y)methyl]-4-
20 methylbçn7imi~ (1.0 g, 2.5 rnmol) was placed. To this mi~tl1re 10
ml of methanol were added, to enhance solubility. The resulting
mixture was stirred at room temperature for about 64 hours, after
which time the reaction ~ e was conc~ntrated in vacuo. The
residue was taken up in 200 ml of methylene chloride. The organic
25 fraction was washed once with 200 ml of water. The organic fraction

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- 1~4-

was dried over potas~ium carbonate and the solvents were removed in
vacuo to yield 0.967 grams of a viscous oil. The crude material was
further purified by flash silica gel chromatography, eluting with a
gradient of methylene chloride to a 1:1 methylene chloride:ethyl acetate
5 mixture. The fractions cont~inin~ the desired mslterial were combined
and concçnt.rated under reduced pressure to yield 306 mg (26%) of the
desired title product as a crystalline material.
mp 169-170.5~C
NMR and IR were consistent with the proposed title structure.
FDMS 461, 462 (M+)
Analysis for C27H2gN3O2Cl:
Theory: C, 70.20; H, 6.11; N, 9.09.
Fou~d: C, 6g.91; H, 5.85; N, 9.09.

~ mnle ~.~2

Preparation of 1-[3-(chlorocarbonyl)butyl~-2-[(4-chlorophenoxy)methyl]-4-
methylben 7:i mi dazole




>--CH3
O=~
Cl
Under a nitrogen atmosphere at room temperature 1-[3-
(carboxy)butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbel~imirl~7:ole (1.2
g, 3.2 mmol) was added in one portion to oxalyl chloride ~ ml) in
25 methylene chloride (1~0 ml). After the material solubilized, one drop of
N,N-dimethylformamide was added to initiate the reaction. Bubbling of
the solution began and was visible for ~p~ xi~ tely fifteen minutes.

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The reaction .~ixl~l~e was stirred at room temperature for two hours.
The reaction m;~tllre was then concentrated under reduced pressure,
reuslting in the formation of a white solid. The solid was triturated in
. 100 ml of h~n~s, ~ltered and dried in a vacuum oven at ~0~C for one
5 hours to yield the title product (1.3 g, 91%) as a white solid.
mp 140-142~C
NMR was consistent with the proposed title structure.
FDMS 39Q, 391 (M~)
Analysis for C2oH2oN2o2cl:
Theory: C, 61.39; H, 5.15; N, 7.16.
Found: C, ~;6.11; H, 5.00; N, 6.61.

le 233

5 Preparation of 1-r3-(carbamoyl)butyl]-2-[(4-chlorophenoxy)methyl]-4-
methylben~imi~ ole




~CH3

NH2

In an ammonium hydroxide solutiorl (28%, 10 rnl) was
placed 1-[3-(chlorocarbonyl)but~rl]-2-[(4-chlorophenoxy)methyl]-4-
methylbenzimidazole (400 mg, 1.0 mmol). To this ~ 10 ml of
methanol were added, to çnh~nce solubility and the ~ e was stirred
for about 64 hours at room temperature. The reaction mixture was then
25 concentrated under reduced pressure to produce a tan foam. The crude
material was further purified by flash silica gel chromatography,
eluting with a gradient solvent of 19:1 ethyl acetate:methanol to 9:1 ethyl

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acetate:methanol. The fractions cont~ining the desired material were
comhined and concentrated in vacuo to yield 300 mg (73%) of the desired
title compound as a white foam.
NMR was consistent with the proposed title structure.
5 FDMS 371.3 (M+)

F,~ml?le ~4

Preparation of 1-[3-(N,N-dimethylcarbamoyl)butyl]-2-[(4-
10 chlorophenoxy)methyl]-4-methylbe~7.imi~ ole


>/~


=~CH3

~N--CH3
H3C

In an dimethylamine (40% in water, 101) was placed 1-[3-
15 (chlorocarbonyl)butyl~-2-~(4-chlorophenoxy)methyl~-4-
methylb~n~imidazole (600 mg, 1.5 mmol). To this ~ 10 ml of
methanol were added, to ~nh~nce solubility and the ~ u~e was stirred
for about 64 hours at room tempeldl,-L~e. The reaction mixture was then
concentrated under reduced pressure to produce 600 mg as a tan foam.
2 o The crude material was further purified by flash silica gel
chromatography, eluting with a gradient solvent of 19:1 ethyl
acetate:methanol to 9:1 ethyl acet~te meth~nol The fractions
cont~inin~ the desired material were combined and concentrated in
vacuo to yield 37~ mg (63%) of the desired title compound as a white
2 5 foam.
NMR was consistent with the proposed title structure.

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F~ 23~

Preparation of 1-[4-(methyl~mino)-3-methylbutyl]-2-[(4-
5 chloroph çn o~y)meth~rl]-4-methylb~n 7i mi dazole dihydrochloride salt
monohydrate



~[~N
~2 HCl

~CH3

NH
H3C

lo Under a nitrogen atmosphere 1-~3-
~(methylamino)carbonyl]butyl~-2-~(4-chloroph en o~y)methyl] -4-
methylben7.inlidazole (100 mg, 0.26 mmol) was added via spatual to a
solution of RED-ALTM (2 ml) in 10 ml dry toluene at room tempe. a~
The reaction ~ ,ul~ was then heated to 56~C for fifteen minutes. The
15 reaction ~ ule was cooled to room temperature and poured into 100
ml of water, and was then extracted with 200 ml ethyl acetate. The
org~nic fraction was washed once with water, and then dried over
potassium carbonate. The solvents were removed in vacuo to yield 107
mg of a viscous oil. The crude material was further purified by flash
2 0 chromatography, eluting with 2% ethyl~mine in methanol. The
- fractions cont~inin~ the desired title product were combined andconcentrated under reduced pressure to yield 30 mg of a viscous oil
~Yield 31%).
The title desired product was collvel ~ed to the
2 5 dihydrochloride salt by placing the free base in 10 ml ethyl acetate and
~tling a saturated solution of hydrochloric acid in diethyl ether, until

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solution turned congo red litmus slightly blue. The solvents were
removed in vacuo and the resulting white residue was triturated in
diethyl ether. Drying at 60~C for one hour yield 32 mg of the
dihydrochloride salt as a white solid.
mp 79-81~C
FDMS 371 (M+)
Analysis for C21H2gN3OCl ~ 2 HCl ~ H20:
Theory: C,64.49; H, 6.63; N, 9.08.
Found: C,54.65; H, 6.23; N, 8.97.
~ ?le 236

Preparation of 1-[4-(methylamino)-3-benzylbutyl]-2-[(4-
chlorophenoxy)methyl]-4-methylben7.imidazole dihydrochloride salt
lS

~" C 'Y'o~3


~2 HCl

NH
H3C

Under a nitrogen atmosphere 1-[3-
[(methyl~mino)carbonyl]-4-phenylbutyl~-2-~(4-chlorophenoxy)methyl]-4-
20 methylbenzimidazole (470 mg, 0.87 mmol) was added via spatual to a
solution of RED-ALTM (3 ml) in 10 ml dry toluene at room temperature.
The reaction mi~l ule was then heated to 55~C~ for fifteen minutes. The
reaction mixture was cooled to room temperature and poured into 100
ml of water, and was then extracted with 200 ml ethyl acetate. The
25 organic fraction was washed once with water, and then dried over
potassium carbonate. The solvents were removed in vacuo to yield 161

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mg of a viscous oil. The crude m~teIi~l was further purified by flash
chromatography, elnting with 2% ethyl~mine in methanol. The
f~ction~ cont~inin~ the desired title product were combined and
concentrated under reduced pressure to yield 117 mg of a viscous oil
5 (Yield 30%).
The title desired product was collvel led to the
dihydrochloride salt by rl~;n~ the free base in 10 ml ethyl acetate and
~lrlin~ a saturated solution of hydrochloric acid in diethyl ether, until
solution turned congo red litmus slightly blue. The solvents were
10 removed in vacuo and the resulting white residue was triturated in
diethyl ether. Drying at 60~C for one hour yield 104 mg of the
dihydrochloride salt as a white solid.
mp 106-109~C
NMR was consistent with the proposed title structure.
FDMS 448 (M+)
Analysis for C27H32N30Cl ~ 2 HCl:
Theory: C, 62.25; H, 6.19; N, 8.07.
Found: C, 63.77; H, 6.33; N, 8.30.

2 o F~n~rle ~-~7

Preparation of 1-[4-(piperidin-1-yl)-3-methylbutyl3-2-[(4-
chlorophenoxy)methyl]-4-methylben~imi~ole dihydrochloride salt

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~N

~2 HCl <
~ CH3




Under a nitrogen atmosphere 1-[3-[(piperidin-1-
yl)carbonyl]butyl~-2-[(4-chlorophenoxy)methyl~-4-methylb~n7imidazole
(800 mg, 1.80 mmol) was added via spatual to a solution of RED-ALTM (~;
ml) in 10 ml dry toluene at room temperature. The reaction mixture
was then heated to 55~C for fifteen minutes. The reaction ~ e was
cooled to room tempe~ and poured into 100 ml of water, and was
then extracted with 200 ml ethyl acetate. The organic fraction was
lo washed once with water, and then dried over potassium carbonate. The
solvents were removed in vacuo to yield 700 mg of a viscous oil. The
crude material was further purified by flash chromatography, eluting
with 2% ethyl~mine in methanol. The fractions contSIining the desired
title product were combined and concen~tated under reduced pressure to
15 yield 200 mg of a light yellow oil (Yield 27%).
The title desired product was converted to the
dihydrochloride salt by pl~ing the free base in 10 ml ethyl acetate and
ing a saturated solution of hydrochloric acid in diethyl ether, until
solution turned congo red litmus slightly blue. The solvents were
2 o removed in vacuo and the resulting white residue was triturated in
diethyl ether. Drging at 60~C for one hour yielded the dihydrochloride
salt as a white solid.
mp 98-102~C
NMR was consistent with the proposed title structure.

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FDMS 42~, 426 (M+)
Analysis for C2sH34N3OCl ~ 2 HCl:
Theory: C, 60.19; H, 6.87; N, 8.42.
Found: C, 60.33; ~I, 6.88; N, 8.69.




~ m~?le ~.~8
Preparation of 1-[3-[(piperidin-~-yl)carbonyl}-4-phenylbutyl]-2-~(4-
chlorophenoxy~methyl]-4-methylbçn7:imi~ 01e


~ \y~O~




To a stirring solution of 1-[3-carboxy-4-phenylbutyl]-2-[~4-
chlorophenoxy)methyl]-4-methylb~n~midazole (1.0 g, 2.2 mmol) in N,N-
dimethylforms~mi-l~ (75 ml) were added seql1P.nti~lly piperidine (206 mg,
1.1 eq), l-hydlo~y-benzotriazole (327 mg, 1.1 eq), and
dicyclohexylcarbodiimide (600 mg, 1.1 eq). The resulting .~ e was
then stirred under a nitrogen atmosphere at room temperature for 64
hours. The reaction mi~t~lre was then filtered and the resulting filtrate
- 20 was concntrated under reduced pressure. This residue was taken into
ethyl acetate ~200 ml) and washed once with water (200 ml), dried over
potassium carbonate~ The solvents were removed in vacuo to yield 1.84
grams of a tan foam.

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This crude material was purif;ed by flash silica gel
chromatography, eluting with a gradient solvent of 9:1 h~ nes:ethyl
acetate to 1:1 he~nes:ethyl acetate. The fractions cont~ining the
desired material were combined and concentrated under reduced
pressure to yield 880 mg (77%) of the desired title product as a VlSCOU8 oil.
The slowly cryst~ ing oil was recrystallized from 10: hq~r~nes:eth
acetate to yield 710 mg as a white solid.
mp 93.5-95~C
NMR and IR were consistent with the proposed title structure.
10 FDMS ~i15, ~16 (M+)
Analysis for C31H34N3O2Cl:
Theory: C, 72.15; H, 6.64; N, 8.14.
Found: C, 71.88; H, 6.73; N, 7.98.

~ le 239

Preparation of 1-[3-[(piperidin-1-yl)carbonyl]butylJ-2-[(4-
chlorophenoxy)methyl]-4-methylbf~n7:irnidazole




> CH3
0~
N~

~
To a stirring solution of l-r3-carboxybutyl]-2-~(4-
chlorophçno~y)methyl]-4-methylb~n~imidazole (1.2 g, 3.2 mmol) in N,N-
dimethylformamide (75 ml) were added sequentially piperidine (299 mg,

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-203-

1.1 eq), 1-lly~o~ybenzotriazole (475 mg, 1.1 eq), and
dicyclohexylcarbotliimi~le (726 mg, 1.1 eq). The resulting mixture was
then stirred under a nitrogen atmosphere at room temperature for 64
hours. The re~ctit~n mi~ re was then filtered and the resulting filtrate
5 was coPl.nt.rated under reduced pressure. This residue was taken into
ethyl acetate (200 ml) and washed once with water (200 ml), dried over
potas~ium carbonate. The solvents were removed in vacuo to yield 1.78
grams of a tan fo~m.
This crude material was purified by flash silica gel
10 chromatography, eluting with a gradient solvent of 1:1 he~ne,q:ethyl
acetate to ethyl acetate. The fractions cont,~ining the desired material
were comhined and coI-centrated under reduced pressure to yield 910
mg (65%) of the desired title product as a white foam.
~MR was consistent with the proposed title structure.
FDMS 439.3 (M+)
Analysis for C2~H30N3O2Cl:
Theory: C, 68.25; H, 6.87; N, 9.55.
Found: C, 68.54; H, 6.97; N, 9.52.

~.~m~le 240

Preparation of 1-[3-[3-(piperidin-1-yl)~ ylcarb~moyl]butyl]-2-[(4-
chlorophenoxy)methyl]-4-methylbçn7imi~1~7.01e

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~ N

,) CH3
~<
N~




To a stirring solution of 1-[3-carboxybutyl]-2-[(4-
chlorophenoxy)methyl~-4-methylb~n~imidazole (1.2 g, 3.2 mmol) in N,N-
5 dimethylformamide (75 ml) were added sequentially 1-~mino-3-
(piperidin-l-y~)propane (500 mg, 1.1 eq), 1-hydroxybenzotriazole (475 mg,
1.1 eq), and dicyclohexylcarbodiimide (726 mg, 1.1 eq). The resulting
u~e was then stirred under a nitrogen atmosphere at room
temperature for 64 hours. The reaction mixture was then filtered and
10 the resulting f;ltrate was concntrated under reduced pressure. This
residue was taken into ethyl acetate (200 ml) and washed once with
water (200 ml), dried over potassium carbonate. The solvents were
removed in vacuo to yield 2.00 grams of a semi-solid material.
This crude material was purified by flash silica gel
15 chromatography, eluting with a gradient solvent of 9:1 hexanes:ethyl
acetate to 1:1 hexanes:ethyl acetate. The fractions cont~;ning the
desired material were combined and concentrated under reduced
pressure to yield 1.04 g (65%) of the desired title product as a white fo m.
The title product was recrystallized from a 9:1 hexanes:ethyl acetate
20 Ill;Y~ule to yield 800 mg as crystals.

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mp 102-103~C
NMR and IR were consistent with the proposed title structure.
FDMS 496, 497 ~M+)
s Analysis for C2gH37N4O2Cl:
Theory: C, 67.66; H, 7.~;0; N, 11.27.
Found: C, 67.41; H, 7.79; N, 11.22.
r~le 241

Preparation of 1-[3-[3-(piperidin-1-yl)propylcarbamoyl~-4-phenylbutyl]-2-
[(4-chlorophenoxy)methyl~-4-methylben7irnidazole
CH3 ~\~Cl

\>~~~
$~3
NH


N
\

To a stirring solution of 1-[3-carboxy-4-phenylbutyl]-2-[(4-
chlorophenoxy)methyl]-4-methylb~n7.imi~7.0le (1.0 g, 2.2 mmol) in N,N-
dimethylform~qmi~e (75 ml) were added sequentially 1-amino-3-
(piperidin-1-yl)propane (345 mg, 1.1 eq), l-hydlo~yl)enzotriazole (327 mg,
1.1 eq), and dicyclohexylcarbodiimide (500 mg, 1.1 eq). The resulting
mixture was then stirred under a nitrogen atmosphere at room

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-206-

tempe, ~uie for 64 hours. The reaction mi~ was then filtered and
the resulting filtrate was conc~nt7~ated under reduced pressure. Tnis
residue was taken into ethyl acetate ~200 ml) and washed once with
water (200 ml), dried over potassium carbonate. The solvents were
removed in vacuo to yield 1.3~ grams of an orange foam.
Tnis crude material was purified by flash silica gel
cllromatography, eluting with a gradient solvent of 19:1 ethyl
acetate:methanol to ethyl acetate:methanol. The fractions conts~inin~
the desired material were comhined and concentrated under reduced
10 pressure to yield 960 mg (75%) ofthe desired title product as a slowly
cryst~lli7.in~ oil. The title product was recrystallized from a 19:1
h~7nes:ethyl acetate ...;x~ e to yield 800 mg as crystals.
mp 91-93~C
NMR and IR were consistent with the proposed title structure.
FDMS 672-673 ~M+)
Analysis for C34H4lN4O2Cl:
Theory: C, 71.25; H, 7.21; N, 9.78.
Found: C, 71.15; H, 7.39; N, 9.67.

F:~7~1e 242

Preparation of 1-~3-~(1,2,3,4-tetrahydroisoql7inolin-l-yl)carbonyl]butyl]-2-
[(4-chlorophenoxy)methyl]-4-methylben 7:imi dazole

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- 207 -

-


1~ 'Y'~


~CH3




To a stirring solution of 1-[3-carboxybutyl]-2-t(4-
chloroph~n--~y)methyl]-4-methylbeIl~imi~ ole (0.800 g, 2.2 mmol) in
5 N,N-dimethylformamide (~0 ml) were added sequentially 1,2,3,4-
tetrahydroisoqllinnline (322 mg, 1.1 eq), 1-hydlv~y~enzotriazole (327 mg,
1.1 eq), and dicyclohexylcarbodiimide (500 mg, 1.1 eq). The resulting
mixture was then stirred under a nitrogen atmosphere at room
temperature for 64 hours. The reaction ~ e was then filtered and
10 the resulting filtrate wa~ concntrated under reduced pressure. This
residue was taken into ethyl acetate (200 ml) and washed once with
water (200 ml), dried over potassium carbonate. The solvents were
removed in ~racuo to yield 1.24 grams of a dark oil.
This crude material was purified by flash silica gel
15 chromatography, eluting with a gradient solvent of 1:1 hç~nes ethyl
acetate to ethyl acetate. The fr~ctionq con~inin~ the desired material
were comhine-l and concentrated under reduced pressure to yield 1.04 g
of the desired title product as a white foam. The title product was
- recrystallized from a 9:1 he~r~nes:ethyl acetate mixture to yield 734 mg
20 (69%) as a white foam.
NMR was consistent with the proposed title structure.
iFl}MS 487, 488 (M+)

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Analysis for C2gH30N302Cl:
Theory: C, 71.37; H, 6.20; N, 8.61.
Found: C, 70.97; H, 6.20; N, 8.52.

F~mnl e 243

Preparation of 1-[3-~(1,2,3,4-tetrahydronaphth-1-yl~mino)carbonyl]butyl]-
2- [(4-chlorophenoxy)methyU-4-methylben ~i mi dazole

CE3 ~C~l

~,~ \>/\~~


CH3
6~

To a stirring solution of 1-[3-carboxybutyl]-2-[(4-
chloropheno~y)methyl]-4-methylben~tmtdazole (0.800 g, 2.2 mmol) in
N,N-dimethylformamide (50 ml) were added sequentially 1,2,3,4-
1~ tetrahydronaphthalene (356 mg, 1.1 eq), 1-hy~o~ylJenzotriazole (327 mg,
1.~ eq), and dicyclohexylcarbodiimide (~00 mg, 1.1 eq). The resulting
~i~1u~e was then stirred under a nitrogen atmosphere at room
temperature for 64 hours. The reaction mixture was then filtered and
the resulting filtrate was concntrated under reduced pressure. This
2 0 residue was taken into ethyl acetate ~200 ml) and washed once with
water (200 ml), dried over potassium carbonate. The solvents were
re~noved in vacuo to yield 1.3 grams of a semi-solid. This crude material

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was purified by recrystallization from 9:1 ethyl acetate:ethanol to yield
741 mg (67%) as a white solid.
mp 192-194~C
.. NMR was consistent with the proposed title structure.
FDMS ~01, ~02 (M+)
Analy~is for C3OH32N3O2Cl:
Theory: C, 71.77; H, ~.43; N, 8.37.
Found: C, 71.43; H, 6.52; N, 8.22.

~m~les ?.44 and 245

Preparation of (R) 1-[3-[[2-[(2-piperidin- 1-yl)ethyl]piperidin- 1-
yl] carbonyl]butyl]-2-[(4-chlorophenoxy)methyl]-4-methylb~n ~i mi dazole
dihydrochloride salt monohydrate[A] and (S~ 1-[3-[[2-[(2-piperidin-1-
15 yl)ethyl]piperidin-1-yl]carbonyl]butyl]-2-[(4-chlorophenoxy)methyl]-4-
methylb~n7.imi-1~7.01e dihydrochloride salt [B]

CH3 I~Cl
~N\~ ,CI


~2 HCl ~CH ~ ~2 HCl
0~ and
N--~ ,~ CH3
f ~> ~N (R)
~J (S) ~

To a ~tirring solution of 1-[3-carboxybutyl]-2-[(4-
chlorophenoxy)methyl]-4-meth;ylbRn~imidazole (0.800 g, 2.2 mmol) in
N,N-dimethylformamide (50 ml) were added seq~ f.i~lly (RS) 2-
[(piperidin-1-yl)ef~yl]piperidine (475 mg, 1.1 eq), 1-hydlo~ybenzotriazole
~32~ mg, 1.1 eq), and dicyclohexylcarbodiimide (~00 mg, 1.1 eq). The

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resulting mi~ule was then stirred under a nitrogen atmosphere at
room tempelatule for 64 hours. The reaction ~;x~u~e was then filtered
and the resulting filtrate was concntrated under reduced pressure.
This residue was taken into ethyl acetate (200 ml) and washed once with
5 water (200 ml), dried over potassium carbonate. The solvents were
removed in vacuo to yield 1.3 gr~ms of the r~c,emP~te as a yellow foam.
The isomers were separated and purified by flash silica gel
chromatography, eluting with a solvent gradient of 9:1 ethyl
acetaet:methanol to 1:1 ethyl acetate:methanol. Fractions cont.zlining
10 each isomer were then conc~ntrated under reduced pressure and
converted to the dihydrochloride salt as a white solid.
Yield: (R) isomer -- 335 mg; (S) isomer 164 mg.
[A]
mp 106-109~C
15 NMR was consistent with the proposed title structure.
FDMS 550, 551 (M+)
Analysis for C32H43N4O2Cl ~ 2HCl, ~ H2O:
Theory: C, 59.85; H, 7.38; N, 8.73.
Found: C, 59.89; H, 7.32; N, g.l1.
E~
mp >146~C
N~aR was consistent with the proposed title structure.
FDMS 551 (M+)
Analysis for C32H43N4O2Cl ~ 2ECl:
Theory: C, 61.59; H, 7.27; N, 8.98.
Found: C, 61.39; H, 7.05; N, 8.78.

le 246
Preparation of (RS) 1-[3-[[3-(2-methylpiperidin-1-
yl~propylamino]carbonyl]butyl]-2-[(4-chlorophenoxy)methyl]-4-
methylb~n~imidazole dihydrochloride salt monohydrate

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CH3 ~Cl

., ~ \>~0

~2HCl
~ CH3
O-~
NH


~CH3


To a stir{ing solution of 1-[3-carboxybutyl]-2-[(4-
chloropheno~y)methyl]-4-methylbçn7.;midazole (1.00 g, 2.7 m~nol) in
N,N-dimethylfo~n~ e (60 ml) were added sequentially (RS) 3-(2-
met~ylpiperidin-l-yl)propyl~mine (464 mg, 1.1 eq), 1-
ll~dl.~Lyl,enzotriazole (402 mg, 1.1 eq), and dicyclohexylcarbodiimide (61
mg, 1.1 eq). The resulting mixture was then stirred under a nitrogen
atmosphere at room temperature for 64 hours. The reaction ll~i~ule
was then filtered and the resulting filtrate was concentrated under
reduced pressure. This residue was taken into ethyl acetate (200 ml)
and washed once with water (200 ml), dried over potassium carbonate.
The solvents were removed in vacuo to yield 1.17 grams of the racemate
as an orange solid.
The material was further purified by flash silica gel
chron~tography, eluting with a solvent gradient of 1:1 ethyl
acetaet:methanol to methanol. Fractions cont7lin;ng the desired title
product were then concentrated under reduced pressure and converted
to the dihydrochloride salt as a white solid.
~leld 500 mg ofthe free base (36%)
mp 8~-87.~~~

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-212-

NMR was consistent with the proposed title structure.
FDMS 510, ~;11 (M+)
Analysis for C32H43N4O2Cl ~ 2HCl ~H20:
Theory: C, 57.8~; H, 7.20; N, 9.31.
Found: C, 58.01; H, 7.1~; N, 9.02.
le 247

Preparation of 1-[3-[~phenylpiperidin-1-yl]carbonyl]butyl]-2-[(4-
chlorophenoxy)methyl]-4-methylberl ~imi dazole hemihydrate
CH3 ~ Cl

~C \y'~~


,~ CH3




To a stirring solution of 1-[3-carboxybutyl]-2-[(4-
chlorophenoxy)methyl]-4-methylbens:imifl~ole (0.800 g, 2.2 mmol) in
N,N-dimethylformamide (50 ml) were added sequentially 4-
phenylpiperidine (390 mg, 1.1 eq), 1-hy~o~y~enzotriazole (327 mg, 1.1
eq), and dicyclohexylcarbodiimide (~00 mg, 1.1 eq). The resulting
..-;x~...e was then stirred under a nitrogen at~nosphere at room
2 o temperature for 64 hours. The reaction mixture was then filtered and
the resulting filtrate was concentrated under reduced pressure. This
residue wa~ taken into ethyl acetate (200 ml) and washed once with r

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-213-

water (200 ml), dried over potassium carbonate. The solvents were
removed in vacuo to yield 1.04 grams of the title product as an orange
foam.
The mAteri~l was fi~rther purified by flash silica gel
5 chromatography, eluting with a solvent gradient of 9:1 ethyl
acetate:met~anol to 1:1 ethyl acetate:meth~n..l Fractions cont~inin~
the desired title product were then concentrated under reduced
pressure.
Yield: 641 mg (56%)
10 NMR was consistent with the proposed title structure.
FDMS 515, 516 (M+)
Analysis for C31H34N3O2Cl ~ 1/2 H2O:
Theory: C, 70.90; H, 6.70; N, 8.00.
Found: C, 70.43; H, 6.96; N, 7.75.
e 248

Preparation of 1-[3-~[3-(piperidin-1-yl)propyl~min~]carbonyl]propyl]-2-[(4-
chlorophenoxy)methyl]-4-methylb~n~imidazole dihydrochloride salt


~~



NH

',' ~

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- 214 -

To a stirring solution of 1-[3-carboxypropyl~-2-[(4-
chloroph~noxy)methyl]-4-methylben~imi-1~7O1e (0.540 g, 1.5 mmol) in
N,N-dimethylformamide (60 ml) were added sequentially 3-(piperidin-1-
yl)propyl~mine (23~ mg, 1.1 eq), 1-hydroxybenzotriazole (223 mg, 1.1 eq),
and dicyclohexylcarbodiimide (340 mg, 1.1 eq). The resulting ..~ e
was then stirred under a nitrogen atmosphere at room temperature for
64 hours. The reaction mixture was then filtered and the resulting
filtrate was concentrated under reduced pressure. This residue was
taken into ethyl acetate (200 ml) and washed once with water (200 ml),
dried over potassium carbonate. The solvents were removed in vacuo to
yield 0.731 grams of the title compound as an orange solid.
The material was further purified by flash silica gel
chromatography, eluting with methanol. Fractions cont~ining the
desired title product were then concentrated under reduced pressure to
yield a slowly cryst~lli7:in~ oil.
Yield: 471 mg (6~;%)
mp 92-94~C
NMR was consistent with the proposed title structure.
FDMS 482,483 (M+)
Analysis for C27H3sN4O2Cl:
Theory: C, 67.14; H, 7.30; N, 11.60.
~ound: C, 66.94; H, 7.23; N, 11.37.

F'~ les 249 and 2~0

Preparation of (RS) 1-[3-[[3-phenylpiperidin- 1-yl]carbonyl~butyl]-2-[(4-
chlorophenoxy)methyl]-4-methylb~n7imidazole and (RS) 1-[3-[[3-

cyclohe~ylpi~eridin-l-yl]carbonyl]butyl]-2-[(4-chlorophenoxy)methyl]-4
30 methylbçn~imidazole

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-216-


~, Cl


C~3 >
~=C and
~ o~CH3


~ G~

To a stirring solution of 1-[3-carboxyl,ulyl]-2-[(4-
chlorophenoxy)methyl]-4-methylber.~imidazole (1.00 g, 2.7 mmol) in
5 N,N-dimethylform~mi-le (50 ml) were added seqllenti~lly a ~0:50
mixture of 3-phenylpiperidine and 3-cyclohexylpiperidine (496 mg total,
1.1 eq), 1-hy~o~yl enzotriazole (402 mg, 1.1 eq), and
dicyclohexylcarbodiimide (615 mg, 1.1 eq). The resulting ~ x ~-.. e was
then stirred under a nitrogen atmosphere at room tempeIdtule for 64
10 hours. The re~ction mi~t~lre was then filtered and the resulting filtrate
was con~ nt.rated under reduced pressure. This residue was taken into
ethyl acetate (200 Tnl) and washed once with water (200 ml), dried over
potassium carbonate. The solvents were removed in vacuo to yield 1.43
grams of a~pl o~ tely a 50:50 ~ u~ e of the title products.
Separation and purification of this mix was ~tt~mpted
using a chromatotron with a 4000 micron rotor and eluting with a
gradient solvent of he~r~nes to 1:1 ethyl acetate l~ nes. Early fractions
cont,~ining an 80:20 mixture of the 3-cyclohexyl derivatives:3-phenyl
derivatives were then concentrated under reduced pressure, yi~.lrling 641
2 o mg. Later fractions c~-nt~ining substantially purified 3-phenyl

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-216-

derivatives were combined and coIlGentrated under reduced pressure to
yield 200 mg as a white foz~m.
NMR was consistent with the proposed title structures.

~ n~les 251 and 252

Preparation of (RS) 1-[3-[[4-benzylpiperidin- 1-yl]carbonyl]butyl]-2-[(4-
chlorophenoxy)methyl]-4-methylben7imidazole and (RS) 1-[3-[[4-
(cyclohexylmethyl)piperidin- 1-yl]carbonyl]butyl]-2-[(4-
1 Q chl orophenoxy)methyl] -4-methylbçn 7i m i dazole



~N>~ ~ , ~Cl

~CH3 and >
O

~3 ~~ C


To a stirring solution of 1-[3-carbu~ybu~yl]-2-[(4-
chloroph~no~y)methyl]-4-methylben7imi~ ole (1.00 g, 2.7 mmol) in
N,N-dimethylformamide (60 ml) were added sequentially a 50:60
u~ e of 4-benzylpiperidine and 4-(cyclohexylmethyl)piperidine (620
mg total, 1.1 eq), l-hydroxybenzotriazole (402 mg, 1.1 eq), and
dicyclohexylcarbodiimide (615 mg, 1.1 eq). The resulting ~uLe was
20 then stirred under a nitrogen atmosphere at room tempeld~u~e for 64
~ hours. The reaction .. ~ix~ e was then filtered and the resulting filtrate
was concntrated under reduced pressure. This residue was taken into
ethyl acetate (200 ml) and washed once with water (200 ml), dried over

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-217-

potassium carbonate. The solvents were removed in vacuo to yield 1.~1
grams of ~ ox;..~tely a 50:50 ~Ul~ of the title products.
Separation and pl~rif;c~ion of this mix was attempted
~ using a chrom~ollon with a 4000 micron rotor and eluting with a
gradient solvent of hç2An~s to 2:1 ethyl acetate h~q~Anes. Early fractions
cont~ining substantially purified the 4-benzyl derivatives were then
cor centrated under reduced pressure, yielding 481 mg as a white foam.
Later fractions contAining subst~ntiAlly purif;ed 4-cyclohexylmethyl
de~iva~iv~s were combined and concentrated under reduced pressure to
yield 356 mg as a white foam.
NMR was consistent with the proposed title structures.

F,~A~le 253

Preparation of (RS) 1-[3-~2-phenylethyl~mino]carbonyUbutyl]-2-~(4-
chlorophenoxy)methyl]-4-methylben~imillA~ole



>~O

>~CH3
O-~
NH




~ 2 o To a stirring solution of (RS) 1-[3-carbo~ylJu~yl]-2-[(4-
chlorophenoxy)methyl]-4-methylben7imi~lA~ole (0.~00 g, 1.4 mmol) in
N,N-dimethylformamide (40 ml) were added seqllenti~lly 2-

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-218-

phenylethyl~mine (187 mg, 1.1 eq), l-hyd~ ybenzotriazole (208 mg, 1.1
eq), and dicyclohexylcarbodiimide (317 mg, 1.1 eq). The resulting
mixture was then stirred under a nitrogen atmosphere at room
temperature for 64 hours. The reaction mixture was then filtered and
5 the resulting filtrate was c--ncentrated under reduced pressure. This
residue was taken into ethyl acetate (200 ml) and washed once with
water (200 ml), dried over potassium carbonate. The solvents were
removed in vacuo to yield 0.731 gr~ms of the title product as a white
foam.
The material was further purified by flash silica gel
chromatography, eluting with a solvent gradient of 1:1 ethyl
acetate h~nes to ethyl acetate. Fractions cont~ining the desired title
product were then concentrated under reduced pressure, yielding 581
mg (8Q%) as a white solid.
F.~ml?le ~54

Preparation of (RS) 1-[3-~[benzyl~rninoamino]carbonyl~butyl]-2-[(4-
chlorophenoxy)methyl~-4-methylbçn~imidazole


>~o


>~CH3
O-~
NH

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..
To a stirring solution of (RS) 1-[3-carbu~ybulyl]-2-~(4-
chlorophenoxy)methyl3-4-methylb~n~imifl~7.ole (0.500 g, 1.4 mmol~ in
N,N-dimethylformamide (40 ml) were added sequentially benzylamine
(16~ mg, 1.1 eq), 1-hydto~ylJenzotriazole (208 mg, 1.1 eq), and
dicyclohexylcarbodiimide (317 mg, 1.1 eq). The resulting ~ e was
then stirred under a nitrogen atmosphere at room temperature for 64
hours. The reaction . . . i x ~ . . . e was then filtered and the resulting filtrate
was crncentrated under reduced pressure. This residue was taken into
ethyl acetate (2()0 ml) and washed once with water (200 ml), dried over
0 potassium carbonate. The solvents were removed in vacuo to yield 0.714
gr~ms of the title product as a white foam.
The material was further purified by flash silica gel
chromatography, eluting with a solvent gradient of hexanes to 1:1 ethyl
acetate he~nes. Fractions cont~inin~ the desired title product were
then concentrated under reduced pressure, yielding 437 mg (68%) as a
white solid.
mp 145-146~C
NMR was consistent with the proposed title structure.
FDMS 461, 462 (M+)
2 o Analysis for C27H2gN302Cl:
Theory: C, 70.20; H, 6.11; N, 9.10.
Found: C, 70.44; H, 6.33; N, 8.7881

u?le 25
Preparation of (RS) 1-[3-[(pyrrolidin-1-yl)carbonyl}butyl]-2-[(4-
chlorophenoxy)methyl]-4-methylben~imidazole

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~N

>~CH3
O-~



To a stirring solution of (RS) 1-[3-carbo~yl~ulyl]-2-[(4-
chlorophenoxy)methyl]-4-methylbenzimidazole (0.700 g, 1.9 mmol) in
5 N,N-dimethylformamide (40 ml) were added ~equentially pyrroldine (165
mg, 1.1 eq), l-hydroxybenzotriazole (282 mg, 1.1 eq), and
dicyclohexylcarbodiimide (431 mg, 1.1 eq). The resulting llLi~u,e was
then stirred under a nitrogen atmosphere at room temperature for 64
hours. The reaction ...i~e was then filtered and the resulting filtrate
10 was concentrated under reduced pressure. This residue was taken into
ethyl acetate (200 ml) and washed once with water (200 ml), dried over
potassium carbonate. The solvents were removed in vacuo to yield 0.835
grams of the title product as a white foam.
The material was further purified by flash silica gel
15 chromatography, eluting with a solvent gradient of 1:1 ethyl
acet,~te:he~n~s to ethyl acetate. Fractions cont~ining the desired title
product were then concentrated under reduced pressure, yielding 560
mg (69%) as a white solid.
mp 140-142~C
2 0 NMR was consistent with the proposed title structure.
FDMS 42~ (M+)
Analysis for C24H2gN3O2Cl:
Theory: C, 67.67; H, 6.63; N, 9.87.
Found: C, 67.76; H, 6.73; N, 9.84.
~"~zlrnrle 256

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-221-
-




Preparation of (RS) 1-[3-(methyl)-4-[3-(piperidin-1-yl)propyl~mine]butyl]-
2-[(4-chloroph en f)~y)methyl~-4-methylban 7i mi dazole trihydrochloride
~ salt monohydrate




~H3
~3 HCl
NEI


N~


~ solution of 1-~3-[3-(piperidin-1-yl)propylcarbamoyl]butyl]-
2-~(4-chlorophenoxy)methyl]-4-methylben~imitl~ole (300 mg, 0.6 mmol)
10 in dry tetrahyLoruldn (5 ml) was stirred at room temperature under a
nitrogen atmosphere. To this solution borane-tetrahydrofuran complex
(3.8 ml of a lM solution in tetrafuran, 6 eq) was syringed dropwise over a
two minute period. The solution was then stirred overnight at room
tempeld~u~e. To the reaction mi~t~lre was then slowly added, by
15 syringe, a 1:1 solution of tetrahydrofuran and methanol. After the
f(!~ming subsided, ~ N sodium hydroxide (2 m-l) was then added by
syrine and the resulting mixture was stirred for about sixteen hours
under a nitrogen atmosphere at ~;0-60~C. The reaction ~ e was
cooled to room temperature and was then diluted with methylene
20 chloride ~10 ml).
The organic fraction was separated and concentrated in
vacuo to yield a semi-solid. This residue was taken up into ethyl acetate

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- 222-

(50 ml), washed once with water, and then dried over potassium
carbonate. The solvents were removed in vacuo, yielding 200 mg of a
viscous oil. This oil was further purified using a chromatotron with a
2000 micron rotor, eluting with a gradient solvent of 9:1 ethyl
5 acet~te:m~thanol (with 1 % ammonium hydroxide) to 1:1 ethyl
acetate:methanol (with 1 % ~n~monium hydroxide3. Fractions
contSIinin~ the desired title product (170 mg, 59%) were collected and the
compound was converted to the tri-hydrochloride salt, yielding a white
solid.
mp 98-100.5~C
NMR was consistent with the proposed title structure.
FDMS 483 (M+)
Analysis for C2gH3gN4OCl ~ 3HCl ~ H2O:
Theory: C, 55.09; H, 7.26; N, 9.18.
Found: C, 55.47; H, 7.12; N, 9.33.

F,~r~mnle ~-~7

Preparation of (RS) 1-~3-(benzyl)-4-[3-(piperidin-1-yl)~opyl~rn;ne]butyl]-
20 2-~(4-chlorophenoxy)methyl]-4-methylbçn~imidazole trihydrochloride
salt monohydrate

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- 223-

Cl
~ '~
~3 HCl
N




A solution of 1-[4-phenyl-3-[3-(piperidin-1-
yl)~ ylcarbamoyl]butyl]-2-[(4-chlorophenoxy)methyl]-4-
methylben7:imidazole (450 mg, 0.78 mmol) in dry tetrahydl~r udll (5 ml)
was stirred at room tempelal ule under a nitrogen atmosphere. To this
solution borane-tetrah~dlorulan complex (4.7 ml of a lM solution in
tetrafuran, 6 eq) was syringed dl~J~wise over a two minute period. The
solution was then stirred overnight at room temperature. To the
0 reaction ~ ule was then slowly added, by syringe, a 1:1 solution of
tetrahy ll.~ruldn and met~n-~l . After the fos~ming subsided, 5 N sodium
hydroxide (2 ml) was then added by syrine and the resulting .-.;x~...e
was stirred for about sixteen hours under a nitrogen atmosphere at 50-
60~C. The re~ctio~ Ule was cooled to room tempela~u~e and was
15 then diluted with methylene chloride (10 ml).
The organic fraction was separated and concentrated in
- vacuo to yield a semi-solid. This residue was taken up into ethyl acetate
({;O ml), washed once with water, and then dried over potassium
carbonate. The solvents were removed in vacuo, yielding 200 mg of a
20 viscous oil. This oil was further purified using a chromatotron with a
2000 micron rotor, eluting with a 9:1 ethyl acetate:methanol (with 1 ~?o
ammonium hydroxidle) solution. Fractions cor t~inin~ the desired title

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- 224-

product (185 mg, 42%) were collected and the compound was converted to
the tri-hydrochloride salt, yielding a white solid.
mp 96-98~C
NMR was consistent with the proposed title structure.
FDMS 559.1 (M+)
Analysis for C34H43N40Cl ~ 3H~1 ~ H20:
Theory: C, 59.47; H, 7.04; N, 8.16.
Found C, 59.39; H, 6.87; N, 8.12.

~mnle 258

Preparation of (RS) 1-~3-benzyl-4-~piperidin-1-yl)butyl]-2-[(4-
chlorophenoxy)methyl}-4-methylben~imidazole trihydrochloride salt


>/~o



~2 HCl

<~
A solution of 1-[4-phenyl-3-[~piperidin-1-yl)carbonyl]butyl]-
2-[(4-chlorophenoxy)methyl]-4-methylben~imidazole (400 mg, 0.7 mmol)
in dry tetrahyd.oru~dll (5 ml) was stirred at room tempeld~ule under a
20 nitrogen atmosphere. To this solution borane-tetrahyd.ofLI.dll complex
(4.5 ml of a lM solution in te~ldru~ , 6 eq) was syringed d-~)~wise over a
two minute period. The solution was then stirred overnight at room
tempe.d~u~e. To the reaction ~ e was then slowly added, by
syringe, a 1:1 solution of tetrahydrofuran and methanol. After the
25 fo~rnin~ subsided, 5 N sodium hydroxide (2 ml) was then added by

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syrine and the resulting l.~;xl~l~e was stirred for about sixteen hours
under a nitrogen atmosphere at ~0-60~C. The reaction mixture was
cooled to room tempe~tule and was then diluted with methylene
chloride (10 ml).
The organic fraction was ~eparated and concentrated in
vacuo to yield a semi-solid. This residue was taken up into ethyl acetate
(50 ml), washed once with water, and then dried over potassium
carbonate. The solvents were removed in vacuo, yielding 350 mg of a
viscous oil. This oil was further purified using a chromatotron with a
10 2000 micron rotor, eluting with a gradient solvent of 9:1 ethyl
acetate:methanol (with 1 % ~mmon;um hydroxide) to 1:1 ethyl
acetate:methanol (with 1 % ammonium hyLo~ide). Fractions
conkiining the desired title product (195 mg, ~6~o) were collected and the
compound was converted to the di-hydrochloride salt, yielding a white
15 solid.
mp 120-123~C
NMR was consistent with the proposed title structure.
FDMS ~01, ~02 (M+)
Analysis for C31H36N30Cl ~ 2HCl:
Theory: C, 64.76; H, 6.66; N, 7.31.
Found: C, 64.60; H, 6.36; N, 7.31.
h',~sln~le 2~9

25 Preparation of (RS~ 1-[3-(methyl)-4-a_inobutyl]-2-[(4-
chlorophenoxy)methyl3-4-methylbçn~imidazole dihydrochloride salt
monohydrate

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- 226-

CH3 ,~\,,Cl

~N

~CH3
< ~2 HCl
NH2

A solution of 1-~3-carbamoylbutyl]-2-U4-
chlorophenoxy)methyl]-4-methylben7imidazole (350 mg, 0.94 mrnol) in
5 dry tetrahyd. or~dn (~ ml) was stirred at room tempela~u~e under a
nitrogen atmosphere. To this solution borane-tetrahydrofuran complex
(~.7 ml of a lM solution in tetrafuran, 6 eq) was syringed d~ wise over a
two minute period. The solution was then stirred overnight at room
temperature. To the reaction mixture was then slowly added, by
lQ syringe, a 1:1 solution of tetrahy~oru.dn and methanol. After the
foaming subsided, 5 N sodium hydroxide (2 ml) was then added by
syrine and the resulting ..~ e was stirred for about sixteen hours
under a nitrogen atrnosphere at 50-60~C. The reaction mixture was
cooled to room temperature and was then diluted with methylene
15 chloride (10 ml).
The organic fraction was separated and concentrated in
vacuo to yield a semi-solid. This residue was taken up into ethyl acetate
(~0 ml), washed once with water, and then dried over potassium
carbonate. The solvents were removed in vacuo, yielding 260 mg of a
20 viscous oil. This oil was further purified using a chromatotron with a
2000 micron rotor, eluting with a gradient solvent of 1:1 ethyl
acetate:methanol to methanol. Fractions Cont~ining the desired 1itle
product (69 mg, 21%) were collected and the compound was converted to
the dihydrochloride salt, yielding a white solid.
25 mp >1~0~C
NMR was consistent with the proposed title structure.
FDMS 3~7.2 (M+)

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Analysis for C20H24N3OCI ~ 2H(~l ~ H20:
Theory: C, 63.51; H, 6.29; N, 9.36.
Found: C, 53.22; H, 6.10; N, 9.28.

F'.~AmI?le 260

Preparation of (RS) 1-[3-(methyl)-4-dimethyl~minobutyl]-2-[(4-
chlorophenoxy)methyl]-4-methylben7imidazole


~~


~CH3

N(CH3)2
A solution of 1-~3-[(N,N-dimethylzlmino)carbonyl]butyl]-2-
[(4-chloroph~noxy)methyl]-4-methylben7imidazole (350 mg, 0.88 mmol)
in dry tetrahydlofuldn (5 ml) was stirred at room temperature under a
nitrogen atmosphere. To this solution borane-tetrahydrofuran complex
(5.3 ml of a lM solution in te~la~uldll, 6 eq) was syringed dro~wise over a
two _inute period. The solution was then stirred overnight at room
temperature. To the reaction ~ ule wa~ then slowly added, by
syringe, a 1:1 solution of tetrahyJ~ofulall and methanol. After the
2 o fo~ming subsided, 5 N sodium hydro~ide (2 ml) was then added by
syrine and the resulting .l~;xl~lle was stirred for about sixteen hours
under a nitrogen atmosphere at 50-60~C. The re~c*o~ mixture was
- cooled to room temperature and was then diluted with methylene
chloride (10 ml).
The organic fraction was separated and concentrated in
vacuo to yield a semi-solid. This residue was taken up into ethyl acetate
(50 ml), washed once with water, and then dried over potassium
carbonate. The solvents were removed in vacuo~ yielding 295 mg of a

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viscous oil. This oil was further purified using a chromatotron with a
2000 micron rotor, eluting with a gradient solvent of 19:1 ethyl
acetate:methanol to 1:1 ethyl acetate:metll~nol Fractions Cont.SIining
the desired title product (200 mg, 21%) were collected.
mp 80-82~C
NMR was consistent with the proposed title structure.
FDMS 385.2 (M+)
Analysis for C22H2gN3OCl:
Theory: C, 68.47; H, 7.31; N, 10.89.
0 Found: C, 68.~ I, 7.45;N, 11.07.

F~r~ ?le 261

Preparation of (R) 1-[4-~2-[(2-piperidin- 1-yl~ethyl]piperidin-1-yl]-3-
15 methylbutyl]-2-[(4-chlorophenoxy)methyl]-4-methylbçn~imidazole
trihydrochloride salt hemihydrate


~ >~o


~3 HCl ~CH

N--~
G~>

2 o A solution of (R) 1-[4-[[2-[(2-piperidin-1-yl)ethyl]piperidin-1-yl~carbonyl]butyl]-2-[(4-chloroph~no}~y)methyl]-4-methylben7imidazole
dihydrochloride salt monohydrate (13~ mg, 0.2~ mmol) in dry
tetrahydrofuran (5 ml) was stirred at room temperature under a
nitrogen atmosphere. To this solution borane-tetrahy~loful~n complex

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(1.8 ml of a lM solution in te~ldru~dn, 6 eq) was syringed dropwise over a
two minute period. The solution was then stirred overnight at room
temperature. To the reaction ~ u~e was then slowly added, by
- syringe, a 1:1 solution of tetrahy~roruldn and methanol. After the
5 ~min~ subsided, ~ N sodium hydro~ide (2 ml) was then added by
syrine and the resulting ~i~e was stirred for about sixteen hours
under a nitrogen atmosphere at ~i0-60~C. The reaction mixture was
cooled to room temperature and was then diluted with methylene
chloride (10 ml).
The org~nic fraction was separated and concentrated in
vacuo to yield a sem;-solid. This residue was taken up into ethyl acetate
(50 ml), washed once with water, and then dried over potassium
carbonate. The solvents were removed in vacuo, yielding 105 mg of a
viscous oil. This oil was further purified using a chromatotron with a
2000 micron rotor, eluting with metll~n.~l. Fractions cont~ininf~ the
desired title product (73 mg, 55%) were collected and converted to the
trihydrochloride salt, yielding a white solid.
mp 103-106~C
NMR was consistent with the proposed title structure.
FDMS 537 (M+)
Analysis for C32H4sN4OCl ~ 3 HCl ~ 1/2 H2O:
Theory: C, 58.62; H, 7.53; N,8.55.
Found: C, 58.32; H, 7.22; N, 7.93.

Analysis for C32H4sN4OCl:
Theory: C, 71.55; H, 8.44; N, 10.43.
Found: C, 71.25; H, 8.49; N, 10.19.

~mnle 262
Preparation of (S) 1-~4-t2-[(2-piperidin-1-yl)ethyl]piperidin-1-yl]-3-
methylbutyl]-2-[(4-chloroph~nc)~y)methyl]-4-methylben7:imidazole
trihydrochloIide salt hemihydrate

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- 230-

CH3 ~,Cl

~C Y'~


~3 HCl (~
<~ CH3

N~
GN \ "" <


The title compound was prepared essentially as described
for the R siomer, except that (S) 1-[4-[[2-[(2-piperidin-1-yl)ethyl]piperidin-
5 1-yl]carbonyl]butyl]-2-[(4-chlorophen oxy)methyl]-4-methylben 7.imi dazole
dihydrochloride salt monohydrate was employed as a starting material.
le 263

Preparation of (RS) 1-[3-(methyl)-4-(1,2,3,4-tetrahydroisoquinolin-1-
yl)butyl]-2-[(4-chlorophenoxy)methyl]-4-methylben ~imi dazole



[~N>~O

<~CH3

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- 231-
.;

A solution of 1-[3-[(1,2,3,4-tetrahydroisoqllinolin-1-
yl)carbonyl]butyl~-2-[(4-chloropheno~y)methyl]-4-methylbçn7imitlsl7Ole
(37~ mg, 0.76 mmol) in dry tetrahydro~uran (5 ml~ was stirred at room
5 temperature under a nitrogen atmosphere. To this solution borane-
tetrah~oru~all complex (4.6 ml of a lM solution in tetrafuran, 6 eq)
was syringed dro~wise over a two minute period. The solution was then
stirred overnight at room temperature. To the reaction ~ ule was
then 810wly added, by syringe, a 1:1 solution of tetrahydrofuran and
10 methanol. After the fo~min~ subsided, 6 N sodium hydroxide (21) was
then added by syrine and the resulting ~ e was stirred for about
sixteen hours under a nitrogen atmLosphere at 50-60~C. The react,ion
mixture was cooled to room temperature and was then diluted with
methylene chloride (10 ml).
The organic fraction was separated and concentrated in
vacuo to yield a semi-solid. This residue was taken up into ethyl acetate
(60 ml), washed once with water, and then dried over potassi7~n
carbonate. The solvents were removed in vacuo, yielding 340 mg of a
slowly c~yst~lli7.in~ viscous oil. This oil was further purified by
2 o recryst,~lli7.~tio~ from ethyl acetate to yield the desired title product (183
mg, 52%) as white crystals.
mp 114.6-116~C
NMR was consistent with the proposed title structure.
FDMS 474 (M+)
25 Analysis for C2gH32N3OCl:
Theory: C, 73.48; H, 6.80; N, 8.86.
Found: C, 73.18; H, 6.82; N, 8.67.

~mJ le 264
Preparation of (RS) 1-[3-(methyl~-4-(1,2,3,4-tetrahydronaphth-1-yl)butyl]-
2-[(4-chlorophenoxy)methyl]-4-methylb~n7imidazole dihydrochloride salt

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-232-


\>~~~


>~CH3 ~2 HCl




A solution of 1-[3-[(1,2,3,4-tetrahydronaphth-1-
yl)carbonyl]butyl]-2-[(4-chlorophenoxy)methyU-4-methylb~n~imidazole
(52~ mg, 1.05 mmol) in dry tetrahydrofu~ (5 ml) was stirred at room
temperature under a nitrogen atmosphere. To this solution borane-
tetrahydrofuran complç~ (6.3 ml of a lM solution in tetl~uran~ 6 eq)
was syringed dropwise over a two minute period. The solution was then
stirred overnight at room temperature. To the reaction mixture was
10 then slowly added, by syringe, a 1:1 solution of tetrahydrofuran and
methanol. ~fter the fo~rning subsided, ~ N sodium hydroxide ~2 ml) was
then added by syrine and the resulting ~il~u~e was stirred for about
sixteen hours under a nitrogen atmosphere at 50-60~C. The reaction
mixture was cooled to room tempe~a~ule and was then diluted with
15 methylene chloride (10 ml).
The organic fraction was separated and concentrated in
vacuo to yield a semi-solid. This residue was taken up into ethyl acetate
(~0 ml), washed once with water, and then dried over potassium
carbonate. The solvents were removed in vacuo, yielding 487 mg of a
20 viscous oil. This oil was further purified via a chromatotron using a
4000 micron rotor, eluting with ethyl acetate to yield the desired title
product (325 mg, 64%) as a clear viscous oil. The title product was then
converted to the dihydrochloride salt, yielding a white solid.
mp 116-118.5~C

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- 233-
-
NMR was consistent with the proposed title ~tructure.
FDMS 487, 488 (M+)
Analysis for C30H34N3OCl ~ 2 HCl:
Theory: C, 64.23; H, 6.47; N, 7.49.
Found: C, 64.04; H, 6.3~; N, 7.35.

~ Tn}?1e 265

Preparation of (RS) 1-~3-(methyl)-~(4-phenylpiperidin-1-yl)butyl]-2-[(4-
10 chl orophenoxy)methyl]-4-methylb~n ~i mi dazole dihydrochloride salt



~~

~CH3




A solution of 1-[3-[(4-phenylpiperidin-1-yl)carbonyl]butyl~-2-
[(4-chlorophenoxy)methyl]-4-methylb~n~imidazole (560 mg, 1.07 mmol)
in dry tetrahyd~or~lan (5 ml) was stirred at room temperature under a
nitrogen atmosphere. To this solution borane-tetrahydrofuran complex
- (6.7 ml of a lM solution in tetrafuran, 6 eq) was syringed dlo~wise over a
two minute period. The solution was then stirred overnight at room
20 temperature. To the reaction ~ure was then slowly added, by
syringe, a 1:1 solution of tetrahydrofuran and methanol. After the
foaming subsided, ~; N sodium hydroxide (2 ml) was then added by
syrine and the resulting ...,~ e was stirred for about sixteen hours

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under a nitrogen atmosphere at 50-60~C. The reaction I~ ule was
cooled to room temperature and was then diluted with methylene
chloride (10 ml).
The organic fraction was separated and crnc.qntrated in
5 vacuo to yield a ~emi-solid. This residue was taken up into ethyl acetate
(50 ml), washed once with water, and then dried over potassium
carbonate. The solvents were removed in vacuo, yielding 531 mg of a a
white solid. This material was further purified by recryst~ tion from
5:1 he~ne,s:ethyl acetate, yielding a white solid (385 mg, 72~o).
mp 124-125~C
NMR was consistent with the proposed title structure.
FDMS 501, 502 (M+)
Analysis for C31H36N3OCl:
Theory: C, 74.16; H, 7.23; N, 8.37.
Found: C, 74.42; ~I, 7.35; N, 8.41.

F.~rr~le 266

Preparation of (RS) 1-~3-(methyl)-4-(3-phenylpiperidin-1-yl)butyl]-2-[(4-
20 chlorophenoxy)methyl]-4-methylb~n~imidazole dihydrochloride salt

CH3 I~C

\>~~~

< ~2 HCl
<~CH3
<~

A solution of 1-[3-[(3-phenylpiperidin-1-yl)carbonyl]butyl]-2-
~(4-chlorophenoxy)methyl]-4-methylben7imidazole (200 mg, 0.380 mmol)
in dry tetrahydlo~u~ (5 ml) was stirred at room temperature under a

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- 235 -

nitrogen atmosphere. To this solution borane-tetrahy~h~rul~l comple~
(6.3 ml of a lM solution in tetrafuran, 6 eq) was syringed dropwise over a
two minute period. The solution was then stirred overnight at room
temperature. To the reaction ~i~ was then slowly ~ lefl~ by
5 syringe, a 1:1 solution of tetrah~ orulan and methanol. A~ter the
fo~rnin~ subsided, 5 N sodium hydroxide (2 ml) was then added by
syrine and the resulting ...;xI...e was stirred for about sixteen hours
under a nitrogen atmosphere at 50-60~C. The reaction ~ a was
cooled to room temperature and was then diluted with methylene
lo chloride (10 ml).
The organic fraction was separated and concentrated in
vacuo to yield a semi-solid. This residue was taken up into ethyl acetate
(50 ml), washed once with water, and then dried over potassium
carbonate. The solvents were removed in vacuo, yielding 176 mg of a
15 yellow oil. T~is oil was further purified via a chromatotron using a 2000
micron rotor, eluting with ethyl acetate to yield the desired title product
~113 mg, 59%) as a clear viscous oil. The title product was then
converted to the dihydrochloride salt, yielding a white solid.
mp 84-86.5~C
2 o NMR was consistent with the proposed title structure.
FDMS 501, ~;02 (M+)
Analysis for C3~H36N30Cl ~ 2 HCl ~ 1 1/2 H20:
Theory: (:, 6L83; H, 6.86; N, 6.98.
Found: C, 61.98; H, 6.46; N, 6.81.
le Z67

Preparation of (RS) l-r3-(met~yl)-4-(2-phenylethyl~mino)butyl]-2-[(4-
chloroph ~n o~y)methyl]-4-methylben 7.i mi dazole dihydrochloride salt

,,

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-236-



~N

~CH3 ~2 HCl
N

6~

A solution of 1-[3-t(2-phenylethyl~min~ )carbonyl]butyl]-2-
[(4-chlorophenoxy)methyl]-4-methylbçn7.iminz~7O1e (62~ mg, 1.06 mmol)
5 in dry tetrahydloru.,m (6 ml) was stirred at room temperat7ure 7lnder a
nitrogen atmosphere. To this solution borane-tetrahydrofuran complex
(6.3 ml of a lM solution in tetrafuran, 6 eq) was syringed dlopwise over a
two minute period. The solution was then stirred overnight at room
te..l~elalu~e. To the reaction mixture was then slowly added, by
10 syringe, a 1:1 solution of tetrahydl~)ru~ and methanol. After the
fo~min~ subsided, 5 N sodil7m hydroxide (2 ml) was then added by
syrine and the resulting ~;x~ l~e was stirred for about sixteen hours
under a nitrogen atmosphere at 60-60~C. The reaction mixture was
cooled to room temperature and was then diluted with methylene
15 cnloride (10 ml).
The organic fraction was separated and concentrated in
vacuo to yield a semi-solid. This residue was taken up into ethyl acetate
(50 ml), washed once with water, and then dried over potassium
carbonate. The solvents were removed in vacuo, yiçl~in~ 370 mg of a
20 viscous oil. This oil was further purified via a chromatotron using a
2000 micron rotor~ eluting with ethyl acetate to yield the desired title

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-237-

product (160 mg, 31%) as a clear viscous oil. The title product was then
converted to the dihydrochloride salt, yielding a white solid.
mp 84-87.5~C
NMR was consistent with the proposed title struc~ure.
5 FDMS 462 (M+)
Analysis for C2gH32N3OCl ~ 2 HC: l ~ 1/2 H20:
Theory: C, 61.81; H, 6.49; N, 7.72.
Found: C, 61.98j H, 6.35; N, 7.79.

~ m~le 268

Preparation of (RS) 1-r3-(methyl)-4-(3-(piperidin-1-yl)propylamino)butyl]-
2-[(4-chlorophenoxy)methyl]-4-methylben~imidazole trihydrochloride
salt


>~o


<?~rCH3 ~3 HCl

NH




A solution of 1-[3-[~3-(piperidin-1-
yl)~ro~ylamino)carbonyl]butyl]-2-[(4-chlorophenoxy)methyl]-4-
methylben~imi~ ole (400 mg, 0.85 mmol) in dry tetrahydrofuran (~; ml)
was stirred at room tempe~a~uLe under a nitrogen atmosphere. To this
solution borane-tetrahy~ rllran complex (6.3 nnl of a lM solution in

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- 238 -

tetrafuran, 6 eq) was syringed dlol~wise over a two minute period. The
solution was then stirred overnight at room temperature. To the
reaction ~ ule was then slowly added, by syringe, a 1:1 solution of
tetrahyLoru~n and methanol. After the fo:~min~ subsided, 6 N sodium
5 hydroxide (2 ml) was then added by syrine and the resulting ~;xL~--e
was stirred for about sixteen hours under a nitrogen atmosphere at 50-
60~C. The reaction mixture was cooled to room tempel~ e and was
then diluted with methylene chloride (10 ml).
The organic fraction was ~eparated and concentrated in
vacuo to yield a semi-solid. This residue was taken up into ethyl acetate
(~;() ml), washed once with water, and then dried over potassium
carbonate. The solvents were removed in vacuo, yielding 380 mg of a
viscous oil. This oil was further purified via a chromatotron using a
2000 micron rotor, eluting with a gradient of ethyl acetate to 1:1 ethyl
acetate:methanol (with 1% ~mmonium hydro~ide) to yield the desired
title product (113 mg, 28%) as a clear viscous oil. The title product was
then col~velled to the trihydrochloride salt, yielding a white solid.
NMR was consistent with the proposed title structure.
FDMS 469 (M+)
Analysis for C27H37N40Cl ~ 3 HCl ~ 1/2 H20.
Theory: C, 67.82; H, 8.01; N, 11.72.
Found: C, 67.73; H, 8.20; N, 11.59.

269
Preparation of (RS) 1-[3-(methyl)-4-(benzyl~mino)butyl]-2-[(4-
chlorophenoxy~methyl]-4-methylb~n7.imidazole

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- 239-



\>~0

~CH3

NH
<3




A solution of 1-[3-[(benzyl~mino)carbonyl]butyl]-2-[(4-
chloroph~no~y)methyU-4-methylben~imidazole (500 mg, 1.05 mmol) in
5 dry tetrahydrofuran (5 ml ) was stirred at room tempel a~ e under a
nitrogen atmosphere. To this solution borane-tetrahydrofuran complex
(6.0 ml of a lM solution in tetrafuran, 6 eq) was sy~inged d~o~wise over a
two minute period. The solution was then stirred overnight at room
temperature. To the reaction ~l u~e was then slowly added, by
10 syringe, a 1:1 solution of tetrahydrofuu~n and methanol. After the
foaming subsided, 5 N sodium hydroxide (2 ml) was then added by
syrine and the resulting ~i~luLe was stirred for about sixteen hours
under a nitrogen atmosphere at 50-60~C. The reaction ~u~e was
cooled to room temperature and was then diluted with methylene
15 chloride (10 ml).
The organic fraction was separated and concentrated in
vacuo to yield a semi-solid. This residue was taken up into ethyl acetate
(50 ml), washed once with water, and then dried over potassium
carbonate. The solvents were removed in vacuo, yielding 315 mg of a
20 semi-solid. This oil was fur~her purified via a chromatotron using a
2000 micron rotor, eluting with ethyl acetate to yield the desired title
product (190 mg, 4()%) as a slowly cryst~ in~ oil.
mp 84.~-87~C
NMR was consistent with the proposed title structure.

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240 -

FDMS 447, 448 (M~)
Analysis for C27H3~N3OCl:
Theory: C, 72.37; H, 6.75; N, 9.38.
Found: C, 72.67; H, 6.75; N, 9.25.




~ rru?le 270

Preparation of (RS) 1-[34methyl)-4-(pyrrolidin-1-yl)butyl]-2-[(4-
chlorophenoxy)methyl]-4-methylb~n~imidazole
CH3 ~ Z Cl

\>~~~


~CH3



A solution of 1-[3-[(pyrrolidin-1-yl)carbonyl~butyl]-2-[(4-
chlorophenoxy)methyl]-4-methylben7imidazole (500 mg, 1.17 mmol) in
15 dry tetrahydfo~uran (5 ml) was stirred at room tempelalule under a
nitrogen atmosphere. To this solution borane-tetral~dl.3rlllan complex
(6.2 ml of a lM solution in tetrafuran, 6 eq) was syringed dropwise over a
two minute period. The solution was then stirred overnight at room
tempeltl~ule. To the reaction mixture was then slowly added, by
20 syringe, a 1:1 solution of tetrahydrofuran and methanol. After the
foaming subsided, 5 N sodium hydroxide (2 ml) was then added by
syrine and the resulting l~ ,Ule was stirred for about sixteen hours
under a nitrogen atmosphere at 50-60~C. The reaction mixture was
cooled to room temperature and was then diluted with methylene
25 chloride (10 ml).

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The organic fraction was separated and concentrated in
vacuo to yield a semi-solid. This residue was taken up into ethyl acetate
(50 ml), washed once with water, and then dried over potassium
carbonate. The solvents were removed in vacuo, yielding 326 mg of a
5 semi-solid. This oil was filrther purified v~a a chromatotron using a
2000 micron rotor, eluting with a gradient of ethyl acetate to 1:1 ethyl
acetate:methanol to yield the desired title product (225 mg, 47%) as a
white solid.
mp 8~-87~C
10 NMR was consistent with the proposed title structure.
FDMS 411 (M~)
Analysis for C24H30N3OCl:
Theory: C, 69.97; H, 7.34; N, 10.20.
Found: C, 69.78; H, 7.29; N, 10.31.
m.l?l e 271

Preparation of (RS) 1-[3-(methyl~-4-(3-benzylpiperidin-1-yl)butylJ-2-[(4-
chlorophenoxy)methyl]-4-methylbçn 7:i mi~ ole dihydrochloride salt


\>~0


~rCH3 f~



solution of 1-[3-[(3-benzylpiperidin-1-yl)carbonyl~butyl3-2-
~4-chloroph~no~y)methyl]-4-methylbcn~imi(l~ole (360 mg, 0.68 mmol)
25 in dry tetrahydrofuran (~ ml) was stirred at room temperature under a
nitrogen atmosphere. To this solution borane-tetrahydrofuran complex

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- 2~2-

(4.1 ml of a lM solution in tetrafuran, 6 eq) was syringed L~wise over a
two minute period. The solution was then stirred overnight at room
tempelaLule. To the reaction ~ u~e was then slowly added, by
syringe, a 1:1 solution of tetrahydrofuran and methanol. After the
5 foaming subsided, 5 N sodium hydroxide (2 ml) was then added by
syrine and the resulting ~i2~u- e was stirred for about sixteen hours
under a nitrogen atmosphere at ~0-60~C. The reaction ..~ ~e was
cooled to room tempe~al u~e and was then diluted with methylene
chloride (10 nnl),
The organic fraction was separated and concentrated in
~acuo to yield a semi-solid. This residue was taken up into ethyl acetate
(50 ml), washed once with water, and then dried over potassium
carbonate. The solvents were removed in vacuo, yielding 330 mg of a
viscous oil. This oil was further purified via a chromatotron using a
15 2000 micron rotor, eluting with ethyl acetate to yield the desired title
product (250 mg, 71%) as a slowly cryst~ inF oil.
mp 95-97~C
NMR was consistent with the proposed title structure.
FDMS 515,516 ~M+)~0 Analysis for C32H3gN3OCl:
Theory: C, 74.46; H, 7.42; N,8.14.
Found: C, 74.74; H, 7.62; N, 8.03.

F~3rr~l?1e 272
Preparation of (RS) 1-[3-(methyl)-4-(3-cyclohexylmethylpiperidin-1-
yl)butyl]-2-[~4-chlorophenoxy)methyl]-4-methylben ~i mi ~ ole
dihydrochloride salt trihydrate

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- 243 -
-




CH3 ~Cl

~C \Y'~~


~CH3 ~2 HCl

N--~



A solution of 1-~3-~(3-cyclohexylmethylpiperidin-1-
yl)carbonyl]butyl]-2-[(4-chlorophenoxy)methyl]-4-methylben~imidazole
(360 mg, 0.67 mmol) in dry tetrahyd~o~u~an (5 ml) was stirred at room
temperature under a nitrogen atmosphere. To this solution borane-
tetrahydl,Jru~ complex (4.0 ml of a lM solution in tetrafuran, 6 eq)
was syringed (Lo~wise over a two minllte period. The solution was then
stirred overnight at room temperature. To the reaction mixture was
then slowly added, by syringe, a 1:1 solution of tetrahydrofuran and
met~nol After the foaming subsided, 5 N sodium hydroxide (2 ml) was
then added by syrine and the resulting mixture was stirred for about
sixteen hours undLer a nitrogen atmosphere at 50-60~C. The reaction
mixture was cooled to room temperature and was then diluted with
methylene chloride (10 ml).
The organic fraction was separated and concentrated in
vacuo to yield a semi-solid. This residue was taken up into ethyl acetate
(~0 ml), washed once with water, and then dried over potassium
carbonate. The solvents were removed in vacuo, yielding 232 mg of a
viscous oil. This oil was further purified via a chromatotron using a
2000 micron rotor, eluting with ethyl acetate to yield the desired title
product (160 mg, 46%) as a clear viscous oil. The title product was then
converted to the dihydrochloride salt, yielding a white solid.
mp 52-56~C

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- 244-

NMR was consistent with the proposed title structure.
FDMS 521,522 ~M+)
Analysis for C32H44N3OCl ~ 2 HCl ~ 3 H20:
Theory: C, 59.20; H, 8.08; N, 6.47.
Found: C, 59.43; H, 7.60; N, 6.37.

Analysis for C32H44N30Cl ~ 1/2 H20:
Theory: C, 72.35; H, 8.54; N, 7.9L
Found: C, 72.7~; H, 8.57; N, 7.86.~0
m~le ~73

Preparation of ~RS) 1-[3-~methyl)-4-t3-(2-methylpiperidin-1-
yl)propylamino]butyl] -2-[(4-chlorophenoxy)methyl]-4-
15 methylben7:imidazole trihydrochloride salt monohydrate


>~o


~CH3 ~3 HCl

NH

CH3



A solution of 1-[3-[3-(2-methylpiperidin-1-
20 yl)propyl~mino]butyl]-2-[(4-chlorophenoxy)methyl]-4-
methylb~n7imi~7ole (350 mg, 0.69 mmol) in dry tetrahydror~dn (5 ml)
was stirred at room temperature under a nitrogen atmosphere. To this

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-245-

solution borane-tetrahy~oru~an complex (4.3 ml of a lM solution in
tetrafuran, 6 eq) was ~y~inged dropwise over a two minute period. The
solution was then stirred overnight at room temperature. To the
reaction ~ ,Ul'e was then slowly added, by syringe, a 1:1 solution of
5 tetrahydrofuran and methanol. After the foaming subsided, 5 N sodium
hydroxide (2 ml) was then added by syrine and the resulting ..,ixl.l~
was stirred for about sixteen hours under a nitrogen atmosphere at ~0-
60~C. The reaction mixture was cooled to room temperature and was
then diluted with methylene chloride (10 ml).
The organic fraction was separated and concentrated in
vacuo to yield a semi-solid. This residue was taken up into ethyl acetate
(50 ml), washed once with water, and then dried over potassium
carbonate. The ~olvents were removed in vacuo, yielding 320 mg of a
viscous oil. This oil was filrther purified via a chromatotron using a
2000 micron rotor, eluting with 1:1 ethyl acetate:methanol (with 1%
~n~m~nium llyLo~de) to yield the desired title product (151 mg, 44%) as
a clear viscous oil. The title product was then converted to the
trihydrochloride salt, yielding a white solid.
NMR was consistent with the proposed title structure.
2 o FDMS 497 ~M+)
Analysis for C2gH44N4OCl ~ 3 HCl ~ H2O:
Theory: C, 55.76; H, 7.42; N, 8.97.
Found: C, 55.70; H, 7.21; N, 9.04.

l~ ?le ~74

Preparation of 2-(4-chloroph~no~ymethyl)-4-[3-[1-(t-
buto~y~ onyl)piperidin-4-yl]propoxy]-1-[3-~1-(~-
butoxycarbonyl)piperidin-4-yl]~l v~l]ben~;midazole


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- 246-

BoC
o




N ~Cl




~ BoC


A solution of 4-hyd~o~y-2-(4-
chlorophçno~ymethyl)ben7:imidazole (500 mg, 1.82 mmol) in dry N,N-

5 dimethylform~mide (8 ml) was treated with sodium hydride (60% inmineral oil, 162 mg, 4.0 mrnol, 2.2 eq). The resulting mi~ e was
stirred at room temperature under a stream of nitrogen for about one
hour. To this reaction mi~tllre 3-[1-(t-buto~ycalbonyl~piperidin-4-
yl)propyl bromide (4.0 mmol, 2.2 eq) was added and the resulting
10 mixture was stirred for three hours at 70~C. The reaction was quenched
by the addition of 10 ml of water. The aqueous fraction was extracted
with ethyl acetate (3 x 10 ml). The organic fractions were comhined and
washed with water (2 x 10 ml), and then brine (1 x 10 ml), and then dried
over magnesium sulfate. The solvents were removed in vacuo to yield a
15 light b.~w.~ish crude material. The desired title product was fi~rther
purified by flash chromatography. There is some substitution at the 7-
position of the bçn~imidazole present, although the 4-substituted is the
major isomer.
NMR was consistent with the proposed title structure.


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- 247 -
-
FDMS (M+) 72~.

~"~m,ple 276

Preparation of 2-(4-chloropheno~ymethyl)-4-[3-(piperidin-4-yl)propoxy~-1-
[3-(piperidin-4-yl)propyl]ben7.imi~ ole




~~~Cl



~,NH

The title compound is prepared from 2-(4-
chloroph~no~ymethyl)-4-[3-~1-(t-buto~yca~l~onyl3piperidin-4-yl]propoxy~-
1-[3-~1-(t-buto~yca bonyl)piperidin-4-yl]propyl]b.3n~imidazole by standard
deprotection techniques using trifluoroacetic acid.
NMR and IR were consistent with the proposed title structure.
FDMS (M+) !i2~;
Ar~alysis for C30H4lClN4O2:
Theory: C, 54.22; H, ~.7~; N, 7.44.
Found: C, 53.97; H, ~.48; N, 7.26.



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-- 248--

~"~ le 276

Preparation of (RS) 2-(4-chlorophenoxymethyl)-4-[3-[1-(t-
buto~ycal l~onyl)piperidin-3-yl]propoxy]- 1-[3-[1-(t-
5 butoxycarbonyl)piperidin-3-yl]~l o~yl]b~n ~im; dazole

S N--BoC




N~ V~ Cl

<~GN~BoC


A solution of 4-hydlo~y-2-(4-
chloropheno~ymethyl)bçn~imidazole (~00 mg, 1.82 mrnol) in dry N,N-
dimethylformamide (8 ml) was treated with sodium hydride (60% in
mineral oil, 162 mg, 4.0 mmol, 2.2 eq). The resulting ~i~u~e was
stilred at room temperature under a stream of nitrogen for about one
hour. To this reaction mixture (RS) 3-[1-(t-butoxycarbonyl)piperidin-3-
15 yl)propyl bromide (4.0 mmol, 2.2 eq) was added and the resulting
ll~i~ule was stirred for three hours at 70~C. The reaction was qll~nrh~d
by the addition of 10 ml of water The aqueous fraction was extracted
with ethyl acetate (3 x 10 ml). The org~nic fractions were combined and
washed with water (2 x 10 ml), and then brine (1 x 10 ml), and then dried
20 over magnesium sulfate. The solvents were removed in vacuo to yield a

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- 249-

light brownish crude material. The desired title product was further
purified by flash chromatography.
NMR and IR were consistent with the proposed title st~ucture.
FDMS (M+) 724.
5 Analysis for C40Hs7clN4o6:
Theory: C, 66.23; H, 7.92; N, 7.72.
Found: C, 66.49; H, 8.04; N, 7.79.
r~ 1e 277

Preparation of (RS) 2-(4-chlorophenoxymethyl)-4-[3-(piperidin-3-
yl)propoxy]-1-[3-(piperidin-3-yl)~ yl]b~n~ ole

~NH



~<

~N~ --~~--~1


~NH


The title compound is prepared from (RS) 2-(4-
chlorophenoxymethyl)-4-[3-[1-(t-butoxycarbonyl~piperidin-3-yl]propogy]-
1-[3-[1-~t-butoxycarbonyl)piperidin-3-yl]~ yl]b~n~in~idazole by standard
deprotection techniques using trifluoroacetic acid.
2 0 NMR and IR were consistent with the proposed title structure.
FDMS (M+) ~i2~

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- 2~0 -

Analysis for C30H4~clN4o2:
Theory: C, 54.22; H, 5.75; N, 7.44.
Found: C, 53.97; H, 5.48; N, 7.26.

nu?le 278

Preparation of (R) 2-(4-chlorophenoxymethyl)-4-[3-[1-(t-
buto~ycall)onyl)piperidin-3-yl]propoxy]-1-[3-[1-(t-
butoxycarbonyl)piperidin-3-yl] lll olJyl]be~ ~imi dazole

~BoC




~~-~Cl


~'GN~ BoC


A solution of 4-hydl oxy-2-~4-
chlorop~eno~ymethyl)b~n7imidazole (~;00 mg, 1.82 mmol) in dry N,N-
15 dimethylformamide (8 ml) was treated with sodium hydride (60% inmineral oil, 162 mg, 4.0 mmol, 2.2 eq). The resulting ~ e was
stiITed at room tempel a~u~e under a stream of nitrogen for about one
hour. To this reaction ~..ix~ e (R) 3-[1-(t-butoxycarbonyl)piperidin-3-
yl)propyl bromide (4.0 mmol, 2.2 eq) was added and the resulting
20 mixture was stirred for three hours at 70~C. The reaction was quenched
by the addition of 10 ml of water. The aqueous fraction was extracted

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- 2~-
-




with ethyl acetate (3 x 10 ml). The organic fractions were c~mhin~d and
washed with water (2 x 10 ml), and then brine (1 x 10 ml), and then dried
over m~gnesium sulfate. The solvents were removed in vacuo to yield a
light brownish crude m aterial. The desired title product was further
5 purified by flash chromatography.
NMR and IR were consistent with the proposed title structure.
FDMS (M~) 724.
Analysis for C4oHs7clN4o6:
Theory: C, 66.23; H, 7.92; Nt 7.72.
Found: C, 66.23; H, 7.86; N, 7.69.

F,~slrn,rle 279

Preparation of ~R) 2-(4-chlorophenoxymethyl)-4-[3-(piperidin-3-
1~ yl)propoxy~-1-[3-(piperidin-3-yl)l~lo~yl]ben7:imidazole




~<

~~~Cl




The title compound is prepared from (R) 2-(4-
2 o chlorophenoxymethyl)-4-[3-[1-(t-butoxycarbonyl)piperidin-3-yl~propoxy]-

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1-[3-[1-(t-buto~y~all onyl)piperidin-3-yl]~ yl]be~imidazole by standard
deprotection techniques using trifluoroacetic acid.
NMR and IR were consistent with the proposed title structure.
FDMS (M+) 525
5 Analysis for C30H4lclN4o2:
Theory: C, 54.22; H, 5.75; N, 7.44.
Found: C, 54.12; H, 5.86; N, 7.47.

~T~le 280

Preparation of (S) 2-(4-chloropheno~y~nethyl)-4-[3-[1-(t-
buto~ycal l)onyl)piperidin-3-yl]propoxy]-1-[3-[1-(t-
butoxycarbonyl)piperidin-3-yl]propyl]ben~im; dazole

~N--BoC




N~~~ GC1


",.~/~N,BoC

~J

A solution of 4-hy l~oky-2-(4-
chloropheno~Fymethyl)ben~imidazole (~00 mg, 1.82 mmol) in dry N,N-
dimethylformamide (8 ml) was treated with sodium hydride (60% in
mineral oil~ 162 mg, 4.0 mmol, 2.2 eq). The resulting ~ e was
stirred at room temperature under a stream of nitrogen for about one

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hour. To ~his reaction ..~ e (S) 3-[1-(t-butoxycarbonyl)piperidin-3-
yl)propyl bromide (4.0 mmol, 2.2 eq) wa6 added and the resulting
, mixture was stirred for three hours at 70~C. The re~ctior- was ~n~,hed
by the addition of 10 ml of water. The aqueous fraction was extracted
5 with ethyl acetate (3 X 10 ml). The organic fractions were cnmh;ned and
washed with water (2 x 10 ml), and then brine (1 x 10 ml)~ and then dried
over m~ne~ium sulfate. The solvents were removed in vacuo to yield a
light brownish crude material. The desired title product was fi~rther
purified by flash chromatography.
10 NMR and IR were consistent with the proposed title structure.
FDMS (M+) 724.
Analysis for C40H57ClN4~6:
Theory: C, 66.23; H, 7.92; N, 7.72.
Found: C, 65.51; H, 7.94; N, 7.80.~5
n~l e 281

Preparation of (S) 2-(4-chloropheno~ymethyl)-4-[3-~piperidin-3-
yl)propoxy}-1-[3-(piperidin-3-yl)~l o~l]b~n7imidazole




"'~/~NH

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The title compound is prepared from (S) 2-(4-
chlorophenoxymeth~l)-4-[3-[1-~t-butoxycarbonyl)piperidin-3-yl]propoxy]-
1-[3-[1-(t-buto~ycall~onyl)piperidin-3-yl]propyl]benzi_idazole by standard
5 deprotection techniques using trifluoroacetic acid.
NMR and IR were consistent with the proposed title structure.
FDMS (M+) 525
Analysis for C30H4lclN4o2:
Theory: C, 54.22; H? 5.75; N, 7.44.
Found: C, 53.96; H, 5.74; N, 7.40.
le 282

Preparation of 2-(4-chlorophenoxymethyl)-4-~5-[1-(t-
butoxycarbonyl)piperidin-4-yl3pentoxy]- 1-[5-r 1-(t-
buto~yca~l~onyl)piperidin-4-yl]pentyl~ben7imidazole

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- 2~5 -
-
BoC




N ~Cl




~ BoC

A solution of 4-hyL o~y-2-(4-
chlorophenoxymethyl)ben7:imidazole (~;00 mg, 1.82 mmol) in dry N,N-
dimethylformamidLe (8 ml) was treated with sodium hydride (60% in
mineral oil, 162 mg, 4.0 mmol, 2.2 eq). The resulting ~ ul.2 was
stirred at room temperature under a stream of nitrogen for about one
hour. To this reaction ~;x~ e 5-Ll-(t-butoxycarbonyl)piperidin-4
yl)pentyl bromide (4.0 mmol, 2.2 eq) was added and t~e resulting
~ 10 mi~t~lre was stirred for three hours at 70~C. The reaction was ql1~nr.h~d
by the addition of 10 ml of water. The aqueous fraction was extracted
c with ethyl acetate (3 x 10 ml). The organic fractions were comh;ned and
washed with water (2 x 10 ml), and then brine (1 x 10 ml), and then dried
over m~nesium sulfate. The solvents were removed in vacuo to yield a
light blowllish crude materialL. The desired title product was further

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-2~6-

purified by flash chromatography. There is some substitution at the 7-
position of the ben7imidazole present, although the 4-substituted is the
maJor ~somer.
NMR was consistent with the proposed title structure.
5 FDMS (M+) 781.
le 283

Preparation of 2-(4-chlorophenoxymethyl)-4-[5-(piperidin-4-yl)pentoxy]-1-
lo ~5-~piperidin-4-yl]pentyl]b~n7.imidazole


>



~0<
~~~Cl




~N'BoC

The title compound is prepared from 2-(4-
15 chlorophenn~ymethyl)-4-[5-[1-(t-butoxycarbonyl)piperidin-4-yl]peIltogy]-

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-
1-[5-[1-(t-butoxycarbonyl)piperidin-4-yl]pentyl]ben7imidazole by standard
deprotection techniques using trifluoroacetic acid.
NMR and IR were consistent with the proposed title structure.
FDMS (M+) !i81
Analysis for C34H4sClN402:
Theory: C, ~i6.40; H, 6.35; N, 6.92.
Found: C, 56.22; H, 6.37; N, 6.90.

Preparation 58
Preparation of 2-(4-chloropheno~ymethyl)-4-benzyloxy-ben7imi~ ole



<O

N
~N~~~Cl

A solution of 4-hydro~yl~e~imi(l~Qle (7.28 mmol, 1.0 eq)
and triphenylphosphine (2.30 mg, 8,74 mmol, 1.2 eq ) in dry
tetrahydro~uran (72 ml, 0.1 M) was treated with a solution of ~enzyl
alcohol (0.9 ml, 8.74 mmol, 1.2 eq) and diethyl azodicarboxylate (1.4 ml,
8.74 mmol, 1.2 eq). The resulting ~ u~e was stirred at 0~C and was
then waImed to room tempela~ule. After five hours, the
tetrahydrofuran was removed in vacuo. The residue was further
purified using flash chromatography to provide the title intermediate in
- ~;-70% yield.
NMR and IR were consistent with the proposed title structure.
- 25 FDMS 364 (M+)
Analysis for C21H16ClN20:
Theory: C, 69.14; H, 4.70; N, 7.68.

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-2~8-
Found: C, 69.35; H, 4.89; N, 7.74.
m~;~le 284
Preparation of 2-(4-chloropheno~ymethyl)-4-benzyloxy-1-[3-[1-(t-
butoxycarbonyl)piperidin-4-yl]~ yl]-b~?n7.imidazole




~N~O~ Cl




N--
BoC

A solution of 2-(4-chlorophenoxymethyl)-4-benzyloxy-
bçn~imitl~ole (720 mg, 1.97 mn~ol, 1.0 eq) in dry N,N-
dimetllylrlJ....Ami(l~ (8 ml, 0.25 M) was treated with sodium hydride
(60% in milleral oil, ~;7 mg, 2.30 mmol, 1.2 eq). The resulting l~ LLe
was stirred at room temperature for thirty minutes and then 3-[1-(t-
butoxyc~ll)onyl)piperidin-4-yl]LJlo~yl bromide (7.24 mg, 2.36 mmol, 1.2
eq) was added to the reaction .. i~ e. The resulting mi~ e was
stirred at 70~C for three hours. The reaction was quenched by the
addition of water (1 x 30 ml). The aqueous fraction was extracted with
diethyl ether (1 x 30 ml). The organic fractions were combined, washed
with water (1 x 30 ml), then ~rine (1 x 30 ml), and then dried over sodium
sulfate. The solvents were removed in vacuo. The desired title product

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-2~9-
-
was further purified by flash chromatography to provide a white foam in
38% yield.
s NMR and IR were consistent with the proposed title structure.
FDMS 589 (M+)




Tr~le 285

Preparation of (RS) 2-(4-chloropheno~ymethyl)-4-benzyloxy-1-[3-[1-(t-
buto~ycall)onyl)piperidin-3-yl~propyl]-ben ~mi dazole



<O


~~~ Cl




BoC

A solution of 2-(4-chloropheno~ymethyl)-4-benzylogy-
bçn7;mi~ole (720 mg, 1.97 mmol, 1.0 eq) in dry N,N-
dimethylform~mirle (8 ml, 0.2~ M) was treated with sodium hydride
(60% in mineral oil, 57 mg, 2.30 mmol, 1.2 eq). The resulting l~ ,UI e
was stirred at room tempel dlure for thirty minutes and then (RS) 3-[1-(t-
but(J~ycall~onyl)piperidin-3-yl]~lo~yl bromide (7.24 mg, 2.36 mmol, 1.2
eq) was added to the re~c*on ~ ure. The resulting mixture was
2 0 stirred at 70~C for three hours. The reaction was quenched by the
t addition of water (1 x 30 ml). The aqueous fraction was extracted with

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- 260-

diethyl ether (1 x 30 ml). The organic fractions were comhined, washed
with water tl x 3Q ml~, then brine (1 x 30 ml), and then dried over sodium
sulfate. The solvents were removed in vacuo. The desired title product
was further purified by flash chromatography to provide a white foam in
38% yield.
NMR and IR were consistent with the proposed title structure.
FDMS 589 (M+)
Arlalysis for C34H40ClN304:
Theory: C, 69.20; H, 6.83; N, 7.12.
Found: C, 69.20; H, 6.90; N, 7.28.

F,~m,ple 286

Preparation of (R) 2-(4-chlorophenoxymethyl)-4-benzyloxy-1-[3-[1-(t-
butoxycarbonyl)piperidin-3-yl]propyl]-ben 7.i mi dazole




N~ ~Cl




BoC

A solution of 2-(4-chloroph~noxymethyl)-4-benzyloxy-
2 o ben~imidazole (720 mg, 1.97 mrnol, 1.0 eq) in dry N,N-
dimethylformamide (8 ml, 0.25 M) was treated with sodium hydride

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(60% in mineral oil, 57 mg, 2.30 m m ol, 1.2 eq). The resulting mixture
was stirred at room temperature for thirty minllte~ and then (R) 3-[1-(t-
buto~y~.bonyl)piperidin-3-yl]~lo~yl bromide (7.24 mg, 2.36 mmol, 1.2
- eq) was added to the reaction mixture. The resulting ~ e was
5 stirred at 70~C for three hours. The reaction was qllenr.he-l by the
addition of water (1 x 30 ml). The aqueous fraction was extracted with
diethyl ether (1 x 30 ml). The org~niC fractions were combined, washed
with water (1 x 30 ml), then brine (1 x 30 ml), and then dried over sodium
sulfate. The solvents were removed im vacuo. The desired title product
10 was further purified by flash chromatography to provide a white foam in
38% yield.
IR was consistent with the proposed title structure.
FDMS 589 (M+)
Analysis for C34H40ClN304:
Theory: ~, 69.20; H, 6.83; N, 7.12.
Found: C, 70.15; H, 7.17; N, 7.07.

?le ?87

Preparation of (S) 2-(4-chloroph~no~ymethyl)-4-benzyloxy-1-[3-[1-(t-
buto~yca~ bonyl~piperidin-3-yl]propyl]-ben ~i mi dazole

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-262-




O

~~~C




N~
~oC

A solution of 2-(4-chlorophenQ~ymethyl)-4-benzyloxy-
b~n~imidazole (720 mg, 1.97 mmol, 1.0 eq) in dry N,N-
dimethylformamide (8 ml, 0.25 M) was treated with sodium hyd~ide
(60~o in mineral oil, 57 mg, 2.30 mmol, 1.2 eq). The resulting llli~Lu~e
was stirred at room temperature for thirty minutes and then (S) 3-[1-(t-
buto~yc~lbonyl)piperidin-3-yl]~ro~yl bromide (7.24 mg, 2.36 mmol, 1.2
eq) was added to the reaction mixture. The resulting ~ u~ e was
10 stirred at 7Q~C for three hours. The reaction was quenched by the
addition of water (1 x 30 ml). The aqueous fraction was extracted with
diethyl ether (1 x 30 ml). The organic fractions were combined, washed
with water (1 x 30 ml), then brine (1 x 30 ml), and then dried over sodium
sulfate. The solvents were removed in vacuo. The desired title product
15 was further purified by flash chromatography to provide a white foam in
38% yield.
IR was consistent with the proposed title structure.
FDMS 589 (M+)
Analysis for C34H40ClN304:
Theory: C, 69.20; H, 6.83; N, 7.12.

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- 263-
-
F ou n d: C, 68.26; H, 7.01; N, 7.25.

~ ml?le 288

Preparation of (:~) 2-(4-chlorophçno~ymethyl)-4-benzyloxy-1-[2-[1-~t-
butu~yca~bonyl)piperidin-3-yl]ethyl]-ben~imidazole
~3
o




N~ ~ Cl


<~ N--BoC

A solution of 2-(4-chloropheno~ymethyl)-4-benzyloxy-
bqn7.imi~0le (720 mg, 1.97 mmol, 1.0 eq) in dry N,N-
dimethylformamide (8 ml, 0.25 M) was treated with sodium hydride
(60% in mineral oil, 57 mg, 2.30 mmol, 1.2 eq). The resulting ~ e
was stirred at room tempe- d~ e for thirty minutes and then (R) 2-[1-(t-
butoxycarbonyl)piperidin-3-yl]ethyl bromide (2.36 mmol, 1.2 eq) was
added to the reaction ~ e. The resulting mixture was stirred at
70~C for three hours. The reaction was quenched by the addition of
water (1 x 30 ml). The aqueous fraction was extracted with diethyl ether
(1 x 30 ml). The organic fractions were comhin~d, washed with water (1
- 20 x 30 ml), then brine (1 x 30 ml), and then dried over sodium sulfate. The
solvents were removed in vacuo. The desired title product was further
purified by flash chromatography to provide a white foam in 40-60%
t yield.

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- 264-

lR and NMR were consistent with the proposed 1itle structure.
FDMS 575 (M+)
Analysis for C33H3gClN3O4:
Theory: C, 68.80; ~I,6.65; N, 7.29.
Found: C, 68.35; H, 7.47; N,8.08.

mrle ~9

Preparation of (S) 2-(4-chlorophenoxymethyl)-4-benzyloxy-1-[2-[1-(t-
10 buto~ycal l~onyl )piperidin-3-yl]ethyl]-b~n 7 i mi dazole



~<

~~~Cl


< N--BoC
\

A solution of 2-(4-chlorophenoxymethyl)-4-benzyloxy-
b~n7imi~ ole (720 mg, 1.97 mmol, 1.Q eq) in dry N,N-
~imethylform~mi~e (8 ml, 0.25 M) was treated with sodillm hydride
(60% in mineral oil, 57 mg, 2.30 mmol, 1.2 eq). The resulting mixture
was stirred at room temperature for thirty minutes and then (S) 2-[1-(t-
butoxycarbonyl)piperidin-3-yl]ethyl bromide (2.36 mmol, 1.2 eq) was
20 added to the reaction mi~ e. The resulting mixture was stirred at
70~C for three hours. The reaction was qll~nl h~d by the addition of
water (1 x 30 ml). The aqueous fraction was extracted with diethyl ether
(1 x 30 1). The organic fractions were combined, washed with water (1

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-265-

x 30 ml), then brine (1 x 30 ml), and then dried over sodium sulfate. The
solvents were removed in vacuo. The desired title product was further
purified by flash chromatography to provide a white foam in 40-50%
yield.
5 IR and NMR were consistent with the proposed title structure.
FDMS 575 (M+)
Analysis for C33H38ClN304:
Theory: C, 68.80; H, 6.65; N, 7.29.
Found: C, 68.03; H, 7.39; N, 7.86.
~ le 290

Preparation of (RS) 2-(4-chloroph~n-)~ymethyl)-4-hyd~o~y-1-[3-~1-(t-
butoxycarbonyl )piperidin-3 -yl]propyl~-ben ~.i mi dazole
OH


~' ~~Cl




BoC

A solution of (RS) 2-~4-chloroph~n-~ymethyl)-4-benzyloxy-1-
[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl]-ben~i~nidazole (24~ mg, 0.42
20 mmol, 1.0 eq) in ethyl acetate (4.2 ml) was degassed and then treated
wit,h 5% palladium on carbon (250 mg). The resulting ~u.e was
stirred under a hydrogen atmosphere. The reaction mixture was then
filtered through a CELITETM cake layer. The catalyst was washed
thoroughly with ethyl ~cet~te and et~l~n~l. The filtrate was con-1en~ed
2 5 on a rotoevaporator to yield the desired title product in 78% yield.

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NMR was consistent with the proposed title structure.
FDMS 589 (M+)

m~le ~91




Preparation of (RS3 2-(4-chlorophenoxyrnethyl)-4-[2-[1-(t-
butoxycarbonyl)piperidin-3-yl]ethoxy]- 1-[3-tl-(t-butol~ycall)onyl)p;peridin
3-yl]propyl]-benzimidazole
,BoC




N~ ~ Cl




N~
Bo~
A solution of (RS) 2-(4-chlorophenoxymethyl)-4-hyLo~y-1-~3-
[l-(~-buto~ycalbonyl)piperidin-3-yl]~v~yl]b~n7.imitl~l)1e (76 mg, 0.1~
mmol, 1.0 eq) in dry N~N-llimethylformamide (1.0 ml) was treated with
sodium hydride (60% in oil, 7.5 mg, 0.18 mmol, 1.20 eq). The resulting
~ mixture was stirred at room temperature for thirty m-inutes, after
which time 2-[1-(t-butoxycarbonyl)piperidin-3-yl3ethyl bromide (0.18
mmol, 1.2 eq) was added. The resulting ~ u~e was stirred for three
hours at 70~C. The reaction was quçn~hçd by the addition of water (10

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-267-

ml). The aqueous fraction was extracted with diethyl ether (3 x 101).
The organic fractions were comhined, washed with water (2 x 10 ml),
then brine (1 x 10 1), and then dried over sodium sulfate. The solvents
were removed in vacuo to give a crude product. The title product wa~
5 further purified by flash chromatography to provide a crystalline
product. Yield: 92%
NMR was consistent with the proposed ~tle structure.
FDMS 711 (M+)

F.~ml le ?~2

Preparation of (RS) 2-(4-chlorophen-l~ymethyl)-4-[[1-(t-
butoxycarbonyl)piperidin-3-yl]methoxy]- 1-[3-~1-(t-
butoxycarbonyl)piperidin-3-yl~lo~yl]-b~n~imidazole

~\N--BoC
o




~<

N~ ~Cl




N~
BoC

- A solution of (RS) 2-(4-chloroph~no~ymethyl)-4-hydroxy-1-[3-
[1-(t-butoxycarbonyl~piperidin-3-yl]propyl]ben~imidazole (76 mg, 0.16
20 mmol, 1.0 eq) in dry N,N-dimethylformamide (1.0 ml) was treated with
sodium hydride (60% in oil, 7.5 mg, 0.18 mmol, 1.20 eq). The resulting

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I 1~ il~LIUl 13 was stirred at room tempel a~ ul e for thirty minutes, after
which time 1-(t-butoxycarbonyl)piperidin-3-yl)methyl bro_ide (0.18
mmol, 1.2 eq) wa~ added. The resulting ...i~ e was stirred for three
hours at 70~C. The reaction was ql~anched by the A~ tion of water (10
5 ml). The aqueous fraction was extracted with diethyl ether (3 x 10 ml).
The organic fractions were comhined, washed with water (2 x 10 ml),
then brine (1 x 10 ml), and then dried over sodium sulfate. The solvents
were removed in vacuo to give a crude product. The title product was
further purified by flash chromatography to provide a crystalline
1 o product.
NMR and IR were consistent with the proposed title structure.
FDMS 696 (M~)

~ m~le 293
Preparation of (RS) 2-(4-chlorophenoxymethyl)-4-[(piperidin-3-
yl)methoxy]-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl]-

ben7.im;dazole



~<

~N~O~ Cl




H

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-269-
=




The title product is prepared from (RS~ 2-(4-
chloropheno~ymethyl)-4-[[1-(t-butoxycarbonyl)piperidin-3-yl]methoxy]-1-
v [3-[1-(t-buto~yca~l)onyl)piperidin-3-yl]~l~pyl]-benzimidazole using a
standard trifluoroacetic acid deprotection protocol.
NMR and IR were consistent with the proposed title structure.
FDMS 497 (M+)

F.~z~m~le 294

0 Preparation of (~S) 2-~4-chloror)heno~ymethyl)-4-[3-[1-(t-
buto~ycarl)onyl)piperidin-4-yl]propoxy]-1-[3-[1-(t-
butoxycarbonyl)piperidin-3-yl]~l v~yl]-bçn 7:i mi dazole
BoC




~~<~

~N~O~ Cl



C~
N~
BoC
A solution of (RS) 2-(4-chloropheno~nethyl)-4-lly~o~y-1-[3-
[1-(t-buto~ycallJonyl)piperidin-3-yl]~o~yl3benzimidazole (75 mg, 0.15

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- 270 -

mmol, 1.0 eq) in dry N,N-d;rr~ll~ylfc.~ amide (1.0 ml) was treated with
sodium hydride (60~o in oil, 7.5 mg, 0.18 mmol, 1.20 eq). The resulting
mixture was stirred at room tempela~ule for thirty minutes, after
which time 3-[1-(t-butoxycarbonyl)piperidin-4-yl)]propyl bromide (0.18
5 mmol, 1.2 eq) was added. The resulting ...ix~,... e was stirred for three
hours at 70~C. The reaction was qll~n~h~l by the addition of water (10
ml). The aqueous fraction was extracted with diethyl e~er (3 x 10 ml).
The organic fractions were cornhined, washed with water ~2 x 10 ml),
then brine (1 x 10 ml~, and then dried over sodium sulfate. The solvents
10 were removed in vacuo to give a crude product. The title product was
further purified by flash chromatography to provide a crystalline
product.
NMR and IR were consistent with the proposed title structure.
FDMS 724 (M+)
Analysis for C40Hs7ClN4O6:
Theory: C, 66.23; E, 7.92; N, 7.72.
Found: C, 66.51; H, 7.99; N, 7.52.

F~nv-le 295
Preparation of (RS) 2-(4-chlorophenoxymethyl)-4-[3-[1-~t-
butoxycarbonyl)piperidin-4-yl]propoxy]-1-[3-[1-(t-
butoxycarbonyl)piperidin-3-yl]~. vl~yl]-ben7imidazole

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- 271-




~; ~~ CI




N

The title product is prepared from (RS) 2-(4-
chloroph.3no~rymethyl)-4-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propoxy~-
1-[3-[1-(t-buto~ycaLllonyl)piperidin-3-yl3~.o~yl]bçn7:imidazole using a
st~nrlslrd trifluoroacetic acid deprotection protocol.
NMR and IR were consistent with the proposed title structure.
FDMS 511.4 ~M+)
Analysis for C2sH3sclN4o2:
Theory: C, 53.62; H, 5.59; N, 7.58.
Found: C, 53.38; H, 5.64; N, 7.63.
m~le 296
Preparation of (RS) 2-(4-chlorophenoxymethyl)-4-[5-[1-(t-
butu~ycalbonyl)piperidin-4-yl]pentoxy]-1-[3-[1-(t-
butoxycarbonyl)piperidin-3-yl]~ yl]-benzimidazole

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-272-

,BoC
~N



<

/~N

~N~ ~ Cl


~>
N~
BoC

A solution of (RS) 2-(4-chlorophenoxymethyl)-4-hy~l,o~y-l-~3
[1-(t-butoxycarhonyl)piperidin-3-yl]~ yl}ben~imidazole(75 mg, 0.15
m mol, 1.0 eq) in dry N,N-dimethylformamide (1.01) was treated with
sodiu_ hydride (60% in oil, 7.5 mg, 0.18 m mol, 1.20 eq). The resulting
ule was stirred at room tempe~a~ule for thirty minutes, after
which time ~-[1-(t-butoxycarbonyl)piperidin-4-yl)]pentyl bromide (0.18
mmol, 1.2 eq) was added. The resulting mi~tllre was stirred for three
hours at 70~C. The reaction was quenched by the addition of water (10
ml). The aqueous fraction was extracted with diethyl ether (3 x 10 ml).
The org~nic fractions were comhine(l, washed with water (2 x 10 ml),
then brine (1 x 10 ml), and then dried over sodium sulfate. The solvents
were remnoved in vacuo to give a crude product. The title product was

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-273-
-
further purified by fla~h chromatography to provide a crystalline
product.
NMR and IR were consistent with the proposed title structure.
- FDMS 752 (M+)




~m.~le 297

Preparation of (RS) 2-(4-chlorophenoxymethyl)-4-[5-(piperidin-4-
yl)pentoxy]-1-[3-(piperidin-3-yl)~l o~yl]-benzimidazole
H


)




N ~Cl




~N
E
The title product is prepared from (RS) 2-(4-
chlorophenoxymethyl)-4-[5-[1-(t-butoxyca. bonyl)piperidin-4-yUpentoxy3-

15 1-[3-[1-(t-but~xycalbonyl)piperidin-3-yl]propyl]ben~midazole using a
standard trifluoroacetic acid deprotection protocol.

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NMR and IR were consistent with the proposed title structure.
FDMS 555 (M+1)
n~le 298




Preparation of (RS) 2-(4-chlorophenoxymethyl)-4-[5-[1-(t-
buto~y~all~onyl)piperidin-3-yl]pentoxy]-1-[3-[1-(t-
buto~ycall)onyl)piperidin-3-yl]~ yl]-ben~imidazole

~N--BoC




/D<~N
~~~Cl




BoC

A solution of (RS) 2-(4-chloroph~noxymethyl)-4-hy~ o~y-1-[3-
[l-(t-butoxycarbonyl)piperidin-3-yl]propyl]b~n7:imidazole (75 mg, 0.15
mmol, 1.0 eq) in dry N,N-dimethylform.qmir~e (1.0 ml) was treated with
sodium hydride (60% in oil, 7.5 mg, 0.18 mmol, 1.20 eq). The resulting
mixture was stirred at room tempe. a~ e for thirty minutes, af~cer
which t.ime 5-[1-(t-buto~ycalbonyl)piperidin-3-yl)]pentyl bromide (0.18

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m m ol, 1.2 eq) was added. The resulting mixture was stirred for three
hours at 70~C. The reactlon was ~llçnrhed by the addition of water (10
ml). The aqueous fraction was extracted with diethyl ether (3 x 10 ml).
The organic fractions were cl)mhinefl, washed with water (2 x 10 ml),
5 then brine (1 x 10 ml), and then dried over sodium sulfate. The solvents
were removed in vacuo to give a crude product. The title product was
further purif;ed by flash chromatography to provide a cryst~lline
product.
NMR and IR were consistent with the proposed title structure.
10 FDMS 7~3 (M~)
ple 299

Preparation of (RS) 2-(4-chl oroph f~!n o~ymethyl)-4-[5-~piperidin-3-
15 yl)pentoxy]-1-[3-(piperidin-3-yl)propyl]-b~n~imidazole

~ BoC




/~N
~N~~~Cl




~N
BoC

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The title product is prepared from (RS) 2-(4-
chlorophenoxymethyl)-4-[~-[1 -(t-butoxycarbonyl3piperidin-3-yl]pentoxy]-
1-~3-[1-(t-butoxycarbonyl)piperidin-3-yl]~o~yl]ben~imi~Qle using a
5 standard trifluoroacetic acid deprotection protocol.
NMR and IR were consi~tent with the proposed title structure.
FDMS 556 (M+1)

Preparation ~;9
Preparation of 2,3~ minophenol dihydrochloride salt
OH
~2
~2 HCl

~n~2

15 In a 2~0 ml single neck round bottom flask was added 2,3-
~i~minophenol (10 g, 80.56 m m ol) to eth~nol (100 ml). This mixture was
he~terl to 50~C to achieve dissolution. The resulting solution is cooled to -
~ to 0~C and an excess of anhydrous hydrogen chloride gas was added to
form a viscous slu~Ty. The resulting ~ re was stirred for two hours
20 at ~0~C, then filtered, and rinsed with chilled methanol (30 ml). The
solvents were removed in vacuo and the residue was dried overnight.
Yield: 1~.29 g (96.3%).

Preparation 60
Preparation of 4-hyLoky-2-[(4-chloropheno2y)methyl]bçn~ ole

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-
OH

\>~~~


In a 50 ml single neck round bottom flask, under a nitrogen
a~nosphere, 4-chlorophenoxyacetonitrile (0.46 g, 2.79 mmol~ was
5 admixed in methanol (11 ml). The contents were stirred to achieve
dissolution. To this solution were added sodillm metho~ide (0.164 g, 3.0
mmol). The resulting mixture was stirred for about 40 rrlinl~tes. To this
mixture was added 2,3~ minophenol dihydrochloride salt (0.~ g, 2.5
mmol) and the resulting mixture was stirred for two hours at room
10 tempe~tLL~e. The reaction mi~tllre was f;ltered and the filtrate was
added to 60 ml of water. A light brown preçipit~te formed and this
precipitate is removed by filtration, and washed with 20 ml of water.
The solid was dried in a vacuum oven overnight.
NMR was consistent with the proposed title structure.
Yield: 0.60 grams (86.1%).

Prep~ratiQn 61

Preparation of 4-llyd~ oxy-2-[(4-methylphenoxy)methyl]bçn~imidazole
OH



~ ~CH8

In a ~0 ml single neck round bottom flask, under a nitrogen
atmosphere, 4-methylphenoxyacetonitrile (2.79 mmol) was admixed in
25 methanol (11 ml). The cont~nts were stirred to achieve dissolution. To
this solution were added sodium metho~ .164 g, 3.0 mmol). The

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resulting ~ ,ule was stirred for about 40 minutes. To this mi~t~re
was added Z,3~ m;nophenol dihydrochloride salt (0.5 g, 2.5 mmol) and
the resulting ~ re was stirred for two hours at room temperature.
The reaction mixture was filtered and the filtrate was added to 60 ml of
5 water. A light brown precipitate formed and this precipitate is removed
by filtration, and washed with 20 ml of water. The solid was dried in a
vacuum oven overnight.
Pre~aration 62
Preparation of 4-benzyloxy-2-[(4-methylphenoxy)methyl]bçn7.imidazole




In a 500 ml single neck round bottom flask, under a
nitrogen atmosphere, 4-benzyloxy-2-[(4-
methylphen--~y)methyl]b~n~imi~ ole (7.0 g, 27.5 mmol) and
triphenylphosphine (9.31 g, 35.5 mmol~ were ~tlmi~d. To this was
added anhydrous tetrahydrorulan (275 ml). The resulting mixture was
20 stirred for five minute to achieve a dark red solution, after which time
benzyl alcohol ~3.79 ml, 36.6 mmol) and diethyl azodicarboxylate (5.9 ml,
37.5 mmol) were added. The resulting mixture was stirred at room
temperature overnight. The re~ctinn ~i~ula was extracted with ethyl
acetate (500 ml). The organic fraction was washed with water ~2 x 500
25 ml). The organic fraction was dried over sodium sulfate and the
solvents were removed in vacuo. The residue was then redissolved in

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methylene chloride (110 ml) and further purified by chromatography.
The desired fractions were collected and the title product was
recrystallized from 80:20 he~nes:diethyl ether.
NMR was consistent with the proposed title structure.




F',~A~u?le 300

Preparation of 4-trifluoromethanesulfonyloxy-2-[(4-
chlorophenoxy)methyl]-l-trifluoromethanesulfonylben~imidazole

~ ,CF3
O
o




~~,
/\s~ o Cl
F3~ O

In a 600 ml flasl~, under a nitrogen atmosphere, were added
4-hydroxy-2-[(4-chloropheno~ry)methyl]bçn7.imidazole (9.10 g, 33.1 mmol)
15 and pyridine (300 ml). The contents were then chilled to 0~C and
trifluoromethaneslllfonic anhydride (23.36 g, 82.8 mrnol) was then added
by syringe. The resulting ...ixl.-.e was st;rred at 0~C for two hours and
then stirred at room temperature overnight. The progress of the
reaction was monitored by thin layer chromatography. The solvents
2 ~ were then removed in vacuo. The residue was redissolved in ethyl
~cet,~te (5001) and washed with water (3 x 500 ml). The organic
fraction was dried over sodium sulfate and the solvents were removed in
vacuo. Yield: 14.64 g(82.0%).
IR was concistent with the proposed title structure.
25 FDMS 537.g~ (M+)
Analysis for Cl6HgClF6N206S2:
Theory: C, 35.76; H, 1.68; N, 5.20.

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Found: C, 34.83; H, 1.66; N, 5.15.
rn~;~le 301

5 Preparation of 4-(prop-2-enyl)-2-~(4-chloroph~no~y)methyl]-1-
trifluoromethanesulfonylben7.imi~01e
~/ H2




~ Cl

In a 250 ml single neck round bottom flask, under a
nitrogen atmosphere, were added 4-trifluoromethanesulfonyloxy-2-~(4-
chloropheno~ry)methyl]-1-trifluoromethanesulfonylbçn7:imidazole (4.97
g, 9.22 mmol), lithium chloride (1.17 g, 27.65 lnmol), allyltributyltin (4.27
g, 12.90 mmol), and bis(triphenylphosphine)p~ ium(II) chloride
(301.03 mg, 0.369 mmol) in anhydrous tetrahydrofuran (99 ml). The
resulting mixture was stirred for five hours at reflux, followed by the
addition of an additional 0.15 mg of the p~ ium catalyst. The contents
were then stirred overnight. The progress of the re~ction was monitored
by thin layer chromatography. The desired title product was further
20 purified by flash chromatography.
~rleld: 3.97 g (3~.8%)
NMR was consistent with the proposed title structure.

~n~ 307
Preparation of 4-(ethenyl)-2-[(4-chlorophenoxy)methyl]-1-
trifluoromethanesulfonylben7imi dazole

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~2C~



~C '>~'~'13
/S~ ~ Cl

In a 250 ml single neck round bottom flask, under a
nitrogen atmosphere, were added 4-trifluoromethanesulfonyloxy-2-[(4-
5 chlorophenoxy)methyl]-1-trifluoromethanesulfonylben~imidazole (5.00
g, 9.28 mmol), lithium chloride (1.18 g, 27.84 mmol), vinyltributyltin
(4.12 g, 12.99 ~nol), and bis(triphenylphosphine)palladium(II) chloride
(303 mg, 0.371 mmol) in anhyLous tetrahydrofuran (99 ml). The
resulting ~ e was stirred for five hours at reflux, followed by the
10 addition of an additional 0.1~ mg of the palladil1m catalyst. The cont~nts
were then stirred overnight. The progress of the reaction was monitored
by thin layer chromatography. An additional 0.15 mg of the pAll~lium
catalyst and 0.~ ml of vinyltributyltin were added to the reaction mixture
and it was refluxed for five hours. The desired title product was further
15 purified by flash chromatography.
Yield: 3.87 g (33.6%)

F,~flml~le 303

2 0 Preparation of 4-(ethenyl)-2-[(4-chlorophenoxy)methyl]-1-
trifluoromethanesulfonylben7imidazole

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H ~
2~9



~CI
F3C O

To a 250 ml round bottom flask were added 4-
trifluoromethanesulfonyloxy-2-[(4-chlorophenoxy)methyl]-1-
trifluoromethanesulfonylbçn7irni~ ole (5.00 g, 9.28 mmol), palladium
tetrakis(triphenylphosphine) (428 mg, 0.371 mmol), lithium chloride
(2.95 g, 69.6 mmol) and vinyltributyltin (2.94 g, 9.28 mmol) to anhydrous
tetrahydrofuran. The reaction mixture was heated to reflux and
m:~int~ined at this temperature overnight. The progress of the reaction
was monitored by thin layer chromatography. An additional 428 mg of
the p~ rlium catalyst was added and the resulting mixture was
refluxed an additional three hours. To the reaction mixture was added
cuprous iodide (36.3 mg, 0.02 eq) and the reAction ...i~ e was refluxed
overnight. The solvents were removed in vacuo. The residue was
redissolved in ethyl acetate (500 ml) and was washed wit~ 1:1 water:28%
aqueous ammonium hydroxide (3x). The organic fraction was dried
over sodium sulfate. The desired title product was further purified by
column chromatography.
~leld: 3.87 g (48.4%)
20 IR was consistent with the proposed title structure.
FDM~; 416.02 (M+)
Analysis for Cl7H12ClF3N2O3S:
Theory: C, 48.99; H, 2.90; N, 6.72.
Found: C, 49.24; H, 3.18; N, 6.48.
Preparation 63

Preparation of 4-(ethenyl)-2-[(4-chlorophenoxy)methyl]ben~imidazole

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-283-

H2C~




In a 1001 round bottom flask, under a nitrogen
5 atmosphere, were added 4-(ethenyl)-2-[(4-chlorophenoxy)methyl]-1-
trifluoromethanesulfonylb~n~imill~ole (1.42 g, 3.29 ~nol) and
anhydrous methanol (20 ml). This solution was cooled to 0~C and
potassium carbonate (911 mg, 6.59 mmolt was added. The resulting
~ix~...e was stirred for two hours at 0~C, permitted to warm to room
10 tempeialufe, and stirred at this temperature for about three days. The
progress of t~e reaction was monitored by thin layer chromatography.
The desired title product was further purified by radial
chromatography.
Yield: 0.74 g (75.1%)
15 IR and FDMS were consistent with the proposed title structure.
Analysis for Cl6Hl3clN2o:
Theory: C, 67.49; H, 4.60; N, 9.84.
Found: C, 67.47; H, 4.86; N, 9.73.

2 0 ~ m~ le 304

Preparation of 4-(ethenyl)-2-[(4-chloroph~no~y)methyl]-1-[3-[1-(t-
butoxycarbonyl)piperidin-4-yl]propyl]beI-~imifl~ole

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H2C9



~C \~~~


~C

N-->
/




BoC

In a 100 ml round bottom flask, under a nitrogen
atmosphere, were added 4-(ethenyl)-2-[(4-
c~loroph~nQ~y)methyl]ben~imidazole (670 mg, 2.24 mmol) and
anhydrous N,N-dimethylformamide (34 ml). To this solution was added
~odium hydride (60% in mineral oil, 98.67 mg, 2.46 mmol). The
resulting mixture was stirred at room temperature for 45 minutes, and
then 3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl bromide (755 mg, 2.47
mmol) was added. The resulting ~ e was heated to 100~C and
stirred at this tempeldl u, e for about four hours. The progress of the
re,qc~;on was monitored by thin layer chromatography. The reaction
11~; X 1 . . e was partitioned between ethyl acetate and brine. The a~ueous
fiaction was extracted twice with brine. The organic fr~ction.q were
combined and dried over sodium sulfate. The solvents were removed in
vacuo. The desired title product was further purified by radial
chromatography .
Yield: 800 mg (68.1%)
IR and FDMS were consistent with the proposed title structure.
Analysis for C2gH36ClN3O3:
Theory: C, 68.29; H, 7.11; N, 8.24.
Found: C, 68.01; H, 7.07; N, 8.30.

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- 28~;-
-

PreDaration 64

Preparation of 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]bçn 7.imi dazole

~CH2




~Cl

In a 100 ml round bottom flask, under a nitrogen
atmosphere, were added 4-(prop-2-enyl)-2-[(4-chloropheno~y)methyl]-1-
trifluoromethanesulfonylb~n7.;midazole (1.00 g, 2.32 mTnol) and
anhydrous methanol (18 ml). This solution was cooled to 0~C and
potassium carbonate (641 mg, 4.64 mmol) was added. The resulting
mi~t.lre was stirred for two hours at 0~C, permitted to warm to room
temperature, and stirred at this temperature for about three days. The
progress of the reaction was monitored by thin layer chromatography.
The desired title product was further purified by radial
chromatography.
eld: 0.90 g (>99%)
IR and FDMS were consistent with the proposed title structure.
Analysis for Cl7Hl~ClN20:
Theory: C, 68.34; H, 5.06; N, 9.38.
Found: C, 68.46; H, 6.24; N, 9.35.

mrle 305

Preparation of 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-
butoxycarbonyl)piperidin-4-yl]~ yl]bçn~imitl~7:ole

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~/CH2



1~ >'--




N
BoC

In a 100 ml round bottom flask, under a nitrogen
atmosphere, were added 4-(prop-2-enyl)-2-[(~
chlorophenoxy)methyl]ben7.imidazole (550 mg, 1.84 mmol) and
anhydrous N,N-dimethylformAmi-le (59 ml). To this solution was added
sodium hydride (60% in mineral oil, 81.04 mg, 2.03 mr~ol). The
resulting mixture was stirred at room temperature for 60 minutes, and
then 3-[1-(t-buto~ycall~onyl)piperidin-4-yl]~ol yl bromide (620 mg, 2.03
10 mmol) was added. The resulting ;xle was heated to 100~C and
stirred at this tempe,alu~e for about three hours. The progress of the
reaction was monitored by thin layer chromatography. The reslc~ion
111; X 1 l l l e was partitioned between ethyl acetate and brîne. The aqueous
fi~action was extracted twice with brine. The organic fractions were
combined and dried over sodillm sulfate. The solvents were removed in
vacuo. The desired title product was further purified by radial
chromatography.
Yield: 622 mg (64.4%)
IR and FDMS were consistent with the proposed title structure.
Analysis for C30H3gClN3O3:
Theory: C, 68.75; H, 7.31; N, 8.02.
Found: C, 68.47; H, 7.35; N, 8.22.

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-287-
c




F,~m~le 306

Preparation of 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-r3-
5 (piperidin-4-yl)propyl]ben7imidazole trifluoroacetate
CH

o,3~




~TFA


In a 1001 single neck round bottom flask, under a
nitrogen atmosphere, 4-(prop-2-enyl)-2-[(4-chloroph~nl)~y)methyl~-1-[3-
[1-(t-butoxycarbonyl)piperidin-4-yl]l~lo~yl]ben7imidazole (300 mg, 0.572
mmol) was added to anhy~Lvus methylene chloride (201). To this was
added trifluoroacetic acid (0.441, 652 mg, ~.72 Inol). The resulting
mixture is stirred overnight at room temperature. The progress of the
re~ on was monitored by thin layer chromatography. The solvents
were removed in vacuo.
Yiel~: 222 mg (72.3%)
NMR was consistent with the proposed title structure.

~ m~I~le 307
-
Preparation of 4-(propyl)-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-
butoxycarbonyl)piperidin-4-yl]~l o~yl]b~n~imifl~7:ole

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-288-

CH3



C




N
BoC

In a 50 ml sinfle neck round bottom ila~k, under a nitrogen
atmosphere, 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-
buto~y~albonyl)piperidin-4-yl~.o~yl]b~n7.imidazole (100 mg, 0.19 mmol)
was added to ethyl acetate (4 ml). To this solution was added 10%
p~ ;um on activated carbon (100 mg), followed by the addition of a
hydrogen balloon. The reaction ~ ule was stirred for three hours at
room temperature, then filtered through a bed of CELITETM. The
desired title product was further purified by radial chromatography.
l~ield 86 mg (85.6%)
IR ~nd NMR were consistent with the proposed title structure.
Analysis for C30H40ClN303:
Theory: C, 68.49; H, 7.66; N, 7.99.
Found: C, 68.76; H, 7.70; N, 8.03.

m1?le 308

Preparation of 4-(prop-2-enyl)-2-[(4-chloropheno~y)methyl]-1-[3-[~-[3-
~piperidin- 1-yl)propyl]piperidin-4-ylJpropyl]ben ~i mi dazole

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- 289-
A

~/




N ~N

In a 25 ml round bottom flask, under a nitrogen
atmosphere, were added 4-(prop-2-enyl)-2-[(4-chlorophenoxy3methyl]-1-
~3-(piperidin-4-yl)~lopyl]bçn~imitl~ole (69.9 mg, 0.13 mmol3, potassium
carbonate (161.9 mg, 1.17 mmol), potassium iodide (21.6 mg, 0.13 mmol),
3-(piperidin-1-yl)~lo~yl chloride (33.52 mg, 0.17 mmol) and N,N-
dimethylform~mir~e (3 ml). The resulting ~ ,Ure was heated to 100~C
and m~int~ined at this temperature. The progress of the reaction was
monitored by thin layer chromatography. The reaction was quenched by
the addition of water. The aqueous fraction was extracted wtih ethyl
acetate. The organic fractions were comhined, washed with water, and
then dried over sodinm sulfate. The solvents were removed in vacuo.
The desired title product was further purified by radial
chromatography.
Yield: 40 mg (55.9%)
NMR was consistent with the proposed title structure.
FD~IS 548.22 (M+)

~.~m3~le 309

Preparation of 4-(prop-2-enyl)-2-[(4-chlorophP~nn~y3methyl]-1-[3-[1-[3-
~phenyl3propyl]piperidin-4-yl]lJL~ rl]b.qn7imi~ ole

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- 290-
,sH2




In a 60 ml round bottom flask, under a nitrogen
5 atmosphere, were added 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-
[3-(piperidin-4-yl3yfopyl]b~n7irnidazole (898 mg, 2.12 mmol), potassium
carbonate (1.46 g, 10.58 mmol), 3-(phenyl)~ yl chloride (0.2 ml, 506 mg,
2.{;4 mmol) and N,N-~imethylIormamide (7 ml). The resulting ~ e
was heated to 60~C and mAint~ined at t_is temperature ovelnight. The
10 progress of the reaction was monitored by thin layer chromatography.
An additional 1 equivalent of potassium carbonate and 0.2 ml of 3-
(phenyl)~lolJyl chloride were added and the resulting contents were
stirred at 60~C for an additional two hours. The reaction was qllen~herl
hy the addition o~ water. The aqueous fraction was extracted wtih ethyl
15 acetate. The organic fractions were coml~ined, washed with water, and
then dried over sodium sulfate. The solvents were removed in vacuo.
The desired title product was further purified by radial
chromatography.
Yield: 920 mg (80.2%)
20 NMR and IR was consi~tent with the proposed title structure.
Analysis for C34H40ClN30:
Theory: C, 7~;.32; H, 7.44; N, 7.7~;.
Found: C, 72.84; H, 7.22; N, 7.64.

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-291-
-

F~mple 310

Preparation of 4-(ethenyl)-2-[(4-chloropheno~y)methyl]-1-r3-[1-[3-
5 (phenyl)propyl]piperidin-4-yl]~ yl]ben 7i mi(~ ole

H2C~




In a 50 ml round bottom flask, under a nitrogen
atmosphere, were added 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-
[3-(piperidin-4-yl)propyl]ben~imidazole (898 mg, 2.12 mmol), potassium
carbonate (1.46 g, 10.~8 mmol~, 3-(phenyl)propyl chloride (0.2 ml, 606 mg,
2.54 m mol) and N,N-dimethylformamide (7 ml). The resulting mixture
was heated to 60~C and rn~int~inef~ at this tempe.alule overnight. The
15 progress of the re~ction was monitored by thin layer chrnm~tography.
The reaction was quenched by the addition of water. The aqueous
fraction was extracted wtih ethyl acetate. The organic fractions were
combined, washed thrice with saturated sodium bicarbonate solution,
and then dried over sodium sulfate. The solvents were removed in
20 vacuo. The desired title product was further purified by radial
chromatography .
Yield: 810 mg (77.2%)
NMR and IR was consistent with the proposed title structure.
Analysis for C33H3gClN3O:

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- 292 -

Theory: C, 7~.05; H, 7.2~; N, 7.96.
Found: C, 74.81; H, 7.05; N, 8.16.

F~rr~le 311




Preparation of 4-methoxy-2-[(4-chlorophenoxy~methyl]-1-[3-[1-(t-
butoxycarbonyl)piperidin-4-yl]propyl]ben~imidazole
OCH3




BoC
A solution of 4-~dl o~y-2-[(4-chloroph.qn-l~y)methyl]-1-~3-rl-
(t-buto~ycalbonyl)piperidin-4-yl]~ yl]ben~imidazole (300 mg, 0.6
m~nol, 1 eq) in anhydrous N,N-dimethylformamide (3 m~ was treated
w}th sodium hydride (60% in mineral oil, 26 mg, 0.66 mmol, 1.1 eq). The
15 resulting mixture was stirred for thirty minutes at room temperature.
Methyl iodide (94 mg, 0.66 mmol, 1 eq) was added to the reaction and the
re~ulting mixture was stirred for two hours at room temperature. The
reaction was quenched with the addition of water (5 ml). The aqueous
fraction was extracted with ethyl acetate (3 x 10 ml). The organic
20 fir~ctions were combined, washed with water (2 x 10 ml), then brine (1 x
10 ml), and then dried over sodium sulfate. The solvents were removed
in vacuo. The residue was further purified by flash column
chromatography to yield the title product as a crystalline product in 50%
yield.
25 NMR and IR were consistent with the proposed title structure.

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- 293 -
;




Analysis for C28H36ClN304:
Theory: C, 65.42; H, 7.06; N, 8.17.
Found: C, 6~.63; E, 7.14; N, 8.30.

~ le 312

Preparation of 4-methoxy-2-C(4-chloroph~no~y)methyl]-1-[3-(piperidin-4-
yl)propyl]b~n7.imi~ ole trifluoroacetate
OCH3

\~0

/ 0 \
F3C OH
N-- \ / 3
H
This product was prepared from 4-methoxy-2-[(4-
chloropheno~y)methyl]-1-[3-(piperidin-4-yl)propyl]b~n ~imidazole
tri~uoroacetate using standard trifluoroacetic acid deprotection
protocols.
IR and NMR were consistent with the proposed title structure.
FDMS 413 (M+)
Analysis for C23H28clN3o2 ~ 3 C2~l~3~2:
Theory: C, 46.07; H, 4.13; N, 5.~;6.
2 0 Found: C, 46.65; H, 4.38; N, 5.74.

~ le 313

Preparation of 4-methoxy-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(3-
2 5 phenylpropyl)piperidin-4-yl~propyl]ben ~; mi dazole

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-294-

OCH3

~ >~ ~




A solution of 4-methoxy-2-[(4-chlorophenoxy)methyl3-1-[3-
5 (piperidin-4-yl)~.o~yl]b~n7.imidazole trifluoroacetate ~177 mg, 0.29
mmol, 1 eq) in anhydrous N,N-dimethylform~mitle (2 ml) was treated
with potassium carbonate (120 mg, 0.87 mmol, 3 eq) and 3-phenylpropyl
bromide (87 mg, 0.43 mmol, 1.5 eq). The resulting ..~ e was stirred
at 80~C for six hours. The reaction was qliensh~d by the addition of
water (5 ml). The aqueous fraction was extracted with ethyl acetate (3 ~
10 ml). The organic fractions were combined, washed with water (3 x 10
ml), and brine (1 x 10 ml), and then dried over sodium sulfate. The
solvents were removed in vacuo. The residue was further purified by
coll~mn chromatography to yield the title product as a w~ite cryst~lline
solid.
Yield: 72%
NMR and IR were consistent with the proposed title structure.
FDMS 631.2, 632 (M+)
Analysis for C32H38ClN302:
Theory: C, 72.23; H, 7.20; N, 7.90.
Fnund: C, 72.14; H, 7.35; N, 7.82.

~ ,~le 314

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-295-

Preparation of 4-cyclopentoxy-2-[(4-chloroph çn o~y)methyl~- 1-[3-[ l-(t-
butoxycarbonyl)piperidin-4-yl]propyl~ben~imidazole trifluoroacetate

0~




N
Bo~




A solution of 4-hy(llo~y-2-C(4-chlorophenoxy)methyl~ [3-[1-
(t-butu~yca,l~onyl)piperidin-4-yl]lJlo~yl]b~n7imitlzl~0le trifluoroacetate
(300 mg, 0.6 mmol, 1 eq) in anhydrous N,N-dimethylformamide (3 m)
was treated with sodium hydride (60% in mineral oil, 26 mg, 0.66 mmol,
10 1.1 eq3. The resulting ~ ue was stirred for thirty minutes at room
tempe~ e. CYC1O~1O1JY1 bromide (0.66 mrrlol, 1 eq) was added to the
reaction and the resulting ~ Lule was stirred for two hours at room
tempel~ e. The reaction was qllen~h~d with the addition of water (~
ml). The aqueous fraction was extracted with ethyl acetate (3 x 10 ml).
15 The org~nic fractions were comhined, washed with water (2 x 10 ml),
then brine (1 x 10 ml), and then dried over sodium sulfate. The solvents
were removed in vacuo. The residue was further purified by flash
coll~mn chromatography to yield the title product as a crystalline
product in 50% yield.
20 NMR and IR were consistent with the proposed title structure.
FDMS 667 (M~)
Analysis for C32H42ClN304:

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-29~-

Theory: C, 67.65; H, 7.45; N, 7.40.
Found: C, 68.82; H,7.87; N, 7.55.

~nl~le 315




Preparation of 4-cyclopentoxy-2-~(4-chlorophenoxy)methyl]-1-[3-
(pipe~din-4-yl) ~ov~l ~ n7imidazole trifluoroucetate




~C >\' ~
/ o \
<~> F3C OH

H-- \ / 3
This product was prepared from 4-cyclopentoxy-2-[(4-
chlorophenoxy~methyl]-1-[3-~piperidin-4-yl)~3l o~yl]bcn ~im;dazole
trifluoroacetate using standard trifluoroacetic acid deprotection
protocols.
15 IR and NMR were consistent with the proposed title structure.
FDMS 468 (M+)
Analysis for C2gH38ClN3O2 ~ 3 C2HF3O2:
Theory: C, 48.93; H, 4.60; N, 5.19.
Found: C, 47.33; H, 4.82; N, 5.37.
ml~le 316

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-297-

Preparation of 4-cyclopentoxy-2-[(4-chlorophel~o~ry)methyl]-1-~3-[1-~3-
phenylpropyl)piperidin-4-yl]~ yl]ben ~imi dazole


0~


\~~~
~> Cl
~ '~

A solution of 4-cyclopentoxy-2-[(4-chlorophenoxy)methyl]-1-
~3-(piperidin-4-yl)propyUb~n7imidazole trifluoroacetate (0.29 mmol, 1 eq)
in anhydrous N,N-dilmethylform~mille ~2 ml~ was treated with
potassium carbonate (120 mg, 0.87 mmol, 3 eq) and 3-phenylpropyl
bromide (87 mg, 0.43 mmol, 1.5 eq). The resulting ~ e was stirred
at 80~C for six hours. The reaction was qn~n~hed by the addition of
water (5 ml). The aqueous fraction was extracted with ethyl acetate (3 x
10 ml). The organic fractions were comhined, washed with water (3 x 10
ml), and brine (1 x 10 ml), and then dried over sodium sulfate. The
solvents were removed in vacuo. The residue was further purified by
column chromatography to yield the title product as a white crystalline
solid.
NMR and IR were consistent with the proposed title structure.
FDMS 586 (M+)
Analysis for C36H44ClN302:
Theory. C, 73.76; H, 7.56; N, 7.17.
Found: C, 75.08; H, 7.85; N, 7.30.

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- 2g8-

F"~slTnrle 317

Preparation of 4-isopropoxy-2-[(4-chlorophenoxy)methyl:l- 1-[3-[1-(t-
butoxycarbonyl)piperidin-4-yl] l l o~yl]bqn 7:i mi dazole trifluoroacetate




~H3

OJ~CH3




BoC

A solution of 4-Lydlo~y-2-[(4-chloropheno~y)methyl]-1-[3-[1-
(t-butoxycarbonyl)piperidin-4-yU~ yl~b~n~im~dazole trifluoroacetate
(300 mg, 0.6 mrnol, 1 eq) in anhydrous N,N-dimethylformamide ~3 m)
was treated with sodium hydride (60% in mineral oil, 26 mg, 0.66 mmol,
1.1 eq). The resulting mi~ule was stirred for thirty minutes at room
temperature. ISO1J1VL~Y1 bromide ~0.66 mmol, 1 eq) was added to the
reaction and the resulting ~i2~ e was stirred for two hours at room
temperature. The reaction was quenched with the addition of water (~;
ml~. The aqueous fraction was extracted with ethyl acetate (3 x 10 ml).
The organic fractions were comhin~d, washed with water (2 x 10 ml),
the~ 1~rine (1 x 10 ml), and then dried over sodium sulfate. The solvents
were removed in vacuo. The residue was further purified by flash
col~mn chromatography to yield the title product as a crystalline r
product.
NMR and IR were consistent with the proposed title structure.
FI~MS 541, 542 (M~)



.

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-299-

Analysis for C2gH36ClN3O4:
Theory: C, 66.47; H, 7.44; N, 7.75.
l~ound: C, 66.31; H, 7.54; N, 7.75.

F"r~nu?le 318

Preparation of 4-isopropoxy-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-
4-yl)~ ~ o ~yl]ben ~i mi dazole tri~uoroacetate
CH3

O CH3


/ o \
(~~ F3C OH
N-- \ / 3
H
This product was prepared from 4-isopropoxy-2-[(4-
chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]ben7;mifi~ole
trifluoroacetate using standard trifluoroacetic acid deprotection
15 protocols.
IR and NMR were consistent with the proposed title structure.
FDMS 413 (M~)
Analysis for C2~H32clN3o2 ~ 3 C2HF3O2:
Theory: C, 47.49; H, 4.50; N, 5.36.
Found: C, 48.46; H, ~.03; N, 5.86.
le 319

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-300-

Preparation of 4-isopropoxy-2-[(4-chloropheno~ry)methyl]-1-[3-[1-(3-
phenyl~o~yl)piperidin-4-yl]~ro~yl3ber 7:imidazole
CH3
olCH3




A solution of 4-isopropoxy-2-[(4-chlorophenoxy)methyl]-1-[3-
(piperidin-4-yl)propyl~bçn7imidazole trifluoroacetate (0.29 mmol, 1 eq) in
anhydrous N,N-dimethylformamide (2 ml) was treated with potassium
carbonate (120 mg, 0.87 mmol, 3 eq) and 3-phenyl~u~yl bromide (87 mg,
0.43 m mol, ~.~ eq). The resulting mixture was stirred at 80~C for six
hours. The reaction was qllenf~h~d by the addition of water (5 ml). The
aqueous fraction was extracted with ethyl acetate (3 x 10 ml). The
organic fractions were comhinetl, washed with water (3 x 10 ml), and
bri~e (1 x 10 ml), and then dried over sodium sulfate. The solvents were
removed in vacuo. The re~idue was further purified by column
chromatography to yield the title product as a white crystalline solid.
NMR and IR were consistent with the proposed title structure.
FDMS 559.1, ~60 (M+)
Analysis for C34H42ClN302:
2 o Theory: C, 72.09; H, 7.56; N, 7.50.
Found: C, 73.09; H, 7.47; N, 7.l;2.

~:lrr~le 320

.
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-301-

Preparation of 4-(cyclohexylmethoxy)-2-~(4-chlorophenoxy)methyl]-1-~3-
[l-(t-butoxycarbonyl)piperidin-4-yl]~-o~yl]ben~imidazole tri~uoroacetate




N
BoC

A solution of 4-~ o~y-2-[(4-chloroph~oxy)methyl]-l-[3
(t-butoxycarbonyl)piperidin-4-yl]~lopyl]benzimidazole trifluoroacetate
(300 mg, 0.6 ~ol, 1 eq) in anhydrous N,N-dimethylformamide (3 m)
was treated with sodium hydride (60% in mineral oil, 26 mg, 0.66 mmol,
1.1 eq~. The resulting mixture was stirred for thirty minutes at room
tempe~al~e. C~yclo~ ylmethyl bromide (0.66 mmol, 1 eq) was added to
the reaction and the resulting lm~ e was stirred for two hours at room
temperature. The reaction was qllenl.h~d with the addition of water (5
ml~. The aqueous fraction was extracted with ethyl acetate ~3 x 10 ml).
The organic fractions were comhined, washed with water (2 x 10 ml~,
then brine (1 x 10 ml), and then dried over sodium sulfate. The solvents
were removed in vacuo. The residue was further purified by ~ash
colllmn chromatography to yield the title product as a crystalline
2 o product.

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- 302-

NMR and IR were consistent with the proposed title structure.
FDMS ~96, {~96 (M+)
Analysis for C34H46ClN304:
Theory: C, 68.~;0; H, 7.78; N, 7.05.
Found: C, 68.62; H, 7.83; N, 7.03.

m~le 321

Preparation of 4-(cyclohexylmethoxy~-2-[(4-chlorophenoxy)methyl]-1-[3-
10 (piperidin-4-yl)propyl]ben~imidazole trifluoroacetate




O \
F3C OH
H-- \ / 3

This product was prepared from 4-(cyclohexylmethoxy)-2-
15 C(4-chlorophenoxy)methYl]- 1-C3-(piperidin-4-yl)propyl]b~n ~imi dazole
trifluoroacetate using ~tandard trifluoroacetic acid deprotection
protocols.
IR and NMR were consistent with the proposed title structure.
F:DMS 496 (M+)
20 Analysis for C3lH42ClN302 ~ 3 C2HF302:
Theory: C, 60.16; H, 4.93; N, 6.01.

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-303-

Found: C, 50.01; H, 5.04; N, 4.96.

m~le 322

5 Preparation of ~-(cyclohexylmethoxy)-2-[(4-chlorophenoxy)methyl]-1-[3-
[1-(3-phenylpropyl)piperidin-4-yl]~l o~yl]ben~imidazole




A solution of 4-(cyclohexylmethoxy)-2-t(4-
chlorophenoxy)methyl3-1-r3-(piperidin-4-yl)~ yl]bçn7imidazole
trifluoroacetate (0.29 mmol, 1 eq) in anhydrous N,N-dimetll~lfo.,.~amide
(2 ml) wae treated with potassium carbonate (120 mg, 0.87 mmol, 3 eq)
and 3-phenylpropyl bromide (87 mg, 0.43 mmol, 1.6 eq). The resulting
15 mixture was stirred at 80~C for six hours. The reaction was qT1en(h~d
- by the addition of water (~ ml). The aqueous fraction was extracted with
ethyl acetate (3 x 10 ml). The organic fractions were comh;ned, washed
with water (3 x 10 ml), and brine (1 x 10 ml), and then dried over sodium
sulfaLte. The solvents were removed in vacuo. The residue was further

CA 02242579 1998-07-08

W O 97/~5041 PCTAJS97tOO511
- 304-

purified by column chromatography to yield the title product as a white
crystalline solid.
NMR and IR were consistent with the proposed title structure.
FDMS 614 (M~)
Analy~is for C38H48clN3o2:
Theory: C, 74.30; E, 7.88; N, 6.84.
Found: C, 74.26; H, 7.93; N, 6.91.

~ ple 323

Preparation of 4-(3-bromopropoxy)-2-[(4-chlorophenoxy)methyl]- 1-[3-[1-(t-
butoxycarbonyl)piperidin-4-yl] ~ yl]ben 7:i mi dazole
Br


~:r~




BoC
A solution of 1,3-dibromopropane (41.3 mg, 0.3 mmol, 1.~ eq)
in anhydrous N,N-dimethylforrn~mi-le (2 ml) was treated with a
solution of 4-hyL o~y-2-[(4-chlorophenoxy)methyl]-1-[3-~1-(t-
butoxycarbonyl)piperidin-4-yl]propyl]b~n~imidazole (100 mg, 0.2 rnrnol~ 1
20 eq3 in anhy~llous N,N-dimethylformamide (1 ml). The resulting

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WO 97/25041 PCT/US97/00511
- 305-

e was stirred for twelve hours. The re~ction was q11~n~hed by the
addition of water (10 ml). The aqueous fraction was extracted with
diethyl ether (3 x 10 ml). The organic fr~cti--n~ were combined, washed
with water (3 x 10 ml), and brine (1 x 10 ml), and then dried over sodium
5 sulfate. The solvents were removed in vacuo. The residue was subjected
to column chromatography to yield the desired title product as a white
crystalline product.
Yield: 80%
NMR and IR were consistent with the proposed title structure.
FDMS 620, 621 (M+)

~ J?le 324

Preparation of 4-[3-t2-(pyrroldin-1-ylmethyl)pyrrolidin-1-yl]propoxy]-2-
[(4-chlorophenoxy)methyl]-1-[3-[1-(t-but~J~ycalbonyl)piperidin-4-
yl]~.oL~yl3ben~imi(1~ole


N




\>~0




N
BoC

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. -306-

A solution of 4-[3-bromopropoxy]-2-[(4-
c:blorophenoxy)methyl]- 1-[3-[1-(t-buto~ycal 1,onyl)piperidin-4-
yl]propyl]ben7imi~n~0le (77 mg, 0.124 mmol, 1 eq) in anhydrous N,N-
5 dimethylformamide (2 ml) was treated with potassium carbonate (51.3mg, 0.37 mmol, 2 eq) and (S)-(+)-2-(pyrroldin-1-ylmethyl)pyrrolidine (28.7
mg, 0.19 mmol, 1.~i eq). The resulting mixture was stirred at 80~C for
six hours. The reaction was ~ nr.hed by the addition of water (10 ml).
The aqueous fraction was extracted with ethyl acetate (3 x 10 ml). The
10 organic fractions were comhined, washed with water (3 x 10 ml), brine (1
x 10 ml), and then dried over sodium sulfate. The solvents were
removed in vacuo to yield an oily crude product which was purified by
flash chromatography to provide the title product.
Yield: 78%
15 NMR and IR were consistent with the proposed title structure.
FDM~3 694 (M+)
le 3~

Preparation of (RS) 4-[3-[2-(pyrroldin-1-ylmethyl)pyrrolidin-1-
yl]propoxy]-2-[(4-chlorophenoxy)methyl]- 1-[3-(piperidin-4-
yl)propyl]ben7.irni-1~701e

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-307-


N~
o




' ~'-- '13
H




The title compound was prepared from (RS) 4-[3-~2-
(pyrroldin- 1-ylmethyI)pyrrolidin- 1-yl]propoxy]-2-~(4-
5 chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-
yl]propyl~b~n~ ole using trifluoroacetic acid deprotection as
described supra.
IR and NMR were consistent with the proposed title structure.
FDMS 594 (M+)
10 Analysis for C34Hs1Cll!~sOz:
Theory: C, 68.72; H, 8.14; N, 11.79.
Found: C, 68.91; H, 8.08; N, 11.70.

ml~le 326
Preparation of (RS) 4-[3-[2-[2-(piperidin-1-yl)ethyl]piperidin-1-
yl]propoxy3-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-
butoxycarbonyl)piperidin-4-yl~ yl]benzimidazole

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-308-


N




\~0~3~

Cl

<~

BoC

A solution of 4-[3-bromopropoxy]-2-[(4-
chlorophenoxy)methyl}-1-[3-[1-(t-buto~yca. 13onyl)piperidin-4-
yl]propyl]ben~imidazole (77 mg, 0.124 mmol, 1 eq) in anhydrous N,N-
flimethylformamide (2 ml) was treated with potassium carbonate (~1.3
mg, 0.37 mmol, 2 eq) and 2-[2-(piperidin-1-yl)ethyl]piperidine (0.19
mmol, 1.5 eq). The resulting mixture was stirred at 80~C for six hours.
The reaction was quenched by the addition of water (10 ml). The
10 aqueous fraction was extracted with ethyl acetate (3 x 10 ml). The
organic fractions were comhined, washed with water (3 x 10 ml), brine (1
x 10 ml), and then dried over sodium sulfate. The solvents were
removed in vacuo to yield an oily crude product which was purified by
flash chromatography to provide the title product.
15 NMR and IR were consistent with the proposed title structure.
FDMS 736.4 (M+)
le 327

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W O 97/25041 PCT~US97/00511
- 3~9-

Pr~l~afd~ion of(RS) 4-~3-[2-[2-(pipe}idin-1-yl)ethyl:lpiperidin-1-
yl]propoxy]-2-[(4-chlorophenoxy)methyl]-1-1:3-(piperidin-4-
yl)propyl]bçn~imidazole
~>
~N~ ~




The title compound was prepared from (RS) 4-[3-~2-[2-
(piperidin-l-yl)ethyl]piperidin-l-yl]propoxy~-2-[14-
chloropheno~y)methylJ- 1-[3-[1-(t-buto~y~al 1,onyl)piperidin-4-
yl]propyl]ben~imidazole using trifluoroacetic acid deprotection as
described supra.
NMR and IR were consistent with the proposed title structure.
FDMS 636 (M+)~~ Analysis for C37~Is4ClNsO2:
Theory: C, 69.84; H, 8.55; N, 11.01.
Found: C, 69.51; H, 8.76; N, 10.13.

~ple 328

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-310-

Preparation of 4-[3-[4-(carboxamido)piperidin-1-yl]propoxy]-2-[(4-
chlorophenoxy)methyl]-1-[3-[1-(t-buto~yc~l)onyl)piperidin-4-
yl3~1 o~yl]ben 7 i mi dazole




~ ~ N H2

N


~\>~~~




BoC

A solution of 4-[3-bromopropoxy]-2-L(4-
chloroph~no~y~methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-
yl]propyl]ben~im~dazole (77 mg, 0.124 rnrnol, 1 eq) in anhydrous N,N-
dimethylform~mi~le (2 ml) was treated with potassium carbonate (61.3
mg, 0.37 mmol, 2 eq) and 4-(carb~ mi-lo)piperidine (0.19 mmol, 1.~ eq).
The resulting ~ . e was sti~red at 80~C~ for six hours. The reaction
was quenched by the addition of water (10 ml). The aqueous fraction was
15 extracted with ethyl acetate (3 x 10 ml). The organic fractions were
combined, washed with water (3 x 10 ml), brine (1 x 10 ml), and then

CA 02242579 1998-07-08

W O 97/25041 PCT~US97/OOSll
-31~-

dried over sodium sulfate. The solvents were removed in vacuo to yield
an oily crude product which was puri~ied by flash chromatography to
provide the title product.
NMR and IR were consistent with the proposed title structure.
5 FDMS 668 (M+)

~ ?le 329

Preparation of 4-[3-[4-(carboxamido)piperidin-1-yl]propoxy]-2-[(4-
10 chlorophenoxy)methyl]-1-[3-[1-(t-butogycarbonyl)piperidin-4-
yl]l~l o~l]bçn~imifl~7:0le

~ ~ N H2

N




Y 15 The title compound was prepared from 4-[3-~4-
(carboxamido)piperidin- l-yl]propoxy]-2-[~4-chlorophenoxy)methyl]-1-[3-

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- 312-

[1-(t-buto~ycalbonyl)piperidin-4-yl]~ yl]be~7irnidazole using standard
trifluoroacetic acid deprotection techniques, as described supra.
NMR and IR were consistent with the proposed title structure.
FDMS 568 (M+)
5 Analysis for C31H43ClNsO3:
Theory: C, 65.53; H, 7.45; N, 12.33.
Found: C, 65.26; H, 7.48; N, 12.11.
m;~?le 330

Preparation of 4-[3-[4-(methyl)piperidin- 1-yl]propoxy]-2-[(4-
chlorophenoxy)methyl]- 1-[3-[ l-(t-buto~y~,al IJonyl)piperidin-4-

yl]propyl]bPn7.imidazole
CH3
~;




IN
BoC

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-313-

A solution of 4-[3-bromopropoxy}-2-t(4-
chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-
yl]~lo~yl]b~n7imidazole (77 mg, 0.124 mmol, 1 eq) in anhydrous N,N-
dimethylforrn~mil1e (2 ml) was treated with potassium carbonate (51.3
mg, 0.37 mmol, 2 eq) and 4-(methyl)piperidine (0.19 mmol, 1.5 eq). The
resulting mixture was stirred at 80~C for six hours. The re~ctioI was
ql~en~h~d by the addition of water (10 ml). The aqueous fraction was
extracted with ethyl acetate (3 x 10 ml). The organic fractions were
co~nhined, washed with water (3 x 10 ml), brine (1 x 10 ml), and then
10 dried over sodium sulfate. The solvents were removed in vacuo to yield
an oily crude product which was purified by flash chromatography to
provide the title product.
NMR and IR were consistent with the proposed title structure.
FDMS 639 (M+)
15 Analysis for C36HslClN4O4:
Theory: C, 67.64; H, 8.04; N, 8.76.
Found: C, 67.89; H, 8.0~; N, 8.84.

rr~le 331
Preparation of 4-~3-[4-(methyl)piperidin- 1-yl]propoxy]-2-~(4-
ch~orophenoxy3methyl] -1-[3-(piperidin-4-yl) ~ . o~yl]ben 7 i mi dazole

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- 314 -

CH3
N




The title compound was prepared from 4-[3-[4-
(methyl)piperidin- 1-yl]propoxy]-2-[(4-chlorophenoxy)methyl]- 1-[3-[1-(t-
5 butoxycarbonyl)piperidin-4-yl]propyl]ben7imi dazole by standard
trifluoroacetic acid deprotection as described supra.
NMR and IR were consistent with the proposed title structure.
FDMS 539 (M+)
Analysis for C3lH43ClN402:
Theory: C, 69.06; H, 8.04;N, 10.39.
Found: C, 69.15; H, 8.02; N, 10.13.

F,~mu?le 332

Preparation of (RS) 4-[3-[3-(methyl)piperidin-1-yl]propoxy]-2-[(4-
cblorophenoxy)methyl]-1-[3-[1-(t-butogycarbonyl)piperidin-4-
yl]~.o~yl]ben7.imi-1~70le

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-31~-


~CH3




BoC

A solution of 4-[3-bromopropoxy]-2-[(4-
5 chloroph~no~y)methyl]-1-~3-[1-(t-but~ycallJonyl)piperidin-4-
yl]~lo~yl]ben7.imirl~0le (77 mg, 0.124 mmol, 1 eq) in anhyd~ous N,N-
dimethylformamide (2 ml) was treated with potassium carbonate (51.3
mg, 0.37 mrllol, 2 eq) and (RS) 3-(methyl)piperidine ~O.lg mmol, 1.5 eq).
The resulting mixture was ~tirred at 80~C for six hours. The reaction
10 was qllçnl~hed by the addition of water (10 ml). The aqueous fraction was
extracted with ethyl acetate (3 X 10 Illl). The organic fr~ction~ were
comhin~d, washed with water (3 x 10 ml), brine (1 x 10 ml), and then
dried over sodium sulfate. The solvents were removed in vacuo to yield
an oily crude product which was purified by flash chromatography to
15 provide the title product.
NMR and IR were consistent with the proposed title structure.
FDMS 639 ~M+)
Analysis for C36Hs1ClN4O4:

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-316-

Theory: C, 67.64; H, 8.04; N, 8.76.
Found: C, 67.91; H, 7.9~; N, 8.82.
le 333




Preparation of (RS) 4-[3-~3-(methyl)piperidin-1-yl]propoxy]-2-[(4-
chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]ben ~imidazole

~CH3
H




The title compound was prepared from (RS) 4-[3-[3-
(methyl)piperidin-1-yl]propoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-
butoxyca~bonyl)piperidin-4-yl]propyl~ben~imidazole by standard
trifluoroacetic acid deprotection as described supra.
15 NMR and IR were consistent with the proposed title structure.
FDMS 639 (M+)
Analysis for C3lH43(~1N402:
Theory: C, 69.06; H, 8.04; N, 10.39.
Found: C, 69.29; H, 8.19; N, 10.24.

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-317-
c




~ le 334

Preparation of (RS) 4-~3-[2-(methyl)piperidin-1-yl]propoxy]-2-[(4-
5 chloroph en o~y)methyl]- 1-[3-[1-(t-butoxycarbonyl)piperidin-4-
yl]~l opyl]ben 7:i mi dazole


CH3




BoC

A solution of 4-[3-bromopropoxy]-2-[(4-
chlorop~ en o~y)methyl]- 1-[3-[1-(t-butoxycarbonyl)piperidin-4-
yl]~ yl]benzimidazole (77 mg, 0.124 mmol, 1 eq) in anhydlous N,N-
dimethylformamide (2 ml) was treated with potassium carbonate (51.3
mg, 0.37 mmol, 2 eq) and (RS) 2-(methyl)piperidine (0.1~ mmol, 1.~ eq).
15 The resulting llli~l,Ulc~ was stirred at 80~C for six hours. The reaction
was quenched by the addition of water (10 ml). The aqueous fraction was
extracted with ethyl acetate (3 x 10 ml)~ The organic fractions were
comhined, washed with water (3 x 10 ml), brine (1 x 10 ml), and then

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- 318 -

dried over sodium sulfate. The solvents were removed in vacuo to yield
an oily crude product which was purified by flash chromatography to
provide the title product.
NMR and IR were consistent with the proposed title structure.
5 FDMS 639 (M+)
Analysis for C36Hs1ClN4O4:
Theory: C, 67.64; H, 8.04; N, 8.76.
Found: C, 67.89; H, 8.05; N, 8.84.

h~ m~le 33~;

Preparation of (~S) 4-[3-[2-(methyl)piperidin-1-yl]propoxy]-2-[(4-
chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]ben7imitl~ole


N C,
CH3




N-
H
The title compound was prepared from (RS) ~-[3-[2-
(methyl)piperidin-1-yl]propoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-

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-319-

but~y.,al~onyl)piperidin-4-yl~o~yl]b~n~imif~ ole by st~nrl~rd
trifluoroacetic acid deprotection as described supra.
NMR and IR were consistent with the proposed title structure.
FDMS ~39 ~M+)
Analysis for C3lH43ClN402:
Theory: C, 69.06; H, 8.04; N, 10.39.
Found: C, 70.89;H, 8.65;N, 9.05.
rnnle 336
Preparation of 2-~4-chlorophenQ~ymethyl)-4-methyl-1-[3-[1-[3-(1,1-
diphenyl)propyl]piperidin-4-yl~propyl]ben~rnidazole trihydrochloride


~N


<~ ~\Cl

~ ~ ,n~ 3 HCl




NMR was consistent with the desired title structure. FDMS ~91 (M+).
Analysis calculated for C3gH42ClN3O ~ 3 HCl ~ 0.26 H20.
Theory: C, 64.64; H, 6.50; N, 5.9~i.
Found: C, 64.61; H, 6.36; N, 5.99.
~ ~le 337

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-320-

Prepartion of 2-(4-chloropheno~ymethyl)-4-methyl-1-[3-~1-
(ben~imitl7.ol-2-ylmethyl)piperidin-4-yl}propyl]ben~imidazole
CH3



~> Cl

HN ~> 3 ~CI


mp 218-20~.
NMR was consistent with the desired title structure. FDMS 528 (M+).
FAB exact mass calculated for C3lH3sclNso: ~
Theory: 528.2530
lo Found: 528.2541

ml?le 338

Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-[3-[1-[3-(2,4-
15 ~limethogybenzoyl)~ yl]piperidin-4-~l]propyl]b~n~imidazole

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- 321-

CH3
~~~

~~N

H3CO~OCH3

NM:E?~ was consistent with desired title structure. ESI MS 604 (M+1).
Single compound of high purity as evidenced by chromatographic
5 methods.

~ m~e 339

Preparation of 2-(4-chlorophenn~ymethyl3-4-methyl-1-[3-[1-[3-(4-
10 me~hoxybenzoyl)~l o~yl]piperidin-4-yl]~. v~yl]bçn7:im;dazole
CH3



~'
Cl

O l l
,N~

H3CO

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- 322-

NMR was consistent with desired title structure. ESI MS 574 (M~1).
Single compound of high purity as evidenced by chromatographic
methods.




le 340
Preparation of 2-(4-chloropheno~ymethyl-4-methyl-1-[3-[1-[2-(~uinazolin-




10 -yloxy)acetyl]piperidin-4-yl]~l o ~yl]be~ 7 i mi dazole


/~N
~~~

~> ~\Cl



~0~ ~


NMR was consistent with desired title structure.
15 FAB exact mass calculated for C33H3~;ClNsO3:
Theory: 584.2420
Found: 584.2428

;?le 341
Preparation of 2-(4-chlorophenoxymethyl)4-methyl-1-~3-[1-[2-~quinolin-2-
yloxy)acetyl]piperidin-4-yl]~lolJyl]ben~imidazole

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- 323 -

CH3


~,0~3~

<> Cl


~ ~o~N~/

FAB exact mass calculated for C34H36ClN403:
Theory: 583.2476
Found: ~83.2484
Single compound of high purity as evidenced by chromatograph~c
methods.

~ nu?le 342

Preparation of 2-(4-chlorophenoxymethyl~-4-methyl- 1-[3-~1-[3-(indol-3-yl)propan-1-oyl]piperidin-4-yl]~l ollyl]ben7:i mi .1~ole
,~H3



~ ~'
¢~ ~ Cl

HN~,N

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-324-

mp 153~C
NMR,Tl~. and W were consistent with the desired title structure.
FDMS 568 (M+).
Analysis calculated for C34H37ClN402:
Theory: C, 71.75; H, 6~55; N, 9.84.
Found: C, 71.56; H, 6.41; N, 9.89.

~le 343

Preparation of 2-(4-chlorophenoxymethyl )-4-methyl- 1-[3-[1-L4-~indol-3 -
yl)butan-l-oyl]piperidin-4-yl]l~l o~yl]ben7:imi-1~7.01e
CH3


~,~
~> Cl
~\~
N~J

H

mp 151~C.
NMR, I:R and W were consistent with the desired title structure.
FDMS 582 ~M+~.
Analysis calculated for C3sH3sClN402:
Theory: C, 72.09; H, 6.74; N, 9.61.
Found: C, 72.22; H, 6.69; N, 9.67.
m~ple 344

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-325-

Preparation of 2-(4-chlorophen-~ymethyl)-~methyl-1-[3-~1-[1-(2-
phenylethyl~mino)butan-4-oyl]piperidin-4-yl~ yl]ben~imidazole




~Cl


~--N~
H
mp 112~C.
NMR, IR and UV were consistent with the desired title structure.
FDMS ~87 (M+).
Single compound of high purity as evidenced by chromatographic
methods.
m~?le 34~
Preparation of 2-(4-chlorop~eno~ymethyl)-4-methyl-1-[3-[1-[1-(3-
phenylpl o~yl ~min())butan-4-oyupiperidin-4-yl}propyl]benzimidazole

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- 326-

CH3




¢ ~H'

mp 113~C.
NMR, IR and W were consistent with the desired title structure.
5 FDMS 601 (M~).
Analysis calculated for C36H45ClN4O2:
Theory: C, 71.92; H, 7.54, N, 9.32.
Found: C, 71.72; H, 7.49; N, 9.24.

~~ le 346

Preparation of 2-(4-chlorophenoxymethyl-4-methyl-1-t3-[1-[4-(1-indol-3-
yl)butyl]piperidin-4-yl]~ yl]ban~.imidazole

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- 327-



~0~ 3~

~> Cl
~\~

"N~J

N

NMR was consistent with the desired title structure. ESI MS l;69 (M~1).
Single compound of high purity as endenced by chromAto~raphic
5 methods.

F,XArn1?1e 347

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl- 1-[3-[1-r3-( 1-indol-3-
10 yl~propyl]piperidin-4-yl]propyl]ben~imi~7.01e




Cl

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- 328-

NMR was consistent with the desired title structure. ESI MS ~55 (M~1).
Single compound of high purity as evidenced by chromatographic
methods.

F,~ le 348

Preparation of 2-(4-chlorophel o~ymethyl-4-methyl-1-~3-~1-[3-(4-
iodophenyl)~- o~yl]piperidin-4-yl]~ yl]ben7.imidazole
CH3



~> Cl
I~~N~>


NMR was consistent with the desired title structure. ESI MS 642 (M+1~.
Single compound of high purity as evidenced by chromatographic
methods .
?le 349

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[2-(4-
iodophenyl)ethyl]piperidin-4-yl]propyl]b~n ~imidazole


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- 329-
.
CH3


~0~3~

<~ Cl
~




~N~

~J
I~

mp 121-122~C
NMR and IR were cons;stent with the de~ired title structure.
5 ESI MS 628 (M+1).
Analysis calculated for C31H3sClN3O:
Theory~ , 59.29; H, 5.62; N, 6.69.
Found: C, 59.22; H, ~;.62; N, 6.70.

~,~r~ml?le 3~0

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(3-
acetylpropyl)piperidin-4-yl]~ yl]ben7:imidazole

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-330-

CH3



~'
(~ Cl

~ .N~
H3C

NMR was consistent with the desired title structure. ESI MS 482 (M+1~.
Single compound of high purity as evidenced by chromatographic
5 methods.

~ rn~le 3~;1

Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-[3-[1,1-
10 dimethylpiperidin-4-ium]propyl]ben~imidazole iodide


~N


~\Cl

H3C~ I ~J

I-

mp 198-199~C.
15 NMR, IR and W were consistent with the desired title structure.

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-331-

FDMS 426 (M+ for C2sH33N30).
Analysis for C2sH33N3ClIN30 ~ 0.5 H20:
Theory: C, 53.34; H, 6.09; N, 7.49.
Found: C, ~3.19; H, 6.07; N, 7.46.




~ le 352
Preparation of 2-(4-chloroph~no~ymethyl)-4-methyl-1-[3-[1-
methylpiperidin-4-yl].~l o~yl]bçn7imidazole




~N~0 3



H3C ~

The NMR was consistent with the desired title structure.
FAB exact mass calculated for C24H3lClN30:
Theory: 41~ ~1fi6
Found: 412.2146
Single compound of high purity as evidenced by chromatographic
methods.

F~n~le 353
-




Preparation of 2-(4-chloroph~nn~ymethyl)-4-meyhyl-1-[3-[1-[4-
(phenyl)buty~]piperidin-4-yl]~rulJyl]b~n~i~nidazole

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- 332-



~~~




0~

The NMR was consistent with the desired title s~ructure. ESI MS 530
(M~1).
5 Single compound of high purity as evidenced hy chromatographic
methods.

F,~mnle 354

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[5-
(phenyl)pentyl]piperidin-4-yl]propyl]bçn~imidazole
,~<CH3



~N~-- '13,
~> Cl


N~

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-333-

The NMR was consistent with the desired title structure.
FDMS 643 (M+). ESI MS ~44 (M+1).
t Analysi~ calculated for C34H42clN3O:
Theory: C, 75.04; H, 7.78; N, 7.72.
Found: C, 74.84; H, 7.78; N, 7.89.

~.xAnn~le 354

Preparation of 2-(4-methylphenox9~nethyl)-4-benz~loxy-b~n~imidazole
Yield: 53%
NMR was consistent with the proposed title structure.
mp 1~6-1~8~C
Analysis for C22H20N2O2:
Theory: C, 76.72; H, 6.8~; N, 8.13.
Found: C, 77.00; H, 5.84; N, 8.11.

~,~A~u?le 355

Preparation of 2-(4-chlorophenoxymethyl)-4-benzyloxy-1-[3-[1-(t-
butoxycarbonyl)piperidin-4-yl]~l o~yl]b~n~imidazole
Yield: 9.0 grams
NMR was consistent with the proposed title structure.
mp 116-118~C
Analysis for C3~H40N304Cl:
Theory: C, 69.20; H, 6.83; N, 7.12.
Found: C, 69.43; H, 6.69; N, 7.17.

h ~Arnple 356

Preparation of 2-(4-chloroph~ncl~ymethyl)-7-benzyloxy-1-[3-[1-(t-
- butoxycarbonyl)piperidin-4-yl]~l o~yl]ben7imi(1A~ole
Yield: ~.27 grams
NMR was consistent with the proposed title structure.
Analysis for C34H40N3O4Cl:
Theory: C, 69.20; H, 6.83; N, 7.12.
~ound: C, 69.75; H, 7.23; N, 7.26.

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- 334-

F',~m,~le 357

r. e~ ion of 2-(4-methylphenoxymethyl)-4-benzyloxy-1-[3-[1-(t-
butoxycarbonyl)piperidin-4-yl]~l~,p~rl]ben~imidazole
Yield: 7.60 grams
NMR was consistent with the proposed title structure.
mp 116-118~C
Analysis for C35H43N304:
Theory: C, 73.78; H, 7.61; N, 7.37.
Found: C, 73.85; H, 7.72; N, 7.~0.

~r~m~le 358

15 Preparation of 2-(4-methylpheno~ymethyl)-7-benzylogy-1-[3-[1-(t-
butoxycarbonyl)piperidin-4-yl],lJlo~yl]ben~imi~ole
Yield: 4.50 grams
NMR was consistent with the proposed title structure.
mp 153-1~4.5~C
20 Analysis for C36H43N304:
Theory: C, 73.78; H, 7.61; N, 7.37.
Found: C, 73.62; H, 7.66; N, 7.34.

~mnle 359
Preparation of 2-(4-chlorophenoxymethyl~-4-benzyloxy-1-[3-(piperidin-4-
yl)propyl]ben ~im;dazole
Yield: 55%
NMR was consi~tent with the proposed title structure.
30 mp 140-141~C
Analysis for C2"H3~N302Cl:
Theory: C, 71.08; H, 6.58; N, 8.58.
Found: C, 71.20; H, 6.64; N, 8.61.

F,~z~rr~?le 360

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-336-

Preparation of 2-(4-chloropheno~ymethyl)-7-benzyloxy-1-[3-(piperidin-4-
yl)propyl]b~n7.imir~ole
Yield: 98%
NMR was consistent with the proposed title structure.
5 Analysis for C~3~302Cl:
Theory: C, 71.08; H, 6.58; N, 8.58.
Found: C, 71.00;11, 6.80; N, 8.67.

F.~ ?le 361

Preparation of 2-(4-chloropheno~ymethyl)-4-benzyloxy~ 3-[1-
(ethoxycarbonylpropyl)piperidin-4-yl31~l ol~yl]ben7imidazole
The title compound was prepared from the compound of
rnrle 360 by re~3ctin~ the compound with sodium bicarbonate and 3-
(ethoxycarbonyl)~Lo~yl bromide in N,N-dimethylformamide, essentially
as described supra.
Yield: 78%
NMR was consistent with the proposed title structure.
mp 63-65~C
AIlalysis for C35H42N3O2Cl:
Theory: C, 69.58; H, 7.01; N, 6.9~.
Found: C, 69.77; E~, 7.21; N, 6.70.

F'~nu?le 362
Preparation of 2-(4-chloropheno~ymethyl)-~benzylogy-~-[3-[1-[3-
(piperidin- l-yl)propyl]piperidin-4-yl]~l olJ~l]ben 7.i mi ~ ole
The title compound was prepared from the compound of
rnple 360 by re~ctin~ the compound with sodium bicarbonate,
sodium iodide, and 1-t3-chlo.o~o~yl)piperidine hydrochloride in N,N-
- dimethylform~m;~e, essentially as described supra.
Yield: 64%
NMR was consistent with the proposed title structure.
mp 58-60~C~
Ana~ysis for C37H47N402Cl:
Theory: C, 72.23; H, 7.70; N, 9.11.

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- 336-

Found: C, 72.08; H, 7.53; N, 8.86.

nu?le 363

Preparation of 2-(4-chlorophenl~ymethyl)-4-benzyloxy-1-[3-[1-[3-
(carboxy)~ yl]piperidin-4-yl]propyl]ben 7i mi dazole
Yield: 74%
NMR wa~ consistent with the proposed title structure.
mp 101-103~C
Analysis for C33H38N3O4Cl:
Theory: C, 68.80; H, 6.65; N, 7.29.
Found: C, 68.60; H, 6.89; N, 7.~2.

F,~mnle 364
Preparation of 2-(4-chlorophenoxymethyl)-4-benzyloxy- 1-[3-[1-[3-
(piperidin- 1-ylcarbonyl)propyl]piperidin-4-yl]~l o~yl]ben 7.imi dazole
Yield: 47%
NMR was consistent with the proposed title structure.
mp 145.5-147~C
Analysis for C38H47N4O3Cl:
Theory: C, 70.95; H, 7.37; N, 8,71.
Found: C, 70.86; H, 7.34; N,8.68.

~ le 365

Preparation of 2-(4-chlorophenoxymethyl)-4-benzyloxy-1-[3-[1-[4-
(piperidin-1-yl)butyl]piperidin-4-yl]propyl]b~n~imidazole hernihydrate
Yield: 34%
30 NMR was consistent with the proposed title structure.
mp 98-100~C
Analysis for C38H49N4O2Cl:
Theory: C, 71.49; H, 7.90; N, 8.78.
Found: C, 71.15; H, 7.73; N,8.71.~5
rnrle 366

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-337-

Preparation of 2-(4-chlorophenn~rymethyl)-4-benzyloxy-1-[3-[1-[3-
(piperidin-l-yl~lo~yl]piperidin-4-yl]~-o~l]ben~imidazole hemihydrate
Yield: 86%
NMR was consistent with the proposed title structure.
mp 108-110~C
Analysis for C37H47N4O2Cl:
Theory: C~, 72.23; H, 7.70; N, 9.11.
Found: C, 72.48; H, 7.8~; N, 9.05.
~m;~le 367

Preparation of 2-(4-chlorophenoxymethyl)-7-[3-[1-(t-
buto~yc~ bonyl)piperidin-3-yupropoxy] -1-[3-[1-[3-(piperidin- 1-
yl)~o~ piperidin-4-yl]lJ~o~yl~bçn7.imidazole hemihydrate
Yield: 86%
NMR was consistent with the proposed title structure.
mp 108-110~C
Analysis for C37H47N4OaCl:
Theory: C, 72.23; H, 7.70; N, 9.11.
Found: C, 72.48; H, 7.85; N, 9.05.

By subst~nti~lly following the procedures desc~ibed above
one skilled in the art can prepare the other compounds of Formula I.

The compounds of the present invention bind to receptors
specific for neuropeptide Y as well as the closely related neuropeptides.
[For a review of neuropeptide Y receptors, see, D. Gehlert, T.ife Sciences,
3 0 65:5~ 62 (1994); P.A. Hipskind and D.R. Gehlert, Annual Re~orts in
- Medicinal Ch~mi~try, 31:1 (1996)]. Receptors for neuropeptide Y and
peptide YY have considerable overlap while pancreatic polypeptide
- appears to have its own distinct set of receptors. Many, but not all, of the
effects of neuropeptide Y can be replicated using peptide YY.
3 5 Two subtypes of receptors for neuropeptide Y were init.i~lly
proposed on the basis of the afffnity of the 13-36 fr~FmPnt of neuropeptide

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-338-

Y using a preparation of the sympathetic nervous system. VVhile these
are the best est~hli~h~d receptors for neuropeptide Y, a substantial body
of evidence e~ists that there are additional receptor subtypes. The best
est~hl;~herl is a Y-3 receptor that is responsive to neuropeptide Y, but not
5 to peptide YY. Another recently ~l~lin~ted receptor has been described
that binds peptide YY with high ~fr~ y and neuropeptide Y with lower
~ ily. While the pharm~colQgy of the feeding response to
neuropeptide Y appears to be Y-1 in nature, a separate "feeding
receptor" has been proposed. Several of the receptors have been
10 successfully cloned to date. The following paragraphs s1lmm~rize the
available information on the known neuropeptide Y receptor subtypes
and their potqnti~l role in physiological function.

Y-l Receptor
The Y-1 receptor is the best characterized receptor for
neuropeptide Y. This receptor is generally con~itlered to be postsynaptic
and mediates many of the known actions of neuropeptide Y in the
periphery. Ori~in~lly, this receptor was described as having poor
affinity for C-terminal fr~Tnents of neuropeptide Y, such as the 13-36
20 fr~grnent, but interacts with the full length neuropeptide Y and peptide
YY with equal affinity. C. Wahlestedt, e~ al., Re~ulatory Pel~tides,
13:307-318 (1986); C. Wahlestedt, et al, NEURONAL M~ ~J~GERS IN
VASCUI,AR FUNCTION, 231-241 (Nobin, et al., eds. 1987). Substitution of
the amino acid at position 34 with a proline (Pro34) results in a protein
25 which is speci~c for the Y-1 receptor. E.K. Potter, et al., h:1~ro~ean
Jour~al of Ph~rm~rolo~y, 193:~5-19 (1991). This tool has been used to
estP.hliRh a role for the Y-l receptor in a va~ety of functions. The
receptor is thought to be coupled to adenylate cyclase in an inhibitory
m~nner in cerebral cortex, vascular smooth muscle cells, and SK-N-MC
30 cells. [For a review, see, B.J. McDermott, et al., Cardiovascular
Rese~rch. 27:893-90~ (1993~. This action is ~L~v~llted by applic~q1ion of
pertussis to~in confirming the role of a G-protein coupled receptor. The
Y-l receptor mediates the mohili~hon of intracellular calcium in a
porcine vascular smooth muscle cells and human erythroleukemia
cells.

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The cloned human Y-1 receptor can couple to either
phosphotidylinositol hydrolysis or the inhibition of adenylate cyclase,
dep~n~in~ on the type of cell in which the receptor is expressed. H.
Eerzog, ~, Procee~linFs of the National Academv of Sciences (U~
89:~i794-5798 (1992~. The Y-1 receptor has been reported to couple to
either second messenger system when studied using tissue
preparations or cell lines naturally expressing the receptor. D. Gehlert,
supra. at 653. The Y-1 receptor cannot, thelefole, be distinguished
solely on the basis of coupling to a single second messenger.
Modulation of a Y-1 receptor (either a typical or an atypical
Y-l receptor) is believed to influence multiple physiological conditions,
including, but not limited to, obesity or appetite disorder, adult onset
diabetes, blllimiA nervosa, pheochromocytoma-induced hypertension,
subarachnoid hemorrhage, neurogenic vascular hypertrophy,
hyperte~ion, anxiety, and anorexia nervosa. PCT Patent Publication
WO 96/16542, pllhli~h~ June 6, 1996, at page 135, and the ,er~- el.ces
cited therein.

~-2 Receptor
As with the Y-l receptor, this receptor subtype was first
delineated using vascular preparations. Pharmacologically, the Y-2
receptor is distinguished from Y-l by exhibiting affinity for C-terminal
fr~rnents of neuropeptide Y. The receptor is most often differentiated
by the use of neuropeptide Y(13-36), though the 3-36 fr~ment of
neuropeptide Y and peptide YY provides improved ~ll~i~y and
selectivity. Y. Dumont, ~, ~society for Ne~7roscience Abstracts, 19:726
(1993). Like Y-l receptor, this receptor is coupled to the inhibition of
adenylate cyclase, though in some preparations it may not be sensitive to
pertussis toxin. The Y-2 receptor was found to reduce the intracellular
3 o levels of calcium in the synapse by selective inhibition of N-type calcillrn
- cl~nne.l~. Like the Y-1 receptor, the Y-2 receptor may exhibit
erential coupling to second me~sengers. The Y2 receptor is believed
to be involved in morllllAting hypertension, epileptic seizure, and
neurogenic vascular hypertrophy. PCT Patent Publication WO 96/16542,
3 5 published June 6, 1996, at page 135, and the references cited therein.

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The Y-2 receptors are found in a variety of brain regions,
including the hippocampus, substantia nigra-lateralis, t~ mus,
hypot.hAlSlmus, and brainstem. In the periphery, Y-2 is found in the
peripheral nervous system, such as sympathetic, parasympathetic, and
5 sensory neurons. In all these tissues, Y-2 receptors mediate a decrease
in the release of neul~Ldllsmitters. The Y-2 receptor has been cloned
using expression cloning techniques. P.M. Rose, çt al., Jollrnal of
Riolo~ical Chemistry. 270:22661 (1995); C. G~erald, et al., Journal of
BioloFical Ch~mistry, 27():26758 (199~;); D.R. Gehlert, ~1., Molecular
Ph~rmacolo~y 49:224(1996).

Y-3Receptor
This receptor has high afflnity for neuropeptide Y while
having lower affinity for peptide YY. While neuropeptide Y is a fully
efficacious agonist at this receptor population, peptide YY is weakly
efflcacious. This pharmacological property is used to define this
receptor. A receptor that has ~imil~r pharmacology to the Y-3 receptor
has been i~len~ified in the CA3 region of the hippocampus using
electrophysiological techniques. This receptor may potentiate the
excitatory response of these neurons to N-methyl-D-aspartate (NMDA).
F.P. Monnet, et al~ uropean Journal of Pharmacolo~y, 182:2û7-208
~1990). This receptor is believed to mo~ te hypertension. PCT Patent
pllhlic~tion WO 96/16542, pllhli~hed June 6, 1996, at page 136, and the
references cited therein.
The presence of this receptor is best est~hli~he-l in the rat
brainstem, specifically in the nucleus tractus solitarius. Application of
neuropeptide Y to this region produces a dose-dep~n-l~nt reduction in
blood pressure and heart rate. This area of the brain also may have
significant contributions from the Y-1 and Y-2 receptor. Neuropeptide Y
also inhibits the acetylcholine-induced release of cate-hol~rnines from
the adrenal medulla, presumably through a Y-3 receptor. C.
Wahlestedt, ~L, T.;fe ~:ciences, 50:PL7-PL14 (1992).

Pe};~ti~e ~Y Preferrin~ Rece~tor
3 5 A fourth receptor has been described that e~hibits a modest
preference for peptide YY over neuropeptide Y. I~is receptor was first

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-341-

flesrrihed in the rat small intestine as having a 5-10 fold higher affinity
for peptide YY over neuropeptide Y. M. Laburthe, et al., Endocrinolo~v.
118:1910-1917 (1986). Subsequently, this receptor was found in the
adipocyte and a kidney ~loxi..~l tubule cell line. This receptor is
5 coupled in an inhibitory m~nner to adenylate cyclase and is sensitive to
pertussis toxin.
In the intestine, this receptor produces a potent inhibition of
~uid and electrolyte secretion. The receptor is localized to the crypt cells
where intestinal chloride secretion is believed to take place. The peptide
10 ~Y preferring receptor in adipocytes mediates a reduction in lipolysis by
way of a cyclic adenosine monophosphate (cAMP)-dependent
mechanism.

"FeeAin~ Receptorn
One of the earliest discovered central effects of neuropeptide
Y was a profound increase in food intake that was observed following the
hypothalmic ~Amini.et~ation of the peptide to rats. The response was
greatest when the peptide was infused into the perifornical region of the
hypotllAl~mus. B.G. Stanley, et al., Br~in Research.604:30~317 (1993).
VVhile the pharmacology of this response resembled the Y-1 receptor, the
2-36 fr~grnent of neuropeptide Y was significantly more potent than
neuropeptide Y. In addition, intracerebroventricular neuropeptide Y(2-
36) fully stimulates feeding, but does not reduce body temperature as
does full length neuropeptide Y. F.B. Jolicoeur, ~, P~r~in Research
Rlllle~in, 26:309-311 (1991). Two recent patent public~tion~ describe the
t~lor~in~ and expression of the Y5 receptor, believed to be the "feeding
receptor". Patent Cooperation Treaty Pl]hlic~qtion WO 96/16542,
published June 6, 1996; and Australian Patent Pl]hliç~tion AU 956467
A0, pl~hli~h~ Novem1~er 30, 1995.
- The biological activity of the compounds of the present
in~ention was evaluated employing an initial screening assay which
rapidly and accurately measured the hintlin~ of the tested compound to
known neuropeptide Y receptor sites. Assays useful for evaluating
neuropeptide Y receptor antagonists are well known in the art. See, e.~.,
United States Patents 5,284,839, issued February 8, 1994, which is herein

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- 342 -

incorporated by reference. See also. M.W. Walker, et al., Journal of
Nel7rosciences, 8:2438-2446 (1988).

Nellro~e~tide Y Bintlin~ Assay
The ability of the compounds of the instant invention were
assessed as to their ability to bind to neuropeptide Y using a protocol
essentially as described in M.W. Walker, et al.. supra. In this assay the
cell line SK-N-MC was employed. This cell line was received from
Sloane-Kettering Memorial Hospital, New York. These cells were
cultured in T-150 flasks using Dulbecco's lVrinims~l Essential Media
(DMEM) supplemented with 5% fetal calf serum. The cells were
manually removed from the flasks by scraping, pelleted, and stored at -
70~C.
The pellets were resuspended using a glass homogenizer in
2~ mM HEPES (pH 7.4) buffer COI-t~ining 2.5 mM calcium chloride, 1
mM magnesium chloride, and 2 g/L bacitracin. Incubations were
performed in a final volume of 200 ~l cont~inin~ 0.1 nM 125I-peptide YY
(2200 Ci/mmol) and 0.2-0.4 mg protein for about two hours at room
temperature.
Nonspecific hin-ling was defined as the amount of
radioactivity rçm~ining bound to the tissue after incllh~ting in the
presence of 1 ~LM neuropeptide Y. In some experiments various
concentrations of compounds were included in the incubation mixture.
Incubations were terminated by rapid filtration through
glass fiber filters which had been presoaked in 0.3% polyethylen~imine
using a 96-well harvester. The filters were washed with 5 ml of 50 mM
Tris (pH 7.4) at 4~C and rapidly dried at 60~C. The filters were then
treated with melt-on srintill~ on sheets and the radioactivity retained
on the filters were counted. The results were analyzed using various
software packages. Protein conc~nt.rations were measured using
standard col~m~sie protein assay reagents using bovine serum
al~umin as st~n~rds.

Many of the compounds prepared supra showed siFni~c~nt
3 5 activity as neuropeptide Y receptor antagonists (Ki = 10 ,u~ to 0.1 nM).
As the compounds of Formula I are effective neuropeptide Y receptor

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- 34'3 -
,s
antagonists, these compounds are of value in the tre~t.m~nt of a wide
variety of clinical conditions which are characterized by the presence of
an excess of neuropeptide Y. Thus, the invention provides methods for
the treatment or 1~ evel~tion of a physiological disorder associated with
an excess of neuropeptide Y, which method co~l~.ise6 ~mini~tering to
a m~mmAl in need of said treatment an effective amount of a compound
of Formula I or a pharmaceutically acceptable salt, solvate or prodrug
thereo~ The term "physiological disorder associated with an excess of
neuropeptide ~ encomr~ses those disorders associated with an
inappropriate stimulation of neuropeptide Y receptors, regardless of the
actual amount of neuropeptide Y present in the locale.
These physiological disorders include:
disorders or diseases pert~ining to the heart, blood vessels
or the renal system, such as vasospasm, heart failure, shock? cardiac
hypertrophy, increased blood pressure, anginA, myocardial infarction,
sudden cardiac death, congestive heart failure, arrythmia, peripheral
vascular disease, and abnormal renal conditions such as impaired flow
of fluid, abnormal mass transport, or renal failure;
conditions related to increased sympathetic nerve activity
for ~mple, during or after coronary artery ~ y, and operations
and s~ely in the gastrointestinal tract;
cerebral diseases and diseases related to the central
nervous system, such as cerebral infarction, neurodegeneration,
epilepsy, stroke, and conditions related to stroke, cerebral vasospasm
and hemorrhage, depression, anxiety, schizophrenia, dementia,
seizure, and epilepsy;
conditions related to pain or nociception;
diseases related to abnormal gastrointestinal motility and
secretion, such as different forms of ileus, urinary incontinence, and
3 0 ~rohn's disease;
abnormal drink and food intake disorders, such as obesity,
anorexia, bl~limi~, and metabolic disorders;
- diseases related to sexual d~sfunction and reproductive
disorders;
conditions or disorders associated with infl~mm~tion;

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respiratory diseases, such as asthma and conditions
related to asthma and bronchoconstriction; and
diseases related to abnormal hormone release, such as
leutini7:in~ hormone, growth hormone, insulin, and prolactin.




The compounds of Formula I are usually ~(lmini~tered in
the form of pharmaceutical compositions. These compounds can be
~rnini.~tered by a variety of routes including oral, rectal, transdermal,
subcutaneous, intravenous, intramuscular, and intr~n~l These
10 compounds are effective as both injectable and oral compositions. Such
compositions are prepared in a m~nner well known in the
pharmaceutical art and co~ ise at Ieast one act*e compound.
The present invention also includes methods e~ploying
pharmaceutical compositions which contain, as the active ingredient, a
5 compound of Formula I associated with pharmaceutically acceptable
carriers. In m~king the compositions of the present invention the active
ingredient is usually mixed with an excipient, diluted by an excipient or
enclosed within such a carrier which can be in the form of a capsule,
sachet, paper or other cont~iner. VVhen the excipient serves as a
20 diluent, it can be a solid, semi-solid, or liquid material, which acts as a
vehicle, carTier or medil~n for the active ingredient. Thus, the
compositions can be in the form of tablets, pills, powders, lozenges,
sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,
aerosols (as a solid or in a liquid medium), ointments co~t~ining for
25 ~ nple up to 10% by weight of the active compound, soft and hard
gelatin capsules, suppositories, sterile injectable solutions, and sterile
packaged powders.
In preparing a formulation, it may be necessary to mill the
active compound to provide the h~lo~l;ate particle size prior to
3 0 coTnhining with the other ingredients. If the active compound is
subs~n1;~l1y insoluble, it ordinarily is milled to a particle size of less
than 200 mesh. If the active compound is substantially water soluble,
the particle ~ize is normally adjusted by milling to provide a
substantially uniform distribution in the formulation, e.g. about 40
3 5 mesh.

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Some e~Amrles of suitable excipients include lactose,
dextrose, sucrose, sorbitol, mAnnitol, starches, gum ~c~ci~q, calcium
phosphate, alginates, tragacanth, gelatin, calcium silicate,
microcrystalline cellulose, polyvinyll~yllolidone, cellulose, water, syrup,
5 and methyl cellulose. The formulations can additionally include:
lubricating agents such as talc, mA~nesium stearate, and mineral oil;
wetting agents; emulsifying and suspen~lin~ agents; preserving agents
such as methyl- and propylhydio~{ylJ~n7:0Ates; sweetening agents; and
flavoring agents. The compositions of the invention can be form~ ted
10 so as to provide quick, sustained or delayed release of the active
ingredient after A~mini~tration to the patient by employing procedures
known in the art.
The compositions are preferably formulated in a unit
dosage form, each dosage c- ntAinin~ from about 6 to about 100 mg, more
5 usually about 10 to about 30 mg, of the active ingredient. The term "unit
dosage form" refers to physically discrete units suitable as unitary
dosages dosages for hllmAn subjects and other mAm~nAl.$~ each unit
conf~ining a predetermined quantity of active material calculated to
produce the desired therapeutic effect, in association vwith a suitable
2 o pharmaceutical excipient.
The active compound is effective over a wide dosage range.
For ~lr~mrles, dosages per day normally fall within the range of about
O.~i to about 3{~ mg/kg of body weight. In the tre~t.ment of adult hllmAnfi,
the range of about 1 to about 15 mg/kg/day, in single or divided dose, is
2 5 especially preferred. Eowever, it will be understood that the amount of
the compound actually ~mini~tered will be determined by a physician,
in the light of the relevant Cil. u-~lstances~ including the condition to be
treated, the chosen route of ~ m;ni~tration, the actual compound
f3flmini~tered, the age, weight, and response of the individual patient,
3 o and the severity of the p~tient~s symptoms, and therefore the above
dosage ranges are not in~en~1ed to limit the scope of the invention in any
way. In some instances dosage levels below the lower limit of the
aforesaid range mLay be more than adequate, while in other cases still
larger doses may be employed without r~ll~in~ any harmful side effect,
35 provided that such larger doses are first divided into several smaller
doses for ~mini~tration throughout the day.

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For preparing solid compositions such as tablets the
principal active ingredient is mixed with a phaImaceutical excipient to
form a solid preform~ t;on composition cont,~inin~ a homogeneous
mixture of a compound of the present invention. When referring to
5 these l~efo...~ tirn compositions as homogeneous, it is meant that the
active ingredient is dipser~ed evenly throughout the composition so that
the composition may be readily subdivided into equally effective unit
dosage forms such as tablets, pills and capsules. This solid
preformlll~tion is then subdivided into unit dosage forms of the type
desc~ibed above Cont~ininF from 0.1 to about 500 mg of the active
ingredient of the present invention.
The tablets or pills of the present invention may be coated or
otherwise compounded to provide a dosage form affording the advantage
of prolonged action. For e~rnple, the tablet or pill can comprise an
15 inner dosage and an outer dosage component, the latter bein~ in the
form of an envelope over the former. The two components can be
separated by enteric layer which serves to resist disintegration in the
stomach and permit the inner component to pass intact into the
duo~l~nllm or to be delayed in release. A variety of materials can be used
20 for such enteric layers or co~tin~ such materials including a number
of polymeric acids and mixtures of polymeric acids with such materials
as .shPll:~c, cetyl alcohol, and cellulose acetate.
The liquid forms in which the novel compositions of the
pre~ent invention may be inco~porated for Arlministration orally or by
25 injection include aqueous solutions, suitably flavored syrups, aqueous or
oil suspensions, and flavored emulsions with edible oils such as
cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs
and ~irnil~r pharmaceutical vehicles.
Compositions for inh~l~tion or insufflation include
30 solutions and suspensions in pharmaceutically acceptable, aqueous or
orgAnic solvents, or mixtures thereof, and powders. The liquid or solid
compositions may contain suitable pharmaceutically acceptable
e~ip;~nts as described supra. r~relably the compositions are
~lmin;.~tered by the oral or nasal respiratory route for local or systemic
35 effect. Compositions in ~lefe.ably pharmaceutically acceptable solvents
may be nebulized by use of inert gases. Nebulized solutions may be

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- 347-

breathed directly from the nebl~ti~in~ device or the neb~ in~ device
may be attached to a face mask, tent, or intermittent positive pressure
breathing m~qrh;ne. Solution, suspension, or powder compsoitions may
be ~11mini~tered, preferably orally or nasally, from devices which deliver
5 the forlm~ tion in an a~rol.l;ate m~nner

The following ex~mrles illustrate the pharmaceutical
compositions of the present invention.
-


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Formulation Pre~aration 1

Hard gelatin capsules cont~ining the following ingredients
are prepared:




Quantity
In~redient ~m~/capsule)
Active Ingredient 30 0

Starch 305.0

Magnesium stearate 5-0

The above ingredients are mixed and filled into hard gelatin
15 capsules in 340 mg quantities.

Formulation Pre~arati-.n 2

A tablet formula is prepared using ~e ingredients below:
Quantity
~n~redient (m~/tablet)
Active Ingredient 25.0

Cellulose, microcrystalline 200.0

Colloidal silicon dioxide 10.0

Stearic acid 5.0
The components are blended and compressed to form
tablets, each waighing 240 mg.

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Formulation Preparation 3

A dry powder inhaler formulation is prepared cont~ining
the following components:




Tn~redient Wai~ht ~o
Active Ingredient

Lactose 96

The active ~ ule is mixed with the lactose and the
mixture is added to a dry powder inh~l;ng appliance.

Formulation Prel~aration 4
Tablets, each cont~inin~ 30 mg of active ingredient, are
prepared as follows:

Quantity
Tn~redient ~m~/tablet)
Active Ingredient 30.0 mg

Starch 45.0 mg

Microcrystalline cellulose 35.0 mg

Polyvinylpyrrolidone
~as 10% solution in water) 4.0 mg

Sodium carbogymethyl starch 4.5 mg

M~gnesium stearate 0.5 mg

Talc 1.0 m~
Total 120 mg

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The active ingredient, starch and cellulose are passed
through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of
polyvinyl~yll~lidone is mixed with the resultant powders, which are
5 then passed through a 16 mesh U.S. sieve. The granules so produced
are dried at 50-60~C and passed through a 16 mesh U.S. sieve. The
sodium carbo~rmethyl starch, mAgneSium stearate, and talc,
previously passed through a No. 30 mesh U.S. sieve, are then added to
the granules which, after mi~ing, are compressed on a tablet m~rhine
10 to yield tablets each w~ighing 120 mg.

Forrmll~tion Preparation 5

Capsules, each cont~inin~ 40 mg of medir~mer-t. are _ade
as follows:

Quantity
Tn~redient (m~/capsule)
Active Ingredient 40.0 mg
Starch 109.0 mg

Magnesium stearate l.O m~

Total 150.0 mg

The active ingredient, cellulose, starch, and m~gnesium
~tearate are blended, passed through a No. 20 mesh U.S. sieve, and filled
into hard gelatin capsules in 150 mg quantities.


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-3~1-

Formulation Preparation 6

Suppositories, each cont~ining 25 mg of active ingredient
are made as follows:




Tn ~redient ~m 017 nt
Active Ingredient 25 mg

Saturated fatty acid glycerides to2,000 mg
The active ingredient is passed through a No. 60 mesh U.S.
sieve and suspended in the saturated fatty acid glycerides previously
melted using the minimum heat necessary. The mixture is then poured
into a suppository mold of nominal 2.0 g capacity and allowed to cool.
Formulation Preparation 7

Suspensions, each cont~ining 50 mg of medi~ment per 5.0
ml dose are :made as follows:
Tn ~redient ~m ount
Active Ingredient 50.0 mg

Xanthan gum 4.0 mg
Sodium carboxymethyl cellulose (11%)
Microcryst~lline cellulose (89%) 50.0 mg

Sucrose 1.76 g
Sodium bçn7:o~te 10.0 mg

Flavor and Color q.v.

3 5 Purified water to 6.0 ml

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-362-

The medicament, sucrose and xanthan gum are blended,
passed through a No. 10 mesh U.S. sieve, and then mixed vwith a
previously made solution of the microcrystalline cellulose and sodium
carboxymethyl cellulose in water. The sodium b~n~o~te, flavor, and
5 color are diluted with some of the water and added with stirriIlg.
Sufficient water is then added to produce the required volume.

Form~ tion Pre~aration 8

Capsules, each cont~q;ning 1~ mg of medicament, are made
as follows:

Quantity
Tn~re~lient (m~/capsule)
Active Ingredient 1~.0 mg

Starch 407.0 mg

Magnesium stearate 3.0 m
Total 425.0 mg

The active ingredient, cellulose, starch, and magnesium
steara~e are blended, passed through a No. 20 mesh U.S. sieve, and filled
25 into hard gelatin capsules in 425 mg quantities.

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Form~ tion Preparation 9

An intravenous formulation may be prepared as follows:

Tn ~redient G~uantitv
Active Ingredient 2~;0.0 mg

Isotonic saline 1000 ml
1~
Formulation PreI?aration 10

A topical for~nulation may be prepared as follows:

TnPredient Quantitv
Active Ingredient 1-10 g

Emulsifying Wax 30 g

Liquid Paraffin 20g

White Soft Paraffin to 100 g

The white soflG paraffin is heated until molten. The liquid praffin and25 emulsifying wax are incorporated and stirred until dissolved. The
active ingredient is added and stirring is continued until dispersed. The
mixture is then cooled until solid.

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Formulation Pre~aration 11

Su~lingual or buccal tablets, each c--nt~ining 10 mg of
active ingredient, may be prepared as follows:
Quantity
~n~redient Per Tablet
Active Ingredient(s) 10.0 mg

Glycerol Z10.6 mg

Water 143.0 mg

Sodium Citrate 4.5 mg
Polyvinyl Alcohol 26.5 mg

Polyvinyl~ oli-lnne 16.~ m~
Total 410.0 mg
The glycerol, water, sodium citrate, polyvinyl alcohol, and
polyvinylE~yllolidone are ~l~lmi~ed together by continuous stirring and
maint~ining the temperature at about 90~C. When the polymers have
gone into solution, the solution is cooled to about ~0-56~C and the
25 medir~m~nt is slowly ~rlmi~d. The homogenous .. i~,~e is poured
into forms made of an inert material to produce a drug-contS~inin~
diffusion matrix having a thickness of about 2-4 mm. This diffusion
matrix is then cut to form individual tablets having the a~lo~.iate size.

Another preferred forrn~ ion employed in the methods of
the present invention employs tr~n~tlermal delivery devices ("patches").
Such transdermal patches may be used to provide continuous or
discontinuous infusion of the compounds of the present invention in
cont~olled amounts. The construction and use of transdermal patches
3 5 for the delivery of pharmaceutical agents is well known in the art. See.
~.~., U.S. Patent ~,023,2~i2, issued June 11, 1991, herein incorporated by

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-355-

efe. ellce. Such patches may be constructed for continuous, pulsatile,
or on dem~n~ delivery of pharmaceutical agents.
Frequently, it will be desirable or necessary to introduce the
pharmaceutical composition to the brain, either directly or indirectly.
5 Direct techni~ues usually involve pl~cempnt of a drug delivery catheter
into the host's ventricular ~y~le~ to bypass the blood-brain bamer. One
such impl~nt.~hle delivery system, used for the transport of biological
factors to specif;c ~nz~tQrnical regions of the body, is described in U.S.
Patent ~,011,472, issued April 30, 1991, which is herein incorporated by
10 refernce.
Indirect techniques, which are generally preferred, usually
involve form~ tin~ the compositions to provide for drug l~tPnti~tion by
the conversion of hydrophilic drugs into lipid-soluble drugs or prodrugs.
T.~tenti~tion is generally achieved through blocking of the hydlo~y,
15 carbonyl, sulfate, and primary amine groups present on the drug to
render the drug more lipid soluble and amenable to transportation
across the blood-brain barrier. Alternatively, the delivery of hydrophilic
drugs may be ~nh~n~ed by intra-arterial infusion of hypertonic solutions
which can transiently open the blood-brain barrier.