U.S. patent application number 12/541447 was filed with the patent office on 2010-01-07 for non-imidazole aryloxyalkylamines.
Invention is credited to Richard Apodaca, Nicholas I. Carruthers, Curt A. Dvorak, Dale A. Rudolph, Chandravadan R. Shah, Wei Xiao.
Application Number | 20100004241 12/541447 |
Document ID | / |
Family ID | 26918111 |
Filed Date | 2010-01-07 |
United States Patent
Application |
20100004241 |
Kind Code |
A1 |
Apodaca; Richard ; et
al. |
January 7, 2010 |
NON-IMIDAZOLE ARYLOXYALKYLAMINES
Abstract
Substituted aryloxyalkylamines of formula (I), compositions
containing them, and methods of making and using them to treat
histamine-mediated conditions.
Inventors: |
Apodaca; Richard; (San
Diego, CA) ; Carruthers; Nicholas I.; (Poway, CA)
; Dvorak; Curt A.; (San Diego, CA) ; Rudolph; Dale
A.; (San Diego, CA) ; Shah; Chandravadan R.;
(San Diego, CA) ; Xiao; Wei; (San Diego,
CA) |
Correspondence
Address: |
PHILIP S. JOHNSON;JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
26918111 |
Appl. No.: |
12/541447 |
Filed: |
August 14, 2009 |
Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
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12194653 |
Aug 20, 2008 |
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12541447 |
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11453422 |
Jun 15, 2006 |
7429586 |
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12194653 |
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09922631 |
Aug 6, 2001 |
7186732 |
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11453422 |
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60223768 |
Aug 8, 2000 |
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Current U.S.
Class: |
514/235.5 ;
514/253.01; 514/254.01; 514/255.01; 514/269; 514/278; 514/300;
514/307; 514/314; 514/315; 514/316; 514/326; 514/343 |
Current CPC
Class: |
C07C 335/32 20130101;
C07D 401/04 20130101; C07D 333/20 20130101; A61P 11/06 20180101;
C07C 323/25 20130101; A61P 25/28 20180101; C07D 317/28 20130101;
C07D 401/14 20130101; C07D 211/46 20130101; C07D 235/26 20130101;
A61P 25/20 20180101; A61K 31/4465 20130101; C07D 233/88 20130101;
A61P 9/00 20180101; C07D 231/12 20130101; A61P 25/00 20180101; C07D
233/84 20130101; C07D 249/08 20130101; C07D 471/08 20130101; C07D
211/58 20130101; C07D 295/088 20130101; C07D 295/112 20130101; A61P
27/16 20180101; A61P 43/00 20180101; A61P 25/06 20180101; A61P
25/18 20180101; A61P 3/00 20180101; C07D 213/74 20130101; C07D
213/36 20130101; C07D 295/205 20130101; A61K 31/4402 20130101; C07D
215/06 20130101; C07D 233/56 20130101; C07D 211/22 20130101; C07D
233/54 20130101; C07D 307/52 20130101; C07D 295/096 20130101; A61P
25/24 20180101; C07D 233/42 20130101; C07D 235/06 20130101; C07D
257/04 20130101; C07D 295/135 20130101; A61P 11/00 20180101; C07D
401/12 20130101; A61P 25/08 20180101; C07D 207/325 20130101; C07D
207/335 20130101; C07D 277/36 20130101; C07D 239/34 20130101; A61K
45/06 20130101; A61P 37/08 20180101; C07C 217/22 20130101; A61K
31/4402 20130101; A61K 2300/00 20130101; A61K 31/4465 20130101;
A61K 2300/00 20130101 |
Class at
Publication: |
514/235.5 ;
514/315; 514/255.01; 514/254.01; 514/253.01; 514/326; 514/314;
514/316; 514/307; 514/269; 514/343; 514/278; 514/300 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/445 20060101 A61K031/445; A61P 25/28 20060101
A61P025/28; A61P 25/18 20060101 A61P025/18; A61P 25/24 20060101
A61P025/24; A61K 31/496 20060101 A61K031/496; A61K 31/4523 20060101
A61K031/4523; A61K 31/4725 20060101 A61K031/4725; A61K 31/4545
20060101 A61K031/4545; A61K 31/4709 20060101 A61K031/4709; A61K
31/506 20060101 A61K031/506; A61K 31/4439 20060101 A61K031/4439;
A61K 31/438 20060101 A61K031/438; A61K 31/439 20060101
A61K031/439 |
Claims
1-53. (canceled)
54. A method of treating dementia, mild cognitive impairment
(pre-dementia), cognitive dysfunction, schizophrenia, depression
manic disorders, bipolar disorders, and learning and memory
disorders in a subject, comprising administering an effective
amount of a compound of formula I to a subject in need of such
treatment: ##STR00113## wherein R.sub.a and R.sub.b are
independently C.sub.1-8 alkyl, C.sub.3-8 alkenyl, C.sub.3-8
cycloakyl, (C.sub.3-8 cycloalkyl) C.sub.1-6 alkyl, or taken
together with the nitrogen to which they are attached form a 4-7
membered heterocyclyl optionally including up to 3 additional
heteroatoms; n is 0-4; one of R.sub.1, R.sub.2 and R.sub.3 is G,
and the remaining two are hydrogen or halo; G is a
nitrogen-containing group selected from one of the following:
--OL.sub.1Q, -L.sub.2Q, --N(L.sub.1Q)R.sub.5,
-L.sub.3C(L.sub.1Q)R.sub.6R.sub.7, --C(L.sub.1Q)R.sub.6R.sub.7,
##STR00114## wherein: L.sub.1 is C.sub.2-6 alkylene, C.sub.3-8
cycloalkylene, C.sub.4-6 alkenylene, C.sub.4-6 alkynylene,
C.sub.2-5 alkanoyl, (phenyl)C.sub.1-6 alkylene, (naphthyl)C.sub.1-6
alkylene, (C.sub.2-5 heteroaryl)C.sub.1-6 alkylene,
(phenoxy)C.sub.1-6 alkylene, or (C.sub.2-5 heteroaryoxy)C.sub.1-6
alkylene; L.sub.2 is C.sub.1-6 alkylene, C.sub.3-8 cycloalkylene,
C.sub.3-6 alkenylene, C.sub.3-6 alkynylene, C.sub.2-5 alkanoyl,
(phenyl)C.sub.1-6 alkylene, (naphthylC.sub.1-6 alkylene, (C.sub.1-5
heteroaryl)C.sub.1-6 alkylene, (phenoxy)C.sub.1-6 alkylene,
(C.sub.1-5 heteroaryloxy)C.sub.1-6 alkylene, or (C.sub.1-5
heteroarylthio)C.sub.1-6 alkylene; L.sub.3 is C.sub.1-6 alkylene,
C.sub.2-6 alkenylene, C.sub.2-6 alkynylene, C.sub.2-5 alkanoyl,
(phenyl)C.sub.1-6 alkylene, phenyl, naphthyl, (naphthl)C.sub.1-6
alkylene, C.sub.1-5 heteroaryl)C.sub.1-6 alkylene,
(phenoxy)C.sub.1-6 alkylene, (C.sub.1-5 heteroaryloxy)C.sub.1-6
alkylene, or C.sub.2-5 heteroaryl; L.sub.4 is C.sub.1-5 alkylene;
L.sub.5is C.sub.1-5 alkylene; L.sub.6 is C.sub.1-5 alkylene;
L.sub.7 is C.sub.1-5 alkylene or absent; Q is --NR.sub.8R.sub.9 or
a non-aromatic C.sub.2-15 heterocyclyl ring system containing at
least one nitrogen atom and optionally between 1 and 3 additional
heteroatoms selected from O, S, and N in each ring; each of R.sub.5
and R.sub.6 is independently selected from hydrogen, C.sub.1-8
alkyl, C.sub.2-8 alkenyl, C.sub.3-7 cycloalkyl, (C.sub.3-7
cycloalkyl)C.sub.1-6 alkylene, C.sub.2-15 heterocyclyl, and
(C.sub.2-7 heterocyclyl)C.sub.1-6 alkylene; R.sub.7 is H, hydroxyl
halo, C.sub.2-6 alkoxy or absent where the carbon linking L.sub.6
and L.sub.7 (or bonded to R.sub.6) participates in a double bond;
each of R.sub.8 and R.sub.9 is independently selected from
hydrogen, C.sub.1-8 alkyl, C.sub.3-8 alkenyl, C.sub.3-7 cycloalkyl,
(C.sub.3-7 cycloalkyl)C.sub.1-6 alkylene, C.sub.2-15 heterocyclyl,
phenyl, (C.sub.2-15 heterocyclyl)C.sub.1-6 alkylene, and (phenyl)
C.sub.1-6 alkylene; R.sub.10 is H, C.sub.1-8 alkyl, C.sub.3-8
alkenyl, C.sub.3-7 cycloalkyl, (C.sub.3-7 cycloalkyl)C.sub.1-6
alkylene, (C.sub.2-15 heterocyclyl)C.sub.1-6 alkylene, or (phenyl)
C.sub.1-6 alkylene; wherein each of the above alkyl, alkylene,
alkenyl, alkenylene, alkynyl, alkynylene, heterocyclyl cycloalkyl
and aryl groups may each be independently and optionally
substituted with between 1 and 3 substituents selected from halo,
amino, nitro, hydroxyl and C.sub.1-3 alkyl; wherein substituents of
Q can be further selected from carboxamide, C.sub.2-6 alkyl,
C.sub.1-8 heterocyclyl, N(C.sub.1-6 alkyl)(C.sub.1-8 heterocyclyl),
NH(C.sub.1-8 heterocyclyl), (C.sub.1-8 heterocyclyl) C.sub.1-3
alkylene, O(C.sub.1-8 heterocyclyl), C.sub.1-6 alkoxy,
(phenyl)C.sub.3-6 cycloalkyl-O--, phenyl, (phenyl)C.sub.1-3
alkylene, N(C.sub.1-6 alkyl)[(phenyl)C.sub.1-3 alkylene], and
(phenyl)C.sub.1-3 alkylene-O-- where each of above heterocyclyl,
phenyl, and alkyl groups may be optionally substituted with from 1
to 3 substituents independently selected from halogen, nitro,
cyano, and C.sub.1-3 alkyl; or a pharmaceutically acceptable salt,
ester, or amide thereof.
55-56. (canceled)
57. The method of claim 54 comprising (a) administering to a
subject a jointly effective amount of a histamine H.sub.1 receptor
antagonist compound, and (b) administering to the subject a jointly
effective amount of a compound of claim 54, said method providing a
jointly therapeutically effective amount of said compounds.
58. The method of claim 57 wherein the histamine H.sub.1 receptor
antagonist and the compound of claim 54, are present in the same
dosage form.
59. The method of claim 54 comprising (a) administering to the
subject a jointly effective amount of a histamine H.sub.2 receptor
antagonist compound, and (b) administering to the subject a jointly
effective amount of a compound of claim 54, said method providing a
jointly therapeutically effective amount of said compounds.
60. The method of claim 59 wherein the histamine H.sub.2 receptor
antagonist and the compound of claim 54, are present in the same
dosage form.
61-65. (canceled)
66. The method of claim 54, wherein R.sub.a and R.sub.b taken
together with the nitrogen to which they are attached form a 4-7
membered heterocyclyl optionally including up to 3 additional
heteroatoms.
67. The method of claim 54, wherein R.sub.1 is hydrogen or halo,
and one of R.sub.2 and R.sub.3 is G and the other is hydrogen or
halo.
68. The method of claim 67, wherein R.sub.2 is G.
69. The method of claim 67, wherein R.sub.3 is G.
70. A method of treating schizophrenia in a subject, comprising
administering an effective amount of a compound of formula I to a
subject in need of such treatment: ##STR00115## wherein R.sub.a and
R.sub.b are independently C.sub.1-8 alkyl, C.sub.3-8 alkenyl,
C.sub.3-8 cycloalkyl, (C.sub.3-8 cycloalkyl) C.sub.1-6 alkyl, or
taken together with the nitrogen to which they are attached form a
4-7 membered heterocyclyl optionally including up to 3 additional
heteroatoms; n is 0-4; one of R.sub.1, R.sub.2, and R.sub.3 is G,
and the remaining two are hydrogen or halo; G is a
nitrogen-containing group selected from one of the following:
--OL.sub.1Q, -L.sub.2Q, --N(L.sub.1Q)R.sub.5,
-L.sub.3C(L.sub.1Q)R.sub.6R.sub.7, --C(L.sub.1Q)R.sub.6R.sub.7,
##STR00116## wherein: L.sub.1 is C.sub.2-6 alkylene, C.sub.3-8
cycloalkylene, C.sub.4-6 alkenylene, C.sub.4-6 alkynylene,
C.sub.2-5 alkanoyl, (phenyl)C.sub.1-6 alkylene, (naphthyl)C.sub.1-6
alkylene, (C.sub.2-5 heteroaryl)C.sub.1-6 alkylene,
(phenoxy)C.sub.1-6 alkylene, or (C.sub.2-5 heteroaryloxy)C.sub.1-6
alkylene; L.sub.2 is C.sub.1-6 alkylene, C.sub.3-8 cycloalkylene,
C.sub.3-6 alkenylene, C.sub.3-6 alkynylene, C.sub.2-5 alkanoyl,
(phenyl)C.sub.1-6 alkylene, (naphthyl)C.sub.1-6 alkylene,
(C.sub.1-5 heteroaryl)C.sub.1-6 alkylene, (phenoxy)C.sub.1-6
alkylene, (C.sub.1-5 heteroaryloxy)C.sub.1-6 alkylene, or
(C.sub.1-5 heteroarylthio)C.sub.1-6 alkylene; L.sub.3 is C.sub.1-6
alkylene, C.sub.2-6 alkenylene, C.sub.2-6 alkynylene, C.sub.2-5
alkanoyl, (phenyl)C.sub.1-6 alkylene, phenyl, naphthyl,
(naphthyl)C.sub.1-6 alkylene, C.sub.1-5 heteroaryl)C.sub.1-6
alkylene, (phenoxy)C.sub.1-6 alkylene, (C.sub.1-5
heteroaryloxy)C.sub.1-6 alkylene, or C.sub.2-5 heteroaryl; L.sub.4
is C.sub.1-5 alkylene; L.sub.5 is C.sub.1-5 alkylene; L.sub.6 is
C.sub.1-5 alkylene; L.sub.7 is C.sub.1-5 alkylene or absent; Q is
--NR.sub.8R.sub.9 or a non-aromatic C.sub.2-15 heterocyclyl ring
system containing at least one nitrogen atom and optionally between
1 and 3 additional heteroatoms selected from O, S, and N in each
ring; each of R.sub.5 and R.sub.6 is independently selected from
hydrogen, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.3-7 cycloalkyl,
(C.sub.3-7 cycloalkyl)C.sub.1-6 alkylene, C.sub.2-15 heterocyclyl,
and (C.sub.2-7 heterocyclyl)C.sub.1-6 alkylene; R.sub.7 is H,
hydroxyl, halo, C.sub.2-6 alkoxy or absent where the carbon linking
L.sub.6 and L.sub.7 (or bonded to R.sub.6) participates in a double
bond; each of R.sub.8 and R.sub.9 is independently selected from
hydrogen, C.sub.1-8 alkyl, C.sub.3-8 alkenyl, C.sub.3-7 cycloalkyl,
(C.sub.3-7 cycloalkyl)C.sub.1-6 alkylene, C.sub.2-15 heterocyclyl,
phenyl, (C.sub.2-15 heterocyclyl)C.sub.1-6 alkylene, and (phenyl)
C.sub.1-6 alkylene; R.sub.10 is H, C.sub.1-8 alkyl, C.sub.3-8
alkenyl, C.sub.3-7 cycloalkyl, (C.sub.3-7 cycloalkyl)C.sub.1-6
alkylene, (C.sub.2-15 heterocyclyl)C.sub.1-6 alkylene, or (phenyl)
C.sub.1-6 alkylene; wherein each of the above alkyl, alkylene,
alkenyl, alkenylene, alkynyl, alkynylene, heterocyclyl, cycloalkyl,
and aryl groups may each be independently and optionally
substituted with between 1 and 3 substituents selected from halo,
amino, nitro, hydroxyl, and C.sub.1-3 alkyl; wherein substituents
of Q can be further selected from carboxamide, C.sub.2-6 alkyl,
C.sub.1-8 heterocyclyl, N(C.sub.1-6 alkyl)(C.sub.1-8 heterocyclyl),
NH(C.sub.1-8 heterocyclyl), (C.sub.1-8 heterocyclyl) C.sub.1-3
alkylene, O(C.sub.1-8 heterocyclyl), C.sub.1-6 alkoxy,
(phenyl)C.sub.3-6 cycloalkyl-O--, phenyl, (phenyl) C.sub.1-3
alkylene, N(C.sub.1-6 alkyl)[(phenyl)C.sub.1-3 alkylene], and
(phenyl)C.sub.1-3 alkylene-O-- where each of above heterocyclyl,
phenyl, and alkyl groups may be optionally substituted with from 1
to 3 substituents independently selected from halogen, nitro,
cyano, and C.sub.1-3 alkyl; or a pharmaceutically acceptable salt,
ester, or amide thereof.
71. The method of claim 70, wherein R.sub.a and R.sub.b taken
together with the nitrogen to which they are attached form a 4-7
membered heterocyclyl optionally including up to 3 additional
heteroatoms.
72. The method of claim 70, wherein R.sub.1 is hydrogen or halo,
and one of R.sub.2 and R.sub.3 is G and the other is hydrogen or
halo.
73. The method of claim 72, wherein R.sub.2 is G.
74. The method of claim 72, wherein R.sub.3 is G.
75. A method of treating depression in a subject, comprising
administering an effective amount of a compound of formula I to a
subject in need of such treatment: ##STR00117## wherein R.sub.a and
R.sub.b are independently C.sub.1-8 alkyl, C.sub.3-8 alkenyl,
C.sub.3-8 cycloalkyl, (C.sub.3-8 cycloalkyl) C.sub.1-6 alkyl, or
taken together with the nitrogen to which they are attached form a
4-7 membered heterocyclyl optionally including up to 3 additional
heteroatoms; n is 0-4; one of R.sub.1, R.sub.2, and R.sub.3 is G,
and the remaining two are hydrogen or halo; G is a
nitrogen-containing group selected from one of the following:
--OL.sub.1Q, -L.sub.2Q, --N(L.sub.1Q)R.sub.5,
-L.sub.3C(L.sub.1Q)R.sub.6R.sub.7, --C(L.sub.1Q)R.sub.6R.sub.7,
##STR00118## wherein: L.sub.1 is C.sub.2-6 alkylene, C.sub.3-8
cycloalkylene, C.sub.4-6 alkenylene, C.sub.4-6 alkynylene,
C.sub.2-5 alkanoyl, (phenyl)C.sub.1-6 alkylene, (naphthyl)C.sub.1-6
alkylene, (C.sub.2-5 heteroaryl)C.sub.1-6 alkylene,
(phenoxy)C.sub.1-6 alkylene, or (C.sub.2-5 heteroaryloxy)C.sub.1-6
alkylene; L.sub.2 is C.sub.1-6 alkylene, C.sub.3-8 cycloalkylene,
C.sub.3-6 alkenylene, C.sub.3-6 alkynylene, C.sub.2-5 alkanoyl,
(phenyl)C.sub.1-6 alkylene, (naphthyl)C.sub.1-6 alkylene,
(C.sub.1-5 heteroaryl)C.sub.1-6 alkylene, (phenoxy)C.sub.1-6
alkylene, (C.sub.1-5 heteroaryloxy)C.sub.1-6 alkylene, or
(C.sub.1-5 heteroarylthio)C.sub.1-6 alkylene; L.sub.3 is C.sub.1-6
alkylene, C.sub.2-6 alkenylene, C.sub.2-6 alkynylene, C.sub.2-5
alkanoyl, (phenyl)C.sub.1-6 alkylene, phenyl, naphthyl,
(naphthyl)C.sub.1-6 alkylene, C.sub.1-5 heteroaryl)C.sub.1-6
alkylene, (phenoxy)C.sub.1-6 alkylene, (C.sub.1-5
heteroaryloxy)C.sub.1-6 alkylene, or C.sub.2-5 heteroaryl; L.sub.4
is C.sub.1-5 alkylene; L.sub.5 is C.sub.1-5 alkylene; L.sub.6 is
C.sub.1-5 alkylene; L.sub.7 is C.sub.1-5 alkylene or absent; Q is
--NR.sub.8R.sub.9 or a non-aromatic C.sub.2-15 heterocyclyl ring
system containing at least one nitrogen atom and optionally between
1 and 3 additional heteroatoms selected from O, S, and N in each
ring; each of R.sub.5 and R.sub.6 is independently selected from
hydrogen, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.3-7 cycloalkyl,
(C.sub.3-7 cycloalkyl)C.sub.1-6 alkylene, C.sub.2-15 heterocyclyl,
and (C.sub.2-7 heterocyclyl)C.sub.1-6 alkylene; R.sub.7 is H,
hydroxyl, halo, C.sub.2-6 alkoxy or absent where the carbon linking
L.sub.6 and L.sub.7 (or bonded to R.sub.6) participates in a double
bond; each of R.sub.8 and R.sub.9 is independently selected from
hydrogen, C.sub.1-8 alkyl, C.sub.3-8 alkenyl, C.sub.3-7 cycloalkyl,
(C.sub.3-7 cycloalkyl)C.sub.1-6 alkylene, C.sub.2-15 heterocyclyl,
phenyl, (C.sub.2-15 heterocyclyl)C.sub.1-6 alkylene, and (phenyl)
C.sub.1-6 alkylene; R.sub.10 is H, C.sub.1-8 alkyl, C.sub.3-8
alkenyl, C.sub.3-7 cycloalkyl, (C.sub.3-7 cycloalkyl)C.sub.1-6
alkylene, (C.sub.2-15 heterocyclyl)C.sub.1-6 alkylene, or (phenyl)
C.sub.1-6 alkylene; wherein each of the above alkyl, alkylene,
alkenyl, alkenylene, alkynyl, alkynylene, heterocyclyl, cycloalkyl,
and aryl groups may each be independently and optionally
substituted with between 1 and 3 substituents selected from halo,
amino, nitro, hydroxyl, and C.sub.1-3 alkyl; wherein substituents
of Q can be further selected from carboxamide, C.sub.2-6 alkyl,
C.sub.1-8 heterocyclyl, N(C.sub.1-6 alkyl)(C.sub.1-8 heterocyclyl),
NH(C.sub.1-8 heterocyclyl), (C.sub.1-8 heterocyclyl) C.sub.1-3
alkylene, O(C.sub.1-8 heterocyclyl), C.sub.1-6 alkoxy,
(phenyl)C.sub.3-6 cycloalkyl-O--, phenyl, (phenyl) C.sub.1-3
alkylene, N(C.sub.1-6 alkyl)[(phenyl)C.sub.1-3 alkylene], and
(phenyl)C.sub.1-3 alkylene-O-- where each of above heterocyclyl,
phenyl, and alkyl groups may be optionally substituted with from 1
to 3 substituents independently selected from halogen, nitro,
cyano, and C.sub.1-3 alkyl; or a pharmaceutically acceptable salt,
ester, or amide thereof.
76. The method of claim 75, wherein R.sub.a and R.sub.b taken
together with the nitrogen to which they are attached form a 4-7
membered heterocyclyl optionally including up to 3 additional
heteroatoms.
77. The method of claim 75, wherein R.sub.1 is hydrogen or halo,
and one of R.sub.2 and R.sub.3 is G and the other is hydrogen or
halo.
78. The method of claim 77, wherein R.sub.2 is G.
79. The method of claim 77, wherein R.sub.3 is G.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to aryloxyalkylamines, their
synthesis and their use, for example, for the treatment of
disorders and conditions mediated by the histamine receptor.
BACKGROUND OF THE INVENTION
[0002] Histamine [2-(imidazol-4-yl)ethylamine] is a transmitter
substance. Histamine exerts a physiological effect via multiple
distinct G-protein coupled receptors. It plays a role in immediate
hypersensitivity reactions and is released from mast cells
following antigen IgE antibody interaction. The actions of released
histamine on the vasculature and smooth muscle system account for
the symptoms of the allergic response. These actions occur at the
H.sub.1 receptor (Ash, A. S. F. and Schild, H. O., Br. J.
Pharmacol., 1966, 27, 427) and are blocked by the classical
antihistamines (e.g. diphenhydramine). Histamine is also an
important regulator of gastric acid secretion through its action on
parietal cells. These effects of histamine are mediated via the
H.sub.2 receptor (Black, J. W., Duncan, W. A. M., Durant, C. J.,
Ganellin, C. R. and Parsons, E. M., Nature, 1972, 236, 385) and are
blocked by H.sub.2 receptor antagonists (e.g. cimetidine). The
third histamine receptor --H.sub.3-- was first described as a
presynaptic autoreceptor in the central nervous system (CNS)
(Arrang, J.-M., Garbarg, M., and Schwartz, J.-C., Nature 1983, 302,
832) controlling the synthesis and release of histamine. Recent
evidence has emerged showing that the H.sub.3 receptors are also
located presynaptically as heteroreceptors on serotonergic,
noradrenergic, dopaminergic, cholinergic, and GABAergic
(gamma-aminobutyric acid containing) neurons. These H.sub.3
receptors have also recently been identified in peripheral tissues
such as vascular smooth muscle. Consequently there are many
potential therapeutic applications for histamine H.sub.3 agonists,
antagonists, and inverse agonists. (See: "The Histamine H.sub.3
Receptor--A Target for New Drugs", Leurs, R., and Timmerman, H.,
(Editors), Elsevier, 1998; Morisset et al., Nature, 2000, 408,
860-864.) A fourth histamine receptor --H.sub.4-- was recently
described by Oda et al., (J. Biol. Chem., 2000, 275,
36781-36786).
[0003] The potential use of histamine H.sub.3 agonists in
sleep/wake and arousal/vigilance disorders is suggested based on
animal studies (Lin et al, Br. Res., 1990, 523, 325; Monti et al
Eur. J. Pharmacol., 1991, 205, 283). Their use in the treatment of
migraine has also been suggested (McLeod et al Abstr. Society
Neuroscience, 1996, 22, 2010) based on their ability to inhibit
neurogenic inflammation. Other applications could be a protective
role in myocardial ischemia and hypertension where blockade of
norepinephrine release is beneficial (Imamura et al J. Pharmacol.
Expt. Ther., 1994, 271, 1259). It has been suggested that histamine
H.sub.3 agonists may be beneficial in asthma due to their ability
to reduce non-adrenergic non-cholinergic (NANC) neurotransmission
in airways and to reduce microvascular leakage (Ichinose et al Eur.
J. Pharmacol., 1989, 174, 49).
[0004] Several indications for histamine H.sub.3 antagonists and
inverse agonists have similarly been proposed based on animal
pharmacology experiments with known histamine H.sub.3 antagonists
(e.g. thioperamide). These include dementia, Alzheimer's disease
(Panula et al Abstr. Society Neuroscience, 1995, 21, 1977),
epilepsy (Yokoyama et al Eur. J. Pharmacol., 1993, 234, 129)
narcolepsy, eating disorders (Machidori et al Brain Research 1992,
590, 180), motion sickness, vertigo, attention deficit
hyperactivity disorders (ADHD), learning and memory (Barnes et al
Abstr. Society Neuroscience, 1993, 19, 1813), schizophrenia
(Schlicker et al Naunyn-Schmiedeberg's Arch. Pharmacol., 1996, 353,
290-294); (also see; Stark et al Drugs Future, 1996, 21, 507 and
Leurs et al Progress in Drug Research, 1995, 45, 107 and references
cited therein). Histamine H.sub.3 antagonists, alone or in
combination with a histamine H.sub.1 antagonist, are reported to be
useful for the treatment of upper airway allergic response (U.S.
Pat. Nos. 5,217,986; 5,352,707 and 5,869,479). Recently, a
histamine H.sub.3 antagonist (GT-2331) was identified and is being
developed by Gliatech Inc. (Gliatech Inc. Press Release Nov. 5,
1998; Bioworld Today, Mar. 2, 1999) for the treatment of CNS
disorders.
[0005] As noted, the prior art related to histamine H.sub.3 ligands
has been comprehensively reviewed ("The Histamine H.sub.3
Receptor--A Target for New Drugs", Leurs, R., and Timmerman, H.,
(Editors), Elsevier, 1998). Within this reference the medicinal
chemistry of histamine H.sub.3 agonists and antagonists was
reviewed (see Krause et al and Phillips et al respectively). The
importance of an imidazole moiety containing only a single
substitution in the 4 position was noted together with the
deleterious effects of additional substitution on activity.
Particularly methylation of the imidazole ring at any of the
remaining unsubstituted positions was reported to strongly decrease
activity. Additional publications support the hypothesis that an
imidazole function is essential for high affinity histamine H.sub.3
receptor ligands (See, Ali et al J. Med. Chem., 1999, 42, 903 and
Stark et al, Drugs Future, 1996, 21, 507 and references cited
therein). However many imidazole containing compounds are
substrates for histamine methyl transferase, the major histamine
metabolizing enzyme in humans, which leads to shortened half lives
and lower bioavailability (See, Rouleau et al J. Pharmacol. Exp.
Ther. 1997, 281, 1085). In addition, imidazole containing drugs,
via their interaction with the cytochrome P450 monooxygenase
system, can result in unfavorable biotransformations due to enzyme
induction or enzyme inhibition. (Kapetanovic et al Drug Metab.
Dispos. 1984, 12, 560; Sheets et al Drug Metab. Dispos. 1984, 12,
603; Back, et al Br. J. Pharmacol. 1985, 85, 121; Lavrijsen et al
Biochem. Pharmacol. 1986, 35, 1867; Drug Saf., 1998, 18, 83). The
poor blood brain barrier penetration of earlier histamine H.sub.3
receptor ligands may also be associated with the imidazole fragment
(Ganellin et al Arch. Pharm. (Weinheim, Ger.) 1998, 331, 395).
[0006] More recently, several publications have described histamine
H.sub.3 ligands that do not contain an imidazole moiety. For
example; Ganellin et al Arch. Pharm. (Weinheim, Ger.) 1998, 331,
395; Walczynski et al Arch. Pharm. (Weinheim, Ger.) 1999, 332, 389;
Walczynski et al Farmaco 1999, 684; Linney et al J. Med. Chem.
2000, 2362; Tozer and Kalindjian Exp. Opin. Ther. Patents 2000, 10,
1045-1055; U.S. Pat. No. 5,352,707; PCT Application W099/42458,
Aug. 26, 1999; and European Patent Application 0978512, Feb. 9,
2000.
[0007] The compounds of the present invention do not contain the
imidazole moiety, and its inherent liabilities, and maintain
potency at the human H.sub.3 receptor. Thus in the present
invention receptor binding was determined using the human histamine
H.sub.3 receptor (See Lovenberg et al Mol. Pharmacol. 1999, 1107).
Screening using the human receptor is particularly important for
the identification of new therapies for the treatment of human
disease. Conventional binding assays for example are determined
using rat synaptosomes (Garbarg et al J. Pharmacol. Exp. Ther.
1992, 263, 304), rat cortical membranes (West et al Mol. Pharmacol.
1990, 610), and guinea pig brain (Korte et al Biochem. Biophys.
Res. Commun. 1990, 978). Only limited studies have been performed
previously using human tissue but these allude to significant
differences in the pharmacology of rodent and primate receptors
(West et al Eur. J. Pharmacol. 1999, 233).
[0008] We now describe a series of aryloxyalkylamines with the
ability to modulate the activity of the histamine receptor,
specifically the H.sub.3 receptor, without the inherent problems
associated with the presence of an imidazolyl moiety.
SUMMARY OF THE INVENTION
[0009] The present invention is directed to a compound of formula
(I):
##STR00001##
[0010] wherein R.sub.a and R.sub.b are independently C.sub.1-8
alkyl, C.sub.3-8 alkenyl, C.sub.3-8 cycloalkyl,
[0011] (C.sub.3-8 cycloalkyl) C.sub.1-6 alkyl, or taken together
with the nitrogen to which they are attached form a 4-7 membered
heterocyclyl optionally including up to 3 additional
heteroatoms;
[0012] n is 0-4;
[0013] one of R.sub.1, R.sub.2, and R.sub.3 is G, and the remaining
two are hydrogen or halo;
[0014] G is a nitrogen-containing group selected from one of the
following:
[0015] --OL.sub.1Q, -L.sub.2Q, --N(L.sub.1Q)R.sub.5,
-L.sub.3C(L.sub.1Q)R.sub.6R.sub.7, --C(L.sub.1Q)R.sub.6R.sub.7,
##STR00002##
[0016] wherein:
[0017] L.sub.1 is C.sub.2-6 alkylene, C.sub.3-8 cycloalkylene,
C.sub.4-6 alkenylene, C.sub.4-6 alkynylene, C.sub.2-5 alkanoyl,
(phenyl)C.sub.1-6 alkylene, (naphthyl)C.sub.1-6 alkylene,
(C.sub.2-5 heteroaryl)C.sub.1-6 alkylene, (phenoxy)C.sub.1-6
alkylene, or (C.sub.2-5 heteroaryloxy)C.sub.1-6 alkylene;
[0018] L.sub.2 is C.sub.1-6 alkylene, C.sub.3-8 cycloalkylene,
C.sub.3-6 alkenylene, C.sub.3-6 alkynylene, C.sub.2-5 alkanoyl,
(phenyl)C.sub.1-6 alkylene, (naphthyl)C.sub.1-6 alkylene,
(C.sub.1-5 heteroaryl)C.sub.1-6 alkylene, (phenoxy)C.sub.1-6
alkylene, (C.sub.1-5 heteroaryloxy)C.sub.1-6 alkylene, or
(C.sub.1-5 heteroarylthio)C.sub.1-6 alkylene;
[0019] L.sub.3 is C.sub.1-6 alkylene, C.sub.2-6 alkenylene,
C.sub.2-6 alkynylene, C.sub.2-5 alkanoyl, (phenyl)C.sub.1-6
alkylene, phenyl, naphthyl, (naphthyl)C.sub.1-6 alkylene, C.sub.1-5
heteroaryl)C.sub.1-6 alkylene, (phenoxy)C.sub.1-6 alkylene,
(C.sub.1-5 heteroaryloxy)C.sub.1-6 alkylene, or C.sub.2-5
heteroaryl;
[0020] L.sub.4 is C.sub.1-5 alkylene;
[0021] L.sub.5 is C.sub.1-5 alkylene;
[0022] L.sub.6 is C.sub.1-5 alkylene;
[0023] L.sub.7 is C.sub.1-5 alkylene or absent;
[0024] Q is --NR.sub.8R.sub.9 or a non-aromatic C.sub.2-15
heterocyclyl ring system containing at least one nitrogen atom and
optionally between 1 and 3 additional heteroatoms selected from O,
S, and N in each ring;
[0025] each of R.sub.5 and R.sub.6 is independently selected from
hydrogen, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.3-7 cycloalkyl,
(C.sub.3-7 cycloalkyl)C.sub.1-6 alkylene, C.sub.2-15 heterocyclyl,
and (C.sub.2-7 heterocyclyl)C.sub.1-6 alkylene;
[0026] R.sub.7 is H, hydroxyl, halo, C.sub.2-6 alkoxy or absent
where the carbon linking L.sub.6 and L.sub.7 (or bonded to R.sub.6)
participates in a double bond;
[0027] each of R.sub.8 and R.sub.9 is independently selected from
hydrogen, C.sub.1-8 alkyl, C.sub.3-8 alkenyl, C.sub.3-7 cycloalkyl,
(C.sub.3-7 cycloalkyl)C.sub.1-6 alkylene, C.sub.2-15 heterocyclyl,
phenyl, (C.sub.2-15 heterocyclyl)C.sub.1-6 alkylene, and (phenyl)
C.sub.1-6 alkylene;
[0028] R.sub.10 is H, C.sub.1-8 alkyl, C.sub.3-8 alkenyl, C.sub.3-7
cycloalkyl, (C.sub.3-7 cycloalkyl)C.sub.1-6 alkylene, (C.sub.2-15
heterocyclyl)C.sub.1-6 alkylene, or (phenyl) C.sub.1-6
alkylene;
[0029] wherein each of the above alkyl, alkylene, alkenyl,
alkenylene, alkynyl, alkynylene, heterocyclyl, cycloalkyl, and aryl
groups may each be independently and optionally substituted with
between 1 and 3 substituents selected from halo, amino, nitro,
hydroxyl, and C.sub.1-3 alkyl;
[0030] wherein substituents of Q can be further selected from
carboxamide, C.sub.2-6 alkyl, C.sub.1-8 heterocyclyl, N(C.sub.1-6
alkyl)(C.sub.1-8 heterocyclyl), NH(C.sub.1-8 heterocyclyl),
(C.sub.1-8 heterocyclyl) C.sub.1-3 alkylene, O(C.sub.1-8
heterocyclyl), C.sub.1-6 alkoxy, (phenyl)C.sub.3-6 cycloalkyl-O--,
phenyl, (phenyl) C.sub.1-3 alkylene, N(C.sub.1-6
alkyl)[(phenyl)C.sub.1-3 alkylene], and (phenyl)C.sub.1-3
alkylene-O-- where each of above heterocyclyl, phenyl, and alkyl
groups may be optionally substituted with from 1 to 3 substituents
independently selected from halogen, nitro, cyano, and C.sub.1-3
alkyl;
[0031] or a pharmaceutically acceptable salt, ester, or amide
thereof.
[0032] The invention also features a pharmaceutical composition
comprising a compound of the invention and a pharmaceutically
acceptable carrier; and methods of preparing or formulating such
compositions. A composition of the invention may further include
more than one compound of the invention, or a combination therapy
(combination formulation or combination of differently formulated
active agents).
[0033] The invention also provides methods of treating certain
conditions and diseases, each of which methods includes
administering a therapeutically effective (or jointly effective)
amount of a compound or composition of the invention to a subject
in need of such treatment. The disclosed compounds are useful in
methods for treating or preventing neurologic disorders including
sleep/wake and arousal/vigilance disorders (e.g. insomnia and jet
lag), attention deficit hyperactivity disorders (ADHD), learning
and memory disorders, cognitive dysfunction, migraine, neurogenic
inflammation, dementia, mild cognitive impairment (pre-dementia),
Alzheimer's disease, epilepsy, narcolepsy, eating disorders,
obesity, motion sickness, vertigo, schizophrenia, substance abuse,
bipolar disorders, manic disorders and depression, as well as other
histamine H.sub.3 receptor mediated disorders such as upper airway
allergic response, asthma, itch, nasal congestion and allergic
rhinitis in a subject in need thereof. For example, the invention
features methods for preventing, inhibiting the progression of, or
treating upper airway allergic response, asthma, itch, nasal
congestion and allergic rhinitis.
[0034] In yet another embodiment, the disclosed compounds may be
used in a combination therapy method including administering a
jointly effective dose of an H.sub.3 antagonist and administering a
jointly effective dose of a histamine H.sub.1 antagonist, such as
loratidine (CLARITIN.TM.), desloratidine (CLARINEX.TM.),
fexofenadine (ALLEGRA.TM.) and cetirizine (ZYRTEC.TM.), for the
treatment of allergic rhinitis, nasal congestion, and allergic
congestion.
[0035] In yet another embodiment, the disclosed compounds may be
used in a combination therapy method, including administering a
jointly effective dose of an H.sub.3 antagonist and administering a
jointly effective dose of a neurotransmitter re-uptake blocker,
such as a selective serotonin re-uptake inhibitor (SSRI) or a
non-selective serotonin, dopamine or norepinephrine re-uptake
inhibitor, including fluoxetine (PROZAC.TM.), sertraline
(ZOLOFT.TM.), paroxetine (PAXIL.TM.) and amitryptyline, for the
treatment of depression, mood disorders or schizophrenia.
[0036] Additional features and advantages of the invention will
become apparent from the detailed description and examples below,
and the appended claims.
DETAILED DESCRIPTION OF THE INVENTION
[0037] The present invention provides non-imidazole
aryloxyalkylamines useful for the treatment of disorders and
conditions modulated by a histamine receptor.
A. Terms
[0038] Certain terms are defined below and by their usage
throughout this disclosure.
[0039] As used herein, "halogen" shall mean chlorine, bromine,
fluorine and iodine, or monovalent radicals thereof.
[0040] As used herein, the term "alkyl", whether used alone or as
part of a substituent group, shall include straight and branched
carbon chains. For example, alkyl radicals include methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and
the like. Unless otherwise noted, "lower" when used with alkyl
means a carbon chain composition of 1-4 carbon atoms. "Alkylene"
refers to a bivalent hydrocarbyl group, such as methylene
(CH.sub.2), ethylene (--CH.sub.2--CH.sub.2--) or propylene
(--CH.sub.2CH.sub.2CH.sub.2--).
[0041] As used herein, unless otherwise noted, "alkoxy" shall
denote an oxygen ether radical of the above described straight or
branched chain alkyl groups. For example, methoxy, ethoxy,
n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like.
[0042] As used herein, unless otherwise noted, "cycloalkyl" shall
denote a three- to eight-membered, saturated monocyclic carbocyclic
ring structure. Suitable examples include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
[0043] As used herein, unless otherwise noted, "cycloalkenyl" shall
denote a three- to eight-membered, partially unsaturated,
monocyclic, carbocyclic ring structure, wherein the ring structure
contains at least one double bond. Suitable examples include
cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl,
cyclohex-1,3-dienyl and the like.
[0044] As used herein, unless otherwise noted, "aryl" shall refer
to carbocyclic aromatic groups such as phenyl, naphthyl, and the
like. Divalent radicals include phenylene (--C.sub.6H.sub.4--)
which is preferably phen-1,4-diyl, but may also be
phen-1,3-diyl.
[0045] As used herein, unless otherwise noted, "aralkyl" shall mean
any alkyl group substituted with an aryl group such as phenyl,
naphthyl and the like. Examples of aralkyls include benzyl,
phenethyl, and phenylpropyl.
[0046] As used herein, unless otherwise noted, the terms
"heterocycle", "heterocyclyl" and "heterocyclo" shall denote any
five-, six-, or seven-membered monocyclic, nine or ten membered
bicyclic or thirteen or fourteen membered tricyclic ring structure
containing at least one heteroatom moiety selected from the group
consisting of N, O, SO, SO.sub.2, (C.dbd.O), and S, and preferably
N, O, or S, optionally containing one to four additional
heteroatoms in each ring. In some embodiments, the heterocyclyl
contains between 1 and 3 or between 1 and 2 additional heteroatoms.
Unless otherwise specified, a heterocyclyl may be saturated,
partially unsaturated, aromatic or partially aromatic. The
heterocyclyl group may be attached at any heteroatom or carbon atom
which results in the creation of a stable structure.
[0047] Exemplary monocyclic heterocyclic groups can include
pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl,
imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl,
isoxazolinyl, isoxazolyl, thiazaolyl, thiadiazolyl, thiazolidinyl,
isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl,
oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,
2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl,
hexahydroazepinyl, 4-piperidinyl, pyridyl, N-oxo-pyridyl,
pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl,
tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl,
thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl
sulfone, 1,3-dixolane and tetrahydro-1,1-dioxothienyl, dioxanyl,
isothiazolidinyl, thietanyl, thiiranyl, triazinyl, triazolyl,
tetrazolyl, azetidinyl and the like.
[0048] For example, where Q is a non-aromatic nitrogen-containing
heterocyclyl, preferred values for Q include piperidyl,
piperazinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, and N--(C1-6
alkyl) piperazinyl. These may be linked to the rest of the molecule
by a nitrogen or a carbon atom; in general, N-linked heterocyclyls
are preferred. Q can be substituted with between 1 and 3
substituents selected from pyridyl, pyrimidyl, furyl, thiofuryl,
imidazolyl, (imidazolyl)C.sub.1-6 alkylene, oxazolyl, thiazolyl,
2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl,
(tetrazolyl)C.sub.1-6 alkylene, tetrazolyl, (triazolyl)C.sub.1-6
alkylene, triazolyl, (pyrrolyl)C.sub.1-6 alkylene, and pyrrolyl.
Examples of substituted Q, wherein the substituent comprises a
heterocyclyl, include:
4-(4-chloropyridin-2-yl)amino-piperidin-1-yl;
4-(4-chloropyrimidin-2-yl)amino-piperidin-1-yl;
2-([1,2,4]triazol-1-yl)methyl-morpholin-1-yl;
3-(pyrazin-2-yl)piperidin-1-yl; 4-(pyrazol-1-yl)piperidin-1-yl;
4-(pyrimidin-2-yl)piperazin-1-yl;
4-(furan-2-yl)methylpiperazin-1-yl;
4-(thiophen-2-yl)methylpiperazin-1-yl;
4-(4-chloropyridin-2-yl)-[1,4]diazepan-1-yl; and
5-(isoxazol-5-yl)-2,5-diaza-bicyclo[2.2.1]heptan-2-yl.
[0049] Exemplary bicyclic heterocyclic groups include
benzthiazolyl, benzoxazolyl, benzoxazinyl, benzothienyl,
quinuclidinyl, quinolinyl, quinolinyl-N-oxide,
tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl,
benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl,
cinnolinyl, quinoxalinyl, indazolyl, pyrrolopridyl, furopyridinyl
(such as furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl), or
furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such
as 3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl (such as
1,2,3,4-tetrahydroquinolinyl), tetrahydroisoquinolinyl (such as
1,2,3,4-tetrahydroisoquiunolinyl), benzisothiazolyl,
benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl,
benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl,
dihydrobenzothienyl, dihydrobenzothiopyranyl,
dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl,
isoindolyl, tetrahydroindoazolyl (such as
4,5,6,7-tetrahydroindazolyl), isochromanyl, isoindolinyl,
naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl,
quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl,
thienothienyl,
##STR00003##
and the like.
[0050] Exemplary tricyclic heterocylclic groups include acridinyl,
phenoxazinyl, phenazinyl, phenothiazinyl, carbozolyl, perminidinyl,
phenanthrolinyl, carbolinyl, naphthothienyl, thianthrenyl, and the
like.
[0051] Preferred heterocyclyl groups include morpholinyl,
piperidinyl, piperazinyl, pyrrolidinyl, pyrimidinyl, pyridyl,
pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, acridinyl, azepinyl,
hexahydroazepinyl, azetidinyl, indolyl, isoindolyl, thiazolyl,
thiadiazolyl, quinolinyl, isoquinolinyl,
1,2,3,4-tetrahydroquinolinyl, 1,3,4-trihydroisoquinolinyl,
4,5,6,7-tetrahydroindadolyl, benzoxazinyl, benzoaxzolyl,
benzthiazolyl, benzimidazolyl, tetrazolyl, oxadiazolyl,
##STR00004##
[0052] As used herein, unless otherwise noted, the term
"heterocyclyl-alkyl" or "heterocyclyl-alkylene" shall denote any
alkyl group substituted with a heterocyclyl group, wherein the
heterocycly-alkyl group is bound through the alkyl portion to the
central part of the molecule. Suitable examples of
heterocyclyl-alkyl groups include, but are not limited to
piperidinylmethyl, pyrrolidinylmethyl, piperidinylethyl,
piperazinylmethyl, pyrrolylbutyl, piperidinylisobutyl,
pyridylmethyl, pyrimidylethyl, and the like.
[0053] When a particular group is "substituted" (e.g., alkyl,
alkylene, cycloalkyl, aryl, heterocyclyl, heteroaryl), that group
may have one or more substituents, preferably from one to five
substituents, more preferably from one to three substituents, most
preferably from one to two substituents, independently selected
from the list of substituents.
[0054] It is intended that the definition of any substituent or
variable at a particular location in a molecule be independent of
its definitions elsewhere in that molecule. It is understood that
substituents and substitution patterns on the compounds of this
invention can be selected by one of ordinary skill in the art to
provide compounds that are chemically stable and that can be
readily synthesized by techniques known in the art as well as those
methods set forth herein.
[0055] Under standard nomenclature used throughout this disclosure,
the terminal portion of the designated side chain is described
first, followed by the adjacent functionality toward the point of
attachment. Thus, for example, a "phenyl(alkyl)amido(alkyl)"
substituent refers to a group of the formula
##STR00005##
[0056] The term "subject" as used herein, refers to an animal,
preferably a mammal, most preferably a human, who has been the
object of treatment, observation or experiment.
[0057] The term "therapeutically effective amount" as used herein,
means that amount of active compound or pharmaceutical agent that
elicits the biological or medicinal response in a tissue system,
animal or human that is being sought by a researcher, veterinarian,
medical doctor or other clinician, which includes prevention,
inhibition of onset, or alleviation of the symptoms of the disease
or disorder being treated.
[0058] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combinations of the specified ingredients in
the specified amounts.
[0059] Abbreviations used in the specification, particularly in the
Schemes and Examples, are as follows:
TABLE-US-00001 DBAD = di-tert-butyl azodicarboxylate DCE =
1,2-dichloroethane DCM = dichloromethane DEAD = diethyl
azodicarboxylate DMA = N,N-dimethylacetamide DMAP =
4-N,N-dimethylamino- pyridine DME = 1,2-dimethoxyethane DMF =
dimethylformamide DMSO = dimethylsulfoxide RT = room temperature
TEA = triethylamine TFA = trifluoroacetic acid THF =
tetrahydrofuran
[0060] The next section describes the compounds provided by the
invention in more detail.
B. Compounds
[0061] The invention features compounds of formula (I) as
described, for example, in the above Summary section and in the
claims. Preferred compounds include those wherein: [0062] (a)
NR.sub.aR.sub.b taken together form piperidyl, methylpiperidyl,
dimethylamino, pyrrolidinyl, diethylamino, methylethylamino,
ethylpropylamino, or dipropylamino; [0063] (b) NR.sub.aR.sub.b
taken together form piperidyl, pyrrolidinyl, or diethylamino;
[0064] (c) NR.sub.aR.sub.b taken together form piperidyl or
pyrrolidinyl; [0065] (d) one of R.sub.2 and R.sub.3 is G; [0066]
(e) R.sub.2 is G; [0067] (f) R.sub.3 is G; [0068] (g) n is between
1 and 4, inclusive; [0069] (h) n is 1; [0070] (i) L.sub.1 is
C.sub.2-3 alkylene; [0071] (j) L.sub.2 is C.sub.1-6 alkylene,
(C.sub.1-5 heteroaryl)C.sub.1-6 alkylene, or -phenyl-C.sub.1-6
alkylene; [0072] (k) L.sub.2 is methylene; [0073] (l) L.sub.3 is
ethylene, vinylene, ethynylene, and phenylene; [0074] (m) Q is a
non-aromatic nitrogen-containing C.sub.2-5 heterocyclyl; [0075] (n)
Q is selected from piperidyl, N--(C.sub.1-6 alkyl)piperazinyl,
piperazinyl, pyrrolinyl, pyrrolidinyl, and morpholinyl; [0076] (o)
Q is N-morpholinyl or N-piperidinyl, optionally substituted with
between 1 and 3 substituents selected from hydroxyl, carboxamide,
C.sub.1-6 alkyl, C.sub.1-8 heterocyclyl, N(C.sub.1-6
alkyl)(C.sub.1-8 heterocyclyl), NH(C.sub.1-8 heterocyclyl),
(C.sub.1-8 heterocyclyl)C.sub.1-3 alkylene, C.sub.1-8
heterocyclyl-O--, C.sub.1-6 alkoxy, (C.sub.3-6 cycloalkyl)-O--,
phenyl, (phenyl)C.sub.1-3 alkylene, N(C.sub.1-6
alkyl)[(phenyl)C.sub.1-3 alkylene, and (phenyl)C.sub.1-3
alkylene-O-- where each of above heterocyclyl, phenyl, and alkyl
groups may be optionally substituted with from 1 to 3 substituents
independently selected from halogen, nitro, cyano, and C.sub.1-3
alkyl; [0077] (p) Q is substituted with a substituent comprising a
C.sub.1-6 heterocyclyl group selected from: pyridyl, pyrimidyl,
furyl, thiofuryl, imidazolyl, (imidazolyl)C.sub.1-6 alkylene,
oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl,
2-oxobenzimidazolyl, (tetrazolyl)C.sub.1-6 alkylene, tetrazolyl,
(triazolyl)C.sub.1-6 alkylene, triazolyl, (pyrrolyl)C.sub.1-6
alkylene, and pyrrolyl; [0078] (q) Q is a substituted or
unsubstituted N-morpholinyl; [0079] (r) Q is NR.sub.8R.sub.9
wherein each of R.sub.8 or R.sub.9 is independently selected from
hydrogen, C.sub.1-8 alkyl, C.sub.3-8 alkenyl, C.sub.3-7 cycloalkyl,
(C.sub.3-7 cycloalkyl)C.sub.1-6 alkylene, C.sub.2-5 heterocyclyl,
phenyl, (C.sub.2-5 heterocyclyl)C.sub.1-6 alkylene, and (phenyl)
C.sub.1-6 alkylene; [0080] (s) one of R.sub.8 and R.sub.9 is
hydrogen; [0081] (t) R.sub.8 is H and R.sub.9 is phenyl or aromatic
C.sub.1-8 heterocyclyl optionally substituted with 1-3 substituents
selected from halo, nitro, cyano, and C.sub.1-3 alkyl; [0082] (u)
R.sub.9 is phenyl, pyridyl, pyrimidyl, furyl, thiofuryl,
imidazolyl, (imidazolyl)C.sub.1-6 alkylene, oxazolyl, thiazolyl,
2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl,
(tetrazolyl)C.sub.1-6 alkylene, tetrazolyl, (triazolyl)C.sub.1-6
alkylene, triazolyl, (pyrrolyl)C.sub.1-6 alkylene, and pyrrolyl;
[0083] (v) NR.sub.aR.sub.b taken together form piperidyl,
methylpiperidyl, dimethylamino, pyrrolidinyl, diethylamino,
methylethylamino, ethylpropylamino, or dipropylamino; (w)
NR.sub.aR.sub.b taken together form piperidyl, pyrrolidinyl, or
diethylamino; [0084] (x) n is 1; [0085] (y) G is selected from:
[0086] (1) formula (i) wherein L.sub.4 and L.sub.5 are
independently selected from C.sub.2-3 alkylene, [0087] (2) formula
(iii) wherein L.sub.6 is C.sub.2-3 alkylene and L.sub.7 is C 2-3
alkylene or absent, [0088] (3) L.sub.2Q wherein L.sub.2 is
C.sub.1-6 alkylene, phenyl C.sub.1-4 alkylene, or (aromatic
C.sub.1-5 heterocyclyl)C.sub.1-4 alkylene, and [0089] (4) OL.sub.1Q
wherein L.sub.1 is C.sub.2-3 alkylene; [0090] (z') G is selected
from: [0091] (1) formula (i) wherein L.sub.4 and L.sub.5 are each
C.sub.2 alkylene, [0092] (2) formula (iii) wherein each of L.sub.6
and L.sub.7 is C.sub.2 alkylene, and [0093] (3) L.sub.2Q wherein
L.sub.2 is methylene; [0094] (z) G is L.sub.2Q; [0095] (aa)
R.sub.10 is H, branched C.sub.3-6 alkyl, or benzyl; [0096] (bb)
R.sub.10 is isopropyl or benzyl; [0097] (cc) Q is a non-aromatic
C.sub.2-5 heterocyclyl; [0098] (dd) Q is selected from piperidyl,
N--(C.sub.1-6 alkyl)piperazinyl, piperazinyl, pyrrolinyl,
pyrrolidinyl, and morpholinyl; [0099] (ee) Q is a non-aromatic
C.sub.2-5 heterocyclyl; [0100] (ff) Q is selected from piperidyl,
N--(C.sub.1-6 alkyl)piperazinyl, piperazinyl, pyrrolinyl,
pyrrolidinyl, and morpholinyl; [0101] (gg) Q is selected from
piperidyl, N--(C.sub.1-6 alkyl)piperazinyl, piperazinyl,
pyrrolinyl, pyrrolidinyl, and morpholinyl; [0102] (hh)
NR.sub.aR.sub.b taken together form piperidyl, pyrrolidinyl, or
diethylamino; [0103] (ii) n is 1; [0104] (jj) R.sub.7 is hydroxyl,
halo, or absent where one of L.sub.6 and L.sub.7 provides a double
bond to the carbon atom to which R.sub.6 and R.sub.7 are attached;
or [0105] (kk) Combinations of the above.
[0106] Examples of preferred compounds include:
Methyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-(2-pyridin-2-yl-ethyl)-amine-
, Benzyl-methyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,
Methyl-(1-methyl-piperidin-4-yl)-[4-(3-piperidin-1-yl-propoxy)-benzyl]-am-
ine,
Ethyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-pyridin-4-ylmethyl-amine,
[2-(3,4-Dimethoxy-phenyl)-ethyl]-methyl-[4-(3-piperidin-1-yl-propoxy)-ben-
zyl]-amine,
Methyl-phenethyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,
Dimethyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,
Dimethyl-{2-[4-(3-piperidin-1-yl-propoxy)-phenoxy]-ethyl}-amine,
Methyl-phenethyl-[3-(3-piperidin-1-yl-propoxy)-benzyl]-amine, and
Dibenzyl-(3-{2-[4-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrol-1-yl}-propyl)-
-amine.
[0107] Additional preferred compounds include:
Indan-1-yl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,
Cyclohexyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,
Cyclopropyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,
Pyridin-2-yl-[4-(3-pyrrolidin-1-yl-propoxy)-benzyl]-amine,
[4-(3-Piperidin-1-yl-propoxy)-benzyl]-pyridin-2-yl-amine,
Phenyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,
[3-(3-Piperidin-1-yl-propoxy)-benzyl]-pyridin-2-yl-amine,
(4-Chloro-phenyl)-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine, and
(4-Chloro-phenyl)-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine.
[0108] Additional examples of preferred compounds include:
4-[3-(3-Piperidin-1-ylmethyl-phenoxy)-propyl]-morpholine,
1-[3-(4-Piperidin-1-ylmethyl-phenoxy)-propyl]-piperidine,
Benzyl-methyl-{1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-am-
ine,
1-[3-(4-Piperidin-1-ylmethyl-phenoxy)-propyl]-decadeuterio-piperidine-
,
1-(3-{4-[5-(3-Piperidin-1-yl-propylsulfanyl)-tetrazol-1-yl]-phenoxy}-pro-
pyl)-piperidine,
1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-ol,
4-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-morpholine, 2-[4-(
3-Piperidin-1-yl-propoxy)-benzyl]-1,2,3,4-tetrahydro-isoquinoline,
{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-pyridin-2-yl-ami-
ne, 1-Benzyl-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine,
Indan-1-yl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,
Cyclohexyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,
Cyclopropyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,
8-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-1,4-dioxa-8-aza-spiro[4.5]decane,
1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidine-4-carboxylic
acid amide,
Methyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-(2-pyridin-2-yl-ethyl
)-amine, Benzyl-methyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,
4-Phenyl-1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-ol,
1-Phenyl-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine,
Methyl-phenethyl-{1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-
-amine,
2-Methyl-1-[3-(4-piperidin-1-ylmethyl-phenoxy)-propyl]-piperidine,
Methyl-(1-methyl-piperidin-4-yl)-[4-(3-piperidin-1-yl-propoxy)-benzyl]-am-
ine,
{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-pyridin-2-yl-
-(2-pyrrolidin-1-yl-ethyl)-amine,
2-{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-ethanol,
1-[3-(4-Pyrrolidin-1-ylmethyl-phenoxy)-propyl]-piperidine,
1-{3-[4-(4-Benzylidene-piperidin-1-ylmethyl)-phenoxy]-propyl}-piperidine,
Ethyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-pyridin-4-ylmethyl-amine,
1-{3-[4-(4-Benzyl-piperidin-1-ylmethyl)-phenoxy]-propyl}-piperidine,
2-(4-Chloro-phenyl)-5-[4-(3-piperidin-1-yl-propoxy)-benzyl]-2,5-diaza-bic-
yclo[2.2.1]heptane,
1-[3-(2'-Piperidin-1-ylmethyl-biphenyl-4-yloxy)-propyl]-piperidine,
1-{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-1,3-dihydro-be-
nzoimidazol-2-one,
1-(3-{4-[1-(3-Piperidin-1-yl-propyl)-1H-pyrrol-2-yl]-phenoxy}-propyl)-pip-
eridine.
[0109] The invention also features compounds such as:
1-(3-Phenyl-allyl)-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine,
[2-(3,4-Dimethoxy-phenyl)-ethyl]-methyl-[4-(3-piperidin-1-yl-propoxy)-ben-
zyl]-amine,
Methyl-phenethyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,
1-{3-[3-(4-Benzylidene-piperidin-1-ylmethyl)-phenoxy]-propyl}-piperidine,
4-(4-Chloro-phenyl)-1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-o-
l,
1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-4-(3-phenyl-propyl)-piperidine,
Dimethyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,
1-{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-1H-benzoimidaz-
ole,
1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-1,2,3,4,5,6-hexahydro-[2,3']b-
ipyridinyl,
1-{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-2,3-dihydro-1H-
-indole,
1-Isopropyl-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine,
1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-azacyclotridecane,
1-Methyl-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine,
5-Bromo-1-{1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-2,3-di-
hydro-1H-indole,
Methyl-phenethyl-[3-(3-piperidin-1-yl-propoxy)-benzyl]-amine,
2-{1-[3-(4-Piperidin-1-ylmethyl-phenoxy)-propyl]-piperidin-2-yl}-ethanol,
4-[3-(4-Piperidin-1-ylmethyl-phenoxy)-propyl]-morpholine,
2-[4-(2-Piperidin-1-yl-ethoxy)-benzyl]-1,2,3,4-tetrahydro-isoquinoline,
Pyridin-2-yl-[4-(3-pyrrolidin-1-yl-propoxy)-benzyl]-amine,
1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-1,2,3,4-tetrahydro-quinoline,
[4-(3-Piperidin-1-yl-propoxy)-benzyl]-pyridin-2-yl-amine,
1-[2-(4-Piperidin-1-ylmethyl-phenoxy)-ethyl]-piperidine,
Dibenzyl-(3-{2-[4-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrol-1-yl}-propyl)-
-amine, Dimethyl-[3-(4-piperidin-1-ylmethyl-phenoxy)-propyl]-amine,
Phenyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,
[3-(3-Piperidin-1-yl-propoxy)-benzyl]-pyridin-2-yl-amine,
5-(3-Piperidin-1-yl-propoxy)-2-[4-(3-piperidin-1-yl-propoxy)-phenyl]-pyri-
midine,
(4-Chloro-phenyl)-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,
1-Methyl-4-[3-(4-piperidin-1-ylmethyl-phenoxy)-propyl]-piperazine,
1-[4-(2-Piperidin-1-yl-ethoxy)-benzyl]-1,2,3,4-tetrahydro-quinoline,
and
(4-Chloro-phenyl)-[3-(3-piperidin-1-yl-propoxy)-benzyl]-amine.
[0110] Additional examples include:
4-[3-(3-Piperidin-1-ylmethyl-phenoxy)-propyl]-morpholine,
1-[3-(4-Piperidin-1-ylmethyl-phenoxy)-propyl]-piperidine,
Benzyl-methyl-{1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-am-
ine,
1-[3-(4-Piperidin-1-ylmethyl-phenoxy)-propyl]-decadeuterio-piperidine-
,
1-(3-{4-[5-(3-Piperidin-1-yl-propylsulfanyl)-tetrazol-1-yl]-phenoxy}-pro-
pyl)-piperidine,
1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-ol,
4-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-morpholine,
2-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-1,2,3,4-tetrahydro-isoquinoline,
{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-pyridin-2-yl-ami-
ne, 1-Benzyl-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine,
Indan-1-yl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,
Cyclohexyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,
Cyclopropyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,
8-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-1,4-dioxa-8-aza-spiro[4.5]decane,
1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidine-4-carboxylic
acid amide,
Methyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-(2-pyridin-2-yl-ethyl-
)-amine, Benzyl-methyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,
4-Phenyl-1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-ol,
1-Phenyl-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine,
Methyl-phenethyl-{1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-
-amine,
2-Methyl-1-[3-(4-piperidin-1-ylmethyl-phenoxy)-propyl]-piperidine,
Methyl-(1-methyl-piperidin-4-yl)-[4-(3-piperidin-1-yl-propoxy)-benzyl]-am-
ine,
{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-pyridin-2-yl-
-(2-pyrrolidin-1-yl-ethyl)-amine,
2-{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-ethanol,
1-[3-(4-Pyrrolidin-1-ylmethyl-phenoxy)-propyl]-piperidine,
1-{3-[4-(4-Benzylidene-piperidin-1-ylmethyl)-phenoxy]-propyl}-piperidine,
and
Ethyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-pyridin-4-ylmethyl-amine.
[0111] More preferred compounds of the invention include:
1-{3-[4-(4-Benzyl-piperidin-1-ylmethyl)-phenoxy]-propyl}-piperidine,
2-(4-Chloro-phenyl)-5-[4-(3-piperidin-1-yl-propoxy)-benzyl]-2,5-diaza-bic-
yclo[2.2.1]heptane,
1-[3-(2'-Piperidin-1-ylmethyl-biphenyl-4-yloxy)-propyl]-piperidine,
1-{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-1,3-dihydro-be-
nzoimidazol-2-one,
1-(3-{4-[1-(3-Piperidin-1-yl-propyl)-1H-pyrrol-2-yl]-phenoxy}-propyl)-pip-
eridine,
1-(3-Phenyl-allyl)-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-pipera-
zine,
[2-(3,4-Dimethoxy-phenyl)-ethyl]-methyl-[4-(3-piperidin-1-yl-propoxy-
)-benzyl]-amine,
Methyl-phenethyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,
1-{3-[3-(4-Benzylidene-piperidin-1-ylmethyl)-phenoxy]-propyl}-piperidine,
4-(4-Chloro-phenyl)-1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-o-
l,
1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-4-(3-phenyl-propyl)-piperidine,
Dimethyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,
1-{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-1H-benzoimidaz-
ole,
1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-1,2,3,4,5,6-hexahydro-[2,3']b-
ipyridinyl,
1-{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-2,3-dihydro-1H-
-indole,
1-Isopropyl-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine,
1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-azacyclotridecane,
1-Methyl-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine,
5-Bromo-1-{1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-2,3-di-
hydro-1H-indole,
Methyl-phenethyl-[3-(3-piperidin-1-yl-propoxy)-benzyl]-amine,
2-{1-[3-(4-Piperidin-1-ylmethyl-phenoxy)-propyl]-piperidin-2-yl}-ethanol,
4-[3-(4-Piperidin-1-ylmethyl-phenoxy)-propyl]-morpholine,
2-[4-(2-Piperidin-1-yl-ethoxy)-benzyl]-1,2,3,4-tetrahydro-isoquinoline,
Pyridin-2-yl-[4-(3-pyrrolidin-1-yl-propoxy)-benzyl]-amine,
1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-1,2,3,4-tetrahydro-quinoline,
[4-(3-Piperidin-1-yl-propoxy)-benzyl]-pyridin-2-yl-amine,
1-[2-(4-Piperidin-1-ylmethyl-phenoxy)-ethyl]-piperidine,
Dibenzyl-(3-{2-[4-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrol-1-yl}-propyl)-
-amine, Dimethyl-[3-(4-piperidin-1-ylmethyl-phenoxy)-propyl]-amine,
Phenyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine, and
[3-(3-Piperidin-1-yl-propoxy)-benzyl]-pyridin-2-yl-amine.
[0112] The invention also features compounds such as:
1-Isopropyl-4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine,
1-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-piperazine hydrochloride,
1-Benzyl-4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-piperazine,
1-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-piperazine hydrochloride,
and 1-Benzyl-4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine.
More preferred compounds include:
1-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-piperazine,
1-Isopropyl-4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine,
1-Benzyl-4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-piperazine, and
1-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-piperazine.
[0113] Further examples include: (A)
1-{3-[2'-(1-Isopropyl-piperidin-4-yl)-biphenyl-4-yloxy]-propyl}-piperidin-
e,
1-(3-{4-[2-(1-Methyl-pyrrolidin-2-yl)-ethyl]-phenoxy}-propyl)-piperidin-
e, and
1-{3-[4-(1-Isopropyl-piperidin-4-ylmethyl)-phenoxy]-propyl}-piperid-
ine; (B)
1-{3-[4-(1-Methyl-pyrrolidin-2-yl)-phenoxy]-propyl}-piperidine,
1-Benzyl-4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperidin-4-ol,
and
1-Isopropyl-4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperidin-4-ol;
(C) 1-{3-[4-(1-Methyl-pyrrolidin-2-yl)-phenoxy]-propyl}-piperidine,
and
1-Benzyl-4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperidin-4-ol;
(D)
{3-Furan-2-yl-3-[4-(3-piperidin-1-yl-propoxy)-phenyl]-propyl}-dimethyl-am-
ine,
4-{3-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-3-pyrimidin-2-yl-propyl}-m-
orpholine,
4-{4,4,4-Trifluoro-3-[4-(3-piperidin-1-yl-propoxy)-phenyl]-buty-
l}-morpholine, and
4-{4,4,4-Trifluoro-3-[4-(3-piperidin-1-yl-propoxy)-phenyl]-butyl}-morphol-
ine; and (E)
(2-Morpholin-4-yl-ethyl)-[4-(3-piperidin-1-yl-propoxy)-phenyl]-pyridin-2--
yl-amine,
Isopropyl-(2-morpholin-4-yl-ethyl)-[4-(3-piperidin-1-yl-propoxy)-
-phenyl]-amine, and
(2-Morpholin-4-yl-ethyl)-[4-(3-piperidin-1-yl-propoxy)-phenyl]-thiazol-2--
ylmethyl-amine.
[0114] The invention also provides compounds that are useful as
synthetic intermediates of the compounds of the invention. Such
compounds, which themselves may or may not have pharmaceutical
activity, include those provided in the schemes and synthetic
examples.
[0115] The invention also contemplates compounds
isotopically-labelled to be detectable by positron emission
tomography (PET) or single-photon emission computed tomography
(SPECT) useful for studying H.sub.3-mediated disorders.
[0116] During any of the processes for preparation of the compounds
of the present invention, it may be necessary and/or desirable to
protect sensitive or reactive groups on any of the molecules
concerned. In addition, compounds of the invention may be modified
by using protecting groups; such compounds, precursors, or prodrugs
are also within the scope of the invention. This may be achieved by
means of conventional protecting groups, such as those described in
"Protective Groups in Organic Chemistry", ed. J. F. W. McOmie,
Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts,
"Protective Groups in Organic Synthesis", 3.sup.rd ed., John Wiley
& Sons, 1999. The protecting groups may be removed at a
convenient subsequent stage using methods known from the art.
[0117] Hydroxyl Protecting Groups
[0118] Protection for the hydroxyl group includes methyl ethers,
substituted methyl ethers, substituted ethyl ethers, substitute
benzyl ethers, and silyl ethers.
[0119] Substituted Methyl Ethers
[0120] Examples of substituted methyl ethers include
methyoxymethyl, methylthiomethyl, t-butylthiomethyl,
(phenyldimethylsilyl)methoxymethyl, benzyloxymethyl,
p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl, guaiacolmethyl,
t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl,
2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,
bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl,
tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl,
1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,
4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl
S,S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,
1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and
2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.
[0121] Substituted Ethyl Ethers
[0122] Examples of substituted ethyl ethers include 1-ethoxyethyl,
1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,
1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,
2,2,2-trichloroethyl, 2-trimethylsilylethyl,
2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl,
p-methoxyphenyl, 2,4-dinitrophenyl, and benzyl.
[0123] Substituted Benzyl Ethers
[0124] Examples of substituted benzyl ethers include
p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl,
p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-
and 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl,
p,p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl,
.alpha.-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl,
di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl,
4-(4'-bromophenacyloxy)phenyldiphenylmethyl,
4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl,
4,4',4''-tris(levulinoyloxyphenyl)methyl,
4,4',4''-tris(benzoyloxyphenyl)methyl,
3-(Imidazol-1-ylmethyl)bis(4',4''-dimethoxyphenyl)methyl,
1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl,
9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,
1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.
[0125] Silyl Ethers
[0126] Examples of silyl ethers include trimethylsilyl,
triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl,
diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl,
t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl,
triphenylsilyl, diphenylmethylsilyl, and
t-butylmethoxyphenylsilyl.
[0127] Esters
[0128] In addition to ethers, a hydroxyl group may be protected as
an ester. Examples of esters include formate, benzoylformate,
acetate, chloroacetate, dichloroacetate, trichloroacetate,
trifluoroacetate, methoxyacetate, triphenylmethoxyacetate,
phenoxyacetate, p-chlorophenoxyacetate, p-P-phenylacetate,
3-phenylpropionate, 4-oxopentanoate(levulinate),
4,4-(ethylenedithio)pentanoate, pivaloate, adamantoate, crotonate,
4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-tri
methylbenzoate(mesitoate)
[0129] Carbonates
[0130] Examples of carbonates include methyl, 9-fluorenylmethyl,
ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,
2-(phenylsulfonyl)ethyl, 2-(triphenylphosphonio)ethyl, isobutyl,
vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl,
3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl
thiocarbonate, 4-ethoxy-1-naphthyl, and methyl dithiocarbonate.
[0131] Assisted Cleavage
[0132] Examples of assisted cleavage include 2-iodobenzoate,
4-azidobutyrate, 4-nitro-4-methylpentanoate,
o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate,
2-(methylthiomethoxy)ethyl carbonate,
4-(methylthiomethoxy)butyrate, and
2-(methylthiomethoxymethyl)benzoate.
[0133] Miscellaneous Esters
[0134] Examples of miscellaneous esters include
2,6-dichloro-4-methylphenoxyacetate,
2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,
2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,
isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate(tigloate),
o-(methoxycarbonyl)benzoate, p-P-benzoate, .alpha.-naphthoate,
nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate,
N-phenylcarbamate, borate, dimethylphosphinothioyl, and
2,4-dinitrophenylsulfenate
[0135] Sulfonates
[0136] Examples of sulfonates include sulfate,
methanesulfonate(mesylate), benzylsulfonate, and tosylate.
[0137] Protection for 1,2- and 1,3-diols
[0138] Cyclic Acetals and Ketals
[0139] Examples of cyclic acetals and ketals include methylene,
ethylidene, 1-t-butylethylidene, 1-phenylethylidene,
(4-methoxyphenyl)ethylidene, 2,2,2-trichloroethylidene, acetonide
(isopropylidene), cyclopentylidene, cyclohexylidene,
cycloheptylidene, benzylidene, p-methoxybenzylidene,
2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and
2-nitrobenzylidene.
[0140] Cyclic Ortho Esters
[0141] Examples of cyclic ortho esters include methoxymethylene,
ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene,
1-ethoxyethylidine, 1,2-dimethoxyethylidene,
.alpha.-methoxybenzylidene, 1-(N,N-dimethylamino)ethylidene
derivative, .alpha.-(N,N-dimethylamino)benzylidene derivative, and
2-oxacyclopentylidene.
[0142] Silyl Derivatives
[0143] Examples of silyl derivatives include di-t-butylsilylene
group, and 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene)
derivative.
[0144] Amino Protecting Groups
[0145] Protection for the amino group includes carbamates, amides,
and special --NH protective groups.
[0146] Examples of carbamates include methyl and ethyl carbamates,
substituted ethyl carbamates, assisted cleavage carbamates,
photolytic cleavage carbamates, urea-type derivatives, and
miscellaneous carbamates.
[0147] Carbamates
[0148] Examples of methyl and ethyl carbamates include methyl and
ethyl, 9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl,
9-(2,7-dibromo)fluorenylmethyl,
2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl,
and 4-methoxyphenacyl.
[0149] Substituted Ethyl
[0150] Examples of substituted ethyl carbamates include
2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl,
1-(1-adamantyl)-1-methylethyl, 1,1-dimethyl-2-haloethyl,
1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl,
1-methyl-1-(4-biphenylyl)ethyl,
1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2'- and
4'-pyridyl)ethyl, 2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl,
1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl,
4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio,
benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl,
p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl,
9-anthrylmethyl and diphenylmethyl.
[0151] Assisted Cleavage
[0152] Examples of assisted cleavage include 2-methylthioethyl,
2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl,
[2-(1,3-dithianyl)]methyl, 4-methylthiophenyl,
2,4-dimethylthiophenyl, 2-phosphonioethyl,
2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl,
m-chloro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl,
5-benzisoxazolylmethyl, and
2-(trifluoromethyl)-6-chromonylmethyl.
[0153] Photolytic Cleavage
[0154] Examples of photolytic cleavage include m-nitrophenyl,
3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl,
and phenyl(o-nitrophenyl)methyl.
[0155] Urea-Type Derivatives
[0156] Examples of urea-type derivatives include
phenothiazinyl-(10)-carbonyl derivative,
N'-p-toluenesulfonylaminocarbonyl, and
N'-phenylaminothiocarbonyl.
[0157] Miscellaneous Carbamates
[0158] Examples of miscellaneous carbamates include t-amyl,
S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl,
cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl,
diisopropylmethyl, 2,2-dimethoxycarbonylvinyl,
o-(N,N-dimethylcarboxamido)benzyl,
1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl,
1,1-dimethylpropynyl, di(2-pyridyl)methyl, 2-furanylmethyl,
2-iodoethyl, isobornyl, isobutyl, isonicotinyl,
p-(p'-methoxyphenylazo)benzyl, 1-methylcyclobutyl,
1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,
1-methyl-1-(3,5-dimethoxyphenyl)ethyl,
1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl,
1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl,
2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl, and
2,4,6-trimethylbenzyl.
[0159] Examples of Amides Include:
[0160] Amides
[0161] N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl,
N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl,
N-picolinoyl, N-3-pyridylcarboxamide, N-benzoylphenylalanyl
derivative, N-benzoyl, N-p-phenylbenzoyl.
[0162] Assisted Cleavage
[0163] N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl,
N-acetoacetyl, (N'-dithiobenzyloxycarbonylamino)acetyl,
N-3-(p-hydroxyphenyl)propionyl, N-3-(o-nitrophenyl)propionyl,
N-2-methyl-2-(o-nitrophenoxy)propionyl,
N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl,
N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethionine
derivative, N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, and
4,5-diphenyl-3-oxazolin-2-one.
[0164] Cyclic Imide Derivatives
[0165] N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl,
N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentane
adduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one,
5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, and
1-substituted 3,5-dinitro-4-pyridonyl.
[0166] Special --NH Protective Groups
[0167] Examples of special NH protective groups include:
[0168] N-Alkyl and N-Aryl Amines
[0169] N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxy]methyl,
N-3-acetoxypropyl, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl),
quaternary ammonium salts, N-benzyl, N-4-methoxybenzyl,
N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl, N-triphenylmethyl,
N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl,
N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, and
N-2-picolylamine N'-oxide.
[0170] Imine Derivatives
[0171] N-1,1-dimethylthiomethylene, N-benzylidene,
N-p-methoxybenzylidene, N-diphenylmethylene,
N-[(2-pyridyl)mesityl]methylene, and
N-(N',N'-dimethylaminomethylene).
[0172] Protection for the Carbonyl Group
[0173] Acyclic Acetals and Ketals
[0174] Examples of acyclic acetals and ketals include dimethyl,
bis(2,2,2-trichloroethyl), dibenzyl, bis(2-nitrobenzyl) and
diacetyl.
[0175] Cyclic Acetals and Ketals
[0176] Examples of cyclic acetals and ketals include 1,3-dioxanes,
5-methylene-1,3-dioxane, 5,5-dibromo-1,3-dioxane,
5-(2-pyridyl)-1,3-dioxane, 1,3-dioxolanes,
4-bromomethyl-1,3-dioxolane, 4-(3-butenyl)-1,3-dioxolane,
4-phenyl-1,3-dioxolane, 4-(2-nitrophenyl)-1,3-dioxolane,
4,5-dimethoxymethyl-1,3-dioxolane, O,O'-phenylenedioxy and
1,5-dihydro-3H-2,4-benzodioxepin.
[0177] Acyclic Dithio Acetals and Ketals
[0178] Examples of acyclic dithio acetals and ketals include
S,S'-dimethyl, S,S'-diethyl, S,S'-dipropyl, S,S'-dibutyl,
S,S'-dipentyl, S,S'-diphenyl, S,S'-dibenzyl and S,S'-diacetyl.
[0179] Cyclic Dithio Acetals and Ketals
[0180] Examples of cyclic dithio acetals and ketals include
1,3-dithiane, 1,3-dithiolane and
1,5-dihydro-3H-2,4-benzodithiepin.
[0181] Acyclic Monothio Acetals and Ketals
[0182] Examples of acyclic monothio acetals and ketals include
O-trimethylsilyl-S-alkyl, O-methyl-S-alkyl or -S-phenyl and
O-methyl-S-2-(methylthio)ethyl.
[0183] Cyclic Monothio Acetals and Ketals
[0184] Examples of cyclic monothio acetals and ketals include
1,3-oxathiolanes.
[0185] Miscellaneous Derivatives
[0186] O-Substituted Cyanohydrins
[0187] Examples of O-substituted cyanohydrins include O-acetyl,
O-trimethylsilyl, O-1-ethoxyethyl and O-tetrahydropyranyl.
[0188] Substituted Hydrazones
[0189] Examples of substituted hydrazones include N,N-dimethyl and
2,4-dinitrophenyl.
[0190] Oxime Derivatives
[0191] Examples of oxime derivatives include O-methyl, O-benzyl and
O-phenylthiomethyl.
[0192] Imines
[0193] Substituted Methylene Derivatives, Cyclic Derivatives
[0194] Examples of substituted methylene and cyclic derivatives
include oxazolidines, 1-methyl-2-(1'-hydroxyalkyl)imidazoles,
N,N'-dimethylimidazolidines, 2,3-dihydro-1,3-benzothiazoles,
diethylamine adducts, and methylaluminum
bis(2,6-di-t-butyl-4-methylphenoxide)(MAD)complex.
[0195] Monoprotection of Dicarbonyl Compounds
[0196] Selective Protection Of .alpha.- and .beta.-Diketones
[0197] Examples of selective protection of .alpha.- and
.beta.-diketones include enamines, enol acetates, enol ethers,
methyl, ethyl, i-butyl, piperidinyl, morpholinyl,
4-methyl-1,3-dioxolanyl, pyrrolidinyl, benzyl, S-butyl, and
trimethylsilyl.
[0198] Cyclic Ketals, Monothio and Dithio Ketals
[0199] Examples of cyclic ketals, monothio and dithio ketals
include bismethylenedioxy derivatives and
tetramethylbismethylenedioxy derivatives.
[0200] Protection for the Carboxyl Group
[0201] Esters
[0202] Substituted Methyl Esters
[0203] Examples of substituted methyl esters include
9-fluorenylmethyl, methoxymethyl, methylthiomethyl,
tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl,
2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, phenacyl,
p-bromophenacyl, .alpha.-methylphenacyl, p-methoxyphenacyl,
carboxamidomethyl, and N-phthalimidomethyl.
[0204] 2-Substituted Ethyl Esters
[0205] Examples of 2-substituted ethyl esters include
2,2,2-trichloroethyl,
[0206] 2-haloethyl, .omega.-chloroalkyl, 2-(trimethylsilyl)ethyl,
2-methylthioethyl, 1,3-dithianyl-2-methyl,
2-(p-nitrophenylsulfenyl)ethyl, 2-(p-toluenesulfonyl)ethyl,
[0207] 2-(2'-pyridyl)ethyl, 2-(diphenylphosphino)ethyl,
1-methyl-1-phenylethyl, t-butyl, cyclopentyl, cyclohexyl, allyl,
3-buten-1-yl, 4-(trimethylsilyl)-2-buten-1-yl, cinnamyl,
.alpha.-methylcinnamyl, phenyl, p-(methylmercapto)phenyl and
benzyl.
[0208] Substituted Benzyl Esters
[0209] Examples of substituted benzyl esters include
triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl,
9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl, 5-dibenzosuberyl,
1-pyrenylmethyl, 2-(trifluoromethyl)-6-chromylmethyl,
2,4,6-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl,
p-methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl,
4-sulfobenzyl, piperonyl, 4-picolyl and p-P-benzyl.
[0210] Silyl Esters
[0211] Examples of silyl esters include trimethylsilyl,
triethylsilyl, t-butyldimethylsilyl, i-propyldimethylsilyl,
phenyldimethylsilyl and di-t-butylmethylsilyl.
[0212] Activated Esters
[0213] Examples of activated esters include thiols.
[0214] Miscellaneous Derivatives
[0215] Examples of miscellaneous derivatives include oxazoles,
2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines,
5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group and
pentaaminocobalt(III) complex.
[0216] Stannyl Esters
[0217] Examples of stannyl esters include triethylstannyl and
tri-n-butylstannyl.
[0218] Amides and Hydrazides
[0219] Amides
[0220] Examples of amides include N,N-dimethyl, pyrrolidinyl,
piperidinyl, 5,6-dihydrophenanthridinyl, o-nitroanilides,
N-7-nitroindolyl, N-8-Nitro-1,2,3,4-tetrahydroquinolyl, and
p-P-benzenesulfonamides.
[0221] Hydrazides
[0222] Examples of hydrazides include N-phenyl and
N,N'-diisopropyl.
[0223] The compounds of the invention can be prepared according to
the methods described in the next section.
C. Synthesis
[0224] The compounds of the invention can be prepared according to
traditional synthetic organic methods and matrix or combinatorial
chemistry methods, as shown in Schemes 1-10 below and in Examples
1-97. A person of ordinary skill will be aware of variations and
adaptations of the schemes and examples provided to achieve the
compounds of the invention.
[0225] One skilled in the art will recognize that synthesis of the
compounds of the present invention may be effected by purchasing
intermediate or protected intermediate compounds described in any
of the Schemes disclosed herein. Throughout the schemes when the
reacting functionality is located at R.sub.3, one skilled in the
art will recognize that the choice of R.sub.3 is illustrative only
and that the reacting functionality could also be located at
R.sub.1 and R.sub.2 also.
[0226] One skilled in the art will further recognize that during
any of the processes for preparation of the compounds of the
present invention, it may be necessary and/or desirable to protect
sensitive or reactive groups on any of the molecules concerned.
This may be achieved by means of conventional protecting groups,
such as those described in "Protective Groups in Organic
Chemistry", ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.
Greene & P. G. M. Wuts, "Protective Groups in Organic
Synthesis", John Wiley & Sons, 1991. The protecting groups may
be removed at a convenient subsequent stage using methods known
from the art.
[0227] Compounds of formula (I) may be prepared according to the
process outlined in Scheme 1.
##STR00006##
[0228] Generally, a compound of formula (II), a known compound or
compound prepared by known methods is reacted in Step A to form the
compound of formula (IV) and then reacted in Step B to form the
compound of formula (I). Alternatively, the compound of formula
(II) is reacted with a compound of formula (VI) in Step C to form
the compound of formula (I). Specifically, a compound of formula
(II), wherein R.sub.1, R.sub.2, R.sub.3 are as defined is reacted
with a compound of formula (III) where X.sub.1 and X.sub.2 are each
independently selected from the group consisting Cl, Br, I,
tosylate, mesylate, and the like wherein X.sub.1 is selected such
that under the reaction conditions, X.sub.1 is preferentially
displaced (rather than X.sub.2; i.e. such that the compound of
formula (III) is selectively coupled in terms of which end of the
molecule is bonded to the compound of formula (II)), in the
presence of a base such as sodium hydroxide, TEA, sodium hydride,
potassium carbonate, and the like, in an organic solvent such as
DCM, THF, DMF, DMA, and the like, to yield the corresponding
compound of formula (IV). The compound of formula (IV) is reacted
with a compound of formula (V), in the presence of a base such as
sodium hydroxide, TEA, potassium carbonate, and the like, in an
organic solvent such as DCM, THF, DMF, and the like, to yield the
corresponding compound of formula (I).
[0229] In an alternative embodiment a compound of formula (II) may
be reacted with a compound of formula (VI) where X.sub.1 is as
defined, in the presence of a base such as sodium hydroxide, TEA,
sodium hydride, potassium carbonate, and the like, in an organic
solvent such as DCM, THF, DMF, DMA, and the like, to yield the
corresponding compound of formula (I).
[0230] In a further alternative embodiment a compound of formula
(II) is reacted with a compound formula (III), or a compound of
formula (VI) in which X.sub.1 is OH, under Mitsunobu conditions,
(in the presence of triphenylphosphine or polymer supported
triphenyl phosphine and DBAD or DEAD, in an organic solvent such as
DCM, THF, and the like), to yield the corresponding compounds of
formula (IV) or (I).
##STR00007##
[0231] A compound of formula (VIII) may be prepared according to
the process outlined in Scheme 2. More particularly, a compound of
formula (I), wherein R.sub.3 is --COR.sub.5 is reacted with an
amine of formula (VII), in the presence of a reducing agent such as
sodium borohydride, sodium cyanoborohydride, sodium
triacetoxyborohydride, hydrogen gas in the presence of a catalyst,
and the like, in a solvent such as methanol, ethanol,
1,2-dichloroethane, trifluoroethanol, and the like, to yield the
compound of formula (VIII). One skilled in the art will recognize
that addition of acid to decrease the pH of the reaction mixture to
a pH of less than about 7 may be necessary to effect the reaction,
wherein the acid is added as needed. Examples of appropriate acids
include acetic acid, hydrochloric acid, and the like. When R.sub.20
is H, the compound of formula (VII) is preferably reacted with a
reducing agent such as sodium cyanoborohydride or sodium
triacetoxyborohydride.
[0232] In an alternative embodiment, a compound of formula (VIII)
may be prepared according to the processes outlined in Scheme
3.
##STR00008##
[0233] A compound of formula (II) wherein R.sub.3 is --COR.sub.20
is reacted with a compound of formula (VII) according to the
procedures of Scheme 2 to afford a compound of formula (IX) which
is further reacted according to the procedures of Scheme 1, either
Steps A and B or Step C, to afford a compound of formula
(VIII).
[0234] Scheme 4 provides guidance for the preparation of compounds
of formula (XV) and (XVI) where Z can be substituted or
unsubstituted phenyl or heterocycle and W is absent or
--COR.sub.20, or --OY, where Y is a protecting group. Preferred
compounds are those in which Z is substituted phenyl, thienyl,
pyridinyl, pyrimidinyl or pyrrolyl.
##STR00009##
[0235] A compound of formula (II) or (I) is reacted with a compound
of formula (XI) in the presence of a catalyst such as
tetrakis(triphenylphosphine) palladium (0), and the like, in the
presence of a base such as sodium carbonate, potassium carbonate,
and the like, in an organic solvent such as toluene, benzene,
xylene, and the like, to yield the corresponding compounds of
formula (XII) and (XIII) respectively. A compound of formula (XIII)
wherein W is --COR.sub.20 is reacted with a compound of formula
(VII) according to the procedures of Scheme 2 to afford a compound
of formula (XVI). Alternatively a compound of formula (XV) may be
prepared from a compound of formula (XIII) wherein W is --OY. The
protecting group Y is first removed under the appropriate
conditions to afford the corresponding hydroxyl compound which is
reacted with a compound of formula (XIV), wherein X.sub.1 is as
defined, under the conditions described for Step A, Scheme 1, to
afford a compound of formula (XV).
##STR00010##
[0236] Compounds of formula (XXI) may be prepared according to the
processes outlined in Scheme 5. A compound of formula (XII) where Y
is a protecting group and R.sub.3 is a halogen, preferably Br or I,
more preferably I, is reacted with an organolithium reagent such as
n-butyllithium in an organic solvent such as THF, diethyl ether and
the like, and then reacted with a compound of formula (XVII) to
afford a compound of formula (XVIII). The compound of formula
(XVIII) is then reacted with a reducing agent such as sodium
borohydride or sodium cyanoborohydride, and the like, in the
presence of an acid such as TFA, HCl or acetic acid in an organic
solvent such as THF or diethyl ether to yield the corresponding
compound of formula (XIX). Alternatively the compound of formula
(XVIII) may be reacted with hydrogen in the presence of a catalyst
such as palladium on carbon or triethylsilane in the presence of
TFA to yield a compound of formula (XIX). A compound of formula
(XX) may be obtained upon removal of the protecting group Y from
the compound of formula (XIX) followed by reaction under the
conditions described in Scheme 1. A compound of formula (XXI) may
be obtained from a compound of formula (XX) via removal of the
group Y.sub.2. One skilled in the art will recognize that in this
Scheme both Y and Y.sub.2 may be protecting groups. One skilled in
the art will further recognize and understand the concept of
orthogonal protection such that the groups Y and Y.sub.2 may be
removed separately and at the appropriate points in the synthetic
procedure. The compound of formula (XXI) may also be reacted
further via the procedures of Scheme 2 (reductive amination) or via
N-alkylation with a compound of formula (XIVa) to afford a compound
of formula (XXII).
[0237] Compounds of formula (XXVII) may be prepared according to
the processes outlined in Scheme 6. Thus a compound of formula
(XII) where R.sub.3 is selected from Br and I, and is preferably I,
is reacted with a compound of formula (XXIII) in the presence of a
catalyst such as tris(dibenzylidineacetone)dipalladium(0), and the
like, in the presence of a base such as sodium t-butoxide, cesium
carbonate, triethylamine, potassium carbonate, and the like, in an
organic solvent such as THF or dioxane, and the like, preferably in
the presence of BINAP (2,2'-bis(diphenylphosphino)-1,1'-dinaphthyl)
and 18-Crown-6 (a crown ether), to yield the corresponding compound
of formula (XXIV).
##STR00011##
[0238] A compound of formula (XXV) may be obtained upon removal of
the protecting group Y from the compound of formula (XXIV) followed
by reaction under the conditions described in Scheme 1. A compound
of formula (XXVI) may be obtained from a compound of formula (XXV)
via removal of the group Y.sub.2. The compound of formula (XXVI)
may also be reacted further via the procedures of Scheme 2
(reductive amination) or via N-alkylation with a compound of
formula (XIVa) to afford a compound of formula (XXVII).
[0239] In an alternative embodiment a compound of formula (XXVI)
may be obtained from a compound of formula (XXVIII) according to
the processes outlined in Scheme 7. A compound of formula (XXVIII)
where R.sub.10 is H is reacted with an alkyl chloroformate or
dialkyldicarbonate and the like if necessary in the presence of an
amine base to yield the corresponding compound of formula (XXIX)
where Y represents a carbamate protecting group. In a preferred
embodiment the chloroformate is ethylchloroformate,
benzylchloroformate, 2,2,2-trichloroethylchloroformate,
alpha-chloroethylchloroformate and the dialkyldicarbonate is
di-tert-butyldicarbonate. A particularly preferred embodiment uses
di-tert-butyldicarbonate. The compound of formula (XXIX) is reacted
according to the procedures of Scheme 1 to afford compound (XXX)
whereupon removal of the carbamate protecting group affords
compound of formula (XXVI). In a preferred embodiment a tert-butyl
carbamate is removed under acidic conditions using TFA or HCl in a
solvent, for example TFA in DCM or HCl in ether.
##STR00012##
[0240] Compounds of formula (XXXV) may be prepared according to the
procedures outlined in Scheme 8. Compounds of formula (XXXI) are
reacted according to the processes outlined in Scheme 1 to give
compounds of formula (XXXII). Removal of the protecting group Y
affords compound of formula (XXXIII). In a preferred embodiment the
group Y is a benzyl group, thus the compound of formula (XXXII) is
reacted with with hydrogen gas or ammonium formate, in the presence
of a catalyst such as palladium on carbon, and the like, in a
solvent such as methanol, ethanol, and the like, (i.e. catalytic
hydrogenolysis) to yield the corresponding compound of formula
(XXXIII). The compound of formula (XXXIII) is reacted with a
compound of formula (XXXIV) to afford a compound of formula (XXXV).
Thus the compound of formula (XXXIII) is reacted with a compound of
formula (XXXIV) under Mitsunobu conditions, (in the presence of
triphenylphosphine or polymer supported triphenyl phosphine and
DBAD or DEAD, in an organic solvent such as DCM, THF, and the
like), to yield the corresponding compound of formula (XXXV).
##STR00013##
[0241] In a particular embodiment of Scheme 8, illustrated in
Scheme 9, the compound of formula (XXXVI) may be prepared via a
double Mitsunobu reaction between a compound of formula (XXXVII)
and a compound of formula (XXXIV). Thus the compound of formula
(XXXVII) is reacted with a compound of formula (XXXIV) under
Mitsunobu conditions, (in the presence of triphenylphosphine or
polymer supported triphenyl phosphine and DBAD or DEAD, in an
organic solvent such as DCM, THF, and the like), to yield the
corresponding compound of formula (XXXVI).
##STR00014##
##STR00015##
[0242] Compounds of formula (XXXVIII) are prepared as outlined in
Scheme 10, by reacting compounds of formula (XL), prepared as
outlined in Scheme 4, with a compound of formula (XLI) to afford a
compound of formula (XLII). The compound of formula (XLII) may be
reacted further to give a compound of formula (XXXVIII). In a
particular embodiment compound of formula (XXXIX) contains the
protecting group Y which is removed to afford a compound of formula
(XL). The compound of formula (XL) is reacted with a compound of
formula (XLI) in the presence of a base to yield a compound of
formula (XLII). In a preferred embodiment the compound of formula
(XLI) contains NY where NY is
2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane. The protecting
group Y of the compound of formula (XXXXII) is removed and the
primary amine product reacted via alkylation or reductive amination
to afford compound of formula (XXXVIII). In an alternative
embodiment a compound of formula (XXXVIII) may be prepared from a
compound of formula (XL) according to the procedures outlined in
Scheme 1.
D. Formulation, Administration, and Therapy
[0243] The disclosed compounds, alone or in combination (with, for
example, a histamine H.sub.1 receptor antagonist), are useful for
treating or preventing neurologic disorders including sleep/wake
and arousal/vigilance disorders (e.g. insomnia and jet lag),
attention deficit hyperactivity disorders (ADHD), learning and
memory disorders, cognitive dysfunction, migraine, neurogenic
inflammation, dementia, mild cognitive impairment (pre-dementia),
Alzheimer's disease, epilepsy, narcolepsy, eating disorders,
obesity, motion sickness, vertigo, schizophrenia, substance abuse,
bipolar disorders, manic disorders and depression, as well as other
histamine H.sub.3 receptor mediated disorders such as upper airway
allergic response, asthma, itch, nasal congestion and allergic
rhinitis in a subject in need thereof.
[0244] 1. Formulation and Administration
[0245] The compounds or compositions of the invention may be
formulated and administered to a subject by any conventional route
of administration, including, but not limited to, intravenous,
oral, subcutaneous, intramuscular, intradermal and parenteral
administration. The quantity of the compound which is effective for
treating each condition may vary, and can be determined by one of
ordinary skill in the art.
[0246] For use in medicine, the salts of the compounds of this
invention refer to non-toxic "pharmaceutically acceptable salts."
Other salts may, however, be useful in the preparation of compounds
according to this invention or of their pharmaceutically acceptable
salts. Suitable pharmaceutically acceptable salts of the compounds
include acid addition salts which may, for example, be formed by
mixing a solution of the compound with a solution of a
pharmaceutically acceptable acid such as hydrochloric acid,
sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic
acid, benzoic acid, citric acid, tartaric acid, carbonic acid or
phosphoric acid. Furthermore, where the compounds of the invention
carry an acidic moiety, suitable pharmaceutically acceptable salts
thereof may include alkali ml salts, e.g., sodium or potassium
salts; alkaline earth ml salts, e.g., calcium or magnesium salts;
and salts formed with suitable organic ligands, e.g., quaternary
ammonium salts.
[0247] Thus, representative pharmaceutically acceptable salts
include the following: acetate, benzenesulfonate, benzoate,
bicarbonate, bisulfate, bitartrate, borate, bromide, calcium
edetate, camsylate, carbonate, chloride, clavulanate, citrate,
dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,
gluceptate, gluconate, glutamate, glycollylarsanilate,
hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,
hydroxynaphthoate, iodide, isothionate, lactate, lactobionate,
laurate, malate, maleate, mandelate, mesylate, methylbromide,
methylnitrate, methylsulfate, mucate, napsylate, nitrate,
N-methylglucamine ammonium salt, oleate, pamoate (embonate),
palmitate, pantothenate, phosphate/diphosphate, polygalacturonate,
salicylate, stearate, sulfate, subacetate, succinate, tannate,
tartrate, teoclate, tosylate, triethiodide and valerate.
[0248] The present invention includes within its scope prodrugs of
the compounds of this invention. In general, such prodrugs will be
functional derivatives of the compounds which are readily
convertible in vivo into the required compound. Thus, in the
methods of treatment of the present invention, the term
"administering" shall encompass the treatment of the various
disorders described with the compound specifically disclosed or
with a compound which may not be specifically disclosed, but which
converts to the specified compound in vivo after administration to
the patient. Conventional procedures for the selection and preption
of suitable prodrug derivatives are described, for example, in
"Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. In addition
to salts, the invention provides the esters, amides, and other
protected or derivatized forms of the described compounds.
[0249] Where the compounds according to this invention have at
least one chiral center, they may accordingly exist as enantiomers.
Where the compounds possess two or more chiral centers, they may
additionally exist as diastereomers. It is to be understood that
all such isomers and mixtures thereof are encompassed within the
scope of the present invention. Furthermore, some of the
crystalline forms for the compounds may exist as polymorphs and as
such are intended to be included in the present invention. In
addition, some of the compounds may form solvates with water (i.e.,
hydrates) or common organic solvents, and such solvates are also
intended to be encompassed within the scope of this invention.
[0250] The present invention also provides pharmaceutical
compositions comprising one or more compounds of this invention in
association with a pharmaceutically acceptable carrier and
optionally additional pharmaceutical agents such as H.sub.1
antagonists or SSRIs. Preferably these compositions are in unit
dosage forms such as pills, tablets, caplets, capsules (each
including immediate release, timed release and sustained release
formulations), powders, granules, sterile parenteral solutions or
suspensions (including syrups and emulsions), metered aerosol or
liquid sprays, drops, ampoules, autoinjector devices or
suppositories; for oral parenteral, intranasal, sublingual or
rectal administration, or for administration by inhalation or
insufflation. Alternatively, the composition may be presented in a
form suitable for once-weekly or once-monthly administration; for
example, an insoluble salt of the active compound, such as the
decanoate salt, may be adapted to provide a depot preparation for
intramuscular injection. For preparing solid compositions such as
tablets, the principal active ingredient is mixed with a
pharmaceutical carrier, e.g. conventional tableting ingredients
such as corn starch, lactose, sucrose, sorbitol, talc, stearic
acid, magnesium stearate, dicalcium phosphate or gums, and other
pharmaceutical diluents, e.g. water, to form a solid preformulation
composition containing a homogeneous mixture of a compound of the
present invention, or a pharmaceutically acceptable salt thereof.
When referring to these preformulation compositions as homogeneous,
it is meant that the active ingredient is dispersed evenly
throughout the composition so that the composition may be readily
subdivided into equally effective dosage forms such as tablets,
pills and capsules. This solid preformulation composition is then
subdivided into unit dosage forms of the type described above
containing from 5 to about 1000 mg of the active ingredient of the
present invention. Examples include 5 mg, 7 mg, 10 mg, 15 mg, 20
mg, 35 mg, 50 mg, 75 mg, 100 mg, 120 mg, 150 mg, and so on. The
tablets or pills of the disclosed compositions can 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 septed by an enteric layer which serves to resist
disintegration in the stomach and permits the inner component to
pass intact into the duodenum or to be delayed in release. A
variety of material can be used for such enteric layers or
coatings, such materials including a number of polymeric acids with
such materials as shellac, cetyl alcohol and cellulose acetate.
[0251] The liquid forms in which the compounds and compositions of
the present invention may be incorporated for administration orally
or by injection include, aqueous solutions, suitably flavoured
syrups, aqueous or oil suspensions, and flavoured emulsions with
edible oils such as cottonseed oil, sesame oil, coconut oil or
peanut oil, as well as elixirs and similar pharmaceutical vehicles.
Suitable dispersing or suspending agents for aqueous suspensions,
include synthetic and natural gums such as tragacanth, acacia,
alginate, dextran, sodium carboxymethylcellulose, methylcellulose,
polyvinyl-pyrrolidone or gelatin.
[0252] Where the processes for the preparation of the compounds
according to the invention give rise to mixture of stereoisomers,
these isomers may be separated by conventional techniques such as
preparative chromatography. The compounds may be prepared in
racemic form, or individual enantiomers may be prepared either by
enantiospecific synthesis or by resolution. The compounds may, for
example, be resolved into their component enantiomers by standard
techniques, such as the formation of diastereomeric pairs by salt
formation with an optically active acid, such as
(-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric
acid followed by fractional crystallization and regeneration of the
free base. The compounds may also be resolved by formation of
diastereomeric esters or amides, followed by chromatographic
separation and removal of the chiral auxiliary. Alternatively, the
compounds may be resolved using a chiral HPLC column.
[0253] Advantageously, compounds of the present invention may be
administered in a single daily dose, or the total daily dosage may
be administered in divided doses of two, three or four times daily.
Furthermore, compounds for the present invention can be
administered in intranasal form via topical use of suitable
intranasal vehicles, or via transdermal skin patches well known to
those of ordinary skill in that art. To be administered in the form
of a transdermal delivery system, the dosage administration will,
of course, be continuous rather than intermittent throughout the
dosage regimen.
[0254] For instance, for oral administration in the form of a
tablet or capsule, the active drug component can be combined with
an oral, non-toxic pharmaceutically acceptable inert carrier such
as ethanol, glycerol, water and the like. Moreover, when desired or
necessary, suitable binders, lubricants, disintegrating agents and
coloring agents can also be incorporated into the mixture. Suitable
binders include, without limitation, starch, gelatin, natural
sugars such as glucose or beta-lactose, corn sweeteners, natural
and synthetic gums such as acacia, tragacanth or sodium oleate,
sodium stearate, magnesium stearate, sodium benzoate, sodium
acetate, sodium chloride and the like. Disintegrators include,
without limitation, starch, methyl cellulose, agar, bentonite,
xanthan gum and the like.
[0255] The compound of the present invention can also be
administered in the form of liposome delivery systems, such as
small unilamellar vesicles, large unilamellar vesicles, and
multilamellar vesicles. Liposomes can be formed from a variety of
phospholipids, such as cholesterol, stearylamine or
phophatidylcholines.
[0256] Compounds of the present invention may also be delivered by
the use of monoclonal antibodies as individual carriers to which
the compound molecules are coupled. The compounds of the present
invention may also be coupled with soluble polymers as targetable
drug carriers. Such polymers can include polyvinylpyrrolidone,
pyran copolymer, polyhydroxypropylmethacrylamidephenol,
polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine
substituted with palmitoyl residue. Furthermore, the compounds of
the present invention may be coupled to a class of biodegradable
polymers useful in achieving controlled release of a drug, for
example, polylactic acid, polyepsilon caprolactone, polyhydroxy
butyric acid, polyoesters, polyacetals, polydihydropyrans,
polycyanoacrylates and cross-linked or amphipathic block copolymers
of hydrogels.
[0257] Compounds of this invention may be administered in any of
the foregoing compositions and according to dosage regimens
established in the art whenever treatment of ADHD is required.
[0258] The daily dosage of the products may be varied over a wide
range from 1 to 1,000 mg per adult human per day. For oral
administration, the compositions are preferably provided in the
form of tablets containing 1.0, 5.0, 10.0, 15.0, 25.0, 50.0, 100,
250 and 500 milligrams of the active ingredient for the symptomatic
adjustment of the dosage to the subject to be treated. An effective
amount of the drug is ordinarily supplied at a dosage level of from
about 0.01 mg/kg to about 20 mg/kg of body weight per day.
Preferably, the range is from about 0.02 mg/kg to about 10 mg/kg of
body weight per day, and especially from about 0.05 mg/kg to about
10 mg/kg of body weight per day. The compounds may be administered
on a regimen of 1 to 4 times per day.
[0259] Optimal dosages to be administered may be readily determined
by those skilled in the art, and will vary with the particular
compound used, the mode of administration, the strength of the
preparation, the mode of administration, and the advancement of the
disease condition. In addition, factors associated with the
particular patient being treated, including patient age, weight,
diet and time of administration, will result in the need to adjust
dosages.
[0260] 2. Combination Therapy
[0261] The disclosed compounds are useful in combination with other
therapeutic agents, including H.sub.1 receptor antagonists, H.sub.2
receptor antagonists, and neurotransmitter modulators such as SSRIs
and non-selective serotonin re-uptake inhibitors (NSSRIs).
[0262] Methods are known in the art for determining effective doses
for therapeutic and prophylactic purposes for the disclosed
pharmaceutical compositions or the disclosed drug combinations,
whether or not formulated in the same composition. For therapeutic
purposes, the term "jointly effective amount" as used herein, means
that amount of each active compound or pharmaceutical agent, alone
or in combination, that elicits the biological or medicinal
response in a tissue system, animal or human that is being sought
by a researcher, veterinarian, medical doctor or other clinician,
which includes alleviation of the symptoms of the disease or
disorder being treated. For prophylactic purposes (i.e., inhibiting
the onset or progression of a disorder), the term "jointly
effective amount" refers to that amount of each active compound or
pharmaceutical agent, alone or in combination, that inhibits in a
subject the onset or progression of a disorder as being sought by a
researcher, veterinarian, medical doctor or other clinician, the
delaying of which disorder is mediated, at least in part, by the
modulation of one or more histamine receptors. Thus, the present
invention provides combinations of two or more drugs wherein, for
example, (a) each drug is administered in an independently
therapeutically or prophylactically effective amount; (b) at least
one drug in the combination is administered in an amount that is
sub-therapeutic or sub-prophylactic if administered alone, but is
therapeutic or prophylactic when administered in combination with
the second or additional drugs according to the invention; or (c)
both drugs are administered in an amount that is sub-therapeutic or
sub-prophylactic if administered alone, but are therapeutic or
prophylactic when administered together. Combinations of three or
more drugs are analogously possible. Methods of combination therapy
include co-administration of a single formulation containing all
active agents; essentially contemporaneous administration of more
than one formulation; and administration of two or more active
agents separately formulated.
E. Examples
Example 1
##STR00016##
[0263] 3-Piperidin-1-yl-propan-1-ol
[0264] A solution of potassium carbonate (24.9 g) and piperidine
(130 mL) in 1:1 ethanol-water (130 mL) was treated with
3-bromopropan-1-ol (25.0 g). The resulting mixture was stirred
vigorously for 20 h. Dichloromethane (200 mL) and water (50 mL)
were added and the aqueous phase was extracted with dichloromethane
(2.times.100 mL). The combined organic extracts were dried
(magnesium sulfate) and evaporated in vacuo. Kugelrohr distillation
of the residue (5-10 mm Hg, 120.degree. C.) gave the title compound
as a colorless oil (13.9 g).
Example 2
##STR00017##
[0265] 1-(3-Chloro-propoxy)-4-iodo-benzene
[0266] A suspension of 4-iodophenol (20 g), 1-bromo-3-chloropropane
(18 mL), and potassium carbonate (38 g) in acetone (250 mL) was
heated at reflux for 16 h and allowed to cool to room temperature.
The suspension was filtered, and the filtrate was evaporated in
vacuo. Kugelrohr distillation of the residue (5-10 mm Hg,
210.degree. C.) gave the title compound as a white crystalline
solid (22 g).
Example 3
##STR00018##
[0267] 4-(4-Hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl
ester
[0268] To a solution of 1-(4-hydroxyphenyl)piperazine (12.0 g) in
tetrahydrofuran (50 mL) was added dropwise a solution of di-tert
butyl dicarbonate (72 ml of a 1M solution). Saturated aqueous
sodium bicarbonate (60 ml) was added and the resulting mixture was
stirred at room temperature for 16 h. The reaction was extracted
with ethyl acetate (700 ml). The organic phase was washed with
water (50 ml), brine (5 ml), and dried (magnesium sulfate). Solvent
was removed in vacuo and the residue was triturated with hexanes,
giving the title compound as a brown solid (16.3 g).
Example 4
##STR00019##
[0269] 4-[4-(3-Chloro-propoxy)-phenyl]-piperazine-1-carboxylic acid
tert-butyl ester
[0270] A suspension of tert-butyl 1-(4-(4-hydroxy)phenyl)piperazine
carboxylate (5.0 g), 1-bromo-3-chloropropane (3.6 mL), and
potassium carbonate (7.4 g) in acetone (60 mL) was heated at reflux
for 24 h and allowed to cool to room temperature. The suspension
was filtered, and the filtrate was evaporated in vacuo. Silica gel
chromatography of the residue (30% ethyl acetate/hexane) gave the
title compound as a light yellow solid (5.3 g).
Example 5
##STR00020##
[0271] 1-[3-(4-Iodo-phenoxy)-propyl]-piperidine
[0272] A suspension of 4-(3-chloro-1-propoxy)iodobenzene (5 g),
piperidine (2.2 mL), sodium carbonate (2.7 g), and potassium iodide
(140 mg) in n-butanol (30 mL) was heated in a 105.degree. C. bath
for 18 h. The resulting mixture was allowed to cool to room
temperature, diluted with water (50 mL), and extracted with
methylene chloride (2.times.20 mL). The combined organic phases
were dried (magnesium sulfate), and evaporated in vacuo. Kugelrohr
distillation of the residue (5 mm Hg, 260.degree. C.) gave the
title compound as a white crystalline solid (4.8 g).
Example 6
##STR00021##
[0273] 1-[3-(4-Benzyloxy-phenoxy)-propyl]-piperidine
[0274] A suspension of 4-benzyloxyphenol (30 g),
1-bromo-3-chloropropane (30 mL) and potassium carbonate (62 g) in
acetone (400 mL) was heated at reflux for 25 h and allowed to cool
to room temperature. The suspension was filtered, and the filtrate
was evaporated in vacuo. Recrystallization of the residue (hexanes)
gave fine needles (29 g). A suspension of this material (32 g),
piperidine (14.8 mL), sodium carbonate (18.3 g), and potassium
iodide (95 mg) in n-butanol (140 mL) was heated in a 105.degree. C.
bath for 28 h. The resulting mixture was allowed to cool to room
temperature, diluted with water (100 mL), and extracted with
methylene chloride (3.times.100 mL). The combined organic phases
were dried (magnesium sulfate), and evaporated in vacuo.
Recrystallization of the residue (ethanol) gave the title compound
as a white crystalline solid (29 g).
Example 7
##STR00022##
[0275]
4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-piperazine-1-carboxylic
acid tert-butyl ester
[0276] A suspension of the product of Example 4 (1.0 g),
pyrrolidine (435 mg), sodium carbonate (297 mg), and potassium
iodide (9.3 mg) in n-butanol (5 mL) was heated in a 100.degree. C.
bath for 16 h. The resulting mixture was allowed to cool to room
temperature, and filtered through celite. The filtrate evaporated
in vacuo. Silica gel chromatography of the residue (5% 2M
ammonia-methanol/dichloromethane) gave the title compound as a
yellow solid (900 mg).
Example 8
##STR00023##
[0277]
4-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-piperazine-1-carboxylic
acid tert-butyl ester
[0278] A suspension of the product of Example 4 (3.0 g), piperidine
(1.4 g), sodium carbonate (900 mg), and potassium iodide (28 mg) in
n-butanol (15 mL) was heated in a 100.degree. C. bath for 16 h. The
resulting mixture was allowed to cool to room temperature, and
filtered through celite. The filtrate evaporated in vacuo. Silica
gel chromatography of the residue (5% 2M methanolic
ammonia/dichloromethane) gave the title compound as a brown solid
(2.3 g).
Example 9
##STR00024##
[0279] 4-(3-Piperidin-1-yl-propoxy)-benzaldehyde
[0280] A solution the product of Example 11 (10 g), piperidine (6.5
mL), sodium carbonate (8.1 g), and potassium iodide (422 mg) in
1-butanol (60 mL) was heated to 105.degree. C. for 18 h, cooled to
RT, diluted with water (50 mL) and extracted with DCM (3.times.50
mL). The combined organic phases were dried (magnesium sulfate) and
evaporated, giving the title compound as a yellow oil (11.5 g).
Example 10
##STR00025##
[0281] 3-(3-Chloro-propoxy)-benzaldehyde
[0282] A suspension of 3-hydroxybenzaldenyde (25.0 g),
1-bromo-3-chloropropane (30.4 mL) and potassium carbonate (50.9 g)
in acetone (300 mL) was heated under reflux. After 16 h, the
resulting mixture was cooled to RT and filtered through a pad of
celite. The pad was washed with acetone (3.times.20 mL). The
combined filtrates were concentrated. Chromatography of the residue
(15-25% ethyl acetate/hexane) gave the title compounds as a yellow
oil (14.2 g).
Example 11
##STR00026##
[0283] 4-(3-Chloro-propoxy)-benzaldehyde
[0284] A suspension of 4-hydroxybenzaldehyde (40 g),
1-bromo-3-chloropropane (63 mL), and potassium carbonate (136 g) in
acetone (920 mL) was heated to reflux for 16 h. The resulting
mixture was filtered, and the filtrate was evaporated. Distillation
of the residue (0.5 mm Hg, 220.degree. C.) gave the title compound
as a pale yellow oil that crystallized on standing (46 g).
Example 12
##STR00027##
[0285] 1-[4-(3-Chloro-propoxy)-benzyl]-piperidine
[0286] A solution of the product of Example 11 (5.0 g), piperidine
(3.1 mL), and acetic acid (2.0 mL) in DCE (100 mL) was treated with
sodium triacetoxyborohydride (9.3 g). After 16 h, the resulting
mixture was diluted with water (100 mL) and extracted with DCM
(3.times.50 mL). The combined organic phases were dried (magnesium
sulfate) and evaporated, giving the title compound as an amber oil
(5.3 g).
Example 13
##STR00028##
[0287] 3-(3-Piperidin-1-yl-propoxy)-benzaldehyde
[0288] A suspension of the product of Example 10 (4.16 g),
potassium carbonate (5.52 g) and piperidine (5.0 mL) in DMF (25.0
mL) was heated to 80.degree. C. for 12 h. The resulting mixture was
poured into water (400 mL) and extracted with ethyl acetate
(3.times.50 mL) and the combined extracts were dried over sodium
sulfate. Chromatography of the residue (1 to 10% 2M methanolic
ammonia/DCM) gave the title compound as a yellow oil (3.14 g).
Example 14
##STR00029##
[0289] 2-(3-Piperidin-1-yl-propoxy)-benzaldehyde
[0290] A suspension of 2-hydroxybenzaldenyde (5.43 g),
1-bromo-3-chloropropane (6.5 mL) and potassium carbonate (13.11 g)
in acetone (100 mL) was heated under reflux. After 16 h, the
resulting mixture was cooled to RT and poured into water (400 mL)
and extracted with ether (3.times.100 mL). The organics were washed
with water (3.times.50 mL) and 1M NaOH (2.times.50 mL) and brine.
The combined filtrates were concentrated. The excess
1-bromo-3-chloropropane was removed by distillation (80.degree. C.,
2 mm Hg) to give 1-(3-chloro-propoxy)-benzaldehyde as a yellow oil
(8.80 g). A suspension of this material (4.81 g), potassium
carbonate (5.04 g) and piperidine (5.0 mL) in DMF (5.0 mL) was then
heated to 80.degree. C. for 12 h. The resulting mixture was poured
into water (400 mL) and extracted with DCM (3.times.50 mL) and the
combined extracts were dried over sodium sulfate. Chromatography of
the residue (1-10% 2M methanolic ammonia/DCM) gave the title
compound as a yellow oil (1.53 g).
Example 15
##STR00030##
[0291] 4-(3-Piperidin-1-yl-propoxy)-phenol
[0292] A suspension of the product of Example 6 (2.5 g), ammonium
formate (2.7 g), and 10% palladium on carbon (2.5 g) in methanol
(100 mL) was heated in a 68.degree. C. bath for 3 h, and allowed to
cool to room temperature. The mixture was filtered through Celite,
and the filtrate was evaporated in vacuo. Saturated aqueous sodium
bicarbonate was added, and the mixture was extracted with
dichloromethane (4.times.30 mL). The combined organic phases were
dried (magnesium sulfate) and evaporated in vacuo, yielding the
title compound as a pink microcrystalline solid (1.3 g) which was
used without further purification. A small sample (100 mg) was
recrystallized (ethanol) to obtain the title compound as beige
prisms (68 mg).
Example 16
##STR00031##
[0293] 4'-(3-Piperidin-1-yl-propoxy)-biphenyl-2-carbaldehyde
[0294] A solution of the product of Example 5 (593 mg),
tetrakis(triphenylphosphine)palladium(0) (116 mg), and
2-formylphenylboronic acid (270 mg) in tetrahydrofuran (11 mL) was
treated with a solution of sodium carbonate (191 mg) in water (2.7
mL). The resulting mixture was heated in a 65.degree. C. bath for
14 h, and allowed to cool to room temperature. Ether (20 mL) and
water (10 mL) were added, and the aqueous phase was extracted with
ether (2.times.20 mL). The combined organic phases were dried
(magnesium sulfate) and evaporated in vacuo. Silica gel
chromatography of the residue (2.5% 2M
ammonia-methanol/dichloromethane) gave the title compound as a pale
yellow oil (175 mg).
Example 17
##STR00032##
[0295] 4-Piperidin-1-ylmethyl-phenol
[0296] A solution of 4-hydroxybenzaldehyde (10 g), piperidine (8.9
mL), and acetic acid (4.7 mL) in DCE (200 mL) was treated with
sodium triacetoxyborohydride (24 g). After 16 h, the resulting
mixture was treated with saturated aqueous sodium bicarbonate (100
mL) and extracted with DCM (5.times.100 mL). The combined organic
phases were dried (magnesium sulfate) and evaporated. Trituration
of the residue with ethyl acetate gave the title compound as a
white crystalline solid (5.5 g).
Example 18
##STR00033##
[0297] 1-{3-[4-(1H-Pyrrol-2-yl)-phenoxy]-propyl}-piperidine
[0298] To a stirred solution of the product of Example 5 (4 g) in
tetrahydrofuran (30 mL) was added
tetrakis(triphenylphosphine)palladium (0.76 g). The mixture was
stirred at RT for 30 min and then treated with a solution of
1-(tert-butoxycarbonyl)pyrrole-2-boronic acid (2.57 g) and sodium
carbonate (1.29 g) in water (20 mL). The mixture was heated to
reflux for 1.5 d. The tetrahydrofuran was removed under reduced
pressure and the aqueous layer was extracted several times with
methylene chloride. The combined organic layers were dried (sodium
sulfate), filtered and concentrated under reduced pressure to give
a black oil (5.42 g). Chromatography (50% ethyl acetate/hexane
containing 2% triethylamine) afforded an orange-red oil (3.63 g).
This material (3.63 g) was dissolved in a mixture of methanol (75
mL) and tetrahydrofuran (40 mL) and treated with sodium methoxide
(3.12 g). The mixture was stirred at RT for 12 h and then
additional sodium methoxide was added (1.7 g). After stirring at RT
for 12 additional hours, the mixture was concentrated under reduced
pressure, and the residue partitioned between diethyl ether and
water. The organic layer was separated and the aqueous layer
extracted several times with diethyl ether. The combined organic
layers were dried (sodium sulfate), filtered and concentrated,
yielding the title compound (2.68 g).
Example 19
##STR00034##
[0299]
1-[4-(2-Piperidin-1-yl-ethoxy)-benzyl]-1,2,3,4-tetrahydro-quinoline
[0300] A solution of 4-(2-piperidylethoxy)-benzaldehyde (200 mg),
1,2,3,4-tetrahydroquinoline (126 mg), and acetic acid (0.11 mL) in
dichloroethane (2 mL) was treated with sodium triacetoxyborohydride
(254 mg). After 15 h, the reaction was quenched with saturated
aqueous sodium bicarbonate, and the aqueous phase was extracted
with dichloromethane (2x2 mL). The combined organic phases were
dried (magnesium sulfate) and evaporated in vacuo. Silica gel
chromatography of the residue (2% 2M
ammonia-methanol/dichloromethane) gave the title compound as a
colorless viscous oil (51 mg). .sup.1H NMR (400 MHz, CDCl.sub.3):
7.17 (d, J=8.8 Hz, 2H), 6.97 (d, J=7.4 Hz, 2H), 6.86 (d, J=8.8 Hz,
2H), 6.60-6.52 (m, 2H), 4.41 (s, 2H), 4.09 (t, J=6.2 Hz, 2H),
3.36-3.32 (m, 2H), 2.83-2.75 (m, 4H), 2.54-2.47 (m, 4H), 2.03-1.97
(m, 2H), 1.64-1.57 (m, 4H), 1.49-1.42 (m, 2H).
Example 20
##STR00035##
[0301] 1-[2-(4-Piperidin-1-ylmethyl-phenoxy)-ethyl]-piperidine
[0302] A solution of 4-(2-piperidylethoxy)-benzaldehyde (200 mg),
piperidine (80 mg), and acetic acid (1 mL of a solution prepared
from acetic acid (0.5 mL) in dichloroethane (10 mL)) in
dichloroethane (1 mL) was treated with sodium triacetoxyborohydride
(254 mg). After 17 h, the reaction was quenched with saturated
aqueous sodium bicarbonate, and the aqueous phase was extracted
with dichloromethane (2.times.1 mL). The combined organic phases
were dried (magnesium sulfate) and evaporated in vacuo. Silica gel
chromatography of the residue (5% 2M ammonia-methanol/ethyl
acetate) gave the title compound as a pale yellow oil (69 mg).
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.20 (d, J=8.4 Hz, 2H), 6.84 (d,
J=8.4 Hz, 2H), 4.08 (t, J=6.1 Hz, 2H), 3.39 (s, 2H), 2.75 (t, J=6.1
Hz, 2H), 2.54-2.45 (m, 4H), 2.38-2.30 (m, 4H), 1.63-1.52 (m, 8H),
1.47-1.37 (m, 4H).
Example 21
##STR00036##
[0303]
2-[4-(2-Piperidin-1-yl-ethoxy)-benzyl]-1,2,3,4-tetrahydro-isoquinol-
ine
[0304] 1,2,3,4-Tetrahydroisoquinoline (126 mg) was treated with a
solution of acetic acid (1 mL of a solution of acetic acid (1 mL)
in dichloroethane (10 mL)) and the resulting solution was added to
4-(2-piperidylethoxy)-benzaldehyde (200 mg). The resulting mixture
was treated with sodium triacetoxyborohydride (254 mg). After 15 h,
the reaction was quenched with saturated aqueous sodium
bicarbonate, and the aqueous phase was extracted with
dichloromethane (2.times.2 mL). The combined organic phases were
dried (magnesium sulfate) and evaporated in vacuo. Silica gel
chromatography of the residue (2% 2M
ammonia-methanol/dichloromethane) gave the title compound as a
colorless viscous oil (218 mg). .sup.1H NMR (400 MHz, CDCl.sub.3):
7.31 (d, J=8.4 Hz, 2H), 7.13-7.06 (m, 3H), 7.01-6.96 (m, 1H),
6.91-6.86 (m, 2H), 4.12 (t, J=6.1 Hz, 2H), 3.62 (s, 4H), 2.90 (t,
J=5.7 Hz, 2H), 2.81-2.71 (m, 4H), 2.56-2.47 (m, 4H), 1.66-1.57 (m,
4H), 1.50-1.42 (m, 2H).
Example 22
##STR00037##
[0305]
1-Benzyl-4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperidin-4-ol
[0306] A solution of the product of Example 5 (297 mg) in
tetrahydrofuran (2 mL) was cooled in a dry-ice/acetone bath and
treated with n-butyllithium (0.44 mL of a 2.5 M solution in
hexane). After 30 min, the resulting solution was treated with a
solution of 1-benzyl-4-piperidone (0.19 mL) in tetrahydrofuran (1
mL). After 15 min, the reaction was allowed to warm to room
temperature, and quenched with water (3 mL). Volatiles were removed
in vacuo, and the residue was extracted with ether (3.times.5 mL).
The combined organic phases were dried (magnesium sulfate) and
evaporated in vacuo. Silica gel chromatography of the residue (3%
2M ammonia-methanol/dichloromethane) gave the title compound as a
white microcrystalline solid (80 mg). .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.42-7.22 (m, 7H), 6.86 (d, J=8.8 Hz, 2H), 3.97 (t,
J=6.4 Hz, 2H), 3.57 (s, 2H), 2.79-2.72 (m, 2H), 2.50-2.33 (m, 7H),
2.16-2.06 (m, 2H), 1.99-1.91 (m, 2H), 1.77-1.65 (m, 3H), 1.61-1.54
(m, 4H), 1.47-1.39 (m, 2H)
Example 23
##STR00038##
[0307] 1-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-piperazine
hydrochloride
[0308] A solution of the product of Example 7 (300 mg) in dioxane
(5 mL) was treated with a solution of 4N hydrogen chloride in
dioxane (2 mL) for 48 h. Volatiles were removed in vacuo, and the
residue was triturated with ether, giving the title compound as an
ivory solid (230 mg). .sup.1H NMR (400 MHz, MeOH-d.sub.4):
7.35-7.33 (d, J=8.9 Hz, 2H), 7.05-7.03 (d, J=8.9 Hz, 2H), 4.13 (t,
J=5.5 Hz, 2H), 3.73-3.69 (m, 2H), 3.60(bs, 8H), 3.45-3.41 (m, 2H),
3.16-3.11 ( m, 2H), 2.27-2.15 (m, 4H), 2.10-2.05 (m, 2H)
Example 24
##STR00039##
[0309]
1-Benzyl-4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-piperazine
[0310] A solution of the product of Example 23 (148 mg),
benzaldehyde (520 mg), and acetic acid (25 mg) in dichloroethane (3
mL) was treated with sodium triacetoxyborohydride (121 mg). After
14 h, the reaction was quenched with saturated aqueous sodium
bicarbonate, and the aqueous phase was extracted with
dichloromethane (120 mL). The organic phase was dried (magnesium
sulfate) and evaporated in vacuo. Silica gel chromatography of the
residue (5% 2M ammonia-methanol/dichloromethane) gave the title
compound as a light yellow solid (8 mg). .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.36-7.24 (m, 5H), 6.94-6.81 (m, 4H), 3.96 (t, J=6.4
Hz, 2H), 3.56 (s, 2H), 3.08 (t, J=4.9 Hz, 4H), 2.64-2.60 ( m, 4H),
2.04-1.94 (m, 2H), 1.80-1.75 (m, 4H).
Example 25
##STR00040##
[0311] 1-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-piperazine
hydrochloride
[0312] A solution of the product of Example 8 (520 mg) in dioxane
(6 mL) was treated with a solution of 4N hydrogen chloride in
dioxane (4 mL) for 48 h. Volatiles were removed in vacuo, and the
residue was triturated with ether, giving the title compound as an
ivory solid (750 mg). .sup.1H NMR (400 MHz, MeOH-d.sub.4):
7.16-7.14 (d, J=9.0 Hz, 5H), 6.84-6.96 (d, J=8.9 Hz, 4H), 4.10 (t,
J=5.6 Hz, 2H), 3.62 (d, J=12.0 Hz, 2H), 3.00 (t, J=12.1 Hz, 2H),
2.67-2.21 ( m, 2H), 2.01-1.98 (m, 2H), 1.90-1.76 (m, 3H), 1.70-1.52
(m, 1H).
Example 26
##STR00041##
[0313]
1-Isopropyl-4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine
[0314] A solution of the product of Example 25 (122 mg), acetone
(23 mg), and acetic acid (19 mg) in dichloroethane (3 mL) was
treated with sodium triacetoxyborohydride (96 mg). After 14 h, the
reaction was quenched with saturated aqueous sodium bicarbonate,
and the aqueous phase was extracted with dichloromethane (120 mL).
The organic phase was dried (magnesium sulfate) and evaporated in
vacuo. Silica gel chromatography of the residue (5% 2M
ammonia-methanol/dichloromethane) gave the title compound as a
white solid (31 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.91-6.87
(m, 2H), 6.85-6.81 (m, 2H), 3.95 (t, J=6.4 Hz, 2H), 3.10 (t, J=4.9
Hz, 4H), 2.69 (t, J=4.9 Hz, 4H), 2.48-2.44 (m, 2H), 2.39 (bs, 4H),
1.98-1.91 (m, 2H), 1.61-1.56 (m, 4H), 1.46-1.40 (m, 2H), 1.09 (d,
J=6.5 Hz, 6H).
Example 27
##STR00042##
[0315]
1-Benzyl-4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine
[0316] A solution of the product of Example 25 (151 mg),
benzaldehyde (54 mg), and acetic acid (24 mg) in dichloroethane (3
mL) was treated with sodium triacetoxyborohydride (119 mg). After
14 h, the reaction was quenched with saturated aqueous sodium
bicarbonate, and the aqueous phase was extracted with
dichloromethane (120 mL). The organic phase was dried (magnesium
sulfate) and evaporated in vacuo. Silica gel chromatography of the
residue (5% 2M ammonia-methanol/dichloromethane) gave the title
compound as an ivory solid (73 mg). .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.36-7.24 (m, 5H), 6.89-6.80 (m, 4H), 3.94 (t, J=6.4
Hz, 2H), 3.56 (s, 2H), 3.08 (t, J=4.9 Hz, 4H), 2.61 (t, J=5.0 Hz,
4H), 2.48-2.44 (m, 2H), 2.39 (bs, 4H), 1.98-1.91 (m, 2H), 1.61-1.56
(m, 4H), 1.46-1.40 (m, 2H).
Example 28
##STR00043##
[0317] 4-[3-(3-Piperidin-1-ylmethyl-phenoxy)-propyl]-morpholine
dihydrochloride
[0318] A solution of the product of Example 10 (1.0 g), piperidine
(0.55 mL), and acetic acid (0.29 mL) in DCE (10 mL) was treated
with sodium triacetoxyborohydride (1.5 g). After 16 h, saturated
aqueous sodium bicarbonate was added. The resulting mixture was
extracted with DCM (3.times.10 mL). The combined organic phases
were dried (magnesium sulfate) and evaporated, giving a material
which was dissolved in n-butanol (20 mL), treated with piperidine
(0.65 mL), sodium carbonate (800 mg), and potassium iodide (42 mg),
and heated to 105.degree. C. After 16 h, the reaction was cooled to
RT, treated with water (10 mL), and extracted with DCM (3.times.20
mL). The combined organic phases were dried (magnesium sulfate) and
evaporated. The residue was treated with ether (20 mL), and
filtered. The filtrate was treated with hydrogen chloride (2.5 mL
of a 2 M solution in ether) followed by methanol (3 mL). The
resulting solution was stirred for 1 h, and evaporated. Methanol
(10 mL) was added, and the resulting suspension was heated to
dissolve all solids. The mixture was cooled to RT, and ether (30
mL) was slowly added. Filtration gave the title compound as an
amorphous white powder (0.74 g). .sup.1H NMR (400 MHz,
MeOH-d.sub.4): 7.19 (t, J=8.1 Hz, 1H), 6.89-6.87 (m, 2H), 6.79-6.76
(m, 1H), 4.00 (t, J=6.4 Hz, 2H), 3.43 (s, 2H), 2.47 (d, J=7.6 Hz,
10H), 2.04-1.94 (m, 2H), 1.62-1.54 (m, 8H), 1.45-1.42 (m, 4H).
Example 29
##STR00044##
[0319] Dimethyl-{2-[4-(3-piperidin-
1-yl-propoxy)-phenoxy]-ethyl}-amine
[0320] A suspension of the product of Example 15 (217 mg),
2-piperidylethan-1-ol (119 mg), and polymer-supported
triphenylphosphine (613 mg, 3 mmol/g phosphorus content) in
dichloromethane (4 mL) was treated with a solution of di-tert-butyl
azodicarboxylate (318 mg) in dichloromethane (1 mL). The resulting
mixture was stirred for 3 h and filtered. Chromatography of the
filtrate (2% 2M ammonia-methanol/dichloromethane) gave the title
compound as a white waxy solid (58 mg). .sup.1H NMR (400 MHz,
CDCl.sub.3): 6.86-6.79 (m, 4H), 4.01 (t, J=5.7 Hz, 2H), 3.94 (t,
J=6.4 Hz, 2H), 2.70 (t, J=5.8 Hz, 2H), 2.51-2.37 (m, 6H), 2.33 (s,
6H), 2.00-1.92 (m, 2H), 1.64-1.57 (m, 4H), 1.47-1.40 (m, 2H).
Example 30
##STR00045##
[0321]
1-{3-[4-(2-Piperidin-1-yl-ethoxy)-phenoxy]-propyl}-piperidine
[0322] A suspension of the product of Example 15 (217 mg),
2-piperidylethan-1-ol (119 mg), and polymer-supported
triphenylphosphine (613 mg, 3 mmol/g phosphorus content) in
dichloromethane (4 mL) was treated with a solution of di-tert-butyl
azodicarboxylate (318 mg) in dichloromethane (1 mL). The resulting
mixture was stirred for 3 h and filtered. Chromatography of the
filtrate (2% 2M ammonia-methanol/dichloromethane) gave the title
compound as a white waxy solid (58 mg). .sup.1H NMR (400 MHz,
CDCl.sub.3): 6.82 (s, 4H), 4.05 (t, J=6.2 Hz, 2H), 3.94 (t, J=6.5
Hz, 2H), 2.74 (t, J=6.2 Hz, 2H), 2.53-2.30 (m, 10H), 1.99-1.90 (m,
2H), 1.64-1.55 (m, 8H), 1.49-1.39 (m, 4H).
Example 31
##STR00046##
[0323]
1-{3-[4-(3-Piperidin-1-yl-propoxy)-phenoxy]-propyl}-piperidine
[0324] A suspension of the product of Example 15 (132 mg),
1-(3-hydroxypropyl)piperidine (132 mg), and polymer-supported
triphenylphosphine (613 mg, 3 mmol/g phosphorus content) in
dichloromethane (4 mL) was treated with a solution of di-tert-butyl
azodicarboxylate (318 mg) in dichloromethane (1 mL). The resulting
mixture was stirred for 3 h and filtered. Chromatography of the
filtrate (2% 2M ammonia-methanol/dichloromethane) gave the title
compound as a waxy solid (39 mg). .sup.1H NMR (400 MHz,
CDCl.sub.3): 6.81 (s, 4H), 3.94 (t, J=3.94, 4H), 2.49-2.34 (m,
12H), 1.99-1.90 (m, 4H), 1.63-1.55 (m, 8H), 1.47-1.40 (m, 4H).
Example 32
##STR00047##
[0325]
1-(3-{4-[5-(3-Piperidin-1-yl-propylsulfanyl)-tetrazol-1-yl]-phenoxy-
}-propyl)-piperidine
[0326] A suspension of 1-(4-hydroxyphenyl)-1H-tetrazole-5-thiol
(175 mg), the product of Example 1 (256 mg), and polymer-supported
triphenylphosphine (600 mg, 3 mmol/g phosphorus content) in
dichloromethane (5 mL) was treated with di-tert-butyl
azodicarboxylate (456 mg). The resulting mixture was stirred for 24
h and filtered. Chromatography of the filtrate (5% 2M
ammonia-methanol/dichloromethane) gave the title compound as a
colorless oil (25 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.40-7.35
(m, 2H), 7.07-6.94 (m, 2H), 4.00 (t, J=6.4 Hz, 2H), 3.33 (t, J=7.1
Hz, 2H), 2.43-2.40 (m, 2H), 2.36-2.29 (m, 10H), 1.97-1.89 (m, 4H),
1.56-1.46 (m, 8H), 1.40-1.35 (m, 4H).
Example 33
##STR00048##
[0327]
5-(3-Piperidin-1-yl-propoxy)-2-[4-(3-piperidin-1-yl-propoxy)-phenyl-
]-pyrimidine
[0328] A suspension of 2-(4-hyroxyphenyl)-5-pyrimidinol (169 mg),
the product of Example 1 (256 mg), and polymer-supported
triphenylphosphine (600 mg, 3 mmol/g phosphorus content) in
dichloromethane (5 mL) was treated with di-tert-butyl
azodicarboxylate (456 mg). The resulting mixture was stirred for 24
h and filtered. Chromatography of the filtrate (5% 2M
ammonia-methanol/dichloromethane) gave the title compound as a
white solid (6.7 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.24 (s,
2H), 8.06 (d, J=8.8 Hz, 2H), 6.77 (d, J=8.8 Hz, 2H), 4.10 (t, J=6.1
Hz, 2H), 3.82 (t, J=5.2 Hz, 2H), 2.60-2.36 (m, 12H), 2.07-2. (m,
2H), 1.73-1.63 (m, 6H), 1.61-1.55 (m, 4H), 1.48-1.44 (m, 4H).
Example 34
##STR00049##
1-[3-(2'-Piperidin-1-ylmethyl-biphenyl-4-yloxy)-propyl]-piperidine
[0329] The product of Example 16 (75 mg), was treated with 1 mL of
a solution prepared from piperidine (0.28 mL) and acetic acid (0.29
mL) in dichloroethane (10 mL). The resulting solution was treated
with sodium triacetoxyborohydride (68 mg). After 16 h, the reaction
was quenched with saturated aqueous sodium bicarbonate, and the
aqueous phase was extracted with dichloromethane (3.times.1 mL).
The combined organic phases were dried (magnesium sulfate) and
evaporated in vacuo. Silica gel chromatography of the residue (4%
2M ammonia-methanol/dichloromethane) gave the title compound as a
colorless oil (43 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.52 (dd,
J=6.9, 2.0 Hz, 1H), 7.34-7.20 (m, 5H), 6.92 (d, J=6.92 Hz, 2H),
4.05 (t, J=4.5 Hz, 2H), 2.35 (s, 2H), 2.54-2.25 (m, 10H), 2.06-1.98
(m, 2H), 1.64-1.35 (m, 12H).
Example 35
##STR00050##
[0330] 1-[3-(4-Piperidin-1-ylmethyl-phenoxy)-propyl]-piperidine
[0331] A solution of the product of Example 12 (6.13 g), piperidine
(3.0 mL), sodium carbonate (3.6 g), and potassium iodide (190 mg)
in n-butanol (50 mL) was heated to 105.degree. C. for 21 h, cooled
to RT, and treated with water (50 mL). The resulting mixture was
extracted with DCM (4.times.50 mL), and the combined organic phases
were dried (magnesium sulfate) and evaporated. Chromatography of
the residue (5% 2M methanolic ammonia/methanol) gave the title
compound as a waxy solid (3.2 g). .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.19 (d, J=8.6 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 3.97
(t, J=6.5 Hz, 2H), 3.4 (s, 2H), 2.48-2.31 (m, 1OH), 2.00-1.92 (m,
2H), 1.62-1.52 (m, 8H), 1.47-1.38 (m, 4H).
Example 36
##STR00051##
[0332]
2-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-1,2,3,4-tetrahydro-isoquino-
line
[0333] A solution of the product of Example 11 (1.0 g),
1,2,3,4-tetrahydro-isoquinoline (0.0.69 mL), and acetic acid (0.29
mL) in DCE (10 mL) was treated with sodium triacetoxyborohydride
(1.5 g). After 16 h, saturated aqueous sodium bicarbonate was
added. The resulting mixture was extracted with DCM (3.times.10
mL). The combined organic phases were dried (magnesium sulfate) and
evaporated, giving a material which was dissolved in n-butanol (20
mL), treated with piperidine (0.65 mL), sodium carbonate (800 mg),
and potassium iodide (42 mg), and heated to 105.degree. C. After 16
h, the reaction was cooled to RT, treated with water (10 mL), and
extracted with DCM (3.times.20 mL). The combined organic phases
were dried (magnesium sulfate) and evaporated. The residue was
treated with ether (20 mL), and filtered. The filtrate was treated
with hydrogen chloride (2.5 mL of a 2 M solution in ether) followed
by methanol (3 mL). The resulting solution was stirred for 1 h, and
evaporated. The residue was dried in vacuo, and ether was added,
followed by enough methanol to cause a precipitate to form.
Filtration gave the title compound as an amorphous pink powder
(0.86 g). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.27 (d, J=8.6 Hz,
2H), 7.13-7.05 (m, 4H), 6.99-6.96 (m,1H), 6.89-6.83 (m, 2H), 4.00
(t, J=6.3 Hz, 2H), 3.60 (s, 4H), 2.89 (t, J=5.7 Hz, 2H), 2.72 (t,
J=5.8 Hz, 2H), 2.53-2.37 (m, 6H), 2.03-1.95 (m, 2H), 1.64-1.57 (m,
4H), 1.49-1.40 (m, 2H).
Example 37
##STR00052##
[0334]
1-{3-[4-(1-Methyl-pyrrolidin-2-yl)-phenoxy]-propyl}-piperidine
[0335] The product of Example 5 (0.345 g) in diethylether (10 mL)
was cooled to -78.degree. C. and treated with n-butyllithium (0.5
mL, 2.5 M in hexane) and stirred at -78.degree. C. for an
additional 10 minutes whereupon the reaction mixture was warmed to
0.degree. C. for 2-3 minutes then recooled to -78.degree. C. To the
cold solution was then added N-methylpyrrolidinone (0.099 g) and
the reaction mixture warmed to ambient temperature. Separately a
solution of sodium borohydride (0.04 g) and trifluoroacetic acid
(0.08 mL) in diethylether (5 mL) was prepared and the reaction
mixture added to this solution dropwise with rapid stirring. After
75 minutes the reaction mixture was treated with a solution of 20%
sodium carbonate and extracted with ethyl acetate (3.times.25 mL).
The organic extracts were combined, dried over sodium sulfate,
filtered and evaporated. The residue was purified by silica gel
chromatography (4% methanolic ammonia/DCM) to give the title
compound (0.03 g). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.21(d, J=8.3
Hz, 2H), 6.85 (d, J=8.3 Hz, 2H), 3.98 (t, J=6.3, 6.56 Hz, 2H), 3.20
(t, J=8.5 Hz, 1H), 2.95 (t, J=8.3 Hz, 1H), 2.17-2.57 (m, 7H), 2.11
(s, 3H ), 1.95 (m, 3H), 1.74 ( m, 3H), 1.57 (m, 4H), 1.37-1.48 (m,
2H).
Example 38
##STR00053##
[0336]
{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-pyridin-2--
yl-(2-pyrrolidin-1-yl-ethyl)-amine
[0337] A solution of the product of Example 9 (30 mg),
piperidin-4-yl-pyridin-2-yl-(2-pyrrolidin-1-yl-ethyl)-amine (29.8
mg), and acetic acid (0.015 mL) in DCM (1 mL) was treated with
sodium triacetoxyborohydride (38 mg). After 16 h, the resulting
mixture was treated with 10% sodium hydroxide (1 mL) and extracted
with DCM (3.times.3 mL). The combined organic phases were dried
(sodium sulfate) and evaporated. Chromatography of the residue
(1-10% 2 M methanolic ammonia/DCM) gave the title compound as a
colorless oil (26 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.12 (m,
1H), 7.39 (m, 1H), 7.21 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H),
6.53-6.47 (m, 2H), 4.44 (m, 1H), 3.99 (t, J=6.3 Hz, 2H), 3.51-3.47
(m, 2H), 3.46 (s, 2H), 2.95 (m, 2H), 2.62 (m, 6H), 2.49 (m, 2H),
2.42 (m, 4H), 2.12 (m, 2H), 1.98 (m, 2H), 1.84-1.78 (m, 5H), 1.75
(m, 1H), 1.68 (m, 2H), 1.63-1.57 (m, 4H), 1.44 (m, 2H).
Example 39
##STR00054##
[0338]
Pyridin-2-yl-[4-(3-pyrrolidin-1-yl-propoxy)-benzyl]-amine
[0339] A solution of 4-(3-Pyrrolidin-1-yl-propoxy)-benzaldehyde
(0.51 g), 2-aminopyridine (0.24 g), and acetic acid (0.13 mL) in
DCM (7 mL) was treated with sodium triacetoxyborohydride (650 mg).
After 16 h, the resulting mixture was treated with 10% sodium
hydroxide (10 mL) and extracted with DCM (3.times.10 mL). The
combined organic phases were dried (sodium sulfate) and evaporated.
Chromatography of the residue (1-4% 2 M methanolic ammonia/DCM)
gave the title compound as an off white solid (500 mg). .sup.1H NMR
(400 MHz, CDCl.sub.3): 8.09 (m, 1H), 7.39 (m, 1H), 7.26 (d, J=8.8
Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 6.58 (m, 1H), 6.36 (m, 1H), 4.79
(m, 1H), 4.41 (d, J=5.5, 2H), 4.01 (t, J=6.3 Hz, 2H), 2.63 (t,
J=7.6 Hz, 2H), 2.54 (m, 4H), 2.04-1.96 (m, 2H), 1.79 (m, 4H).
Example 40
##STR00055##
[0340]
Dimethyl-[3-(4-piperidin-1-ylmethyl-phenoxy)-propyl]-amine
[0341] A suspension of 3-dimethylamino-1-propanol (0.178 mL), the
product of example Example 17 (191 mg), polymer supported triphenyl
phosphine (667 mg; loading: 3 mmol/g) and
di-tert-butylazodicarboxylate (345 mg) in DCM (15 mL) was shaken
for 16 h. The resulting mixture was filtered through a pad of
ceilite and washed with DCM (3.times.3 mL). The combined filtrates
were concentrated. Chromatography of the residue (1-6% 2 M
methanolic ammonia/DCM) gave the title compound as a colorless oil
(90 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.20 (d, J=8.6 Hz, 2H),
6.84 (d, J=8.6 Hz, 2H), 4.00 (d, J=6.5 Hz, 1H), 3.40 (s, 2H), 2.44
(t, J=7.4, 2H), 2.35 (bs, 4H), 2.25 (s, 6H), 1.98-1.91 (m, 2H),
1.58-1.53 (m, 4H), 1.44-1.39 (m, 2H).
Example 41
##STR00056##
[0342]
{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-pyridin-2--
yl-amine
[0343] A solution of the product of Example 9 (240 mg),
piperidin-4-yl-pyridin-2-yl-amine (166 mg), and acetic acid (0.12
mL) in DCM (5 mL) was treated with sodium triacetoxyborohydride
(290 mg). After 16 h, the resulting mixture was treated with 10%
sodium hydroxide (7 mL) and extracted with DCM (3.times.10 mL). The
combined organic phases were dried (sodium sulfate) and evaporated.
Chromatography of the residue (3% 2 M methanolic ammonia/DCM) gave
the title compound as a colorless oil (188 mg). .sup.1H NMR (400
MHz, CDCl.sub.3): 8.06 (m, 1H), 7.38 (m, 1H), 7.20 (d, J=8.8 Hz,
2H), 6.84 (d, J=8.8 Hz, 2H), 6.53 (m, 1H), 6.34 (d, J=8.3 Hz, 1H),
4.36 (br, m, 1H), 3.99 (t, J=6.6 Hz, 2H), 3.60 (m, 1H), 3.45 (s,
2H), 2.81 (m, 2H), 2.47 (m, 2H), 2.47 (br, 3H), 2.15 (m, 2H),
2.05-1.93 (m, 4H), 1.62-1.54 (m, 4H), 1.50 (m, 1H), 1.44 (m,
2H).
Example 42
##STR00057##
[0344]
Methyl-phenethyl-{1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-
-4-yl}-amine
[0345] A solution of the product of Example 9 (152 mg),
methyl-phenethyl-piperidin-4-yl-amine (128 mg), and acetic acid
(0.11 mL) in DCM (3 mL) was treated with sodium
triacetoxyborohydride (190 mg). After 16 h, the resulting mixture
was treated with 10% sodium hydroxide (5 mL) and extracted with DCM
(3.times.10 mL). The combined organic phases were dried (sodium
sulfate) and evaporated. Chromatography of the residue (1-5% 2 M
methanolic ammonia/DCM) gave the title compound as a colorless oil
(148 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.29-7.25 (m, 2H),
7.21-7.16 (m, 5H), 6.83 (j, J=8.6 Hz, 2H), 3.99 (d, J=6.3 Hz, 2H),
3.41 (s, 2H), 2.92 (m, 2H), 2.77-2.66 (m, 4H), 2.47 (m, 2H), 2.40
(m, 4H), 2.34 (s, 3H), 2.00-1.88 (m, 4H), 1.71 (m, 2H), 1.62-1.55
(m, 6H), 1.44 (m, 2H).
Example 43
##STR00058##
[0346]
Benzyl-methyl-{1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4--
yl}-amine
[0347] A solution of the product of Example 9 (155 mg),
benzyl-methyl-piperidin-4-yl-amine (123 mg), and acetic acid (0.11
mL) in DCM (3 mL) was treated with sodium triacetoxyborohydride
(190 mg). After 16 h, the resulting mixture was treated with 10%
sodium hydroxide (5 mL) and extracted with DCM (3.times.10 mL). The
combined organic phases were dried (sodium sulfate) and evaporated.
Chromatography of the residue (1-5% 2 M methanolic ammonia/DCM)
gave the title compound as a colorless oil (155 mg). .sup.1H NMR
(400 MHz, CDCl.sub.3): 7.31-7.28 (m, 4H), 7.24-7.18 (m, 3H), 6.84
(d, J=8.8 Hz, 2H), 3.99 (t, J=6.3 Hz, 2H), 3.56 (s, 2H), 3.42 (s,
2H), 2.94 (m, 2H), 2.47 (m, 2H), 2.40 (m, 4H), 2.19 (s, 3H),
2.01-1.88 (m, 4H), 1.77 (m, 2H), 1.67 (m, 2H), 1.59 (m, 4H), 1.44
(m, 2H)
Example 44
##STR00059##
[0348]
1-[3-(4-Piperidin-1-ylmethyl-phenoxy)-propyl]-decadeuterio-piperidi-
ne
[0349] A suspension of the product of Example 12 (1.0 g),
perdeuteropiperidine (0.58 mL), sodium carbonate (3.6 g), and
potassium iodide (30 mg) in 1-butanol (15 mL) was heated to
105.degree. C. for 16 h, cooled to RT, diluted with water (6 mL)
and extracted with DCM (3.times.12 mL). The combined organic phases
were dried (magnesium sulfate) and evaporated. Chromatography of
the residue (3% 2 M methanolic ammonia/DCM) gave the title compound
as a yellow oil (872 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.19
(d, J=8.2 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 3.98 (t, J=6.5 Hz, 2H),
3.41 (s, 2H), 2.46 (t, J=7.4 Hz, 2H), 2.38-2.28 (br s, 4H),
2.00-1.92 (m, 2H), 1.59-1.50 (m, 4H), 1.45-1.34 (m, 2H).
Example 45
##STR00060##
[0350]
1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-azacyclotridecane
[0351] A solution of the product of Example 9 (175 mg),
dodecamethyleneamine (143 mg), and acetic acid (0.09 mL) in DCE (3
mL) was treated with sodium triacetoxyborohydride (210 mg). After
16 h, the resulting mixture was treated with 10% sodium hydroxide
(1 mL) and extracted with DCM (3.times.3 mL). The combined organic
phases were dried (magnesium sulfate) and evaporated.
Chromatography of the residue (3% 2 M methanolic ammonia/DCM) gave
the title compound as a colorless oil (140 mg). .sup.1H NMR (400
MHz, CDCl.sub.3): 7.20 (d, J=8.8 Hz 2H), 6.82 (d, J=8.6 Hz, 2H),
3.99 (t, J=6.5 Hz, 2H), 3.40 (s, 2H), 2.50-2.31 (m, 10H), 2.01-1.93
(m, 2H), 1.63-1.56 (m, 4H), 1.48-1.34 (m, 22H).
Example 46
##STR00061##
[0352]
2-{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-ethanol
[0353] A solution of the product of Example 9 (175 mg),
4-hydroxyethylpiperidine (101 mg), (143 mg), and acetic acid (0.02
mL) in DCE (3 mL) was treated with sodium triacetoxyborohydride
(210 mg). After 16 h, the resulting mixture was treated with 10%
sodium hydroxide (1 mL) and extracted with DCM (3.times.3 mL). The
combined organic phases were dried (magnesium sulfate) and
evaporated. Chromatography of the residue (3% 2 M methanolic
ammonia/DCM) gave the title compound as a colorless oil (80 mg).
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.19 (d, J=8.6 Hz, 2H), 6.83 (d,
J=8.6 Hz, 2H), 3.98 (t, J=6.4 Hz, 2H), 3.65 (t, J=6.7 Hz, 2H), 3.41
(s, 2H), 2.88-2.82 (m, 2H), 2.50-2.33 (m, 7H), 2.01-1.86 (m, 4H),
1.68-1.55 (m, 6H), 1.52-1.37 (m, 5H), 1.31-1.20 (m, 2H).
Example 47
##STR00062##
[0354] Indan-1-yl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine
[0355] A solution of the product of Example 9 (175 mg),
1-aminoindane (0.10 mL), and acetic acid (0.09 mL) in DCE (3 mL)
was treated with sodium triacetoxyborohydride (210 mg). After 16 h,
the resulting mixture was treated with 10% sodium hydroxide (1 mL)
and extracted with DCM (3.times.3 mL). The combined organic phases
were dried (magnesium sulfate) and evaporated. Chromatography of
the residue (2.5% 2 M methanolic ammonia/DCM) gave the title
compound as a colorless oil (119 mg). .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.37-7.34 (m, 1H), 7.28 (d, J=8.8 Hz, 2H), 7.25-7.17
(m, 3H), 6.86 (d, J=8.8 Hz, 2H), 4.28 (t, J=6.7 Hz, 1H), 3.99 (t,
J=6.5 Hz, 2H), 3.86 (d, J=13 Hz,1H), 3.81 (d, J=13 Hz, 1H),
3.05-2.96 (m, 1H), 2.85-2.76 (m,1H), 2.49-2.36 (m, 6H), 2.00-1.82
(m, 3H), 1.62-1.55 (m, 4H), 1.47-1.39 (m, 2H)
Example 48
##STR00063##
[0356]
1-[3-(4-Pyrrolidin-1-ylmethyl-phenoxy)-propyl]-piperidine
[0357] A solution of the product of Example 9 (175 mg), pyrrolidine
(0.07 mL), and acetic acid (0.09 mL) in DCE (3 mL) was treated with
sodium triacetoxyborohydride (210 mg). After 16 h, the resulting
mixture was treated with 10% sodium hydroxide (1 mL) and extracted
with DCM (3.times.3 mL). The combined organic phases were dried
(magnesium sulfate) and evaporated. Chromatography of the residue
(3% 2 M methanolic ammonia/DCM) gave the title compound as a
colorless oil (27 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.21 (d,
J=8.6 Hz, 2H), 7.0 (d, J=8.8 Hz, 2H), 3.99 (t, J=6.3 Hz, 2H), 3.52
(s, 2H), 2.50-2.32 (m,1 OH), 2.01-1.92 (m, 2H), 1.79-1.72 (m, 4H),
1.61-1.54 (m, 4H), 1.49-1.40 (m, 2H).
Example 49
##STR00064##
[0358] Cyclohexyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine
[0359] A solution of the product of Example 9 (175 mg),
aminocyclohexane (0.09 mL), and acetic acid (0.09 mL) in DCE (3 mL)
was treated with sodium triacetoxyborohydride (210 mg). After 16 h,
the resulting mixture was treated with 10% sodium hydroxide (1 mL)
and extracted with DCM (3.times.3 mL). The combined organic phases
were dried (magnesium sulfate) and evaporated. Chromatography of
the residue (2.5% 2 M methanolic ammonia/DCM) gave the title
compound as a colorless oil (84 mg). .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.21 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H), 3.98
(t, J=6.5 Hz, 2H), 3.73 (s, 2H), 2.50-2.35 (m, 7H), 2.00-1.86 (m,
4H), 1.76-1.68 (m, 2H), 1.64-1.55 (m, 5H), 1.47-1.39 (m, 2H),
1.30-1.04 (m, 5H).
Example 50
##STR00065##
[0360] Cyclopropyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine
[0361] A solution of the product of Example 9 (175 mg),
aminocyclopropane (0.05 mL), and acetic acid (0.09 mL) in DCE (3
mL) was treated with sodium triacetoxyborohydride (210 mg). After
16 h, the resulting mixture was treated with 10% sodium hydroxide
(1 mL) and extracted with DCM (3.times.3 mL). The combined organic
phases were dried (magnesium sulfate) and evaporated.
Chromatography of the residue (4% 2 M methanolic ammonia/DCM) gave
the title compound as a colorless oil (113 mg). .sup.1H NMR (400
MHz, CDCl.sub.3): 7.20 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H),
3.98 (t, J=6.5 Hz, 2H), 3.76 (s, 2H), 2.49-2.35 (m, 6H), 2.16-2.09
(m, 1H), 2.00-1.92 (m, 2H), 1.62-1.55 (m, 4H), 1.47-1.39 (m, 2H),
0.45-0.34 (m, 4H).
Example 51
##STR00066##
[0362] 4-[3-(4-Piperidin-1-ylmethyl-phenoxy)-propyl]-morpholine
[0363] A suspension of the product of Example 12 (268 mg),
morpholine (0.11 mL), sodium carbonate (159 g), and potassium
iodide (8.3 mg) in 1-butanol (4 mL) was heated to 105 C for 16 h,
cooled to RT, diluted with water (2 mL) and extracted with DCM
(3.times.3 mL). The combined organic phases were dried (magnesium
sulfate) and evaporated. Chromatography of the residue (2.5% 2 M
methanolic ammonia/DCM) gave the title compound as a yellow oil (93
mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.20 (d, J=8.6 Hz, 2H),
6.84 (d, J=8.8 Hz, 2H), 4.01 (t, J=6.5 Hz, 2H), 3.72 (t, J=4.5 Hz,
4H), 3.40 (s, 2H), 2.54-2.44 (m, 6H), 2.34 (br s, 4H), 1.99-1.92
(m, 2H), 1.58-1.52 (m, 4H), 1.45-1.38 (m, 2H).
Example 52
##STR00067##
[0364]
1-Methyl-4-[3-(4-piperidin-1-ylmethyl-phenoxy)-propyl]-piperazine
[0365] A suspension of the product of Example 12 (268 mg),
N-methylpiperazine (0.14 mL), sodium carbonate (159 g), and
potassium iodide (8.3 mg) in 1-butanol (4 mL) was heated to
105.degree. C. for 16 h, cooled to RT, diluted with water (2 mL)
and extracted with DCM (3.times.3 mL). The combined organic phases
were dried (magnesium sulfate) and evaporated. Chromatography of
the residue (4% 2 M methanolic ammonia/DCM) gave the title compound
as a yellow oil (86 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.19
(d, J=8.6 Hz, 2H), 6.81 (d, J=8.6 Hz, 2H), 3.99 (t, J=6.3 Hz, 2H),
3.40 (s, 2H), 2.53-2.30 (m, 14H), 2.28 (s, 3H), 2.00-1.91 (m, 2H),
1.59-1.50 (m, 4H), 1.44-1.38 (m, 2H).
Example 53
##STR00068##
[0366]
1-Methyl-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine
[0367] A solution of the product of Example 9 (175 mg),
N-methylpiperazine (0.09 mL), and acetic acid (0.09 mL) in DCE (3
mL) was treated with sodium triacetoxyborohydride (210 mg). After
16 h, the resulting mixture was treated with 10% sodium hydroxide
(1 mL) and extracted with DCM (3.times.3 mL). The combined organic
phases were dried (magnesium sulfate) and evaporated.
Chromatography of the residue (4% 2 M methanolic ammonia/DCM) gave
the title compound as a colorless oil (79 mg). .sup.1H NMR (400
MHz, CDCl.sub.3): 7.20 (d, J=8.6 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H),
3.97 (t, J=6.3 Hz, 2H), 3.43 (s, 2H), 2.50-2.35 (m, 14H), 2.28 (s,
3H), 2.00-1.93 (m, 2H), 1.62-1.55 (m, 4H), 1.47-1.40 (m, 2H).
Example 54
##STR00069##
[0368]
8-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-1,4-dioxa-8-aza-spiro[4.5]d-
ecane
[0369] A solution of the product of Example 9 (175 mg),
1,4-dioxa-8-azaspiro[4.5]-decane (112 mg), and acetic acid (0.01
mL) in DCE (3 mL) was treated with sodium triacetoxyborohydride
(210 mg). After 16 h, the resulting mixture was treated with 10%
sodium hydroxide (1 mL) and extracted with DCM (3.times.3 mL). The
combined organic phases were dried (magnesium sulfate) and
evaporated. Chromatography of the residue (2.5% 2 M methanolic
ammonia/DCM) gave the title compound as a colorless oil (68 mg).
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.20 (d, J=8.6 Hz, 2H), 6.84 (d,
J=8.6 Hz, 2H), 3.98 (t, J=6.5 Hz, 2H), 3.94 (s, 4H), 3.45 (s, 2H),
2.53-2.35 (m, 10H), 2.00-1.92 (m, 2H), 1.75-1.71 (m, 4H), 1.62-1.55
(m, 4H), 1.47-1.39 (m, 2H).
Example 55
##STR00070##
[0370]
2-(4-Chloro-phenyl)-5-[4-(3-piperidin-1-yl-propoxy)-benzyl]-2,5-dia-
za-bicyclo[2.2.1]heptane
[0371] A solution of the product of Example 9 (175 mg),
2-phenyl-2,5-diaza-bicyclo[2.2.1]heptane hydrobromide(162 mg), and
acetic acid (0.09 mL) in DCE (3 mL) was treated with sodium
triacetoxyborohydride (210 mg). After 16 h, the resulting mixture
was treated with 10% sodium hydroxide (1 mL) and extracted with DCM
(3.times.3 mL). The combined organic phases were dried (magnesium
sulfate) and evaporated. Chromatography of the residue (2.5% 2 M
methanolic ammonia/DCM) gave the title compound as a colorless oil
(111 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.19 (d, J=8.8 Hz,
2H), 7.14 (d, J=9.0 Hz, 2H), 6.82 (d, J=8.6 Hz, 2H), 6.47 (d, J=9.0
H2, 2H), 4.15 (brs, 1H), 3.97 (t, J=6.5 Hz, 2H), 3.59 (s, 2H), 3.52
(brs, 1H), 3.35 (dd, J=8.8, 2.2 Hz, 1H), 3.27 (dd, J=9.0 Hz, 0.8
Hz, 1H), 2.89 (dd, J=9.6, 2.0 Hz, 1H), 2.63 (dd, J=9.6, 1.1 Hz,
1H), 2.48-2.35 (m, 5H), 2.05-1.83 (m, 5H), 1.62-1.54 (m, 4H),
1.47-1.39 (m, 2H).
Example 56
##STR00071##
[0372]
1-{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-1,3-dihy-
dro-benzoimidazol-2-one
[0373] A solution of the product of Example 9 (175 mg),
1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (170 mg), and
acetic acid (0.09 mL) in DCE (3 mL) was treated with sodium
triacetoxyborohydride (210 mg). After 16 h, the resulting mixture
was treated with 10% sodium hydroxide (1 mL) and extracted with DCM
(3.times.3 mL). The combined organic phases were dried (magnesium
sulfate) and evaporated. Chromatography of the residue (2.5% 2 M
methanolic ammonia/DCM) gave the title compound as a colorless oil
(111 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 10.47 (br s,1H),
7.30-7.23 (m, 3H), 7.12-7.01 (m, 3H), 6.86 (d, J=8.8 Hz, 2H),
4.42-4.32 (m, 1H), 4.00 (t, J=6.5 Hz, 2H), 3.51 (s, 2H), 3.07-3.01
(m, 2H), 2.52-2.30 (m, 8H), 2.15 (dd, J=12, 12 Hz, 2H), 2.02-1.94
(m, 2H), 1.83-1.76 (m, 2H), 1.64-1.55 (m, 4H), 1.48-1.40 (m,
2H).
Example 57
##STR00072##
[0374]
1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidine-4-carboxylic
acid amide
[0375] A solution of the product of Example 9 (175 mg),
piperidine-4-carboxylic acid amide (100 mg), and acetic acid (0.1
mL) in DCE (3 mL) was treated with sodium triacetoxyborohydride
(210 mg). After 16 h, the resulting mixture was treated with 10%
sodium hydroxide (1 mL) and extracted with DCM (3.times.3 mL). The
combined organic phases were dried (magnesium sulfate) and
evaporated. Chromatography of the residue (5% 2 M methanolic
ammonia/DCM) gave the title compound as a colorless oil (84 mg).
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.19 (d, J=8.8 Hz, 2H), 6.84 (d,
J=8.6 Hz, 1H), 5.91 (br s, 1H), 5.61 (br s,1H), 3.99 (t, J=6.4 Hz,
2H), 3.42 (s, 2H), 2.94-2.88 (m, 2H), 2.49-2.35 (m, 6H), 2.17-2.08
(m, 1H), 2.01-1.91 (m, 4H), 1.87 -1.67 (m, 4H), 1.62-1.55 (m, 4H),
1.47-1.40 (m, 2H).
Example 58
##STR00073##
[0376]
1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-4-(3-phenyl-propyl)-piperid-
ine
[0377] A solution of the product of Example 9 (175 mg),
4-(3-phenyl-propyl)-piperidine (158 mg), and acetic acid (0.09 mL)
in DCE (3 mL) was treated with sodium triacetoxyborohydride (210
mg). After 16 h, the resulting mixture was treated with 10% sodium
hydroxide (1 mL) and extracted with DCM (3.times.3 mL). The
combined organic phases were dried (magnesium sulfate) and
evaporated. Chromatography of the residue (2% 2 M methanolic
ammonia/DCM) gave the title compound as a colorless oil (107 mg).
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.28-7.13 (m, 7H), 6.82 (d,
J=8.6 Hz, 2H), 3.97 (t, J=6.3 Hz, 2H), 3.40 (s, 2H), 2.87-2.81 (m,
2H), 2.57 (dd, J=7.7, 7.7 Hz, 2H), 2.49-2.35 (m, 6H), 2.00-1.82 (m,
4H), 1.66-1.55 (m, 8H), 1.47-1.39 (m, 2H), 1.30-1.16 (m, 5H).
Example 59
##STR00074##
[0378] Dimethyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine
[0379] A solution of the product of Example 9 (175 mg),
dimethylamine hydrochloride (64 mg), and acetic acid (0.05 mL) in
DCE (3 mL) was treated with sodium triacetoxyborohydride (210 mg).
After 16 h, the resulting mixture was treated with 10% sodium
hydroxide (1 mL) and extracted with DCM (3.times.3 mL). The
combined organic phases were dried (magnesium sulfate) and
evaporated. Chromatography of the residue (3% 2 M methanolic
ammonia/DCM) gave the title compound as a colorless oil (70 mg).
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.19 (d, J=8.6 Hz, 2H), 6.85 (d,
J=8.6 Hz, 2H), 3.99 (t, J=6.4 Hz, 2H), 3.35 (s, 2H), 2.50-2.35 (m,
6H), 2.22 (s, 6H), 2.01-1.94 (m, 2H), 1.63-1.55 (m, 4H), 1.46-1.40
(m, 2H).
Example 60
##STR00075##
[0380]
1-{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-1H-benzo-
imidazole
[0381] A solution of the product of Example 9 (82 mg),
1-Piperidin-4-yl-1H-benzoimidazole (62 mg), and acetic acid (0.03
mL) in DCM (3 mL) was treated with sodium triacetoxyborohydride
(110 mg). After 16 h, the resulting mixture was treated with 10%
sodium hydroxide (5 mL) and extracted with DCM (3.times.10 mL). The
combined organic phases were dried (sodium sulfate) and evaporated.
Chromatography of the residue (1-5% 2 M methanolic ammonia/DCM)
gave the title compound as a colorless oil (81 mg). .sup.1H NMR
(400 MHz, CDCl.sub.3): 7.98 (s, 1H), 7.80 (m, 1H), 7.42 (m, 1H),
7.30-7.20 (m, 4H), 6.87 (d, J=8.6 Hz, 2H), 4.18 (m, 1H), 4.00 (t,
J=6.3 Hz, 2H), 3.52 (s, 2H), 3.10-3.03 (m, 2H), 2.48 (m, 2H), 2.41
(br, 4H), 2.21-2.10 (m, 5H), 2.01-1.94 (m, 2H), 1.62-1.55 (m, 4H),
1.47-1.39 (m, 2H).
Example 61
##STR00076##
[0382]
1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-1,2,3,4,5,6-hexahydro-[2,3'-
]bipyridinyl
[0383] A solution of the product of Example 9 (174 mg),
1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl (111 mg), and acetic acid
(0.05 mL) in DCM (3 mL) was treated with sodium
triacetoxyborohydride (240 mg). After 16 h, the resulting mixture
was treated with 10% sodium hydroxide (5 mL) and extracted with DCM
(3.times.10 mL). The combined organic phases were dried (sodium
sulfate) and evaporated. Chromatography of the residue (1-5% 2 M
methanolic ammonia/DCM) gave the title compound as a colorless oil
(112 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.63 (m, 1H), 8.49 (m,
1H), 7.80 (m, 1H), 7.27 (m, 1H), 7.11 (d, J=8.6 Hz, 2H) 6.80 (d,
J=8.6 Hz, 2H), 3.97 (t, J=6.3 Hz, 2H), 3.61 (d, J=13.4 Hz, 1H),
3.13 (m, 1H), 2.97 (m, 1H), 2.79 (d, J=13.4 Hz, 1H), 2.48 (m, 2H),
2.41 (br, 4H), 2.01-1.98 (m, 5H), 2.01-1.89 (m, 3H), 1.82-1.72 (m,
2H) 1.63-1.51 (m, 4H), 1.48-1.39 (m, 2H).
Example 62
##STR00077##
[0384] Phenyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine
[0385] A solution of the product of Example 9 (277 mg), aniline
(108 mg), and acetic acid (0.07 mL) in DCM (5 mL) was treated with
sodium triacetoxyborohydride (340 mg). After 16 h, the resulting
mixture was treated with 10% sodium hydroxide (10 mL) and extracted
with DCM (3.times.10 mL). The combined organic phases were dried
(sodium sulfate) and evaporated. Chromatography of the residue
(1-5% 2 M methanolic ammonia/DCM) gave the title compound as a
colorless oil (256 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.27 (m,
2H), 7.18 (m, 2H), 6.88 (m, 2H), 6.72 (m, 2H), 6.64 (m, 2H), 4.24
(s, 2H), 4.00 (t, J=6.6 Hz, 2H), 3.94 (br,1H), 2.48 (m, 2H), 2.41
(br, 4H), 1.98 (m, 2H), 1.64-1.57 (m, 4H), 1.48-1.41 (m, 2H).
Example 63
##STR00078##
[0386]
5-Bromo-1-{1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}--
2,3-dihydro-1H-indole
[0387] A solution of the product of Example 9 (93 mg) and
5-bromo-1-piperidin-4-yl-2,3-dihydro-1H-indole*2 TFA (191 mg) in
DCM (2 mL) was treated with sodium triacetoxyborohydride (150 mg).
After 16 h, the resulting mixture was treated with 10% sodium
hydroxide (5 mL) and extracted with DCM (3.times.10 mL). The
combined organic phases were dried (sodium sulfate) and evaporated.
Chromatography of the residue (1-5% 2 M methanolic ammonia/DCM)
gave the title compound as a colorless oil (79 mg). .sup.1H NMR
(400 MHz, CDCl.sub.3): 7.20 (d, J=8.6 Hz, 2H), 7.11-7.07 (m, 2H),
6.84 (d, J=8.6 Hz, 2H), 6.23 (d, J=9.1 Hz, 1H), 4.00 (t, J=6.1 Hz,
2H), 3.46 (s, 2H), 3.37 (7, J=8.3 Hz, 2H), 3.28 (m, 1H), 2.97 (m,
2H), 2.90 (t, J=8.3 Hz, 2H), 2.54 (m, 2H), 2.47 (br, 4H), 2.06-1.97
(m, 4H), 1.75-1.60 (m, 8H), 1.50-1.43 (m, 2H).
Example 64
##STR00079##
[0388]
1-{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-2,3-dihy-
dro-1H-indole
[0389] A solution of the product of Example 9 (112 mg) and
1-piperidin-4-yl-2,3-dihydro-1H-indole*2TFA (194 mg) in DCM (2 mL)
was treated with sodium triacetoxyborohydride (150 mg). After 16 h,
the resulting mixture was treated with 10% sodium hydroxide (5 mL)
and extracted with DCM (3.times.10 mL). The combined organic phases
were dried (sodium sulfate) and evaporated. Chromatography of the
residue (1-5% 2 M methanolic ammonia/DCM) gave the title compound
as a colorless oil (78 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.22
(d, J=8.6 Hz, 2H), 7.06-7.00 (m, 2H), 6.85 (d, J=8.6 Hz, 2H), 6.59
(t, J=7.1 Hz, 1H), 6.39(d, J=7.8 Hz, 1H), 4.00 (t, J=6.3 Hz, 2H),
3.48 (s, 2H), 3.41-3.32 (m, 3H), 2.99 (m, 2H), 2.93 (t, J=8.3 Hz,
2H), 2.54 (m, 2H), 2.47 (br, 4H), 2.09-1.98 (m, 4H), 1.79-1.70 (m,
4H), 1.67-1.61 (m, 4H), 1.50-1.43 (m, 2H).
Example 65
##STR00080##
[0390] [2-(3-Piperidin-1-yl-propoxy)-benzyl]-pyridin-2-yl-amine
[0391] A solution of 2-(3-piperidin-1-yl-propoxy)-benzaldehyde (269
mg), 2-aminopyridine (110 mg), and acetic acid (0.07 mL) in DCM (5
mL) was treated with sodium triacetoxyborohydride (410 mg). After
16 h, the resulting mixture was treated with 10% sodium hydroxide
(6 mL) and extracted with DCM (3.times.10 mL). The combined organic
phases were dried (sodium sulfate) and evaporated. Chromatography
of the residue (1-5% 2 M methanolic ammonia/DCM) gave the title
compound as a colorless oil (128 mg). .sup.1H NMR (400 MHz,
CDCl.sub.3): 8.07 (m, 1H), 7.37 (m, 1H), 7.29 (m, 1H), 7.22 (m,
1H), 6.91-6.84 (m, 2H), 6.54 (m, 1H), 6.37 (m, 1H), 5.00 (m, 1H),
4.48 (d, J=5.6, 2H), 4.04 (t, J=6.3 Hz, 2H), 2.52 (m, 2H), 2.41
(br, 4H), 2.02 (m, 2H), 1.64-1.57 (m, 4H), 1.47-1.40 (m, 2H).
Example 66
##STR00081##
[0392] [3-(3-Piperidin-1-yl-propoxy)-benzyl]-pyridin-2-yl-amine
[0393] A solution of the product of Example 13 (262 mg),
2-aminopyridine (104 mg), and acetic acid (0.07 mL) in DCM (5 mL)
was treated with sodium triacetoxyborohydride (410 mg). After 16 h,
the resulting mixture was treated with 10% sodium hydroxide (6 mL)
and extracted with DCM (3.times.10 mL). The combined organic phases
were dried (sodium sulfate) and evaporated. Chromatography of the
residue (1-5% 2 M methanolic ammonia/DCM) gave the title compound
as a colorless oil (114 mg). .sup.1H NMR (400 MHz, CDCl.sub.3):
8.10 (m, 1H), 7.39 (m, 1H), 7.22 (m, 1H), 6.94-6.89 (m, 2H), 6.79
(m, 1H), 6.58 (m, 1H), 6.36 (m, 1H), 4.89 (m, 1H), 4.46 (d, J=5.6,
2H), 3.98 (t, J=6.3 Hz, 2H), 2.47 (m, 2H), 2.41 (br, 4H), 1.97 (m,
2H), 1.63-1.56 (m, 4H), 1.47-1.40 (m, 2H).
Example 67
##STR00082##
[0394]
(4-Chloro-phenyl)-[2-(3-piperidin-1-yl-propoxy)-benzyl]-amine
[0395] A solution of 2-(3-piperidin-1-yl-propoxy)-benzaldehyde (266
mg), 4-chloroaniline (146 mg), and acetic acid (0.07 mL) in DCM (5
mL) was treated with sodium triacetoxyborohydride (400 mg). After
16 h, the resulting mixture was treated with 10% sodium hydroxide
(6 mL) and extracted with DCM (3.times.10 mL). The combined organic
phases were dried (sodium sulfate) and evaporated. Chromatography
of the residue (1-5% 2 M methanolic ammonia/DCM) gave the title
compound as a colorless oil (246 mg). .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.28-7.20 (m, 2H), 7.09 (d, J=8.9 Hz, 2H), 6.89 (m,
2H), 6.55 (d, J=8.9 Hz, 2H), 4.30 (d, J=5.6, 2H), 4.18 (m, 1H),
4.05 (t, J=6.3 Hz, 2H), 2.47 (m, 2H), 2.37 (br, 4H), 1.96 (m, 2H),
1.62-1.56 (m, 4H), 1.49-1.42 (m, 2H).
Example 68
##STR00083##
[0396]
(4-Chloro-phenyl)-[3-(3-piperidin-1-yl-propoxy)-benzyl]-amine
[0397] A solution of the product of Example 13 (268 mg),
4-chloroaniline (145 mg), and acetic acid (0.07 mL) in DCM (5 mL)
was treated with sodium triacetoxyborohydride (400 mg). After 16 h,
the resulting mixture was treated with 10% sodium hydroxide (6 mL)
and extracted with DCM (3.times.10 mL). The combined organic phases
were dried (sodium sulfate) and evaporated. Chromatography of the
residue (1-5% 2 M methanolic ammonia/DCM) gave the title compound
as a colorless oil (154 mg). .sup.1H NMR (400 MHz, CDCl.sub.3):
7.24 (m, 2H),7.10 (d, J=8.9 Hz, 2H), 6.93-6.88 (m, 2H), 6.81 (m,
1H), 6.54 (d, J=8.9 Hz, 2H), 4.26 (d, J=5.6, 2H), 4.07 (m, 1H),
3.99 (t, J=6.3 Hz, 2H), 2.46 (m, 2H), 2.40 (br, 4H), 1.96 (m, 2H),
1.62-1.56 (m, 4H), 1.49-1.42 (m, 2H).
Example 69
##STR00084##
[0398]
2-{1-[3-(4-Piperidin-1-ylmethyl-phenoxy)-propyl]-piperidin-2-yl}-et-
hanol
[0399] A suspension of the product of Example 12 (268 mg),
2-hydroxyethylpiperidine (168 mg), sodium carbonate (159 g), and
potassium iodide (8.3 mg) in 1-butanol (4 mL) was heated to
105.degree. C. for 16 h, cooled to RT, diluted with water (2 mL)
and extracted with DCM (3.times.5 mL). The combined organic phases
were dried (magnesium sulfate) and evaporated. Chromatography of
the residue (4% 2 M methanolic ammonia/DCM) gave the title compound
as a colorless glassy solid (53 mg). .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.20 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 3.97
(t, J=6.3 Hz, 2H), 3.91-3.84 (m,1H), 3.78-3.71 (m, 1H), 3.40 (s,
2H), 3.10-2.94 (m, 2H), 2.74-2.64 (m, 2H), 2.39-2.31 (m, 5H),
2.02-1.86 (m, 3H), 1.75-1.35 (m,14H).
Example 70
##STR00085##
[0400]
1-{3-[2-(4-Benzylidene-piperidin-1-ylmethyl)-phenoxy]-propyl}-piper-
idine
[0401] A solution of 2-(3-piperidin-1-yl-propoxy)-benzaldehyde (212
mg), 4-benzylidene-piperidine (154 mg), and acetic acid (0.05 mL)
in DCM (3 mL) was treated with sodium triacetoxyborohydride (290
mg). After 16 h, the resulting mixture was treated with 10% sodium
hydroxide (6 mL) and extracted with DCM (3.times.10 mL). The
combined organic phases were dried (sodium sulfate) and evaporated.
Chromatography of the residue (1-5% 2 M methanolic ammonia/DCM)
gave the title compound as a colorless oil (148 mg). .sup.1H NMR
(400 MHz, CDCl.sub.3): 7.37 (m, 1H), 7.30 (m, 2H), 7.23-7.16 (m,
4H), 6.92 (m, 1H), 6.86 (m, 1H), 6.27 (s, 1H), 4.00 (t, J=6.3 Hz,
2H), 3.60 (s, 2H), 2.60 (m, 2H), 2.55-2.46 (m, 6H), 2.44-2.37 (m,
6H), 2.00 (m, 2H), 1.64-1.56 (m, 4H), 1.47-1.40 (m, 2H).
Example 71
##STR00086##
[0402]
1-{3-[3-(4-Benzylidene-piperidin-1-ylmethyl)-phenoxy]-propyl}-piper-
idine
[0403] A solution of the product of Example 13 (210 mg),
4-Benzylidene-piperidine (153 mg), and acetic acid (0.05 mL) in DCM
(3 mL) was treated with sodium triacetoxyborohydride (290 mg).
After 16 h, the resulting mixture was treated with 10% sodium
hydroxide (6 mL) and extracted with DCM (3.times.10 mL). The
combined organic phases were dried (sodium sulfate) and evaporated.
Chromatography of the residue (1-5% 2 M methanolic ammonia/DCM)
gave the title compound as a colorless oil (189 mg). .sup.1H NMR
(400 MHz, CDCl.sub.3): 7.30 (m, 2H), 7.23-7.16 (m, 3H), 6.89 (m,
2H), 6.79 (m, 1H), 6.27 (s, 1H), 4.00 (t, J=6.3 Hz, 2H), 3.49 (s,
2H), 2.55-2.46 (m, 6H), 2.45-2.37 (m, 6H), 1.99 (m, 2H), 1.64-1.56
(m, 4H), 1.47-1.40 (m, 2H).
Example 72
##STR00087##
[0404]
1-{3-[4-(4-Benzylidene-piperidin-1-ylmethyl)-phenoxy]-propyl}-piper-
idine
[0405] A solution of the product of Example 9 (204 mg),
4-Benzylidene-piperidine (145 mg), and acetic acid (0.05 mL) in DCM
(3 mL) was treated with sodium triacetoxyborohydride (300 mg).
After 16 h, the resulting mixture was treated with 10% sodium
hydroxide (5 mL) and extracted with DCM (3.times.10 mL). The
combined organic phases were dried (magnesium sulfate) and
evaporated. Chromatography of the residue (1 to 5% 2 M methanolic
ammonia/DCM) gave the title compound as a colorless oil (308 mg).
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.30 (m, 2H), 7.24-7.16 (m, 4H),
6.84 (m, 2H), 6.26 (s,1H), 3.99 (t, J=6.3 Hz, 2H), 3.46 (s, 2H),
2.54-2.44 (m, 6H), 2.43-2.35 (m, 6H), 1.97 (m, 2H), 1.74 (br, 1H),
1.63-1.56 (m, 4H), 1.47-1.40 (m, 2H).
Example 73
##STR00088##
[0406]
2-Methyl-1-[3-(4-piperidin-1-ylmethyl-phenoxy)-propyl]-piperidine
[0407] A suspension of the product of Example 17 (176 mg),
3-(2-methyl-piperidin-1-yl)-propan-1-ol (145 mg), and polymer
supported triphenylphosphine (613 mg; loading: 3 mmol/g) in DCM (5
mL) was treated with di-tert-butylazodicarboxylate (316 mg). After
2 h, the resulting mixture was filtered, and the filtrate was
evaporated. Chromatography of the residue (2.5% 2 M methanolic
ammonia/DCM) gave the title compound as a colorless oil (60 mg).
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.20 (d, J=8.6 Hz, 2H), 6.83 (d,
J=8.6 Hz, 2H), 4.01-3.92 (m, 2H), 3.40 (s, 2H), 2.90-2.81 (m, 2H),
2.56-2.47 (m, 1H), 2.40-2.25 (m, 5H), 2.21-2.14 (m, 1H), 1.97-1.88
(m, 2H), 1.70-1.51 (m, 8H), 1.45-1.25 (m, 4H), 1.07 (d, J=6.2 Hz,
3H).
Example 74
##STR00089##
[0408]
Methyl-phenethyl-[3-(3-piperidin-1-yl-propoxy)-benzyl]-amine
[0409] A solution of the product of Example 13 (103 mg),
methyl-phenethyl-amine (56 mg), and acetic acid (0.03 mL) in DCM (2
mL) was treated with sodium triacetoxyborohydride (150 mg). After
16 h, the resulting mixture was treated with 10% sodium hydroxide
(5 mL) and extracted with DCM (3.times.10 mL). The combined organic
phases were dried (sodium sulfate) and evaporated. Chromatography
of the residue (1-5% 2 M methanolic ammonia/DCM) gave the title
compound as a colorless oil (26 mg). .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.30-7.25 (m, 2H), 7.22-7.16 (m, 4H), 6.87-6.84 (m,
2H), 6.78 (m,1H), 3.97 (t, J=6.3 Hz, 2H), 3.52 (s, 2H), 2.82 (m,
2H), 2.64 (m, 2H), 2.48 (m, 2H), 2.40 (br, 4H), 2.28 (s, 3H), 1.97
(m, 2H), 1.63-1.56 (m, 4H), 1.47-1.40 (m, 2H).
Example 75
##STR00090##
[0410]
1-(3-Phenyl-allyl)-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazi-
ne
[0411] A solution of the product of Example 9 (215 mg),
1-(3-phenyl-allyl)-piperazine (176 mg), and acetic acid (0.06 mL)
in DCM (3 mL) was treated with sodium triacetoxyborohydride (290
mg). After 16 h, the resulting mixture was treated with 10% sodium
hydroxide (5 mL) and extracted with DCM (3.times.10 mL). The
combined organic phases were dried (sodium sulfate) and evaporated.
Chromatography of the residue (1-5% 2 M methanolic ammonia/DCM)
gave the title compound as a colorless oil (303 mg). .sup.1H NMR
(400 MHz, CDCl.sub.3): 7.36 (m, 2H), 7.30 (m, 2H), 7.24-7.18 (m,
3H), 6.83 (d, J=8.6 Hz, 2H), 6.51 (d, J=15.9 Hz, 1H), 6.31-6.23 (m,
1H), 3.98 (t, J=6.3 Hz, 2H), 3.45 (s, 2H), 3.15 (m, 2H), 2.60-2.32
(m, 12H), 1.67 (br, 1H), 1.62-1.56 (m, 4H), 1.47-1.40 (m, 2H).
Example 76
##STR00091##
[0412]
Methyl-(1-methyl-piperidin-4-yl)-[4-(3-piperidin-1-yl-propoxy)-benz-
yl]-amine
[0413] A solution of the product of Example 9 (227 mg),
methyl-(1-methyl-piperidin-4-yl)-amine (118 mg), and acetic acid
(0.06 mL) in DCM (3 mL) was treated with sodium
triacetoxyborohydride (290 mg). After 16 h, the resulting mixture
was treated with 10% sodium hydroxide (5 mL) and extracted with DCM
(3.times.10 mL). The combined organic phases were dried (sodium
sulfate) and evaporated. Chromatography of the residue (1-5% 2 M
methanolic ammonia/DCM) gave the title compound as a colorless oil
(270 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.19 (d, J=8.6 Hz,
2H), 6.83 (d, J=8.6 Hz, 2H), 3.98 (t, J=6.3 Hz, 2H), 3.49 (s, 2H),
2.90 (m, 2H), 2.78 (m, 2H), 2.46 (m, 2H), 2.43-2.35 (m, 4H), 2.26
(s, 3H), 2.17 (s, 3H), 2.00-1.87 (m, 5H), 1.78 (m, 2H), 1.68 (m,
2H), 1.61-1.54 (m, 4H), 1.47-1.40 (m, 2H).
Example 77
##STR00092##
[0414]
1-Isopropyl-4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperidin-4-ol
[0415] A solution of the product of Example 5 (297 mg) in THF (2
mL) was cooled in a -78.degree. C. bath and treated with a 1.6 M
solution of butyllithium in hexanes (0.69 mL). After 1 h, a
solution of 1-benzyl-piperidin-4-one (0.19 mL) in THF (1 mL) was
added, and the mixture was allowed to warm to RT. After 1 h, water
(2 mL) was added. The mixture was extracted with ether (2.times.2
mL), and the combined organic phases were dried (magnesium
sulfate), and evaporated. Chromatography of the residue (3% 2 M
methanolic ammonia/DCM) gave the title compound as an amorphous
white solid (94 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.42 (d,
J=9.0 Hz, 2H), 6.87 (d, J=9.0 Hz, 2H), 3.99 (t, J=6.5 Hz, 2H),
2.82-2.74 (m, 3H), 2.66-2.58 (m, 2H), 2.48-2.34 (m, 5H), 2.18-2.08
(m, 2H), 2.01-1.74 (m, 5H), 1.63-1.52 (m, 5H), 1.47-1.39 (m, 2H),
1.10 (d, J=6.7Hz, 6H).
Example 78
##STR00093##
[0416]
Methyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-(2-pyridin-2-yl-ethyl)-
-amine
[0417] A solution of the product of Example 9 (256 mg),
methyl-(2-pyridin-2-yl-ethyl)-amine (143 mg), and acetic acid (0.06
mL) in DCM (4 mL) was treated with sodium triacetoxyborohydride
(330 mg). After 16 h, the resulting mixture was treated with 10%
sodium hydroxide (5 mL) and extracted with DCM (3.times.10 mL). The
combined organic phases were dried (sodium sulfate) and evaporated.
Chromatography of the residue (1-5% 2 M methanolic ammonia/DCM)
gave the title compound as a colorless oil (325 mg). .sup.1H NMR
(400 MHz, CDCl.sub.3): 8.51 (m, 1H), 7.57 (m, 1H), 7.18-7.12 (m,
3H),7.10 (m, 1H), 6.82 (d, J=8.6 Hz, 2H), 3.98 (t, J=6.3 Hz, 2H),
3.49 (s, 2H), 2.99 (m, 2H), 2.78 (m, 2H), 2.46 (m, 2H), 2.39 (br,
4H), 2.25 (s, 3H), 2.96 (m, 2H), 1.61-1.54 (m, 4H), 1.47-1.40 (m,
2H).
Example 79
##STR00094##
[0418]
Ethyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-pyridin-4-ylmethyl-amin-
e
[0419] A solution of the product of Example 9 (222 mg)
ethyl-pyridin-4-ylmethyl-amine (122 mg), and acetic acid (0.06 mL)
in DCM (3 mL) was treated with sodium triacetoxyborohydride (290
mg). After 16 h, the resulting mixture was treated with 10% sodium
hydroxide (5 mL) and extracted with DCM (3.times.10 mL). The
combined organic phases were dried (sodium sulfate) and evaporated.
Chromatography of the residue (1-5% 2 M methanolic ammonia/DCM)
gave the title compound as a colorless oil (246 mg). .sup.1H NMR
(400 MHz, CDCl.sub.3): 8.51 (m, 2H), 7.29 (m, 2H), 7.24 (m, 2H),
6.84 (d, J=8.6 Hz, 2H), 3.98 (t, J=6.3 Hz, 2H), 3.52 (s, 2H), 3.50
(s, 2H), 2.51-2.44 (m, 4H), 2.40 (br, 4H), 1.97 (m, 2H), 1.62-1.55
(m, 4H), 1.47-1.40 (m, 2H), 1.06 (t, J=7.0 Hz, 3H).
Example 80
##STR00095##
[0420]
Benzyl-methyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine
[0421] A solution of the product of Example 9 (218 mg), benzyl
methylamine (108 mg), and acetic acid (0.05 mL) in DCM (3 mL) was
treated with sodium triacetoxyborohydride (300 mg). After 16 h, the
resulting mixture was treated with 10% sodium hydroxide (5 mL) and
extracted with DCM (3.times.10 mL). The combined organic phases
were dried (sodium sulfate) and evaporated. Chromatography of the
residue (1-5% 2 M methanolic ammonia/DCM) gave the title compound
as a colorless oil (269 mg). .sup.1H NMR (400 MHz, CDCl.sub.3):
7.37-7.28 (m, 4H), 7.27-7.22 (m, 5H), 6.85 (d, J=8.6 Hz, 2H), 3.99
(t, J=6.3 Hz, 2H), 3.49 (s, 2H), 3.45 (s, 2H), 2.50-2.31 (m, 6H),
2.16 (s, 3H), 1.97 (m, 2H), 1.62-1.55 (m, 4H), 1.47-1.40 (m,
2H).
Example 81
##STR00096##
[0422] Diethyl-[2-(4-piperidin-1-ylmethyl-phenoxy)-ethyl]-amine
[0423] A suspension of the product of Example 17 (176 mg),
2-Diethylamino-ethanol (0.12 mL), and polymer supported
triphenylphosphine (613 mg; loading: 3 mmol/g) in DCM (5 mL) was
treated with di-tert-butylazodicarboxylate (316 mg). After 2 h, the
resulting mixture was filtered, and the filtrate was evaporated.
Chromatography of the residue (3% 2 M methanolic ammonia/DCM) gave
the title compound as a pale yellow oil (37 mg). .sup.1H NMR (400
MHz, CDCl.sub.3): 7.20 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H),
4.03 (t, J=6.5 Hz, 2H), 3.40 (s, 2H), 2.87 (t, J=6.5 Hz, 2H), 2.63
(q, J=7.0 Hz, 4H), 2.35 (br s, 4H), 1.59-1.52 (m, 4H), 1.46-1.37
(m, 2H), 1.07 (t, J=7.1 Hz, 6H).
Example 82
##STR00097##
[0424]
[2-(3,4-Dimethoxy-phenyl)-ethyl]-methyl-[4-(3-piperidin-1-yl-propox-
y)-benzyl]-amine
[0425] A solution of the product of Example 9 (214 mg),
[2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amine (170 mg), and acetic
acid (0.05 mL) in DCM (3 mL) was treated with sodium
triacetoxyborohydride (300 mg). After 16 h, the resulting mixture
was treated with 10% sodium hydroxide (5 mL) and extracted with DCM
(3.times.10 mL). The combined organic phases were dried (sodium
sulfate) and evaporated. Chromatography of the residue (1-5% 2 M
methanolic ammonia/DCM) gave the title compound as a colorless oil
(350 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.18 (d, J=8.6 Hz,
2H), 6.85-6.69 (m, 5H), 3.99 (t, J=6.3 Hz, 2H), 3.85 (s, 6H), 3.48
(s, 2H), 2.79-2.74 (m, 2H), 2.63-2.58 (m, 2H), 2.50-2.35 (m, 6H),
2.25 (s, 3H), 1.97 (m, 2H), 1.63-1.56 (m, 4H), 1.47-1.40 (m,
2H).
Example 83
##STR00098##
[0426]
Methyl-phenethyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine
[0427] A solution of the product of Example 9 (208 mg),
methyl-phenethyl-amine (113 mg), and acetic acid (0.05 mL) in DCM
(3 mL) was treated with sodium triacetoxyborohydride (290 mg).
After 16 h, the resulting mixture was treated with 10% sodium
hydroxide (5 mL) and extracted with DCM (3.times.10 mL). The
combined organic phases were dried (sodium sulfate) and evaporated.
Chromatography of the residue (1-5% 2 M methanolic ammonia/DCM)
gave the title compound as a colorless oil (300 mg). .sup.1H NMR
(400 MHz, CDCl.sub.3): 7.30-7.25 (m, 2H), 7.21-7.16 (m, 5H), 6.83
(d, J=8.6 Hz, 2H), 3.99 (t, J=6.3 Hz, 2H), 3.49 (s, 2H),2.84-2.79
(m, 2H), 2.65-2.62 (m, 2H), 2.51-2.37 (m, 6H), 2.26 (s, 3H), 1.98
(m, 2H), 1.63-1.56 (m, 4H), 1.47-1.40 (m, 2H).
Example 84
##STR00099##
[0428] [4-(3-Piperidin-1-yl-propoxy)-benzyl]-pyridin-2-yl-amine
[0429] A solution of the product of Example 9 (0.51 g),
2-aminopyridine (0.24 g), and acetic acid (0.12 mL) in DCM (7 mL)
was treated with sodium triacetoxyborohydride (650 mg). After 16 h,
the resulting mixture was treated with 10% sodium hydroxide (10 mL)
and extracted with DCM (3.times.10 mL). The combined organic phases
were dried (sodium sulfate) and evaporated. Chromatography of the
residue (1-4% 2 M methanolic ammonia/DCM) gave the title compound
as an off white solid (440 mg). .sup.1H NMR (400 MHz, CDCl.sub.3):
8.05 (m, 1H), 7.35 (m, 1H), 7.23 (d, J=8.6 Hz, 2H), 6.83 (d, J=8.6
Hz, 2H), 6.53 (m, 1H), 6.32 (m, 1H), 5.05 (m, 1H), 4.37 (d, J=5.6,
2H), 3.95 (t, J=6.3 Hz, 2H), 2.44 (m, 2H), 2.37 (br, 4H), 1.94 (m,
2H), 1.59-1.53 (m, 4H), 1.45-1.38 (m, 2H).
Example 85
##STR00100##
[0430]
(4-Chloro-phenyl)-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine
[0431] A solution of the product of Example 9 (260 mg),
4-chloroaniline (180 mg), and acetic acid (0.06 mL) in DCE (3 mL)
was treated with sodium triacetoxyborohydride (360 mg). After 16 h,
the resulting mixture was treated with 10% sodium hydroxide (5 mL)
and extracted with DCM (3.times.10 mL). The combined organic phases
were dried (sodium sulfate) and evaporated. Chromatography of the
residue (1-5% 2 M methanolic ammonia/DCM) gave the title compound
as a colorless oil (168 mg). .sup.1H NMR (400 MHz, CDCl.sub.3):
7.25 (d, J=8.8 Hz, 2H),7.10 (d, J=8.9 Hz, 2H), 6.87 (d, J=8.8 Hz,
2H), 6.54 (d, J=8.9 Hz, 2H), 4.21 (d, J=4.7, 2H), 3.99 (t, J=6.3
Hz, 2H), 2.52-2.38 (m, 6H), 1.99 (m, 2H), 1.64-1.57 (m, 4H),
1.49-1.42 (m, 2H).
Example 86
##STR00101##
[0432]
4-(4-Chloro-phenyl)-1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperid-
in-4-ol
[0433] A solution of the product of Example 9 (200 mg),
4-(4-chloro-phenyl)-piperidin-4-ol (170 mg), and acetic acid (0.05
mL) in DCM (3 mL) was treated with sodium triacetoxyborohydride
(300 mg). After 16 h, the resulting mixture was treated with 10%
sodium hydroxide (5 mL) and extracted with DCM (3.times.10 mL). The
combined organic phases were dried (sodium sulfate) and evaporated.
Chromatography of the residue (1-5% 2 M methanolic ammonia/DCM)
gave the title compound as a colorless oil (203 mg). .sup.1H NMR
(400 MHz, CDCl.sub.3): 7.46-7.42 (m, 2H), 7.32-7.28 (m, 2H),
7.25-7.22 (m, 2H), 6.87-6.84 (m, 2H), 3.99 (t, J=6.3 Hz, 2H), 3.51
(s, 2H), 2.78 (m, 2H), 2.51-2.36 (m, 8H), 2.11 (m, 2H), 1.98 (m,
2H), 1.69 (m, 2H), 1.63-1.56 (m, 4H), 1.48-1.40 (m, 2H).
Example 87
##STR00102##
[0434]
4-Phenyl-1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-ol
[0435] A solution of the product of Example 9 (210 mg),
4-Phenyl-piperidin-4-ol (150 mg), and acetic acid (0.05 mL) in DCM
(3 mL) was treated with sodium triacetoxyborohydride (290 mg).
After 16 h, the resulting mixture was treated with 10% sodium
hydroxide (5 mL) and extracted with DCM (3.times.10 mL). The
combined organic phases were dried (sodium sulfate) and evaporated.
Chromatography of the residue (1-5% 2 M methanolic ammonia/DCM)
gave the title compound as a colorless oil (225 mg). .sup.1H NMR
(400 MHz, CDCl.sub.3): 7.54-7.49 (m, 2H), 7.37-7.33 (m, 2H),
7.28-7.23 (m, 3H), 6.88-6.84 (m, 2H), 3.99 (t, J=6.3 Hz, 2H), 3.51
(s, 2H), 2.78 (m, 2H), 2.50-2.36 (m, 8H), 2.15 (m, 2H), 1.97 (m,
2H), 1.73 (m, 2H), 1.63-1.55 (m, 4H), 1.47-1.40 (m, 2H).
Example 88
##STR00103##
[0436]
1-Isopropyl-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine
[0437] A solution of the product of Example 9 (200 mg),
1-isopropyl-piperazine (100 mg), and acetic acid (0.05 mL) in DCM
(3 mL) was treated with sodium triacetoxyborohydride (290 mg).
After 16 h, the resulting mixture was treated with 10% sodium
hydroxide (5 mL) and extracted with DCM (3.times.10 mL). The
combined organic phases were dried (sodium sulfate) and evaporated.
Chromatography of the residue (1-5% 2 M methanolic ammonia/DCM)
gave the title compound as a colorless oil (225 mg). .sup.1H NMR
(400 MHz, CDCl.sub.3): 7.19 (d, J=8.6 Hz, 2H), 6.83 (d, J=8.6 Hz,
2H), 3.98 (t, J=6.6 Hz, 2H), 3.43 (s, 2H), 2.63 (m, 1H), 2.53 (br,
4H), 2.46 (m, 4H), 2.39 (br, 4H), 1.96 (m, 2H), 1.58 (m, 4H),
1.46-1.40 (m, 2H), 1.03 (d, J=6.5 Hz, 6H).
Example 89
##STR00104##
[0438] 1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-ol
[0439] A solution of the product of Example 9 (175 mg),
4-hydroxypiperidine (79 mg), and acetic acid (0.01 mL) in DCE (3
mL) was treated with sodium triacetoxyborohydride (231 mg). After
16 h, the resulting mixture was treated with 10% sodium hydroxide
(1 mL) and extracted with DCM (3.times.3 mL). The combined organic
phases were dried (magnesium sulfate) and evaporated.
Chromatography of the residue (6% 2 M methanolic ammonia/DCM) gave
the title compound as a white crystalline solid (63 mg). .sup.1H
NMR (400 MHz, CDCl.sub.3): 7.19 (d, J=8.6 Hz, 2H), 6.84 (d, J=8.6
Hz, 2H), 3.99 (t, J=6.5 Hz, 2H), 3.71-3.62 (m,1H), 3.43 (s, 2H),
2.77-2.69 (m, 2H), 2.49-2.34 (m, 6H), 2.15-2.05 (m, 2H), 2.01-1.92
(m, 2H), 1.91-1.82 (m, 2H), 1.76 (br s,1H), 1.62-1.52 (m, 6H),
1.47-1.40 (m, 2H).
Example 90
##STR00105##
[0440]
1-Benzyl-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine
[0441] A solution of the product of Example 9 (175 mg),
1-benzylpiperazine (0.14 mL), and acetic acid (0.09 mL) in DCE (3
mL) was treated with sodium triacetoxyborohydride (210 mg). After
16 h, the resulting mixture was treated with 10% sodium hydroxide
(1 mL) and extracted with DCM (3.times.3 mL). The combined organic
phases were dried (magnesium sulfate) and evaporated.
Chromatography of the residue (2% 2 M methanolic ammonia/DCM) gave
the title compound as a white solid (63 mg). .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.32-7.17 (m, 7H), 6.83 (d, J=8.6 Hz, 2H), 3.98 (t,
6.4 Hz, 2H), 3.50 (s, 2H), 3.44 (s, 2H), 2.52-2.35 (m, 14H),
2.00-1.92 (m, 2H), 1.62-1.55 (m, 4H), 1.47-1.39 (m, 2H).
Example 91
##STR00106##
[0442]
1-Phenyl-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine
[0443] A solution of the product of Example 9 (175 mg),
1-phenylpiperazine (0.12 mL), and acetic acid (0.09 mL) in DCE (3
mL) was treated with sodium triacetoxyborohydride (210 mg). After
16 h, the resulting mixture was treated with 10% sodium hydroxide
(1 mL) and extracted with DCM (3.times.3 mL). The combined organic
phases were dried (magnesium sulfate) and evaporated.
Chromatography of the residue (2% 2 M methanolic ammonia/DCM) gave
the title compound as a white solid (70 mg). .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.28-7.22 (m, 4H), 6.94-6.81 (m, 5H), 4.00 (t, J=6.5
Hz, 2H), 3.50 (s, 2H), 3.21-3.16 (m, 4H), 2.61-2.56 (m, 4H),
2.50-2.35 (m, 6H), 2.02-1.94 (m, 2H), 1.63-1.56 (m, 4H), 1.48-1.40
(m, 2H).
Example 92
##STR00107##
[0444]
Dibenzyl-(3-{2-[4-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrol-1-yl}-p-
ropyl)-amine
[0445] To a stirred suspension of sodium hydride (0.14 g) in DMF (9
mL) at RT was added dropwise a solution of the product of Example
18 (1 g) in DMF (9 mL). After 20 min,
1-(3-bromopropyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane
(0.876 mL) was added dropwise. After 20 min, the mixture was
carefully treated with water (30 mL) and then extracted several
times with methylene chloride. The combined organic layers were
washed with brine, dried (sodium sulfate), filtered, and
concentrated under reduced, giving a dark red oil (1.2 g). To a
solution of this oil (0.211 g) in dichloroethane (6 mL) was added
benzaldehyde (0.138 mL), acetic acid (0.138 mL), and sodium
triacetoxyborohydride (0.367 g). The mixture was stirred for 12 h
at RT and then diluted with methylene chloride and saturated
aqueous sodium bicarbonate solution. The organic layer was
separated and the aqueous layer extracted with several portions of
methylene chloride. The combined organic layers were washed with
brine, dried (sodium sulfate), filtered and concentrated under
reduced pressure to give an orange oil (0.289 g). Silica gel
chromatography (2% methanol/ethyl acetate) afforded the title
compound as a yellow oil (0.103 g). .sup.1H NMR (400 MHz,
MeOH-d.sub.4): 7.30-7.17 (m, 12H), 6.90-6.86 (m, 2H), 6.58-6.57 (m,
1H), 6.01 (t, 3 Hz, 1H), 5.97-5.95 (m, 1H), 3.95 (t, J=6.3 Hz, 2H),
3.88 )t, J=7.6 Hz), 3.37 (s, 4H), 2.55-2.4 (m, 6H), 2.29 (t, J=6.6
Hz, 2H), 2.02-1.95 (m, 2H), 1.75-1.68 (m, 2H), 1.66-1.58 (m, 4H),
1.53-1.43 (m, 2H).
Example 93
##STR00108##
[0446]
1-{3-[4-(4-Benzyl-piperidin-1-ylmethyl)-phenoxy]-propyl}-piperidine
[0447] A solution of the product of Example 9 (175 mg),
4-benzylpiperidine (0.14 mL), and acetic acid (0.09 mL) in DCE (3
mL) was treated with sodium triacetoxyborohydride (210 mg). After
16 h, the resulting mixture was treated with 10% sodium hydroxide
(1 mL) and extracted with DCM (3.times.3 mL). The combined organic
phases were dried (magnesium sulfate) and evaporated.
Chromatography of the residue (1.5% 2 M methanolic ammonia/DCM)
gave the title compound as a colorless oil (97 mg). .sup.1H NMR
(400 MHz, CDCl.sub.3): 7.29-7.10 (m, 7H), 6.81 (d, J=8.3 Hz, 2H),
3.99 (t, J=6.3 Hz, 2H), 3.40 (s, 2H), 2.86-2.81 (m, 2H), 2.54-2.44
(m, 4H), 2.00-1.81 (m, 4H), 1.65-1.40 (m, 13H), 1.35-1.23 (m,
2H).
Example 94
##STR00109##
[0448] 4-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-morpholine
[0449] A solution of the product of Example 9 (175 mg), morpholine
(0.07 mL), and acetic acid (0.09 mL) in DCE (3 mL) was treated with
sodium triacetoxyborohydride (210 mg). After 16 h, the resulting
mixture was treated with 10% sodium hydroxide (1 mL) and extracted
with DCM (3.times.3 mL). The combined organic phases were dried
(magnesium sulfate) and evaporated. Chromatography of the residue
(3.5% 2 M methanolic ammonia/DCM) gave the title compound as a
colorless oil (145 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.21 (d,
J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 3.99 (t, J=6.4 Hz, 2H),
3.71-3.67 (m, 4H), 3.42 (s, 2H), 2.50-2.36 (m, 10H), 2.01-1.93 (m,
2H), 1.63-1.56 (m, 4H), 1.49-1.40 (m, 2H).
Example 95
##STR00110##
[0450]
1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-1,2,3,4-tetrahydro-quinolin-
e
[0451] A solution of the product of Example 9 (175 mg),
1,2,3,4-tetrahydro-quinoline (0.10 mL), and acetic acid (0.09 mL)
in DCE (3 mL) was treated with sodium triacetoxyborohydride (210
mg). After 16 h, the resulting mixture was treated with 10% sodium
hydroxide (1 mL) and extracted with DCM (3.times.3 mL). The
combined organic phases were dried (magnesium sulfate) and
evaporated. Chromatography of the residue (1.5% 2 M methanolic
ammonia/DCM) gave the title compound as a colorless oil (77 mg).
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.13 (d, J=8.8 Hz, 2H), 6.96 (t,
J=7.3 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 6.58-6.51 (m, 2H), 4.40 (s,
2H), 3.97 (t, J=6.3 Hz, 2H), 3.32 (dd, J=5.7, 5.7 Hz, 2H), 2.79 (t,
J=6.3 Hz, 2H), 2.50-2.35 (m, 6H), 2.02-1.92 (m, 4H), 1.62-1.55 (m,
4H), 1.47-1.39 (m, 2H).
Example 96
##STR00111##
[0452]
1-(3-{4-[1-(3-Piperidin-1-yl-propyl)-1H-pyrrol-2-yl]-phenoxy}-propy-
l)-piperidine
[0453] To a stirred suspension of sodium hydride (0.051 g) in DMF
(3 mL) at RT was added dropwise the product of Example 18 (0.2 g)
in DMF (4 mL). After 20 min, 1-(3-chloro-propyl)-piperdine (0.139
g) was added dropwise and the mixture stirred for 12 h. The mixture
was diluted with water and extracted several times with diethyl
ether. The combined organic layers were washed with brine, dried
(sodium sulfate), filtered and concentrated under reduced pressure,
giving the title compound as a dark red oil (0.257 g). .sup.1H NMR
(400 MHz, C.sub.6D.sub.6): 7.35 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.8
Hz, 2H), 6.72 (t, J=2.5 Hz, 1H), 6.44 (d, J=2.5 Hz), 3.82 (m, 4H),
2.37-2.16 (m, 8H), 2.06 (br s, 4H), 1.96 (t, J=6.6 Hz, 2H),
1.87-1.81 (m, 2H), 1.59-1.22 (m, 16H).
Example 97
##STR00112##
[0454]
Diethyl-[3-(4-piperidin-1-ylmethyl-phenoxy)-propyl]-amine
[0455] A suspension of the product of Example 17 (176 mg),
3-diethylaminolpropan-1-ol (0.14 mL), and polymer-supported
triphenylphosphine (613 mg, 3 mmol/g phosphorus content) in
dichloromethane (4 mL) was treated with a solution of di-tert-butyl
azodicarboxylate (318 mg) in dichloromethane (1 mL). The resulting
mixture was stirred for 3 h and filtered. Chromatography of the
filtrate (0-8% 2M methanolic ammonia/dichloromethane) gave the
title compound as a pale yellow oil (130 mg). .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.20 (d, J=8.6 Hz, 2H), 6.82 (d, J=8.6 Hz, 2H), 3.98
(t, J=3.98 Hz, 2H), 3.42 (s, 2H), 2.64-2.52 (m, 6H), 2.41-2.33 (m,
4H), 1.96-1.86 (m, 2H), 1.59-1.53 (m, 4H), 1.44-1.38 (m, 2H).1.04
(t, J=7.2 Hz, 6H).
Example 98
Biological Methods
In Vitro
[0456] Transfection of Cells with Human Histamine Receptor
[0457] A 10 cm tissue culture dish with a confluent monolayer of
SK--N-MC cells was split two days prior to transfection. Using
sterile technique the media was removed and the cells were detached
from the dish by the addition of trypsin. One fifth of the cells
were then placed onto a new 10 cm dish. Cells were grown in a
37.degree. C. incubator with 5% CO.sub.2 in Minimal Essential Media
Eagle with 10% Fetal Bovine Serum. After two days cells were
approximately 80% confluent. These were removed from the dish with
trypsin and pelleted in a clinical centrifuge. The pellet was then
re-suspended in 400 .mu.L complete media and transferred to an
electroporation cuvette with a 0.4 cm gap between the electrodes
(Bio-Rad #165-2088). One microgram of supercoiled H.sub.3 receptor
cDNA was added to the cells and mixed. The voltage for the
electroporation was set at 0.25 kV, the capacitance was set at 960
.mu.F. After electroporation the cells were diluted into 10 mL
complete media and plated onto four 10 cm dishes. Because of the
variability in the efficiency of electroporation, four different
concentrations of cells were plated. The ratios used were; 1:20,
1:10, 1:5, with the remainder of the cells being added to the
fourth dish. The cells were allowed to recover for 24 hours before
adding the selection media (complete media with 600 .mu.g/mL G418).
After 10 days dishes were analyzed for surviving colonies of cells.
Dishes with well isolated colonies were used. Cells from individual
colonies were isolated and tested. SK--N-MC cells were used because
they give efficient coupling for inhibition of adenylate cyclase.
The clones that gave the most robust inhibition of adenylate
cyclase in response to histamine were used for further study.
[.sup.3H]-N-methylhistamine Binding
[0458] Cell pellets from histamine H.sub.3 receptor-expressing
SK--N-MC cells were homogenized in 20 mM TrisHCl/0.5 mM EDTA.
Supernatants from a 800 g spin were collected, recentrifuged at
30,000 g for 30 minutes. Pellets were re-homogenized in 50 mM
Tris/5 mM EDTA (pH 7.4). Membranes were incubated with 0.8 nM
[.sup.3H]-N-methylhistamine plus/minus test compounds for 45 min at
25.degree. C. and harvested by rapid filtration over GF/C glass
fiber filters (pretreated with 0.3% polyethylenimine) followed by
four washes with ice cold buffer. Filters were dried, added to 4 mL
scintillation cocktail and then counted on a liquid scintillation
counter. Non-specific binding was defined with 10 .mu.M histamine.
The pK.sub.i values were calculated based on a K.sub.d of 800 pM
and a ligand concentration ([L]) of 800 pM according to the
formula:
K.sub.i=(IC.sub.50)/(1+([L]/(K.sub.d))
In Vivo
[0459] Elucidation of oral absorption and blood-brain barrier
penetration profiles of H.sub.3 receptor antagonists in the rat
[0460] A rat in vivo system was used to determine the blood-brain
barrier penetration profiles and kinetics of various H.sub.3
receptor antagonists after single bolus oral administration.
[0461] Female Sprague Dawley Rats (.about.300 gram body weight)
were housed in accordance with institutional standards and allowed
to acclimate for at least 7 days prior to the study. Each H.sub.3
antagonist was formulated in 0.5% hydroxypropylmethyl cellulose at
a concentration of 1 mg/mL for oral dosing. The test compound was
administered to each of eight animals as a single oral dose of 10
mL/kg (10 mg/kg). Remaining dosing solution was retained for
analysis. Two animals from each original group of eight were
euthanized via CO.sub.2 asphyxiation at t=1, 6, 24, and 48 hours.
After each animal was euthanized, 0.1 mL of its blood was sampled
via cardiac puncture, and its brain was removed via dissection of
the cranial bones and placed in a pre-weighed 50 mL conical tube on
dry ice.
[0462] The blood was added to 0.3 mL of 6% trichloroacetic acid,
and the acidified sample was vortexed and then centrifuged (5
minutes at 14,000 rpm in a microcentrifuge). The clear supernatant
was retained for analysis. The frozen brain was weighed,
homogenized in 6% trichloroacetic acid (3 mL/g wet weight of
tissue), and then centrifuged. The clear supernatant was retained
for analysis. The supernatants from the blood and brain samples
were analyzed by liquid chromatography with mass spectral detection
utilizing selective reaction monitoring (LC--MS/MS). The LC method
used a Phenomonex Polar RP column (2.times.50 mm) and a linear
solvent gradient of water and acetonitrile (both 1% in acetic
acid).
[0463] Graphs of H.sub.3 receptor antagonist concentration versus
time for blood and brain were generated from the LC-MS/MS results.
The mean residency time (MRT) of the H.sub.3 receptor antagonist,
in blood or in the brain, was calculated from the ratio of the area
under the first moment curve (AUMC) to the area under the
concentration time curve (AUC): AUMC/AUC. The Blood Brain Barrier
index was calculated from the log of
AUC.sub.brain/AUC.sub.blood.
F. Other Embodiments
[0464] The features and advantages of the invention will be
apparent to one of ordinary skill in view of the discussion,
examples, embodiments, and claims relating to the invention. The
invention also contemplates variations and adaptations, based on
the disclosure herein concerning the key features and advantages of
the invention, and within the abilities of one of ordinary
skill.
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