U.S. patent application number 09/726276 was filed with the patent office on 2002-01-17 for benzimidzolyl neuropeptide y receptor antagonists.
Invention is credited to Britton, Thomas Charles, Bruns, Robert Frederick JR., Cantrell, Buddy Eugene, Hipskind, Philip Arthur, Howbert, James Jeffry, Lobb, Karen Lynn, Nixon, James Arthur, Nunes, Anne Marie, Ornstein, Paul Leslie, Smith, Edward C. R., Zarrinmayeh, Hamideh, Zimmerman, Dennis Michael.
Application Number | 20020007071 09/726276 |
Document ID | / |
Family ID | 10786752 |
Filed Date | 2002-01-17 |
United States Patent
Application |
20020007071 |
Kind Code |
A1 |
Britton, Thomas Charles ; et
al. |
January 17, 2002 |
Benzimidzolyl neuropeptide Y receptor antagonists
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 with comprise as an active ingredient
one or more of these compounds.
Inventors: |
Britton, Thomas Charles;
(Carmel, IN) ; Bruns, Robert Frederick JR.;
(Carmel, IN) ; Cantrell, Buddy Eugene;
(Fountaintown, IN) ; Hipskind, Philip Arthur; (New
Palestine, IN) ; Lobb, Karen Lynn; (Indianapolis,
IN) ; Nixon, James Arthur; (Indianapolis, IN)
; Ornstein, Paul Leslie; (Carmel, IN) ; Smith,
Edward C. R.; (Indianapolis, IN) ; Zarrinmayeh,
Hamideh; (Carmel, IN) ; Zimmerman, Dennis
Michael; (Zionsville, IN) ; Nunes, Anne Marie;
(Andover, MA) ; Howbert, James Jeffry; (Bellevue,
WA) |
Correspondence
Address: |
MANISHA A. DESAI
Eli Lilly and Company
Lilly Corporate Center
Patent Division DC: 1104
Indianapolis
IN
46285
US
|
Family ID: |
10786752 |
Appl. No.: |
09/726276 |
Filed: |
November 30, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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09726276 |
Nov 30, 2000 |
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08775538 |
Jan 9, 1997 |
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6255494 |
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60021636 |
Jul 12, 1996 |
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Current U.S.
Class: |
548/304.1 ;
548/310.7 |
Current CPC
Class: |
C07D 401/06 20130101;
C07D 401/14 20130101; C07D 235/12 20130101; C07D 403/12 20130101;
C07D 401/12 20130101; C07D 417/14 20130101; A61K 31/454
20130101 |
Class at
Publication: |
548/304.1 ;
548/310.7; 514/393 |
International
Class: |
C07D 235/02; A61K
031/415; A01N 043/52 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 9, 1996 |
GB |
9600344.7 |
Claims
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 442wherein: R.sup.1 is phenyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkenyl,
phenyl(C.sub.1-C.sub.6 alkylenyl)-, phenyl(C.sub.1-C.sub.6 alkoxy),
phenoxy(C.sub.1-C.sub.6 alkylenyl)-, phenyl(C.sub.1-C.sub.6
alkoxy)-(C.sub.1-C.sub.6 alkylenyl)-, naphthyl,
naphthyl(C.sub.1-C.sub.6 alkylenyl)-, naphthyl(C.sub.1-C.sub.6
alkoxy), naphthyloxy(C.sub.1-C.sub.6 alkylenyl)-, or naphthyl(Cl
-C.sub.6 alkoxy)-(C.sub.1-C.sub.6 alkylenyl)-, any one of which
phenyl, C.sub.3-C.sub.8 cycloalkyl, phenoxy, naphthyl, or
naphthyloxy moieties may be substituted with one or groups selected
from the group consisting of halo, trifluoromethyl, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6
alkylamino, heterocyclic, unsaturated heterocyclic, C.sub.3-C.sub.8
cycloalkyl, C.sub.3-C.sub.8 cycloalkenyl, phenyl, phenoxy,
phenyl(C.sub.1-C.sub.6 alkylenyl)-, phenyl(C.sub.1-C.sub.6
alkoxy)-, benzoyl, phenyl(C.sub.2-C.sub.7 alkanoyl)-, and
phenyl(C.sub.2-C.sub.7 alkanoyloxy)-; R.sup.2 is C.sub.1-C.sub.12
alkyl, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl,
C.sub.2-C.sub.7 alkanoyl, C.sub.1-C.sub.6 alkoxy,
heterocyclic(C.sub.1-C.- sub.6 alkylenyl)-, C.sub.3-C.sub.8
cycloalkyl, C.sub.3-C.sub.8 cycloalkenyl, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkylenyl)-,
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, phenyl,
phenyl(C.sub.1-C.sub.6 alkylenyl)-, naphthyl,
naphthyl(C.sub.1-C.sub.6 alkylenyl)-, phenoxy(C.sub.1-C.sub.6
alkylenyl)-, naphthyloxy(C.sub.1-C.sub.6 alkylenyl)-,
benzoyl(C.sub.1-C.sub.6 alkylenyl)-, C.sub.2-C.sub.7 alkenyl,
C.sub.2-C.sub.7 carbamoyl, C.sub.2-C.sub.7 amido, C.sub.1-C.sub.6
alkoxycarbonyl-, or C.sub.1-C.sub.6 haloalkyl, any one of which
C.sub.1-C.sub.12 alkyl, phenyl, naphthyl, phenoxy, naphthyloxy,
benzoyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkenyl,
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, heterocyclic, or unsaturated
heterocyclic moieties may be substituted with one or more groups
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, phenyl, naphthyl, phenyl(C.sub.1-C.sub.6
alkylenyl)-, naphthyl(C.sub.1-C.sub.6 alkylenyl)-, halo,
trifluoromethyl, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl,
C.sub.1-C.sub.6 alkoxy, heterocyclic, unsaturated heterocyclic,
heterocyclic(C.sub.1-C.sub.6 alkylenyl)-, unsaturated heterocyclic(
C.sub.1-C.sub.6 alkylenyl)-, heterocyclic(C.sub.1-C.sub.6 alkoxy)-,
unsaturated heterocyclic(C.sub.1-C.sub.6 alkoxy)-, C.sub.3-C.sub.8
cycloalkyl, C.sub.3-C.sub.8 cycloalkenyl, C.sub.2-C.sub.7 alkanoyl,
C.sub.2-C.sub.7 alkanoyloxy, C.sub.1-C.sub.6 alkylamino,
C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 haloalkyl, amino, nitro,
and hydroxy, or R.sup.2 may also be
--(CH.sub.2).sub.n--NR.sup.7R.sup.8, where, n is 0 to 10, and
R.sup.7 and R.sup.8 are independently hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.7 alkanoyl, C.sub.1-C.sub.6 alkoxy,
heterocyclic(C.sub.1-C.- sub.6 alkylenyl)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkylenyl)-, phenyl,
phenyl(C.sub.1-C.sub.6 alkylenyl)-, naphthyl,
naphthyl(C.sub.1-C.sub.6 alkylenyl)-, phenoxy(C.sub.1-C.sub.6
alkylenyl)-, naphthyloxy(C.sub.1-C.sub.6 alkylenyl)-,
benzoyl(C.sub.1-C.sub.6 alkylenyl)-, heterocyclic(C.sub.1-C.sub.6
alkoxy)-, unsaturated heterocyclic(C.sub.1-C.sub.6 alkoxy)-,
C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7
alkynyl, C.sub.3-C.sub.8 cycloalkenyl, or C.sub.3-C.sub.8
cycloalkyl, any one of which phenyl, naphthyl, phenoxy,
naphthyloxy, C.sub.3-C.sub.8 cycloalkyl, benzoyl, heterocyclic,
unsaturated heterocyclic, heterocyclic(C.sub.1-C.sub.6 alkoxy)-, or
unsaturated heterocyclic(C.sub.1-C.sub.6 alkoxy)- moieties may be
substituted with one or more groups selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halo,
trifluoromethyl, alkoxy, C.sub.3-C.sub.8 cycloalkyl,
C.sub.3-C.sub.8 cycloalkenyl, heterocyclic, unsaturated
heterocyclic, heterocyclic(C.sub.1-C.sub.6 alkylenyl)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkylenyl)-,
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, C.sub.2-C.sub.7 alkanoyl,
C.sub.2-C.sub.7 alkanoyloxy, C.sub.1-C.sub.6 alkylamino,
C.sub.1-C.sub.6 alkylthio, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7
alkynyl, C.sub.1-C.sub.6 haloalkyl, amino, nitro, and hydroxy; and
R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are independently hydrogen,
halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl, C.sub.2-C.sub.7
alkanoyl, C.sub.2-C.sub.7 alkanoyloxy, C.sub.1-C.sub.6 alkylamino,
C.sub.1-C.sub.6 alkylthio, benzoyl, phenoxy, phenyl(C.sub.1-C.sub.6
alkylenyl)-, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkenyl, phenyl(C.sub.1-C.sub.6 alkoxy)-,
phenyl(C.sub.1-C.sub.6 alkyleneamino)-, phenyl(C.sub.1-C.sub.6
alkyleneamino)-, phenyl(C.sub.2-C.sub.7 alkanoyl)-,
phenyl(C.sub.2-C.sub.7 alkanoyloxy)-, heterocyclic, unsaturated
heterocyclic, heterocyclic(C.sub.1-C.sub.6 alkylenyl)-,
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkylenyl)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, amino, nitro, hydroxy,
trifluoromethyl, or --(CH.sub.2).sub.n--NR.sup.7R.sup.8; or a
pharmaceutically acceptable salt or solvate thereof.
2. A compound of the formula 443wherein: R.sup.1 is phenyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkenyl,
phenyl(C.sub.1-C.sub.6 alkylenyl)-, phenyl(C.sub.1-C.sub.6 alkoxy),
phenoxy(C.sub.1-C.sub.6 alkylenyl)-, phenyl(C.sub.1-C.sub.6
alkoxy)-(C.sub.1-C.sub.6 alkylenyl)-, naphthyl,
naphthyl(C.sub.1-C.sub.6 alkylenyl)-, naphthyl(C.sub.1-C.sub.6
alkoxy), naphthyloxy(C.sub.1-C.sub.- 6 alkylenyl)-, or
naphthyl(C.sub.1-C.sub.6 alkoxy)-(C.sub.1-C.sub.6 alkylenyl)-, any
one of which phenyl, C.sub.3-C.sub.8 cycloalkyl, phenoxy, naphthyl,
or naphthyloxy moieties may be substituted with one or groups
selected from the group consisting of halo, trifluoromethyl,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7
alkynyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio,
C.sub.1-C.sub.6 alkylamino, heterocyclic, unsaturated heterocyclic,
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkenyl, phenyl,
phenoxy, phenyl(C.sub.1-C.sub.6 alkylenyl)-, phenyl(C.sub.1-C.sub.6
alkoxy)-, benzoyl, phenyl(C.sub.2-C.sub.7 alkanoyl)-, and
phenyl(C.sub.2-C.sub.7 alkanoyloxy)-; R.sup.2 is C.sub.1-C.sub.12
alkyl, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl,
C.sub.2-C.sub.7 alkanoyl, C.sub.1-C.sub.6 alkoxy,
heterocyclic(C.sub.1-C.sub.6 alkylenyl)-, C.sub.3-C.sub.8
cycloalkyl, C.sub.3-C.sub.8 cycloalkenyl, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkylenyl)-,
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, phenyl,
phenyl(C.sub.1-C.sub.6 alkylenyl)-, naphthyl,
naphthyl(C.sub.1-C.sub.6 alkylenyl)-, phenoxy(C.sub.1-C.sub.6
alkylenyl)-, naphthyloxy(C.sub.1-C.s- ub.6 alkylenyl)-,
benzoyl(C.sub.1-C.sub.6 alkylenyl)-, C.sub.2-C.sub.7 alkenyl,
C.sub.2-C.sub.7 carbamoyl, C.sub.2-C.sub.7 amido, C.sub.1-C.sub.6
alkoxycarbonyl-, or C.sub.1-C.sub.6 haloalkyl, any one of which
C.sub.1-C.sub.12 alkyl, phenyl, naphthyl, phenoxy, naphthyloxy,
benzoyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkenyl,
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, heterocyclic, or unsaturated
heterocyclic moieties may be substituted with one or more groups
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, phenyl, naphthyl, phenyl(C.sub.1-C.sub.6
alkylenyl)-, naphthyl(C.sub.1-C.sub.6 alkylenyl)-, halo,
trifluoromethyl, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl,
C.sub.1-C.sub.6 alkoxy, heterocyclic, unsaturated heterocyclic,
heterocyclic(C.sub.1-C.sub.6 alkylenyl)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkylenyl)-,
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, C.sub.3-C.sub.8 cycloalkyl,
C.sub.3-C.sub.8 cycloalkenyl, C.sub.2-C.sub.7 alkanoyl,
C.sub.2-C.sub.7 alkanoyloxy, C.sub.1-C.sub.6 alkylamino,
C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 haloalkyl, amino, nitro,
and hydroxy, or R.sup.2 may also be
--(CH.sub.2).sub.n--NR.sup.7R.sup.8, where, n is 0 to 10, and
R.sup.7 and R.sup.8 are independently hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.7 alkanoyl, C.sub.1-C.sub.6 alkoxy,
heterocyclic(C.sub.1-C.- sub.6 alkylenyl)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkylenyl)-, phenyl,
phenyl(C.sub.1-C.sub.6 alkylenyl)-, naphthyl,
naphthyl(C.sub.1-C.sub.6 alkylenyl)-, phenoxy(C.sub.1-C.sub.6
alkylenyl)-, naphthyloxy(C.sub.1-C.sub.6 alkylenyl)-,
benzoyl(C.sub.1-C.sub.6 alkylenyl)-, heterocyclic(C.sub.1-C.sub.6
alkoxy)-, unsaturated heterocyclic(C.sub.1-C.sub.6 alkoxy)-,
C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7
alkynyl, C.sub.3-C.sub.8 cycloalkenyl, or C.sub.3-C.sub.8
cycloalkyl, any one of which phenyl, naphthyl, phenoxy,
naphthyloxy, C.sub.3-C.sub.8 cycloalkyl, benzoyl, heterocyclic,
unsaturated heterocyclic, heterocyclic(C.sub.1-C.sub.6 alkoxy)-, or
unsaturated heterocyclic(C.sub.1-C.sub.6 alkoxy)- moieties may be
substituted with one or more groups selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halo,
trifluoromethyl, alkoxy, C.sub.3-C.sub.8 cycloalkyl,
C.sub.3-C.sub.8 cycloalkenyl, heterocyclic, unsaturated
heterocyclic, heterocyclic(C.sub.1-C.sub.6 alkylenyl)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkylenyl)-,
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, C.sub.2-C.sub.7 alkanoyl,
C.sub.2-C.sub.7 alkanoyloxy, C.sub.1-C.sub.6 alkylamino,
C.sub.1-C.sub.6 alkylthio, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7
alkynyl, C.sub.1-C.sub.6 haloalkyl, amino, nitro, and hydroxy; and
R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are independently hydrogen,
halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl, C.sub.2-C.sub.7
alkanoyl, C.sub.2-C.sub.7 alkanoyloxy, C.sub.1-C.sub.6 alkylamino,
C.sub.1-C.sub.6 alkylthio, benzoyl, phenoxy, phenyl(C.sub.1-C.sub.6
alkylenyl)-, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkenyl, phenyl(C.sub.1-C.sub.6 alkoxy)-,
phenyl(C.sub.1-C.sub.6 alkyleneamino)-, phenyl(C.sub.1-C.sub.6
alkyleneamino)-, phenyl(C.sub.2-C.sub.7 alkanoyl)-,
phenyl(C.sub.2-C.sub.7 alkanoyloxy)-, heterocyclic, unsaturated
heterocyclic, heterocyclic(C.sub.1-C.sub.6 alkylenyl)-,
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkylenyl)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, amino, nitro, hydroxy,
trifluoromethyl, or --(CH.sub.2).sub.n--NR.sup.7R.sup.8; or a salt
or solvate thereof
3. A pharmaceutical formulation comprising a compound of the
formula 444wherein: R.sup.1 is phenyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.3-C.sub.8 cycloalkenyl, phenyl(C.sub.1-C.sub.6 alkylenyl)-,
phenyl(C.sub.1-C.sub.6 alkoxy), phenoxy(C.sub.1-C.sub.6
alkylenyl)-, phenyl(C.sub.1-C.sub.6 alkoxy)-(C.sub.1-C.sub.6
alkylenyl)-, naphthyl, naphthyl(C.sub.1-C.sub.6 alkylenyl)-,
naphthyl(C.sub.1-C.sub.6 alkoxy), naphthyloxy(C.sub.1-C.sub.6
alkylenyl)-, or naphthyl(C.sub.1-C.sub.6 alkoxy)-(C.sub.1-C.sub.6
alkylenyl)-, any one of which phenyl, C.sub.3-C.sub.8 cycloalkyl,
phenoxy, naphthyl, or naphthyloxy moieties may be substituted with
one or groups selected from the group consisting of halo,
trifluoromethyl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.7 alkenyl,
C.sub.2-C.sub.7 alkynyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkylthio, C.sub.1-C.sub.6 alkylamino, heterocyclic, unsaturated
heterocyclic, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkenyl, phenyl, phenoxy, phenyl(C.sub.1-C.sub.6 alkylenyl)-,
phenyl(C.sub.1-C.sub.6 alkoxy)-, benzoyl, phenyl(C.sub.2-C.sub.7
alkanoyl)-, and phenyl(C.sub.2-C.sub.7 alkanoyloxy)-; R.sup.2 is
C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7
alkynyl, C.sub.2-C.sub.7 alkanoyl, C.sub.1-C.sub.6 alkoxy,
heterocyclic(C.sub.1-C.- sub.6 alkylenyl)-, C.sub.3-C.sub.8
cycloalkyl, C.sub.3-C.sub.8 cycloalkenyl, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkylenyl)-,
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, phenyl,
phenyl(C.sub.1-C.sub.6 alkylenyl)-, naphthyl,
naphthyl(C.sub.1-C.sub.6 alkylenyl)-, phenoxy(C.sub.1-C.sub.6
alkylenyl)-, naphthyloxy(C.sub.1-C.sub.6 alkylenyl)-,
benzoyl(C.sub.1-C.sub.6 alkylenyl)-, C.sub.2-C.sub.7 alkenyl,
C.sub.2-C.sub.7 carbamoyl, C.sub.2-C.sub.7 amido, C.sub.1-C.sub.6
alkoxycarbonyl-, or C.sub.1-C.sub.6 haloalkyl, any one of which
C.sub.1-C.sub.12 alkyl, phenyl, naphthyl, phenoxy, naphthyloxy,
benzoyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkenyl,
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, heterocyclic, or unsaturated
heterocyclic moieties may be substituted with one or more groups
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, phenyl, naphthyl, phenyl(C.sub.1-C.sub.6
alkylenyl)-, naphthyl(C.sub.1-C.sub.6 alkylenyl)-, halo,
trifluoromethyl, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl,
C.sub.1-C.sub.6 alkoxy, heterocyclic, unsaturated heterocyclic,
heterocyclic(C.sub.1-C.sub.6 alkylenyl)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkylenyl)-,
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, C.sub.3-C.sub.8 cycloalkyl,
C.sub.3-C.sub.8 cycloalkenyl, C.sub.2-C.sub.7 alkanoyl,
C.sub.2-C.sub.7 alkanoyloxy, C.sub.1-C.sub.6 alkylamino,
C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 haloalkyl, amino, nitro,
and hydroxy, or R.sup.2 may also be
--(CH.sub.2).sub.n--NR.sup.7R.sup.8, where, n is 0 to 10, and
R.sup.7 and R.sup.8 are independently hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.7 alkanoyl, C.sub.1-C.sub.6 alkoxy,
heterocyclic(C.sub.1-C.- sub.6 alkylenyl)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkylenyl)-, phenyl,
phenyl(C.sub.1-C.sub.6 alkylenyl)-, naphthyl,
naphthyl(C.sub.1-C.sub.6 alkylenyl)-, phenoxy(C.sub.1-C.sub.6
alkylenyl)-, naphthyloxy(C.sub.1-C.sub.6 alkylenyl)-,
benzoyl(C.sub.1-C.sub.6 alkylenyl)-, heterocyclic(C.sub.1-C.sub.6
alkoxy)-, unsaturated heterocyclic(C.sub.1-C.sub.6 alkoxy)-,
C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7
alkynyl, C.sub.3-C.sub.8 cycloalkenyl, or C.sub.3-C.sub.8
cycloalkyl, any one of which phenyl, naphthyl, phenoxy,
naphthyloxy, C.sub.3-C.sub.8 cycloalkyl, benzoyl, heterocyclic,
unsaturated heterocyclic, heterocyclic(C.sub.1-C.sub.6 alkoxy)-, or
unsaturated heterocyclic(C.sub.1-C.sub.6 alkoxy)- moieties may be
substituted with one or more groups selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halo,
trifluoromethyl, alkoxy, C.sub.3-C.sub.8 cycloalkyl,
C.sub.3-C.sub.8 cycloalkenyl, heterocyclic, unsaturated
heterocyclic, heterocyclic(C.sub.1-C.sub.6 alkylenyl)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkylenyl)-,
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, C.sub.2-C.sub.7 alkanoyl,
C.sub.2-C.sub.7 alkanoyloxy, C.sub.1-C.sub.6 alkylamino,
C.sub.1-C.sub.6 alkylthio, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7
alkynyl, C.sub.1-C.sub.6 haloalkyl, amino, nitro, and hydroxy; and
R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are independently hydrogen,
halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl, C.sub.2-C.sub.7
alkanoyl, C.sub.2-C.sub.7 alkanoyloxy, C.sub.1-C.sub.6 alkylamino,
C.sub.1-C.sub.6 alkylthio, benzoyl, phenoxy, phenyl(C.sub.1-C.sub.6
alkylenyl)-, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkenyl, phenyl(C.sub.1-C.sub.6 alkoxy)-,
phenyl(C.sub.1-C.sub.6 alkyleneamino)-, phenyl(C.sub.1-C.sub.6
alkyleneamino)-, phenyl(C.sub.2-C.sub.7 alkanoyl)-,
phenyl(C.sub.2-C.sub.7 alkanoyloxy)-, heterocyclic, unsaturated
heterocyclic, heterocyclic(C.sub.1-C.sub.6 alkylenyl)-,
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkylenyl)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, amino, nitro, hydroxy,
trifluoromethyl, or --(CH.sub.2).sub.n--NR.sup.7R.sup.8; or a
pharmaceutically acceptable salt or solvate thereof, in combination
with one or more pharmaceutically acceptable carriers, excipients,
or diluents therefore.
Description
PRIORITY CLAIM
[0001] This application claims the benefit of U.S. Provisional
Application 60/021,636, filed Jul. 12, 1996 and United Kingdom
Patent Application 9600344.7, filed Jan. 9, 1996.
BACKGROUND OF THE INVENTION
[0002] Neuropeptide Y is a peptide present in the central and
peripheral nervous systems. The peptide coexists with noradrenaline
in many neurons and acts as a neurotransmitter per se or
synergistically together with noradrenaline. Neuropeptide
Y-containing fibers are numerous around arteries in the heart, but
are also found around the arteries in the respiratory tract, the
gastrointestinal tract, and the genitourinary tract. Neuropeptide Y
is also present in the cerebrum with effects on blood pressure,
feeding, and the release of different hormones. Alterations in
central concentrations of neuropeptide Y have been implicated in
the etiology of psychiatric disorders.
[0003] Neuropeptide Y was discovered, isolated and sequenced 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.
[0004] Neuropeptide Y is a member of the pancreatic family of
peptides and shares significant sequence homology with pancreatic
polypeptide and peptide YY.
[0005] 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 amphiphilic .alpha.-helix,
connected with a .beta.-turn, creating a hairpin-like loop, which
is sometimes referred to as the pancreatic polypeptide (PP) fold.
The helices are kept together by hydrophobic interactions. The
amidated C-terminal end projects away from the hairpin loop.
[0006] Subsequent to its discovery neuropeptide Y was identified as
being the most abundant peptide in the central nervous system with
widespread distribution including the cortex, brainstem,
hippocampus, hypotahlamus, amygdala, and thalamus as well as being
present in the peripheral nervous system in sympathetic neurons and
adrenal chromaffin cells.
[0007] Neuropeptide Y seems to fulfill the main criteria for a role
as a neurotransmitter, as it is stored in synaptic granules, is
released upon electrical nerve stimulation, 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
temperature, and catalepsy.
[0008] Neuropeptide Y (as well as its chemical relatives) acts upon
membrane receptors that are dependent on guanyl-nucleotide binding
proteins, known as G protein-coupled receptors. G proteins are a
family of membrane proteins that become activated only after
binding guanosine triphosphate. Activated G proteins in turn
activate an amplifier enzyme on the inner face of a membrane; the
enzyme then converts precursor molecules into second
messengers.
[0009] Neuropeptide Y appears to interact with a family of closely
related receptors. These receptors are generally classified into
several subtypes based upon the ability of different tissues and
receptors to bind different fragments of neuropeptide Y and other
members of the PP family of peptides. The Y1 receptor subtype
appears to be the major vascular neuropeptide Y receptor. The Y2
receptor subtypes can also occur postjunctionally on vascular
smooth muscle. The as-yet-unisolated Y3 receptor subtype appears to
be neuropeptide Y-specific, not binding peptide YY. This receptor
is likely to be present in the adrenal tissues, medulla, heart, and
brain stem, among other areas. [For a review of neuropeptide Y and
neuropeptide Y receptors, see. e.g., C. Wahlestedt and D. Reis,
Annual Review of Pharmacology and Toxicology, 33:309-352 (1993); D.
Gehlert and P. Hipskind, Current Pharmaceutical Design, 1:295304
(1995)].
[0010] In view of the wide number of clinical maladies associated
with an excess of neuropeptide Y, the development of neuropeptide Y
receptor antagonists will serve to control these clinical
conditions. The earliest such receptor antagonists, such as Patent
Cooperation Treaty Patent Publication WO 91/08223, published Jun.
13, 1991, and Patent Cooperation Treaty Patent Publication WO
94/00486, published Jan. 6, 1994, were peptide derivatives. These
antagonists are of limited pharmaceutical utility because of their
metabolic instability.
[0011] This invention provides a class of potent non-peptide
neuropeptide Y receptor antagonists. By virtue of their non-peptide
nature, the compounds of the present invention do not suffer from
the shortcomings, in terms of metabolic instability, of known
peptide-based neuropeptide Y receptor antagonists.
SUMMARY OF THE INVENTION
[0012] This invention encompasses methods for the treatment or
prevention of 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 Formula
I 1
[0013] wherein:
[0014] R.sup.1 is phenyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.3-C.sub.8 cycloalkenyl, phenyl(C.sub.1-C.sub.6 alkylenyl),
phenyl(C.sub.1-C.sub.6 alkoxy), phenoxy(C.sub.1-C.sub.6
alkylenyl)-, phenyl(C.sub.1-C.sub.6-alko-
xy)-(C.sub.1-C.sub.6-alkylenyl)-, naphthyl,
naphthyl(C.sub.1-C.sub.6 alkylenyl)-, naphthyl(C.sub.1-C.sub.6
alkoxy), naphthyloxy(C.sub.1-C.sub.- 6 alkylenyl)-, or
naphthyl(C.sub.1-C.sub.6 alkoxy)-(C.sub.1-C.sub.6 alkylenyl)-,
[0015] any one of which phenyl, C.sub.3-C.sub.8 cycloalkyl,
phenoxy, naphthyl, or naphthyloxy moieties may be substituted with
one or groups selected from the group consisting of halo,
trifluoromethyl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.7 alkenyl,
C.sub.2-C.sub.7 alkynyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkylthio, C.sub.1-C.sub.6 alkylamino, heterocyclic, unsaturated
heterocyclic, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkenyl, phenyl, phenoxy, phenyl(C.sub.1-C.sub.6 alkylenyl)-,
phenyl(C.sub.1-C.sub.6 alkoxy)-, benzoyl, phenyl(C.sub.2-C.sub.7
alkanoyl)-, and phenyl(C.sub.2-C.sub.7 alkanoyloxy)-;
[0016] R.sup.2 is C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.7 alkenyl,
C.sub.2-C.sub.7 alkynyl, C.sub.2-C.sub.7 alkanoyl, C.sub.1-C.sub.6
alkoxy, heterocyclic(C.sub.1-C.sub.6 alkylenyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.3-C.sub.8 cycloalkenyl, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkylenyl)-,
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, phenyl,
phenyl(C.sub.1-C.sub.6 alkylenyl)-, naphthyl,
naphthyl(C.sub.1-C.sub.6 alkylenyl)-, phenoxy(C.sub.1-C.sub.6
alkylenyl)-, naphthyloxy(C.sub.1-C.s- ub.6 alkylenyl)-,
benzoyl(C.sub.1-C.sub.6 alkylenyl)-, C.sub.2-C.sub.7 alkenyl,
C.sub.2-C.sub.7 carbamoyl, C.sub.2-C.sub.7 amido, C.sub.1-C.sub.6
alkoxycarbonyl-, or C.sub.1-C.sub.6 haloalkyl,
[0017] any one of which C.sub.1-C.sub.12 alkyl, phenyl, naphthyl,
phenoxy, naphthyloxy, benzoyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.3-C.sub.8 cycloalkenyl, heterocyclic(C.sub.1-C.sub.6
alkoxy)-, unsaturated heterocyclic(C.sub.1-C.sub.6 alkoxy)-,
heterocyclic, or unsaturated heterocyclic moieties may be
substituted with one or more groups selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
phenyl, naphthyl, phenyl(C.sub.1-C.sub.6 alkylenyl)-,
naphthyl(C.sub.1-C.sub.6 alkylenyl)-, halo, trifluoromethyl,
C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl, C.sub.1-C.sub.6
alkoxy, heterocyclic, unsaturated heterocyclic,
heterocyclic(C.sub.1-C.sub.6 alkylenyl)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkylenyl)-,
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, C.sub.3-C.sub.8 cycloalkyl,
C.sub.3-C.sub.8 cycloalkenyl, C.sub.2C.sub.7 alkanoyl,
C.sub.2C.sub.7 alkanoyloxy, C.sub.1-C.sub.6 alkylamino,
C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 haloalkyl, amino, nitro,
and hydroxy,
[0018] or R.sup.2 may also be --(CH.sub.2).sub.n--NR.sup.7R.sup.8,
where,
[0019] n is 0 to 10, and
[0020] R.sup.7 and R.sup.8 are independently hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.7 alkanoyl, C.sub.1-C.sub.6
alkoxy, heterocyclic(C.sub.1-C.sub.6 alkylenyl)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkylenyl), phenyl,
phenyl(C.sub.1-C.sub.6 alkylenyl)-, naphthyl,
naphthyl(C.sub.1-C.sub.6 alkylenyl)-, phenoxy(C.sub.1-C.sub.6
alkylenyl)-, naphthyloxy(C.sub.1-C.sub.6 alkylenyl)-,
benzoyl(C.sub.1-C.sub.6 alkylenyl)-, heterocyclic(C.sub.1-C.- sub.6
alkoxy)-, unsaturated heterocyclic(C.sub.1-C.sub.6 alkoxy)-,
C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7
alkynyl, C.sub.3-C.sub.8 cycloalkenyl, or C.sub.3-C.sub.8
cycloalkyl,
[0021] any one of which phenyl, naphthyl, phenoxy, naphthyloxy,
C.sub.3-C.sub.8 cycloalkyl, benzoyl, heterocyclic, unsaturated
heterocyclic, heterocyclic(C.sub.1-C.sub.6 alkoxy)-, or unsaturated
heterocyclic(C.sub.1-C.sub.6 alkoxy)- moieties may be substituted
with one or more groups selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halo,
trifluoromethyl, alkoxy, C.sub.3-C.sub.8 cycloalkyl,
C.sub.3-C.sub.8 cycloalkenyl, heterocyclic, unsaturated
heterocyclic, heterocyclic(C.sub.1-C.sub.6 alkylenyl)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkylenyl)-,
heterocyclic(C.sub.1-C.sub.6 alkoxy), unsaturated
heterocyclic(C.sub.1-C.- sub.6 alkoxy)-, C.sub.2-C.sub.7 alkanoyl,
C.sub.2-C.sub.7 alkanoyloxy, C.sub.1-C.sub.6 alkylamino,
C.sub.1-C.sub.6 alkylthio, C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7
alkynyl, C.sub.1-C.sub.6 haloalkyl, amino, nitro, and hydroxy;
[0022] and
[0023] R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are independently
hydrogen, halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.2-C.sub.7 alkenyl, C.sub.2-C.sub.7 alkynyl, C.sub.2-C.sub.7
alkanoyl, C.sub.2-C.sub.7 alkanoyloxy, C.sub.1-C.sub.6 alkylamino,
C.sub.1-C.sub.6 alkylthio, benzoyl, phenoxy, phenyl(C.sub.1-C.sub.6
alkylenyl)-, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkenyl, phenyl(C.sub.1-C.sub.6 alkoxy)-,
phenyl(C.sub.1-C.sub.6 alkyleneamino)-, phenyl(C.sub.1-C.sub.6
alkyleneamino)-, phenyl(C.sub.2-C.sub.7 alkanoyl)-,
phenyl(C.sub.2-C.sub.7 alkanoyloxy)-, heterocyclic, unsaturated
heterocyclic, heterocyclic(C.sub.1-C.sub.6 alkylenyl)-,
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkylenyl)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, amino, nitro, hydroxy,
trifluoromethyl, --O--(CH.sub.2).sub.n--NR.sup.7R.sup.8, or
CH.sub.2).sub.n--NR.sup.7R.sup.8;
[0024] or a pharmaceutically acceptable salt or solvate thereof
[0025] This invention also encompasses, in additional embodiments,
the novel compounds of Formula I, and the salts and solvates
thereof, as well as pharmaceutical formulations comprising a
compound of Formula I, or a pharmaceutically acceptable salt or
solvate thereof, in combination with one or more pharmaceutically
acceptable carriers, excipients, or diluents therefor.
DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS
[0026] The current invention concerns the discovery that a select
group of substituted benzimidazoles, those of Formula I, are useful
as neuropeptide Y receptor antagonists.
[0027] The terms and abbreviations used in the instant examples
have their normal meanings unless otherwise designated. For example
".degree.C." refers to degrees Celsius; "N" refers to normal or
normality; "mmol" refers to millimole or millimoles; "g" refers to
gram or grams; "ml" means milliliter or milliliters; "M" refers to
molar or molarity; "MS" refers to mass spectrometry; "IR" refers to
infrared spectroscopy; and "NMR" refers to nuclear magnetic
resonance spectroscopy.
[0028] As used herein, the term "C.sub.1-C.sub.12 alkyl" refers to
straight or branched, monovalent, saturated aliphatic chains of 1
to 12 carbon atoms and includes, but is not limited to, methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl,
isopentyl, and hexyl. The term "C.sub.1-C.sub.12 alkyl includes
within its definition the terms "C.sub.1-C.sub.6 alkyl" and
"C.sub.1-C.sub.4 alkyl".
[0029] "C.sub.2-C.sub.7 alkanoyloxy" represents a straight or
branched alkyl chain having from one to six carbon atoms attached
to a carbonyl moiety joined through an oxygen atom. Typical
C.sub.2-C.sub.7 alkanoyloxy groups include acetoxy, propanoyloxy,
isopropanoyloxy, butanoyloxy, t-butanoyloxy, pentanoyloxy,
hexanoyloxy, 3-methylpentanoyloxy and the like.
[0030] "C.sub.3-C.sub.8 cycloalkyl" represents a saturated
hydrocarbon ring structure containing from three to eight carbon
atoms. Typical C.sub.3-C.sub.8 cycloalkyl groups include
cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the
like.
[0031] The term "carbamoyl" as employed herein refers to a group of
the structure --NH--C(O). The term "C.sub.2-C.sub.7 carbamoyl" as
employed herein refers to a group of the structure (C.sub.1-C.sub.6
alkyl)--NH--C(O)--
[0032] "Halo" represents chloro, fluoro, bromo or iodo.
[0033] The term "C.sub.1-C.sub.6 haloalkyl" refers to a straight or
branched, monovalent, saturated aliphatic chains of 1 to 6 carbon
atoms substituted with one or more halo groups.
[0034] "C.sub.1-C.sub.10 alkylthio" represents a straight or
branched alkyl chain having from one to ten carbon atoms attached
to a sulfur atom. Typical C.sub.1-C.sub.10 alkylthio groups include
methylthio, ethylthio, propylthio, isopropylthio, butylthio and the
like. The term "C.sub.1-C.sub.10 alkylthio" includes within its
definition the term "C.sub.1-C.sub.6 alkylthio" and
"C.sub.1-C.sub.3 alkylthio".
[0035] "C.sub.1-C.sub.12 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, isopropylenyl, butylenyl, isobutylenyl, t-butylenyl,
pentylenyl, isopentylenyl, hexylenyl, octylenyl, 3-methyloctylenyl,
decylenyl. The term "C.sub.1-C.sub.6 alkylenyl" is encompassed
within the term "C.sub.1-C.sub.12 alkylenyl".
[0036] C.sub.1-C.sub.10 alkylamino" represents a group of the
formula
--NH(C.sub.1-C.sub.10 alkyl)
[0037] wherein a chain having from one to ten carbon atoms is
attached to an amino group. Typical C.sub.1-C.sub.4 alkylamino
groups include methylamino, ethylamino, propylamino,
isopropylamino, butylamino, sec-butylamino and the like.
[0038] The term "C.sub.2-C.sub.10 alkenyl" as used herein
represents a straight or branched, monovalent, unsaturated
aliphatic chain having from two to ten carbon atoms. Typical
C.sub.2-C.sub.10 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.
[0039] The term "C.sub.2-C.sub.10 alkynyl" as used herein
represents a straight or branched, monovalent, unsaturated
aliphatic chain having from two to ten carbon atoms with at least
one triple bond. Typical C.sub.2-C.sub.10 alkynyl groups include
ethynyl, 1-methylethenyl, 1-propynyl, 1-butynyl, 1-hexynyl,
2-propynyl, 2-butynyl, 2-pentynyl, and the like.
[0040] "C.sub.3-C.sub.8 cycloalkenyl" represents a hydrocarbon ring
structure containing 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 independently selected from
halo, halo(C.sub.1-C.sub.4 alkyl), C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, carboxy, C.sub.1-C.sub.4 alkoxycarbonyl,
carbamoyl, N-(C.sub.1-C.sub.4 alkyl)carbamoyl, amino,
C.sub.1-C.sub.4 alkylamino, di(C.sub.1-C.sub.4 alkyl)amino or
--(CH.sub.2).sub.a--R.sup.y where a is 1, 2, 3 or 4 and R.sup.y is
hydroxy, C.sub.1-C.sub.4 alkoxy, carboxy, C.sub.1-C.sub.4
alkoxycarbonyl, amino, carbamoyl, C.sub.1-C.sub.4 alkylamino or
di(C.sub.1-C.sub.4 alkyl)amino.
[0041] "C.sub.1-C.sub.6 alkylamino" represents a straight or
branched alkylamino chain having from one to six carbon atoms
attached to an amino group. Typical C.sub.1-C.sub.6 alkyl-amino
groups include methylamino, ethylamino, propylamino,
isopropylamino, butylamino, sec-butylamino and the like.
"C.sub.1-C.sub.6 alkylamino" encompasses within this term
"C.sub.1-C.sub.4 alkylamino".
[0042] "C.sub.1-C.sub.6 alkoxy" represents a straight or branched
alkyl chain having from one to six carbon atoms attached to an
oxygen atom. Typical C.sub.1-C.sub.6 alkoxy groups include methoxy,
ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the
like. The term "C.sub.1-C.sub.6 alkoxy" includes within its
definition the term "C.sub.1-C.sub.3 alkoxy".
[0043] "C.sub.2-C.sub.7 alkanoyl" represents a straight or branched
alkyl chain having from one to six carbon atoms attached to a
carbonyl moiety. Typical C.sub.2-C.sub.7 alkanoyl groups include
ethanoyl, propanoyl, isopropanoyl, butanoyl, t-butanoyl, pentanoyl,
hexanoyl, 3-methylpentanoyl and the like.
[0044] "C.sub.1-C.sub.6 alkoxycarbonyl" represents a straight or
branched alkoxy chain having from one to six carbon atoms attached
to a carbonyl moiety. Typical C.sub.1-C.sub.6 alkoxycarbonyl groups
include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl and the
like.
[0045] "C.sub.3-C.sub.8 cycloalkyl" represents a saturated
hydrocarbon ring structure containing from three to eight carbon
atoms. Typical C.sub.3-C.sub.8 cycloalkyl groups include
cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the
like.
[0046] In those substitutions employing naphthyl, naphthyloxy,
naphthoyl, or the like groups, the naphthyl moiety may be attached
at the one, two, or three position.
[0047] The term "heterocycle" represents an unsubstituted or
substituted stable 5- to 7-membered monocyclic or 7- to 10-membered
bicyclic heterocyclic ring which is saturated and which consists of
carbon atoms and from one to three heteroatoms selected from the
group consisting of nitrogen, oxygen or sulfur, and wherein the
nitrogen and sulfur heteroatoms may optionally be oxidized, and the
nitrogen heteroatom may optionally be quaternized and including a
bicyclic group in which any of the above-defined heterocyclic rings
is fused to a benzene ring. The heterocyclic ring may be attached
at any heteroatom or carbon atom which affords a stable structure.
The hetero-cycle is unsubstituted or substituted with 1, 2 or 3
substituents independently selected from halo,
halo(C.sub.1-C.sub.4)-alkyl, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, carboxy, C.sub.1-C.sub.4 alkoxycarbonyl, carbamoyl,
N-(C.sub.1-C.sub.4)alkylcarbamoyl, amino, C.sub.1-C.sub.4
alkylamino, di(C.sub.1-C.sub.4)alkylamino or
-(CH.sub.2).sub.a--R.sup.d where a is 1, 2, 3 or 4; and R.sup.d is
hydroxy, C.sub.1-C.sub.4 alkoxy, carboxy, C.sub.1-C.sub.4
alkoxycarbonyl, amino, carbamoyl, C.sub.1-C.sub.4 alkylamino or
di(C.sub.1-C.sub.4)alkylamino.
[0048] The term "unsaturated heterocycle" represents an
unsubstituted or substituted stable 5- 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 heteroatoms selected from the group consisting of nitrogen,
oxygen or sulfur, and wherein the nitrogen and sulfur heteroatoms
may optionally 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 benzene
ring. The Unsaturated heterocyclic ring may be attached at any
heteroatom or carbon atom which affords a stable structure. The
unsaturated heterocycle is unsubstituted or substituted with 1, 2
or 3 substituents independently selected from halo, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, carboxy,
C.sub.1-C.sub.4 alkoxycarbonyl, carbamoyl,
N--(C.sub.1-C.sub.4)alkylcarbamoyl, amino, C.sub.1-C.sub.4
alkylamino, di(C.sub.1-C.sub.4)alkylamino or
--(CH.sub.2).sub.a--R.sup.e where a is 1, 2, 3 or 4; and R.sup.e is
hydroxy, C.sub.1-C.sub.4 alkoxy, carboxy, C.sub.1-C.sub.4
alkoxycarbonyl, amino, carbamoyl, C.sub.1-C.sub.4 alkylamino or
di(C.sub.1-C.sub.4)alkylamino.
[0049] Examples of such heterocycles and unsaturated heterocycles
include piperidinyl, piperazinyl, azepinyl, pyrrolyl,
4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl,
imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl,
morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl,
isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl,
benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl,
benzoazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl,
benzothienyl, thiamorpholinyl, thiamorpholinyl-sulfoxide,
thiamorpholinylsulfone, oxadiazolyl, triazolyl,
tetrahydroquinolinyl, tetrahydrisoquinolinyl, 4,5-dihydrothiazolyl,
3-methylimidazolyl, 3-methoxypyridyl, 4-chloroquinolinyl,
4-aminothiazolyl, 8-methylquinolinyl, 6-chloroquinoxalinyl,
3-ethylpyridyl, 6-methoxybenzimidazolyl, 4-hydroxyfuryl,
4-methylisoquinolinyl, 6,8-dibromoquinolinyl,
4,8-dimethyl-naphthyl, 2-methyl-1,2,3,4-tetrahydro- isoquinolinyl,
N-methyl-quinolin-2-yl, 2-t-butoxycarbonyl-1,2,3,4-isoquino-
lin-7-yl and the like.
[0050] The term "amino-protecting group" as used in the
specification refers to substituents of the amino group commonly
employed to block or protect the amino functionality while reacting
other functional groups on the compound. Examples of such
amino-protecting groups include formyl, trityl, phthalimido,
trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, and
urethane-type blocking groups such as benzyloxycarbonyl,
4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl,
4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl,
4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl,
2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl,
4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl,
4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl,
t-butoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl,
1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl,
2-(p-toluyl)-prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl,
1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl,
1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl,
2-(4-toluylsulfonyl)-ethoxycarbonyl,
2-(methylsulfonyl)ethoxycarbonyl,
2-(triphenylphosphino)-ethoxycarbonyl, fluorenylmethoxy-carbonyl
("FMOC"), 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,
1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,
5-benzisoxalylmethoxycarbonyl, 4-acetozybenzyloxycarbonyl,
2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,
cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl,
isobornyloxycarbonyl, 1-piperidyloxycarbonyl and the like;
benzoylmethylsulfonyl group, 2-nitrophenylsulfenyl,
diphenylphosphine oxide and like amino-protecting groups. The
species of amino-protecting group employed is usually not critical
so long as the derivatized amino group is stable to the condition
of subsequent reactions on other positions of the intermediate
molecule and can be selectively removed at the appropriate point
without disrupting the remainder of the molecule including any
other amino-protecting groups. Preferred amino-protecting groups
are trityl, t-butoxycarbonyl (BoC), allyloxycarbonyl and
benzyloxycarbonyl. Further examples of groups referred to by the
above terms are described by E. Haslam, "Protective Groups in
Organic Chemistry", (J. G. W. McOmie, ed., 1973), at Chapter 2; and
T. W. Greene and P. G. M. Wuts, PROTECTIVE GROUPS IN ORGANIC
SYNTHESIS, (1991), at Chapter 7.
[0051] The term "carboxy-protecting group" as used in the
specification refers to substituents of the carboxy group commonly
employed to block or protect the carboxy functionality while
reacting other functional groups on the compound. Examples of such
carboxy-protecting groups include methyl, p-nitrobenzyl,
p-methylbenzyl, p-methoxy-benzyl, 3,4-dimethoxybenzyl,
2,4-dimethoxybenzyl, 2,4,6-triethoxybenzyl, 2,4,6-trimethylbenzyl,
pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl,
4,4'-dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl,
t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl,
4,4',4"-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl,
t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl,
2-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl,
4-nitrobenzylsulfonylethyl, allyl, cinnamyl,
1-(trimethylsilylmethyl)prop- -1-en-3-yl and like moieties.
Preferred carboxy-protecting groups are allyl, benzyl and t-butyl,
Further examples of these groups are found in E. Haslam, supra at
Chapter 5, and T. W. Greene, et al., supra at Chapter 5.
[0052] The term "hydroxy-protecting groups" as used herein refers
to substituents of the hydroxy group commonly employed to block or
protect the hydroxy functionality while reacting other functional
groups on the compound. Examples of such hydroxy-protecting groups
include methoxymethyl, benzyloxymethyl, methoxyethoxymethyl,
2-(trimethylsilyl)ethoxymethyl, methylthiomethyl,
2,2-dichloro-1,1-difluo- roethyl, tetrahydropyranyl, phenacyl,
cyclopropylmethyl, allyl, C.sub.1-C.sub.6 alkyl,
2,6-dimethylbenzyl, o-nitrobenzyl, 4-picolyl, dimethylsilyl,
t-butyldimethylsilyl, levulinate, pivaloate, benzoate,
dimethylsulfonate, dimethylphosphinyl, isobutyrate, adamantoate and
tetrahydropyranyl. Further examples of these groups may be found in
T. W. Greene and P. G. M. Wuts, PROTECTIVE GROUPS IN ORGANIC
SYNTHESIS, (1991) at Chapter 3.
[0053] The compounds of the present invention may have one or more
asymmetric centers. As a consequence of these chiral centers, those
compounds of the present invention occur as racemates, mixtures of
enantiomers and as individual enantiomers, as well as diastereomers
and mixtures of diastereomers. All asymmetric forms, individual
isomers and combinations thereof, are within the scope of the
present invention.
[0054] The terms "R" and "S" are used herein as commonly used in
organic chemistry to denote specific configuration of a chiral
center. The term "R" (rectus) refers to that configuration of a
chiral center with a clockwise relationship of group priorities
(highest to second lowest) when viewed along the bond toward the
lowest priority group. The term "S" (sinister) refers to that
configuration of a chiral center with a counterclockwise
relationship of group priorities (highest to second lowest) when
viewed along the bond toward the lowest priority group. The
priority of groups is based upon their atomic number (in order of
decreasing atomic number). A partial list of priorities and a
discussion of stereochemistry is contained in NOMENCLATURE OF
ORGANIC COMPOUNDS: PRINCIPLES AND PRACTICE, (J. H. Fletcher, et
al., eds., 1974) at pages 103-120.
[0055] In addition to the (R)-(S) system, the older D-L system may
also be used in this document to denote absolute configuration,
especially with reference to amino acids. In this system a Fischer
projection formula is oriented so that the number 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 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.
[0056] 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 mixture of
enantiomers and then separate the two enantiomers. A commonly
employed method for the resolution of the racemic mixture (or
mixture of enantiomers) into the individual enantiomers is to first
convert the enantiomers to diastereomers by way of forming a salt
with an optically active salt or base. These diastereomers can then
be separated using differential solubility, fractional
crystallization, chromatography, or like methods. Further details
regarding resolution of enantiomeric mixtures can be found in J.
Jacques, et al., ENANTIOMERS, RACEMATES, AND RESOLUTIONS,
(1991).
[0057] In addition to the schemes described above, the practitioner
of this invention may also choose an enantiospecific protocol for
the preparation of the compounds of Formula I. Such a protocol
employs a synthetic reaction design which maintains the chiral
center present in the starting material in a desired orientation.
These reaction schemes usually produce compounds in which greater
than 95 percent of the title product is the desired enantiomer.
[0058] As noted supra 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 accordingly
react with any of a number of organic and inorganic bases, and
inorganic and organic acids, to form a pharmaceutically acceptable
salt.
[0059] The term "pharmaceutically acceptable salt" as used herein,
refers to salts of the compounds of the above formula which are
substantially non-toxic to living organisms. Typical
pharmaceutically acceptable salts include those salts prepared by
reaction of the compounds of the present invention with a
pharmaceutically acceptable mineral or organic acid or an organic
or inorganic base. Such salts are known as acid addition and base
addition salts.
[0060] Acids commonly employed to form acid addition salts are
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.
Examples of such pharmaceutically acceptable salts are the sulfate,
pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,
monohydrogenphosphate, dihydrogenphosphate, metaphosphate,
pyrophosphate, chloride, bromide, iodide, acetate, propionate,
decanoate, caprylate, acrylate, formate, hydrochloride,
dihydrochloride, isobutyrate, caproate, heptanoate, propiolate,
oxalate, malonate, succinate, suberate, sebacate, fumarate,
maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate,
chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate,
phthalate, sulfonate, xylenesulfonate, phenylacetate,
phenylpropionate, phenylbutyrate, citrate, lactate,
.gamma.-hydroxybutyrate, glycolate, tartrate, methanesulfonate,
propanesulfonate, naphthalene-1-sulfonate,
napththalene-2-sulfonate, mandelate and the like. Preferred
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.
[0061] Base addition salts include those derived from inorganic
bases, such as ammonium or alkali or alkaline earth metal
hydroxides, carbonates, bicarbonates, and the like. Such bases
useful in preparing the salts of this invention thus include sodium
hydroxide, potassium hydroxide, ammonium hydroxide, potassium
carbonate, sodium carbonate, sodium bicarbonate, potassium
bicarbonate, calcium hydroxide, calcium carbonate, and the like.
The potassium and sodium salt forms are particularly preferred.
[0062] It should be recognized that the particular counterion
forming a part of any salt of this invention is usually not of a
critical nature, so long as the salt as a whole is
pharmacologically acceptable and as long as the counterion does not
contribute undesired qualities to the salt as a whole.
[0063] This invention further encompasses 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, methanol, ethanol and acetonitrile to form
pharmaceutically acceptable solvates such as the corresponding
hydrate, methanolate, ethanolate and acetonitrilate.
[0064] This invention also encompasses the pharmaceutically
acceptable prodrugs of the compounds of Formula I. A prodrug is a
drug which has been chemically modified and may be biologically
inactive at its site of action, but which may be degraded or
modified by one or more enzymatic or other in vivo processes to the
parent bioactive form. This prodrug should have a different
pharmacokinetic profile than the parent, enabling easier absorption
across the mucosal epithelium, better salt formation or solubility,
or improved systemic stability (an increase in plasma half-life,
for example).
[0065] Typically, such chemical modifications include:
[0066] 1) ester or amide derivatives which may be cleaved by
esterases or lipases;
[0067] 2) peptides which may be recognized by specific or
nonspecific proteases; or
[0068] 3) derivatives that accumulate at a site of action through
membrane selection of a prodrug form or a modified prodrug
form;
[0069] or any combination of 1 to 3, Joan. Conventional procedures
for the selection and preparation of suitable prodrug derivatives
are described, for example, in H, Bundgaard, DESIGN OF PRODRUGS,
(1985).
[0070] The compounds of the present invention are derivatives of
benzimidazole which are named and numbered according to the RING
INDEX, The American Chemical Society, as follows. 2
[0071] The preferred methods of this invention employ those
compounds of Formula I wherein:
[0072] a) R.sup.1 is phenyl, naphthyl, phenyl(C.sub.1-C.sub.6
alkylenyl)-, naphthyl(C.sub.1-C.sub.6 alkylenyl)-,
phenyl(C.sub.1-C.sub.6 alkoxy)-, naphthyl(C.sub.1-C.sub.6 alkoxy)-,
phenoxy(C.sub.1-C.sub.6 alkylenyl)-, naphthyloxy(C.sub.1-C.sub.6
alkylenyl), or substituted derivatives thereof;
[0073] b) R.sup.2 is phenyl, heterocyclic, unsaturated
heterocyclic, phenyl(C.sub.1-C.sub.6 alkylenyl)-,
naphthyl(C.sub.1-C.sub.6 alkylenyl)-, phenyl(C.sub.1-C.sub.6
alkoxy), heterocyclic(C.sub.1-C.sub.6 alkylenyl)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkylenyl)-,
heterocyclic(C.sub.1-C.sub.6 alkoxy)-, unsaturated
heterocyclic(C.sub.1-C.sub.6 alkoxy)-,
--(CH.sub.2).sub.n--NR.sup.7R.sup.- 8, or substituted derivatives
thereof;
[0074] c) R.sup.3, R.sup.4, R.sup.5, and R.sub.6, are independently
hydrogen, chloro, fluoro, bromo, C.sub.1-C.sub.6 alkyl,
trifluoromethyl, C.sub.1-C.sub.6 alkoxy, benzoyl, C.sub.2-C.sub.7
alkanoyl, phenyl(C.sub.1-C.sub.6 alkylenyl)-,
phenyl(C.sub.1-C.sub.6 alkoxy)-, or
--(CH.sub.2).sub.n--NR.sup.7R.sup.8, or substituted derivatives
thereof; and
[0075] d) at least one of R.sup.3, R.sup.4, R.sup.5, and R.sup.6 is
not hydrogen.
[0076] The preferred compounds of this invention are those
compounds which are employed in the preferred methods of this
invention.
[0077] In the scientific literature derivatives of benzimidazole
are already known to possess different biological activities, such
as analgesic and antiinflammatory activity (Japan Kokai 75,126,682;
U.S. Pat. No. 4,925,853), gastric antisecretory activity (European
Patent Publication 246,126), antihistamic activity (U.S. Pat. Nos.
4,200,641 and 5,182,280), dopaminergic and andrenergic activity
(U.S. Pat. No. 4,925,854), bronchodilatory activity, growth
promotion (U.S. Pat. No. 4,960,783), tachykinin receptor antagonist
(U.S. patent application Ser. No. 08/235,401, filed Apr. 29, 1994),
and inhibitor of P-amyloid peptide production (U.S. patent
application Ser. No. 08/235,400, filed Apr. 29, 1994).
[0078] The compounds of Formula I can be prepared by processes
known in the literature. See, e.g., G. W. H. Cheeseman and R. F.
Cookson, THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS, (A. Weissberger,
et al., eds. 1979).
Synthesis of the Benzimidazole Nucleus
[0079] 3
Synthesis of the N-1 Substituted Benzimidazoles
[0080] 4
[0081] Another means of preparing the compounds of Formula I is by
cyclization of an appropriately substituted o-phenylenediamine such
as the one depicted in Formula II 5
[0082] in a solvent or solvent mixture. It is generally preferred
that the solvent or solvent mixture be heated, preferably to the
boiling point of the solvent. Suitable solvents include ethanol,
isopropanol, glacial acetic acid, benzene, toluene, chlorobenzene,
glycol, ethylene glycol, dimethyl ether, diethyl ether,
dimethylformamide, chloroform, ethyl acetate, and the like. It is
generally preferred to add a condensation agent such as phosphorous
oxychloride, thionyl chloride, p-toluenesulfonic acid, hydrochloric
acid, sulfuric acid, phosphoric acid, polyphosphoric acid,
phosphorous pentoxide, methanesulfonyl hydroxide, methanesulfonyl
chloride, and the like. The cyclization reaction may also
optionally be performed in the presence of a base such as sodium
hydroxide, sodium mesylate, or potassium tert-butylate.
[0083] In those compounds in which R.sup.2 is phenyl a derivative
of N-phenyl-o-phenylenediamine was used as the starting material
for the cyclization reaction. The examples infra provide sufficient
guidance in the preparation of those compounds of Formula I wherein
all of R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are hydrogen.
[0084] Those compounds of Formula I wherein at least one of
R.sup.3, R.sup.4, R.sup.5, and R.sup.6 is not hydrogen, can be
prepared by methods taught in the literature. For example, the
compounds of this invention wherein phenyl portion of the
benzimidazole is substituted with C.sub.2-C.sub.7 alkanoyl can be
prepared from the appropriate keto o-phenylenediamine of the
formula 6
[0085] by methods known in the benzimidazole art such as the
procedures described in U.S. Pat. No. 4,401,817, issued Aug. 30,
1983, the entire contents 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 appropriate hydrocarbon or a halobenzene with an
appropriate acid chloride followed by aromatic nitration.
[0086] Alternatively, the keto benzimidazole reactants can be
prepared from acetanilide by a Friedel-Crafts acylation with the
appropriate derivative of C.sub.2-C.sub.7 alkanoic acid. The
resulting 4-keto acetanilide is nitrated to give a 2-nitro
-ketoacetanilide. The acetanilide is hydrolyzed to give a
2-nitro-4-ketoaniline, which can then be catalytically hydrogenated
to yield a 4-keto-o-phenylenediamine which can then be ring closed
to provide the 5 or 6-substituted benzimidazole.
[0087] Those compounds of Formula III wherein phenyl portion of the
benzimidazole is substituted with alkyl or alkylenyl may be
prepared by means of a Friedel-Crafts alkylation with the
appropriate derivative of the substituting moiety using standard
procedures, usually employing an alkyl halide or an olefin in the
presence of a catalyst such as aluminum chloride, aluminum bromide
or another Lewis acid.
[0088] An alternative strategy for preparing those compounds of
Formula I wherein R.sup.5 is C.sub.1-C.sub.6 alkoxy,
R.sup.7R.sup.8N--(C.sub.1-C.su- b.6 alkoxy), or
heterocyclic-(C.sub.1-C.sub.6 alkoxy)-, or a substituted derivative
thereof, involves first reacting a 3-nitroaminophenol with an acyl
halide in the presence of a base 7
[0089] to get substitution of the primary amine as well as
substitution of the hydroxy group, the ester moiety serving as a
hydroxy-protecting group for subsequent reactions. In the next step
of this synthesis the nitro group is then reduced to an amino
group, usually by catalytic hydrogenation. 8
[0090] The primary amine of the above compound is then substituted,
usually using an aldehyde, such as benzaldehyde or a substituted
derivative thereof, followed by hydrogenation, if necessary. In an
alternative embodiment, those compounds of Formula I in which
R.sup.2 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 trialkylamine, potassium
carbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and the like.
9
[0091] Cyclization of this substituted phenylenediamine is then
performed as described supra, followed by cleavage of the ester
group protecting the hydroxy group at the 6-position of the
benzimidazole. Suitable cyclization catalysts include phosphorous
oxychloride, thionyl chloride, phosphorous pentoxide, phosphorous
pentachloride, and other like strong dehydrating agents. 10
[0092] A preferred method of cleaving this ester is by incubation
of the intermediate in a basic solution, such as IN 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. 11
[0093] The skilled artisan understands that compounds of Formula I
substituted at the 5-position of the benzimidazole can be prepared
as described above by employing 3-amino4-nitrophenol as the
starting material instead of the 3-nitro-4-aminophenol shown
supra.
[0094] Those compounds of Formula I wherein R.sup.2 is alkyl or
substituted alkyl may alternatively be prepared by the direct
alkylation of a benzimidazole wherein the nitrogen at the
1-position is substituted with a hydrogen. This type of alkylation
is usually performed by the reaction of the benzimidazole with 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-dimethylformamide, dimethyl sulfoxide,
dimethylacetamide, hexamethylphosphoric triamide, and the like.
[0095] The following Examples further illustrate the compounds of
the present invention and the methods for their synthesis. The
Examples are not intended to be limiting to the scope of the
invention in any respect, and should not be so construed. All
experiments were run under a positive pressure of dry nitrogen or
argon. All solvents and reagents were purchased from commercial
sources and used as received, unless otherwise indicated. Dry
tetrahydrofuran (THF) was obtained by distillation from sodium or
sodium benzophenone ketyl prior to use.
[0096] Proton nuclear magnetic resonance (.sup.1H NMR) spectra were
obtained on a GE QE-300 spectrometer at 300.15 MHz, a Bruker AM-500
spectrometer at 500 MHz, or a Bruker AC-200P spectrometer at 200
MHz. (Unless designated otherwise, the term "NMR" as employed
herein refers to proton nuclear magnetic resonance.) Free atom
bombardment mass spectroscopy (FAB) was performed on a VG ZAB-2SE
instrument. Field desorption mass spectroscopy (FDMS) was performed
using either a VG 70SE or a Varian MAT 731 instrument.
[0097] 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
indicated in the text unless otherwise specified.
[0098] The reactions were generally monitored for completion using
thin layer chromatography (TLC). Thin layer chromatography was
performed using E. Merck Kieselgel 60 F.sub.254 plates, 5
cm.times.10 cm, 0.25 mm thickness. Spots were detected using a
combination of UV and chemical detection (plates dipped in a ceric
ammonium molybdate solution [75 g of ammonium molybdate and 4 g of
cerium (IV) sulfate in 500 ml of 10% aqueous sulfuric acid] and
then heated on a hot plate). Preparative centrifugal thin layer
chromatography was performed on a Harrison Model 7924A Chromatotron
using Analtech silica gel GF rotors.
[0099] Cation exchange chromatography was performed with Dowex.RTM.
50XB-100 ion exchange resin Anion exchange chromatography was
performed with Bio-Rad AG.RTM. 1-X8 anion-exchange resin (acetate
form converted to hydroxide form). Flash chromatography was
performed as described by Still, et al., Journal of Organic
Chemistry, 43:2923 (1978).
[0100] Optical rotations are reported at the sodium-D-line (354
nm). Elemental analyses for carbon, hydrogen, and nitrogen were
determined on a Control Equipment Corporation 440 Elemental
Analyzer. Melting points were determined in open glass capillaries
on a Thomas Hoover capillary melting point apparatus or a Buchi
melting point apparatus, and are uncorrected.
GENERAL PROCEDURE FOR BENZIMIDAZOLE SYNTHESIS
[0101] 12
[0102] To a 0.4M solution of the optionally substituted
1,2-diaminobenzene in methanol, anhydrous hydrogen chloride gas was
bubbled until saturation. The solution was permitted to cool to
room temperature. The precipitate was collected, dried and then
used in the next step.
[0103] A solution of 4-chlorophenoxynitrile (1.05 eq) in dry
methanol (0.3M) was treated with sodium methoxide (1.05 eq). The
mixture was stirred at room temperature. The mixture was treated
with the dihydrochloride salt of the diamine (1.0 eq) and stirred
at room temperature for about one hour. In most of the cases the
precipitate was observed upon addition. The crude crystals were
washed with diethyl ether and dried in vacuo.
[0104] Whne diaminotoluene was treated with 4-chlorophenoxynitrile
there was no precipitate observed immediately. The reaction mixture
was condensed under vacuum. The crude brownish solid was dissolved
in ethyl acetate. The resulting solution 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.
Preparation 1
[0105] Preparation of 2-benzylbenzimidazole 13
[0106] A 1M solution of benzyl cyanide in anhydrous methanol was
treated with hydrogen chloride gas at 0.degree. C. for about thirty
minutes. The mixture was stirred for two hours at 0.degree. C. and
then a 1M solution of diaminobenzene was added and the resulting
solution was stirred at 0.degree. C. The progress of the reaction
was monitored by thin layer chromatography. The reaction mixture
was then poured into water. The unreacted nitrile was extracted
with ethyl acetate. The aqueous layer was neutralized with 1N
sodium hydroxide. The organic fraction was extracted with ethyl
acetate and condensed. The desired title product was recrystallized
from methanol/water.
Preparation 2
[0107] Preparation of 2-(4-chlorophenyl)benzimidazole 14
[0108] The title compound was prepared essentially as described in
Preparation 1 except that an equimolar amount of
4-chlorobenzonitrile was employed instead of the benzyl cyanide
employed therein.
Preparation 3
[0109] Preparation of 2-(4-chlorobenzyl)benzimidazole 15
[0110] The title compound was prepared essentially as described in
Preparation 1 except that an equimolar amount of 4-chlorobenzyl
cyanide was employed instead of the benzyl cyanide employed
therein.
Preparation 4
[0111] Preparation of 2-(benzyloxymethyl)-7-hydroxybenzimidazole
16
[0112] A mixture of the 2,3-diaminophenol (5 g, 40.3 mmol, 1 eq)
and benzyloxyacetic acid (5.6 g, 48.3 mmol, 1.2 eq) in 40 ml of a
10% aqueous solution of sodium bicarbonate was stirred and refluxed
at 140.degree. C. for one hour. The mixture was allowed to cool
down to room temperature. Ethyl acetate was poured into the
mixture. The organic fraction was extracted with ethyl acetate,
washed with water, and then dried over sodium 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.
[0113] The following intermediates were prepared essentially as
described above.
Preparation 5
[0114] Preparation of
6-methyl-2-(4-chlorophenoxymethyl)benzimidazole 17
[0115] IR and NMR were consistent with the desired title product.
FDMS 272 (M+).
Preparation 6
[0116] Preparation of 2-(4-chlorophenoxymethyl)benzimidazole 18
[0117] IR and NMR were consistent with the desired title product.
FDMS 258 (M+).
Preparation 7
[0118] Preparation of
2-(4-chlorophenoxymethyl)-7-nitrobenzimidazole 19
[0119] IR and NMR were consistent with the desired title product.
FDMS 303 (M+).
Preparation 8
[0120] Preparation of
2-(4-chlorophenoxymethyl)-6-methoxybenzimidazole 20
[0121] IR and NMR were consistent with the desired title product.
FDMS 288 (M+).
Preparation 9
[0122] Preparation of
2-(4-chlorophenoxymethyl)-6,7-dimethylbenzimidazole 21
[0123] NMR was consistent with the desired title product.
Preparation 10
[0124] Preparation of
2-(4-chlorophenoxymethyl)-7-methylbenzimidazole 22
[0125] NMR was consistent with the desired title product.
Preparation 11
[0126] Preparation of
2-(4-chlorophenoxymethyl)-6-methoxycarbonylbenzimida- zole 23
[0127] 1.9 grams (57% yield).
Preparation 12
[0128] Preparation of
2-(4-chlorophenoxymethyl)-7-hydroxybenzimidazole 24
[0129] NMR was consistent with the desired title product. Yield 5.3
grams (91%).
Preparation 13
[0130] Preparation of 2-benzylbenzimidazole 25
[0131] NMR was consistent with the desired title product. Yield
1.26 grams (14%).
Preparation 14
[0132] Preparation of 2-(3-chlorophenoxymethyl)benzimidazole 26
[0133] NMR was consistent with the desired title product. Yield 1.5
grams (>99%).
Preparation 15
[0134] Preparation of 2-(2-chlorophenoxymethyl)benzimidazole 27
[0135] NMR was consistent with the desired title product. Yield
1.36 grams (91%).
Preparation 16
[0136] Preparation of 2-(4-chlorophenyl)benzimidazole 28
Preparation 17
[0137] Preparation of 2-(4-chlorobenzyl)benzimidazole 29
[0138] NMR was consistent with the desired title product.
Preparation 18
[0139] Preparation of 2-(phenoxymethyl)benzimidazole 30
[0140] NMR was consistent with the desired title product. Yield
1.06 grams (65%).
Preparation 19
[0141] Preparation of 2-(3,5-dichlorophenoxymethyl)benzimidazole
31
[0142] IR and NMR were consistent with the desired title product.
Yield 0.28 grams (>99%). FDMS 292 (M+).
[0143] Analysis for C.sub.14H.sub.10Cl.sub.2N.sub.2O:
[0144] Theory: C, 57.36; H, 3.44; N, 9.56.
[0145] Found: C, 57.45; H, 3.48; N, 9.41.
Preparation 20
[0146] Preparation of
2-(3,5-dichorophenoxymethyl)-7-methylbenzimidazole 32
[0147] IR and NMR were consistent with the desired title product.
Yield 0.448 grams (75%). FDMS 306 (M+).
[0148] Analysis for C.sub.15H.sub.12Cl.sub.2N.sub.2O:
[0149] Theory: C, 58.65; H, 3.94; N, 9.12.
[0150] Found: C, 58.45; H, 3.95; N, 9.18.
Preparation 21
[0151] Preparation of
2-(3,5-dichlorophenoxymethyl)-7-hydroxybenzimidazole 33
[0152] IR and NMR were consistent with the desired title product.
Yield 0.46 grams (78%). FDMS 308 (M+).
[0153] Analysis for C.sub.14H.sub.10Cl.sub.2N.sub.2O.sub.2:
[0154] Theory: C, 54.39; H, 3.26; N, 9.06.
[0155] Found: C, 54.26; H, 3.22; N, 8.99.
Preparation 22
[0156] Preparation of
2-[4-(thiazol-2-yl)phenoxymethyl]-benzimidazole 34
[0157] NMR was consistent with the desired title product. Yield 2.7
grams (>99%).
Preparation 23
[0158] Preparation of
2-[3-chlorophenoxymethyl]-7-methylbenzimidazole 35
[0159] NMR was consistent with the desired title product.
Preparation 24
[0160] Preparation of
2-[3-chlorophenoxymethyl]-7-hydroxybenzimidazole 36
[0161] NMR was consistent with the desired title product. Yield 1.5
grams (>99%).
Preparation 25
[0162] Preparation of 2-[1,6-dichlorophenoxymethyl]benzimidazole
37
[0163] IR and NMR were consistent with the desired title product.
Yield 0.27 grams (>99%). FDMS 292 (M+).
[0164] Analysis for C.sub.14H.sub.10Cl.sub.2N.sub.2O:
[0165] Theory: C, 57.36; H, 3.44; N, 9.50.
[0166] Found: C, 57.50; H, 3.43; N, 9.54.
Preparation 26
[0167] Preparation of
2-[1,6-dichlorophenoxymethyl]-7-methylbenzimidazole 38
[0168] IR and NMR were consistent with the desired title product
Yield 0.5 grams (94%). FDMS 306 (M+).
[0169] Analysis for C.sub.15H.sub.12Cl.sub.2N.sub.2O:
[0170] Theory: C, 58.66; H, 3.94; N, 9.12.
[0171] Found: C, 58.36; H, 3.92; N, 9.32.
Preparation 27
[0172] Preparation of
2-[1,6-dichlorophenoxymethyl]-7-hydroxybenzimidazole 39
[0173] IR and NMR were consistent with the desired title product.
Yield 0.52 grams (88%). FDMS 308 (M+).
[0174] Analysis for C.sub.14H.sub.10Cl.sub.2N.sub.2O.sub.2:
[0175] Theory: C, 54.39; H, 3.26; N, 9.06.
[0176] Found: C, 54.51; H, 3.22; N, 9.22.
Preparation 28
[0177] Preparation of
2-[3-trifluoromethylphenoxymethyl]-benzimidazole 40
[0178] NMR was consistent with the desired title product. Yield
0.62 grams (89%).
Preparation 29
[0179] Preparation of
2-[3-trifluoromethylphenoxymethyl]-7-methylbenzimida- zole 41
[0180] NMR was consistent with the desired title product.
Preparation 30
[0181] Preparation of
2-[4-chlorophenoxymethyl]-6-chlorobenzimidazole 42
[0182] NMR and IR were consistent with the desired title product.
Yield 8.20 grams (>99%). FDMS 292 (M+).
Preparation 31
[0183] Preparation of
2-[4-chlorophenoxymethyl]-5,6-dichlorobenzimidazole 43
[0184] NMR and IR were consistent with the desired title product.
Yield 9.20 grams (>99%). FDMS 328 (M+).
Preparation 32
[0185] Preparation of
2-[4-chlorophenoxymethyl]-5,6-dimethylbenzimidazole 44
[0186] NMR and IR were consistent with the desired title product.
Yield 4,4 grams (52%). FDMS 286 (M+).
Preparation 33
[0187] Preparation of
2-[chlorophenoxymethyl]-4,5,6,7-tetramethylbenzimida- zole 45
[0188] NMR was consistent with the desired title structure. Yield
0.5 grams (38%).
Preparation 33
[0189] Preparation of
2-[4-chlorophenoxymethyl]-6-(t-butyl)benzimidazole 46
[0190] NMR was consistent with the desired title product. Yield 1.5
grams (40%).
Preparation 34
[0191] Preparation of 2-[2,4-dichlorophenoxymethyl]benzimidazole
47
[0192] IR and NMR were consistent with the desired title product.
Yield 6.7 grams (96%). FDMS 292 (M+).
[0193] Analysis for C.sub.14H.sub.10Cl.sub.2N.sub.2O:
[0194] Theory. C, 57.36; H, 3.44; N, 9.56.
[0195] Found: C, 57.11; H, 3.54; N, 9.31.
Preparation 35
[0196] Preparation of
2-[2,4-dichlorophenoxymethyl]-5,6-dichlorobenzimidaz- ole 48
[0197] NMR and IR were consistent with the desired title product.
Yield 3.2 grams (91%).
Preparation 36
[0198] Preparation of (3'R) ethyl 2-(piperidin-3-yl)acetate 49
[0199] Ethyl-3-pyridylacetate (10 g, 0.606 mol) was dissolved in
ethanol (1.8 liters), treated with 5% rhodium on alumina (100 g)
and hydrogenated at 60.degree. C. and 60 psi hydrogen gas
overnight. The catalyst was removed by filtration 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(+)-mandelic acid in warm ethyl acetate (600 ml). After cooling in
the refrigerator for four hours, the solid was collected and the
crystallization fluid reserved for processing to the other
enantiomer, infra. The solid was again recrystallized from ethyl
acetate (1.55-1.6 liters, overnight at ambient temperature) to give
the desired title product as white needles. Yield: 81.6, 41%.
[0200] O.R. (EtOH) @589 nm=+44.9.degree., @365 nm=+173.73.degree..
mp 118-119.degree. C.
Preparation 37
[0201] Preparation of (3'S) ethyl 2-(piperidin-3-yl)acetate 50
[0202] The crystallization fluid from Preparation 36, supra, was
evaporated to give a dark oil (100.3 g). This was dissolved in a
cold solution of potassium carbonate (52 g, 0.377 mol) in water
(250 ml) and extracted with ethyl acetate (5.times.150 ml). The
extracts were combined and dried over magnesium sulfate. The
solvents were removed in vacuo to give a dark liquid (40.25 g). The
dark liquid was treated with a warm solution of D-(-)-mandelic acid
(36 g) in ethyl acetate (650 ml) and cooled at ambient temperatures
overnight. The crystals were recrystallized twice more from ethyl
acetate (1.2 liters and 1.1 liters, respectively) to give the
desired title product as white needles. Yield: 48.7 g, 24.9%.
[0203] O.R. (EtOH) @589 nm=-43.14.degree., @365 nm=-164.31.degree..
mp 115.5-117.degree. C.
CHIRAL ANALYTICAL METHOD
[0204] Cold aqueous potassium carbonate (0.15 g in 10 ml of water)
was treated with 0.3 g of the mandelic acid salt and the mixture
was extracted with ethyl acetate (3.times.5 ml). The combined
extracts were dried over magnesium sulfate and the solvents were
removed in vacuo. The residue was dissolved in diethyl ether (10
ml) and treated with S(-)-.alpha.-methylbenzylisocyanate (0.12 ml).
After 2.5 hours, the reaction was treated with 1N hydrochloric acid
(2 ml). The ether was separated and then washed sequentially with
brine, a saturated aqueous sodium bicarbonate solution, and brine.
The organic fraction was dried over magnesium sulfate and the
solvents were removed by evaporation. The residue was analyzed on a
CHIRACEL OJ.TM. high performance liquid chromatography column
(4.6.times.250 mm), eluting with 5% ethanol in hexanes at a flow
rate of 2.5 ml/minute. The slower component comes from the
1-(+)-mandelic acid salt and the faster from the d-(-)-mandelic
acid salt. HPLC analysis of the final crystallization products of
both enantiomers show less than three percent of the opposite
enantiomer.
Preparation 38
[0205] Preparation of (3R) ethyl
2-[N-(t-butoxycarbonyl)piperidin-3-yl]ace- tate 51
[0206] (3'R)-Ethyl-2-(piperidin-3-yl)acetate (10.9 g, 34 mmol) as
prepared in Preparation 36 was dissolved in 50 ml of a 12% 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 liquid
was dissolved in ether (50 ml) and treated dropwise with
di-t-butyldicarbonate (7.9 g) in ether (10 ml). After stirring
overnight, the solution was cooled in an ice water bath and treated
dropwise with saturated aqueous citric acid (25 ml). The aqueous
fraction was extracted with diethyl ether. The organic fractions
were combined, washed with water, a saturated sodium bicarbonate
solution, and then brine, and then dried over magnesium 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
[0207] Preparation of (3'S) ethyl
2-[N-(t-butoxycarbonyl)piperidin-3-yl]ac- etate 52
[0208] (3'S)-Ethyl-2-(piperidin-3-yl)acetate (48.6 g, 150 mmol), as
prepared 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.times.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
ether gave a brownish liquid (25 g, 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 dropwise with stirring. Cooling was removed
and reaction was stirred overnight. The solution was gain cooled in
ice water and a solution of saturated aqueous citric acid (100 ml)
was added dropwise. The organics were washed with brine, a
saturated aqueous sodium bicarbonate solution, the brine, and then
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
[0209] Preparation of (RS) ethyl 3-[pyrid-3-yl]prop-2-enoate 53
[0210] A solution of ethylphosphinoacetate (98.6 g, 0.44 mol) in
dry tetrahydrofuran (1200 ml) was treated with 60% sodium hydride
(17.5 g, 0.44 mol). The mixture was stirred at room temperature for
two hours and was then cooled down to 0.degree. C. To this mixture
3-pyridine carboxaldehyde (38.9 g, 0.36 mol) was added and the
resulting reaction mixture was stirred for 1'2 hours while warming
to room temperature. The progress of the reaction was monitored by
thin layer chromatography.
[0211] Water (1000 ml) was added to the reaction mixture. The
organic fraction was extracted with ethyl acetate (3.times.1000
ml). The organic fractions were combined, washed with water
(2.times.1000 ml), brine (1.times.1000 ml), and the dried over
sodium sulfate. The solvents were removed in vacuo to yield 62.5
grams (97%) of the desired title product.
Preparation 41
[0212] Preparation of (RS) ethyl 3-[piperidin-3-yl]propionoate
54
[0213] A solution of (RS) ethyl-1-[pyrid-3-yl]prop-1-enoate (60 g,
0.34 mol) in ethanol (600 ml) was treated with 5% rhodium on
alumina powder (17.2 g). The mixture was placed under a hydrogen
atmosphere (55 psi) for five hours at 60.degree. C. The reaction
was stopped by removing the hydrogen and the reaciton mixture was
filtered through a layer of CELITE.TM.. The residue was washed with
hot ethanol. The filtrate was concentrated and purified by flash
chromatography to provide 39.6 grams (63%) of the desired title
product.
[0214] IR, NMR, and IR were consistent with the proposed title
structure.
Preparation 42
[0215] Preparation of (3'S) ethyl 3-[piperidin-3-yl]propionoate
mandelic acid salt 55
[0216] A solution of (RS) ethyl 3-[piperidin-3-yl]propionoate (52.0
g, (-) mandelic acid (42.7 g, 281 mmol). The resulting mixture was
then filtered and the clear solution was left at room temperature
overnight. The newly formed white crystals of the salt were
filtered from the solution. These crystals were recrystallized
twice by dissolution in hot ethyl acetate (300 ml) and letting it
cool down 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 confirmed by X-ray crystallography.
Preparation 43
[0217] Preparation of (3R) ethyl 3-[piperidin-3-yl]propionoate
mandelic acid salt 56
[0218] The title compound was prepared essentially as described in
Preparation 42, supra, except that S(+) mandelic acid was employed
instead of the R-(-) mandelic acid employed therein. NMR and IR
were consistent with the desired title product.
Preparation 44
[0219] Preparation of (3'S) ethyl 3-[piperidin-3-yl]propionoate
57
[0220] A suspension of (3'S) ethyl 3-[piperidin-3-yl]propionoate
mandelic acid 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.times.300 ml). The combined organic fraction was washed
with water (2.times.300 ml), then brine (1.times.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.
Preparation 45
[0221] Preparation of (3R) ethyl 3-[piperidin-3-yl]propionoate
58
[0222] The title compound was prepared essentially as described in
Preparation 44, supra except that (3R) ethyl
3-[piperidin-3-yl]propionoat- e mandelic acid salt was employed
instead of the (3'S) ethyl 3-[piperidin-3-yl]propionoate mandelic
acid salt therein. NMR and IR were consistent with the desired
title product.
Preparation 46
[0223] Preparation of (3'S) ethyl
3-[1(t-butoxycarbonyl)piperidin-3-yl]pro- pionoate 59
[0224] A solution of (3'S) ethyl 3-[piperidin-3-yl]propionoate
(12.5 g, 67.5 mmol) in tetrahydrofuran:water (2:1, 335:168 ml) was
treated with potassium carbonate (14 g, 101 mmol) and di-tert-butyl
dicarbonate (17.7 g, 81 mmol). The reaction mixture was stirred at
room temperature for five hours. The mixture was then poured into
water (200 ml). The organic fraction was extracted with ethyl
acetate (3.times.200 ml). The organic fractions were combined,
washed with water (2.times.200 ml) and then brine (1.times.200 ml),
and then dried over sodium sulfate. The solvents were removed in
vacuo and the title product was further purified by flash
chromatography. Yield: 19.1 grams (99.2%). NMR and IR were
consistent with the desired title product.
Preparation 47
[0225] Preparation of (3'R) ethyl
3-[1-(t-butoxycarbonyl)piperidin-3-yl]pr- opionoate 60
[0226] The title product was prepared essentially as described in
Preparation 46, supra, except that an equimolar 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
[0227] Preparation of (3'S)
3-[1-(t-butoxycarbonyl)piperidin-3-yl]propanol 61
[0228] A solution of (3'S) ethyl
3-[1-(t-butoxycarbonyl)piperidin-3-yl]pro- pionoate (17.1 g, 60
mmol) in dry diethyl acetate (600 ml) was cooled to 0.degree. C.
Lithium aluminum hydride powder (2.5 g, 65 mmol) was gradually
added to the mixture. The resulting mixture was stirred at
0.degree. C and slowly warmed to room temperature within two hours.
The reaciton was stopped by the slow addition of water (200 ml) and
15% aqueous sodium hydroxide (50 ml). The organic fraction was
extracted with diethyl ether (3.times.300 ml). The combined layer
was washed with water (2.times.200 ml) and then brine (1.times.200
ml) and then dried over sodium sulfate. The solvents were removed
in vacuo to provide 13.2 grams (90% yield) of the title
product.
[0229] NMR and IR were consistent with the desired title
product.
Preparation 49
[0230] Preparation of (3'S)
3-[1-(t-butoxycarbonyl)piperidin-3-yl]propanol 62
[0231] The title product was prepared essentially as described in
Preparation 48, supra, except that an equimolar amount of (3'S)
ethyl 3-[1-(t-butoxycarbonyl)piperidin-3-yl]propionoate was
employed instead of the (3R) ethyl
3-[1-(t-butoxycarbonyl)piperidin-3-yl]propionoate employed
therein.
Preparation 50
[0232] Preparation of (3'S)
3-[1-(t-butoxycarbonyl)piperidin-3-yl]propane bromide 63
[0233] To a cold (0.degree. C.) solution of triphenylphosphine
(19.95 g, 76 mmol) in anhydrous methylene chloride (110 ml) was
added bromine dropwise until the solution turned pale yellow. A few
crystals of triphenylphosphine were added to the mixture to bring
the color back to white. To this mixture was added a suspension of
(3'S) 3-[1-(t-butoxycarbonyl)piperidin-3-yl]propanol (13.2 g, 54.4
mmol) and pyridine (8.0 g, 76 mmol) in dry methylene chloride (110
ml). The resulting mixture was stirred for five hours while warming
to room temperature.
[0234] The reaction was stopped by adding water (200 ml). The
organic fraction was extracted with methylene chloride (3.times.200
ml). The combined organic layer was washed with water (2.times.200
ml), then brine (1.times.100 ml), and then dried over sodium
sulfate. The solvents were removed in vacuo to provide a light
brownish crude product, which was further purified by flash
chromatography to yield 11.6 grams (70%) of the desired title
product.
[0235] NMR and IR were consistent with the title product.
Preparation 51
[0236] Preparation of (3'R)
3-[1-(t-butoxycarbonyl)piperidin-3-yl]propane bromide 64
[0237] The title product was prepared essentially as described in
Preparation 50, supra, except that an equimolar amount of (3'R)
3-[1-(t-butoxycarbonyl)piperidin-3-yl]propanol was employed instead
of the (3'S) 3-[1-(t-butoxycarbonyl)piperidin-3-yl]propanol
employed therein.
GENERAL PROCEDURE FOR PREPARING COMPOUNDS OF THE FORMULA
[0238] 65
[0239] A solution of benzimidazole (1.0 g, 3.9 mmol, 1.0 eq) in
anhydrous N,N-dimethylformamide (10 ml) was treated with 60%
disperson of sodium hydride (0.163 g, 4.1 mmol, 1.05 eq). The
reaction mixture was stirred at room temperature for about thirty
minutes. Bromopropanol (0.6 g, 4.3 mmol, 1.1 eq) was added to the
mixture and the resulting mixture was stirred at 70.degree. C. for
five hours. The progress of the reaction was monitored by thin
layer chromatography.
[0240] The reaction mixture was poured into water (20 ml). The
organic fraction was extracted with diethyl ether (3.times.50 ml).
The organic fractions were combined, washed with water (2.times.20
ml), and then brine (1.times.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 performed on this
product.
[0241] The following examples were prepared essentially as
described above in the general procedure.
EXAMPLE 1
[0242] Preparation of
2-[4-chlorophenoxymethyl-1-(3-hydroxypropyl)benzimid- azole 66
[0243] NMR was consistent with the desired title structure.
EXAMPLE 2
[0244] Preparation of
2-[4-chlorophenoxymethyl]-1-(3-hydroxypropyl)-5-chlo-
robenzimidazole 67
[0245] NMR was consistent with the desired title structure.
EXAMPLE 3
[0246] Preparation of
2-[4-chlorophenoxymethyl]-1-(3-hydroxypropyl)-5,6-di-
chlorobenzimidazole 68
[0247] NMR was consistent with the desired title structure.
EXAMPLE 4
[0248] Preparation of
2-[4-chlorophenoxymethyl]-1-(3-hydroxypropyl)-5,6-di-
methylbenzimidazole 69
[0249] NMR was consistent with the desired title structure.
EXAMPLE 5
[0250] Preparation of
2-[4-chlorophenoxymethyl]-1-(3-hydroxypropyl)-4-meth-
ylbenzimidazole 70
[0251] NMR was consistent with the desired title structure.
GENERAL PROCEDURE FOR PREPARATION OF COMPOUNDS OF THE FORMULA
[0252] 71
[0253] To a solution of triphenylphosphine (1.52 g, 5.8 mmol, 1.5
eq) in dry dichloromethane (10 ml) at 0.degree. C. was added
bromine solution until it was pale yellow. To the resulting mixture
as added additional triphenylphosphine until the solution was
white. To this mixture was then added the hydroxyalkyl-substituted
benzimidazole (1.2 g, 3.9 mmol, 1.5 eq) and pyridine (0.5 ml, 5.8
mmol, 1.5 eq) in dry dichloromethane. The resulting mixture was
stirred at 0.degree. C. and then warmed to room temperature at
which temperature it was maintained for about six hours. The
progress of the reaction was monitored by thin layer
chromatography.
[0254] White precipitate was removed by filtration, washed with
dichloromethane, and dried in vacuo to provide the crude
product.
[0255] The following compounds were prepared essentially as
described above.
EXAMPLE 6
[0256] Preparation of
2-[4-chlorophenoxymethyl]-1-(3-bromopropyl)benzimida- zole 72
[0257] NMR and IR were consistent with the desired title structure.
FDMS 380 (M+).
EXAMPLE 7
[0258] Preparation of
2-[4-chlorophenoxymethyl]-1-(3-bromopropyl)-5-chloro- benzimidazole
73
[0259] NMR was consistent with the desire title structure.
EXAMPLE 8
[0260] Preparation of
2-[4-chlorophenoxymethyl]-1-(3-bromopropyl)-5,6-dich-
lorobenzimidazole 74
[0261] NMR was consistent with the desired title structure.
EXAMPLE 9
[0262] Preparation of
2-[4-chlorophenoxymethyl]-1-(3-bromopropyl)-5,6-dime-
thylbenzimidazole 75
EXAMPLE 10
[0263] NMR was consistent with the desired title structure.
Preparation of
2-(4-chlorophenoxymethyl]-1-(3-bromopropyl)-4-methylbenzimidazole
76
[0264] NMR was consistent with the desired title structure. FDMS
393 (M+).
GENERAL PROCEDURE FOR PREPARATION OF COMPOUNDS OF THE FORMULA
[0265] 77
[0266] A solution of the benzimidazole (100 mg, 0.26 mmol, 1.0 eq)
in anhydrous N,N-dimethylformamide (2 ml) was treated with
potassium carbonate (90 mg, 0.65 mmol, 2.5 eq) and piperidine
hydrochloride (35 mg, 0.29 mmol, 1.1 eq). The mixture was stirred
at 70.degree. C. for about five hours. The resulting mixture was
poured into water (5 ml). The organic fraction was extracted with
diethyl ether (3.times.10 ml). The combined ether layers were
washed with water (3.times.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.
[0267] The following compounds were prepared essentially as
described above.
EXAMPLE 11
[0268] Preparation of
2-(4-chlorophenoxymethyl)-1-[3-(piperidin-1-yl)propy-
l]benzimidazole 78
[0269] IR and NMR were consistent with the desired tide product.
FDMS 384 (M+).
[0270] Analysis for C.sub.22H.sub.26ClN.sub.3O:
[0271] Theory. C, 68.83; H, 6.83; N, 10.94.
[0272] Found: C, 68.21; H, 6.90; N, 10.98.
EXAMPLE 12
[0273] Preparation of
2-(4-chlorophenoxymethyl)-1-[3-(piperidin-1-yl)propy-
l]benzimidazole 79
[0274] IR and NMR were consistent with the desired title product.
FDMS 384 (M+).
[0275] Analysis for C.sub.22H.sub.26ClN.sub.3O:
[0276] Theory: C, 68.83; H, 6.83; N, 10.94.
[0277] Found: C, 68.21; H, 6.90; N, 10.98.
EXAMPLE 13
[0278] Preparation of
5-chloro-2-(4-chlorophenoxymethyl)-1-[3-(piperidin-1-
-yl)propyl]benzimidazole 80
[0279] IR and NMR were consistent with the desired title product.
FDMS 418 (M+).
EXAMPLE 14
[0280] Preparation of
5,6-dichloro-2-(4-chlorophenoxymethyl)-1-[3-(piperid-
in-1-yl)propyl]benzimidazole 81
[0281] IR and NMR were consistent with the desired title product.
FDMS 452 (M+).
EXAMPLE 15
[0282] Preparation of
2-(4-chlorophenoxymethyl)-5,6-dimethyl-1-[3-(piperid-
in-1-yl)propyl]benzimidazole 82
EXAMPLE 16
[0283] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-(piperidin-1-
-yl)propyl]benzimidazole 83
[0284] IR and NMR were consistent with the desired title product.
FDMS 397 (M+).
EXAMPLE 17
[0285] Preparation of
2-(4-chlorophenoxymethyl)-5,6-dichloro-1-[3-(morphol-
in-1-yl)propyl]benzimidazole 84
[0286] IR and NMR were consistent with the desired title product.
FDMS 453, 454 (M+).
EXAMPLE 18
[0287] Preparation of
2-(4-chlorophenoxymethyl)-5-chloro-1-[3-(morpholin-1-
-yl)propyl]benzimidazole 85
[0288] IR and NMR were consistent with the desired title product.
FDMS 419, 420 (M+).
EXAMPLE 19
[0289] Preparation of
2-(4-chlorophenoxymethyl)-1-[3-(morpholin-1-yl)propy-
l]benzimidazole 86
[0290] IR and NMR were consistent with the desired title product.
FDMS 385, 386 (M+).
EXAMPLE 20
[0291] Preparation of
2-(4-chlorophenoxymethyl)-1-[3-(piperazin-1-yl)propy-
l]benzimidazole 87
EXAMPLE 21
[0292] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-(piperazin-1-
-yl)propyl]benzimidazole 88
[0293] IR and NMR were consistent with the desired title product.
FDMS 512 (M+).
EXAMPLE 22
[0294] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[4-(pyrimidi-
n-2-yl)piperazin-1-yl]propyl]benzimidazole 89
[0295] IR and NMR were consistent with the desired title product.
FDMS 476.2 (M+).
EXAMPLE 22
[0296] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[4-(pyrid-2--
yl)piperazin-1-yl]propyl]benzimidazole 90
[0297] IR and NMR were consistent with the desired title product.
FDMS 475.2 (M+).
EXAMPLE 23
[0298] Preparation of
2-(4-chlorophenoxymethyl)-1-[3-[4-(N,N-dimethylamino- )
piperidin-1-yl]propyl]benzimidazole 91
EXAMPLE 24
[0299] Preparation of
2-(4-chlorophenoxymethyl)-5,6-dichloro-1-[3-[4-(N,N--
dimethylamino)piperidin-1-yl]propyl]benzimidazole 92
[0300] IR and NMR were consistent with the desired title product.
FDMS 495.2 (M+).
EXAMPLE 25
[0301] Preparation of
2-(4-chlorophenoxymethyl)-5-chloro-1-[3-[4-(N,N-dime-
thylamino)piperidin-1-yl]propyl]benzimidazole 93
[0302] IR and NMR were consistent with the desired title product.
FDMS 495.2 (M+).
EXAMPLE 26
[0303] Preparation of
2-(4-chlorophenoxymethyl)-5,6-dimethyl-1-[3-[4-(N,N--
dimethylamino)piperidin-1-yl]propyl]benzimidazole 94
[0304] IR and NMR were consistent with the desired title product.
FDMS 455.4 (M+).
EXAMPLE 27
[0305] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[3-(N,N-dime-
thylamino)piperidin-1-yl]propyl]benzimidazole 95
[0306] IR and NMR were consistent with the desire title product.
FDMS 441 (M+).
EXAMPLE 27
[0307] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[4-(piperidi- n-1-yl)
piperidin-1-yl]propyl]benzimidazole 96
[0308] IR and NMR were consistent with the desired title product.
FDMS 481 (M+).
GENERAL PROCEDURE FOR PREPARING COMPOUNDS OF THE FOLLOWING
FORMULA
[0309] 97
[0310] where n is 0, 1, or 2, and APG is an amino protecting group.
98
[0311] A solution of the 1-unsubstituted benzimidazole (0.77 mmol,
1.0 eq) in anhydrous N,N-dimethylformamide (3 ml) was treated with
a 60% disperson of sodium hydride (33 mg, 0.80 mmol, 1.05 eq). The
mixture was stirred at room temperature for thirty minutes under a
stream of nitrogen. To this mixture was added
[1-(t-butoxycarbonyl)piperidin-3-yl]p- ropyl bromide (260 mg, 0.85
mmol, 1.1 eq) and the resulting mixture was stirred at 80.degree.
C. for about three hours. The progress of the reaction was
monitored by thin layer chromatography.
[0312] The reaction mixture was then poured into water (10 ml). The
organic fraction was extracted with diethyl ether (3.times.15 ml).
The organic fractions were combined, washed with water (2.times.10
ml), brine (1.times.10 ml), and then dried over sodium sulfate. The
solvents were removed in vacuo, leaving a light brown crude
material which was farther purified by flash chromatography to
yield the desired title product as a white crystalline solid in
70-100% yield.
EXAMPLE 28
[0313] Preparation of
2-(4-chlorophenoxymethyl)-1-[3-[1-(t-butoxycarbonyl)-
piperidin-2-yl]propyl]benzimidazole 99
[0314] IR and NMR were consistent with the desired title product.
FDMS 483, 484 (M+).
[0315] Analysis for C.sub.27H.sub.34ClN.sub.3O.sub.3:
[0316] Theory: C, 67.00; H, 7.08; N, 8.60.
[0317] Found: C, 66.93; H, 7.09; N, 8.43.
EXAMPLE 29
[0318] Preparation of
2-(4-chlorophenoxymethyl)-5-methoxy-1-[3-[1-(t-butox-
ycarbonyl)piperidin-2-yl]propyl]benzimidazole and
2-(4-chlorophenoxymethyl-
)-6-methoxy-1-[3-[1-(t-butoxycarbonyl)piperidin-2-yl]propyl]benzimidazole
100
[0319] IR and NMR were consistent with the desired title products.
FDMS 513, 514 (M+).
[0320] Analysis for C.sub.28H.sub.30ClN.sub.3O.sub.4:
[0321] Theory C, 65.42; H, 7.06; N, 8.17.
[0322] Found: C, 65.12; H, 6.96; N, 8.29.
EXAMPLE 30
[0323] Preparation of
2-(4-chlorophenoxymethyl)-4,5-dimethyl-1-[3-[1-(t-bu-
toxycarbonyl)piperidin-2-yl]propyl]benzimidazole and
2-(4-chlorophenoxymethyl)-6,7-dimethyl-1-[3-[1-(t-butoxycarbonyl)piperidi-
n-2-yl]propyl]benzimidazole 101
[0324] IR and NMR were consistent with the desired title products.
FDMS 511, 512 (M+).
[0325] Analysis for C.sub.29H.sub.38ClN.sub.3O.sub.3:
[0326] Theory: C, 68.02; H, 7.48; N, 8.20.
[0327] Found: C, 68.32; H, 7.54; N, 8.36.
EXAMPLE 31
[0328] Preparation of
2-(4-chlorophenoxymethyl)-5-methyl-1-[3-[1-(t-butoxy-
carbonyl)piperidin-2-yl]propyl]benzimidazole and
2-(4-chlorophenoxymethyl)-
-6-methyl-1-[3-[1-(t-butoxycarbonyl)piperidin-2-yl]propyl]benzimidazole
102
[0329] IR and NMR were consistent with the desired title products.
FDMS 497, 498 (M+). 3:2 mixture of the 5-methyl isomer to the
6-methyl isomer.
[0330] Analysis for C.sub.28H.sub.36ClN.sub.3O.sub.3:
[0331] Theory: C, 67.52; H, 7.28; N, 8.44.
[0332] Found: C, 68.37; H, 7.40; N, 8.60.
EXAMPLE 31
[0333] Preparation of
2-(4-chlorophenoxymethyl)methyl-1-[3-[1-(t-butoxycar-
bonyl)piperidin-2-yl]propyl]benzimidazole 103
[0334] IR and NMR were consistent with the desired title product.
FDMS 497, 498 (M+).
[0335] Analysis for C.sub.28H.sub.36ClN.sub.3O.sub.3:
[0336] Theory: C, 67.52; H, 7.29; N, 8.44.
[0337] Found: C, 67.14; H, 7.65; N, 8.85.
EXAMPLE 32
[0338] Preparation of
2-(4-chlorophenoxymethyl)-5-benzoyl-1-[3-[1-(t-butox-
ycarbonyl)piperidin-2-yl]propyl]benzimidazole 104
[0339] IR and NMR were consistent with the desired title product.
FDMS 587, 588 (M+).
EXAMPLE 33
[0340] Preparation of
2-(4-chlorophenoxymethyl)-5,6-dichloro-1-[3-[1-(t-bu-
toxycarbonyl)piperidin-2-yl]propyl]benzimidazole 105
[0341] IR and NMR were consistent with the desired title product.
FDMS 587, 588 (M+).
EXAMPLE 34
[0342] Preparation of
2-(2,4-dichlorophenoxymethyl)-1-[3-[1-(t-butoxycarbo-
nyl)piperidin-2-yl]propyl]benzimidazole 106
[0343] NMR was consistent with the desired title product.
EXAMPLE 35
[0344] Preparation of
2-(2,4-dichlorophenoxymethyl)-5,6-dichloro-1-[3-[1-(-
t-butoxycarbonyl)piperidin-2-yl]propyl]benzimidazole 107
[0345] NMR and IR were consistent with the desired title product.
FDMS 587 (M+).
[0346] Analysis for C.sub.27H.sub.31Cl.sub.4N.sub.3O.sub.3:
[0347] Theory: C, 55.21; H, 5.32; N, 7.15.
[0348] Found: C, 56.19; H, 5.69; N, 7.44.
EXAMPLE 36
[0349] Preparation of
2-(4-chlorophenoxymethyl)-5-methyl-1-[3-[1-(t-butoxy-
carbonyl)piperidin-3-yl]propyl]benzimidazole and
2-(4-chlorophenoxymethyl)-
-6-methyl-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl]benzimidazole
108
[0350] NMR and IR were consistent with the desired title products.
FDMS 497, 498 (M+).
[0351] Analysis for C.sub.28H.sub.36ClN.sub.3O.sub.3:
[0352] Theory: C, 67.52; H, 7.28; N, 8.44.
[0353] Found: C, 67.58; H, 7.42; N, 8.52.
EXAMPLE 37
[0354] Preparation of
2-(4-chlorophenoxymethyl)-5-methoxy-1-[3-[1-(t-butox-
ycarbonyl)piperidin-3-yl]propyl]benzimidazole and
2-(4-chlorophenoxymethyl-
)-6-methoxy-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl]benzimidazole
109
[0355] NMR and IR were consistent with the desired title products.
FDMS 513, 514 (M+).
[0356] Analysis for C.sub.28H.sub.36ClN.sub.3O.sub.4:
[0357] Theory: C, 65.42; H, 7.06; N, 8.17.
[0358] Found: C, 65.18; H, 7.22; N, 7.94.
EXAMPLE 38
[0359] Preparation of
2-(4-chlorophenoxymethyl)-4,5-dimethyl-1-[3-[1-(t-bu-
toxycarbonyl)piperidin-3-yl]propyl]benzimidazole 110
[0360] NMR and IR were consistent with the desired title product.
FDMS 511, 512 (M+).
EXAMPLE 39
[0361] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(t-butoxy-
carbonyl)piperidin3-yl]propyl]benzimidazole 111
[0362] NMR and IR were consistent with the desired title product.
FDMS 497, 498 (M+).
EXAMPLE 39a
[0363] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[5-[1-(t-butoxy-
carbonyl)piperidin-3-yl]pentyl]benzimidazole 112
[0364] NMR was consistent it the desire title product.
EXAMPLE 40
[0365] Preparation of
2-(4-chlorophenoxymethyl)-5-benzoyl-1-(3-[1-(t-butox-
ycarbonyl)piperidin-3-yl]propyl]benzimidazole 113
[0366] NMR and IR were consistent with the desired title product.
FDMS 497, 498 (M+).
EXAMPLE 41
[0367] Preparation of
2-(4-chlorophenoxymethyl)-5,6-dichloro-1-[3-[1-(t-bu-
toxycarbonyl)piperidin-3-yl]propyl]benzimidazole 114
[0368] NMR and IR were consistent with the desired title product.
FDMS 552.5, 554.5 (M+).
EXAMPLE 42
[0369] Preparation of
2-(4-chlorophenoxymethyl)-5-chloro-1-[3-[1-(t-butoxy-
carbonyl)piperidin-3-yl]propyl]benzimidazole 115
[0370] NMR and IR were consistent with the desired title product.
FDMS 518 (M+).
EXAMPLE 43
[0371] Preparation of
2-(4-chlorophenoxymethyl)-5,6-dimethyl-1-[3-[1-(t-bu-
toxycarbonyl)piperidin-3-yl]propyl]benzimidazole 116
[0372] NMR and IR were consistent with the desired title product
FDMS 512.4 (M+).
EXAMPLE 44
[0373] Preparation of
2-(2,4-dichlorophenoxymethyl)-1-[3-[1-(t-butoxycarbo- nyl)
piperidin-3-yl]propyl]benzimidazole 117
[0374] NMR and IR were consistent with the desired title product.
FDMS 517, 518 (M+).
[0375] Analysis for C.sub.27H.sub.33Cl.sub.2N.sub.3O.sub.3:
[0376] Theory C, 62.58; H, 6.41; N, 8.10.
[0377] Found: C, 62.54; H, 6.39; N, 8.20.
EXAMPLE 45
[0378] Preparation of
2-(2,4-dichlorophenoxymethyl)-5,6-dichloro-1-[3-[1-(-
t-butoxycarbonyl)piperidin-3-yl]propyl]benzimidazole 118
[0379] NMR and IR were consistent with the desired title product.
FDMS 587 (M+).
EXAMPLE 46
[0380] Preparation of
2-(4-chlorophenoxymethyl)-4,5-dimethyl-1-[3-[1-(t-bu-
toxycarbonyl)piperidin-4-yl]propyl]benzimidazole 119
EXAMPLE 47
[0381] Preparation of
2-(4-chlorophenoxymethyl)-1-[3-[1-(t-butoxycarbonyl)-
piperidin-4-yl]propyl]benzimidazole 120
[0382] NMR and IR were consistent with the desired title product.
FDMS 484 (M+).
EXAMPLE 48
[0383] Preparation of
2-(4-chlorophenoxymethyl)-4,5,6,7-tetramethyl-1-[-3--
[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole 121
EXAMPLE 49
[0384] Preparation of
2-(4-chlorophenoxymethyl)-5-methoxycarbonyl-1-[3-[1--
(t-butoxycarbonyl)piperidin-4 -yl]propyl]benzimidazole and
2-(4-chlorophenoxymethyl)methoxycarbonyl-1-[3-[1-(t-butoxycarbonyl)piperi-
din-4-yl]propyl]benzimidazole 122
[0385] NMR and IR were consistent with the desired title products.
FDMS 541 (M+).
[0386] Analysis for C.sub.29H.sub.36ClN.sub.3O.sub.5:
[0387] Theory: C, 64.26; H, 6.69; N, 7.75.
[0388] Found: C, 64.07; H, 6.63; N, 7.95.
EXAMPLE 50
[0389] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(t-butoxy-
carbonyl)piperidin-4-yl]propyl]benzimidazole 123
[0390] NMR and IR were consistent with the desired title product.
FDMS 497, 498 (M+).
EXAMPLE 50a
[0391] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[5-[1-(t-butoxy-
carbonyl)piperidin-4-yl]pentyl]benzimidazole 124
[0392] NMR was consistent with the desired title product.
EXAMPLE 51
[0393] Preparation of
2-(4-chlorophenoxymethyl)-4-(t-butyl)-1-[3-[1-(t-but-
oxycarbonyl)piperidin-4-yl]propyl]benzimidazole and
2-(4-chlorophenoxymethyl)-7-(t-butyl)-1-[3-[1-(t-butoxycarbonyl)piperidin-
-4-yl]propyl]benzimidazole 125
[0394] NMR and IR were consistent with the desired title products.
FDMS 539, 540 (M+).
EXAMPLE 52
[0395] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[4-[1-(t-butoxy-
carbonyl)piperidin-4-yl]butyl]benzimidazole 126
[0396] NMR and IR were consistent with the desired title product.
FDMS 511 (M+).
EXAMPLE 53
[0397] Preparation of
2-(4-chlorophenoxymethyl)-5,6-dimethyl-1-[4-[1-(t-bu-
toxycarbonyl)piperidin-4-yl]butyl]benzimidazole 127
[0398] NMR and IR were consistent with the desired title product.
FDMS 526 (M+).
EXAMPLE 54
[0399] Preparation of
2-(4-chlorophenoxymethyl)-4,5-dimethyl-1-[4-[1-(t-bu-
toxycarbonyl)piperidin-4-yl]butyl]benzimidazole and
2-(4-yl]butyl]benzimidazole 128
[0400] NMR and IR were consistent with the desired title
products.
EXAMPLE 55
[0401] Preparation of
2-benzyl-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]pr-
opyl]benzimidazole 129
[0402] NMR and IR were consistent with the desired title product.
FDMS 433 (M+).
EXAMPLE 56
[0403] Preparation of
2-(4-chlorophenyl)-1-[3-[1-(t-butoxycarbonyl)piperid-
in-3-yl]propyl]benzimidazole 130
[0404] NMR and IR were consistent with the desired title product.
FDMS 453 (M+).
[0405] Analysis for C.sub.26H.sub.32ClN.sub.3O.sub.2:
[0406] Theory: C, 68.78; H, 7.10; N, 9.25.
[0407] Found: C, 68.56; H, 7.03; N, 9.54.
EXAMPLE 57
[0408] Preparation of
2-(2-chlorophenoxymethyl)-1-[3-[1-(t-butoxycarbonyl)-
piperidin-3-yl]propyl]benzimidazole 131
[0409] NMR and IR were consistent with the desired title product.
FDMS 483 (M+).
[0410] Analysis for C.sub.27H.sub.34ClN.sub.3O.sub.3:
[0411] Theory: C, 67.00; H, 7.08; N, 8.08.
[0412] Found: C, 67.25; H, 7.27; N, 8.81.
EXAMPLE 58
[0413] Preparation of
2-(3-chlorophenoxymethyl)-1-[3-[1-(t-butoxycarbonyl)-
piperidin-3-yl]propyl]benzimidazole 132
[0414] NMR and IR were consistent with the desired title product.
FDMS 483 (M+).
EXAMPLE 59
[0415] Preparation of
2-(4-chlorobenzyl)-1-[3-[1-(t-butoxycarbonyl)piperid-
in-3-yl]propyl]benzimidazole 133
[0416] NMR and IR were consistent with the desired title product.
FDMS 467 (M+).
[0417] Analysis for C.sub.27H.sub.34ClN.sub.3O.sub.2:
[0418] Theory: C, 69.30; H, 7.32; N, 9.98.
[0419] Found: C, 69.54; H, 7.49; N, 9.08.
EXAMPLE 60
[0420] Preparation of
2-(phenoxymethyl)-1-[3-[1-(t-butoxycarbonyl)piperidi-
n-3-yl]propyl]benzimidazole 134
[0421] NMR and IR were consistent with the desired title product.
FDMS 449 (M+).
[0422] Analysis for C.sub.27H.sub.35N.sub.3O.sub.3:
[0423] Theory: C, 72.13; H, 7.85; N, 9.35.
[0424] Found: C, 71.85; H, 7.81; N, 9.25.
EXAMPLE 61
[0425] Preparation of
2-(3,5-dichlorophenoxymethyl)-1-[3-[1-(t-butoxycarbo-
nyl)piperidin-3-yl]propyl]benzimidazole 135
[0426] NMR and IR were consistent math the desire title product.
FDMS 517 (M+).
[0427] Analysis for C.sub.27H.sub.33Cl.sub.2N.sub.3O.sub.3:
[0428] Theory. C, 62.55; H, 6.41; N, 8.10.
[0429] Found: C, 62.33; H, 6.35; N, 8.12.
EXAMPLE 62
[0430] Preparation of
2-[4-(4,5-dihydrothiazol-2-yl)phenoxymethyl]-1-[3-[1-
-(t-butoxycarbonyl)piperidin-3-yl]propyl]benzimidazole 136
[0431] NMR and IR were consistent with the desired title product.
FDMS 534 (M+).
[0432] Analysis for C.sub.30H.sub.38N.sub.4O.sub.3S:
[0433] Theory: C, 67.38; H, 7.16; N, 10.48.
[0434] Found: C, 66.78; H, 7.09; N, 10.00.
EXAMPLE 63
[0435] Preparation of
2-(2,6-dichlorophenoxymethyl)-1-[3-[1-(t-butoxycarbo-
nyl)piperidin-3-yl]propyl]benzimidazole 137
[0436] NMR and IR were consistent with the desired title product.
FDMS 517 (M+).
[0437] Analysis for C.sub.27H.sub.33Cl.sub.2N.sub.3O.sub.3:
[0438] Theory: C, 62.55; H, 6.41; N, 8.10.
[0439] Found: C, 62.76; H, 6.44; N, 8.33.
EXAMPLE 64
[0440] Preparation of
2-(3-trifluoromethylphenoxymethyl)-1-[3-[1-(t-butoxy-
carbonyl)piperidin-3-yl]propyl]benzimidazole 138
[0441] NMR and IR were consistent with the desired title product.
FDMS 517 (M+).
[0442] Analysis for C.sub.28H.sub.34F.sub.3N.sub.3O.sub.3:
[0443] Theory: C, 64.98; H, 6.42; N, 8.12.
[0444] Found: C, 64.89; H, 6.48; N, 8.31.
EXAMPLE 65
[0445] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl]-(3-phenylpropyl)- benzimidazole
139
[0446] NMR and IR were consistent with the desired title product.
FDMS 390 (M+).
[0447] Analysis for C.sub.24H.sub.23ClN.sub.2O:
[0448] Theory: C, 73.74; H, 5.93; N, 7.17.
[0449] Found: C, 73.87; H, 5.99; N, 7.27.
EXAMPLE 66
[0450] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-(3-cyclohexylpr-
opyl)benzimidazole 140
[0451] NMR and IR were consistent with the desired title product.
FDMS 390 (M+).
EXAMPLE 67
[0452] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-pyrid-3-yl)p-
ropyl]benzimidazole and
2-(4-chlorophenoxymethyl)-7-methyl-1-[3-(pyrid-3-y-
l)propyl]benzimidazole 141
[0453] NMR and IR were consistent with the desired title
products.
[0454] Analysis for C.sub.23H.sub.22ClN.sub.3O:
[0455] Theory C, 70.49; H, 5.66; N, 10.72.
[0456] Found: C, 70.20; H, 5.76; N, 10.50.
GENERAL PROCEDURE FOR REMOVAL OF THE t-Butoxycarbonyl PROTECTING
GROUP
[0457] 142
[0458] To the amino-protected benzimidazole was added a 1:1 mixture
of trifluoroacetic acid in dichloromethane. The resulting mixture
was stirred at room temperature for about one hour. The progress of
the reaction was monitored by thin layer chromatography. The
solvents were removed in vacuo and the residue was triturated with
diethyl ether (3.times.10 ml) and dried under vacuum to yield white
crystalline hydroscopic solids.
EXAMPLE 68
[0459] Preparation of
2-(4-chlorophenoxymethyl)-1-[3-(piperidin-3-yl)propy-
l]benzimidazole trifluoroacetate salt 143
[0460] NMR and IR were consistent with the desired title product.
FDMS 383, 384 (M+).
EXAMPLE 69
[0461] Preparation of
2-(4-chlorophenoxymethyl)-5-methoxy-1-[3-(piperidin--
3-yl)propyl]benzimidazole trifluoroacetate salt 144
[0462] NMR and IR were consistent with the desired title product.
FDMS 413, 414 (+).
[0463] Analysis for C.sub.23H.sub.28ClN.sub.3O.sub.3:
[0464] Theory: C, 56.87; H, 5.54; N, 7.96.
[0465] Found: C, 55.93; H, 5.31; N, 8.01.
EXAMPLE 70
[0466] Preparation of
2-(4-chlorophenoxymethyl)-4,5-dimethyl-1-[3-(piperid-
in-3-yl)propyl]benzimidazole trifluoroacetate salt 145
[0467] NMR and IR were consistent with the desired title product.
FDMS 411, 412 (M+).
EXAMPLE 71
[0468] Preparation of
2-(4-chlorophenoxymethyl)-5-methyl-1-[3-(piperidin-3-
-yl)propyl]benzimidazole trifluoroacetate salt and
2-(4-chlorophenoxymethy-
l)-6-methyl-1-[3-(piperidin-3-yl)propyl]benzimidazole
trifluoroacetate salt 146
[0469] NMR and IR were consistent with the desired title products.
FDMS 397 (M+).
[0470] Analysis for C.sub.23H.sub.28ClN.sub.3O:
[0471] Theory: C, 58.65; H, 5.54; N, 7.96.
[0472] Found: C, 58.26; H, 5.56; N, 9.17.
EXAMPLE 72
[0473] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-(piperidin-2-
-yl)propyl]benzimidazole trifluoroacetate salt 147
[0474] NMR and IR were consistent with the desired title product.
FDMS 397, 398 (M+).
EXAMPLE 72a
[0475] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[5-(piperidin-3-
-yl)pentyl]benzimidazole 148
[0476] NMR and M were consistent with the desired title product.
FDMS 427 (M+).
[0477] Analysis for C.sub.25H.sub.32ClN.sub.3O:
[0478] Theory: C, 60.05; H, 6.16; N, 7.78.
[0479] Found: C, 59.75; H, 6.11; N, 7.78.
EXAMPLE 73
[0480] Preparation of
2-(4-chlorophenoxymethyl)-5-benzoyl-1-[3-(piperidin--
2-yl)propyl]benzimidazole trifluoroacetate salt 149
[0481] NMR and IR were consistent with the desired title product.
FDMS 487, 488 (M+).
EXAMPLE 74
[0482] Preparation of
2-(4-chlorophenoxymethyl)-5,6-dichloro-1-[3-(piperid-
in-3-yl)propyl]benzimidazole trifluoroacetate salt 150
[0483] NMR and IR were consistent with the desired title product.
FDMS 451, 452 (M+).
EXAMPLE 75
[0484] Preparation of
2-(2,4-dichlorophenoxymethyl)-5,6-dichloro-1-[3-(pip-
eridin-2-yl)propyl]benzimidazole trifluoroacetate salt 151
[0485] NMR and IR were consistent with the desired title product.
FDMS 487 (M+).
EXAMPLE 76
[0486] Preparation of
2-(2,4-dichlorophenoxymethyl)-1-[3-(piperidin-2-yl)p-
ropyl]benzimidazole trifluoroacetate salt 152
[0487] NMR and IR were consistent with the desired title product.
FDMS 418 (M+).
EXAMPLE 78
[0488] Preparation of
2-(4-chlorophenoxymethyl)-5-methoxy-1-[3-(piperidin--
3-yl)propyl]benzimidazole 153
[0489] NMR and IR were consistent with the desired title product.
FDMS 413 (M+).
EXAMPLE 79
[0490] Preparation of
2-(4-chlorophenoxymethyl)-6-methoxy-1-[3-(piperidin--
3-yl)propyl]benzimidazole 154
[0491] NMR and IR were consistent with the desired title product.
FDMS 413 (M+).
EXAMPLE 80
[0492] Preparation of
2-(4-chlorophenoxymethyl)-4,5-dimethyl-1-[3-(piperid-
in-3-yl)propyl]benzimidazole 155
[0493] NMR and IR were consistent with the desired title product.
FDMS 411, 412 (M+).
EXAMPLE 81
[0494] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-(piperidin-3-
-yl)propyl]benzimidazole and
2-(4-chlorophenoxymethyl)-7-methyl-1-[3-(pipe-
ridin-3-yl)propyl]benzimidazole 156
[0495] NMR and IR were consistent with the desired title products.
FDMS 397, 398 (M+).
EXAMPLE 82
[0496] Preparation of
2-(4-chlorophenoxymethyl)-5-benzoyl-1-[3-(piperidin--
3-yl)propyl]benzimidazole 157
[0497] NMR and IR were consistent with the desired title product.
FDMS 487, 488 (M+).
EXAMPLE 83
[0498] Preparation of
2-(4-chlorophenoxymethyl)-5,6-dichloro-1-[3-(piperid-
in-3-yl)propyl]benzimidazole 158
[0499] NMR and IR were consistent with the desired title product.
FDMS 452.2 (M+).
EXAMPLE 84
[0500] Preparation of
2-(4-chlorophenoxymethyl)-5-chloro-1-[3-(piperidin-3-
-yl)propyl]benzimidazole 159
[0501] NMR and IR were consistent with the desired title product.
FDMS 418.2 (M+).
EXAMPLE 85
[0502] Preparation of
2-(4-chlorophenoxymethyl)-5,6-dimethyl-1-[3-(piperid-
in-3-yl)propyl]benzimidazole 160
[0503] NMR and IR were consistent with the desired title product.
FDMS 418.2 (M+).
EXAMPLE 86
[0504] Preparation of
2-(2,4-dichlorophenoxymethyl)-1-[3-(piperidin-3-yl)p-
ropyl]benzimidazole 161
[0505] NMR and IR were consistent with the desired title product.
FDMS 417, 418 (M+).
[0506] Analysis for C.sub.22H.sub.25Cl.sub.2N.sub.3O:
[0507] Theory: C, 53.14; H, 4.92; N, 7.89.
[0508] Found: C, 53.02; H, 4.74; N, 7.59.
EXAMPLE 87
[0509] Preparation of
2-(2,4-dichlorophenoxymethyl)-5,6-dichloro-1-[3-(pip-
eridin-3-yl)propyl]benzimidazole 162
[0510] NMR and IR were consistent with the desired title product.
FDMS 487 (M+).
EXAMPLE 88
[0511] Preparation of
2-(4-chlorophenoxymethyl)-4,5-dimethyl-1-[3-(piperid-
in-4-yl)propyl]benzimidazole 163
[0512] NMR and IR were consistent with the desired title product.
FDMS 411 (M+).
EXAMPLE 89
[0513] Preparation of
2-(4-chlorophenoxymethyl)-1-[3-(piperidin-4-yl)propy-
l]benzimidazole 164
[0514] NMR and IR were consistent with the desired title product.
FDMS 383 (M+).
[0515] Analysis for C.sub.22H.sub.26ClN.sub.3O:
[0516] Theory: C, 57.89; H, 5.46; N, 8.44.
[0517] Found: C, 57.06; H, 5.44; N, 8.31.
EXAMPLE 90
[0518] Preparation of
2-(4-chlorophenoxymethyl)-4,5,6,7-tetramethyl-1-[3-(-
piperidin-4-yl)propyl]benzimidazole 165
[0519] NMR and IR were consistent with the proposed title
structure.
EXAMPLE 91
[0520] Preparation of
2-(4-chlorophenoxymethyl)-5-methoxycarbonyl-1-[3-(pi-
peridin-4-yl)propyl]benzimidazole and
2-(4-chlorophenoxymethyl)-6-methoxyc-
arbonyl-1-[3-(piperidin-4-yl)propyl]benzimidazole 166
[0521] NMR and IR were consistent with the desired title products.
FDMS 541 (M+).
[0522] Analysis for C.sub.24H.sub.28ClN.sub.3O:
[0523] Theory: C, 56.17; H, 5.26; N, 7.50.
[0524] Found: C, 55.91; H, 5.32; N, 7.58.
EXAMPLE 92
[0525] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-(piperidin-4-
-yl)propyl]benzimidazole 167
[0526] IR and NMR were consistent with the desired title structure.
FDMS 397 (M+).
EXAMPLE 92a
[0527] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-(5-(piperidin-4-
-yl)pentyl]benzimidazole 168
[0528] IR and NMR were consistent with the desired title structure.
FDMS 426 (M+).
[0529] Analysis for C.sub.25H.sub.32ClN.sub.3O:
[0530] Theory: C, 60.05; H, 6.16; N, 7.78.
[0531] Found: C, 60.30; H, 6.19; N, 7.65.
EXAMPLE 93
[0532] Preparation of
2-(4-chlorophenoxymethyl)-4-(t-butyl)-1-[3-(piperidi-
n-4-yl)propyl]benzimidazole and
2-(4-chlorophenoxymethyl)-7-(t-butyl)-1-[3-
-(piperidin-4-yl)propyl]benzimidazole 169
[0533] IR and NMR were consistent with the desired title
structures. FDMS 439 (M+).
EXAMPLE 94
[0534] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[4-(piperidin-4-
-yl)butyl]benzimidazole 170
[0535] IR and NMR were consistent with the desired title structure.
FDMS 411 (M+).
EXAMPLE 95
[0536] Preparation of
2-(4-chlorophenoxymethyl-5,6-dimethyl-1-[4-(piperidi-
n-4-yl)butylbenzimidazole 171
[0537] IR and NMR were consistent with the desired title structure.
FDMS 425 (M+).
EXAMPLE 96
[0538] Preparation of
2-(4-chlorophenoxymethyl)-4,5-dimethyl-1-[4-(piperid-
in-4-yl)butyl]benzimidazole and
2-(4-chlorophenoxymethyl)-6,7-dimethyl-1-[-
4-(piperidin-4-yl)butyl]benzimidazole 172
[0539] IR and NMR were consistent with the desired title
structures. FDMS 425 (M+).
EXAMPLE 97
[0540] Preparation of
2-benzyl-1-[3-(piperidin-3-yl)propyl]benzimidazole 173
[0541] IR and NMR were consistent with the desired title structure.
FDMS 344 (M+).
EXAMPLE 98
[0542] Preparation of
2-(4-chlorophenyl)-1-[3-(piperidin-3-yl)propyl]benzi- midazole
174
[0543] IR and NMR were consistent with the desired title structure.
FDMS 354 (M+).
EXAMPLE 99
[0544] Preparation of
2-(2-chlorophenoxymethyl)-1-[3-(piperidin-3-yl)propy-
l]benzimidazole 175
[0545] IR and NMR were consistent with the desired title structure.
FDMS 384 (M+).
EXAMPLE 100
[0546] Preparation of
2-(3chlorophenoxymethyl)-1-[3-(piperidin-3-y)propyl]- benzimidazole
176
[0547] IR and NMR were consistent with the desired title structure.
FDMS 384 (M+).
EXAMPLE 101
[0548] Preparation of
2-(4-chlorobenzyl)-1-[3-(piperidin-3-yl)propyl]benzi- midazole
177
[0549] IR and NMR were consistent with the desired title structure.
FDMS 368 (M+).
EXAMPLE 102
[0550] Preparation of
2-(phenoxymethyl)-1-[3-(piperidin-3-yl)propyl]benzim- idazole
178
[0551] IR and NMR were consistent with the desired title structure.
FDMS 349 (M+).
[0552] Analysis for C.sub.22H.sub.27N.sub.3O:
[0553] Theory: C, 62.19; H, 6.09; N, 9.07.
[0554] Found: C, 61.08; H, 6.01; N, 9.01.
EXAMPLE 103
[0555] Preparation of
2-(3,5-dichlorophenoxymethyl)-1-[3-(piperidin-3-yl)p-
ropyl]benzimidazole 179
[0556] IR and NMR were consistent with the desired title structure.
FDMS 417 (M+).
[0557] Analysis for C.sub.22H.sub.25Cl.sub.2N.sub.3O:
[0558] Theory: C, 54.14; H, 4.92; N, 7.89.
[0559] Found: C, 54.05; H, 4.87; N, 7.82.
EXAMPLE 104
[0560] Preparation of
2-[4-(4,5-dihydrothiazol-2-yl)phenoxymethyl]-1-[3-(p-
iperidin-3-yl)propyl]benzimidazole 180
[0561] IR and NMR were consistent with the desired title structure.
FDMS 435 (M+).
EXAMPLE 105
[0562] Preparation of
2-(2,6-dichlorophenoxymethyl)-1-[3-(piperidin-3-yl)p-
ropyl]benzimidazole 181
[0563] IR and NMR were consistent with the desired title structure.
FDMS 420 (M+).
EXAMPLE 106
[0564] Preparation of
2-(3-trifluoromethylphenoxymethyl)-1-[3-(piperidin-3-
-yl)propyl]benzimidazole 182
[0565] IR and NMR were consistent with the desired title structure.
FDMS 418 (M+).
[0566] Analysis for C.sub.23H.sub.26F.sub.3N.sub.3O:
[0567] Theory: C, 56.50; H, 5.12; N, 7.91.
[0568] Found: C, 55.49; H, 5.03; N, 7.64.
EXAMPLE 107
[0569] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[4-[3-piperidin-
-1-yl)propylamino]-3-methylbutyl]benzimidazole 183
EXAMPLE 108
[0570] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[4-amino-3-meth-
ylbutyl]benzimidazole 184
EXAMPLE 109
[0571] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[4-dimethylamin-
o-3-methylbutyl]benzimidazole 185
EXAMPLE 110
[0572] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[4-(1,2,3,4-tet-
rahydroisoquinolin-2-yl)-3-methylbutyl]benzimidazole 186
EXAMPLE 111
[0573] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[2-[2-(piper-
idin-1-yl)ethyl]piperidin-1-yl]carbonyl]butyl]benzimidazole 187
EXAMPLE 112
[0574] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-{4-[2-2-(piperi-
din-1-yl)ethyl]piperidin-1-yl]-3-methylbutyl}benzimidazole 188
EXAMPLE 113
[0575] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-{4-[(1,2,3,4-te-
trahydronaphth-1-yl)amino]-3-methylbutyl}benzimidazole 189
EXAMPLE 114
[0576] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[3-[(2-methy-
lpiperidin-1-yl)propylamino]carbonyl]-3-methylpropyl}benzimidazole
190
EXAMPLE 115
[0577] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-{4-[3-(2-methyl-
piperidin-1-yl)propylamino]-3-methylbutyl}benzimidazole 191
EXAMPLE 116
[0578] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[1-(3-ethoxy-
carbonylbutyl)piperidin-3-yl]propyl}benzimidazole 192
EXAMPLE 117
[0579] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[1-(3-ethoxy-
carbonyl4-phenylbutyl)piperidin-3-yl]propyl}benzimidazole 193
EXAMPLE 118
[0580] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[1-(2-ethoxy-
carbonyl-4-phenylbutyl)piperidin-3-yl]propyl}benzimidazole 194
EXAMPLE 119
[0581] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[1-(3-carbox-
ybutyl)piperidin-3-yl]propyl}benzimidazole 195
EXAMPLE 120
[0582] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[4-[2-[2-(piper-
idin-1-yl)ethyl]piperidin-1-yl]-3-methyl]butyl]benzimidazole
196
EXAMPLE 121
[0583] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(3-phenyl-
-3-carboxypropyl)piperidin-3-yl]propyl]benzimidazole 197
EXAMPLE 122
[0584] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(4phenyl--
3-carboxybutyl)piperidin-3-yl]propyl]benzimidazole 198
EXAMPLE 123
[0585] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(3-benzoy-
lbutyl)piperidin-3-yl]propyl]benzimidazole 199
EXAMPLE 124
[0586] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(3-benzoy-
l-3-phenylpropyl)piperidin-3-yl]propyl]benzimidazole 200
EXAMPLE 125
[0587] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(3-benzoy-
l-3-phenylpropyl)piperidin-3-yl]propyl]benzimidazole 201
EXAMPLE 126
[0588] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(3-benzoy-
l-3-benzylpropyl)piperidin-3-yl]propyl]benzimidazole 202
EXAMPLE 127
[0589] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-4-(piperi-
din-1-yl)-3-methylbutyl]piperidin-3-yl]propyl]benzimidazole 203
EXAMPLE 128
[0590] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[4-(piper-
idin-1-yl)-3-phenylbutyl]piperidin-3-yl]propyl]benzimidazole
204
EXAMPLE 130
[0591] Preparation of
2-(chlorophenoxymethyl)-4-methyl-1-[3-[1-[4-(piperid-
in-1-yl)-3-benzylbutyl]piperidin-3-yl]propyl]benzimidazole 205
EXAMPLE 131
[0592] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(3-ethoxy-
carbonyl-4-phenylbutyl)piperidin-3-yl]propyl]benzimidazole 206
EXAMPLE 132
[0593] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(3-carbox-
y-4-phenylbutyl)piperidin-4-yl]propyl]benzimidazole 207
EXAMPLE 133
[0594] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[3-(piper-
idin-1-ylcarbonyl)-4-phenylbutyl]piperidin-4-yl]propyl]benzimidazole
208
EXAMPLE 134
[0595] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[3-(piper-
idin-1-ylmethyl)-4-phenylbutyl]piperidin-4-yl]propyl]benzimidazole
209
EXAMPLE 135
[0596] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[3-(ethox-
ycarbonyl)butyl]piperidin-4-yl]propyl]benzimidazole 210
EXAMPLE 136
[0597] Preparation of
2-(4-chlorophenoxymethyl)-4methyl-1-[3-[1-[3-(ethoxy-
carbonyl)propyl]piperidin-4-yl]propyl]benzimidazole 211
EXAMPLE 137
[0598] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[3-(carbo-
xy)butyl]piperidin-4-yl]propyl]benzimidazole 212
EXAMPLE 138
[0599] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(3-carbox-
ypropyl)piperidin-4-yl]propyl]benzimidazole 213
EXAMPLE 139
[0600] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-1-[3-(piperi-
din-1-ylcarbonyl)butyl]piperidin-4-yl]propyl]benzimidazole 214
EXAMPLE 140
[0601] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[3-(piper-
idin-1-ylcarbonyl)propyl]piperidin-4-yl]propyl]benzimidazole
215
EXAMPLE 141
[0602] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[3-methyl-
-4-(piperidin-1-yl)butyl]piperidin-4-yl]propyl]benzimidazole
216
EXAMPLE 142
[0603] Preparation of
2-(4-chlorophenoxymethyl)-4methyl-1-[3-[1-[4-(piperi-
din-1-yl)butyl]piperidin-4-yl]propyl]benzimidazole 217
EXAMPLE 143
[0604] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(ethoxyca-
rbonyl)piperidin-4-yl]propyl]benzimidazole 218
EXAMPLE 144
[0605] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[3-(amino-
carbonyl)propyl]piperidin-4-yl]propyl]-benzimidazole 219
EXAMPLE 145
[0606] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[4-[3-(benzy-
lamino)propyl]piperidin-1-yl]propyl]-benzimidazole 220
EXAMPLE 146
[0607] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[4-[2-[(benz-
ylamino)carbonyl]ethyl]piperidin-1-yl]propyl]-benzimidazole 221
EXAMPLE 147
[0608] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[4-[2-[(4-me-
thoxybenzylamino)carbonyl]ethyl]piperidin-1-yl]propyl]-benzimidazole
222
EXAMPLE 147
[0609] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[4-[2-(benzy-
loxycarbonylamino)ethyl]piperidin-1-yl]propyl]-benzimidazole
223
EXAMPLE 148
[0610] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[4-(4-phenylpip-
eridin-1-yl)butyl]benzimidazole 224
EXAMPLE 149
[0611] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-methyl-4-[4--
phenyl-4-(acetamidomethyl)piperidin-1-yl]butyl]benzimidazole
225
EXAMPLE 150
[0612] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[4-(propylam-
inocarbonylethyl)piperidin-1-yl]propyl]benzimidazole 226
EXAMPLE 151
[0613] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[3-piperidin-
-1-yl)propylamino]propyl]benzimidazole 227
EXAMPLE 152
[0614] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-(4-phenylpip-
eridin-1-yl)propyl]benzimidazole 228
EXAMPLE 153
[0615] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[4-phenyl-4-(4--
phenyl-4-methylaminocarbonylpiperidin-1-yl)butyl]benzimidazole
229
EXAMPLE 154
[0616] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[3-(piperidi-
n-1-yl)propylamino]propyl]benzimidazole 230
EXAMPLE 155
[0617] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-(4-benzylpip-
eridin-1-yl)propyl]benzimidazole 231
EXAMPLE 156
[0618] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[N-benzoyl-N-
-[3-(piperidin-1-yl)propyl]amino]propyl}benzimidazole 232
EXAMPLE 157
[0619] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[4-(ethoxyca-
rbonylethyl)piperidin-1-yl]propyl}benzimidazole 233
EXAMPLE 158
[0620] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[4-hydroxy-4-
-benzylpiperidin-1-yl]propyl}benzimidazole 234
EXAMPLE 159
[0621] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-{4-(1,2,3,4-tet-
rahydroisoquinolin-1-yl)butyl}benzimidazole 235
EXAMPLE 160
[0622] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-{4-(4-(propoxy--
4-phenylpiperidin-1-yl)pentyl}benzimidazole 236
EXAMPLE 161
[0623] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[N-benzyl-N--
(3-piperidin-1-ylpropyl)amino]propyl}benzimidazole 237
EXAMPLE 162
[0624] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[N-(benzylox-
ycarbonylmethyl)-N-(3-piperidin-1-ylpropyl)amino]propyl}benzimidazole
238
EXAMPLE 163
[0625] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-{3-methyl-4-[4--
phenyl-4-(ethoxycarbonyl)piperidin-1-yl]butyl}benzimidazole 239
EXAMPLE 164
[0626] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[(1,2,3,4-te-
trahydronaphth-1-yl)amino]propyl}benzimidazole 240
EXAMPLE 165
[0627] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-(benzylamino-
)propyl]benzimidazole 241
EXAMPLE 166
[0628] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[4-(piperidi-
n-1-ylcarbonylethyl)piperidin-1-yl]propyl]benzimidazole 242
EXAMPLE 167
[0629] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-(piperidin-1-
-yl)propyl]benzimidazole 243
EXAMPLE 168
[0630] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-(4-phenyl-1,-
2,5,6-tetrahydropyridin-1-ylpropyl]benzimidazole 244
EXAMPLE 169
[0631] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-(4-phenyl-4--
ethoxycarbonylpiperidin-1-yl)propyl]benzimidazole 245
EXAMPLE 170
[0632] Preparation of
2-(4-chlorophenoxymethyl)-1-[2-(4-dimethylaminopiper-
idin-1-yl)ethyl]benzimidazole 246
EXAMPLE 171
[0633] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-(3-hydroxypropy-
l)benzimidazole 247
EXAMPLE 172
[0634] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-(3-cyanopropyl)- benzimidazole
248
[0635] mp 112.degree.. NMR, IR and UV were consistent with the
desired title structure. FDMS 339 (M+).
[0636] Analysis calculated for C.sub.19H.sub.18ClN.sub.3O:
[0637] Theory: C, 67.16; H, 5.34; N, 12.37.
[0638] Found: C, 66.95; H, 5.26; N, 12.16.
EXAMPLE 173
[0639] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-(3-azidopropyl)- benzimidazole
249
[0640] mp 68.degree.. NMR, IR and UV were consistent with the
desired title structure. FDMS 355 (M+).
[0641] Analysis calculated for C.sub.18H.sub.18N.sub.5O.sub.3:
[0642] Theory: C, 60.76; H, 5.10; N, 19.68.
[0643] Found: C, 61.00; H, 5.13; N, 19.70.
EXAMPLE 174
[0644] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[N-methyl-N--
(7-dimethylaminoheptyl)amino]propyl]benzimidazole 250
EXAMPLE 175
[0645] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[4-(2-phenyl-
ethyl)piperazin-1-yl]propyl]benzimidazole 251
EXAMPLE 176
[0646] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[(4-cyclohex-
ylpiperazin-1-yl)acetoxy]propyl]benzimidazole 252
[0647] NMR was consistent with the the desired title structure.
[0648] FAB exact mass calculated for
C.sub.30H.sub.40ClN.sub.4O.sub.3:
[0649] Theory: 539.2803
[0650] Found: 539.2789
EXAMPLE 177
[0651] Preparation of (RS)
2-(4-chlorophenoxyethyl)-4-methyl-1-[3-(pyrroli-
din-3-yloxy)propyl]benzimidazole. 253
[0652] NMR was consistent with the desired title structure. FDMS
399 (M+).
[0653] FAB exact mass calculated for
C.sub.22H.sub.27ClN.sub.3O.sub.2:
[0654] Theory: 400.1792
[0655] Found: 400.1805
EXAMPLE 178
[0656] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[3-(1-ben-
zoyl)propyl]piperidin-4-ylpropyl]benzimidazole 254
[0657] NMR, IR and UV were consistent with the desired title
structure.
[0658] FDMS 544 (M+).
[0659] Analysis calculated for
C.sub.33H.sub.38ClN.sub.3O.sub.2:
[0660] Theory C, 72.84; H, 7.04; N, 7.72.
[0661] Found: C, 72.58; H, 7.22: N, 7.72.
EXAMPLE 179
[0662] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[[4-2-phenyl-
ethyl)piperazin-1-yl]carbonyl]butyl]benzimidazole 255
EXAMPLE 180
[0663] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-methyl-4-[4--
(2-phenylethyl)piperazin-1-yl]butyl]benzimidazole 256
EXAMPLE 181
[0664] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-(1-benzylpip-
eridin-4-yl)propyl]benzimidazole 257
EXAMPLE 182
[0665] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(2-phenyl-
ethyl)piperidin-4-yl]propyl]benzimidazole 258
EXAMPLE 183
[0666] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(3-phenyl-
propyl)piperidin-4-yl]propyl]benzimidazole 259
[0667] MP 59.degree.. NMR was consistent with the desired title
structure.
[0668] FDMS 515 (M+).
[0669] Analysis calculated for C.sub.32H.sub.38ClN.sub.3O:
[0670] Theory: C, 74.47; H, 7.42; N, 8.14.
[0671] Found: C, 74.20; H, 7.23; N, 8.17.
EXAMPLE 184
[0672] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(benzoylm-
ethyl)piperidin-4-yl]propyl]benzimidazole 260
[0673] NMR and IR were consistent with the desired title structure.
Analysis calculated for C.sub.3H.sub.34ClN.sub.3O.sub.2:
[0674] Theory: C, 72.15; H, 6.64; N, 8.14.
[0675] Found: C, 72.35; H, 6.61; N, 8.34.
EXAMPLE 185
[0676] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(2-benzoy-
lethyl)piperidin-4-yl]propyl]benzimidazole 261
[0677] NMR was consistent with the desired title structure.
[0678] FAB exact mass calculated for
C.sub.32H.sub.37ClN.sub.3O.sub.2:
[0679] Theory: 530.2574
[0680] Found: 530.2584
[0681] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(3-hydrox-
y-3-phenylpropyl)piperidin-4-yl]propyl]benzimidazole 262
[0682] NMR was consistent with the desired title structure.
[0683] FAB exact mass calculated for
C.sub.32H.sub.39ClN.sub.3O.sub.2:
[0684] Theory: 532.2731
[0685] Found: 532.2738
EXAMPLE 187
[0686] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[2-formylethyl]- benzimidazole
263
EXAMPLE 188
[0687] Preparation of
2-(4-chloraphenoxymethyl)-4-methyl-1-(prop-1-en-3-yl-
)benzimidazole 264
EXAMPLE 189
[0688] Preparation of
2-(4-chlorophenoxymethyl)-7-methyl-1-(prop-1-en-3-yl-
)benzimidazole 265
EXAMPLE 190
[0689] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[4-phenyl-4--
acetamidomethyl)piperidin-1-yl]propyl]benzimidazole 266
EXAMPLE 191
[0690] Preparation of
2-(4-chlorophenoxymethyl)methyl-1-(4-aminobutyl)benz- imidazole
267
EXAMPLE 192
[0691] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-(piperidin-1-
-yl)propyl)benzimidazole 268
EXAMPLE 193
[0692] Preparation of
2-(chlorophenoxymethyl)methyl-1-[3-[[2-(phenylethylc-
arbamoyl)ethyl]piperidin-1-yl]propyl]benzimidazole 269
EXAMPLE 194
[0693] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl1-13-[[N-[3-(piper-
idin-1-yl)propyl]-N-2-phenylethyl]amino]propyl]benzimidazole
270
EXAMPLE 195
[0694] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-N-[3-(piperi-
din-1-yl)propyl]-N-(2-phenylethyl)amino]propyl]benzimidazole
271
EXAMPLE 196
[0695] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[N-(2-phenyl-
ethyl)amino]propyl]benzimidazole 272
EXAMPLE 197
[0696] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-(1,2,3,4-tet-
rahydroisoquinolin-1-yl)propyl]benzimidazole 273
EXAMPLE 198
[0697] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-(4-phenylpip-
erazin-1-yl)propyl]benzimidazole 274
EXAMPLE 199
[0698] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[N-[3-(piper-
idin-1-yl)propyl]-N-(biphenylacetyl)amino]propyl]benzimidazole
275
EXAMPLE 200
[0699] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[N-[3-(piper-
idin-1-yl)propyl]-N-(biphenylacetyl)amino]propyl]benzimidazole
276
EXAMPLE 201
[0700] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-(4-ethoxycar-
bonylpiperidin-1-yl)propyl]benzimidazole 277
EXAMPLE 202
[0701] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-(3-aminopropyl)- benzimidazole
278
EXAMPLE 203
[0702] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-(4-hydroxybutyl-
)benzimidazole 279
EXAMPLE 204
[0703] Preparation of
2-(4-chlorophenoxymethyl)-5-[2-(piperidin-1-yl)ethyl-
carbamoyl]-1-[3-(piperidin-4-yl)propyl]benzimidazole 280
EXAMPLE 205
[0704] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-(3-bromopropyl)- benzimidazole
281
EXAMPLE 206
[0705] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-(ethoxycarbo-
nyl)propyl]benzimidazole 282
EXAMPLE 207
[0706] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-(3-hydroxypropy-
l)benzimidazole 283
EXAMPLE 208
[0707] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[N-ethyl-N-(-
3-piperidin-1-ylpropyl)amino]propyl}benzimidazole 284
EXAMPLE 209
[0708] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[N-acetyl-N--
(3-piperidin-1-ylpropyl)amino]propyl}benzimidazole 285
EXAMPLE 210
[0709] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[N-(benzoylm-
ethyl)-N-(3-piperidin-1-ylpropyl)amino]propyl}benzimidazole 286
EXAMPLE 211
[0710] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[N-(benzylox-
ycarbonylmethyl)-N-(3-piperidin-1-ylpropyl)amino]propyl}benzimidazole
287
EXAMPLE 212
[0711] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[4-benzoylpi-
peridin-1-yl]propyl}benzimidazole 288
EXAMPLE 212A
[0712] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[2-(piperidi-
n-1-ylethyl)piperidin-1-yl]propyl}benzimidazole 289
EXAMPLE 213
[0713] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[4-(propylca-
rbanoylethyl)piperidin-1-yl]propyl}benzimidazole 290
EXAMPLE 214
[0714] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[4-[2-(pheny-
lethylcarbamoyl)ethyl]piperidin-1-yl]propyl}benzimidazole 291
EXAMPLE 215
[0715] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-(4-methylamino--
3-methylbutyl)benzimidazole 292
EXAMPLE 216
[0716] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-(4-methylamino--
3-benzylbutyl)benzimidazole 293
EXAMPLE 217
[0717] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[4-(piperidin-1-
-yl)-3-methylbutyl]benzimidazole 294
EXAMPLE 218
[0718] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[4-(piperidin-1-
-yl)-3-benzylbutyl]benzimidazole 295
EXAMPLE 219
[0719] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[3-[(piperid-
in-1-yl)amino]carbonyl]-3-methylpropyl]benzimidazole 296
EXAMPLE 220
[0720] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[3-[(piperid-
in-1-yl)amino]carbonyl]-3-benzylpropyl]benzimidazole 297
EXAMPLE 221
[0721] Preparation of
2-(4-nitrophenoxymethyl)-4-methyl-1-[3-[1-(t-butoxyc-
arbonyl)piperidin-3-yl]propyl]benzimidazole 298
[0722] NMR and IR were consistent with the desired title product.
FDMS 508 (M+).
[0723] Analysis for C.sub.28H.sub.36N.sub.4O.sub.5:
[0724] Theory: C, 66.12; H, 7.13; N, 11.01.
[0725] Found: C, 65.86; H, 7.09; N, 10.98.
EXAMPLE 222
[0726] Preparation of
2-(4-aminophenoxymethyl)-4-methyl-1-[3-[1-(t-butoxyc-
arbonyl)piperidin-3-yl]propyl]benzimidazole 299
[0727] A mixture of
2-(4-nitrophenoxymethyl)-4-methyl-1-[3-[1-(t-butoxycar-
bonyl)piperidin-3-yl]propyl]benzimidazole (395 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
hours, the reaction mixture was filtered through a CELITE.TM. cake.
The filtrate was condensed on a rotoevaporator to yield 310 mg
(83%) of the desired title product.
[0728] NMR and IR were consistent with the desired tide product.
FDMS 478 (M+).
[0729] Analysis for C.sub.28H.sub.38N.sub.4O.sub.3:
[0730] Theory: C, 70.26; H, 8.00; N, 11.70.
[0731] Found: C, 70.00; H, 7.97; N, 11.60.
EXAMPLE 223
[0732] Preparation of
2-[4-(t-butoxycarbonylamino)phenoxymethyl]-4-methyl--
1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl]benzimidazole
300
[0733] A solution of
2-(4-aminophenoxymethyl)-4-methyl-1-[3-[1-(t-butoxyca-
rbonyl)piperidin-3-yl]propyl]benzimidazole (160 mg, 0.33 mmol, 1.0
eq.) in a 1:1 mixture of anhydrous tetrahydrofuran and water (2 ml
total) was treated with potassium carbonate (56 mg, 0.4 mmol, 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 mixture. The organic fraction was extracted
with ethyl acetate (3.times.10 ml). The combined organic fraction
was washed with water (10 ml), brine (1.times.10 ml), 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
[0734] Preparation of .alpha.-benzyl-.gamma.-butyrolactone
(3-benzyl-3,4-dihydrofuran-2-one) 301
[0735] To a solution of diisopropylamine (15.18 g, 0.15 mol) in dry
tetrahydrofuran (200 ml) at -78.degree. C. under a nitrogen
atmosphere, n-butyllithium (1.6M in hexanes, 94 ml, 0.15 mol) was
added dropwise. After twenty minutes of sting at -78.degree. C.,
.gamma.-butyrolactone (12.91 g, 0.15 mol) was added dropwise, such
that the reaction temperature was maintained below -70.degree. C.
After twenty minutes of stirring at -78.degree. C., a mixture of
benzyl bromide (25.65 g, 0.15 mol) and hexamethylphosphoramide
(26.85 g, 0.15 mol) was added dropwise to the reaction mixture. The
reaction mixture was then permitted to warm to -30.degree. C. and
stirred at this temperature for two hours.
[0736] The reaction mixture was partitioned between a saturated
ammonium chloride solution (500 ml) and diethyl ether (500 ml). The
organic fraction was dried over potassium carbonate and the
solvents were removed in vacuo to yield 36.13 grams of the desired
intermediates as a dark yellow oil.
[0737] The crude material was further purified by flash silica gel
chromatography eluting with a solvent gradient beginning at 19:1
hexanes/ethyl acetate and ending with 3:1 hexanes/ethyl acetate.
The fractions containing 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.
[0738] FDMS 177 (M+1)
[0739] Analysis for C.sub.11H.sub.12O.sub.2:
[0740] Theory C, 74.98; H, 6.86.
[0741] Found: C, 74.76; H, 6.73.
Preparation 53
[0742] Preparation of ethyl 2-benzyl-4-bromobutanoate 302
[0743] In absolute ethanol (78 ml),
.alpha.-benzyl-.gamma.-butyrolactone (14 g, 80 mmol) was added and
then saturated for thirty minutes with gaseous hydrogen bromide,
maintaining the temperature below 50.degree. C. The reaction was
then heated to 45.degree. C. and stirred at this temperature for 16
hours. The solution was concentrated under reduced pressure and the
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 to yield 15.13 grams of tan oil.
[0744] The crude mixture was further purified by flask silica gel
chromatography, eluting with a gradient solvent of hexanes to a 1:1
mixture of hexanes/methylene chloride. The fractions containing the
desired intermediate were combined and concentrated under reduced
pressure to yield 13.47 grams (67%).
[0745] IR and NMR were consistent with the proposed title
structure. FDMS 286.1 (M+1)
[0746] Analysis for C.sub.13H.sub.17O.sub.2Br:
[0747] Theory: C, 54.75; H, 6.01.
[0748] Found: C, 54.99; H, 6.02.
Preparation 54
[0749] Preparation of ethyl 2-methyl-4-bromobutanoate 303
[0750] In absolute ethanol (78 ml),
.alpha.-methyl-.gamma.-butyrolactone (8 g, 8 mmol) was added and
then saturated for thirty minutes with gaseous hydrogen bromide,
maintaining the temperature below 50.degree. C. The reaction was
then heated to 45.degree. C. and stirred at this temperature for 16
hours. The solution was concentrated under reduced pressure and the
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.
[0751] The crude mixture was further purified by flask silica gel
chromatography, eluting with a gradient solvent of hexanes to a 1:1
mixture of hexanes/methylene chloride. The fractions containing the
desired intermediate were combined and concentrated under reduced
pressure to yield 7.1 grams (44%).
[0752] IR and NMR were consistent with the proposed title
structure. FDMS 208, 209, 210
[0753] Analysis for C.sub.7H.sub.13O.sub.2Br:
[0754] Theory: C, 40.21; H, 6.27.
[0755] Found: C, 39.24; H, 6.19.
Preparation 55
[0756] Preparation of (RS) ethyl 2-phenyl-4-chlorobutanoate 304
[0757] To a solution of diisopropylamine (23 ml, 0.16 mol) in dry
tetrahydrofuran (100 ml) at -78.degree. C., under a nitrogen
atmosphere, was added dropwise n-butyllithium (100 ml of a 1.6M
solution, 160 mmol). After stirring for thirty minutes at
-78.degree. C., ethyl phenylacetate (25 g, 0.15 mol) in dry
tetrahydrofuran (172 ml) was added dropwise to the reaction
mixture. The resulting mixture was permitted to warm to -30.degree.
C. After stirring for fifteen minutes at -30.degree. C.,
N,N-dimethylpropylene urea (18 ml, 0.15 mol) in dry tetrahydrofuran
(30 ml) was added dropwise and the resulting mixture was stirred
for ten minutes.
[0758] The reaction mixture was added via cannula under nitrogen
atmosphere into a flask containing 1-bromo-2-chloroethane (63 ml,
0.75 mol) in diethyl ether (200 ml) at -15.degree. C. This reaction
mixture was then stirred at -15.degree. C. for three hours. The
reaction mixture was partitioned between a saturated ammonium
chloride in water solution (500 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.
[0759] The crude material was further purified by flash silica gel
chromatography, eluting with a solvent gradient of hexanes to 1:1
hexanes:methylene chloride. Fractions containing the desired title
product were combined and concentrated under reduced pressure to
yield 15.0 grams (44%) as a clear oil.
[0760] NMR was consistent with the proposed title structure.
[0761] FDMS 226.1 (M+)
[0762] Analysis for C.sub.12H.sub.15O.sub.2Cl:
[0763] Theory: C, 63.58; H, 6.67.
[0764] Found: C, 63.29; H, 6.80.
Preparation 56
[0765] Preparation of 4-(cyclohexyl)piperidine and
4-phenylpiperidine 305
[0766] 3-Phenylpyridine (25 g, 0.16 mol) was placed in ethanol (470
ml) along with rhodium (5% on alumina, 5.0 g) and was subjected to
hydrogenation at room temperature 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 grams of a tan oil. The mixture of compounds was
further purified by flash chromatography, eluting with methanol.
The fractions containing the desired title intermediates were
combined and concentrated in vacuo to yield 22.41 grams (86%) of a
clear oil.
[0767] NMR and FDMS were consistent with the proposed title
structures.
Preparation 57
[0768] Preparation of 4-(cyclohexylmethyl)piperidine and
4-benzylpiperidine 306
[0769] 3-Benzylpyridine (5 g, 0.029 mol) was placed in ethanol (145
ml) along with rhodium (5% on alumina, 0.125 g) and was subjected
to hydrogenation at room temperature 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 4.71 grams of a tan oil. The mixture of compounds was
further purified by flash chromatography, eluting with methanol.
The fractions containing the desired title intermediates were
combined and concentrated in vacuo to yield 3.64 grams (71%) of a
clear oil.
[0770] NMR and FDMS were consistent with the proposed title
structures.
EXAMPLE 224
[0771] Preparation of
1-[3-(ethoxycarbonyl)butyl]-2-[(4-chlorophenoxy)meth-
yl]-4-methylbenzimidazole 307
[0772] A sodium hydride solution (60% in oil, 810 mg, 20.3 mmol)
was washed with hexanes; (2.times.50 ml) and then diluted with
N,N-dimethylformamide (100 ml). At room temperature, under a
nitrogen atmosphere,
2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (5 g, 18.3 mmol)
was then added in one portion. The resulting mixture was then
stirred at room temperature for thirty minutes, and then
3-(ethoxycarbonyl)butyl bromide (4.25 g, 20.3 mmol) in
N,N-dimethylformamide (10 ml) was added dropwise. Upon completion
of this addition, the reaction mixture was stirred for about six
hours at a temperature of 70-80.degree. C. The reaction mixture 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 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 acetate. The
fractions containing the desired title product were combined and
concentrated in vacuo to yield 7.21 grams (98%) of a viscous yellow
oil.
[0773] NMR and IR were consistent with the proposed title
structure.
[0774] FDMS 401 (M+)
[0775] Analysis for C.sub.22H.sub.25N.sub.2O.sub.3Cl:
[0776] Theory: C, 65.91; H, 6.29; N, 6.99.
[0777] Found: C, 66.13; H, 6.50; N, 7.11.
EXAMPLE 225
[0778] Preparation of
1-[3-(ethoxycarbonyl)-4-phenylbutyl]-2-[(4-chlorophe-
noxy)methyl]-4-methylbenzimidazole 308
[0779] A sodium hydride solution (60% in oil, 810 mg, 20.3 mmol)
was washed with hexanes (2.times.50 ml) and then diluted with
N,N-dimethylformamide (100 ml). At room temperature, under a
nitrogen atmosphere,
2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (5.0 g, 18.3
mmol) was then added in one portion. The resulting mixture was then
stirred at room temperature for thirty minutes, and then
3-(ethoxycarbonyl)-4-phenylbutyl bromide (5.79 g, 20.3 mmol) in
N,N-dimethylformamide (10 ml) was added dropwise. Upon completion
of this addition, the reaction mixture was stirred for about six
hours at a temperature of 70-80.degree. C. The reaction mixture 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 containing the desired title product were combined and
concentrated in vacuo to yield 8.08 grams (93%) of a viscous yellow
oil.
[0780] NMR and IR were consistent with the proposed title
structure.
[0781] FDMS 476, 477 (M+)
[0782] Analysis for C.sub.28H.sub.29N.sub.2O.sub.3Cl:
[0783] Theory: C, 70.50; H, 6.13; N, 5.87.
[0784] Found: C, 67.56; H, 6.22; N, 6.37.
EXAMPLE 226
[0785] Preparation of
1-[3-(ethoxycarbonyl)propyl]-2-[(4-chlorophenoxy)met-
hyl]-4-methylbenzimidazole 309
[0786] A sodium hydride solution (60% in oil, 325 mg, 8.1 mmol) was
washed with hexanes (2.times.50 ml) and then diluted with
N,N-dimethylformamide (100 ml). At room temperature, under a
nitrogen atmosphere,
2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (2.0 g, 7.3 mmol)
was then added in one portion. The resulting mixture was then
stirred at room temperature for thirty minutes, and then
3-(ethoxycarbonyl)propyl bromide (1.58 g, 8.1 mmol) in
N,N-dimethylformamide (10 ml) was added dropwise. Upon completion
of this addition, the reaction mixture was stirred for about six
hours at a temperature of 70-80.degree. C. The reaction mixture 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 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 containing the desired title product were combined and
concentrated in vacuo to yield 2.21 grams (78%) of a viscous yellow
oil.
[0787] mp 78.5-80.degree. C.
[0788] NMR was consistent with the proposed title structure.
[0789] FDMS 386 (M+)
[0790] Analysis for C.sub.21H.sub.23N.sub.2O.sub.3Cl:
[0791] Theory C, 65.20; H, 5.99; N, 7.24.
[0792] Found: C, 64.97; H, 6.05; N, 7.23.
EXAMPLE 227
[0793] Preparation of
1-(3-carboxybutyl)-2-[(4-chlorophenoxy)methyl]-4-met-
hylbenzimidazole 310
[0794] To a mixture of tetrahydrofuran (42 ml), methanol (14 ml),
and water (14 ml), were added
1-[3{ethoxycarbonyl)butyl]-2-[(4-chlorophenoxy)-
methyl]-4-methylbenzimidazole (1.3 g, 3.2 mmol) and lithium
hydroxide (403 mg, 3 eq.). The resulting mixture 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
butanol:toluene solution. The organic fraction was washed once with
200 ml of water and then dried over magnesium sulfate. The solvents
were removed in vacuo to yield 1.22 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 containing the desired material
were combined and concentrated under reduced pressure to yield 1.12
grams (94%) of the desired title product as a white solid.
[0795] mp 149-151.degree. C.
[0796] NMR and IR were consistent with the proposed title
structure.
[0797] FDMS 373 (M+)
[0798] Analysis for C.sub.20H.sub.21N.sub.2O.sub.3Cl:
[0799] Theory C, 64.43; H, 5.68; N, 7.51.
[0800] Found: C, 64.62; H, 5.91; N, 7.26.
EXAMPLE 228
[0801] Preparation of
1-(4-phenyl-3-carboxybutyl)-2-[(4-chlorophenoxy)meth-
yl]-4-methylbenzimidazole 311
[0802] To a mixture of tetrahydrofuran (84 ml), methanol (28 ml),
and water (28 ml), were added
1-[3-(ethoxycarbonyl)-4-phenylbutyl]-2-[(4-chlo-
rophenoxy)methyl]-4-methylbenzimidazole (3.05 g, 6.4 mmol) and
lithium hydroxide (788 mg, 3 eq.). The resulting mixture 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 butanol:toluene solution. The organic fraction was washed
once with 200 ml of water and then dried over magnesium 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 containing the desired material
were combined and concentrated under reduced pressure to yield 2.71
grams (94%) of the desired title product as a white solid.
[0803] mp 190-191.5.degree. C.
[0804] NMR and IR were consistent with the proposed title
structure.
[0805] FDMS 448 (M+)
[0806] Analysis for C.sub.26H.sub.25N.sub.2O.sub.3Cl:
[0807] Theory: C, 69.56; H, 5.61; N, 6.24.
[0808] Found: C, 69.77; H, 5.68; N, 6.46.
EXAMPLE 229
[0809] Preparation of
1-(3-carboxypropyl)-2-[(4-chlorophenoxy)methyl]-4-me-
thylbenzimidazole 312
[0810] To a mixture of tetrahydrofuran (72 ml), methanol (24 ml),
and water (24 ml), were added
1-[3-(ethoxycarbonyl)propyl]-2-[(4-chlorophenox-
y)methyl]-4-methylbenzimidazole (2.0 g, 5.2 mmol) and lithium
hydroxide (642 mg, 3 eq.). The resulting mixture 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
butanol:toluene solution. The organic fraction was washed once with
200 ml of water and then dried over magnesium sulfate. The solvents
were removed in vacuo to yield 1.56 grams of tan solid, which was
further purified by flash chromatography, elutin with a gradient
solvent of 19:1 ethyl acetate:methanol to 9:1 ethyl
acetate:methanol. The fractions containing 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.
[0811] NMR was consistent with the proposed title structure.
[0812] FDMS 359 (M+)
[0813] Analysis for C.sub.19H.sub.19N.sub.2O.sub.3Cl:
[0814] Theory: C, 63.60; H, 5.34; N, 7.81.
[0815] Found: C, 63.32; H, 5.26; N, 7.82.
EXAMPLE 230
[0816] Preparation of
1-[3-(N-methylcarbamoyl)butyl]-2-[(4-chlorophenoxy)m-
ethyl]-4-methylbenzimidazole 313
[0817] In methylamine (40% in water, 20 ml,
1-[3-(ethoxycarbonyl)butyl]-2--
(4-chlorophenoxy)methyl]-4-methylbenzimidazole (1.50 g, 3.7 mmol)
was placed. To this mixture 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
mixture was concentrated in vacuo. The 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 chromatography, eluting with a gradient of
methylene chloride to a 1:1 methylene chloride:ethyl acetate
mixture. The fractions containing the desired material were
combined and concentrated under reduced pressure to yield 510 mg
(36%) of the desired title product as a white solid.
[0818] mp 167.5-168.5.degree. C.
[0819] NMR and IR were consistent with the proposed title
structure.
[0820] FDMS 386 (M+)
[0821] Analysis for C.sub.21H.sub.24N.sub.3O.sub.2Cl:
[0822] Theory: C, 65.36; H, 6.27; N, 10.89.
[0823] Found: C, 65.10; H, 6.46; N, 10.96.
EXAMPLE 231
[0824] Preparation of
1-[3-(N-methylcarbamoyl)-4-phenylbutyl]-2-[(4-chloro-
phenoxy)methyl]-4-methylbenzimidazole 314
[0825] In methylamine (40% in water, 10 ml),
1-[3-(ethoxycarbonyl)-4-pheny-
lbutyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (1.0 g,
2.5 mmol) was placed. To this mixture 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
mixture was concentrated in vacuo. The 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 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
mixture. The fractions containing the desired material were
combined and concentrated under reduced pressure to yield 305 mg
(26%) of the desired title product as a crystalline material.
[0826] mp 169-170.5.degree. C.
[0827] NMR and IR were consistent with the proposed title
structure.
[0828] FDMS 461, 462 (M+)
[0829] Analysis for C.sub.27H.sub.28N.sub.3O.sub.2Cl:
[0830] Theory: C, 70.20; H, 6.11; N, 9.09.
[0831] Found: C, 69.91; H, 5.85; N, 9.09.
EXAMPLE 232
[0832] Preparation of
1-[3-(chlorocarbonyl)butyl]-2-[(4-chlorophenoxy)meth-
yl]-4-methylbenzimidazole 315
[0833] Under a nitrogen atmosphere at room temperature
1-[3-(carboxy)butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole
(1.2 g, 3.2 mmol) was added in one portion to oxalyl chloride (5
ml) in methylene chloride (150 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
approximately fifteen minutes. The reaction mixture was stirred at
room temperature for two hours. The reaction mixture was then
concentrated under reduced pressure, resulting in the formation of
a white solid. The solid was triturated in 100 ml of hexanes,
filtered and dried in a vacuum oven at 50.degree. C. for one hours
to yield the title product (1.3 g, 91%) as a white solid.
[0834] mp 140-142.degree. C.
[0835] NMR was consistent with the proposed title structure.
[0836] FDMS 390, 391 (M+)
[0837] Analysis for C.sub.20H.sub.20N.sub.2O.sub.2Cl:
[0838] Theory: C, 61.39; H, 5.15; N, 7.16.
[0839] Found: C, 56.11; H, 5.00; N, 6.61.
EXAMPLE 233
[0840] Preparation of
1-[3-(carbamoyl)butyl]-2-[(4-chlorophenoxy)methyl]-4-
-methylbenzimidazole 316
[0841] In an ammonium hydroxide solution (28%, 10 ml) was placed
1-[3-(chlorocarbonyl)butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimida-
zole (400 mg, 1.0 mmol). To this mixture 10 ml of methanol were
added, to enhance solubility and the mixture was stirred for about
64 hours at room temperature. The reaction mixture was then
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 acetate:methanol. The fractions
containing the desired material were combined and concentrated in
vacuo to yield 300 mg (73%) of the desired title compound as a
white foam.
[0842] NMR was consistent with the proposed title structure.
[0843] FDMS 371.3 (M+)
EXAMPLE 234
[0844] Preparation of
1-[3-(N,N-dimethylcarbamoyl)butyl]-2-[(4-chloropheno-
xy)methyl]-4-methylbenzimidazole 317
[0845] In an dimethylamine (40% in water, 10 ml) was placed
1-[3-(chlorocarbonyl)butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimida-
zole (600 mg, 1.5 mmol). To this mixture 10 ml of methanol were
added, to enhance solubility and the mixture was stirred for about
64 hours at room temperature. The reaction mixture was then
concentrated under reduced pressure to produce 600 mg as a tan
foam. The crude material was further purified by flash silica gel
chromatography, elute with a gradient solvent of 19:1 ethyl
acetate:methanol to 9:1 ethyl acetate:methanol. The fractions
containing the desired material were combined and concentrated in
vacuo to yield 375 mg (63%) of the desired title compound as a
white foam.
[0846] NMR was consistent with the proposed title structure.
EXAMPLE 235
[0847] Preparation of
1-[4-(methylamino)-3-methylbutyl]-2-[(4-chlorophenox-
y)methyl]-4-methylbenzimidazole dihydrochloride salt monohydrate
318
[0848] Under a nitrogen atmosphere
1-[3-[(methylamino)carbonyl]butyl]-2-[(-
4-chlorophenoxy)methyl]methylbenzimidazole (100 mg, 0.26 mmol) was
added via spatual to a solution of RED-AL.TM. (2 ml) in 10 ml dry
toluene at room temperature. The reaction mixture was then heated
to 55.degree. 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 organic 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
chromatography, eluting with 2% ethylamine in methanol. The
fractions containing the desired title product were combined and
concentrated under reduced pressure to yield 30 mg of a viscous oil
(Yield 31%).
[0849] The title desired product was converted to the
dihydrochloride salt by placing the free base in 10 ml ethyl
acetate and adding a saturated solution of hydrochloric acid in
diethyl ether, until 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.degree. C.
for one hour yield 32 mg of the dihydrochloride salt as a white
solid.
[0850] mp 79-81.degree. C.
[0851] FDMS 371 (M+)
[0852] Analysis for C.sub.21H.sub.28N.sub.3OCl.circle-solid.2
HCl.circle-solid.H.sub.2O:
[0853] Theory: C, 54.49; H, 6.53; N, 9.08.
[0854] Found: C, 54.55; H, 6.23; N, 8.97.
EXAMPLE 236
[0855] Preparation of
1-[4-(methylamino)-3-benzylbutyl)-2-[(4-chlorophenox-
y)methyl]-4-methylbenzimidazole dihydrochloride salt 319
[0856] Under a nitrogen atmosphere
1-[3-[(methylamino)carbonyl]-4-phenylbu-
tyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (470 mg,
0.87 mmol) was added via spatual to a solution of RED-AL.TM. (3 ml)
in 10 ml dry toluene at room temperature.
[0857] The reaction mixture was then heated to 55.degree. 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 organic fraction was washed once
with water, and then dried over potassium carbonate. The solvents
were removed in vacuo to yield 161 mg of a viscous oil. The crude
material was further purified by flash chromatography, eluting with
2% ethylamine in methanol. The fractions containing the desired
title product were combined and concentrated under reduced pressure
to yield 117 mg of a viscous oil (Yield 30%).
[0858] The title desired product was converted to the
dihydrochloride salt by placing the free base in 10 ml ethyl
acetate and adding a saturated solution of hydrochloric acid in
diethyl ether, until 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.degree. C.
for one hour yield 104 mg of the dihydrochloride salt as a white
solid.
[0859] mp 106-109.degree. C.
[0860] NMR was consistent with the proposed title structure.
[0861] FDMS 448 (M+)
[0862] Analysis for C.sub.27H.sub.32N.sub.3OCl.circle-solid.2
HCl:
[0863] Theory: C, 62.25; H, 6.19; N, 8.07.
[0864] Found: C, 63.77; H, 6.33; N, 8.30.
EXAMPLE 237
[0865] Preparation of
1-[4-(piperidin-1-yl)-3-methylbutyl]-2-[(4-chlorophe-
noxy)methyl]-4-methylbenzimidazole dihydrochloride salt 320
[0866] Under a nitrogen atmosphere
1-[3-[(piperidin-1-yl)carbonyl]butyl]-2-
-[(4-chlorophenoxy)methyl)-4-methylbenzimidazole (800 mg, 1.80
mmol) was added via spatual to a solution of RED-AL.TM. (5 ml) in
10 ml dry toluene at room temperature. The reaction mixture was
then heated to 55.degree. 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
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% ethylamine in
methanol. The fractions containing the desired title product were
combined and concentrated under reduced pressure to yield 200 mg of
a light yellow oil (Yield 27%).
[0867] The title desired product was converted to the
dihydrochloride salt by placing the free base in 10 ml ethyl
acetate and adding a saturated solution of hydrochloric acid in
diethyl ether, until 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.degree. C.
for one hour yielded the dihydrochloride salt as a white solid.
[0868] mp 98-102.degree. C.
[0869] NMR was consistent with the proposed title structure.
[0870] FDMS 425, 426 (M+)
[0871] Analysis for C.sub.25H.sub.34N.sub.3OCl.circle-solid.2
HCl:
[0872] Theory: C, 60.19; H, 6.87; N, 8.42.
[0873] Found: C, 60.33; H, 6.88; N, 8.69.
EXAMPLE 238
[0874] Preparation of
1-[3-[(piperidin-1-yl)carbonyl]-4-phenylbutyl]-2-[(4-
-chlorophenoxy)methyl]-4-methylbenzimidazole 321
[0875] To a stirring solution of
1-[3-carboxy-4-phenylbutyl]-2-[(4-chlorop-
henoxy)methyl]-4-methylbenzimidazole (1.0 g, 2.2 mmol) in
N,N-dimethylformamide (75 ml) were added sequentially piperidine
(206 mg, 1.1 eq), 1-hydroxy-benzotriazole (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 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 1.84 grams of a tan foam.
[0876] This crude material was purified by flash silica gel
chromatography, eluting with a gradient solvent of 9:1
hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate. The fractions
containing the desired material were combined and concentrated
under reduced pressure to yield 880 mg (77%) of the desired title
product as a viscous oil. The slowly crystallizing oil was
recrystallized from 10: hexanes:ethyl acetate to yield 710 mg as a
white solid.
[0877] mp 93.5-95.degree. C.
[0878] NMR and IR were consistent with the proposed title
structure.
[0879] FDMS 515, 516 (M+)
[0880] Analysis for C.sub.31H.sub.34N.sub.3O.sub.2Cl:
[0881] Theory: C, 72.15; H, 6.64; N, 8.14.
[0882] Found: C, 71.88; H, 6.73; N, 7.98.
EXAMPLE 239
[0883] Preparation of
1-[3-[(piperidin-1-yl)carbonyl]butyl]-2-[(4-chloroph-
enoxy)methyl]-4-methylbenzimidazole 322
[0884] To a stirring solution of
1-[3-carboxybutyl]-2-[(4-chlorophenoxy)me-
thyl]-4-methylbenzimidazole (1.2 g, 3.2 mmol) in
N,N-dimethylformamide (75 ml) were added sequentially piperidine
(299 mg, 1.1 eq), 1-hydroxybenzotriazole (475 mg, 1.1 eq), and
dicyclohexylcarbodiimide (726 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 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 1.78 grams of a tan foam.
[0885] This crude material was purified by flash silica gel
chromatography, eluting with a gradient solvent of 1:1
hexanes:ethyl acetate to ethyl acetate. The fractions containing
the desired material were combined and concentrated under reduced
pressure to yield 910 mg (65%) of the desired title product as a
white foam.
[0886] NMR was consistent with the proposed title structure.
[0887] FDMS 439.3 (M+)
[0888] Analysis for C.sub.25H.sub.30N.sub.3O.sub.2Cl:
[0889] Theory: C, 68.25; H, 6.87; N, 9.55.
[0890] Found: C, 68.54; H, 6.97; N, 9.52.
EXAMPLE 240
[0891] Preparation of
1-[3-[3-(piperidin-1-yl)propylcarbamoyl]butyl]-2-[(4-
-chlorophenoxy)methyl]-4-methylbenzimidazole 323
[0892] To a stirring solution of
1-[3-carboxybutyl)-2-[(4-chlorophenoxy)me-
thyl]-4-methylbenzimidazole (1.2 g, 3.2 mmol) in
N,N-dimethylformamide (75 ml) were added sequentially
1-amino-3-(piperidin-1-yl)propane (500 mg, 1.1 eq),
1-hydroxybenzotriazole (475 mg, 1.1 eq), and
dicyclohexylcarbodiimide (726 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 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 2.00 grams of a semisolid material.
[0893] This crude material was purified by flash silica gel
chromatography, eluting with a gradient solvent of 9:1
hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate. The fractions
containing the desired material were combined and concentrated
under reduced pressure to yield 1.04 g (65%) of the desired title
product as a white foam. The title product was recrystallized from
a 9:1 hexanes:ethyl acetate mixture to yield 800 mg as
crystals.
[0894] mp 102-103.degree. C.
[0895] NMR and IR were consistent with the proposed title
structure.
[0896] FDMS 496, 497 (M+)
[0897] Analysis for C.sub.28H.sub.37N.sub.4O.sub.2Cl:
[0898] Theory: C, 67.66; H, 7.50; N, 11.27.
[0899] Found: C, 67.41; H, 7.79; N, 11.22.
EXAMPLE 241
[0900] Preparation of
1-[3-[3-(piperidin-1-yl)propylcarbamoyl]-4-phenylbut-
yl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole 324
[0901] To a stirring solution of
1-[3-carboxy-4-phenylbutyl]-2-[(4-chlorop-
henoxy)methyl]-4-methylbenzimidazole (1.0 g, 2.2 mmol) in
N,N-dimethylformamide (75 ml) were added sequentially
1-amino-3-(piperidin-1-yl)propane (345 mg, 1.1 eq),
1-hydroxybenzotriazole (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 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 1.35 grams of an orange foam.
[0902] This crude material was purified by flash silica gel
chromatography, eluting with a gradient solvent of 19:1 ethyl
acetate:methanol to ethyl acetate:methanol. The fractions
containing the desired material were combined and concentrated
under reduced pressure to yield 950 mg (75%) of the desired title
product as a slowly crystallizing oil. The title product was
recrystallized from a 19:1 hexanes:ethyl acetate mixture to yield
800 mg as crystals.
[0903] mp 91-93.degree. C.
[0904] NMR and IR were consistent with the proposed title
structure.
[0905] FDMS 572-573 (M+)
[0906] Analysis for C.sub.34H.sub.41N.sub.4O.sub.2Cl:
[0907] Theory: C, 71.25, H, 7.21; N, 9.78.
[0908] Found: C, 71.15; H, 7.39; N, 9.67.
EXAMPLE 242
[0909] Preparation of
1-[3-[(1,2,3,4-tetrahydroisoquinolin-1-yl)carbonyl]b-
utyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole 325
[0910] To a stirring solution of
1-[3-carboxybutyl]-2-[(4-chlorophenoxy)me-
thyl]-4-methylbenzimidazole (0.800 g, 2.2 mmol) in
N,N-dimethylformamide (50 ml) were added sequentially
1,2,3,4-tetrahydroisoquinoline (322 mg, 1.1 eq),
1-hydroxybenzotriazole (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 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 1.24 grams of a dark oil.
[0911] This crude material was purified by flash silica gel
chromatography, eluting with a gradient solvent of 1:1
hexanes:ethyl acetate to ethyl acetate. The fractions containing
the desired material were combined 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 hexanes:ethyl
acetate mixture to yield 734 mg (69%) as a white foam
[0912] NMR was consistent with the proposed title structure.
[0913] FDMS 487, 488 (M+)
[0914] Analysis for C.sub.29H.sub.3N.sub.3O.sub.2Cl:
[0915] Theory: C, 71.37; H, 6.20; N, 8.61.
[0916] Found: C, 70.97; H, 6.20; N, 8.52.
EXAMPLE 243
[0917] Preparation of
1-[3-[(1,2,3,4-tetrahydronaphth-1-ylamino)carbonyl]b-
utyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole 326
[0918] To a stirring solution of
1-[3-carboxybutyl]-2-[(4-chlorophenoxy)me-
thyl]-4-methylbenzimidazole (0.800 g, 2.2 mmol) in
N,N-dimethylformamide (50 ml) were added sequentially
1,2,3,4-tetrahydronaphthalene (356 mg, 1.1 eq),
1-hydroxybenzotriazole (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 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 1.3 grams of a semi-solid. This crude
material was purified by recrystallization from 9:1 ethyl
acetate:ethanol to yield 741 mg (67%) as a white solid
[0919] mp 192-194.degree. C.
[0920] NMR was consistent with the proposed title structure.
[0921] FDMS 501, 502 (M+)
[0922] Analysis for C.sub.30H.sub.32N.sub.3O.sub.2Cl:
[0923] Theory: C, 71.77; H, 6.43; N, 8.37.
[0924] Found: C, 71.43; H, 6.52; N, 8.22.
EXAMPLES 244 AND 245
[0925] Preparation of (R)
1-[3-[[2-[(2-piperidin-1-yl)ethyl]piperidin-1-yl-
]carbonyl]butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole
dihydrochloride salt monohydrate[A] and (S)
1-[3-[[2-[(2-piperidin-1-yl)e-
thyl]piperidin-1-yl]carbonyl]butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbe-
nzimidazole dihydrochloride salt [B] 327
[0926] To a stirring solution of
1-[3-carboxybutyl]2-[(4-chlorophenoxymeth-
yl]-4-methylbenzimidazole (0.800 g, 2.2 mmol) in N,N
dimethylformamide (50 ml) were added sequentially (RS)
2-[(piperidin-1-yl)ethylpiperidine (475 mg, 1.1 eq),
1-hydroxybenzotriazole (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 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 1.3 grams of the racemate as a yellow
foam.
[0927] The isomers were separated and purified by flash silica gel
chromatography, eluting with a solvent gradient of 9:1 ethyl
acetate:methanol to 1:1 ethyl acetate:methanol. Fractions
containing each isomer were then concentrated under reduced
pressure and converted to the dihydrochloride salt as a white
solid. Yield: (R) isomer--335 mg; (S) isomer 164 mg.
[0928] [A]
[0929] mp 106-109.degree. C.
[0930] NMR was consistent with the proposed title structure.
[0931] FDMS 550, 551 (M+)
[0932] Analysis for
C.sub.32H.sub.43N.sub.4O.sub.2Cl.circle-solid.2HCl,
.circle-solid.H.sub.2O:
[0933] Theory: C, 59.85; H, 7.38; N, 8.73.
[0934] Found: C, 59.89; H, 7.32; N, 9.11.
[0935] [B]
[0936] mp >146.degree. C.
[0937] NMR was consistent with the proposed title structure.
[0938] FDMS 551 (M+)
[0939] Analysis for
C.sub.32H.sub.43N.sub.4O.sub.2Cl.circle-solid.2HCl:
[0940] Theory: C, 61.59; H, 7.27; N, 8.98.
[0941] Found: C, 61.39; H, 7.05; N, 8.78.
EXAMPLE 246
[0942] Preparation of (RS)
1-[3-[[3-(2-methylpiperidin-1-yl)propylamino]ca-
rbonyl]butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole
dihydrochloride salt monohydrate 328
[0943] To a stirring solution of
1-[3-carboxybutyl]-2-[(4-chlorophenoxy)me-
thyl]-4-methylbenzimidazole (1.00 g, 2.7 mmol) in
N,N-dimethylformamide (60 ml) were added sequentially (RS)
3-(2-methylpiperidin-1-yl)propylamin- e (464 mg, 1.1 eq),
1-hydroxybenzotriazole (402 mg, 1.1 eq), and
dicyclohexylcarbodiimide (615 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 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.
[0944] The material was further purified by flash silica gel
chromatography, eluting with a solvent gradient of 1:1 ethyl
acetate:methanol to methanol. Fractions containing the desired
title product were then concentrated under reduced pressure and
converted to the dihydrochloride salt as a white solid.
[0945] Yield: 500 mg of the free base (36%)
[0946] mp 85-87.5.degree. C.
[0947] NMR was consistent with the proposed title structure.
[0948] FDMS 510, 511 (M+)
[0949] Analysis for
C.sub.32H.sub.43N.sub.4O.sub.2Cl.circle-solid.2HCl.cir-
cle-solid.H.sub.2O:
[0950] Theory: C, 57.85; H, 7.20; N, 9.31.
[0951] Found: C, 58.01; H, 7.15; N, 9.02.
EXAMPLE 247
[0952] Preparation of
1-[3-[4-phenylpiperidin-1-yl]carbonyl]butyl]-2-[(4-c-
hlorophenoxy)methyl]-4-methylbenzimidazole hemihydrate 329
[0953] To a stirring solution of
1-[3-carboxybutyl]-2-[(4-chlorophenoxy)me-
thyl]-4-methylbenzimidazole (0.800 g, 2.2 mmol) in
N,N-dimethylformamide (50 ml) were added sequentially
4-phenylpiperidine (390 mg, 1.1 eq), 1-hydroxybenzotriazole (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 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 1.04 grams of the title
product as an orange foam.
[0954] The material was further purified by flash silica gel
chromatography, eluting with a solvent gradient of 9:1 ethyl
acetate:methanol to 1:1 ethyl acetate:methanol. Fractions
containing the desired title product were then concentrated under
reduced pressure.
[0955] Yield: 641 mg (56%)
[0956] NMR was consistent with the proposed title structure.
[0957] FDMS 515, 516 (M+)
[0958] Analysis for
C.sub.31H.sub.34N.sub.3O.sub.2Cl.circle-solid.1/2 H.sub.2O:
[0959] Theory: C, 70.90; H, 6.70; N, 8.00.
[0960] Found: C, 70.43; H, 6.96; N, 7.75.
EXAMPLE 248
[0961] Preparation of
1-[3-[[3-(piperidin-1-yl)propylamino]carbonyl]propyl-
]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole dihydrochloride
salt 330
[0962] To a stirring solution of
1-[3-carboxypropyl]-2-[(4-chlorophenoxy)m-
ethyl]-4-methylbenzimidazole (0.540 g, 1.5 mmol) in
N,N-dimethylformamide (60 ml) were added sequentially
3-(piperidin-1-yl)propylamine (235 mg, 1.1 eq),
1-hydroxybenzotriazole (223 mg, 1.1 eq), and
dicyclohexylcarbodiimide (340 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 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.
[0963] The material was further purified by flash silica gel
chromatography, eluting with methanol. Fractions containing the
desired title product were then concentrated under reduced pressure
to yield a slowly crystallizing oil.
[0964] Yield: 471 mg (65%)
[0965] mp 92-94.degree. C.
[0966] NMR was consistent with the proposed title structure.
[0967] FDMS 482, 483 (M+)
[0968] Analysis for C.sub.27H.sub.35N.sub.4O.sub.2Cl:
[0969] Theory: C, 67.14; H, 7.30; N, 11.60.
[0970] Found: C, 66.94; H, 7.23; N, 11.37.
EXAMPLES 249 AND 250
[0971] Preparation of (RS)
1-[3-[[3-phenylpiperidin-1-yl]carbonyl]butyl]-2-
-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole and (RS)
1-[3-[[3-cyclohexylpiperidin-1-yl]carbonyl]butyl]-2-[(4-chlorophenoxy)met-
hyl]-4-methylbenzimidazole 331
[0972] To a stirring solution of
1-[3-carboxybutyl]-2-[(4-chlorophenoxy)me-
thyl]-4-methylbenzimidazole (1.00 g, 2.7 mmol) in
N,N-dimethylformamide (50 ml) were added sequentially a 50:50
mixture of 3-phenylpiperidine and 3-cyclohexylpiperidine (496 mg
total, 1.1 eq), 1-hydroxybenzotriazole (402 mg, 1.1 eq), and
dicyclohexylcarbodiimide (615 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 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 1.43 grams of approximately a 50:50
mixture of the title products.
[0973] Separation and purification of this mix was attempted using
a chromatotron with a 4000 micron rotor and eluting with a gradient
solvent of hexanes to 1:1 ethyl acetate:hexanes. Early fractions
containing an 80:20 mixture of the 3-cyclohexyl
derivatives:3-phenyl derivatives were then concentrated under
reduced pressure, yielding 641 mg. Later fractions containing
substantially purified 3-phenyl derivatives were combined and
concentrated under reduced pressure to yield 200 mg as a white
foam.
[0974] NMR was consistent with the proposed title structures.
EXAMPLES 251 AND 252
[0975] Preparation of (RS)
1-[3-[4-benzylpiperidin-1-yl]carbonyl]butyl]-2--
[(4-chlorophenoxy)methyl]-4-methylbenzimidazole and (RS)
1-[3-[[4-(cyclohexylmethyl)piperidin-1-yl]carbonyl]butyl]-2-[(4-chlorophe-
noxy)methyl]-4-methylbenzimidazole 332
[0976] To a stirring solution of
1-[3-carboxybutyl]-2-[(4-chlorophenoxy)me-
thyl]-4-methylbenzimidazole (1.00 g, 2.7 mmol) in
N,N-dimethylformamide (50 ml) were added sequentially a 50:50
mixture of 4-benzylpiperidine and 4-(cyclohexylmethyl)piperidine
(520 mg total, 1.1 eq), 1-hydroxybenzotriazole (402 mg, 1.1 eq),
and dicyclohexylcarbodiimide (615 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 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 1.51 grams of approximately a 50:50
mixture of the title products.
[0977] Separation and purification of this mixture was attempted
using a chromatotron with a 4000 micron rotor and eluting with a
gradient solvent of hexanes to 2:1 ethyl acetate:hexanes. Early
fractions containing substantially purified the 4-benzyl
derivatives were then concentrated under reduced pressure, yielding
481 mg as a white foam. Later fractions containing substantially
purified 4-cyclohexylmethyl derivatives were combined and
concentrated under reduced pressure to yield 356 mg as a white
foam.
[0978] NMR was consistent with the proposed title structures.
EXAMPLE 253
[0979] Preparation of (RS)
1-[3-[2-phenylethylamino]carbonyl]butyl]-2-[(4--
chlorophenoxy)methyl]-4-methylbenzimidazole 333
[0980] To a stirring solution of (RS)
1-[3-carboxybutyl]-2-[(4-chloropheno-
xy)methyl]-4-methylbenzimidazole (0.500 g, 1.4 mmol) in
N,N-dimethylformamide (40 ml) were added sequentially
2-phenylethylamine (187 mg, 1.1 eq), 1-hydroxybenzotriazole (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 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 product as a white foam.
[0981] The material was further purified by flash silica gel
chromatography, eluting with a solvent gradient of 1:1 ethyl
acetate:hexanes to ethyl acetate. Fractions containing the desired
title product were then concentrated under reduced pressure,
yielding 581 mg (80%) as a white solid.
EXAMPLE 254
[0982] Preparation of (RS)
1-[3-[[benzylaminoamino]carbonyl]butyl]-2-[(4-c-
hlorophenoxy)methyl]-4-methylbenzimidazole 334
[0983] To a stinting solution of (RS)
1-[3-carboxybutyl]-2-[(4-chloropheno-
xy)methyl]-4-methylbenzimidazole (0.500 g, 1.4 mmol) in
N,N-dimethylformamide (40 ml) were added sequentially benzylamine
(165 mg, 1.1 eq), 1-hydroxybenzotriazole (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 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 0.714 grams of the title product as a
white foam
[0984] The material was further purified by flash silica gel
chromatography, eluting with a solvent gradient of hexanes to 1:1
ethyl acetate:hexanes. Fractions containing the desired title
product were then concentrated under reduced pressure, yielding 437
mg (68%) as a white solid.
[0985] mp 145-146.degree. C.
[0986] NMR was consistent with the proposed title structure.
[0987] FDMS 461, 462 (M+)
[0988] Analysis for C.sub.27H.sub.28N.sub.3O.sub.2Cl:
[0989] Theory: C, 70.20; H, 6.11; N, 9.10.
[0990] Found: C, 70.44; H, 6.33; N, 8.7881
EXAMPLE 255
[0991] Preparation of (RS)
1-[3-[(pyrrolidin-1-yl)carbonyl]butyl]-2-[(4-ch-
lorophenoxy)methyl]-4-methylbenzimidazole 335
[0992] To a stirring solution of (RS)
1-[3-carboxybutyl]-2-[(4-chloropheno-
xy)methyl]-4-methylbenzimidazole (0.700 g, 1.9 mmol) in
N,N-dimethylformamide (40 ml) were added sequentially pyrroldine
(155 mg, 1.1 eq), 1-hydroxybenzotriazole (282 mg, 1.1 eq), and
dicyclohexylcarbodiimide (431 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 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 0.835 grams of the title product as a
white foam.
[0993] The material was fiber purified by flash silica gel
chromatography, eluting with a solvent gradient of 1:1 ethyl
acetate:hexanes to ethyl acetate. Fractions containing the desired
title product were then concentrated under reduced pressure,
yielding 560 mg (69%) as a white solid.
[0994] mp 140-142.degree. C.
[0995] NMR was consistent with the proposed title structure.
[0996] FDMS 425 (M+)
[0997] Analysis for C.sub.24H.sub.28N.sub.3O.sub.2Cl:
[0998] Theory: C, 67.67; H, 6.63; N, 9.87.
[0999] Found: C, 67.76; H, 6.73; N, 9.84.
EXAMPLE 256
[1000] Preparation of (RS)
1-[3-(methyl)-4-[3-(piperidin-1-yl)propylamine]-
butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole
trihydrochloride salt monohydrate 336
[1001] A solution of
1-[3-[3-(piperidin-1-yl)propylcarbamoyl]butyl]-2-[(4--
chlorophenoxy)methyl]-4-methylbenzimidazole (300 mg, 0.6 mmol) in
dry tetrahydrofuran (5 ml) was stirred at room temperature under a
nitrogen atmosphere. To this solution borane-tetrahydrofuran
complex (3.8 ml of a 1M 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 mixture was then
slowly added, by is syringe, a 1:1 solution of tetrahydrofuran and
methanol. After the foaming subsided, 5N sodium hydroxide (2 ml)
was then added by syringe and the resulting mixture was stirred for
about sixteen hours under a nitrogen atmosphere at 50-60.degree. C.
The reaction mixture was cooled to room temperature and was then
diluted with methylene chloride (10 ml).
[1002] The organic fraction was separated and concentrated in vacuo
to yield a semisolid. 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 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 acetate:methanol (with 1% ammonium hydroxide) to 1:1 ethyl
acetate:methanol (with 1% ammonia hydroxide). Fractions containing
the desired title product (170 mg, 59%) were collected and the
compound was converted to the tri-hydrochloride salt, yielding a
white solid.
[1003] mp 98-100.5.degree. C.
[1004] NMR was consistent with the proposed title structure.
[1005] FDMS 483 (M+)
[1006] Analysis for
C.sub.28H.sub.39N.sub.4OCl.circle-solid.3HCl.circle-so-
lid.H.sub.2O:
[1007] Theory: C, 55.09; H, 7.26; N, 9.18.
[1008] Found: C, 55.47; H, 7.12; N, 9.33.
EXAMPLE 257
[1009] Preparation of (RS)
1-[3-(benzyl)-4-[3-(piperidin-1-yl)propylamine]-
butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole
trihydrochloride salt monohydrate 337
[1010] A solution of
1-[4-phenyl-3-[3-(piperidin-1-yl)propylcarbamoyl]buty-
l]-2-(4-chlorophenoxy)methyl]methylbenzimidazole (450 mg, 0.78
mmol) in dry tetrahydrofuran (5 ml) was stirred at room temperature
under a nitrogen atmosphere. To this solution boranetetrahydrofuran
complex (4.7 ml of a 1M 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 mixture was then
slowly added, by syringe, a 1:1 solution of tetrahydrofuran and
methanol. After the foaming subsided, 5N sodium hydroxide (2 ml)
was then added by syringe and the resulting mixture was stirred for
about sixteen hours under a nitrogen atmosphere at 50-60.degree. C.
The reaction mixture was cooled to room temperature and was then
diluted with methylene chloride (10 ml).
[1011] 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 200 mg of a
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% ammonium hydroxide) solution. Fractions containing the
desired title product (185 mg, 42%) were collected and the compound
was converted to the tri-hydrochloride salt, yielding a white
solid.
[1012] mp 96-98.degree. C.
[1013] NMR was consistent with the proposed title structure.
[1014] FDMS 559.1 (M+)
[1015] Analysis for
C.sub.34H.sub.43N.sub.4OCl.circle-solid.3HCl.circle-so-
lid.H.sub.2O:
[1016] Theory C, 59.47; H, 7.04; N, 8.16.
[1017] Found: C, 59.39; H, 6.87; N, 8.12.
EXAMPLE 258
[1018] Preparation of (RS)
1-[3-benzyl-4-(piperidin-1-yl)butyl]-2-[(4-chlo-
rophenoxy)methyl]-4-methylbenzimidazole trihydrochloride salt
338
[1019] A solution of
1-[4-phenyl-3-[(piperidin-1-yl)carbonyl]butyl]-2-[(4--
chlorophenoxy)methyl]-4-methylbenzimidazole (400 mg, 0.7 mmol) in
dry tetrahydrofuran (5 ml) was stirred at room temperature under a
nitrogen atmosphere. To this solution borane-tetrahydrofuran
complex (4.5 ml of a 1M 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 mixture was then
slowly added, by syringe, a 1:1 solution of tetrahydrofuran and
methanol. After the foaming subsided, 5 N sodium hydroxide (2 ml)
was then added by syringe and the resulting mixture was stirred for
about sixteen hours under a nitrogen atmosphere at 50-60.degree. C.
The reaction mixture was cooled to room temperature and was then
diluted with methylene chloride (10 ml).
[1020] The organic fraction was separated and concentrated in vacuo
to yield a semisolid. 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 2000 micron rotor, eluting with a gradient solvent of 9:1
ethyl acetate:methanol (with 1% ammonium hydroxide) to 1:1 ethyl
acetate:methanol (with 1% ammonium hydroxide). Fractions containing
the desired title product (195 mg, 56%) were collected and the
compound was converted to the di-hydrochloride salt, yielding a
white solid.
[1021] mp 120-123.degree. C.
[1022] NMR was consistent with the proposed title structure.
[1023] FDMS 501, 502 (M+)
[1024] Analysis for
C.sub.31H.sub.36N.sub.3OCl.circle-solid.2HCl:
[1025] Theory: C, 64.75; H, 6.66; N, 7.31.
[1026] Found: C, 64.50; H, 6.36; N, 7.31.
EXAMPLE 259
[1027] Preparation of (RS)
1-[3-(methyl)-4-aminobutyl]-2-[(4-chlorophenoxy-
)methyl]-4-methylbenzimidazole dihydrochloride salt monohydrate
339
[1028] A solution of
1-[3-carbamoylbutyl]-2-[(4-chlorophenoxy)methyl]-4-me-
thylbenzimidazole (350 mg, 0.94 mmol) in dry tetrahydrofuran (5 ml)
was stirred at room temperature under a nitrogen atmosphere. To
this solution borane-tetrahydrofuran complex (5.7 ml of a 1M
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 mixture was then slowly added, by
syringe, a 1:1 solution of tetrahydrofuran and methanol. After the
foaming subsided, 5N sodium hydroxide (2 ml) was then added by
syringe and the resulting mixture was stirred for about sixteen
hours under a nitrogen atmosphere at 50-60.degree. C. The reaction
mixture was cooled to room temperature and was then diluted with
methylene chloride (10 ml).
[1029] 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 260 mg of a
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 containing the
desired title product (69 mg, 21%) were collected and the compound
was converted to the dihydrochloride salt, yielding a white
solid.
[1030] mp >150.degree. C.
[1031] NMR was consistent with the proposed title structure.
[1032] FDMS 357.2 (M+)
[1033] Analysis for
C.sub.20H.sub.24N.sub.3OCl.circle-solid.2HCl.circle-so-
lid.H.sub.2O:
[1034] Theory: C, 53.51; H, 6.29; N, 9.36.
[1035] Found: C, 53.22; H, 6.10; N, 9.28.
EXAMPLE 260
[1036] Preparation of (RS)
1-[3-(methyl)-4-dimethylaminobutyl]-2-[(4-chlor-
ophenoxy)methyl]-4-methylbenzimidazole 340
[1037] A solution of
1-[3-[(N,N-dimethylamino)carbonyl]butyl]-2-[(4-chloro-
phenoxy)methyl]-4-methylbenzimidazole (350 mg, 0.88 mmol) in dry
tetrahydrofuran (5 ml) was stirred at room temperature under a
nitrogen atmosphere. To this solution borane-tetrahydrofuran
complex (5.3 ml of a 1M 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 mixture was then
slowly added, by syringe, a 1:1 solution of tetrahydrofuran and
methanol. After the foaming subsided, 5N sodium hydroxide (2 ml)
was then added by syringe and the resulting mixture was stirred for
about sixteen hours under a nitrogen atmosphere at 50-60.degree. C.
The reaction mixture was cooled to room temperature and was then
diluted with methylene chloride (10 ml).
[1038] 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
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:methanol. Fractions
containing the desired title product (200 mg, 21%) were
collected.
[1039] mp 80-82.degree. C.
[1040] NMR was consistent with the proposed title structure.
[1041] FDMS 385.2 (M+)
[1042] Analysis for C.sub.22H.sub.28N.sub.3OCl:
[1043] Theory: C, 68.47; H, 7.31; N, 10.89.
[1044] Found: C, 68.51; H, 7.45; N, 11.07.
EXAMPLE 261
[1045] Preparation of (R)
1-[4-[2-[(2-piperidin-1-yl)ethyl]piperidin-1-yl]-
-3-methylbutyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole
trihydrochloride salt hemihydrate 341
[1046] A solution of (R)
1-[4-[[2-[(2-piperidin-1-yl)ethyl]piperidin-1-yl]-
carbonyl]butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole
dihydrochloride salt monohydrate (135 mg, 0.25 mmol) in dry
tetrahydrofuran (5 ml) was stirred at room temperature under a
nitrogen atmosphere. To this solution borane-tetrahydrofuran
complex (1.8 ml of a 1M 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 mixture was then
slowly added, by syringe, a 1:1 solution of tetrahydrofuran and
methanol. After the foaming subsided, 5N sodium hydroxide (2 ml)
was then added by syringe and the resulting mixture was stirred for
about sixteen hours under a nitrogen atmosphere at 50-60.degree. C.
The reaction mixture was cooled to room temperature and was then
diluted with methylene chloride (10 ml).
[1047] 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 105 mg of a
viscous oil. This oil was further purified using a chromatotron
with a 2000 micron rotor, eluting with methanol. Fractions
containing the desired title product (73 mg, 55%) were collected
and converted to the trihydrochloride salt, yielding a white
solid.
[1048] mp 103-106.degree. C.
[1049] NMR was consistent with the proposed title structure.
[1050] FDMS 537 (M+)
[1051] Analysis for C.sub.32H.sub.45N.sub.4OCl.circle-solid.3
HCl.circle-solid.1/2 H.sub.2O:
[1052] Theory: C, 58.62; H, 7.53; N, 8.55.
[1053] Found: C, 58.32; H, 7.22; N, 7.93.
[1054] Analysis for C.sub.32H.sub.45N.sub.4OCl:
[1055] Theory: C, 71.55; H, 8.44; N, 10.43.
[1056] Found: C, 71.25; H, 8.49; N, 10.19.
EXAMPLE 262
[1057] Preparation of (S)
1-[4-[2-[(2-piperidin-1-yl)ethyl]piperidin-1-yl]-
-3-methylbutyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole
trihydrochloride salt hemihydrate 342
[1058] The title compound was prepared essentially as described for
the R isomer, except that (S)
1-[4-[[2-[(2-piperidin-1-yl)ethyl]piperidin-1-yl]-
carbonyl]butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole
dihydrochloride salt monohydrate was employed as a starting
material.
EXAMPLE 263
[1059] Preparation of (RS)
1-[3-(methyl)-4-(1,2,3,4-tetrahydroisoquinolin--
1-yl)butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole
343
[1060] A solution of
1-[3-[(1,2,3,4-tetrahydroisoquinolin-1-yl)carbonyl]bu-
tyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (375 mg,
0.76 mmol) in dry tetrahydrofuran (5 ml) was stirred at room
temperature under a nitrogen atmosphere. To this solution
borane-tetrahydrofuran complex (4.5 ml of a 1M 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 mixture was then slowly added, by syringe, a 1:1 solution
of tetrahydrofuran and methanol. After the foaming subsided, 5N
sodium hydroxide (2 ml) was then added by syringe and the resulting
mixture was stirred for about sixteen hours under a nitrogen
atmosphere at 50-60.degree. C. The reaction mixture was cooled to
room temperature and was then diluted with methylene chloride (10
ml).
[1061] 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 340 mg of a
slowly crystallizing viscous oil. This oil was further purified by
recrystallization from ethyl acetate to yield the desired title
product (183 mg, 52%) as white crystals.
[1062] mp 114.5-116.degree. C.
[1063] NMR was consistent with the proposed title structure.
[1064] FDMS 474 (M+)
[1065] Analysis for C.sub.29H.sub.32N.sub.3OCl:
[1066] Theory: C, 73.48; H, 6.80; N, 8.86.
[1067] Found: C, 73.18; H, 6.82; N, 8.67.
EXAMPLE 264
[1068] Preparation of (RS)
1-[3-(methyl)-4-(1,2,3,4-tetrahydronaphth-1-yl)-
butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole
dihydrochloride salt 344
[1069] A solution of
1-[3-[(1,2,3,4-tetrahydronaphth-1-yl)carbonyl]butyl]--
2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (525 mg, 1.05
mmol) in dry tetrahydrofuran (5 ml) was stirred at room temperature
under a nitrogen atmosphere. To this solution
borane-tetrahydrofuran complex (6.3 ml of a 1M 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 mixture was then slowly added, by syringe, a 1:1 solution
of tetrahydrofuran and methanol. After the foaming subsided, 5N
sodium hydroxide (2 ml) was then added by syringe and the resulting
mixture was stirred for about sixteen hours under a nitrogen
atmosphere at 50-60.degree. C. The reaction mixture was cooled to
room temperature and was then diluted with methylene chloride (10
ml).
[1070] 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 487 mg of a
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.
[1071] mp 116-118.5.degree. C.
[1072] NMR was consistent with the proposed title structure.
[1073] FDMS 487, 488 (M+)
[1074] Analysis for C.sub.30H.sub.34N.sub.3OCl.circle-solid.2
HCl:
[1075] Theory: C, 64.23; H, 6.47; N, 7.49.
[1076] Found: C, 64.04; H, 6.35; N, 7.35.
EXAMPLE 265
[1077] Preparation of (RS)
1-[3-(methyl)-4-(4-phenylpiperidin-1-yl)butyl]--
2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole dihydrochloride
salt 345
[1078] A solution of
1-[3-[(4-phenylpiperidin-1-yl)carbonyl]butyl]-2-[(4-c-
hlorophenoxy)methyl)-4-methylbenzimidazole (550 mg, 1.07 mmol) in
dry tetrahydrofuran (5 ml) was stirred at room temperature under a
nitrogen atmosphere. To this solution borane-tetrahydrofuran
complex (6.7 ml of a 1M 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 mixture was then
slowly added, by syringe, a 1:1 solution of tetrahydrofuran and
methanol. After the foaming subsided, 5N sodium hydroxide (2 ml)
was then added by syringe and the resulting mixture was stirred for
about sixteen hours under a nitrogen atmosphere at 50-60.degree. C.
The reaction mixture was cooled to room temperature and was then
diluted with methylene chloride (10 ml).
[1079] 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 531 mg of a
a white solid. This material was further purified by
recrystallization from 5:1 hexanes:ethyl acetate, yielding a white
solid (385 mg, 72%).
[1080] mp 124-125.degree. C.
[1081] NMR was consistent with the proposed title structure.
[1082] FDMS 501, 502 (M+)
[1083] Analysis for C.sub.31H.sub.36N.sub.3OCl:
[1084] Theory: C, 74.16; H, 7.23; N, 8.37.
[1085] Found: C, 74.42; H, 7.35; N, 8.41.
EXAMPLE 266
[1086] Preparation of (RS)
1-[3-(methyl)-4-(3-phenylpiperidin-1-yl)butyl]--
2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole dihydrochloride
salt 346
[1087] A solution of
1-[3-[(3-phenylpiperidin-1-yl)carbonyl]butyl]-2-[(4-c-
hlorophenoxy)methyl]-4-methylbenzimidazole (200 mg, 0.380 mmol) in
dry tetrahydrofuran (5 ml) was stirred at room temperature under a
nitrogen atmosphere. To this solution borane-tetrahydrofuran
complex (6.3 ml of a 1M 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 mixture was then
slowly added, by syringe, a 1:1 solution of tetrahydrofuran and
methanol. After the foaming subsided, 5N sodium hydroxide (2 ml)
was then added by syringe and the resulting mixture was stirred for
about sixteen hours under a nitrogen atmosphere at 50-60.degree. C.
The reaction mixture was cooled to room temperature and was then
diluted with methylene chloride (10 ml).
[1088] 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
yellow oil. This 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.
[1089] mp 84-86.5.degree. C.
[1090] NMR was consistent with the proposed title structure.
[1091] FDMS 501, 502 (M+)
[1092] Analysis for C.sub.31H.sub.36N.sub.3OCl.circle-solid.2
HCl.circle-solid.11/2 H.sub.2O:
[1093] Theory: C, 61.83; H, 6.86; N, 6.98.
[1094] Found: C, 61.98; H, 6.46; N, 6.81.
EXAMPLE 267
[1095] Preparation of (RS)
1-[3-(methyl)-4-(2-phenylethylamino)butyl]-2-[(-
4-chlorophenoxy)methyl]-4-methylbenzimidazole dihydrochloride salt
347
[1096] A solution of
1-[3-[(2-phenylethylamino)carbonyl]butyl]-2-[(4-chlor-
ophenoxy)methyl]-4-methylbenzimidazole (525 mg, 1.05 mmol) in dry
tetrahydrofuran (5 ml) was stirred at room temperature under a
nitrogen atmosphere. To this solution borane-tetrahydrofuran
complex (6.3 ml of a 1M 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 mixture was then
slowly added, by syringe, a 1:1 solution of tetrahydrofuran and
methanol. After the foaming subsided, 5N sodium hydroxide (2 ml)
was then added by syringe and the resulting mixture was stirred for
about sixteen hours under a nitrogen atmosphere at 50-60.degree. C.
The reaction mixture was cooled to room temperature and was then
diluted with methylene chloride (10 ml).
[1097] 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 370 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 (150 mg, 31%) as a clear viscous oil. The
title product was then converted to the dihydrochloride salt,
yielding a white solid.
[1098] mp 84-87.5.degree. C.
[1099] NMR was consistent with the proposed title structure.
[1100] FDMS 462 (M+)
[1101] Analysis for C.sub.28H.sub.32N.sub.3OCl.circle-solid.2
HCl.circle-solid.1/2 H.sub.2O:
[1102] Theory: C, 61.81; H, 6.49; N, 7.72.
[1103] Found: C, 61.98; H, 6.35; N, 7.79.
EXAMPLE 268
[1104] Preparation of (RS)
1-[3-(methyl)-4-(3-(piperidin-1-yl)propylamino)-
butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole
trihydrochloride salt 348
[1105] A solution of
1-[3-[(3-(piperidin-1-yl)propylamino)carbonyl]butyl]--
2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (400 mg, 0.85
mmol) in dry tetrahydrofuran (5 ml) was stirred at room temperature
under a nitrogen atmosphere. To this solution
borane-tetrahydrofuran complex (6.3 ml of a 1M 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 mixture was then slowly added, by syringe, a 1:1 solution
of tetrahydrofuran and methanol. After the foaming subsided, 5N
sodium hydroxide (2 ml) was then added by syringe and the resulting
mixture was stirred for about sixteen hours under a nitrogen
atmosphere at 50-60.degree. C. The reaction mixture was cooled to
room temperature and was then diluted with methylene chloride (10
ml).
[1106] 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 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% ammonium hydroxide) to yield
the desired title product (113 mg, 28%) as a clear viscous oil. The
title product was then converted to the trihydrochloride salt,
yielding a white solid.
[1107] NMR was consistent with the proposed title structure.
[1108] FDMS 469 (M+)
[1109] Analysis for C.sub.27H.sub.37N.sub.4OCl.circle-solid.3
HCl.circle-solid.1/2 H.sub.2O:
[1110] Theory: C, 67.82; H, 8.01; N, 11.72.
[1111] Found: C, 67.73; H, 8.20; N, 11.59.
EXAMPLE 269
[1112] Preparation of (RS)
1-[3-(methyl)-4-(benzylamino)butyl]-2-[(4-chlor-
ophenoxy)methyl]-4-methylbenzimidazole 349
[1113] A solution of
1-[3-[(benzylamino)carbonyl]butyl]-2-[(4-chlorophenox-
y)methyl]-4-methylbenzimidazole (500 mg, 1.05 mmol) in dry
tetrahydrofuran (5 ml) was stirred at room temperature under a
nitrogen atmosphere. To this solution borane-tetrahydrofuran
complex (6.0 ml of a 1M 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 mixture was then
slowly added, by syringe, a 1:1 solution of tetrahydrofuran and
methanol. After the foaming subsided, 5N sodium hydroxide (2 ml)
was then added by syringe and the resulting mixture was stirred for
about sixteen hours under a nitrogen atmosphere at 50-60.degree. C.
The reaction mixture was cooled to room temperature and was then
diluted with methylene chloride (10 ml).
[1114] 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
semi-solid. This oil was further purified via a chromatotron using
a 2000 micron rotor, eluting with ethyl acetate to yield the
desired title product (190 mg, 40%) as a slowly crystallizing
oil.
[1115] mp 84.5-87.degree. C.
[1116] NMR was consistent with the proposed title structure.
[1117] FDMS 447, 448 (M+)
[1118] Analysis for C.sub.27H.sub.30N.sub.3OCl:
[1119] Theory: C, 72.37; H, 6.75; N, 9.38.
[1120] Found: C, 72.67; H, 6.75; N, 9.25.
EXAMPLE 270
[1121] Preparation of (RS)
1-[3-(methyl)-4-(pyrrolidin-1-yl)butyl]-2-[(4-(-
chlorophenoxy)methyl]-4-methylbenzimidazole 350
[1122] A solution of
1-[3-[(pyrrolidin-1-yl)carbonyl]butyl)-2-[(4-chloroph-
enoxy)methyl]-4-methylbenzimidazole (500 mg, 1.17 mmol) in dry
tetrahydrofuran (5 ml) was stirred at room temperature under a
nitrogen atmosphere. To this solution borane-tetrahydrofuran
complex (6.2 ml of a 1M 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 mixture was then
slowly added, by syringe, a 1:1 solution of tetrahydrofuran and
methanol. After the foaming subsided, 5N sodium hydroxide (2 ml)
was then added by syringe and the resulting mixture was stirred for
about sixteen hours under a nitrogen atmosphere at 50-60.degree. C.
The reaction mixture was cooled to room temperature and was then
diluted with methylene chloride (10 ml).
[1123] 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
semisolid. 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 to yield the desired title product (225 mg,
47%) as a white solid.
[1124] mp 85-87.degree. C.
[1125] NMR was consistent with the proposed title structure.
[1126] FDMS 411 (M+)
[1127] Analysis for C.sub.24H.sub.30N.sub.3OCl:
[1128] Theory: C, 69.97; H, 7.34; N, 10.20.
[1129] Found: C, 69.78; H, 7.29; N, 10.31.
EXAMPLE 271
[1130] Preparation of (RS)
1-[3-(methyl)-4-(3-benzylpiperidin-1-yl)butyl]--
2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole dihydrochloride
salt 351
[1131] A solution of
1-[3-[(3-benzylpiperidin-1-yl)carbonyl]butyl]-2-[(4-c-
hlorophenoxy)methyl]-4-methylbenzimidazole (360 mg, 0.68 mmol) in
dry tetrahydrofuran (5 ml) was stirred at room temperature under a
nitrogen atmosphere. To this solution borane-tetrahydrofuran
complex (4.1 ml of a 1M 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 mixture was then
slowly added, by syringe, a 1:1 solution of tetrahydrofuran and
methanol. After the foaming subsided, 5N sodium hydroxide (2 ml)
was then added by syringe and the resulting mixture was stirred for
about sixteen hours under a nitrogen atmosphere at 50-60.degree. C.
The reaction mixture was cooled to room temperature and was then
diluted with methylene chloride (10 ml).
[1132] 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 330 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 (250 mg, 71%) as a slowly crystallizing
oil.
[1133] mp 95-97.degree. C.
[1134] NMR was consistent with the proposed title structure.
[1135] FDMS 515, 516 (M+)
[1136] Analysis for C.sub.32H.sub.38N.sub.3OCl:
[1137] Theory: C, 74.46; H, 7.42; N, 8.14.
[1138] Found: C, 74.74; H, 7.62; N, 8.03.
EXAMPLE 272
[1139] Preparation of (RS)
1-[3-(methyl)-4-(3-cyclohexylmethylpiperidin-1--
yl)butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole
dihydrochloride salt trihydrate 352
[1140] A solution of
1-[3-[(3-(cyclohexylmethylpiperidin-1-yl)carbonyl]but-
yl]-2-[(4-chlorophenoxy)methyl)-4-methylbenzimidazole (350 mg, 0.67
mmol) in dry tetrahydrofuran (5 ml) was stirred at room temperature
under a nitrogen atmosphere. To this solution
borane-tetrahydrofuran complex (4.0 ml of a 1M 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 mixture was then slowly added, by syringe, a 1:1 solution
of tetrahydrofuran and methanol. After the foaming subsided, 5N
sodium hydroxide (2 ml) was then added by syringe and the resulting
mixture was stirred for about sixteen hours under a nitrogen
atmosphere at 50-60.degree. C. The reaction mixture was cooled to
room temperature and was then diluted with methylene chloride (10
ml).
[1141] The organic fraction was separated and concentrated in vacuo
to yield a semisolid. 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 232 mg of a
viscous oil. Tis 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.
[1142] mp 52-56.degree. C.
[1143] NMR was consistent with the proposed title structure.
[1144] FDMS 521, 522 (M+)
[1145] Analysis for C.sub.32H.sub.44N.sub.3OCl.circle-solid.2
HCl.circle-solid.3 H.sub.2O:
[1146] Theory: C, 59.20; H, 8.08; N, 6.47.
[1147] Found: C, 59.43; H, 7.50; N, 6.37.
[1148] Analysis for C.sub.32H.sub.44N.sub.3OCl.circle-solid.1/2
H.sub.2O:
[1149] Theory: C, 72.35; H, 8.54; N, 7.91.
[1150] Found: C, 72.75; H, 8.57; N, 7.86.
EXAMPLE 273
[1151] Preparation of (RS)
1-[3-(methyl)-4-[3-(2-methylpiperidin-1-yl)prop-
ylamino]butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole
trihydrochloride salt monohydrate 353
[1152] A solution of
1-[3-[3-(2-methylpiperidin-1-yl)propylamino]butyl]-2--
[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (350 mg, 0.69 mmol)
in dry tetrahydrofuran (5 ml) was stirred at room temperature under
a nitrogen atmosphere. To this solution borane-tetrahydrofuran
complex (4.3 ml of a 1M 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 mixture was then
slowly added, by syringe, a 1:1 solution of tetrahydrofuran and
methanol. After the foaming subsided, 5N sodium hydroxide (2 ml)
was then added by syringe and the resulting mixture was stirred for
about sixteen hours under a nitrogen atmosphere at 50-60.degree. C.
The reaction mixture was cooled to room temperature and was then
diluted with methylene chloride (10 ml).
[1153] 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 320 mg of a
viscous oil. This oil was further purified via a chromatotron using
a 2000 micron rotor, eluting with 1:1 ethyl acetate:methanol (with
1% ammonium hydroxide) 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.
[1154] NMR was consistent with the proposed title structure.
[1155] FDMS 497 (M+)
[1156] Analysis for C.sub.29H.sub.44N.sub.4OCl.circle-solid.3
HCl.circle-solid.H.sub.2O:
[1157] Theory: C, 55.76; H, 7.42; N, 8.97.
[1158] Found: C, 55.70; H, 7.21; N, 9.04.
EXAMPLE 274
[1159] Preparation of
2-(4-chlorophenoxymethyl)[3-[1-(t-butoxycarbonyl)pip-
eridin-4-yl]propoxy]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzi-
midazole 354
[1160] A solution of
4-hydroxy-2-(4-chlorophenoxymethyl)benzimidazole (500 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 mixture was stirred at room temperature under a stream of
nitrogen for about one hour. To this reaction mixture
3-[1-(t-butoxycarbonyl)piperidin-4-yl)propyl bromide (4.0 mmol, 2.2
eq) was added and the resulting mixture was stirred for three hours
at 70.degree. C. The reaction was quenched by the addition of 10 ml
of water. The aqueous fraction was extracted with ethyl acetate
(3.times.10 ml). The organic fractions were combined and washed
with water (2.times.10 ml), and then brine (1.times.10 ml), and
then dried over magnesium sulfate. The solvents were removed in
vacuo to yield a light brownish crude material. The desired title
product was further purified by flash chromatography. There is some
substitution at the 7-position of the benzimidazole present,
although the 4-substituted is the major isomer.
[1161] NMR was consistent with the proposed title structure.
[1162] FDMS (M+) 725.
EXAMPLE 275
[1163] Preparation of
2-(4-chlorophenoxymethyl)-4-[3-(piperidin-4-yl)propo-
xyl-1-[3-(piperidin-4-yl)propyl]benzimidazole 355
[1164] The title compound is prepared from
2-(4-chlorophenoxymethyl)-4-[3--
[1-(t-butoxycarbonyl)piperidin-4-yl]propoxyl]-1-[3-[1-(t-butoxycarbonyl)pi-
peridin-4-yl]propyl]benzimidazole by standard deprotection
techniques using trifluoroacetic acid.
[1165] NMR and IR were consistent with the proposed title
structure.
[1166] FDMS (+) 525
[1167] Analysis for C.sub.30H.sub.41ClN.sub.4O.sub.2:
[1168] Theory: C, 54.22; H, 5.75; N, 7.44.
[1169] Found: C, 53.97; H, 5.48; N, 7.26.
EXAMPLE 276
[1170] Preparation of (RS)
2-(4-chlorophenoxymethyl)-4-[3-[1-(t-butoxycarb-
onyl)piperidin-3-yl]propoxy-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propy-
l]benzimidazole 356
[1171] A solution of
4-hydroxy-2-(4-chlorophenoxymethyl)benzimidazole (500 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 mixture was stirred at room temperature under a stream of
nitrogen for about one hour. To this reaction mixture (RS)
3-[1-(t-butoxycarbonyl)piperidin-3-yl)propyl bromide (4.0 mmol, 2.2
eq) was added and the resulting mixture was stirred for three hours
at 70.degree. C. The reaction was quenched by the addition of 10 ml
of water. The aqueous fraction was extracted with ethyl acetate
(3.times.10 ml). The organic fractions were combined and washed
with water (2.times.10 ml), and then brine (1.times.10 ml), and
then dried over magnesium sulfate. The solvents were removed in
vacuo to yield a light brownish crude material. The desired title
product was further purified by flash chromatography.
[1172] NMR and IR were consistent with the proposed title
structure.
[1173] FDMS (M+) 724.
[1174] Analysis for C.sub.40H.sub.57ClN.sub.4O.sub.6:
[1175] Theory: C, 66.23; H, 7.92; N, 7.72.
[1176] Found: C, 66.49; H, 8.04; N, 7.79.
EXAMPLE 277
[1177] Preparation of (RS)
2-(4-chlorophenoxymethyl)-4-(3-(piperidin-3-yl)-
propoxy]-1-[3-(piperidin-3-yl)propyl]benzimidazole 357
[1178] The title compound is prepared from (RS)
2-(4-chlorophenoxymethyl)--
4-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propoxyl
1-[3-[1-(t-butoxycarbony- l)piperidin-3-yl]propyl]benzimidazole by
standard deprotection techniques using trifluoroacetic acid.
[1179] NMR and IR were consistent with the proposed title
structure.
[1180] FDMS (M+) 525
[1181] Analysis for C.sub.30H.sub.41ClN.sub.4O.sub.2:
[1182] Theory: C, 64.22; H, 5.75; N, 7.44.
[1183] Found: C, 53.97; H, 5.48; N, 7.26.
EXAMPLE 278
[1184] Preparation of (R)
2-(4-chlorophenoxymethyl)-4-[3-[1-(t-butoxycarbo-
nyl)piperidin-3-yl]propoxyl-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propy-
l]benzimidazole 358
[1185] A solution of
4-hydroxy-2-(4-chlorophenoxymethyl)benzimidazole (500 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 mixture was stirred at room temperature under a stream of
nitrogen for about one hour. To this reaction mixture (R)
3-[1-(t-butoxycarbonyl]piperidin-3-yl)propyl bromide (4.0 mmol, 2.2
eq) was added and the resulting mixture was stirred for three hours
at 70.degree. C. The reaction was quenched by the addition of 10 ml
of water. The aqueous fraction was extracted with ethyl acetate
(3.times.10 ml). The organic fractions were combined and washed
with water (2.times.10 ml), and then brine (1.times.10 ml), and
then dried over magnesium sulfate. The solvents were removed in
vacuo to yield a light brownish crude material. The desired title
product was further purified by flash chromatography.
[1186] NMR and IR were consistent with the proposed title
structure.
[1187] FDMS (M+) 724.
[1188] Analysis for C.sub.40H.sub.57ClN.sub.4O.sub.6:
[1189] Theory: C, 66.23; H, 7.92; N, 7.72.
[1190] Found: C, 66.23; H, 7.86; N, 7.69.
EXAMPLE 279
[1191] Preparation of (R)
2-(4-chlorophenoxymethyl)-4-[3-(piperidin-3-yl)p-
ropoxyl-1-[3-(piperidin-3-yl)propyl]benzimidazole 359
[1192] The title compound is prepared from (R)
2-(4-chlorophenoxymethyl)-4-
-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propoxy1-1-[3-[1-(t-butoxycarbonyl-
)piperidin-3-yl]propyl]benzimidazole by standard deprotection
techniques using trifluoroacetic acid.
[1193] NMR and IR were consistent with the proposed title
structure.
[1194] FDMS (M+) 525
[1195] Analysis for C.sub.30H.sub.41ClN.sub.4O.sub.2:
[1196] Theory C, 54.22; H, 5.75; N, 7.44.
[1197] Found: C, 54.12; H, 5.86; N, 7.47.
EXAMPLE 280
[1198] Preparation of (S)
2-(4-chlorophenoxymethyl)-4-[3-[1-(t-butoxycarbo-
nyl)piperidin-3-yl]propoxy-
1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propy- l]benzimidazole
360
[1199] A solution of
4-hydroxy-2-(4-chlorophenoxymethyl)benzimidazole (500 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 mixture was stirred at room temperature under a stream of
nitrogen for about one hour. To this reaction mixture (S)
3-[1-(t-butoxycarbonyl)piperidin-3-yl)propyl bromide (4.0 mmol, 2.2
eq) was added and the resulting mixture was stirred for three hours
at 70.degree. C. The reaction was quenched by the addition of 10 ml
of water. The aqueous fraction was extracted with ethyl acetate
(3.times.10 ml). The organic fractions were combined and washed
with water (2.times.10 ml), and then brine (1.times.10 ml), and
then dried over magnesium sulfate. The solvents were removed in
vacuo to yield a light brownish crude material. The desired title
product was further purified by flash chromatography.
[1200] NMR and IR were consistent with the proposed title
structure.
[1201] FDMS (M+) 724.
[1202] Analysis for C.sub.4OH.sub.57ClN.sub.4O.sub.6:
[1203] Theory: C, 66.23; H, 7.92; N, 7.72.
[1204] Found: C, 65.51; H, 7.94; N, 7.80.
EXAMPLE 281
[1205] Preparation of (S)
2-(4-chlorophenoxymethyl)-4-[3-(piperidin-3-yl)p-
ropoxy]-1-[3-(piperidin-3-yl)propyl]benzimidazole 361
[1206] The title compound is prepared from (S)
2-(4-chlorophenoxymethyl)-4-
-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propoxy]-1-[3-[1-(t-butoxycarbonyl-
)piperidin-3-yl]propyl]benzimidazole by standard deprotection
techniques using trifluoroacetic acid.
[1207] NMR and IR were consistent with the proposed title
structure.
[1208] FDMS (M+) 525
[1209] Analysis for C.sub.30H.sub.41ClN.sub.4O.sub.2:
[1210] Theory: C, 54.22; H, 5.75; N, 7.44.
[1211] Found: C, 53.96; H, 5.74; N, 7.40.
EXAMPLE 282
[1212] Preparation of
2-(4-chlorophenoxymethyl)-4-[5-[1-(t-butoxycarbonyl)-
piperidin-4-yl]pentoxy]-1-[5-[1-(t-butoxycarbonyl)piperidin-4-yl]pentyl]be-
nzimidazole 362
[1213] A solution of
4-hydroxy-2-(4-chlorophenoxymethyl)benzimidazole (500 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 mixture was stirred at room temperature under a stream of
nitrogen for about one hour. To this reaction mixture
5-[1-(t-butoxycarbonyl)piperidin-4-yl)pentyl bromide (4.0 mmol, 2.2
eq) was added and the resulting mixture was stirred for three hours
at 70.degree. C. The reaction was quenched by the addition of 10 ml
of water. The aqueous fraction was extracted with ethyl acetate
(3.times.10 ml). The organic fractions were combined and washed
with water (2.times.10 ml), and then brine (1.times.10 ml), and
then dried over magnesium sulfate. The solvents were removed in
vacuo to yield a light brownish crude material. The desired title
product was further purified by flash chromatography. There is some
substitution at the 7-position of the benzimidazole present,
although the 4substituted is the major isomer.
[1214] NMR was consistent with the proposed title structure.
[1215] FDMS (M+) 781.
EXAMPLE 283
[1216] Preparation of
2-(4-chlorophenoxymethyl)-4-[5-(piperidin-4-yl)pento-
xy]-1-[5-(piperidin-4-yl]pentyl]benzimidazole 363
[1217] The title compound is prepared from
2-(4-chlorophenoxymethyl)-4-[5--
[1-(t-butoxycarbonyl)piperidin-4-yl]pentoxy]-1-[5-[1-(t-butoxycarbonyl)pip-
eridin-4-yl]pentyl]benzimidazole by standard deprotection
techniques using trifluoroacetic acid.
[1218] NMR and IR were consistent with the proposed title
structure.
[1219] FDMS (M+) 581
[1220] Analysis for C.sub.34H.sub.49ClN.sub.4O.sub.2:
[1221] Theory: C, 56.40; H, 6.35; N, 6.92.
[1222] Found: C, 56.22; H, 6.37; N, 6.90.
Preparation 58
[1223] Preparation of
2-(4-chlorophenoxymethyl)-4-benzyloxy-benzimidazole 364
[1224] A solution of 4-hydroxybenzimidazole (7.28 mmol, 1.0 eq) and
triphenylphosphine (2.30 mg, 8.74 mmol, 1.2 eq) in dry
tetrahydrofuran (72 ml, 0.1M) was treated with a solution of benzyl
alcohol (0.9 ml, 8.74 mmol, 1.2 eq) and diethyl azodicarboxylate
(1.4 ml, 8.74 mmol, 1.2 eq). The resulting mixture was stirred at
0.degree. C. and was then warmed to room temperature. After five
hours, the tetrahydrofuran was removed in vacuo. The residue was
further purified using flash chromatography to provide the title
intermediate in 55-70% yield.
[1225] NMR and IR were consistent with the proposed title
structure.
[1226] FDMS 364 (M+)
[1227] Analysis for C.sub.21H.sub.16ClN.sub.2O:
[1228] Theory: C, 69.14; H, 4.70; N, 7.68.
[1229] Found: C, 69.35; H, 4.89; N, 7.74.
EXAMPLE 284
[1230] Preparation of
2-(4-chlorophenoxymethyl)-4-benzyloxy-1-[3-[1-(t-but-
oxycarbonyl)piperidin-4-yl]propyl]-benzimidazole 365
[1231] A solution of
2-(4-chlorophenoxymethyl)-4-benzyloxy-benzimidazole (720 mg, 1.97
mmol, 1.0 eq) in dry N,N-dimethylformamide (8 ml, 0.25M) was
treated with sodium 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
3-[1-(t-butoxycarbonyl)piperidin-4-yl)propyl bromide (7.24 mg, 2.36
mmol, 1.2 eq) was added to the reaction mixture. The resulting
mixture was stirred at 70.degree. C. for three hours. The reaction
was quenched by the addition of water (1.times.30 ml). The aqueous
fraction was extracted with diethyl ether (1.times.30 ml). The
organic fractions were combined, washed with water (1.times.30 ml),
then brine (1.times.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.
[1232] NMR and IR were consistent with the proposed title
structure.
[1233] FDMS 589 (M+)
EXAMPLE 285
[1234] Preparation of (RS)
2-(4-chlorophenoxymethyl)-4-benzyloxy-1-[3-[1-(-
t-butoxycarbonyl)piperidin-3-yl]propyl]-benzimidazole 366
[1235] A solution of
2-(4-chlorophenoxymethyl)-4-benzyloxy-benzimidazole (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 mixture was stirred at room temperature for
thirty minutes and then (RS)
3-[1-(t-butoxycarbonyl]piperidin-3-yl]propyl bromide (7.24 mg, 2.36
mmol, 1.2 eq) was added to the reaction mixture. The resulting
mixture was stirred at 70.degree. C. for three hours. The reaction
was quenched by the addition of water (1.times.30 ml). The aqueous
fraction was extracted with diethyl ether (1.times.30 ml). The
organic fractions were combined, washed with water (1.times.30 ml),
then brine (1.times.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.
[1236] NMR and IR were consistent with the proposed title
structure.
[1237] FDMS 589 (M+)
[1238] Analysis for C.sub.34H.sub.40ClN.sub.3O.sub.4:
[1239] Theory: C, 69.20; H, 6.83; N, 7.12.
[1240] Found: C, 69.20; H, 6.90; N, 7.28.
EXAMPLE 286
[1241] Preparation of (R)
2-(4-chlorophenoxymethyl)-4-benzyloxy-1-[3-[1-(t-
-butoxycarbonyl)piperidin-3-yl]propyl]-benzimidazole 367
[1242] A solution of
2-(4-chlorophenoxymethyl)-4-benzyloxy-benzimidazole (720 mg, 1.97
mmol, 1.0 eq) in dry N,N-dimethylformamide (8 ml, 0.25M) was
treated with sodium 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 (R)
3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl bromide (7.24 mg, 2.36
mmol, 1.2 eq) was added to the reaction mixture. The resulting
mixture was stirred at 70.degree. C. for three hours. The reaction
was quenched by the addition of water (1.times.30 ml). The aqueous
fraction was extracted with diethyl ether (1.times.30 ml). The
organic fractions were combined, washed with water (1.times.30 ml),
then brine (1.times.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.
[1243] IR was consistent with the proposed title structure.
[1244] FDMS 589 (M+)
[1245] Analysis for C.sub.34H.sub.40ClN.sub.3O.sub.4:
[1246] Theory: C, 69.20; H, 6.83; N, 7.12.
[1247] Found: C, 70.15; H, 7.17; N, 7.07.
EXAMPLE 287
[1248] Preparation of (S)
2-(4-chlorophenoxymethyl)-4-benzyloxy-1-[3-[1-(t-
-butoxycarbonyl)piperidin-3-yl]propyl]-benzimidazole 368
[1249] A solution of
2-(4-chlorophenoxymethyl)-4-benzyloxy-benzimidazole (720 mg, 1.97
mmol, 1.0 eq) in dry N,N-dimethylformamide (8 ml, 0.25M) was
treated with sodium 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)
3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl bromide (7.24 mg, 2.36
mmol, 1.2 eq) was added to the reaction mixture. The resulting
mixture was stirred at 7000 for three hours. The reaction was
quenched by the addition of water (1.times.30 ml). The aqueous
fraction was extracted with diethyl ether (1.times.30 ml). The
organic fractions were combined, washed with water (1.times.30 ml),
then brine (1.times.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.
[1250] IR was consistent with the proposed title stricture.
[1251] FDMS 589 (M+)
[1252] Analysis for C.sub.34H.sub.40ClN.sub.3O.sub.4:
[1253] Theory: C, 69.20; H, 6.83; N, 7.12.
[1254] Found: C, 68.25; H, 7.01; N, 7.25.
EXAMPLE 288
[1255] Preparation of (R)
2-(4-chlorophenoxymethyl)-4benzyloxy-1-[2-[1-(t--
butoxycarbonyl)piperidin-3-yl]ethyl]-benzimidazole 369
[1256] A solution of
2-(4-chlorophenoxymethyl)-4-benzyloxy-benzimidazole (720 mg, 1.97
mmol, 1.0 eq) in dry N,N-dimethylformamide (8 ml, 0.25M) was
treated with sodium 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 (R)
2-[1-(t-butoxycarbonyl)piperidin-3-yl]ethyl bromide (2.36 mmol, 1.2
eq) was added to the reaction mixture. The resulting mixture was
stirred at 70.degree. C. for three hours. The reaction was quenched
by the addition of water (1.times.30 ml). The aqueous fraction was
extracted with diethyl ether (1.times.30 ml). The organic fractions
were combined, washed with water (1.times.30 ml), then brine
(1.times.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.
[1257] IR and NMR were consistent with the proposed title
structure.
[1258] FDMS 575 (M+)
[1259] Analysis for C.sub.33H.sub.38ClN.sub.3O.sub.4:
[1260] Theory: C, 68.80; H, 6.65; N, 7.29.
[1261] Found: C, 68.35; H, 7.47; N, 8.08.
EXAMPLE 289
[1262] Preparation of (S)
2-(4-chlorophenoxymethyl-4-benzyloxy-1-[2-[1-(t--
butoxycarbonyl)piperidin-3-yl]ethyl]-benzimidazole 370
[1263] A solution of
2-(4-chlorophenoxymethyl)-4-benzyloxy-benzimidazole (720 mg, 1.97
mmol, 1.0 eq) in dry N,N-dimethylformamide (8 ml, 0.25M) was
treated with sodium 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 added to the reaction mixture. The resulting mixture was
stirred at 7000 for three hours. The reaction was quenched by the
addition of water (1.times.30 mil). The aqueous fraction was
extracted with diethyl ether (1.times.30 mil). The organic
fractions were combined, washed with water (1 .times.30 ml), then
brine (1.times.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.
[1264] IR and NMR were consistent with the proposed title
structure.
[1265] FDMS 575 (M+)
[1266] Analysis for C.sub.33H.sub.38ClN.sub.3O.sub.4:
[1267] Theory: C, 68.80; H, 6.65; N, 7.29.
[1268] Found: C, 68.03; H, 7.39; N, 7.86.
EXAMPLE 290
[1269] Preparation of (RS)
2-(4-chlorophenoxymethyl)-4-hydroxy-1-[3-[1-(t--
butoxycarbonyl)piperidin-3-yl]propyl]-benzimidazole 371
[1270] A solution of (RS)
2-(4-chlorophenoxymethyl)-4-benzyloxy-1-[3-[1-(t-
-butoxycarbonyl)piperidin-3-yl]propyl]-benzimidazole (245 mg, 0.42
mmol, 1.0 eq) in ethyl acetate (4.2 ml) was degassed and then
treated with 5% palladium on carbon (250 mg). The resulting mixture
was stirred under a hydrogen atmosphere. The reaction mixture was
then filtered through a CELITE.TM. cake layer. The catalyst was
washed thoroughly with ethyl acetate and ethanol. The filtrate was
condensed on a rotoevaporator to yield the desired title product in
78% yield.
[1271] NMR was consistent with the proposed title structure.
[1272] FDMS 589 (M+)
EXAMPLE 291
[1273] Preparation of (RS)
2-(4-chlorophenoxymethyl)-4-[2-[1-(t-butoxycarb-
onyl)piperidin-3-yl]ethoxy]-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propy-
l]-benzimidazole 372
[1274] A solution of (RS)
2-(4-chlorophenoxymethyl)-4-hydroxyl-[3-[1-(t-bu-
toxycarbonyl)piperidin-3-yl]propyl]benzimidazole (75 mg, 0.15 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 mixture was stirred at room temperature for thirty
minutes, after which time
2-[1-(t-butoxycarbonyl)piperidin-3-yl]ethyl bromide (0.18 mmol, 1.2
eq) was added. The resulting mixture was stirred for three hours at
70.degree. C. The reaction was quenched by the addition of water
(10 ml). The aqueous fraction was extracted with diethyl ether
(3.times.10 ml). The organic fractions were combined, washed with
water (2.times.10 ml), then brine (1.times.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 product. Yield: 92%
[1275] NMR was consistent with the proposed title structure.
[1276] FDMS 711 (M+)
EXAMPLE 292
[1277] Preparation of (RS)
2-(4-chlorophenoxymethyl)-4-[[1-(t-butoxycarbon-
yl)piperidin-3-yl]methoxy]-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl-
]-benzimidazole 373
[1278] A solution of (RS)
2-(4-chlorophenoxymethyl)-4hydroxy-1-[3-[1-(t-bu-
toxycarbonyl)piperidin-3-yl]propyl]benzimidazole (75 mg, 0.15 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 mixture was stirred at room temperature for thirty
minutes, after which time 1-(t-butoxycarbonyl)piperidin-3-yl)methyl
bromide (0.18 mmol, 1.2 eq) was added. The resulting mixture was
stirred for three hours at 70.degree. C. The reaction was quenched
by the addition of water (10 ml). The aqueous fraction was
extracted with diethyl ether (3.times.10 ml). The organic fractions
were combined, washed with water (2.times.10 ml), then brine
(1.times.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 product.
[1279] NMR and IR were consistent with the proposed title
structure.
[1280] FDMS 696 (M+)
EXAMPLE 293
[1281] Preparation of (RS)
2-(4-chlorophenoxymethyl)-4-[(piperidin-3-yl)me-
thoxy]-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl]-benzimidazole
374
[1282] The title product is prepared from (RS)
2-(4-chlorophenoxymethyl)-4-
-[[1-(t-butoxycarbonyl)piperidin-3-yl]methoxy]-1-[3-[1-(t-butoxycarbonyl)p-
iperidin-3-yl]propyl]-benzimidazole using a standard
trifluoroacetic acid deprotection protocol.
[1283] NMR and IR were consistent with the proposed title
structure.
[1284] FDMS 497 (M+)
EXAMPLE 294
[1285] Preparation of (RS)
2-(4-chlorophenoxymethyl)-4-[3-[1-(t-butoxycarb-
onyl)piperidin-4-yl]propoxyl-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]prop-
yl]-benzimidazole 375
[1286] A solution of (RS)
2-(4-chlorophenoxymethyl)-4hydroxy-1-[3-[1-(t-bu-
toxycarbonyl)piperidin-3-yl]propyl]benzimidazole (75 mg, 0.15 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 mixture was stirred at room temperature for thirty
minutes, after which time
3-[1-(t-butoxycarbonyl)piperidin-4-yl)]propyl bromide (0.18 mmol,
1.2 eq) was added. The resulting mixture was stirred for three
hours at 70.degree. C. The reaction was quenched by the addition of
water (10 ml). The aqueous fraction was extracted with diethyl
ether (3.times.10 ml). The organic fractions were combined, washed
with water (2.times.10 ml), then brine (1.times.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 product.
[1287] NMR and IR were consistent with the proposed title
structure.
[1288] FDMS 724 (M+)
[1289] Analysis for C.sub.40H.sub.57ClN.sub.4O.sub.6:
[1290] Theory: C, 66.23; H, 7.92; N, 7.72.
[1291] Found: C, 66.51; H, 7.99; N, 7.52.
EXAMPLE 295
[1292] Preparation of (RS)
2-(4-chlorophenoxymethyl)-4-[3-[1-(t-butoxycarb-
onyl)piperidin-4-yl]propoxyl-1-[3-(1-(t-butoxycarbonyl)piperidin-3-yl]prop-
yl]-benzimidazole 376
[1293] The title product is prepared from (RS)
2-(4-chlorophenoxymethyl)-4-
-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propoxy]-1-[3-[1-(t-butoxycarbonyl-
)piperidin-3-yl]propyl]benzimidazole using a standard
trifluoroacetic acid deprotection protocol.
[1294] NMR and IR were consistent with the proposed title
structure.
[1295] FDMS 511.4 (M+)
[1296] Analysis for C.sub.29H.sub.39ClN.sub.4O.sub.2:
[1297] Theory: C, 53.62; H, 5.59; N, 7.58.
[1298] Found: C, 53.38; H, 5.64; N, 7.63.
EXAMPLE 296
[1299] Preparation of (RS)
2-(4-chlorophenoxymethyl)-4-[5-[1-(t-butoxycarb-
onyl)piperidin-4-yl]pentoxy]-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]prop-
yl]-benzimidazole 377
[1300] A solution of (RS)
2-(4-chlorophenoxymethyl)-4-hydroxy-1-[3-[1-(t-b-
utoxycarbonyl)piperidin-3-yl]propyl]benzimidazole (75 mg, 0.15
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 mixture was stirred at room temperature for thirty
minutes, after which time
5-[1-(t-butoxycarbonyl)piperidin-4-yl)]pentyl bromide (0.18 mmol,
1.2 eq) was added. The resulting mixture was stirred for three
hours at 7000. The reaction was quenched by the addition of water
(10 ml). The aqueous fraction was extracted with diethyl ether
(3.times.10 ml). The organic fractions were combined, washed with
water (2.times.10 ml), then brine (1.times.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 product.
[1301] NMR and IR were consistent with the proposed title
structure.
[1302] FDMS 752 (M+)
EXAMPLE 297
[1303] Preparation of (RS)
2-(4-chlorophenoxymethyl)-4-[5-(piperidin-4-yl)-
pentoxy]-1-[3-(piperidin-3-yl)propyl]-benzimidazole 378
[1304] The title product is prepared from (RS)
2-(4-chlorophenoxymethyl)-4-
-[5-[1-(t-butoxycarbonyl)piperidin-4-yl]pentoxy]-1-[3-[1-(t-butoxycarbonyl-
)piperidin-3-yl]propyl]benzimidazole using a standard
trifluoroacetic acid deprotection protocol.
[1305] NMR and IR were consistent with the proposed title
structure.
[1306] FDMS 555 (M+1)
EXAMPLE 298
[1307] Preparation of (RS)
2-(4-chlorophenoxymethyl)-4-[5-[1-(t-butoxycarb-
onyl)piperidin-3-yl]pentoxy]-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]prop-
yl]-benzimidazole 379
[1308] A solution of (RS)
2-(4-chlorophenoxymethyl)-4-hydroxy-1-[3-[1-(t-b-
utoxycarbonyl)piperidin-3-yl]propyl]benzimidazole (75 mg, 0.15
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 mixture was stirred at room temperature for thirty
minutes, after which time
5-[1-(t-butoxycarbonyl)piperidin-3-yl)]pentyl bromide (0.18 mmol,
1.2 eq) was added. The resulting mire was stirred for three hours
at 70.degree. C. The reaction was quenched by the addition of water
(10 ml). The aqueous fraction was extracted with diethyl ether
(3.times.10 ml). The organic fractions were combined, washed with
water (2.times.10 ml), then brine (1.times.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 product.
[1309] NMR and IR were consistent with the proposed title
structure.
[1310] FDMS 753 (M+)
EXAMPLE 299
[1311] Preparation of (RS)
2-(4-chlorophenoxymethyl)-4-[5-(piperidin-3-yl)-
pentoxy]-1-[3-(piperidin-3-yl)propyl]-benzimidazole 380
[1312] The title product is prepared from (RS)
2-(4-chlorophenoxymethyl)-4-
-[5-[1-(t-butoxycarbonyl)piperidin-3-yl]pentoxy]-1-[3-[1-(t-butoxycarbonyl-
)piperidin-3-yl]propyl]benzimidazole using a standard
trifluoroacetic acid deprotection protocol.
[1313] NMR and IR were consistent with the proposed title
structure.
[1314] FDMS 555 (M+1)
Preparation 59
[1315] Preparation of 2,3-diaminophenol dihydrochloride salt
381
[1316] In a 250 ml single neck round bottom flask was added
2,3-diaminophenol (10 g, 80.55 mmol) to ethanol (100 ml). This
mixture was heated to 50.degree. C. to achieve dissolution. The
resulting solution is cooled to -5 to 0.degree. C. and an excess of
anhydrous hydrogen chloride gas was added to form a viscous slurry.
The resulting mixture was stirred for two hours at .about.0.degree.
C., then filtered, and rinsed with chilled methanol (30 ml). The
solvents were removed in vacuo and the residue was dried
overnight.
Preparation 60
[1317] Yield: 15.29 g (96.3%).
[1318] Preparation of
4-hydroxy-2-[(4-chlorophenoxy)methyl]benzimidazole 382
[1319] In a 50 ml single neck round bottom flask, under a nitrogen
atmosphere, 4-chlorophenoxyacetonitrile (0.46 g, 2.79 mmol) was
admixed in methanol (11 ml). The contents were stirred to achieve
dissolution. To this solution were added sodium methoxide (0.164 g,
3.0 mmol). The resulting mixture was stirred for about 40 minutes.
To this mixture was added 2,3-diaminophenol dihydrochloride salt
(0.5 g, 2.5 mmol) and the resulting mixture was stirred for two
hours at room temperature. The reaction mixture was filtered and
the filtrate was added to 60 ml of 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.
[1320] NMR was consistent with the proposed title structure.
[1321] Yield: 0.60 grams (86.1%).
Preparation 61
[1322] Preparation of
4-hydroxy-2-[(4-methylphenoxy)methyl]benzimidazole 383
[1323] In a 50 ml single neck round bottom flask, under a nitrogen
atmosphere, 4-methylphenoxyacetonitrile (2.79 mmol) was admixed in
methanol (11 ml). The contents were stirred to achieve dissolution.
To this solution were added sodium methoxide (0.164 g, 3.0 mmol).
The resulting mixture was stirred for about 40 minutes. To this
mixture was added 2,3-diaminophenol dihydrochloride salt (0.5 g,
2.5 mmol) and the resulting mixture was stirred for two hours at
room temperature. The reaction mixture was filtered and the
filtrate was added to 60 ml of 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.
Preparation 62
[1324] Preparation of
4-benzyloxy-2-[(4-methylphenoxy)methyl]benzimidazole 384
[1325] In a 500 ml single neck round bottom flask, under a nitrogen
atmosphere, 4-benzyloxy-2-[(4-methylphenoxy)methyl]benzimidazole
(7.0 g, 27.5 mmol) and triphenylphosphine (9.31 g, 35.5 mmol) were
admixed. To this was added anhydrous tetrahydrofuran (275 ml). The
resulting mixture was 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
reaction mixture was extracted with ethyl acetate (500 ml). The
organic fraction was washed with water (2.times.500 ml). The
organic fraction was dried over sodium sulfate and the solvents
were removed in vacuo. The residue was then redissolved in
methylene chloride (110 ml) and further purified by chromatography.
The desired fractions were collected and the title product was
recrystallized from 80:20 hexanes:diethyl ether.
[1326] NMR was consistent with the proposed title structure.
EXAMPLE 300
[1327] Preparation of
4-trifluoromethanesulfonyloxy-2-[(4-chlorophenoxy)me-
thyl]-1-trifluoromethanesulfonylbenzimidazole 385
[1328] In a 500 ml flask, under a nitrogen atmosphere, were added
4-hydroxy-2-[(4-chlorophenoxy)methyl]benzimidazole (9.10 g, 33.1
mmol) and pyridine (300 ml). The contents were then chilled to
0.degree. C. and trifluoromethanesulfonic anhydride (23.36 g, 82.8
mmol) was then added by syringe. The resulting mixture was stirred
at 0.degree. C. for two hours and then stirred at room temperature
overnight. The progress of the reaction was monitored by thin layer
chromatography. The solvents were then removed in vacuo. The
residue was redissolved in ethyl acetate (500 ml) and washed with
water (3.times.500 ml). The organic fraction was dried over sodium
sulfate and the solvents were removed in vacuo. Yield: 14.64 g
(82.0%).
[1329] IR was consistent with the proposed title structure.
[1330] FDMS 537.95 (M+)
[1331] Analysis for
C.sub.16H.sub.9ClF.sub.6N.sub.2O.sub.6S.sub.2:
[1332] Theory: C, 35.76; H, 1.68; N, 5.20.
[1333] Found: C, 34.83; H, 1.56; N, 5.15.
EXAMPLE 301
[1334] Preparation of
4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-triflu-
oromethanesulfonylbenzimidazole 386
[1335] In a 250 ml single neck round bottom flask, under a nitrogen
atmosphere, were added
4-trifluoromethanesulfonyloxy-2-[(4-chlorophenoxy)-
methyl]-1-trifluoromethanesulfonylbenzimidazole (4.97 g, 9.22
mmol), lithium chloride (1.17 g, 27.65 mmol), allyltributyltin
(4.27 g, 12.90 mmol), and bis(triphenylphosphine)palladium(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 palladium
catalyst. The contents were then stirred overnight. The progress of
the reaction was monitored by thin layer chromatography. The
desired title product was further purified by flash
chromatography.
[1336] Yield: 3.97 g (35.8%)
[1337] NMR was consistent with the proposed title structure.
EXAMPLE 302
[1338] Preparation of
4-(ethenyl)-2-[(4-chlorophenoxy)methyl]-1-trifluorom-
ethanesulfonylbenzimidazole 387
[1339] In a 250 ml single neck round bottom flask, under a nitrogen
atmosphere, were added
4-trifluoromethanesulfonyloxy-2-[(4-chlorophenoxy)-
methyl]-1-trifluoromethanesulfonylbenzimidazole (5.00 g, 9.28
mmol), lithium chloride (1.18 g, 27.84 mmol), vinyltributyltin
(4.12 g, 12.99 mmol), and bis(triphenylphosphine)palladium(II)
chloride (303 mg, 0.371 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 palladium
catalyst. The contents were then stirred overnight. The progress of
the reaction was monitored by thin layer chromatography. An
additional 0.15 mg of the palladium catalyst and 0.5 ml of
vinyltributyltin were added to the reaction mixture and it was
refluxed for five hours. The desired title product was further
purified by flash chromatography.
[1340] Yield: 3.87 g (33.6%)
EXAMPLE 303
[1341] Preparation of
4-(ethenyl)-2-[(4-chlorophenoxy)methyl]-1-trifluorom-
ethanesulfonylbenzimidazole 388
[1342] To a 250 ml round bottom flask were added
4-trifluoromethanesulfony-
loxy-2-[(4-chlorophenoxy)methyl]-1-trifluoromethanesulfonylbenzimidazole
(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 maintained at this
temperature overnight. The progress of the reaction was monitored
by thin layer chromatography. An additional 428 mg of the palladium
catalyst was added and the resulting mixture was refluxed an
additional three hours. To the reaction mixture was added cuprous
iodide (35.3 mg, 0.02 eq) and the reaction mixture was refluxed
overnight. The solvents were removed in vacuo. The residue was
redissolved in ethyl acetate (500 ml) and was washed with 1:1
water:28% aqueous ammonium hydroxide (3.times.). The organic
fraction was dried over sodium sulfate. The desired title product
was further purified by column chromatography.
[1343] Yield: 3.87 g (48.4%)
[1344] IR was consistent with the proposed title structure.
[1345] FDMS 416.02 (M+)
[1346] Analysis for C.sub.17H12ClF.sub.3N.sub.2O.sub.3S:
[1347] Theory: C, 48.99; H, 2.90; N, 6.72.
[1348] Found: C, 49.24; H, 3.18; N, 6.48.
Preparation 63
[1349] Preparation of
4-(ethenyl)-2-[(4-chlorophenoxy)methyl]benzimidazole 389
[1350] In a 100 ml round bottom flask, under a nitrogen atmosphere,
were added
4-(ethenyl)-2-[(4-chlorophenoxy)methyl-1-trifluoromethanesulfonylbe-
nzimidazole (1.42 g, 3.29 mmol) and anhydrous methanol (20 ml).
This solution was cooled to 0.degree. C. and potassium carbonate
(911 mg, 6.59 mmol) was added. The resulting mixture was stirred
for two hours at 0.degree. 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.
[1351] Yield: 0.74 g (75.1%)
[1352] IR and FDMS were consistent with the proposed title
structure.
[1353] Analysis for C.sub.16H.sub.13ClN.sub.2O:
[1354] Theory: C, 67.49; H, 4.60; N, 9.84.
[1355] Found: C, 67.47; H, 4.86; N, 9.73.
EXAMPLE 304
[1356] Preparation of
4-(ethenyl)-2-[(4-chlorophenoxy)methyl-1-[3-[1-(t-bu-
toxycarbonyl)piperidin-4-yl]propyl]benzimidazole 390
[1357] In a 100 ml round bottom flask, under a nitrogen atmosphere,
were added 4-(ethenyl)-2-[(4-chlorophenoxy)methyl]benzimidazole
(670 mg, 2.24 mmol) and anhydrous N,N-dimethylformamide (34 ml). To
this solution was added sodium 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 mixture was heated to 100.degree. C.
and stirred at this temperature for about four hours. The progress
of the reaction was monitored by thin layer chromatography. The
reaction mixture was partitioned between ethyl acetate and brine.
The aqueous fraction was extracted twice with brine. The organic
fractions were combined and dried over sodium sulfate. The solvents
were removed in vacuo. The desired title product was further
purified by radial chromatography.
[1358] Yield: 800 mg (68.1%)
[1359] IR and FDMS were consistent with the proposed title
structure.
[1360] Analysis for C.sub.29H.sub.36ClN.sub.3O.sub.3:
[1361] Theory: C, 68.29; H, 7.11; N, 8.24.
[1362] Found: C, 68.01; H, 7.07; N, 8.30.
Preparation 64
[1363] Preparation of
4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]benzimida- zole 391
[1364] In a 100 ml round bottom flask, under a nitrogen atmosphere,
were added
4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-trifluoromethanesulfo-
nylbenzimidazole (1.00 g, 2.32 mmol) and anhydrous methanol (18
ml). This solution was cooled to 0.degree. C. and potassium
carbonate (641 mg, 4.64 mmol) was added. The resulting mixture was
stirred for two hours at 0.degree. 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.
[1365] Yield: 0.90 g (>99%)
[1366] IR and FDMS were consistent with the proposed title
structure.
[1367] Analysis for C.sub.17H.sub.15ClN.sub.2O:
[1368] Theory: C, 68.34; H, 5.06; N, 9.38.
[1369] Found: C, 68.46; H, 5.24; N, 9.35.
EXAMPLE 305
[1370] Preparation of
4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-[3-[1--
(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole 392
[1371] In a 100 ml round bottom flask, under a nitrogen atmosphere,
were added 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]benzimidazole
(550 mg, 1.84 mmol) and anhydrous N,N-dimethylformamide (59 ml). To
this solution was added sodium hydride (60% in mineral oil, 81.04
mg, 2.03 mmol). The resulting mixture was stirred at room
temperature for 60 minutes, and then
3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl bromide (620 mg, 2.03
mmol) was added. The resulting mixture was heated to 100.degree. C.
and stirred at this temperature for about three hours. The progress
of the reaction, was monitored by thin layer chromatography. The
reaction mixture was partitioned between ethyl acetate and brine.
The aqueous fraction was extracted twice with brine. The organic
fractions were combined and dried over sodium sulfate. The solvents
were removed in vacuo. The desired title product was further
purified by radial chromatography.
[1372] Yield: 622 mg (64.4%)
[1373] IR and FDMS were consistent with the proposed title
structure.
[1374] Analysis for C.sub.30H.sub.38ClN.sub.3O.sub.3:
[1375] Theory: C, 68.75; H, 7.31; N, 8.02.
[1376] Found: C, 68.47; H, 7.35; N, 8.22.
EXAMPLE 306
[1377] Preparation of
4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-[3-(pi-
peridin-4-yl)propyl]benzimidazole trifluoroacetate 393
[1378] In a 100 ml single neck round bottom flask, under a nitrogen
atmosphere,
4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxy-
carbonyl)piperidin-4-yl]propyl]benzimidazole (300 mg, 0.572 mmol)
was added to anhydrous methylene chloride (20 ml). To this was
added trifluoroacetic acid (0.44 ml, 652 mg, 5.72 mmol). The
resulting mixture is stirred overnight at room temperature. The
progress of the reaction was monitored by thin layer
chromatography. The solvents were removed in vacuo.
[1379] Yield: 222 mg (72.3%)
[1380] NMR was consistent with the proposed title structure.
EXAMPLE 307
[1381] Preparation of
4-(propyl)-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-bu-
toxycarbonyl)piperidin-4-yl]propyl]benzimidazole 394
[1382] In a 50 ml single neck round bottom flask, under a nitrogen
atmosphere,
4-(prop-2-enyl)-2-[4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxyc-
arbonyl)piperidin-4-yl]propyl]benzimidazole (100 mg, 0.19 mmol) was
added to ethyl acetate (4 ml). To this solution was added 10%
palladium on activated carbon (100 mg), followed by the addition of
a hydrogen balloon. The reaction mixture was stirred for three
hours at room temperature, then filtered through a bed of
CELITE.TM.. The desired title product was further purified by
radial chromatography.
[1383] Yield: 86 mg (85.6%)
[1384] IR and NMR were consistent with the proposed title
structure.
[1385] Analysis for C.sub.39H.sub.40ClN.sub.3O.sub.3:
[1386] Theory: C, 68.49; H, 7.66; N, 7.99.
[1387] Found: C, 68.76; H, 7.70; N, 8.03.
EXAMPLE 308
[1388] Preparation of
4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]--[3-[1-[-
3-(piperidin-1-yl)propyl]piperidin-4-yl]propyl]benzimidazole
395
[1389] In a 25 ml round bottom flask, under a nitrogen atmosphere,
were added
4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)pr-
opyl]benzimidazole (69.9 mg, 0.13 mmol), potassium carbonate (161.9
mg, 1.17 mmol), potassium iodide (21.6 mg, 0.13 mmol),
3-(piperidin-1-yl)propyl chloride (33.52 mg, 0.17 mmol) and
N,N-dimethylformamide (3 ml). The resulting mixture was heated to
100.degree. C. and maintained 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 with ethyl acetate. The organic fractions
were combined, 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.
[1390] Yield: 40 mg (55.9%)
[1391] NMR was consistent with the proposed title structure.
[1392] FDMS 548.22 (M+)
EXAMPLE 309
[1393] Preparation of
4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-[3-[1--
[3-(phenyl)propyl]piperidin-4-yl]propyl]benzimidazole 396
[1394] 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)pr-
opyl]benzimidazole (898 mg, 2.12 mmol), potassium carbonate (1.46
g, 10.58 mmol), 3-(phenyl)propyl chloride (0.2 ml, 506 mg, 2.54
mmol) and N,N-dimethylformamide (7 ml). The resulting mixture was
heated to 60.degree. C. and maintained at this temperature
overnight. The progress of the reaction was monitored by thin layer
chromatography. An additional 1 equivalent of potassium carbonate
and 0.2 ml of 3-(phenyl)propyl chloride were added and the
resulting contents were stirred at 60.degree. C. for an additional
two hours. The reaction was quenched by the addition of water. The
aqueous fraction was extracted with ethyl acetate. The organic
fractions were combined, 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.
[1395] Yield: 920 mg (80.2%)
[1396] NMR and IR was consistent with the proposed title
structure.
[1397] Analysis for C.sub.34H.sub.40ClN.sub.3O:
[1398] Theory: C, 75.32; H, 7.44; N, 7.75.
[1399] Found: C, 72.84; H, 7.22; N, 7.64.
EXAMPLE 310
[1400] Preparation of
4-(ethenyl)-2-[(4-chlorophenoxy)methyl]-1-[3-[1-[3-(-
phenyl)propyl]piperidin-4-yl]propyl]benzimidazole 397
[1401] 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)pr-
opyl]benzimidazole (898 mg, 2.12 mmol), potassium carbonate (1.46
g, 10.58 mmol), 3-(phenyl)propyl chloride (0.2 ml, 506 mg, 2.54
mmol) and N,N-dimethylformamide (7 ml). The resulting mixture was
heated to 60.degree. C. and maintained at this temperature
overnight. 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 with 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 vacuo. The desired title product was
further purified by radial chromatography.
[1402] Yield: 810 mg (77.2%)
[1403] NMR and IR was consistent with the proposed title
structure.
[1404] Analysis for C.sub.33H.sub.38ClN.sub.3O:
[1405] Theory: C, 75.05; H, 7.25; N, 7.96.
[1406] Found: C, 74.81; H, 7.05; N, 8.15.
EXAMPLE 311
[1407] Preparation of
4-methoxy-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-but-
oxycarbonyl)piperidin-4-yl]propyl]benzimidazole 398
[1408] A solution of
4-hydroxy-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-buto-
xycarbonyl)piperidin-4-yl]propyl]benzimidazole (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, 1.1 eq). The
is 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 resulting 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.times.10 ml). The organic fractions were combined, washed with
water (2.times.10 ml), then brine (1.times.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.
[1409] NMR and IR were consistent with the proposed title
structure.
[1410] Analysis for C.sub.28H.sub.36ClN.sub.3O.sub.4:
[1411] Theory: C, 65.42; H, 7.06; N, 8.17.
[1412] Found: C, 65.63; H, 7.14; N, 8.30.
EXAMPLE 312
[1413] Preparation of
4-methoxy-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidi-
n-4-yl)propyl]benzimidazole trifluoroacetate 399
[1414] This product was prepared from
4-methoxy-2-[(4-chlorophenoxy)methyl-
]-1-[3-(piperidin-4-yl)propyl]benzimidazole trifluoroacetate using
standard trifluoroacetic acid deprotection protocols.
[1415] IR and NMR were consistent with the proposed title
structure.
[1416] FDMS 413 (M+)
[1417] Analysis for C.sub.23H.sub.28ClN.sub.3O.sub.2.circle-solid.3
C.sub.2HF.sub.3O.sub.2:
[1418] Theory: C, 46.07; H, 4.13; N, 5.56.
[1419] Found: C, 46.55; H, 4.38; N, 5.74.
EXAMPLE 313
[1420] Preparation of
4-methoxy-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(3-phe-
nylpropyl)piperidin-4-yl]propyl]benzimidazole 400
[1421] A solution of
4-methoxy-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-
-4-yl)propyl]benzimidazole trifluoroacetate (177 mg, 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-phenylpropyl
bromide (87 mg, 0.43 mmol, 1.5 eq). The resulting mixture was
stirred at 80.degree. C. for six hours. The reaction was quenched
by the addition of water (5 ml). The aqueous fraction was extracted
with ethyl acetate (3.times.10 ml). The organic fractions were
combined, washed with water (3.times.10 ml), and brine (1.times.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.
[1422] Yield: 72%
[1423] NMR and IR were consistent with the proposed title
structure.
[1424] FDMS 531.2, 532 (M+)
[1425] Analysis for C.sub.32H.sub.38ClN.sub.3O.sub.2:
[1426] Theory: C, 72.23; H, 7.20; N, 7.90.
[1427] Found: C, 72.14; H, 7.35; N, 7.82.
EXAMPLE 314
[1428] Preparation of
4-cyclopentoxy-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(-
t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole
trifluoroacetate 401
[1429] A solution of
4-hydroxy-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-buto-
xycarbonyl)piperidin-4-yl]propyl]benzimidazole 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, 1.1 eq). The resulting mixture was stirred for thirty minutes
at room temperature. Cyclopropyl bromide (0.66 mmol, 1 eq) was
added to the reaction and the resulting 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.times.10 ml). The organic fractions were combined,
washed with water (2.times.10 ml), then brine (1.times.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.
[1430] NMR and IR were consistent with the proposed title
structure.
[1431] FDMS 567 (M+)
[1432] Analysis for C.sub.32H.sub.42ClN.sub.3O.sub.4:
[1433] Theory: C, 67.65; H, 7.45; N, 7.40.
[1434] Found: C, 68.82; H, 7.87; N, 7.55.
EXAMPLE 315
[1435] Preparation of
4-cyclopentoxy-2-[(4-chlorophenoxy)methyl]-1-[3-(pip-
eridin-4-yl)propyl]benzimidazole trifluoroacetate 402
[1436] This product was prepared from
4-cyclopentoxy-2-[(4-chlorophenoxy)m-
ethyl]-1-[3-(piperidin-4-yl)propyl]benzimidazole trifluoroacetate
using standard trifluoroacetic acid deprotection protocols.
[1437] IR and NMR were consistent with the proposed title
structure.
[1438] FDMS 468 (M+)
[1439] Analysis for C.sub.29H.sub.38ClN.sub.3O.sub.2.circle-solid.3
C.sub.2HF.sub.3O.sub.2:
[1440] Theory: C, 48.93; H, 4.60; N, 5.19.
[1441] Found: C, 47.33; H, 4.82; N, 5.37.
EXAMPLE 316
[1442] Preparation of
4-cyclopentoxy-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(-
3-phenylpropyl)piperidin-4-yl]propyl]benzimidazole 403
[1443] A solution of
4-cyclopentoxy-2-[(4-chlorophenoxy)methyl]-1-[3-(pipe-
ridin-4-yl)propyl]benzimidazole 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-phenylpropyl
bromide (87 mg, 0.43 mmol, 1.5 eq). The resulting mixture was
stirred at 80.degree. C. for six hours. The reaction was quenched
by the addition of water (5 ml). The aqueous fraction was extracted
with ethyl acetate (3.times.10 ml). The organic fractions were
combined, washed with water (3.times.10 ml), and brine (1.times.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.
[1444] NMR and IR were consistent with the proposed title
structure.
[1445] FDMS 586 (M+)
[1446] Analysis for C.sub.36H.sub.44ClN.sub.3O.sub.2:
[1447] Theory: C, 73.76; H, 7.56; N, 7.17.
[1448] Found: C, 75.08; H, 7.85; N, 7.30.
EXAMPLE 317
[1449] Preparation of
4-isopropoxy-2-[(4-chlorophenoxy)methyl]-1-[3-[3-(t--
butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole trifluoroacetate
404
[1450] A solution of
4-hydroxy-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-buto-
xycarbonyl)piperidin-4-yl]propyl]benzimidazole 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, 1.1 eq). The resulting mixture was stirred for thirty minutes
at room temperature. Isopropyl bromide (0.66 mmol, 1 eq) was added
to the reaction and the resulting 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.times.10 ml). The organic fractions were combined, washed with
water (21.times.10 ml), then brine (1.times.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.
[1451] NMR and IR were consistent with the proposed title
structure.
[1452] FDMS 541, 542 (M+)
[1453] Analysis for C.sub.28H.sub.36ClN.sub.3O.sub.4:
[1454] Theory: C, 66.47; H, 7.44; N, 7.75.
[1455] Found: C, 66.31; H, 7.54; N, 7.75.
EXAMPLE 318
[1456] Preparation of
4-isopropoxy-2-[(4-chlorophenoxy)methyl]-1-[3-(piper-
idin-4-yl)propyl]benzimidazole trifluoroacetate 405
[1457] This product was prepared from
4-isopropoxy-2-[(4-chlorophenoxy)met-
hyl]-1-[3-(piperidin&yl)propyl]benzimidazole trifluoroacetate
using standard trifluoroacetic acid deprotection protocols.
[1458] IR and NMR were consistent with the proposed title
structure.
[1459] FDMS 413 (M+)
[1460] Analysis for C.sub.25H.sub.32ClN.sub.3O.sub.2.circle-solid.3
C.sub.2HF.sub.3O.sub.2:
[1461] Theory: C, 47.49; H, 4.50; N, 5.36.
[1462] Found: C, 48.46; H, 5.03; N, 5.86.
EXAMPLE 319
[1463] Preparation of
4-isopropoxy-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(3--
phenylpropyl)piperidin-4-yl]propyl]benzimidazole 406
[1464] A solution of
4-isopropoxy-2-[(4-chlorophenoxy)methyl]-1-[3-(piperi-
din-4-yl)propyl]benzimidazole 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-phenylpropyl bromide (87
mg, 0.43 mmol, 1.5 eq). The resulting mixture was stirred at
80.degree. C. for six hours. The reaction was quenched by the
addition of water (5 ml). The aqueous fraction was extracted with
ethyl acetate (3.times.10 ml). The organic fractions were combined,
washed with water (3.times.10 ml), and brine (1.times.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.
[1465] NMR and IR were consistent with the proposed title
structure.
[1466] FDMS 559.1, 560 (M+)
[1467] Analysis for C.sub.34H.sub.42ClN.sub.3O.sub.2:
[1468] Theory: C, 72.09; H, 7.56; N, 7.50.
[1469] Found: C, 73.09; H, 7.47; N, 7.52.
EXAMPLE 320
[1470] Preparation of
4-(cyclohexylmethoxy)-2-[(4-chlorophenoxy)methyl]-1--
[3-[1(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole
trifluoroacetate 407
[1471] A solution of
4-hydroxy-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-buto-
xycarbonyl)piperidin-4-yl]propyl]benzimidazole 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, 1.1 eq). The resulting mixture was stirred for thirty minutes
at room temperature. Cyclopropylmethyl bromide (0.66 mmol, 1 eq)
was added to the reaction and the resulting 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.times.10 ml). The organic fractions were combined,
washed with water (2.times.10 ml), then brine (1.times.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.
[1472] NMR and IR were consistent with the proposed title
structure.
[1473] FDMS 595, 596 (M+)
[1474] Analysis for C.sub.34H.sub.46ClN.sub.3O.sub.4:
[1475] Theory C, 68.50; H, 7.78; N, 7.05.
[1476] Found: C, 68.62; H, 7.83; N, 7.03.
EXAMPLE 321
[1477] Preparation of
4-(cyclohexylmethoxy)-2-[(4-chlorophenoxy)methyl]-1--
[3-(piperidin-4-yl)propylbenzimidazole trifluoroacetate 408
[1478] This product was prepared from
4-(cyclohexylmethoxy)-2-[(4-chloroph-
enoxy)methyl]-1-[3-(piperidin-4-yl)propyl]benzimidazole
trifluoroacetate using standard trifluoroacetic acid deprotection
protocols.
[1479] IR and NMR were consistent with the proposed title
structure.
[1480] FDMS 496 (M+)
[1481] Analysis for C.sub.31H.sub.42ClN.sub.3O.sub.2.circle-solid.3
C.sub.2HF.sub.3O.sub.2:
[1482] Theory: C, 50.16; H, 4.93; N, 5.01.
[1483] Found: C, 50.01; H, 5.04; N, 4.96.
EXAMPLE 322
[1484] Preparation of
4-(cyclohexylmethoxy)-2-[(4-chlorophenoxy)methyl]-1--
[3-[1-(3-phenylpropyl)piperidin-4-yl]propyl]benzimidazole 409
[1485] A solution of
4-(cyclohexylmethoxy)-2-[(4-chlorophenoxy)methyl]-1-[-
3-(piperidin-4-yl)propyl]benzimidazole 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-phenylpropyl
bromide (87 mg, 0.43 mmol, 1.5 eq). The resulting mixture was
stirred at 80.degree. C. for six hours. The reaction was quenched
by the addition of water (5 ml). The aqueous fraction was extracted
with ethyl acetate (3.times.10 ml). The organic fractions were
combined, washed with water (3.times.10 ml), and brine (1.times.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.
[1486] NMR and IR were consistent with the proposed title
structure.
[1487] FDMS 614 (M+)
[1488] Analysis for C.sub.38H.sub.48ClN.sub.3O.sub.2:
[1489] Theory C, 74.30; H, 7.88; N, 6.84.
[1490] Found: C, 74.26; H, 7.93; N, 6.91.
EXAMPLE 323
[1491] Preparation of
4-(3-bromopropoxy)-2-[(4-chlorophenoxy)methyl]-1-[3--
[1-(t-butoxycarbonyl)piperidin-4-ylpropyl]benzimidazole 410
[1492] A solution of 1,3-dibromopropane (41.3 mg, 0.3 mmol, 1.5 eq)
in anhydrous N,N-dimethylformamide (2 ml) was treated with a
solution of
4-hydroxy-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-
-4-yl]propyl benzimidazole (100 mg, 0.2 mmol, 1 eq) in anhydrous
N,N-dimethylformamide (1 ml). The resulting mixture was stirred for
twelve hours. The reaction was quenched by the addition of water
(10 ml). The aqueous fraction was extracted with diethyl ether
(3.times.10 ml). The organic fractions were combined, washed with
water (3.times.10 ml), and brine (1.times.10 ml), and then dried
over sodium 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.
[1493] Yield: 80%
[1494] NMR and IR were consistent with the proposed title
structure.
[1495] FDMS 620, 621 (M+)
EXAMPLE 324
[1496] Preparation of
4-[3-[2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]propo-
xyl-2-[(4-chlorophenoxy)methyl-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]pr-
opyl]benzimidazole 411
[1497] A solution of
4-[3-bromopropoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[-
1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole (77 mg,
0.124 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 ml) was
treated with potassium carbonate (51.3 mg, 0.37 mmol, 2 eq) and
(S)-(+)-2-pyrrolidin-1-ylmethyl)pyrrolidine (28.7 mg, 0.19 mmol,
1.5 eq). The resulting mixture was stirred at 80.degree. C. for six
hours. The reaction was quenched by the addition of water (10 ml).
The aqueous fraction was extracted with ethyl acetate (3.times.10
ml). The organic fractions were combined, washed with water
(3.times.10 ml), brine (1 .times.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.
[1498] Yield: 78%
[1499] NMR and IR were consistent with the proposed title
structure.
[1500] FDMS 694 (M+)
EXAMPLE 325
[1501] Preparation of (RS)
4-[3-[2-pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]p-
ropoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]benzimidaz-
ole 412
[1502] The title compound was prepared from (RS)
4-[3-[2-(pyrrolidin-1-ylm-
ethyl)pyrrolidin-1-yl]propoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-buto-
xycarbonyl)piperidin-4-yl]propyl]benzimidazole using
trifluoroacetic acid deprotection as described supra.
[1503] IR and NMR were consistent with the proposed title
structure.
[1504] FDMS 594 (M+)
[1505] Analysis for C.sub.34H.sub.51ClN.sub.5O.sub.2:
[1506] Theory: C, 68.72; H, 8.14; N, 11.79.
[1507] Found: C, 68.91; H, 8.08; N, 11.70.
EXAMPLE 326
[1508] Preparation of (RS)
4-[3-[2-[2-piperidin1-yl)ethyl]piperidin-1-yl]p-
ropoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4--
yl]propyl]benzimidazole 413
[1509] A solution of
4-[3-bromopropoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[-
1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole (77 mg,
0.124 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 ml) was
treated with potassium carbonate (51.3 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.degree. C. for six hours. The
reaction was quenched by the addition of water (101ml). The aqueous
fraction was extracted with ethyl acetate (3.times.10 ml). The
organic fractions were combined, washed with water (3.times.10 ml),
brine (1 .times.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.
[1510] NMR and IR were consistent with the proposed title
structure.
[1511] FDMS 736.4 (M+)
EXAMPLE 327
[1512] Preparation of (RS)
4-[3-[2-[2-(piperidin-1-yl)ethyl]piperidin-1-yl-
]propoxy]-2-[(4-chlorophenoxy)methyl-1-[3-(piperidin-4-yl)propyl]benzimida-
zole 414
[1513] The title compound was prepared from (RS)
4-[3-[2-[2-(piperidin-1-y-
l)ethyl]piperidin-1-yl]propoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-but-
oxycarbonyl)piperidin-4-yl]propyl]benzimidazole using
trifluoroacetic acid deprotection as described supra.
[1514] NMR and IR were consistent with the proposed title
structure.
[1515] FDMS 636 (M+)
[1516] Analysis for C.sub.37H.sub.54ClN.sub.5O.sub.2:
[1517] Theory: C, 69.84; H, 8.55; N, 11.01.
[1518] Found: C, 69.51; H, 8.76; N, 10.13.
EXAMPLE 328
[1519] Preparation of
4-[3-[4-(carboxamido)piperidin-1-yl]propoxy]-2-[(4-c-
hlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzi-
midazole 415
[1520] A solution of
4-[3-bromopropoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[-
1-(t-butoxycarbonyl]piperidin-4-yl]propyl]benzimidazole (77 mg,
0.124 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 ml) was
treated with potassium carbonate (51.3 mg, 0.37 mmol, 2 eq) and
4-(carboxamido)piperidine (0.19 mmol, 1.5 eq). The resulting
mixture was stirred at 80.degree. C. for six hours. The reaction
was quenched by the addition of water (10 ml). The aqueous fraction
was extracted with ethyl acetate (3.times.10 ml). The organic
fractions were combined, washed with water (3.times.10 ml), brine
(1.times.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.
[1521] NMR and IR were consistent with the proposed title
structure.
[1522] FDMS 668 (M+)
EXAMPLE 329
[1523] Preparation of
4-[3-[4-(carboxamido)piperidin-1-yl]propoxy]-2-[(4-c-
hlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzi-
midazole 416
[1524] The title compound was prepared from
4-[3-[4-(carboxamido)piperidin-
-1-yl]propoxy]2-[4-(chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperi-
din-4-yl]propyl]benzimidazole using standard trifluoroacetic acid
deprotection techniques, as described supra.
[1525] NMR and IR were consistent with the proposed title
structure.
[1526] FDMS 568 (M+)
[1527] Analysis for C.sub.31H.sub.43ClN.sub.5O.sub.3:
[1528] Theory: C, 65.53; H, 7.45; N, 12.33.
[1529] Found: C, 65.26; H, 7.48; N, 12.11.
EXAMPLE 330
[1530] Preparation of
4-[3-[4-(methyl)piperidin-1-yl]propoxy]-2-[(4-chloro-
phenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidaz-
ole 417
[1531] A solution of
4-[3-bromopropoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[-
1-(t-butoxycarbonyl]piperidin-4-yl]propyl]benzimidazole (77 mg,
0.124 mmol, 1 eq) in anhydrous N,N-dimethylformamide (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.degree. C. for six hours. The reaction was quenched
by the addition of water (10 ml). The aqueous fraction was
extracted with ethyl acetate (3.times.10 ml). The organic fractions
were combined, washed with water (3.times.10 ml), brine (1.times.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.
[1532] NMR and IR were consistent with the proposed title
structure.
[1533] FDMS 639 (M+)
[1534] Analysis for C.sub.36H.sub.51ClN.sub.4O.sub.4:
[1535] Theory: C, 67.64; H, 8.04; N, 8.76.
[1536] Found: C, 67.89; H, 8.05; N, 8.84.
EXAMPLE 331
[1537] Preparation of
4-[3-[4-(methyl)piperidin-1-yl]propoxy]-2-[(4-chloro-
phenoxy)methyl]-1-[3-(piperidin-4yl)propyl]benzimidazole 418
[1538] The title compound was prepared from
4-[3-[4-(methyl]piperidin-1-yl-
]propoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin--
4-yl]propyl]benzimidazole by standard trifluoroacetic acid
deprotection as described supra.
[1539] NMR and IR were consistent with the proposed title
structure.
[1540] FDMS 539 (M+)
[1541] Analysis for C.sub.31H.sub.43ClN.sub.4O.sub.2:
[1542] Theory: C, 69.06; H, 8.04; N, 10.39.
[1543] Found: C, 69.15; H, 8.02; N, 10.13.
EXAMPLE 332
[1544] Preparation of (RS)
4-[3-[3-(methyl)piperidin-1-ylpropoxy]-2-[(4-ch-
lorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl]piperidin
yl]propyl]benzimidazole 419
[1545] A solution of
4-[3-bromopropoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[-
1-(t-butoxycarbonyl]piperidin-4-yl]propyl]benzimidazole (77 mg,
0.124 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 ml) was
treated with potassium carbonate (51.3 mg, 0.37 mmol, 2 eq) and
(RS) 3-(methyl)piperidine (0.19 mmol, 1.5 eq). The resulting
mixture was stirred at 80.degree. C. for six hours. The reaction
was quenched by the addition of water (10 ml). The aqueous fraction
was extracted with ethyl acetate (3.times.10 ml). The organic
fractions were combined, washed with water (3.times.10 ml), brine
(1.times.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.
[1546] NMR and IR were consistent with the proposed title
structure.
[1547] FDMS 639 (M+)
[1548] Analysis for C.sub.36H.sub.51ClN.sub.4O.sub.4:
[1549] Theory: C, 67.64; H, 8.04; N, 8.76.
[1550] Found: C, 67.91; H, 7.95; N, 8.82.
EXAMPLE 333
[1551] Preparation of (RS)
4-[3-[3-(methyl)piperidin-1-yl]propoxy]-.sup.2--
[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propylbenzimidazole
420
[1552] The title compound was prepared from (RS)
4-[3-[3-(methyl)piperidin-
-1-yl]propoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piper-
idin-4-yl]propyl]benzimidazole by standard trifluoroacetic acid
deprotection as described supra.
[1553] NMR and IR were consistent with the proposed title
structure.
[1554] FDMS 539 (M+)
[1555] Analysis for C.sub.31H.sub.43ClN.sub.4O.sub.2:
[1556] Theory: C, 69.06; H, 8.04; N, 10.39.
[1557] Found: C, 69.29; H, 8.19; N, 10.24.
EXAMPLE 334
[1558] Preparation of (RS)
4-[3-[2-(methyl)piperidin-1-yl]propoxy]-2-[(4-c-
hlorophenoxymethyl]-1-[3-[1-(butoxycarbonyl)piperidin-4-yl]propyl]benzimid-
azole 421
[1559] A solution of
4-[3-bromopropoxy]-2-[(4-yl]propyl]benzimidazole (77 mg, 0.124
mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 ml) was treated
with potassium carbonate (51.3 mg, 0.37 mmol, 2 eq) and (RS)
2-(methyl)piperidine (0.19 mmol, 1.5 eq). The resulting mixture was
stirred at 80.degree. C. for six hours. The reaction was quenched
by the addition of water (10 ml). The aqueous fraction was
extracted with ethyl acetate (3.times.10 ml). The organic fractions
were combined, washed with water (3.times.10 ml), brine (1.times.10
ml), and the 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.
[1560] NMR and IR were consistent with the proposed title
structure.
[1561] FDMS 639 (M+)
[1562] Analysis for C.sub.36H.sub.51ClN.sub.4O.sub.4:
[1563] Theory: C, 67.64; H, 8.04; N, 8.76.
[1564] Found: C, 67.89; H, 8.05; N, 8.84.
EXAMPLE 335
[1565] Preparation of (RS)
4-[3-[2-(methyl)piperidin-1-yl]propoxy]-2-[(4-c-
hlorophenoxy)methyl-1-[3-(piperidin-4-yl)propyl]benzimidazole
422
[1566] The title compound was prepared from (RS)
4-[3-[2-(methyl)piperidin-
-1-yl]propoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piper-
idin-4-yl]propyl]benzimidazole by standard trifluoroacetic acid
deprotection as described supra.
[1567] NMR and IR were consistent with the proposed title
structure.
[1568] FDMS 539 (M+)
[1569] Analysis for C.sub.31H.sub.43ClN.sub.4O.sub.2:
[1570] Theory: C, 69.06; H, 8.04; N, 10.39.
[1571] Found: C, 70.89; H, 8.65; N, 9.05.
EXAMPLE 336
[1572] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[3-(1,1-d-
iphenyl)propyl]piperidin-4-yl]propyl]benzimidazole trihydrochloride
423
[1573] NMR was consistent with the desired title structure. FDMS
591 (M+).
[1574] Analysis calculated for
C.sub.38H.sub.42ClN.sub.3O.circle-solid.3 HCl.circle-solid.0.25
H.sub.2O.
[1575] Theory: C, 64.64; H, 6.50; N, 5.95.
[1576] Found: C, 64.61; H, 6.36; N, 5.99.
EXAMPLE 337
[1577] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(benzimid-
azole-2-ylmethyl)piperidin-4-yl]propyl]benzimidazole 424
[1578] mp 218-20.degree..
[1579] NMR was consistent with the desired title structure. FDMS
528 (M+).
[1580] FAB exact mass calculated for
C.sub.31H.sub.35ClN.sub.5O:
[1581] Theory 528.2530
[1582] Found: 528.2541
EXAMPLE 338
[1583] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[3-(2,4-d-
imethoxybenzoyl)propyl]piperidin-4-yl]propyl]benzimidazole 425
[1584] NMR was consistent with desired title structure. ESI MS 604
(M+1). Single compound of high purity as evidenced by
chromatographic methods.
EXAMPLE 339
[1585] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[3-(4-met-
hoxybenzoyl)propyl]piperidin-4-yl]propyl]benzimidazole 426
[1586] NMR was consistent with desired title structure. ESI MS 574
(M+1). Single compound of high purity as evidenced by
chromatographic methods.
EXAMPLE 340
[1587] Preparation of
2-(4-chlorophenoxymethyl-4-methyl-1-[3-[1-[2-(quinaz-
olin-4-yloxy)acetyl]piperidin-4-yl]propyl]benzimidazole 427
[1588] NMR was consistent with desired title structure.
[1589] FAB exact mass calculated for
C.sub.33H.sub.35ClN.sub.5O.sub.3:
[1590] Theory: 584.2420
[1591] Found: 584.2428
EXAMPLE 341
[1592] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[2-(quino-
lin-2-yloxy)acetyl]piperidin-4-yl]propyl]benzimidazole 428
[1593] FAB exact mass calculated for
C.sub.34H.sub.36ClN.sub.4O.sub.3:
[1594] Theory: 583.2476
[1595] Found: 583.2484
[1596] Single compound of high purity as evidenced by
chromatographic methods.
EXAMPLE 342
[1597] Preparation of
2-(4-chlorophenoxymethyl)methyl-1-[3-[1-[3-(indol-3--
yl)propan-1-oyl]piperidin-4-yl]propyl]benzimidazole 429
[1598] mp 153.degree. C.
[1599] NMR, IR and UV were consistent with the desired title
structure.
[1600] FDMS 568 (M+).
[1601] Analysis calculated for
C.sub.34H.sub.37ClN.sub.4O.sub.2:
[1602] Theory: C, 71.75; H, 6.55; N, 9.84.
[1603] Found: C, 71.56; H, 6.41; N, 9.89.
EXAMPLE 343
[1604] Preparation of
2-(4-chlorophenoxymethyl)methyl-4-[3-[1-[4-(indol-3--
yl)butan-1-oyl]piperidin-4-yl]propyl]benzimidazole 430
[1605] mp 151.degree..
[1606] NMR, IR and UV were consistent with the desire title
structure.
[1607] FDMS 582 (M+).
[1608] Analysis calculated for
C.sub.35H.sub.39ClN.sub.4O.sub.2:
[1609] Theory: C, 72.09; H, 6.74;, N, 9.61.
[1610] Found: C, 72.22; H, 6.69; N, 9.67.
EXAMPLE 344
[1611] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[1-(2-phe-
nylethylamino)butan-4-oyl]piperidin-4-yl]propyl]benzimidazole
431
[1612] mp 112.degree. C.
[1613] NMR, IR and UV were consistent with the desired title
structure.
[1614] FDMS 587 (M+).
[1615] Single compound of high purity as evidenced by
chromatographic methods.
EXAMPLE 345
[1616] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[1-(3-phe-
nylpropylamino)butan-4-oyl]piperidin-4-yl]propyl]benzimidazole
432
[1617] mp 113.degree. C.
[1618] NMR, IR and UV were consistent with the desired title
structure.
[1619] FDMS 601 (M+).
[1620] Analysis calculated for
C.sub.36H.sub.4.sub.5ClN.sub.4O.sub.2:
[1621] Theory. C, 71.92; H, 7.54, N, 9.32.
[1622] Found: C, 71.72; H, 7.49; N, 9.24.
EXAMPLE 346
[1623] Preparation of
2-(4-chlorophenoxymethyl-4-methyl-1-[3-[1-[4-(1-indo-
l-3-yl)butyl]piperidin-4-yl]propyl]benzimidazole 433
[1624] NMR was consistent with the desired title structure. ESI MS
569 (M+1). Single compound of high purity as evidenced by
chromatographic methods.
EXAMPLE 347
[1625] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[3-(1-ind-
ol-3-yl)propyl]piperidin-4-yl]propyl]benzimidazole 434
[1626] NMR was consistent with the desired title structure. ESI MS
555 (M+1). Single compound of high purity as evidenced by
chromatographic methods.
EXAMPLE 348
[1627] Preparation of
2-(4-chlorophenoxymethyl-4-methyl-1-[3-[1-[3-(4-iodo-
phenyl)propyl]piperidin-4-yl]propyl]benzimidazole 435
[1628] NMR was consistent with the desired title structure. ESI MS
642 (M+1). Single compound of high purity as evidenced by
chromatographic methods.
EXAMPLE 349
[1629] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[2-(4-iod-
ophenyl)ethyl]piperidin-4-yl]propyl]benzimidazole 436
[1630] mp 121-122.degree. C.
[1631] NMR and IR were consistent with the desired title
structure.
[1632] ESI MS 628 (M+1).
[1633] Analysis calculated for C.sub.31H.sub.35ClN.sub.3O:
[1634] Theory: C, 59.29; H, 5.62; N, 6.69.
[1635] Found: C, 59.22; H, 5.62; N, 6.70.
EXAMPLE 350
[1636] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(3-acetyl-
propyl)piperidin-4-yl]propyl]benzimidazole 437
[1637] NMR was consistent with the desired title structure. ESI MS
482 (M+1). Single compound of high purity as evidenced by
chromatographic methods.
EXAMPLE 351
[1638] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1,1-dimethy-
lpiperidin-4-ium]propyl]benzimidazole iodide 438
[1639] mp 198-199.degree. C.
[1640] NMR, IR and UV were consistent with the desired title
structure.
[1641] FDMS 426 (M+ for C.sub.25H.sub.33N.sub.3O).
[1642] Analysis for
C.sub.25H.sub.33N.sub.3ClIN.sub.3O.circle-solid.0.5 H.sub.2O:
[1643] Theory: C, 53.34; H, 6.09; N, 7.49.
[1644] Found: C, 53.19; H, 6.07; N, 7.46.
EXAMPLE 352
[1645] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-methylpip-
eridin-4-yl]propyl]benzimidazole 439
[1646] The NMR was consistent with the desired title structure.
[1647] FAB exact mass calculated for
C.sub.24H.sub.31ClN.sub.3O:
[1648] Theory: 412.2156
[1649] Found: 412.2146
[1650] Single compound of high purity as evidenced by
chromatographic methods.
EXAMPLE 353
[1651] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[4-(pheny-
l)butyl]piperidin-4-yl]propyl]benzimidazole 440
[1652] The NMR was consistent with the desired title structure. ESI
MS 530 (M+1).
[1653] Single compound of high purity as evidenced by
chromatographic methods.
EXAMPLE 354
[1654] Preparation of
2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[5-(pheny-
l)pentyl]piperidin-4-yl]propyl]benzimidazole 441
[1655] The NMR was consistent with the desired title structure.
[1656] FDMS 543 (M+). ESI MS 544 (M+1).
[1657] Analysis calculated for C.sub.34H.sub.42ClN.sub.3O:
[1658] Theory: C, 75.04; H, 7.78; N, 7.72.
[1659] Found: C, 74.84; H, 7.78; N, 7.89.
EXAMPLE 355
[1660] Preparation of
2-(4-methylphenoxymethyl)-4-benzyloxy-benzimidazole
[1661] Yield: 53%
[1662] NMR was consistent with the proposed title structure.
[1663] mp 156-158.degree. C.
[1664] Analysis for C.sub.22H.sub.20N.sub.2O.sub.2:
[1665] Theory: C, 76.72; H, 5.85; N, 8.13.
[1666] Found: C, 77.00; H, 5.84; N, 8.11.
[1667] Preparation of
2-(4-chlorophenoxymethyl)-4-benzyloxy-1-[3-[1-(t-but-
oxycarbonyl)piperidin-4-yl]propyl]benzimidazole
[1668] Yield: 9.0 grams
[1669] NMR was consistent with the proposed title structure.
[1670] Analysis for C.sub.34H.sub.40N.sub.3O.sub.4Cl:
[1671] Theory: C, 69.20; H, 6.83; N, 7.12.
[1672] Found: C, 69.43; H, 6.69; N, 7.17.
EXAMPLE 356
[1673] Preparation of
2-(4-chlorophenoxymethyl)-7-benzyloxy-1-[3-[1-(t-but-
oxycarbonyl)piperidin-4-yl]propyl]benzimidazole
[1674] Yield: 5.27 grams
[1675] NMR was consistent with the proposed title structure.
[1676] Analysis for C.sub.34H.sub.40N.sub.3O.sub.4Cl:
[1677] Theory: C, 69.20; H, 6.83; N. 7.12.
[1678] Found: C, 69.75; H, 7.23; N, 7.26.
EXAMPLE 357
[1679] Preparation of
2-(4-methylphenoxymethyl)-4-benzyloxy-1-[3-[1-(t-but-
oxycarbonyl)piperidin-4-yl]propyl]benzimidazole
[1680] Yield: 7.50 grams
[1681] NMR was consistent with the proposed title structure.
[1682] mp 116-118.degree. C.
[1683] Analysis for C.sub.35H.sub.43N.sub.3O.sub.4:
[1684] Theory: C, 73.78; H, 7.61; N, 7.37.
[1685] Found: C, 73.85; H, 7.72; N, 7.50.
EXAMPLE 358
[1686] Preparation of
2-(4-methylphenoxymethyl)-7-benzyloxy-1-[3-[1-(t-but-
oxycarbonyl)piperidin-4-yl]propyl]benzimidazole
[1687] Yield: 4.50 grams
[1688] NMR was consistent with the proposed title structure.
[1689] mp 153-154.5.degree. C.
[1690] Analysis for C.sub.35H.sub.43N.sub.3O.sub.4:
[1691] Theory: C, 73.78; H, 7.61; N, 7.37.
[1692] Found: C, 73.62; H, 7.66; N, 7.34.
EXAMPLE 359
[1693] Preparation of
2-(4-chlorophenoxymethyl)-4-benzyloxy-1-[3-(piperidi-
n-4-yl)propyl]benzimidazole
[1694] Yield: 55%
[1695] NMR was consistent with the proposed title structure.
[1696] mp 140-141.degree. C.
[1697] Analysis for C.sub.29H.sub.32N.sub.3O.sub.2Cl:
[1698] Theory: C, 71.08; H, 6.58; N, 8.58.
[1699] Found: C, 71.20; H, 6.54; N, 8.61.
EXAMPLE 360
[1700] Preparation of
2-(4-chlorophenoxymethyl)-7-benzyloxy-1-[3-(piperidi-
n-4-yl)propyl]benzimidazole
[1701] Yield: 98%
[1702] NMR was consistent with the proposed title structure.
[1703] Analysis for C.sub.29H.sub.32N.sub.3O.sub.2Cl:
[1704] Theory: C, 71.08; H, 6.58; N, 8.58.
[1705] Found: C, 71.00; H, 6.80; N, 8.67.
EXAMPLE 361
[1706] Preparation of
2-(4-chlorophenoxymethyl)-4-benzyloxy-1-[3-[1-(ethox-
ycarbonylpropyl)piperidin-4-yl]propyl]benzimidazole
[1707] The title compound was prepared from the compound of Example
360 by reacting the compound with sodium bicarbonate and
3-(ethoxycarbonyl)propy- l bromide in N,N-dimethylformamide,
essentially as described supra.
[1708] Yield: 78%
[1709] NMR was consistent with the proposed title structure.
[1710] mp 63-65.degree. C.
[1711] Analysis for C.sub.35H.sub.42N.sub.3O.sub.2Cl:
[1712] Theory: C, 69.58; H, 7.01; N. 6.95.
[1713] Found: C, 69.77; H, 7.21; N, 6.70.
EXAMPLE 362
[1714] Preparation of
2-(4-chlorophenoxymethyl)-4-benzyloxy-1-[3-[1-[3-(pi-
peridin-1-yl)propyl]piperidin-4-yl]propyl]benzimidazole
[1715] The title compound was prepared from the compound of Example
360 by reacting the compound with sodium bicarbonate, sodium
iodide, and 1-(3-chloropropyl)piperidine hydrochloride in
N,N-dimethylformamide, essentially as described supra.
[1716] Yield: 64%
[1717] NMR was consistent with the proposed title structure.
[1718] mp 58-60.degree. C.
[1719] Analysis for C.sub.37H.sub.47N.sub.4O.sub.2Cl:
[1720] Theory: C, 72.23; H, 7.70; N, 9.11.
[1721] Found: C, 72.08; H, 7.53; N, 8.86.
EXAMPLE 363
[1722] Preparation of
2-(4-chlorophenoxymethyl)-4-benzyloxy-1-[3-[1-[3-(ca-
rboxy)propyl]piperidin-4-yl]propyl]benzimidazole
[1723] Yield: 74%
[1724] NMR was consistent with the proposed title structure.
[1725] mp 101-103.degree. C.
[1726] Analysis for C.sub.33H.sub.38N.sub.3O.sub.4Cl:
[1727] Theory: C, 68.80; H, 6.65; N, 7.29.
[1728] Found: C, 68.60; H, 6.89; N, 7.52.
EXAMPLE 364
[1729] Preparation of
2-(4-chlorophenoxymethyl)-4-benzyloxy-1-[3-[1-[3-(pi-
peridin-1-ylcarbonyl)propyl]piperidin-4-yl]propyl]benzimidazole
[1730] Yield: 47%
[1731] NMR was consistent with the proposed title structure.
[1732] mp 145.5-147.degree. C.
[1733] Analysis for C.sub.38H.sub.47N.sub.4O.sub.3Cl:
[1734] Theory: C, 70.95; H, 7.37; N, 8.71.
[1735] Found: C, 70.86; H, 7.34; N, 8.68.
EXAMPLE 365
[1736] Preparation of
2-(4-chlorophenoxymethyl)-4-benzyloxy-1-[3-[1-[4-(pi-
peridin-1-yl)butyl]piperidin-4-yl]propyl]benzimidazole
hemihydrate
[1737] Yield: 34%
[1738] NMR was consistent with the proposed title structure.
[1739] mp 98-100.degree. C.
[1740] Analysis for C.sub.38H.sub.49N.sub.4O.sub.2Cl:
[1741] Theory: C, 71.49; H, 7.90; N, 8.78.
[1742] Found: C, 71.15; H, 7.73; N, 8.71.
EXAMPLE 366
[1743] Preparation of
2-(4-chlorophenoxymethyl)-4-benzyloxy-1-[3-[1-[3-(pi-
peridin-1-yl)propyl]piperidin-4-yl]propyl]benzimidazole
hemihydrate
[1744] Yield: 86%
[1745] NMR was consistent with the proposed title structure.
[1746] mp 108-110.degree. C.
[1747] Analysis for C.sub.37H.sub.47N.sub.4O.sub.2Cl:
[1748] Theory: C, 72.23; H, 7.70; N, 9.11.
[1749] Found: C, 72.48; H, 7.85; N, 9.05.
EXAMPLE 367
[1750] Preparation of
2-(4-chlorophenoxymethyl)-7-[3-[1-(t-butoxycarbonyl)-
piperidin-3-yl]propoxy]-143-[1-[3-(piperidin-1-yl)propyl]piperidin-4-yl]pr-
opyl]benzimidazole hemihydrate
[1751] Yield: 86%
[1752] NMR was consistent with the proposed title structure.
[1753] mp 108-110.degree. C.
[1754] Analysis for C.sub.37H.sub.47N.sub.4O.sub.2Cl:
[1755] Theory: C, 72.23; H, 7.70; N, 9.11.
[1756] Found: C, 72.48; H, 7.85; N, 9.05.
[1757] By substantially following the procedures described above
one skilled in the art can prepare the other compounds of Formula
I.
[1758] 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, Life Sciences 55:551-562 (1994); P. A. Hipskind and D. R.
Gehlert, Annual Reports in Medicinal Chemistry, 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.
[1759] Two subtypes of receptors for neuropeptide Y were initially
proposed on the basis of the affinity of the 13-36 fragment of
neuropeptide Y using a preparation of the sympathetic nervous
system. While these are the best established receptors for
neuropeptide Y, a substantial body of evidence exists that there
are additional receptor subtypes. The best established is a Y-3
receptor that is responsive to neuropeptide Y, but not to peptide
YY. Another recently delineated receptor has been described that
binds peptide YY with high affinity and neuropeptide Y with lower
affinity. While the pharmacology 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
successfully cloned to date. The following paragraphs summarize the
available information on the known neuropeptide Y receptor subtypes
and their potential role in physiological function.
[1760] Y-1 Receptor
[1761] The Y-1 receptor is the best characterized receptor for
neuropeptide Y. This receptor is generally considered to be
postsynaptic and mediates many of the known actions of neuropeptide
Y in the periphery. Originally, this receptor was described as
having poor affinity for C-terminal fragments of neuropeptide Y,
such as the 13-36 fragment, but interacts with the full length
neuropeptide Y and peptide YY with equal affinity. C. Wahlestedt,
et al., Regulatory Peptides, 13:307-318 (1986); C. Wahlestedt, et
al., NEURONAL MESSENGERS IN VASCULAR FUNCTION, 231-241 (Nobin, et
al., eds. 1987). Substitution of the amino acid at position 34 with
a proline (Pro.sup.34) results in a protein which is specific for
the Y-1 receptor. E. K. Potter, et al., European Journal of
Pharmacology, 193:15-19 (1991). This tool has been used to
establish a role for the Y-1 receptor in a variety of functions.
The receptor is thought to be coupled to adenylate cyclase in an
inhibitory manner in cerebral cortex, vascular smooth muscle cells,
and SK-N-MC cells. [For a review, see, B. J. McDermott, et al.,
Cardiovascular Research, 27:893-905 (1993)]. This action is
prevented by application of pertussis toxin confirming the role of
a C-protein coupled receptor. The Y-1 receptor mediates the
mobilization of intracellular calcium in a porcine vascular smooth
muscle cells and human erythroleukemia cells.
[1762] The cloned human Y-1 receptor can couple to either
phosphotidylinositol hydrolysis or the inhibition of adenylate
cyclase, depending on the type of cell in which the receptor is
expressed. H. Herzog, et al., Proceedings of the National Academy
of Sciences (USA), 89:5794-5798 (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 553. The Y-1 receptor cannot,
therefore, 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-1 receptor) is believed to influence
multiple physiological conditions, including, but not limited to,
obesity or appetite disorder, adult onset diabetes, bulimia
nervosa, pheochromocytoma-induced hypertension, subarachnoid
hemorrhage, neurogenic vascular hypertrophy, hypertension, anxiety,
and anorexia nervosa. PCT Patent Publication WO 96,16542, published
Jun. 6, 1996, at page 135, and the references cited therein.
[1763] Y-2 Receptor
[1764] As with the Y-1 receptor, this receptor subtype was first
delineated using vascular preparations. Pharmacologically, the Y-2
receptor is distinguished from Y-1 by exhibiting affinity for
C-terminal fragments of neuropeptide Y. The receptor is most often
differentiated by the use of neuropeptide Y(13-36), though the 3-36
fragment of neuropeptide Y and peptide YY provides improved
affinity and selectivity. Y. Dumont, et al., Society for
Neuroscience Abstracts, 19:726 (1993). Like Y-1 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 levels of
calcium in the synapse by selective inhibition of N-type calcium
channels. Like the Y-1 receptor, the Y-2 receptor may exhibit
differential coupling to second messengers. The Y2 receptor is
believed to be involved in modulating hypertension, epileptic
seizure, and neurogenic vascular hypertrophy. PCT Patent
Publication WO 96/16542, published Jun. 6, 1996, at page 135, and
the references cited therein.
[1765] The Y-2 receptors are found in a variety of brain regions,
including the hippocampus, substantia nigra-lateralis, thalamus,
hypothalamus, and brainstem. In the periphery, Y-2 is found in the
peripheral nervous system, such as sympathetic, parasympathetic,
and sensory neurons. In all these tissues, Y-2 receptors mediate a
decrease in the release of neurotransmitters. The Y-2 receptor has
been cloned using expression cloning techniques. P. M. Rose, et
al., Journal of Biological Chemistry, 270:22661(1995); C. Gerald,
et al., Journal of Biological Chemistry, 270:26758 (1995); D. R.
Gehlert, et al., Molecular Pharmacology, 49:224 (1996).
[1766] Y-3 Receptor
[1767] This receptor has high affinity 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 efficacious. This pharmacological property is used to
define this receptor. A receptor that has similar pharmacology to
the Y-3 receptor has been identified 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., European Journal
of Pharmacology 182:207-208 (1990). This receptor is believed to
modulate hypertension. PCT Patent Publication WO 96/16542,
published Jun. 6, 1996, at page 135, and the references cited
therein.
[1768] The presence of this receptor is best established in the rat
brainstem, specifically in the nucleus tractus solitarius.
Application of neuropeptide Y to this region produces a
dose-dependent 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 catecholamines from the adrenal
medulla, presumably through a Y-3 receptor. C. Wahlestedt, et al.,
Life Sciences, 50:PL7-PL14 (1992).
[1769] Peptide YY Preferring Receptor
[1770] A fourth receptor has been described that exhibits a modest
preference for peptide YY over neuropeptide Y. This receptor was
first described in the rat small intestine as having a 5-10 fold
higher affinity for peptide YY over neuropeptide Y. M. Laburthe, et
al., Endocrinology, 118:1910-1917 (1986). Subsequently, this
receptor was found in the adipocyte and a kidney proximal tubule
cell line. This receptor is coupled in an inhibitory manner to
adenylate cyclase and is sensitive to pertussis toxin.
[1771] In the intestine, this receptor produces a potent inhibition
of fluid and electrolyte secretion. The receptor is localized to
the crypt cells where intestinal chloride secretion is believed to
take place. The peptide YY preferring receptor in adipocytes
mediates a reduction in lipolysis by way of a cyclic adenosine
monophosphate (cAMP)-dependent mechanism.
[1772] "Feeding Receptor"
[1773] One of the earliest discovered central effects of
neuropeptide Y was a profound increase in food intake that was
observed following the hypothalmic administration of the peptide to
rats. The response was greatest when the peptide was infused into
the perifornical region of the hypothalamus. B. G. Stanley, et al.,
Brain Research 604:304-317 (1993). While the pharmacology of this
response resembled the Y-1 receptor, the 2-36 fragment 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, et al., Brain Research
Bulletin, 26:309-311(1991). Two recent patent publications describe
the cloning and expression of the Y5 receptor, believed to be the
"feeding receptor". Patent Cooperation Treaty Publication WO
96/16542, published Jun. 6, 1996; and Australian Patent Publication
AU 956467 A0, published Nov. 30, 1995.
[1774] The biological activity of the compounds of the present
invention was evaluated employing an initial screening assay which
rapidly and accurately measured the binding 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.g., U.S. Pat. No. 5,284,839, issued Feb. 8, 1994,
which is herein incorporated by reference. See also, M. W. Walker,
et al., Journal of Neurosciences, 8:2438-2446 (1988).
[1775] Neuropeptide, Y Binding Assay
[1776] 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 Minimal
Essential Media (DMEM) supplemented with 5% fetal calf serum. The
cells were manually removed from the flasks by scraping, pelleted,
and stored at -70.degree. C.
[1777] The pellets were resuspended using a glass homogenizer in 25
mM HEPES (pH 7.4) buffer containing 2.5 mM calcium chloride, 1 mM
magnesium chloride, and 2 g/L bacitracin. Incubations were
performed in a final volume of 200 .mu.l containing 0.1 nM
.sup.125I-peptide YY (2200 Ci/mmol) and 0.2-0.4 mg protein for
about two hours at room temperature.
[1778] Nonspecific binding was defined as the amount of
radioactivity remaining bound to the tissue after incubating in the
presence of 1 .mu.M neuropeptide Y. In some experiments various
concentrations of compounds were included in the incubation
mixture.
[1779] Incubations were terminated by rapid filtration through
glass fiber filters which had been presoaked in 0.3%
polyethyleneimine using a 96-well harvester. The filters were
washed with 5 ml of 50 mM Tris (pH 7.4) at 4.degree. C. and rapidly
dried at 60.degree. C. The filters were then treated with melt-on
scintillation sheets and the radioactivity retained on the filters
were counted. The results were analyzed using various software
packages. Protein concentrations were measured using standard
coumassie protein assay reagents using bovine serum albumin as
standards.
[1780] Many of the compounds prepared supra showed significant
activity as neuropeptide Y receptor antagonists (K.sub.i=10 .mu.M
to 0.1 nM). As the compounds of Formula I are effective
neuropeptide Y receptor antagonists, these compounds are of value
in the treatment 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 prevention of 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 Formula I or a
pharmaceutically acceptable salt, solvate or prodrug thereof. The
term "physiological disorder associated with an excess of
neuropeptide Y" encompasses those disorders associated with an
inappropriate stimulation of neuropeptide Y receptors, regardless
of the actual amount of neuropeptide Y present in the locale.
[1781] These physiological disorders include:
[1782] disorders or diseases pertaining 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;
[1783] conditions related to increased sympathetic nerve activity
for example, during or after coronary artery surgery, and
operations and surgery in the gastrointestinal tract;
[1784] 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;
[1785] conditions related to pain or nociception;
[1786] diseases related to abnormal gastrointestinal motility and
secretion, such as different forms of ileus, urinary incontinence,
and Crohn's disease;
[1787] abnormal drink and food intake disorders, such as obesity,
anorexia, bulimia, and metabolic disorders;
[1788] diseases related to sexual dysfunction and reproductive
disorders;
[1789] conditions or disorders associated with inflammation;
[1790] respiratory diseases, such as asthma and conditions related
to asthma and bronchoconstriction; and
[1791] diseases related to abnormal hormone release, such as
leutinizing hormone, growth hormone, insulin, and prolactin.
[1792] The compounds of Formula I are usually administered in the
form of pharmaceutical compositions. These compounds can be
administered by a variety of routes including oral, rectal,
transdermal, subcutaneous, intravenous, intramuscular, and
intranasal. These compounds are effective as both injectable and
oral compositions. Such compositions are prepared in a manner well
known in the pharmaceutical art and comprise at least one active
compound.
[1793] The present invention also includes methods employing
pharmaceutical compositions which contain, as the active
ingredient, a compound of Formula I associated with
pharmaceutically acceptable carriers. In making 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 container. When the excipient serves as a diluent, it can be
a solid, semi-solid, or liquid material, which acts as a vehicle,
carrier or medium 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 containing
for example up to 10% by weight of the active compound, soft and
hard gelatin capsules, suppositories, sterile injectable solutions,
and sterile packaged powders.
[1794] In preparing a formulation, it may be necessary to mill the
active compound to provide the appropriate particle size prior to
combining with the other ingredients. If the active compound is
substantially insoluble, it ordinarily is milled to a particle size
of less than 200 mesh. If the active compound is substantially
water soluble, the particle size is normally adjusted by milling to
provide a substantially uniform distribution in the formulation,
e.g. about 40 mesh.
[1795] Some examples of suitable excipients include lactose,
dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,
calcium phosphate, alginates, tragacanth, gelatin, calcium
silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, water, syrup, and methyl cellulose. The formulations can
additionally include: lubricating agents such as talc, magnesium
stearate, and mineral oil; wetting agents; emulsifying and
suspending agents; preserving agents such as methyl- and
propylhydroxybenzoates; sweetening agents; and flavoring agents.
The compositions of the invention can be formulated so as to
provide quick, sustained or delayed release of the active
ingredient after administration to the patient by employing
procedures known in the art.
[1796] The compositions are preferably formulated in a unit dosage
form, each dosage containing from about 5 to about 100 mg, more
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 human subjects and other mammals, each
unit containing a predetermined quantity of active material
calculated to produce the desired therapeutic effect, in
association with a suitable pharmaceutical excipient.
[1797] The active compound is effective over a wide dosage range.
For examples, dosages per day normally fall within the range of
about 0.5 to about 30 mg/kg of body weight. In the treatment of
adult humans, the range of about 1 to about 15 mg/kg/day, in single
or divided dose, is especially preferred. However, it will be
understood that the amount of the compound actually administered
will be determined by a physician, in the light of the relevant
circumstances, including the condition to be treated, the chosen
route of administration, the actual compound administered, the age,
weight, and response of the individual patient, and the severity of
the patient's symptoms, and therefore the above dosage ranges are
not intended to limit the scope of the invention in any way. In
some instances dosage levels below the lower limit of the aforesaid
range may be more than adequate, while in other cases still larger
doses may be employed without causing any harmful side effect,
provided that such larger doses are first divided into several
smaller doses for administration throughout the day.
[1798] For preparing solid compositions such as tablets the
principal active ingredient is mixed with a pharmaceutical
excipient to form a solid preformulation composition containing a
homogeneous mixture of a compound of the present invention. When
referring to these preformulation compositions as homogeneous, it
is meant that the active ingredient is dipsersed 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 preformulation is then subdivided into unit
dosage forms of the type described above containing from 0.1 to
about 500 mg of the active ingredient of the present invention.
[1799] 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 example, the tablet or pill can
comprise an inner dosage and an outer dosage component, the latter
being 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 duodenum or to be delayed in release. A
variety of materials can be used for such enteric layers or
coatings, such materials including a number of polymeric acids and
mixtures of polymeric acids with such materials as shellac, cetyl
alcohol, and cellulose acetate.
[1800] The liquid forms in which the novel compositions of the
present invention may be incorporated for administration orally or
by 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 similar pharmaceutical vehicles.
[1801] Compositions for inhalation or insufflation include
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 excipients as described supra. Preferably the
compositions are administered by the oral or nasal respiratory
route for local or systemic effect. Compositions in preferably
pharmaceutically acceptable solvents may be nebulized by use of
inert gases. Nebulized solutions may be breathed directly from the
nebulizing device or the nebulizing device may be attached to a
face mask, tent, or intermittent positive pressure breathing
machine. Solution, suspension, or powder compositions may be
administered, preferably orally or nasally, from devices which
deliver the formulation in an appropriate manner.
[1802] The following examples illustrate the pharmaceutical
compositions of the present invention.
Formulation Preparation 1
[1803] Hard gelatin capsules containing the following ingredients
are prepared:
1 Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch
305.0 Magnesium stearate 5.0
[1804] The above ingredients are mixed and filled into hard gelatin
capsules in 340 mg quantities.
Formulation Preparation 2
[1805] A tablet formula is prepared using the ingredients
below:
2 Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose,
microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid
5.0
[1806] The components are blended and compressed to form tablets,
each weighing 240 mg.
Formulation Preparation 3
[1807] A dry powder inhaler formulation is prepared containing the
following components:
3 Ingredient Weight % Active Ingredient 5 Lactose 95
[1808] The active mixture is mixed with the lactose and the mixture
is added to a dry powder inhaling appliance.
Formulation Preparation 4
[1809] Tablets, each containing 30 mg of active ingredient, are
prepared as follows:
4 Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mg Starch
45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone 4.0
mg (as 10% solution in water) Sodium carboxymethyl starch 4.5 mg
Magnesium stearate 0.5 mg Talc 1.0 mg Total 120 mg
[1810] The active ingredient, starch and cellulose are passed
through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution
of polyvinylpyrrolidone is mixed with the resultant powders, which
are then passed through a 16 mesh U.S. sieve. The granules so
produced are dried at 50-60.degree. C. and passed through a 16 mesh
U.S. sieve. The sodium carboxymethyl starch, magnesium stearate,
and talc, previously passed through a No. 30 mesh U.S. sieve, are
then added to the granules which, after mixing, are compressed on a
tablet machine to yield tablets each weighing 120 mg.
Formulation Preparation 5
[1811] Capsules, each containing 40 mg of medicament are made as
follows:
5 Quantity Ingredient (mg/capsule) Active Ingredient 40.0 mg Starch
109.0 mg Magnesium stearate 1.0 mg Total 150.0 mg
[1812] The active ingredient, cellulose, starch, and magnesium
stearate are blended, passed through a No. 20 mesh U.S. sieve, and
filled into hard gelatin capsules in 150 mg quantities.
Formulation Preparation 6
[1813] Suppositories, each containing 25 mg of active ingredient
are made as follows:
6 Ingredient Amount Active Ingredient 25 mg Saturated fatty acid
glycerides to 2,000 mg
[1814] 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
[1815] Suspensions, each containing 50 mg of medicament per 5.0 ml
dose are made as follows:
7 Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg
Sodium carboxymethyl cellulose (11%) 50.0 mg Microcrystalline
cellulose (89%) Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and
Color q.v. Purified water to 5.0 ml
[1816] The medicament, sucrose and xanthan gum are blended, passed
through a No. 10 mesh U.S. sieve, and then mixed with a previously
made solution of the microcrystalline cellulose and sodium
carboxymethyl cellulose in water. The sodium benzoate, flavor, and
color are diluted with some of the water and added with stirring.
Sufficient water is then added to produce the required volume.
Formulation Preparation 8
[1817] Capsules, each containing 15 mg of medicament, are made as
follows:
8 Quantity Ingredient (mg/capsule) Active Ingredient 15.0 mg Starch
407.0 mg Magnesium stearate 3.0 mg Total 425.0 mg
[1818] The active ingredient, cellulose, starch, and magnesium
stearate are blended, passed through a No. 20 mesh U.S. sieve, and
filled into hard gelatin capsules in 425 mg quantities.
Formulation Preparation 9
[1819] An intravenous formulation may be prepared as follows:
9 Ingredient Quantity Active Ingredient 250.0 mg Isotonic saline
1000 ml
Formulation Preparation 10
[1820] A topical formulation may be prepared as follows:
10 Ingredient Quantity Active Ingredient 1-10 g Emulsifying Wax 30
g Liquid Paraffin 20 g White Soft Paraffin to 100 g
[1821] The white soft paraffin is heated until molten. The liquid
praffin and 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.
Formulation Preparation 11
[1822] Sublingual or buccal tablets, each containing 10 mg of
active ingredient, may be prepared as follows:
11 Quantity Ingredient Per Tablet Active Ingredient(s) 10.0 mg
Glycerol 210.5 mg Water 143.0 mg Sodium Citrate 4.5 mg Polyvinyl
Alcohol 26.5 mg Polyvinylpyrrolidone 15.5 mg Total 410.0 mg
[1823] The glycerol, water, sodium citrate, polyvinyl alcohol, and
polyvinylpyrrolidone are admixed together by continuous stirring
and maintaining the temperature at about 90.degree. C. When the
polymers have gone into solution, the solution is cooled to about
50-55.degree. C. and the medicament is slowly admixed. The
homogenous mixture is poured into forms made of an inert material
to produce a drug-containing diffusion matrix having a thickness of
about 24 mm. This diffusion matrix is then cut to form individual
tablets having the appropriate size.
[1824] Another preferred formulation employed in the methods of the
present invention employs transdermal delivery devices ("patches").
Such transdermal patches may be used to provide continuous or
discontinuous infusion of the compounds of the present invention in
controlled amounts. The construction and use of transdermal patches
for the delivery of pharmaceutical agents is well known in the art.
See e.g., U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein
incorporated by reference. Such patches may be constructed for
continuous, pulsatile, or on demand delivery of pharmaceutical
agents.
[1825] Frequently, it will be desirable or necessary to introduce
the pharmaceutical composition to the brain, either directly or
indirectly. Direct techniques usually involve placement of a drug
delivery catheter into the host's ventricular system to bypass the
blood-brain barrier. One such implantable delivery system, used for
the transport of biological factors to specific anatomical regions
of the body, is described in U.S. Pat. No. 5,011,472, issued Apr.
30, 1991, which is herein incorporated by reference.
[1826] Indirect techniques, which are generally preferred, usually
involve formulating the compositions to provide for drug
latentiation by the conversion of hydrophilic drugs into
lipid-soluble drugs or prodrugs. Latentiation is generally achieved
through blocking of the hydroxy, 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 bier.
Alternatively, the delivery of hydrophilic drugs may be enhanced by
intra-arterial infusion of hypertonic solutions which can
transiently open the blood-brain barrier.
* * * * *