U.S. patent application number 10/215741 was filed with the patent office on 2003-01-23 for 1,4 substituted piperidinyl nmda/nr2b antagonists.
This patent application is currently assigned to Merck & Co., Inc.. Invention is credited to Claremon, David A., Huscroft, Ian, Kulagowski, Janusz, Munson, Peter M., Thompson, Wayne, Whitter, Willie.
Application Number | 20030018038 10/215741 |
Document ID | / |
Family ID | 22585264 |
Filed Date | 2003-01-23 |
United States Patent
Application |
20030018038 |
Kind Code |
A1 |
Thompson, Wayne ; et
al. |
January 23, 2003 |
1,4 substituted piperidinyl NMDA/NR2B antagonists
Abstract
Novel piperidinyl compounds substituted in the 1- and
4-positions are effective as NMDA NR2B antagonists useful for
relieving pain.
Inventors: |
Thompson, Wayne; (Lansdale,
PA) ; Claremon, David A.; (Maple Glen, PA) ;
Munson, Peter M.; (Harleysville, PA) ; Kulagowski,
Janusz; (Sawbridgeworth, GB) ; Whitter, Willie;
(West Point, PA) ; Huscroft, Ian; (Bishops
Stortford, GB) |
Correspondence
Address: |
MERCK AND CO INC
P O BOX 2000
RAHWAY
NJ
070650907
|
Assignee: |
Merck & Co., Inc.
|
Family ID: |
22585264 |
Appl. No.: |
10/215741 |
Filed: |
August 9, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10215741 |
Aug 9, 2002 |
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09696504 |
Oct 25, 2000 |
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6476041 |
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60162352 |
Oct 29, 1999 |
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Current U.S.
Class: |
514/263.21 ;
514/263.22; 514/266.21; 514/266.22; 514/300; 514/322; 544/269;
544/277; 544/284; 546/118; 546/199 |
Current CPC
Class: |
C07D 401/06 20130101;
C07D 471/04 20130101; A61P 25/04 20180101; A61P 25/22 20180101;
A61P 25/24 20180101; A61P 25/18 20180101; A61P 9/10 20180101; A61P
25/06 20180101; A61P 43/00 20180101; A61P 25/16 20180101; C07D
473/00 20130101 |
Class at
Publication: |
514/263.21 ;
514/263.22; 514/266.21; 514/266.22; 514/300; 514/322; 544/277;
544/269; 544/284; 546/118; 546/199 |
International
Class: |
A61K 031/522; A61K
031/52; A61K 031/517; A61K 031/4745; A61K 031/454 |
Claims
What is claimed is:
1. A compound having the formula: 55or a pharmaceutically
acceptable salt thereof, wherein R.sub.1 is i) 2-benzimidazole,
2-imidazopyridine, 2-indole, purine, or 2-quinazoline, each
optionally substituted with one to five substituents, each
substituent independently being chloro, fluoro, bromo,
C.sub.1-C.sub.4alkyl, trifluoromethyl,
C.sub.1-C.sub.4alkylsulfonamide, hydroxy, or carboxy; or ii)
phenyl, optionally substituted with one to five substituents, each
substituent independently being chloro, fluoro, bromo,
C.sub.1-C.sub.4alkyl, trifluoromethyl,
C.sub.1-C.sub.4alkylsulfonamide, hydroxy, or carboxy; R.sub.2 is a)
2-benzimidazole, 2-imidazopyridine, 2-indole, purine, or
2-quinazoline, each optionally substituted with one to five
substituents, each substituent independently being chloro, fluoro,
bromo, C.sub.1-C.sub.4alkyl, trifluoromethyl,
C.sub.1-C.sub.4alkylsulfonamide, hydroxy, or carboxy; or b) phenyl,
optionally substituted with one to five substituents, each
substituent independently being chloro, fluoro, bromo,
C.sub.1-C.sub.4alkyl, trifluoromethyl, C.sub.1-C.sub.4alkylsulfona-
mide, hydroxy, or carboxy; When R.sub.1 is i, then R.sub.2 is b;
when R.sub.1 is ii, then R.sub.2 is a; When R.sub.1 or R.sub.2 is
2-benzimidazole, respective L.sub.1 or L.sub.2 is not
C.sub.1-C.sub.2alkyl, except when R.sub.1 or R.sub.2 is
hydroxy-substituted 2-benzimidazole, respective L.sub.1 or L.sub.2
includes C.sub.1-C.sub.2alkyl L.sub.1 and L.sub.2 are independently
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkenyl,
C.sub.1-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
aminoC.sub.1-C.sub.4alkyl, hydroxyC.sub.1-C.sub.4a- lkyl, carbonyl,
cycloC.sub.3-C.sub.6alkyl or aminocarbonyl; and optionally
substituted at any of the 2, 3, 5, or 6 positions independently
with X, wherein X is hydroxy, amino, C.sub.1-C.sub.4alkylamino,
di(C.sub.1-C.sub.4)alkylamino, C.sub.1-C.sub.4alkyl, ester,
carbamate, carbonate, or ether.
2. The compound according to claim 1 or a pharmaceutically
acceptable salt thereof, wherein R.sub.1 is 2-imidazopyridine,
optionally substituted with one to five substituents, each
substituent independently being chloro, fluoro, bromo,
C.sub.1-C.sub.4alkyl, trifluoromethyl,
C.sub.1-C.sub.4alkylsulfonamide, hydroxy, or carboxy; R.sub.2 is
phenyl, optionally substituted with one to five substituents, each
substituent independently being chloro, fluoro, bromo,
C.sub.1-C.sub.4alkyl, trifluoromethyl,
C.sub.1-C.sub.4alkylsulfonamide, hydroxy, or carboxy; L.sub.1 and
L.sub.2 are independently C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkenyl, C.sub.1-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, aminoC.sub.1-C.sub.4alkyl,
hydroxyC.sub.1-C.sub.4alkyl, carbonyl, cycloC.sub.3-C.sub.6alkyl or
aminocarbonyl; and optionally substituted at any of the 2, 3, 5, or
6 positions independently with X, wherein X is hydroxy, amino,
C.sub.1-C.sub.4alkylamino, di(C.sub.1-C.sub.4)alkylamino,
C.sub.1-C.sub.4alkyl, ester, carbamate, carbonate, or ether.
3. The compound according to claim 1 or a pharmaceutically
acceptable salt thereof, wherein R.sub.1 is purine, optionally
substituted with one to five substituents, each substituent
independently being chloro, fluoro, bromo, C.sub.1-C.sub.4alkyl,
trifluoromethyl, C.sub.1-C.sub.4alkylsulfona- mide, hydroxy, or
carboxy; R.sub.2 is phenyl, optionally substituted with one to five
substituents, each substituent independently being chloro, fluoro,
bromo, C.sub.1-C.sub.4alkyl, trifluoromethyl,
C.sub.1-C.sub.4alkylsulfonamide, hydroxy, or carboxy; L.sub.1 and
L.sub.2 are independently C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkenyl, C.sub.1-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, aminoC.sub.1-C.sub.4alkyl,
hydroxyC.sub.1-C.sub.4alkyl, carbonyl, cycloC.sub.3-C.sub.6alkyl or
aminocarbonyl; and optionally substituted at any of the 2, 3, 5, or
6 positions independently with X, wherein X is hydroxy, amino,
C.sub.1-C.sub.4alkylamino, di(C.sub.1-C.sub.4)alkylamino,
C.sub.1-C.sub.4alkyl, ester, carbamate, carbonate, or ether.
4. The compound according to claim 1 or a pharmaceutically
acceptable salt thereof, wherein R.sub.1 is 2-benzimidazole,
optionally substituted with one to five substituents, each
substituent independently being chloro, fluoro, bromo,
C.sub.1-C.sub.4alkyl, trifluoromethyl,
C.sub.1-C.sub.4alkylsulfonamide, hydroxy, or carboxy; R.sub.2 is
phenyl, optionally substituted with one to five substituents, each
substituent independently being chloro, fluoro, bromo,
C.sub.1-C.sub.4alkyl, trifluoromethyl,
C.sub.1-C.sub.4alkylsulfonamide, hydroxy, or carboxy; L.sub.1 is
not C.sub.1-C.sub.2alkyl, except when R.sub.1 is
hydroxy-substituted 2-benzimidazole, L.sub.1 includes
C.sub.1-C.sub.2alkyl; L.sub.1 and L.sub.2 are independently
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkenyl,
C.sub.1-C.sub.4alkynyl, C.sub.1-C.sub.4alkoxy,
aminoC.sub.1-C.sub.4alkyl, hydroxyC.sub.1-C.sub.4a- lkyl, carbonyl,
cycloC.sub.3-C.sub.6alkyl or aminocarbonyl; and optionally
substituted at any of the 2, 3, 5, or 6 positions independently
with X, wherein X is hydroxy, amino, C.sub.1-C.sub.4alkylamino,
di(C.sub.1-C.sub.4)alkylamino, C.sub.1-C.sub.4alkyl, ester,
carbamate, carbonate, or ether.
5. The compound according to claim 1, wherein said compound is
2-(4-Benzyl-piperidin-1-ylmethyl)-imidazo[4,5-b]pyridine;
8-(4-Benzyl-piperidin-1-ylmethyl)-purine;
2-(4-Benzyl-piperidin-1-ylmethy- l)-imidazo[4,5-c]pyridine;
2-[3-(4-Benzyl-piperidin-1-yl)-propyl]-1H-benzi- midazole;
2-[3-(4-Benzyl-piperidin-1-yl)-propyl]-imidazo[4,5-b]pyridine;
2-[3-(4-Benzyl-piperidin-1-yl)-propyl]-5-fluoro-1H-benzimidazole;
2-{3-[4-(4-Chloro-benzyl)-piperidin-1-yl]-propyl}-1H-benzimidazole;
2-{3-[4-(4-Methyl-benzyl)-piperidin-1-yl]-propyl}-1H-benzimidazole;
2-[3-(4-Benzyl-piperidin-1-yl)-1-methyl-propyl]-1H-benzimidazole;
2-[3-(4-Benzyl-piperidin-1-yl)-butyl]-1H-benzimidazole;
2-[3-(4-Benzyl-3-methyl-piperidin-1-yl)-propyl]-1H-benzimidazole;
or
N-[2-(4-Benzyl-piperidin-1-ylmethyl)-3H-benzoimidazol-5-yl]-methanesulfon-
amide.
6. The compound according to claim 1, wherein said compound is
56
7. A pharmaceutical composition comprising an inert carrier and an
effective amount of a compound according to claim 1.
8. The pharmaceutical composition according to claim 7 useful for
the treatment of pain.
9. The pharmaceutical composition according to claim 7 useful for
the treatment of migraine, depression, anxiety, schizophrenia,
Parkinson's disease, or stroke.
10. A method of treating pain comprising a step of administering to
one in need of such treatment an effective amount of a compound
according to claim 1.
11. A method of treating migraine, depression, anxiety,
schizophrenia, Parkinson's disease, or stroke comprising a step of
administering to one in need of such treatment an effective amount
of a compound according to claim 1.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention relates to novel 1,4 substituted piperidines.
In particular, this invention relates to piperidines substituted in
the 1- and 4-positions, through a bridge, with i) optionally
substituted 2-benzimidazoles, 2-indoles, 2-quinazolines, or
2-imidazopyridines; or ii) phenyl or substituted phenyl that are
effective as NMDA NR.sub.2B antagonists useful for relieving
pain.
[0003] Ions such as glutamate play a key role in processes related
to chronic pain and pain-associated neurotoxicity--primarily by
acting through N-methyl-D-aspartate ("NMDA") receptors. Thus,
inhibition of such action--by employing ion channel antagonists,
particularly NMDA antagonists--can be beneficial in the treatment
and control of pain.
[0004] Known NMDA antagonists include ketamine, dextromophan, and
3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid ("CPP").
Although these compounds have been reported (J. D. Kristensen, et
al., Pain, 51:249-253 (1992); K. Eide, et al., Pain, 61:221-228
(1995); D. J. Knox, et al., Anaesth. Intensive Care 23:620-622
(1995); and M. B. Max, et al., Clin.Neuropharmacol. 18:360-368
(1995)) to produce symptomatic relief in a number of neuropathies
including postherpetic neuralgia, central pain from spinal cord
injury, and phantom limb pain, widespread use of these compounds is
precluded by their undesirable side effects. Such side effects at
analgesic doses include psychotomimetic effects such as dizziness,
headache, hallucinations, dysphoria, and disturbances of cognitive
and motor function. Additionally, more severe hallucinations,
sedation, and ataxia are produced at doses only marginally higher
than analgesic doses. Thus, it would be desirable to provide novel
NMDA antagonists that are absent of undesirable side effects or
that produce fewer and/or milder side effects.
[0005] NMDA receptors are heteromeric assemblies of subunits, of
which two major subunit families designated NR.sub.1 and NR.sub.2
have been cloned. Without being bound by theory, it is generally
believed that the various functional NMDA receptors in the
mammalian central nervous system ("CNS") are only formed by
combinations of NR.sub.1 and NR.sub.2 subunits, which respectively
express glycine and glutamate recognition sites. The NR.sub.2
subunit family is in turn divided into four individual subunit
types: NR.sub.2A, NR.sub.2B, NR.sub.2C, and NR.sub.2D. I. Ishii, et
al., J. Biol. Chem., 268:2836-2843 (1993), A. Wenel, et al., Neural
Report, 7:45-48 (1995), and D. J. Laurie et al., Mol. Brain Res.,
51:23-32 (1997) describe how the various resulting combinations
produce a variety of NMDA receptors differing in physiological and
pharmacological properties such as ion gating properties, magnesium
sensitivity, pharmacological profile, as well as in anatomical
distribution.
[0006] For example, while NR.sub.1 is found throughout the brain,
NR.sub.2 subunits are differentially distributed. In particular, it
is believed that the distribution map for NR.sub.2B lowers the
probability of side effects while producing pain relief. For
example, S. Boyce, et al., Neuropharmacology, 38:611-623(1999)
describes the effect of selective NMDA NR.sub.2B antagonists on
pain with reduced side-effects. Thus, it would be desirable to
provide novel NMDA antagonists that target the NR.sub.2B
receptor.
[0007] Phenol compounds described as NMDA antagonists are described
in U.S. Pat. Nos. 5,306,723 and 5,436,255, and in International
Patent Publications WO91/17156, WO92/19502, WO93/02052, WO94/29571,
WO95/28057, WO96/37226, and EP 04422506. Benzyl piperidine
substituted with phenols or imidazoles are described in Z. -L.
Zhou, et al., J. Medicinal Chemistry, 42:2993-3000(1999); T. F.
Gregory, et al., Poster #94, 218.sup.th National Meeting American
Chemical Society, New Orleans, La., Aug. 22-26, 1999. Other NMDA
NR.sub.2B selective compounds are described in European Patent
Publication EP 787493 and British J.Pharmacol., 123:463(1998).
However, there continues to be a need for novel NMDA antagonists
that target the NR.sub.2B receptor.
[0008] International Patent Publication WO94/21615 describes
benzimidazole-piperidine compounds utilized as dopamine D4
antagonists.
SUMMARY OF THE INVENTION
[0009] The present invention relates to novel piperidines
substituted in the 1- and 4-positions, through a bridge, with i)
optionally substituted 2-benzimidazoles, 2-indoles, 2-quinazolines,
or 2-imidazopyridines; or ii) phenyl or substituted phenyl. The
present invention also forms pharmaceutical compositions utilizing
the compounds. Further, this invention includes novel methods to
treat pain by utilizing the compounds.
DETAILED DESCRIPTION OF THE INVENTION
[0010] In one aspect, the compounds of this invention are
represented by Formula (I): 1
[0011] or pharmaceutically acceptable salts thereof, wherein
[0012] R.sub.1 is i) 2-benzimidazole, 2-imidazopyridine, 2-indole,
purine, or 2-quinazoline, each optionally substituted with one to
five substituents, each substituent independently being chloro,
fluoro, bromo, C.sub.1-C.sub.4alkyl, trifluoromethyl,
C.sub.1-C.sub.4alkylsulfonamide, hydroxy, or carboxy; or ii)
phenyl, optionally substituted with one to five substituents, each
substituent independently being chloro, fluoro, bromo,
C.sub.1-C.sub.4alkyl, trifluoromethyl, C.sub.1-C.sub.4alkylsulfona-
mide, hydroxy, or carboxy;
[0013] R.sub.2 is a) 2-benzimidazole, 2-imidazopyridine, 2-indole,
purine, or 2-quinazoline, each optionally substituted with one to
five substituents, each substituent independently being chloro,
fluoro, bromo, C.sub.1-C.sub.4alkyl, trifluoromethyl,
C.sub.1-C.sub.4alkylsulfonamide, hydroxy, or carboxy; or b) phenyl,
optionally substituted with one to five substituents, each
substituent independently being chloro, fluoro, bromo,
C.sub.1-C.sub.4alkyl, trifluoromethyl, C.sub.1-C.sub.4alkylsulfona-
mide, hydroxy, or carboxy;
[0014] When R.sub.1 is i, then R.sub.2 is b; when R.sub.1 is ii,
then R.sub.2 is a;
[0015] When R.sub.1 or R.sub.2 is 2-benzimidazole, respective
L.sub.1 or L.sub.2 is not C.sub.1-C.sub.2alkyl, except when R.sub.1
or R.sub.2 is hydroxy-substituted 2-benzimidazole, respective
L.sub.1 or L.sub.2 includes C.sub.1-C.sub.2alkyl
[0016] L.sub.1 and L.sub.2 are independently C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkenyl, C.sub.1-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, aminoC.sub.1-C.sub.4alkyl,
hydroxyC.sub.1-C.sub.4alkyl, carbonyl, cycloC.sub.3-C.sub.6alkyl or
aminocarbonyl; and
[0017] optionally substituted at any of the 2, 3, 5, or 6 positions
independently with X, wherein X is hydroxy, amino,
C.sub.1-C.sub.4alkylamino, di(C.sub.1-C.sub.4)alkylamino,
C.sub.1-C.sub.4alkyl, ester, carbamate, carbonate, or ether.
[0018] In an embodiment of this invention the compound is
represented by Formula (I) or a pharmaceutically acceptable salt
thereof, wherein
[0019] R.sub.1 is 2-imidazopyridine, optionally substituted with
one to five substituents, each substituent independently being
chloro, fluoro, bromo, C.sub.1-C.sub.4alkyl, trifluoromethyl,
C.sub.1-C.sub.4alkylsulfona- mide, hydroxy, or carboxy;
[0020] R.sub.2 is phenyl, optionally substituted with one to five
substituents, each substituent independently being chloro, fluoro,
bromo, C.sub.1-C.sub.4alkyl, trifluoromethyl,
C.sub.1-C.sub.4alkylsulfonamide, hydroxy, or carboxy;
[0021] L.sub.1 and L.sub.2 are independently C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkenyl, C.sub.1-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, aminoC.sub.1-C.sub.4alkyl,
hydroxyC.sub.1-C.sub.4alkyl, carbonyl, cycloC.sub.3-C.sub.6alkyl or
aminocarbonyl; and
[0022] optionally substituted at any of the 2, 3, 5, or 6 positions
independently with X, wherein X is hydroxy, amino,
C.sub.1-C.sub.4alkylamino, di(C.sub.1-C.sub.4)alkylamino,
C.sub.1-C.sub.4alkyl, ester, carbamate, carbonate, or ether.
[0023] In another embodiment of this invention the compound is
represented by Formula (I) or a pharmaceutically acceptable salt
thereof, wherein
[0024] R.sub.1 is purine, optionally substituted with one to five
substituents, each substituent independently being chloro, fluoro,
bromo, C.sub.1-C.sub.4alkyl, trifluoromethyl,
C.sub.1-C.sub.4alkylsulfonamide, hydroxy, or carboxy;
[0025] R.sub.2 is phenyl, optionally substituted with one to five
substituents, each substituent independently being chloro, fluoro,
bromo, C.sub.1-C.sub.4alkyl, trifluoromethyl,
C.sub.1-C.sub.4alkylsulfonamide, hydroxy, or carboxy;
[0026] L.sub.1 and L.sub.2 are independently C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkenyl, C.sub.1-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, aminoC.sub.1-C.sub.4alkyl,
hydroxyC.sub.1-C.sub.4alkyl, carbonyl, cycloC.sub.3-C.sub.6alkyl or
aminocarbonyl; and
[0027] optionally substituted at any of the 2, 3, 5, or 6 positions
independently with X, wherein X is hydroxy, amino,
C.sub.1-C.sub.4alkylamino, di(C.sub.1-C.sub.4)alkylamino,
C.sub.1-C.sub.4alkyl, ester, carbamate, carbonate, or ether.
[0028] In still another embodiment of this invention the compound
is represented by Formula (I) or a pharmaceutically acceptable salt
thereof, wherein
[0029] R.sub.1 is 2-benzirmidazole, optionally substituted with one
to five substituents, each substituent independently being chloro,
fluoro, bromo, C.sub.1-C.sub.4alkyl, trifluoromethyl,
C.sub.1-C.sub.4alkylsulfona- mide, hydroxy, or carboxy;
[0030] R.sub.2 is phenyl, optionally substituted with one to five
substituents, each substituent independently being chloro, fluoro,
bromo, C.sub.1-C.sub.4alkyl, trifluoromethyl,
C.sub.1-C.sub.4alkylsulfonamide, hydroxy, or carboxy;
[0031] L.sub.1 is not C.sub.1-C.sub.2alkyl, except when R.sub.1 is
hydroxy-substituted 2-benzimidazole, L.sub.1 includes
C.sub.1-C.sub.2alkyl;
[0032] L.sub.1 and L.sub.2 are independently C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkenyl, C.sub.1-C.sub.4alkynyl,
C.sub.1-C.sub.4alkoxy, aminoC.sub.1-C.sub.4alkyl,
hydroxyC.sub.1-C.sub.4alkyl, carbonyl, cycloC.sub.3-C.sub.6alkyl or
aminocarbonyl; and
[0033] optionally substituted at any of the 2, 3, 5, or 6 positions
independently with X, wherein X is hydroxy, amino,
C.sub.1-C.sub.4alkylamino, di(C.sub.1-C.sub.4)alkylamino,
C.sub.1-C.sub.4alkyl, ester, carbamate, carbonate, or ether.
[0034] As used herein, "alkyl" as well as other groups having the
prefix "alk" such as, for example, alkoxy, alkanoyl, alkenyl,
alkynyl and the like, means carbon chains which may be linear or
branched or combinations thereof. Examples of alkyl groups include
methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl,
pentyl, hexyl, heptyl and the like. "Alkenyl", "alkynyl" and other
like terms include carbon chains containing at least one
unsaturated C--C bond.
[0035] The term "cycloalkyl" means carbocycles containing no
heteroatoms, and includes mono-, bi- and tricyclic saturated
carbocycles, as well as fused ring systems. Such fused ring systems
can include one ring that is partially or fully unsaturated such as
a benzene ring to form fused ring systems such as benzofused
carbocycles. Cycloalkyl includes such fused ring systems as
spirofused ring systems. Examples of cycloalkyl include
cyclopropyl, cyclobutyl, cyclopentyl; cyclohexyl,
decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl,
1,2,3,4-tetrahydronaphalene and the like. Similarly, "cycloalkenyl"
means carbocycles containing no heteroatoms and at least one
non-aromatic C--C double bond, and include mono-, bi- and tricyclic
partially saturated carbocycles, as well as benzofused
cycloalkenes. Examples of cycloalkenyl include cyclohexenyl,
indenyl, and the like.
[0036] Unless otherwise stated, the terms "carbonyl" and
"aminocarbonyl" include short C.sub.1-C.sub.2 termini. The terms
include, for example, --CH.sub.2CONH--, --CH.sub.2CO--,
--C.sub.2H.sub.4CONHCH.sub.2--, and
--CH.sub.2COC.sub.2H.sub.4--.
[0037] Unless otherwise stated, the term "carbamate" is used to
include --OCOOC.sub.1--C.sub.4alkyl, --NHCOOC.sub.1--C.sub.4alkyl,
and --OCONHC.sub.1--C.sub.4alkyl.
[0038] The term "halogen" includes fluorine, chlorine, bromine and
iodine atoms.
[0039] The term "SEM" is used to describe
--CH.sub.2--O--CH.sub.2CH.sub.2-- -Si(CH.sub.3).sub.3.
[0040] The term "Co" means that the carbon is not present. Thus,
"C.sub.0-C.sub.5" means that there are from none to five carbons
present--that is, five, four, three, two, one, or no carbons
present.
[0041] The term "optionally substituted" is intended to include
both substituted and unsubstituted. Thus, for example, optionally
substituted aryl could represent a pentafluorophenyl or a phenyl
ring.
[0042] Compounds described herein contain one or more asymmetric
centers and may thus give rise to diastereomers and optical
isomers. The present invention includes all such possible
diastereomers as well as their racemic mixtures, their
substantially pure resolved enantiomers, all possible geometric
isomers, and pharmaceutically acceptable salts thereof. The above
Formula I is shown without a definitive stereochemistry at certain
positions. The present invention includes all stereoisomers of
Formula I and pharmaceutically acceptable salts thereof. Further,
mixtures of stereoisomers as well as isolated specific
stereoisomers are also included. During the course of the synthetic
procedures used to prepare such compounds, or in using racemization
or epimerization procedures known to those skilled in the art, the
products of such procedures can be a mixture of stereoisomers.
[0043] The term "pharmaceutically acceptable salts" refers to salts
prepared from pharmaceutically acceptable non-toxic bases or acids.
When the compound of the present invention is acidic, its
corresponding salt can be conveniently prepared from
pharmaceutically acceptable non-toxic bases, including inorganic
bases and organic bases. Salts derived from such inorganic bases
include aluminum, ammonium, calcium, copper (ic and ous), ferric,
ferrous, lithium, magnesium, manganese (ic and ous), potassium,
sodium, zinc and the like salts. Particularly preferred are the
ammonium, calcium, magnesium, potassium and sodium salts. Salts
derived from pharmaceutically acceptable organic non-toxic bases
include salts of primary, secondary, and tertiary amines, as well
as cyclic amines and substituted amines such as naturally occurring
and synthesized substituted amines. Other pharmaceutically
acceptable organic non-toxic bases from which salts can be formed
include ion exchange resins such as, for example, arginine,
betaine, caffeine, choline, N,N'-dibenzylethylenediamine,
diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,
ethanolamine, ethylenediamine, N-ethylmorpholine,
N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine,
isopropylamine, lysine, methylglucamine, morpholine, piperazine,
piperidine, polyamine resins, procaine, purines, theobromine,
triethylamine, trimethylamine, tripropylamine, tromethamine and the
like.
[0044] When the compound of the present invention is basic, its
corresponding salt can be conveniently prepared from
pharmaceutically acceptable non-toxic acids, including inorganic
and organic acids. Such acids include, for example, acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,
lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric,
pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,
p-toluenesulfonic acid and the like. Particularly preferred are
citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric,
and tartaric acids.
[0045] The pharmaceutical compositions of the present invention
comprise a compound represented by Formula I (or pharmaceutically
acceptable salts thereof) as an active ingredient, a
pharmaceutically acceptable carrier and optionally other
therapeutic ingredients or adjuvants. The compositions include
compositions suitable for oral, rectal, topical, and parenteral
(including subcutaneous, intramuscular, and intravenous)
administration, although the most suitable route in any given case
will depend on the particular host, and nature and severity of the
conditions for which the active ingredient is being administered.
The pharmaceutical compositions may be conveniently presented in
unit dosage form and prepared by any of the methods well known in
the art of pharmacy.
[0046] In practice, the compounds represented by Formula I, or
pharmaceutically acceptable salts thereof, of this invention can be
combined as the active ingredient in intimate admixture with a
pharmaceutical carrier according to conventional pharmaceutical
compounding techniques. The carrier may take a wide variety of
forms depending on the form of preparation desired for
administration, e.g., oral or parenteral (including intravenous).
Thus, the pharmaceutical compositions of the present invention can
be presented as discrete units suitable for oral administration
such as capsules, cachets or tablets each containing a
predetermined amount of the active ingredient. Further, the
compositions can be presented as a powder, as granules, as a
solution, as a suspension in an aqueous liquid, as a non-aqueous
liquid, as an oil-in-water emulsion or as a water-in-oil liquid
emulsion. In addition to the common dosage forms set out above, the
compound represented by Formula I, or pharmaceutically acceptable
salts thereof, may also be administered by controlled release means
and/or delivery devices. The compositions may be prepared by any of
the methods of pharmacy. In general, such methods include a step of
bringing into association the active ingredient with the carrier
that constitutes one or more necessary ingredients. In general, the
compositions are prepared by uniformly and intimately admixing the
active ingredient with liquid carriers or finely divided solid
carriers or both. The product can then be conveniently shaped into
the desired presentation.
[0047] Thus, the pharmaceutical compositions of this invention may
include a pharmaceutically acceptable carrier and a compound or a
pharmaceutically acceptable salt of Formula I. The compounds of
Formula I, or pharmaceutically acceptable salts thereof, can also
be included in pharmaceutical compositions in combination with one
or more other therapeutically active compounds.
[0048] The pharmaceutical carrier employed can be, for example, a
solid, liquid, or gas. Examples of solid carriers include lactose,
terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium
stearate, and stearic acid. Examples of liquid carriers are sugar
syrup, peanut oil, olive oil, and water. Examples of gaseous
carriers include carbon dioxide and nitrogen.
[0049] In preparing the compositions for oral dosage form, any
convenient pharmaceutical media may be employed. For example,
water, glycols, oils, alcohols, flavoring agents, preservatives,
coloring agents and the like may be used to form oral liquid
preparations such as suspensions, elixirs and solutions; while
carriers such as starches, sugars, microcrystalline cellulose,
diluents, granulating agents, lubricants, binders, disintegrating
agents, and the like may be used to form oral solid preparations
such as powders, capsules and tablets. Because of their ease of
administration, tablets and capsules are the preferred oral dosage
units whereby solid pharmaceutical carriers are employed.
Optionally, tablets may be coated by standard aqueous or nonaqueous
techniques
[0050] A tablet containing the composition of this invention may be
prepared by compression or molding, optionally with one or more
accessory ingredients or adjuvants. Compressed tablets may be
prepared by compressing, in a suitable machine, the active
ingredient in a free-flowing form such as powder or granules,
optionally mixed with a binder, lubricant, inert diluent, surface
active or dispersing agent. Molded tablets may be made by molding
in a suitable machine, a mixture of the powdered compound moistened
with an inert liquid diluent. Each tablet preferably contains from
about 1 mg to about 500 mg of the active ingredient and each cachet
or capsule preferably containing from about 1 to about 500 mg of
the active ingredient.
[0051] Pharmaceutical compositions of the present invention
suitable for parenteral administration may be prepared as solutions
or suspensions of the active compounds in water. A suitable
surfactant can be included such as, for example,
hydroxypropylcellulose. Dispersions can also be prepared in
glycerol, liquid polyethylene glycols, and mixtures thereof in
oils. Further, a preservative can be included to prevent the
detrimental growth of microorganisms.
[0052] Pharmaceutical compositions of the present invention
suitable for injectable use include sterile aqueous solutions or
dispersions. Furthermore, the compositions can be in the form of
sterile powders for the extemporaneous preparation of such sterile
injectable solutions or dispersions. In all cases, the final
injectable form must be sterile and must be effectively fluid for
easy syringability. The pharmaceutical compositions must be stable
under the conditions of manufacture and storage; thus, preferably
should be preserved against the contaminating action of
microorganisms such as bacteria and fungi. The carrier can be a
solvent or dispersion medium containing, for example, water,
ethanol, polyol (e.g. glycerol, propylene glycol and liquid
polyethylene glycol), vegetable oils, and suitable mixtures
thereof.
[0053] Pharmaceutical compositions of the present invention can be
in a form suitable for topical use such as, for example, an
aerosol, cream, ointment, lotion, dusting powder, or the like.
Further, the compositions can be in a form suitable for use in
transdermal devices. These formulations may be prepared, utilizing
a compound represented by Formula I of this invention, or
pharmaceutically acceptable salts thereof, via conventional
processing methods. As an example, a cream or ointment-is prepared
by mixing hydrophilic material and water, together with about 5 wt
% to about 10 wt % of the compound, to produce a cream or ointment
having a desired consistency.
[0054] Pharmaceutical compositions of this invention can be in a
form suitable for rectal administration wherein the carrier is a
solid. It is preferable that the mixture forms unit dose
suppositories. Suitable carriers include cocoa butter and other
materials commonly used in the art. The suppositories may be
conveniently formed by first admixing the composition with the
softened or melted carrier(s) followed by chilling and shaping in
moulds.
[0055] In addition to the aforementioned carrier ingredients, the
pharmaceutical formulations described above may include, as
appropriate, one or more additional carrier ingredients such as
diluents, buffers, flavoring agents, binders, surface-active
agents, thickeners, lubricants, preservatives (including
anti-oxidants) and the like. Furthermore, other adjuvants can be
included to render the formulation isotonic with the blood of the
intended recipient. Compositions containing a compound described by
Formula I, or pharmaceutically acceptable salts thereof, may also
be prepared in powder or liquid concentrate form.
[0056] Experimental Protocols
Assessing the Activity of Selected Compounds to Inhibit
NR.sub.1A/2B NMDA Receptor Activation (FLIPR Assay)
[0057] The activity of selected compounds to inhibit NR1A/2B NMDA
receptor activation measured as NR.sub.1A/2B receptor-mediated
Ca.sup.2+ influx is assessed by the following procedure:
[0058] NR1A/2B receptor transfected L(tk) cells are plated in
96-well format at 3.times.10.sup.6 cells per plate and grown for
one--two days in normal growth media (Dulbeccos MEM with Na
pyruvate, 4500 mgglucose, pen/strep, glutarine, 10% FCS and 0.5
mg/ml geneticin). NR1A/2B-expression in these cells is induced by
the addition of 4 nM dexamethasone in the presence of 500 .mu.M
ketamine for 16-24 hours. After receptor induction cells are washed
using a Labsystem Cellwasher two times with assay buffer (Hanks
balanced salt solution (HBSS-Mg.sup.++ free) containing 20 mM
HEPES, 0.1% BSA, 2 mM CaCl.sub.2 and 250 .mu.M probenecid). The
cells of each 96 well cell plate are loaded with the Ca.sup.++
sensitive dye Fluo-3 (Molecular Probes, Inc.) at 41M in assay
buffer containing 0.5% FBS, and 0.04% pluronic F-127 (Molecular
Probes, Inc.) for 1 h at 37.degree. C. avoiding light. The cells
are then washed with the Cellwasher four times with assay buffer
leaving them in 100 .mu.l buffer. Test compounds in solution are
pipetted by FLIPR (Fluorometric Imaging Plate Reader) into each
test well for a 2 min pretreatment. During this time the
fluorescence intensity is recorded (excitation at 488 nm and
emission at 530 nm). The glutamate/glycine 50 .mu.l agonist
solution (final concentration 1 .mu.M/1 .mu.M) is then added by
FLIPR into each well already containing 150 .mu.l of buffer
(containing the test compound or vehicle) and the fluorescence is
continuously monitored for 10 min. The endpoint fluorescence values
are used to determine an IC.sub.50 value comparing the
agonist-stimulated signal for the vehicle alone sample and that for
the cells incubated with each concentration of test compound.
Determining the Apparent Dissociation Constant (Ki) of Compounds
for Human NR1A/NR.sub.2B Receptors (Binding Assay)
[0059] The radioligand binding assay is performed at room
temperature in 96-well microtiter plates with a final assay volume
of 1.0 mL in 20 mM Hepes buffer (pH 7.4) containing 150 mM NaCl.
Solutions of test compounds were prepared in DMSO and serially
diluted with DMSO to yield 20 .mu.L of each of 10 solutions
differing by 3-fold in concentration. Non-specific binding (NSB)
using hot AMD-1 (10 .mu.M final concentration) and total binding
(TB) by using DMSO (2% final concentration). A solution of
NR1A/NR.sub.2B receptors (40pM final concentration) and tritiated
AMD-2 (1 nM final concentration) were added to the test compounds.
After 3 h of incubation at room temperature, samples are filtered
through Packard GF/B filters (presoaked in 0.05% PEI,
polyethyleninine Sigma P-3143) and washed 10 times with imL of cold
20 mM Hepes buffer per wash. After vacuum drying of the filter
plates, 40 .mu.L of Packard Microscint-20 was added and bound
radioactivity determined in a Packard TopCount. The apparent
dissociation constant (Ki), the maximum percentage inhibition (%
I.sub.max), the minimum percentage inhibition (% I.sub.min) and the
hill slope (nH) were determined by a non-linear least squares
fitting the bound CPM data to Equation #1 below. 1 E q u a t i o n
#1 : CPM B o u n d = ( S B ) ( % I max - % I min ) ( 1 + ( [ D r u
g ] / ( K i [ L - 844 , 345 ] / K D ) ) n H ) + N S B + ( S B ) ( 1
- % I max )
[0060] where, K.sub.D is the apparent dissociation constant for the
radioligand for the receptor as determined by hot saturation and SB
is the specifically bound CPM determined from the difference of TB
and NSB. 2
[0061] Compounds AMD-1 and AMD-2 can be synthesized in accordance
with the following general reaction schemes. 3
[0062] In accordance with scheme 1, hydrogen chloride is bubbled
through a solution of the appropriately substituted benzonitrile 1
in methanol at room temperature. The volatiles are removed under
reduced pressure and the resulting residue is triturated with ether
and filtered to yield the desired imidate 2. Imidate 2 is dissolved
in methanol at ambient temperature, treated with amine 3 at ambient
temperature and stirred under argon. The volatiles are removed
under reduced pressure and the residue purified by preparative HPLC
or trituration with ether to afford amidine Ia. 4
[0063] In accordance with scheme 2, at room temperature under
argon, amine 3a is dissolved in ether and was treated with 1-M
hydrogen chloride in ether (1 equiv.) in a single portion. The
resulting precipitate is stirred vigorously for 10 minutes. The
volatiles are removed under reduced pressure. The residue is
suspended in toluene, cooled to 0.degree. C. under argon, treated
with 2.0-M trimethylaluminum (1.05 equiv.) in a dropwise manner,
and stirred for 45 minutes at room temperature to afford
intermediate 6 (not isolated). Compound 6 is added to a solution of
nitrile 1 in toluene. The reaction is heated to 80.degree. C.
without stirring in a sealed tube for 18 h, cooled to ambient
temperature, poured onto a silica gel column and eluted with
methanol/dichloromethane to give the amidine 4. 5
[0064] Tritiated AMD-1 was prepared by the following procedure: A
mixture of AMD-1, hydrochloride salt, (5 mg, 0.012 mmol) in dioxane
(0.2 mL) containing triethylamine (4 .mu.L) was treated with
hexamethylditin (5 .mu.L), a catalytic amount of palladium catalyst
and heated at 100.degree. C. for 45 minutes. The reaction was
cooled to room temperature, filtered through a glass wool plug,
rinsed with methanol and concentrated in vacuo to give 10.7 mg of a
brown oil. The oil was dissolved in methylene chloride and passed
through a small silica column eluting with methylene chloride
followed by 5% methanol/methylene chloride. Fractions containing
the trimethylstannane (Rf 0.26 in 10% methanol/methylene chloride)
were pooled and concentrated in vacuo to give 4.5 mg of the
trimethylstannane as a clear colorless oil. This material was
further purified by HPLC (C18 Econosil, 10.times.250 mm, 20 minute
linear gradient, 30% MeCN:70% H.sub.2O (0.1% TFA) to 90% MeCN, 3
mL/min, 254 nm, retention time 15 minutes) to give 3 mg of the
trimethylstannane.
[0065] A Na.sup.125I shipping vial (10 mCi, Amersham) was charged
with a stir bar, an iodobead, 50 .mu.L of methanol and stirred five
minutes at room temperature. A solution of the trimethylstannane
(0.1 mg) in 50 .mu.L of methanol containing 5 .mu.L of
trifluoroacetic acid was added and the reaction was stirred for
five minutes. The reaction was quenched with 50 .mu.L of ammonium
hydroxide and purified by HPLC (C18 Vydac protein and peptide
column, 4.6.times.250 mm, 20 minute linear gradient, 30% MeCN:70%
H.sub.2O (0.1% TFA) to 90% MeCN, 1 mL/min, retention time 11
minutes). Fractions containing the radioactive product were pooled
and concentrated in vacuo to give 989 .mu.Ci of [.sup.125I]AMD-1
with a specific activity of 898 Ci/mmol as measured by UV
absorbance at 272 nm.
Synthesis of Tritiated AMD-2
[0066] Tritiated AMD-2 was prepared by the following procedure: The
phenol of AMD-2 (2 mg, 0.008 mmol) dissolved in dimethylformamide
(0.6 mL) and potasium carbonate (1.2 mg) for 1 hr. High specific
activity tritiated methyl iodide (50 mCi, 0.0006 mmol, in toluene 1
mL, American Radiolabeled Chemicals) was added at room temperature
and stirred for 2 hours. The reaction mixture was filtered using a
Whatman PTFE 0.45 .mu.m syringeless filter device to remove any
insoluable potassium carbonate, washed with Abs. ethanol (2 mL,
Pharmco), and the combined filtrates were concentrated to dryness
at room temperature using a rotary evaporator; this also removed
any unreacted tritiated methyl iodide. The residue was purified by
HPLC chromatography on a Phenomenx Luna C8 semi-prep column (Luna 5
micro C.sub.8(2), 250.times.10.0 mm) using a gradient system of
20/80 acetonitrile/water with 0.1% trifluoroacetic acid to 100%
acetronitrile with 0.1% trifluoroacetic acid in 20 min. Total
activity of the product was 8 mCi. Further purification was
effected by absorption onto a Waters C-18 Sep-pak column (Waters
Sep-Pak PLUS C18) and elution with water followed by absolute
ethanol. The product was diluted with absolute ethanol (10 mL)
before submission for final analysis.
[0067] The compounds of this invention exhibit less than 50 .mu.M
in the FLIBR and binding assays. Thus, the compounds and
pharmaceutical compositions of this invention have been found to
exhibit biological activity as NMDA NR2B antagonists. Accordingly,
another aspect of the invention is the treatment of pain, migraine,
depression, anxiety, schizophrenia, Parkinson's disease, or
stroke--maladies that are amenable to amelioration through
inhibition of NMDA NR.sub.2B receptors--by the administration of an
effective amount of the compounds of this invention.
[0068] The following examples are provided to more fully illustrate
the present invention, and are not to be construed as limiting the
scope of the claims in any manner.
EXAMPLES
[0069] The compounds of this invention can be prepared by
procedures similar to Scheme 1 shown below but modified by the
utilization of other reactants in place of
1-SEM-benzimidole-2-carboxaldehyde. 6
[0070] In Scheme 1 above, in place of the
1-SEM-benzimidole-2-carboxaldehy- de 7
[0071] any of the following aldehydes or ketones can be used to
prepare the compounds of this invention: 8
Known Example
[0072] 9
[0073] 2-(4-Benzyl-piperidin-1-ylmethyl)-1H-benzimidazole
[0074] Example 1 was prepared by the following procedure. 10
[0075] 1-(2-Trimethylsilylethoxymethyl)-1H-benzoimidazole:
[0076] A mixture of KH, from 7 g of 30% oil dispersion, and 5 g of
benzimidazole in 100 mL of THF was stirred under nitrogen at room
temperature for 18 h. To the stirred suspension was added 7 g of
2-trimethylsilylethoxymethyl chloride and the mixture kept at room
temperature for 24 h, cooled in an ice bath, cautiously quenched
with 50 mL of water, and extracted into ether. The combined ether
extracts were dried over magnesium sulfate and concentrated. Low
pressure chromatography over silica gel eluting with a gradient of
3:1 ethyl acetate:hexane to 100% ethyl acetate gave 9.5 g of
1-SEM-benzimidazole as a colorless oil. 11
[0077]
1-(2-Trimethylsilylethoxymethyl)-1H-benzoimidazole-2-carbaldehyde:
[0078] To a solution of 40 mmole of lithium diisopropylamide in 100
mL of THF cooled to -78.degree. C. was added 5 g of
1-SEM-benzimidazole in 50 mL of THF. After 1.5 h at or below
-70.degree. C., the red solution was quenched by rapid addition of
6 mL of methyl formate. After warming to room temperature over 30
min, 50 mL of water and 200 mL of ethyl acetate were added. The
organic layer was separated and dried over magnesium sulfate then
concentrated under reduced pressure to 5.3 g of a thick oil that
solidified in the freezer. 12
[0079] 2-(4-Benzyl-piperidin-1-ylmethyl)-1H-benzimidazole:
[0080] A mixture of 0.5 g of 4-benzyl-piperidine, 0.5 g of
1-(2-trimethylsilylethoxymethyl)-1H-benzoimidazole-2-carbaldehyde,
5 mL of 1,2-dichloroethane and 0.5 g of sodium
triacetoxyborohydride was stirred at room temperature for 48 h. The
reaction mixture was diluted with 50 mL chloroform and 10 mL
saturated aqueous Na.sub.2CO.sub.3 and the layers separated. The
aqueous layer was extracted with 2.times.25 mL of chloroform and
the combined organic layers dried over magnesium sulfate and
concentrated under reduced pressure. The crude SEM ether was heated
to reflux in 50 mL of ethanol containing 5 mL of 3N HCl for 2 h,
cooled, concentrated and partitioned between 10 mL of saturated
aqueous sodium carbonate and 3.times.25 mL of chloroform. The
chloroform extracts were dried over magnesium sulfate and
concentrated. Purification by chromatography eluting with 90:10
CHCl.sub.3:MeOH gave 0.8 g of
2-[4-benzyl-piperidin-1-ylmethyl]-1H-benzimidazole: MS (m+1)=;
.sup.1H NMR (400 MHz, CDCl.sub.3)
Example 1
[0081] 13
[0082] 2-(4-Benzyl-piperidin-1-ylmethyl)-imidazo[4,5-b]pyridine
[0083] Example 1 was prepared in a similar manner to the Known
Example above, but substituting 3H-imidazo[4,5-b]pyridine for
benzimidazole in Step 1. Purification by chromatography eluting
with 90:10 CHCl.sub.3:MeOH gave
2-(4-benzyl-piperidin-1-ylmethyl)-imidazo[4,5-b]pyridine: MS
(m+1)=307.4; .sup.1H NMR (400 MHz, CDCl.sub.3) 9.75 (br, 1H), 8.4
(d, 1H), 7.95 (d, 1H), 7.3-7.1 (m, 5H), 3.9 (s, 2H), 2.9 (d, 2H),
2.6 (d, 2H), 2.2 (dd, 2H), 1.7 (d, 2H), 1.7 (m, 1H), 1.4 (dd,
2H).
Example 2
[0084] 14
[0085] 8-(4-Benzyl-piperidin-1-ylmethyl)-purine
[0086] Example 2 was prepared in a similar manner to the Known
Example above, but substituting purine for benzimidazole in Step 1.
Purification by chromatography eluting with 90:10:1
CHCl.sub.3:MeOH:NH40H gave
8-(4-benzyl-piperidin-1-ylmethyl)-purine: MS (m+1)=308.4; .sup.1H
NMR (400 MHz, CDCl.sub.3) 9.05 (s, 1H), 9.0 (s, 1H), 7.3-7.1 (m,
5H), 3.9 (s, 2H), 2.9 (d, 2H), 2.6 (d, 2H), 2.2 (dd, 2H), 1.7 (d,
2H), 1.7 (m, 1H), 1.4 (dd, 2H).
Example 3
[0087] 15
[0088] 2-(4-Benzyl-piperidin-1-ylmethyl)-imidazo[4,5-c]pyridine
[0089] Example 3 was prepared in a similar manner to the Known
Example above, but substituting 3H-imidazo[4,5-b]pyridine for
benzimidazole in Step 1. Purification by chromatography eluting
with 90:10:1 CHCl.sub.3:MeOH:NH4OH gave
2-(4-benzyl-piperidin-1-ylmethyl)-imidazo[4,5-- c]pyridine: MS
(m+1)=307.4; .sup.1H NMR (400 MHz, CDCl.sub.3) 9.75 (br, 1H), 8.4
(d, 1H), 7.95 (d, 1H), 7.3-7.1 (m, 6H), 3.90 (s, 2H), 2.90 (d, 2H),
2.6 (d, 2H), 2.2 (dd, 2H), 1.7 (d, 2H), 1.7 (m, 1H), 1.4 (dd,
2H).
Example 4
[0090] 16
[0091] 2-[3-(4-Benzyl-piperidin-1-yl)-propyl]-1H-benzimidazole
[0092] Example 4 was prepared by the following procedure. 17
[0093] 3-(1H-Benzimidazol-2-yl)-propan-1-ol:
[0094] A mixture of 5.4 g of 1,2-phenylenediamine and 4.5 g of
dihydro-furan-2-one in 50 mL of 4N hydrochloric acid was heated to
reflux for 20 h, 1 teaspoon of decolorizing carbon added, and after
another 15 min reflux, filtered hot. The filtrate was concentrated
under reduced pressure to near dryness, the residue made basic
(pH=8) with saturated sodium bicarbonate and extracted into
3.times.80 mL of ether. The combined extracts were dried over
magnesium sulfate and concentrated under reduced pressure. After
drying under vacuum, 8.4 g of 3-(1H-benzimidazol-2-yl)-propan-1-ol
was obtained as a solid. 18
[0095]
3-[2-(3-Hydroxy-propyl)-benzimidazol-1-yl]-propionitrile:
[0096] To a stirred solution of 3.8 g of
3-(1H-benzimidazol-2-yl)-propan-1- -ol and 4 g dihydropyran in 500
mL of THF was added p-toluenesulfonic acid monohydrate until the pH
was about 3 (indicator paper). After stirring overnight, an
additional 2 mL of dihydropyran was added. After 2 additional
hours, the conversion was complete. The mixture was concentrated
under reduced pressure and partitioned between 250 .mu.L of 1N NaOH
and 2.times.250 mL of ether. After drying over magnesium sulfate
the combined extracts were concentrated to dryness.
[0097] To a solution of the resulting crude oily
2-[3-(tetrahydro-pyran-2-- yloxy)-propyl]-1H-benzimidazole (14 g)
in 250%L of acetonitrile was added 5 mL of acrylonitrile, 2 drops
of IM tetrabutylammonium fluoride in THF and I drop ION NaOH. After
heating to 85.degree. C. for 16 h, conversion was complete (TLC
elution with 90:10 methylene chloride:methanol). After
concentration under reduced pressure, the residue was partitioned
between 2.times.200 mL of ethyl acetate and 200 mL of water. The
combined extracts were dried over magnesium sulfate and
concentrated under reduced pressure.
[0098] The crude
3-{2-[3-(tetrahydro-pyran-2-yloxy)-propyl]-benzimidazol-1-
-yl}-propionitrile was stirred in 250 mL of methanol with
sufficient p-toluenesulfonic acid monohydrate to make the solution
acidic (pH=1-2). After stirring overnight, the solution was
concentrated under reduced pressure, made basic (pH=8) with 1N
sodium hydroxide and extracted into 8.times.50 mL of ethyl acetate.
The aqueous layer was saturated with NaCl to aid in extraction of
the product. The combined extracts were dried over magnesium
sulfate and concentrated under reduced pressure. Chromatography
using a gradient of ethyl acetate then 10% methanol in ethyl
acetate followed by trituration with ether-hexane gave 4.8 g of
3-[2-(3-hydroxy-propyl)-benzimidazol-1-yl]-propionitrile as a
solid. 19
[0099] 3-[2-(3-Oxo-propyl)-benimidazol-1-yl]-propionitrile:
[0100] To a stirred solution of 0.5 g of oxalyl chloride in 15 mL
of methylene chloride cooled to -78.degree. C. was added 1 mL of
anhydrous DMSO. After 15 min, a solution of 1 g of
3-[2-(3-hydroxy-propyl)-benzimid- azol-1-yl]-propionitrile in 50 mL
of methylene chloride and 10 mL of anhydrous DMSO was added while
keeping the temperature below -50.degree. C. There was considerable
precipitate which redissolved on warming to 0.degree. C. over 20
min. After cooling back down to -50.degree. C., 5 mL of triethyl
amine was added and the mixture allowed to warm to room
temperature. After 15 min, the mixture was diluted with 250 mL of
water, shaken and separated. The organic layer was dried over
magnesium sulfate and concentrated under reduced pressure. The
crude 3-[2-(3-oxo-propyl)-benimidazol-1-yl]-propionitrile was an
amber resin (1 g), and contained only traces of the starting
alcohol by TLC (90:10 methylene chloride:methanol). 20
[0101]
3-{2-[3-(3-Benzyl-8-aza-bicyclo[3.2.1]oct-8-yl)-propyl]-benzimidazo-
l-1-yl}-propionitrile:
[0102] A mixture of 0.25 g of 4-benzyl-piperidine, 0.4 g of
1-3-[2-(3-oxo-propyl)-benimidazol-1-yl]-propionitrile, 5 mL of
1,2-dichloroethane and 0.3 g of sodium triacetoxyborohydride was
stirred at room temperature for 24 h. The reaction mixture was
diluted with 50 mL chloroform and 10 mL saturated aqueous
Na.sub.2CO.sub.3 and the layers separated. The aqueous layer was
extracted with 2.times.25 mL of chloroform and the combined organic
layers dried over magnesium sulfate and concentrated under reduced
pressure. Low pressure chromatography eluting with a gradient of
70:30 ethyl acetate:methanol to 70:30:5 ethyl
acetate:methanol:triethylamine gave 400 mg of
3-{2-[3-(4-benzyl-piperidin-
-1-yl)-propyl]-benzoimidazol-1-yl}-propionitrile as a gum. 21
[0103]
2-[3-(3-Benzyl-8-aza-bicyclo[3.2.1]oct-8-yl)-propyl]-1H-benzimidazo-
le:
[0104] A mixture of 0.4 g of
3-{2-[3-(4-benzyl-piperidin-1-yl)-propyl]-ben-
zoimidazol-1-yl}-propionitrile, 20 mL of isopropanol and 2 mL of
0.4 M sodium in isopropanol was heated to reflux for 2 h.
Conversion was complete by TLC (80:20:1 ethyl
acetate:methanol:triethylamine). The mixture was cooled, diluted
with 10 mL of saturated sodium bicarbonate and concentrated. The
residue was partitioned between 3.times.100 mL of chloroform and
SOmL of water. After drying over magnesium sulfate and
concentration under reduced pressure, the residue was purified by
preparative TLC eluting with 400:100:25 ethyl
acetate:methanol:triethylam- ine. The major band (UV visualization)
was 2-[3-(4-benzyl-piperdin-1-yl)-p- ropyl]-1H-benzimidazole (220
mg): MS (m+1)=334.2; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.4 (d, 2H),
7.32 (m, 2H), 7.25 (m,1H), 7.2 (m, 4H), 3.1 (m, 4H), 2.65 (m, 2H),
2.6 (m, 2H), 2.1 (m, 2H), 2.0 (m, 2H), 1.8 (m, 2H), 1.7 (m, 11),
1.5 (m, 2H).
Example 5
[0105] 22
[0106]
2-[3-(4-Benzyl-piperidin-1-yl)-propyl]-imidazo[4,5-b]pyridine
[0107] Example 5 was prepared by the following procedure. 23
[0108] 4-Bromo-Butyric Acid Benzyl Ester:
[0109] To an ice cold solution of 5 g of 4-bromobutyric acid and
5.5 g of benzylchloroformate in 100 mL of dichloromethane was added
5 mL of triethylamine and then 700 mg of 4-dimethylaminopyridine. A
vigorous exothermic reaction ensued with evolution of carbon
dioxide. After stirring for 3 h, the mixture was diluted with 100
mL of dichloromethane and washed with 200 mL of saturated sodium
bicarbonate, dried over magnesium sulfate, and concentrated to an
oil. Azeotropic drying with toluene gave 8 g of 4-bromobutyric acid
benzyl ester as a clear oil. 24
[0110] 4-(4-Benzyl-piperidin-1-yl)-Butyric Acid:
[0111] A mixture of 0.9 g of 4-bromobutyric acid benzyl ester, 0.5
g of 4-benzylpiperidine, 0.6 mL of N,N-diisopropylethylamine and 20
mL of acetonitrile was heated to 80.degree. C. for 4 h. The mixture
was cooled, concentrated under reduced pressure and partitioned
between chloroform and saturated sodium carbonate. After drying
over magnesium sulfate the extracts were concentrated to a thick
oil, 1.4 g, which was a mixture of the benzyl ester of
4-(4-benzyl-piperidin-1-yl)-butyric acid, benzyl 4-bromobutyrate
and butyrolactone. Hydrogenation over 0.5 g of palladium on carbon
in 100 mL of ethanol under 1 atm of hydrogen overnight gave 0.9 g
of 4-(4-benzyl-piperidin-1-yl)-butyric acid after drying under
vacuum at 100.degree. C. overnight which was homogeneous by TLC
(90:10:1 chloroform:methanol : ammonium hydroxide). 25
[0112]
2-[3-(3-Benzyl-8-aza-bicyclo[3.2.1]oct-8-yl)-propyl]-3H-imidazo[4,5-
-b]pyridine:
[0113] A mixture of 0.6 g of 4-(4-benzyl-piperidin-1-yl)-butyric
acid, 0.25 g of 1,2-diaminopyridine and 6 g of polyphosphoric acid
was heated to 185.degree. C. for 2 h. The mixture was cooled and
stirred with 100 mL of 3N sodium hydroxide for 1 h after becoming
homogeneous. The solution was extracted with 5.times.100 mL of
chloroform and the combined extracts washed 3.times.50 mL of dilute
ammonium hydroxide, heated with 1 g of decolorizing carbon for 10
min, cooled, filtered and concentrated. Purification of the residue
by chromatography, eluting with 400:100:25 ethyl
acetate:methanol:triethylamine gave 210 mg of
2-[3-(4-benzyl-piperidin-1-yl)-propyl]-imidazo[4,5-b]pyridine: MS
(m+1)=335.2; .sup.1H NMR (400 MHz, CDCl.sub.3) 8.36 (d, 1H), 7.8
(d, 1H), 7.6 (d, 0.5H), 7.3-7.1 (complex, 5.5H), 6.85 (d, 0.5H),
6.6 (dd, 0.5H), 3.12 (dd, 2H), 3.0 (d, 2H), 2.6 (d, 2H), 2.55 (dd,
2H), 2.0 (m, 4H), 1.7 (d, 2H), 1.6 (m, 1H), 1.5 (m, 2H).
Example 6
[0114] 26
[0115]
2-[3-(4-Benzyl-piperidin-1-yl)-propyl]-5-fluoro-1H-benzimidazole
[0116] Example 6 was prepared by the following procedure. 27
[0117]
5-[2-(4-Benzyl-piperidin-1-yl)-ethyl]-2,2-dimethyl-[1,3]dioxane-4,6-
-dione:
[0118] Following the procedure described in S. Danishefsky and R.
K. Singh, J. American Chemical Society, 97:3239-3241(1975), a
mixture of 0.5 g of 4-benzylpiperidine, 10 mL of toluene, and 0.5 g
of 6,6-dimethyl-5,7-dioxa-spiro[2.5]octane-4,8-dione was stirred
for 20 h, cooled, and the white solid product collected by
filtration and dried under vacuum. The yield of
5-[2-(4-benzyl-piperidin-1-yl)-ethyl]-2,2-dime-
thyl-[1,3]dioxane-4,6-dione was 0.94 g. 28
[0119]
2-[3-(4-Benzyl-piperidin-1-yl)-propyl]-5-fluoro-1H-benzimidazole:
[0120] A mixture of 0.08 g of
5-[2-(4-benzyl-piperidin-1-yl)-ethyl]-2,2-di-
methyl-[1,3]dioxane-4,6-dione, 10 mL of diglyme and 4 drops of conc
hydrochloric acid was heated to reflux for 18 h. The mixture was
cooled, and partitioned between dilute aqueous ammonium hydroxide
and dichloromethane. The combined extracts were dried over
magnesium sulfate and concentration under reduced pressure. The
residue was purified by preparative TLC eluting with 70:30
chloroform:methanol. The major band (UV visualization) was
2-[3-(4-benzyl-piperidin-1-yl)-propyl]-5-fluoro-1H- -benzimidazole
(80 mg): MS (m+1)=352.4; .sup.1H NMR (400 MHz, CDCl.sub.3) 9.2 (br,
1H), 7.32 (m, 2H), 7.25 (m, 2H), 7:2 (m, 2H), 7.15 (m, 1H), 6.9
(dd, 1H), 3.1 (m, 4H), 2.65 (m, 2H), 2.6 (m, 2H), 2.1 (m, 2H), 2.0
(m, 2H), 1.8 (m, 2H), 1.7 (m, 1H), 1.5 (m, 2H).
Example 7
[0121] 29
[0122]
2-{3-[4-(4-Chloro-benzyl)-piperidin-1-yl]-propyl}-1H-benzimidazole
[0123] Example 7 was prepared by the following procedure. 30
[0124] 4-(4-Chloro-benzylidene)-piperidine-1-carboxylic Acid
Tert-Butyl Ester:
[0125] To a stirred solution of 2 g of
4-oxo-piperidine-1-carboxylic acid tert-butyl ester and 3.5 g of
diethyl 4-chlorobenzylphosphonate in 10 mL of
1,3-dimethyl-2-imidazolidinone dried over 4 .ANG. mol sieves was
added 0.50 g of 60% sodium hydride oil dispersion. The mixture was
allowed to stir overnight, diluted with 200%L of water and
extracted with 3.times.100 mL of ether. Combined extracts were
dried over magnesium sulfate and concentrated under reduced
pressure. Low pressure chromatography over silica gel eluting with
a gradient of 5:95 ethyl acetate:hexane to 1:5 ethyl acetate:hexane
gave 2 g of 4-(4-chloro-benzylidene)-piperidine-1-carboxylic acid
tert-butyl ester as a colorless oil. 31
[0126] 5-(4-Chloro-benzyl)-2-aza-bicyclo[2.2.2]octane-2-carboxylic
Acid Ethyl Ester:
[0127] A solution of 2 g of
4-(4-chloro-benzylidene)-piperidine-1-carboxyl- ic acid tert-butyl
ester and 0.5 g of 5% platinum on carbon in 100 mL of ethanol was
allowed to stir overnight under 1 atm of hydrogen. The catalyst was
filtered off and the solution concentrated to give 2 g of
4-(4-chloro-benzyl)-piperidine-1-carboxylic acid tert-butyl ester
as an oil. 32
[0128] 4-(4-Chloro-benzyl)-piperidine:
[0129] A mixture of 2 g of
4-(4-chloro-benzyl)-piperidine-1-carboxylic acid tert-butyl ester,
dioxane (1.5 mL), and 3N hydrochloric acid (1.0 mL, 4 equiv.) was
heated at reflux for 3.5 hours. The cooled mixture was made basic
with saturated sodium carbonate solution and extracted with
chloroform (3.times.10 mL). The combined extracts were dried over
magnesium sulfate and concentrated under reduced pressure. The
crude product (1.2 g) was an oil. 33
[0130]
2-{3-[4-(4-Chloro-benzyl)-piperidin-1-yl]-propyl}-1H-benzimidazole:
[0131] Steps 4 and 5 were performed in a similar manner to Example
4, but substituting 4-(4-chloro-benzyl)-piperidine for
4-benzylpiperidine in Step 4. Purification by chromatography
eluting with 90:10 CHCl.sub.3:MeOH gave
2-{3-[4-(4-chloro-benzyl)-piperidin-1-yl]-propyl}-1H-benzimidazole:
MS (m+1)=369; .sup.1H NMR (400 MHz, CDCl.sub.3) 9.75 (br, 1H), 7.7
(br, 1H), 7.5 (br, 1H), 7.4 (d, 2H), 7.32 (d, 2H), 7.2 (d, 2H), 3.1
(m, 4H), 2.65 (m, 2H), 2.6 (m, 2H), 2.1 (m, 2H), 2.0 (m, 2H), 1.75
(d, 2H), 1.7 (m, 1H), 1.5 (m, 2H).
Example 8
[0132] 34
[0133]
2-{3-[4-(4-Methyl-benzyl)-piperidin-1-yl]-propyl}-1H-benzimidazole
[0134] Example 8 was prepared in a similar manner to Example 6, but
substituting 4-(4-methyl-benzyl)-piperidine for
4-(4-chloro-benzyl)-piper- idine in Step 4. Purification by
chromatography eluting with 90:10 CHCl.sub.3:MeOH gave
2-{3-[4-(4-methyl-benzyl)-piperidin-1-yl]-propyl}-1H-
-benzimidazole: MS (m+1)=348.5; .sup.1H NMR (400 MHz, CDCl.sub.3)
9.75 (br, 1H), 7.7 (br, 1H), 7.5 (br, 1H), 7.4 (m, 2H), 7.3-7.2 dd,
4H), 3.1 (m, 4H), 2.65 (m, 2H), 2.6 (m, 2H), 2.4 (s, 3H), 2.1 (m,
2H), 2.0 (m, 2H), 1.8 (d, 2H), 1.7 (m, 1H), 1.5 (m, 2H).
Example 9
[0135] 35
[0136]
2-[3-(4-Benzyl-piperidin-1-yl)-1-methyl-propyl]-1H-benzimidazole
[0137] Example 9 was prepared by the following procedure. 36
[0138] 3-(1H-Benzimidazol-2-yl)-butan-1-ol:
[0139] Following the general procedure described in A. R. Friedman,
D. S. Payne and A. R. Day, J. Heterocyclic Chemistry,
3:257-259(1966), a mixture of 9 g of 1,2-phenylenediamine
dihydrochloride and 7 g of 2-methylbutyrolactone in 60 mL of 4N
hydrochloric acid was heated to reflux for 4 days, 1 teaspoon of
decolorizing carbon added, and after another 15 min reflux,
filtered hot. The filtrate was concentrated under reduced pressure
to near dryness, the residue made basic (pH 8) with ammonium
hydroxide and extracted into 3.times.100 mL of ethyl acetate. The
combined extracts were dried over magnesium sulfate and
concentrated under reduced pressure. After drying under vacuum, 12
g of 3-(1H-benzimidazol-2-yl)-butan-1-ol was obtained as a resin.
37
[0140]
3-[2-(3-Hydroxy-1-methyl-propyl)-benzimidazol-1-yl]-propionitrile:
[0141] A mixture of 6 g of 3-(1H-benzimidazol-2-yl)-butan-1-ol, 20
mL of acetic acid and 5 mL of acetic anhydride was heated to reflux
for 4 h. The mixture was cooled, concentrated, added 100 mL of
methanol and again concentrated under reduced pressure.
Azeotropically dried under reduced pressure with 200 mL of toluene,
then under vacuum overnight. To a stirred solution of the crude
acetate of 3-(1H-benzimidazol-2-yl)-butan-1- -ol, 8.3 g, in 250 mL
of acetonitrile was added 5 mL of acrylonitrile, 2 drops of 1M
tetrabutylammonium fluoride in THF and dropwise ION NaOH until
basic. After heating to 85.degree. C. for 16 h, the mixture was
cooled, concentrated under reduced pressure, and partitioned
between 2.times.300 mL of ethyl acetate and 100 mL of water. The
combined extracts were dried over magnesium sulfate and
concentrated under reduced pressure. The residue was triturated
with 25 mL of ethyl acetate, cooled in an ice bath and filtered.
The resulting white solid, 3.0 g, was
3-[2-(3-hydroxy-1-methyl-propyl)-benzimidazol-1-yl]-propionitrile.
38
[0142]
3-[2-(1-Methyl-3-oxo-propyl)-benzoimidazol-1-yl]-propionitrile:
[0143] To a stirred solution of 1.0 mL of oxalyl chloride in 20 mL
of methylene chloride cooled to -78.degree. C. was added 2 mL of
anhydrous DMSO. After 15 min, a solution of 1 g of
3-[2-(3-hydroxy-1-methyl-propyl)-
-benzoimidazol-1-yl]-propionitrile in 20 mL of anhydrous DMSO and
50 mL of methylene chloride was added keeping the temperature below
-50.degree. C. After 10 min, 10 mL of triethyl amine was added and
the mixture allowed to warm to room temperature. After 15 min, the
mixture was diluted with 250 mL of water, shaken and separated. The
organic layer was dried over magnesium sulfate and concentrated
under reduced pressure. The crude
3-[2-(3-oxo-propyl)-benzimidazol-1-yl]-propionitrile was an amber
resin (1.2 g), and contained only traces of the starting alcohol by
TLC (90:10 methylene chloride:methanol). 39
[0144]
3-{2-[3-(4-Benzyl-piperidin-1-yl)-1-methyl-propyl]-benzimidazol-1-y-
l}-propionitrile:
[0145] A mixture of 0.3 g of 4-benzyl-piperidine, 0.2 g of
3-[2-(3-oxo-propyl)-benzimidazol-1-yl]-propionitrile, 5 mL of
1,2-dichloroethane and 0.3 g of sodium triacetoxyborohydride was
stirred at room temperature for 24 h. The reaction mixture was
diluted with 50 mL chloroform and 10 mL saturated aqueous
Na.sub.2CO.sub.3 and the layers separated. The aqueous layer was
extracted with 2.times.25 mL of chloroform and the combined organic
layers dried over magnesium sulfate and concentrated under reduced
pressure. Low pressure chromatography eluting with a gradient of
70:30 ethyl acetate:methanol to 80:20:2 ethyl
acetate:methanol:triethylamine gave 205 mg of
3-{2-[3-(4-benzyl-piperidin-
-1-yl)-1-methyl-propyl]-benzimidazol-1-yl}-propionitrile as a gum.
40
[0146]
2-[3-(3-Benzyl-8-aza-bicyclo[3.2.1]oct-8-yl)-propyl]-1H-benzimidazo-
le:
[0147] A mixture of 0.2 g of
3-{2-[3-(4-benzyl-piperidin-1:-yl)-1-methyl-p-
ropyl]-benzimidazol-1-yl}-propionitrile, 10 mL of tert-butanol and
Ig of potassium tert-butoxide was heated to reflux for 10 min.
Conversion was complete by TLC (80:20:1 ethyl
acetate:methanol:triethylamine). The mixture was cooled, diluted
with 10 mL of saturated sodium bicarbonate and concentrated. The
residue was partitioned between 3.times.100 mL of chloroform and 50
mL of water. After drying over magnesium sulfate and concentration
under reduced pressure, the residue was purified by preparative TLC
eluting with 450:50:10 chloroform:methanol:ammonium hydroxide. The
major band (UV visualization) was 2-[3-(4-benzyl-piperidin-
-1-yl)-1-methyl-propyl]-1H-benzimidazole (82 mg): MS (m+1)=348.5;
.sup.1H NMR (400 MHz, CDCl.sub.3) 7.42 (s, 2H), 7.3 (m, 2H), 7.25
(m, 1H), 7.2 (m, 4H), 3.25 (m, 1H), 3.08 (m, 2H), 2.65 (d, 2H), 2.6
(m, 1H), 2.5 (m, 1H), 2.1 (m, 2H), 1.95 (m, 2H), 1.8 (d, 2H), 1.7
(m, 1H), 1.5 (d, 3H), 1.5 (m, 1H).
Example 10
[0148] 41
[0149] 2-[3-(4-Benzyl-piperidin-1-yl)-butyl]-1H-benzimidazole
[0150] Example 10 was prepared by the following procedure. 42
[0151] 4-(1H-Benzimidazol-2-yl)-butan-2-ol:
[0152] A mixture of 8 g of 1,2-phenylenediamine and 6.6 g of
4-pentenoic acid in 50 mL of 4N hydrochloric acid was heated to
reflux for 18 hours, cooled in an ice bath, made basic (pH=8) with
ammonium hydroxide and extracted into 3.times.100 mL of ethyl
acetate. The combined extracts were dried over magnesium sulfate
and concentrated under reduced pressure. After drying under vacuum,
lOg of 4-(1H-benzimidazol-2-yl)-buta- n-2-ol was obtained as a
thick oil which slowly crystallized. 43
[0153] Acetic Acid
3-[1-(2-cyano-ethyl)-1H-benzoimidazol-2-yl]-1-methyl-pr- opyl
Ester:
[0154] A mixture of 6 g of 4-(1H-benzimidazol-2-yl)-butan-2-ol, 20
mL of acetic acid and 5 mL of acetic anhydride was heated to reflux
for 6 h. The mixture was cooled, concentrated, added 100 mL of
methanol and again concentrated under reduced pressure. Azeotropic
drying under reduced pressure with 200 mL of toluene, then under
vacuum overnight gave 8.3 g of the acetate of
4-(1H-benzimidazol-2-yl)-butan-2-ol as a crystalline solid. To a
stirred solution of 7.5 g of the acetate of
4-(1H-benzimidazol-2-yl)-butan-2-ol in 250 mL of acetonitrile was
added 5 mL of acrylonitrile, 2 drops of 1M tetrabutylammonium
fluoride in THF and dropwise ION NaOH until basic. After heating to
85.degree. C. for 46 h, the mixture was cooled, concentrated under
reduced pressure, and partitioned between 2.times.300 mL of ethyl
acetate and 100 mL of water. The combined extracts were dried over
magnesium sulfate and concentrated under reduced pressure.
Purification of the residue by low pressure chromatography eluting
with ethyl acetate gave 9.2 g of the acetate ester of
3-[2-(3-hydroxy-butyl)-benzimidazol-1-yl]-propionitrile as a resin.
44
[0155] 3-[2-(3-Hydroxy-butyl)-benzimidazol-1-yl]-propionitrile:
[0156] A mixture of 8.1 g of the acetate ester of
3-[2-(3-hydroxy-butyl)-b- enzimidazol-1-yl]-propionitrile (Product
of Step 2), 100 mL of methanol, 25 mL of water and 1.2 g of lithium
hydroxide monohydrate was stirred for 12 h at room temperature,
concentrated under reduced pressure diluted with 50 mL of water and
extracted with 3.times.100 mL portions of ethyl acetate. Combined
extracts were dried over magnesium sulfate, concentrated under
reduced pressure and dried azeotopically with toluene. Drying under
vacuum gave 7.6 g of 3-[2-(3-hydroxy-butyl)-benzimidazol-1-y-
l]-propionitrile as a thick oil. 45
[0157] 3-[2-(3-Oxo-butyl)-benzimidazol-1-yl]-propionitrile:
[0158] To a stirred solution of 1.0 mL of oxalyl chloride in 30 mL
of methylene chloride cooled to -78.degree. C. was added 2 mL of
anhydrous DMSO. After 10 min, a solution of 2.1 g of
3-[2-(3-hydroxy-butyl)-benzimi- dazol-1-yl]-propionitrile in 150 mL
of dichloromethane was added keeping the temperature below
-50.degree. C. After 10 min, 10 mL of triethyl amine was added and
the mixture allowed to warm to room temperature. After 15 min, the
mixture was diluted with 250 mL of water, shaken and separated. The
organic layer was dried over magnesium sulfate and concentrated
under reduced pressure. Drying under vacuum gave 2.2 g of
3-[2-(3-oxo-butyl)-benzimidazol-1-yl]-propionitrile as an amber
resin. 46
[0159]
3-{2-[3-(4-Benzyl-piperidin-1-yl)-butyl]-benzimidazol-1-yl}-propion-
itrile:
[0160] A mixture of 0.3 g of 4-benzyl-piperidine, 0.24 g of
3-[2-(3-oxo-butyl)-benzimidazol-1-yl]-propionitrile, 5 mL of
1,2-dichloroethane and 0.3 g of sodium triacetoxyborohydride was
stirred at room temperature for 3 days. The reaction mixture was
diluted with 50 mL chloroform and 10 mL saturated aqueous
Na.sub.2CO.sub.3 and the layers separated. The aqueous layer was
extracted with 2.times.25 mL of chloroform and the combined organic
layers dried over magnesium sulfate and concentrated under reduced
pressure. Low pressure chromatography eluting with a gradient of
80:20 ethyl acetate:methanol to 80:20:5 ethyl
acetate:methanol:triethylamine gave 320 mg of
3-{2-[3-(4-benzyl-piperidin-
-1-yl)-butyl]-benzimidazol-1-yl}-propionitrile as a resin. 47
[0161] 2-[3-(4-Benzyl-piperidin-1-yl)-butyl]-1H-benzimidazole:
[0162] A mixture of 0.32 g of
3-{2-[3-(4-benzyl-piperidin-1-yl)-butyl]-ben-
zimidazol-1-yl}-propionitrile, 10 mL of tert-butanol and 1 g of
potassium tert-butoxide was heated to reflux for 10 min. Conversion
was complete by TLC (80:20:1 ethyl acetate:methanol:triethylamine).
The mixture was cooled, diluted with 10 mL of saturated sodium
bicarbonate and concentrated. The residue was partitioned between
3.times.100 mL of chloroform and 50 mL of water. After drying over
magnesium sulfate and concentration under reduced pressure, the
residue was purified by preparative TLC eluting with 90:10:2
chloroform:methanol:ammonium hydroxide. The major band (UV
visualization) was 2-[3-(4-benzyl-piperidin-
-1-yl)-butyl]-1H-benzimidazole (250 mg): MS (m+1)=348.5; .sup.1H
NMR (400 MHz, CDCl.sub.3) 7.42 (s, 2H), 7.3 (m, 2H), 7.25 (m, 1H),
7.2 (m, 4H), 3.25 (m, 1H), 3.0 (m, 2H), 2.8 (d, 2H), 2.65 (m, 2H),
2.5 (m, 2H), 2.1 (m, 2H), 1.6 (d, 2H), 1.3 (m, 1H), 1.2 (d, 3H),
1.0 (m, 1H).
Example 11
[0163] 48
[0164]
2-[3-(4-Benzyl-3-methyl-piperidin-1-yl)-propyl]-1H-benzimidazole
[0165] Example 11 was prepared by the following procedure. 49
[0166] 1-Benzyl-4-benzylidene-3-methyl-piperidine:
[0167] To a stirred solution of 2.1 g of
1-benzyl-3-methyl-piperidin-4-one and 2.5 g of diethyl
benzylphosphonate in 5 mL of 1,3-dimethyl-2-imidazol- idinone dried
over 4 .ANG. mol sieves was added 0.50 g of 60% sodium hydride oil
dispersion. The mixture was allowed to stir 2 days, diluted with
400 mL of water and extracted with 3.times.50 mL of ether. Combined
extracts were dried over magnesium sulfate and concentrated under
reduced pressure. Low pressure chromatography over silica gel
eluting with a gradient of 5:95 ethyl acetate:hexane to 1:4 ethyl
acetate:hexane gave 2.7 g of
1-benzyl-4-benzylidene-3-methyl-piperidine as a colorless oil.
50
[0168] 4-Benzyl-3-methyl-piperidine:
[0169] A solution of 2.7 g of
1-benzyl-4-benzylidene-3-methyl-piperidine and 2 g of 20% palladium
hydroxide on carbon in 125 mL of ethanol was shaken 3 days under 55
psi of hydrogen. The catalyst was filtered off and the solution
concentrated to give 2 g of a mixture of cis and
trans-4-benzyl-3-methyl-piperidine as an oil. 51
[0170]
2-[3-(4-Benzyl-3-methyl-piperidin-1-yl)-propyl]-1H-benzimidazole:
[0171] Steps 4 and 5 were performed in a similar manner to Example
5, but substituting 4-benzyl-3-methyl-piperidine for
4-benzylpiperidine in Step 4. Purification by chromatography
eluting with 225:20:5 chloroform:methanol:ammonium hydroxide gave
cis and trans
2-[3-(4-benzyl-3-methyl-piperidin-1-yl)-propyl]-1H-benzimidazole as
close moving bands: MS (m+1)=348.5; .sup.1H NMR (400 MHz,
CDCl.sub.3) 7.58 (d, 2H), 7.2-7.0 (m, 7H), 3.0 (m, 4H), 2.5 (m,
4H), 2.0 (m, 2H), 1.6 (m, 2H), 1.1 (2.times.d, 3H), 1.0 (m,
2H).
Example 12
[0172] 52
[0173]
N-[2-(4-Benzyl-piperidin-1-ylmethyl)-3If-benzoimidazol-5-yl]-methan-
esulfonamide
[0174] Example 12 was prepared by the following general procedure.
53
[0175] To a solution of 4-benzylpiperidine (1.0 g, 5.7 mmol) in DMF
(20 mL) was added ethylbromoacetate (637 .mu.L, 5.7 mmol) and the
reaction mixture was stirred at room temperature for 4 h. The
reaction mixture was partitioned between EtOAc and aqueous
NaHCO.sub.3, the organic layer was dried over Na.sub.2SO.sub.4,
filtered and concentrated. The crude oil was purified by silica gel
chromatography (gradient elution, 4:1 hexanes:EtOAc to EtOAc) to
give the ethyl ester.
[0176] The ethyl ester (700 mg, 2.6 mmol) was dissolved in 6N HCl
(5 mL) and heated to reflux for 1 h. The reaction mixture was
cooled and concentrated to give 54
[0177] Intermed. 15 as a white solid.
[0178] To a solution of carboxylic acid Intermed. 15 (117 mg, 0.5
mmol) in DMF (3 mL) was added EDC (96 mg, 0.5 nmml), HOBt (68 mg,
0.5 mmol), and N-(3,4-diamino-phenyl)-methanesulfonamide (100 mg,
0.5 mmol). The reaction mixture was stirred at room temperature for
1 h followed by quenching with aqueous NaHCO.sub.3 and EtOAc. The
layers were separated and the organic was washed twice with water,
dried over NaSO.sub.4, filtered and concentrated. The crude oil was
dissolved in AcOH and heated to reflux for 15 min. The reaction
mixture was cooled, concentrated and purified by reverse-phase HPLC
to give N-[2-(4-Benzyl-piperidin-1-ylmethy-
l)-3H-benzoimidazol-5-yl]-methanesulfonamide (90 mg): .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 7.82 (d, 1H), 7.77 (s,1H), 7.49
(d,1H), 7.32-7.17 (m, 5H), 4.92 (s, 2H), 3.70 (d, 2H), 3.02 (s,
2H), 2.60 (d, 2H), 2.00-1.88 (m, 3H), 1.70 (m, 2H); mass spectrum
m/z 399 [(M+H).sup.+; calcd for C.sub.21H.sub.27N.sub.4O.sub.2S:
399].
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