U.S. patent application number 11/971265 was filed with the patent office on 2008-05-08 for benzimidazolone carboxylic acid derivatives.
This patent application is currently assigned to Pfizer Inc. Invention is credited to Koji Ando, Satoru Iguchi, Noriaki Murase, Yoshinori Murata, Toyoharu Numata, Hiroki Sone, Chikara Uchida, Tatsuo Ueki.
Application Number | 20080108660 11/971265 |
Document ID | / |
Family ID | 35414645 |
Filed Date | 2008-05-08 |
United States Patent
Application |
20080108660 |
Kind Code |
A1 |
Ando; Koji ; et al. |
May 8, 2008 |
Benzimidazolone Carboxylic Acid Derivatives
Abstract
This invention relates to compounds of the formula (I): ##STR1##
wherein R.sup.1, R.sup.2, R.sup.3, A and m are each as described
herein or a pharmaceutically acceptable salt or solvate thereof,
and compositions containing such compounds and the use of such
compounds in the treatment of a condition mediated by 5-HT.sub.4
receptor activity such as, but not limited to, gastroesophageal
reflux disease, gastrointestinal disease, gastric motility
disorder, non-ulcer dyspepsia, functional dyspepsia, irritable
bowel syndrome (IBS), constipation, dyspepsia, esophagitis,
gastroesophageal disease, nausea, central nervous system disease,
Alzheimer's disease, cognitive disorder, emesis, migraine,
neurological disease, pain, cardiovascular disorders such as
cardiac failure and heart arrhythmia, diabetes and apnea
syndrome.
Inventors: |
Ando; Koji; (Chita-gun,
JP) ; Iguchi; Satoru; (Chita-gun, JP) ;
Murase; Noriaki; (Chita-gun, JP) ; Murata;
Yoshinori; (Chita-gun, JP) ; Numata; Toyoharu;
(Chita-gun, JP) ; Sone; Hiroki; (Chita-gun,
JP) ; Uchida; Chikara; (Chita-gun, JP) ; Ueki;
Tatsuo; (Chita-gun, JP) |
Correspondence
Address: |
PFIZER INC.
PATENT DEPARTMENT, MS8260-1611
EASTERN POINT ROAD
GROTON
CT
06340
US
|
Assignee: |
Pfizer Inc
|
Family ID: |
35414645 |
Appl. No.: |
11/971265 |
Filed: |
January 9, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11153757 |
Jun 14, 2005 |
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11971265 |
Jan 9, 2008 |
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60607008 |
Sep 2, 2004 |
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60607035 |
Sep 2, 2004 |
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60607048 |
Sep 2, 2004 |
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Current U.S.
Class: |
514/323 ;
514/395; 546/199; 548/306.1 |
Current CPC
Class: |
A61P 3/10 20180101; C07D
405/14 20130101; A61P 1/04 20180101; A61P 9/00 20180101; A61P 25/00
20180101; A61P 9/04 20180101; C07D 401/14 20130101; A61P 25/06
20180101; C07D 401/06 20130101; C07D 211/26 20130101; A61P 1/10
20180101; A61P 25/28 20180101; C07D 405/06 20130101; A61P 1/06
20180101; A61P 9/06 20180101; C07D 401/12 20130101; A61P 1/00
20180101 |
Class at
Publication: |
514/323 ;
548/306.1; 514/395; 546/199 |
International
Class: |
A61K 31/445 20060101
A61K031/445; C07D 403/02 20060101 C07D403/02; A61P 1/00 20060101
A61P001/00; C07D 211/06 20060101 C07D211/06; A61K 31/4164 20060101
A61K031/4164 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 15, 2004 |
JP |
2004-177488 |
Claims
1. A compound of the formula: ##STR42## or a pharmaceutically
acceptable salt or solvate thereof, wherein: A is an alkylene group
having 1 to 4 carbon atoms, said alkylene group being unsubstituted
or substituted with 1 to 4 substituents independently selected from
a halogen atom, an alkyl group having 1 to 4 carbon atoms, a
hydroxy-alkyl group having 1 to 4 carbon atoms, or an alkoxy-alkyl
group having 2 to 6 carbon atoms, wherein any 2 non-halogen
substituents can be taken together with the carbon atoms to which
they are attached to form a 3 to 4-membered ring optionally
containing at least one heteroatom selected from N, O, and S;
R.sup.1 is an isopropyl group or a cyclopentyl group; R.sup.2 is a
hydrogen atom, a halogen atom, or a hydroxy group; R.sup.3 is a
carboxy group, a tetrazolyl group, a 5-oxo-1,2,4-oxadiazole-3-yl
group, or a 5-oxo-1,2,4-thiadiazole-3-yl group; and m is the
integer 1 or 2.
2. The compound or the pharmaceutically acceptable salt or solvate
thereof, as claimed in claim 1, wherein R.sup.1 is an isopropyl
group; R.sup.2 is a hydrogen atom, a fluorine atom, or a hydroxy
group; R.sup.3 is a carboxy group or a tetrazolyl group; A is an
alkylene group having 1 to 2 carbon atoms, said alkylene group
being unsubstituted or substituted with 1 to 2 substituents
independently selected from a halogen atom, an alkyl group having 1
to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon
atoms, or an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein
any 2 non-halogen substituents can be taken together with the
carbon atoms to which they are attached to form a 3 to 4-membered
ring optionally containing at least one heteroatom selected from N,
O, and S; and m is the integer 2.
3. The compound or the pharmaceutically acceptable salt or solvate
thereof, as claimed in claim 2, wherein R.sup.3 is a carboxy group;
A is an alkylene group having 1 to 2 carbon atoms, said alkylene
group being unsubstituted or substituted with 1 to 2 substituents
independently selected from a halogen atom, an alkyl group having 1
to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon
atoms, or an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein
any two non-halogen geminal substituents can be taken together with
the carbon atom to which they are attached to form a 3 to
4-membered ring optionally containing at least one heteroatom
selected from N, O, and S; and m is the integer 2.
4. The compound or the pharmaceutically acceptable salt or solvate
thereof, as claimed in claim 1, wherein R.sup.1 is an isopropyl
group; R.sup.2 is a hydrogen atom; R.sup.3 is a carboxy group or a
tetrazolyl group; A is an alkylene group having 1 to 2 carbon
atoms, said alkylene group being substituted with 2 geminal
substituents independently selected from a halogen atom, an alkyl
group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to
4 carbon atoms, or an alkoxy-alkyl group having 2 to 6 carbon
atoms, wherein two non-halogen geminal substituents can be taken
together with the carbon atom to which they are attached to form a
3 to 4-membered ring optionally containing at least one heteroatom
selected from N, O, and S; and m is the integer 2.
5. The compound or the pharmaceutically acceptable salt or solvate
thereof, as claimed in claim 1, wherein R.sup.1 is an isopropyl
group; R.sup.2 is a hydrogen atom; R.sup.3 is a carboxy group or a
tetrazolyl group; A is ##STR43## and m is the integer 2.
6. The compound or the pharmaceutically acceptable salt or solvate
thereof, as claimed in claim 1, wherein R.sup.1 is an isopropyl
group; R.sup.2 is a hydrogen atom, a fluorine atom or a hydroxy
group; R.sup.3 is a carboxy group; A is ##STR44## and m is the
integer 2.
7. A compound selected from:
1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]ami-
no}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylic acid; and
1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]ami-
no}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid; or a
pharmaceutically acceptable salt or solvate thereof.
8. A pharmaceutical composition comprising the compound or the
pharmaceutically acceptable salt or solvate thereof, as claimed in
claim 1, with or without at least one pharmaceutically acceptable
carrier.
9. A pharmaceutical composition comprising the compound or the
pharmaceutically acceptable salt or solvate thereof, as claimed in
claim 7, with or without at least one pharmaceutically acceptable
carrier.
10. A pharmaceutical composition as claimed in claim 1, further
comprising at least one pharmacologically active agent in addition
to the compound.
11. A pharmaceutical composition as claimed in claim 7, further
comprising at least one pharmacologically active agent in addition
to the compound.
12. A method for the treatment of a condition mediated by
5-HT.sub.4 receptor activity, in a mammalian subject, including a
human, which comprises administering to a mammal in need of such
treatment a therapeutically effective amount of the compound or the
pharmaceutically acceptable salt or solvate thereof, as claimed in
claim 1.
13. A method for the treatment of a condition mediated by
5-HT.sub.4 receptor activity, in a mammalian subject, including a
human, which comprises administering to a mammal in need of such
treatment a therapeutically effective amount of the compound or the
pharmaceutically acceptable salt or solvate thereof, as claimed in
claim 7.
14. The method as claimed in claim 12, wherein said condition is
gastroesophageal reflux disease, gastrointestinal disease, gastric
motility disorder, non-ulcer dyspepsia, functional dyspepsia,
irritable bowel syndrome (IBS), constipation, dyspepsia,
esophagitis, gastroesophageal disease, nausea, central nervous
system disease, Alzheimer's disease, cognitive disorder, emesis,
migraine, neurological disease, pain, cardiovascular disorders,
cardiac failure, heart arrhythmia, diabetes, or apnea syndrome.
15. The method as claimed in claim 13, wherein said condition is
gastroesophageal reflux disease, gastrointestinal disease, gastric
motility disorder, non-ulcer dyspepsia, functional dyspepsia,
irritable bowel syndrome (IBS), constipation, dyspepsia,
esophagitis, gastroesophageal disease, nausea, central nervous
system disease, Alzheimer's disease, cognitive disorder, emesis,
migraine, neurological disease, pain, cardiovascular disorders,
cardiac failure, heart arrhythmia, diabetes, or apnea syndrome.
16. A method for treating gastroesophageal reflux disease
comprising administering to a mammal in need of such treatment a
therapeutically effective amount of the compound or the
pharmaceutically acceptable salt or solvate thereof, as claimed in
claim 1.
17. A method for treating gastroesophageal reflux disease
comprising administering to a mammal in need of such treatment a
therapeutically effective amount of the compound or the
pharmaceutically acceptable salt or solvate thereof, as claimed in
claim 7.
18. A compound of formula ##STR45## or a salt thereof, wherein
independently: R.sup.2 is a hydrogen atom, a hydroxy group or a
halogen atom; R.sup.4 is a hydroxy group or a carboxy-protecting
group; R.sup.6 is a hydrogen atom or an amino-protecting group; Y
is an alkoxy group having 1 to 4 carbon atoms, a dialkylamino group
having 2 to 8 carbon atoms, an imidazolyl group, a phtalimidyl
group, succinimidyl group, or sulfonyl group; and A is an alkylene
group having 1 to 4 carbon atoms, said alkylene group being
unsubstituted or substituted with 1 to 4 substituents independently
selected from a halogen atom, an alkyl group having 1 to 4 carbon
atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms, or an
alkoxy-alkyl group having 2 to 6 carbon atoms, wherein any 2
non-halogen substituents can be taken together with the carbon
atoms to which they are attached to form a 3 to 4-membered ring
optionally containing at least one heteroatom selected from N, O,
and S; and m is 1 or 2.
Description
BACKGROUND OF THE INVENTION
[0001] This invention relates to benzimidazolone carboxylic acid
derivatives. These compounds have selective 5-HT.sub.4 receptor
agonistic activity. The present invention also relates to a
pharmaceutical composition, method of treatment and use, comprising
the above derivatives for the treatment of disease conditions
mediated by 5-HT.sub.4 receptor activity; in particular 5-HT.sub.4
receptor agonistic activity.
[0002] In general, 5-HT.sub.4 receptor agonists are found to be
useful for the treatment of a variety of diseases such as
gastroesophageal reflux disease, gastrointestinal disease, gastric
motility disorder, non-ulcer dyspepsia, functional dyspepsia,
irritable bowel syndrome (IBS), constipation, dyspepsia,
esophagitis, gastroesophageal disease, nausea, central nervous
system disease, Alzheimer's disease, cognitive disorder, emesis,
migraine, neurological disease, pain, cardiovascular disorders,
cardiac failure, heart arrhythmia, diabetes and apnea syndrome (See
TiPs, 1992, 13, 141; Ford A. P. D. W. et al., Med. Res. Rev., 1993,
13, 633; Gullikson G. W. et al., Drug Dev. Res., 1992, 26, 405;
Richard M. Eglen et al, TIPS, 1995, 16, 391; Bockaert J. Et al.,
CNS Drugs, 1, 6; Romanelli M. N. et al., Arzheim Forsch./Drug Res.,
1993, 43, 913; Kaumann A. et al., Naunyn-Schmiedeberg's. 1991, 344,
150; and Romanelli M. N. et al., Arzheim Forsch./Drug Res., 1993,
43, 913).
[0003] WO94100449 discloses benzimidazolone compounds as 5-HT.sub.4
agonists or antagonists and/or 5-HT.sub.3 antagonists. Especially,
compounds represented by the following formula is disclosed as
Example 10: ##STR2##
[0004] There is a need to provide new 5-HT.sub.4 agonists that are
good drug candidates. In particular, preferred compounds should
bind potently to the 5-HT.sub.4 receptor whilst showing little
affinity for other receptors and show functional activity as
agonists. They should be well absorbed from the gastrointestinal
tract, be metabolically stable and possess favorable
pharmacokinetic properties. When targeted against receptors in the
central nervous system they should cross the blood brain barrier
freely and when targeted selectively against receptors in the
peripheral nervous system they should not cross the blood brain
barrier. They should be non-toxic and demonstrate few side-effects.
Furthermore, the ideal drug candidate will exist in a physical form
that is stable, non-hygroscopic and easily formulated.
SUMMARY OF THE INVENTION
[0005] In this invention, it has now been found out that (1)
replacing the quinuclidine ring with a piperidine/pyrrolidine ring
improves affinity for 5-HT.sub.4 receptor, and/or (2) introduction
of the carboxy moiety decreases affinity for dofetilide that
results the prevention of the QT prolongation.
[0006] Therefore, it has now surprisingly been found that compounds
of this invention have stronger selective 5-HT.sub.4 agonistic
activity and/or improved dofetilide affinity, compared with the
prior art, and thus are useful for the treatment of disease
conditions mediated by 5-HT.sub.4 activity such as gastroesophageal
reflux disease, gastrointestinal disease, gastric motility
disorder, non-ulcer dyspepsia, functional dyspepsia, irritable
bowel syndrome (IBS), constipation, dyspepsia, esophagitis,
gastroesophageal disease, nausea, central nervous system disease,
Alzheimer's disease, cognitive disorder, emesis, migraine,
neurological disease, pain, cardiovascular disorders, cardiac
failure, heart arrhythmia, diabetes and apnea syndrome (especially
caused by an opioid administration).
[0007] The present invention provides a compound of the following
formula (I): ##STR3## or a pharmaceutically acceptable salt or
solvate thereof, wherein P A is an alkylene group having 1 to 4
carbon atoms, said alkylene group being unsubstituted or
substituted with 1 to 4 substituents independently selected from
the group consisting of a halogen atom, an alkyl group having 1 to
4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms
and an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein any 2
non-halogen substituents can be taken together with the carbon
atoms to which they are attached to form a 3-, 4-, 5- or 6-membered
ring optionally containing at least one heteroatom selected from N,
O, and S; R.sup.1 is an isopropyl group or a cyclopentyl group;
R.sup.2 is a hydrogen atom, a halogen atom or a hydroxy group;
R.sup.3 is a carboxy group, a tetrazolyl group, a
5-oxo-1,2,4-oxadiazole-3-yl group or a 5-oxo-1,2,4-thiadiazole-3-yl
group; and m is the integer 1 or 2.
[0008] One embodiment of the invention provides a compound of
formula (I), as set forth above, or a pharmaceutically acceptable
salt or solvate thereof, wherein:
[0009] A is an alkylene group having 1 to 4 carbon atoms, said
alkylene group being unsubstituted or substituted with 1 to 4
substituents independently selected from the group consisting of a
halogen atom, an alkyl group having 1 to 4 carbon atoms, a
hydroxy-alkyl group having 1 to 4 carbon atoms and an alkoxy-alkyl
group having 2 to 6 carbon atoms, wherein any 2 non-halogen
substituents can be taken together with the carbon atoms to which
they are attached to form a 6-membered ring optionally containing
at least one heteroatom selected from N, O, and S;
R.sup.1 is an isopropyl group or a cyclopentyl group;
R.sup.2 is a hydrogen atom, a halogen atom or a hydroxy group;
R.sup.3 is a carboxy group, a tetrazolyl group, a
5-oxo-1,2,4-oxadiazole-3-yl group or a 5-oxo-1,2,4-thiadiazole-3-yl
group; and
m is the integer 1 or 2.
[0010] One embodiment of the invention provides a compound of
formula (I), as set forth above, or a pharmaceutically acceptable
salt or solvate thereof, wherein:
[0011] A is an alkylene group having 1 to 4 carbon atoms, said
alkylene group being substituted with 1 to 4 substituents
independently selected from the group consisting of a halogen atom,
an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group
having 1 to 4 carbon atoms and an alkoxy-alkyl group having 2 to 6
carbon atoms, wherein any 2 non-halogen substituents can be taken
together with the carbon atoms to which they are attached to form a
5-membered ring optionally containing at least one heteroatom
selected from N, O, and S;
R.sup.1 is an isopropyl group or a cyclopentyl group;
R.sup.2 is a hydrogen atom, a halogen atom or a hydroxy group;
R.sup.3 is a carboxy group, a tetrazolyl group, a
5-oxo-1,2,4-oxadiazole-3-yl group or a 5-oxo-1,2,4-thiadiazole-3-yl
group; and
m is the integer 1 or 2.
[0012] One embodiment of the invention provides a compound of
formula (I), as set forth above, or a pharmaceutically acceptable
salt or solvate thereof, wherein:
[0013] A is an alkylene group having 1 to 4 carbon atoms, said
alkylene group being substituted with 1 to 4 substituents
independently selected from the group consisting of a halogen atom,
an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group
having 1 to 4 carbon atoms and an alkoxy-alkyl group having 2 to 6
carbon atoms, wherein any 2 non-halogen substituents can be taken
together with the carbon atoms to which they are attached to form a
3 to 4-membered ring optionally containing at least one heteroatom
selected from N, O, and S;
R.sup.1 is an isopropyl group or a cyclopentyl group;
R.sup.2 is a hydrogen atom, a halogen atom or a hydroxy group;
R.sup.3 is a carboxy group, a tetrazolyl group, a
5-oxo-1,2,4-oxadiazole-3-yl group or a 5-oxo-1,2,4-thiadiazole-3-yl
group; and
m is the integer 1 or 2.
[0014] Also, the present invention provides the use of a compound
of formula (I), or a pharmaceutically acceptable salt or solvate
thereof, each as described herein, for the manufacture of a
medicament for the treatment of a condition mediated by 5-HT.sub.4
receptor activity; in particular, 5-HT.sub.4 agonistic
activity.
[0015] Preferably, the present invention also provides the use of a
compound of formula (I) or a pharmaceutically acceptable salt or
solvate thereof, each as described herein, for the manufacture of a
medicament for the treatment of diseases selected from
gastroesophageal reflux disease, gastrointestinal disease, gastric
motility disorder, non-ulcer dyspepsia, functional dyspepsia,
irritable bowel syndrome (IBS), constipation, dyspepsia,
esophagitis, gastroesophageal disease, nausea, central nervous
system disease, Alzheimer's disease, cognitive disorder, emesis,
migraine, neurological disease, pain, cardiovascular disorders,
cardiac failure, heart arrhythmia, diabetes and apnea syndrome.
[0016] Also, the present invention provides a pharmaceutical
composition comprising a compound of formula (I) or a
pharmaceutically acceptable salt or solvate thereof, each as
described herein, together with a pharmaceutically acceptable
carrier for said compound.
[0017] Further, the present invention provides a method of
treatment of a condition mediated by 5-HT.sub.4 receptor activity,
in a mammalian subject, which comprises administering to a mammal
in need of such treatment a therapeutically effective amount of a
compound of formula (I) or a pharmaceutically acceptable salt or
solvate thereof each as described herein.
[0018] Examples of conditions mediated by 5-HT.sub.4 receptor
activity include, but are not limited to, gastroesophageal reflux
disease, gastrointestinal disease, gastric motility disorder,
non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome
(IBS), constipation, dyspepsia, esophagitis, gastroesophageal
disease, nausea, central nervous system disease, Alzheimer's
disease, cognitive disorder, emesis, migraine, neurological
disease, pain, cardiovascular disorders, cardiac failure, heart
arrhythmia, diabetes and apnea syndrome.
[0019] Also, the present invention provides a compound of formula
(XI) ##STR4## or a salt thereof, wherein: R.sup.2 is a hydrogen
atom, a hydroxy group or a halogen atom; R.sup.6 is a hydrogen atom
or an amino-protecting group; Y is an alkoxy group having 1 to 4
carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an
imidazolyl group, a phtalimidyl group, succinimidyl group or
sulfonyl group; and m is 1 or 2.
[0020] Also, the present invention provides a compound of formula
(IXa) ##STR5## or a salt thereof, wherein: A is an alkylene group
having 1 to 4 carbon atoms, said alkylene group being unsubstituted
or substituted with 1 to 4 substituents independently selected from
the group consisting of a halogen atom, an alkyl group having 1 to
4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms
and an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein any 2
non-halogen substituents can be taken together with the carbon
atoms to which they are attached to form a 3 to 6-membered ring
optionally containing at least one heteroatom selected from N, O,
and S; R.sup.2 is a hydrogen atom, a hydroxy group or a halogen
atom; R.sup.4 is a hydroxy group or a carboxy-protecting group;
R.sup.6 is a hydrogen atom or an amino-protecting group; and m is 1
or 2.
[0021] The compounds of the present invention may show less
toxicity, good absorption, distribution, good solubility, less
protein binding affinity, less drug-drug interaction, and good
metabolic stability.
DETAILED DESCRIPTION OF THE INVENTION
[0022] In the compounds of the present invention:
[0023] Where A is an alkylene group having 1 to 4 carbon atoms,
this may be a straight chain group, and examples include, but are
not limited to, a methylene, ethylene, trimethylene and
tetramethylene. Of these, methylene and ethylene are preferred; and
ethylene is most preferred.
[0024] Where the substituent of A is an alkyl group having 1 to 4
carbon atoms, this may be a straight or branched chain group, and
examples include, but are not limited to, a methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Of these,
alkyl groups having from 1 to 3 carbon atoms are preferred; methyl,
ethyl, propyl and isopropyl are more preferred; and methyl and
ethyl are most preferred.
[0025] Where the substituent of Y is an alkoxy group having 1 to 4
carbon atoms, this represents the oxygen atom substituted by the
said alkyl group, and examples include, but are not limited to, a
methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy,
sec-butyloxy and tert-butyloxy. Of these, alkyl groups having from
1 to 2 carbon atoms are preferred; methoxy are more preferred.
[0026] Where the substituent of Y is a dialkylamino group having 2
to 8 carbon atoms, this represents the amino group substituted by
two of the said alkyl group, and examples include, but are not
limited to, a dimethylamino, N-methyl-N-ethylamino, diethylamino,
dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, and
N,N-di(1-methylpropyl)amino. Of these, dialkylamino groups having
from 2 to 4 carbon atoms are preferred; dimethylamino,
N-methyl-N-ethylamino, and diethylamino are more preferred.
[0027] Where the substituent of A is a hydroxy-alkyl group having 1
to 4 carbon atoms, this may be a straight or branched chain group,
and examples include, but are not limited to, a hydroxymethyl,
2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl,
2-hydroxy-1-methylethyl, 4-hydroxybutyl, 3-hydroxybutyl,
2-hydroxybutyl, 3-hydroxy-2-methylpropyl and
3-hydroxy-1-methylpropyl. Of these, hydroxy-alkyl groups having
from 1 to 3 carbon atoms are preferred; hydroxymethyl,
2-hydroxyethyl, and 2-hydroxypropyl are more preferred; and
hydroxymethyl and 2-hydroxyethyl are most preferred.
[0028] Where the substituent of A is an alkoxy-alkyl group having 2
to 6 carbon atoms, this may be a straight or branched chain group,
and examples include, but are not limited to, a methoxymethyl,
ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 1-methoxyethyl,
3-methoxypropyl, 3-ethoxypropyl, 2-methoxypropyl,
2-methoxy-1-methylethyl, 4-methoxybutyl, 4-ethoxybutyl,
3-methoxybutyl, 2-methoxybutyl, 3-methoxy-2-methylpropyl and
3-methoxy-1-methylpropyl. Of these, alkyloxy-alkyl groups having
from 2 to 4 carbon atoms are preferred; methoxymethyl,
2-methoxyethyl and 3-methoxypropyl are more preferred; and
2-methoxyethyl and 3-methoxypropyl are most preferred.
[0029] Where any 2 non-halogen substituents of A can be taken
together with the carbon atoms to which they are attached to form a
3, 4, 5, or 6-membered ring optionally containing at least one
heteroatom selected from N, O and S. Such a ring may be a
cycloalkyl or heterocyclyl group and examples include a
cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl,
methylcyclopropyl, ethylcyclopropyl, methylcyclobutyl,
methylcyclopentyl, methylcyclohexyl, ethylcyclohexyl,
hydroxycyclopropyl, hydroxycyclobutyl, hydroxycyclopentyl,
hydroxycyclohexyl, methoxycyclopropyl, methoxycyclobutyl,
methoxycyclopentyl, methoxycyclohexyl, tetrahydrofuryl and
tetrahydropyranyl, preferably cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, methoxycyclohexyl and tetrahydropyranyl, and most
preferably cyclobutyl, cyclopentyl, cyclohexyl and
tetrahydropyranyl.
[0030] Where the R.sup.6 is the amino-protecting group, this
represents a protecting group capable of being cleaved by chemical
means, such as hydrogenolysis, hydrolysis, electrolysis or
photolysis and such amino-protecting groups are described in
Protective Groups in Organic Synthesis edited by T. W. Greene et
al. (John Wiley & Sons, 1999), and examples include, but are
not limited to, benzyl, C.sub.2H.sub.5O(C.dbd.O)--,
CH.sub.3(C.dbd.O)--, t-butyldimethylsilyl, t-butyldiphenylsilyl,
benzyloxycarbonyl and t-buthoxycarbonyl. Of these groups,
t-buthoxycarbonyl is preferred.
[0031] Where the R.sup.4 is the carboxy-protecting group, this
represents a protecting group capable of being cleaved by chemical
means, such as hydrogenolysis, hydrolysis, electrolysis or
photolysis and such carboxy-protecting groups are described in
Protective Groups in Organic Synthesis edited by T. W. Greene et
al. (John Wiley & Sons, 1999), and examples include, methoxy,
ethoxy, t-butyloxy, methoxymethoxy, 2,2,2-trichloroethoxy,
benzyloxy, diphenylmethoxy, trimethylsilyloxy,
t-butyldimethylsilyloxy and allyloxy. Of these groups, t-butyloxy,
methoxy or ethoxy is preferred.
[0032] Where R.sup.1 and the substituent of A represent a halogen
atom, these may be a fluorine, chlorine, bromine or iodine atom. Of
these, a fluorine or a chlorine atom is preferred.
[0033] The term "treating" and "treatment", as used herein, refers
to curative, palliative and prophylactic treatment, including
reversing, alleviating, inhibiting the progress of, or preventing
the disorder or condition to which such term applies, or one or
more symptoms of such disorder or condition.
[0034] As used herein, the article "a" or "an" refers to both the
singular and plural form of the object to which it refers unless
indicated otherwise.
[0035] Preferred classes of compounds of the present invention are
those compounds of formula (I) or a pharmaceutically acceptable
salt or solvate thereof, each as described herein, in which: [0036]
(A) R.sup.1 is an isopropyl group; [0037] (B) R.sup.2 is a hydrogen
atom, a fluorine atom or a hydroxy group; [0038] (C) R.sup.2 is a
hydrogen atom; [0039] (D) R.sup.3 is a carboxy group or a
tetrazolyl group; [0040] (E) R.sup.3 is a carboxy group; [0041] (F)
A is an alkylene group having 1 to 2 carbon atoms, said alkylene
group being unsubstituted or substituted with 1 to 2 substituents
independently selected from the group consisting of a halogen atom,
an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group
having 1 to 4 carbon atoms and an alkoxy-alkyl group having 2 to 6
carbon atoms, wherein any 2 non-halogen substituents can be taken
together with the carbon atoms to which they are attached to form a
6-membered ring optionally containing at least one heteroatom
selected from N, O and S; [0042] (G) A is an alkylene group having
from 1 to 2 carbon atoms, said alkylene group being substituted
with 2 geminal substituents independently selected from the group
consisting of a halogen atom, an alkyl group having 1 to 4 carbon
atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms and an
alkoxy-alkyl group having 2 to 6 carbon atoms, wherein non-halogen
geminal substituents can be taken together with the carbon atom to
which they are attached to form a 6-membered ring optionally
containing at least one heteroatom selected from N, O and S; [0043]
(H) A is an alkylene group having 1 to 2 carbon atoms, said
alkylene group being substituted with 2 substituents independently
selected from the group consisting of an alkyl group having 1 to 4
carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms and
an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein any 2
said substituents can be taken together with the carbon atoms to
which they are attached to form a 5-membered ring optionally
containing at least one heteroatom selected from N, O, and S;
[0044] (I) A is an alkylene group having 1 to 2 carbon atoms, said
alkylene group being substituted with 2 geminal substituents
independently selected from the group consisting of an alkyl group
having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4
carbon atoms and an alkoxy-alkyl group having 2 to 6 carbon atoms,
wherein said geminal substituents can be taken together with the
carbon atom to which they are attached to form a 5-membered ring
optionally containing at least one heteroatom selected from N, O,
and S; [0045] (J) A is an alkylene group having 1 to 2 carbon
atoms, said alkylene group being substituted with 2 substituents
independently selected from the group consisting of an alkyl group
having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4
carbon atoms and an alkoxy-alkyl group having 2 to 6 carbon atoms,
wherein said substituents can be taken together with the carbon
atoms to which they are attached to form a 3 to 4-membered ring
optionally containing at least one heteroatom selected from N, O,
and S; [0046] (K) A is an alkylene group having 1 to 2 carbon
atoms, said alkylene group being substituted with 2 geminal
substituents independently selected from the group consisting of an
alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group
having 1 to 4 carbon atoms and an alkoxy-alkyl group having 2 to 6
carbon atoms, wherein said geminal substituents can be taken
together with the carbon atom to which they are attached to form a
3 to 4-membered ring optionally containing at least one heteroatom
selected from N, O, and S; [0047] (L) A is ##STR6## [0048] (M) A is
##STR7## [0049] (N) A is ##STR8## [0050] (O) A is ##STR9## [0051]
(P) A is ##STR10## [0052] (Q) m is the integer 2.
[0053] Particularly preferred compounds of the present invention
are those compounds of formula (I) or a pharmaceutically acceptable
salt or solvate thereof in which [0054] (R) R.sup.1 is an isopropyl
group; R.sup.2 is a hydrogen atom, a fluorine atom or a hydroxy
group; R.sup.3 is a carboxy group or a tetrazolyl group; A is an
alkylene group having 1 to 2 carbon atoms, said alkylene group
being unsubstituted or substituted with 1 to 2 substituents
independently selected from the group consisting of a halogen atom,
an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group
having 1 to 4 carbon atoms and an alkoxy-alkyl group having 2 to 6
carbon atoms, wherein any 2 non-halogen substituents can be taken
together with the carbon atoms to which they are attached to form a
6-membered ring optionally containing at least one heteroatom
selected from N, O, and S; and m is the integer 2; [0055] (S)
R.sup.1 is an isopropyl group; R.sup.2 is a hydrogen atom; R.sup.3
is a carboxy group or a tetrazolyl group; A is an alkylene group
having 1 to 2 carbon atoms, said alkylene group being substituted
with 2 geminal substituents independently selected from the group
consisting of a halogen atom, an alkyl group having 1 to 4 carbon
atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms and an
alkoxy-alkyl group having 2 to 6 carbon atoms, wherein said geminal
substituents can be taken together with the carbon atom to which
they are attached to form a 6-membered ring optionally containing
at least one heteroatom selected from N, O, and S; and m is the
integer 2; [0056] (T) R.sup.1 is an isopropyl group; R.sup.2 is a
hydrogen atom; R.sup.3 is a carboxy group or a tetrazolyl group; A
is ##STR11## and m is the integer 2; [0057] (U) R.sup.1 is an
isopropyl group; R.sup.2 is a hydrogen atom, a fluorine atom or a
hydroxy group; R.sup.3 is a carboxy group; A is alkylene group
having 1 to 2 carbon atoms, said alkylene group being unsubstituted
or substituted with 1 to 2 substituents independently selected from
the group consisting of a halogen atom, an alkyl group having 1 to
4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms
and an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein any 2
non-halogen geminal substituents can be taken together with the
carbon atom to which they are attached to form a 6-membered ring
optionally containing at least one heteroatom selected from N, O,
and S; and m is the integer 2; [0058] (V) R.sup.1 is an isopropyl
group; R.sup.2 is a hydrogen atom, a fluorine atom or a hydroxy
group; R.sup.3 is a carboxy group; A is ##STR12## and m is the
integer 2; [0059] (W) R.sup.1 is an isopropyl group; R.sup.2 is a
hydrogen atom, a fluorine atom or a hydroxy group; R.sup.3 is a
carboxy group or a tetrazolyl group; A is an alkylene group having
1 to 2 carbon atoms, said alkylene group being substituted with 2
substituents independently selected from the group consisting of an
alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group
having 1 to 4 carbon atoms and an alkoxy-alkyl group having 2 to 6
carbon atoms, wherein any 2 said substituents can be taken together
with the carbon atoms to which they are attached to form a
5-membered ring optionally containing at least one heteroatom
selected from N, O, and S; and m is the integer 2; [0060] (X)
R.sup.1 is an isopropyl group; R.sup.2 is a hydrogen atom; R.sup.3
is a carboxy group or a tetrazolyl group; A is an alkylene group
having 1 to 2 carbon atoms, said alkylene group being substituted
with 2 geminal substituents independently selected from the group
consisting of an alkyl group having 1 to 4 carbon atoms, a
hydroxy-alkyl group having 1 to 4 carbon atoms and an alkoxy-alkyl
group having 2 to 6 carbon atoms, wherein said geminal substituents
can be taken together with the carbon atom to which they are
attached to form a 5-membered ring optionally containing at least
one heteroatom selected from N, O, and S; and m is the integer 2;
[0061] (Y) R.sup.1 is an isopropyl group; R.sup.2 is a hydrogen
atom; R.sup.3 is a carboxy group or a tetrazolyl group; A is
##STR13## and m is the integer 2; [0062] (Z) R.sup.1 is an
isopropyl group; R.sup.2 is a hydrogen atom, a fluorine atom or a
hydroxy group; R.sup.3 is a carboxy group; A is alkylene group
having 1 to 2 carbon atoms, said alkylene group being substituted
with 2 substituents independently selected from the group
consisting of an alkyl group having 1 to 4 carbon atoms, a
hydroxy-alkyl group having Ito 4 carbon atoms and an alkoxy-alkyl
group having 2 to 6 carbon atoms, wherein any 2 said substituents
can be taken together with the carbon atoms to which they are
attached to form a 5-membered ring optionally containing at least
one heteroatom selected from N, O, and S; and m is the integer 2;
[0063] (AA) R.sup.1 is an isopropyl group; R.sup.2 is a hydrogen
atom, a fluorine atom or a hydroxy group; R.sup.3 is a carboxy
group; A is ##STR14## and m is the integer 2; [0064] (AB) R.sup.1
is an isopropyl group; R.sup.2 is a hydrogen atom, a fluorine atom
or a hydroxy group; R.sup.3 is a carboxy group or a tetrazolyl
group; A is an alkylene group having 1 to 2 carbon atoms, said
alkylene group being substituted with 2 substituents independently
selected from the group consisting of an alkyl group having 1 to 4
carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms and
an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein said
substituents can be taken together with the carbon atoms to which
they are attached to form a 3 to 4-membered ring optionally
containing at least one heteroatom selected from N, O, and S; and m
is the integer 2; [0065] (AC) R.sup.1 is an isopropyl group;
R.sup.2 is a hydrogen atom; R.sup.3 is a carboxy group or a
tetrazolyl group; A is an alkylene group having 1 to 2 carbon
atoms, said alkylene group being substituted with 2 geminal
substituents independently selected from the group consisting of an
alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group
having 1 to 4 carbon atoms and an alkoxy-alkyl group having 2 to 6
carbon atoms, wherein said geminal substituents can be taken
together with the carbon atom to which they are attached to form a
3 to 4-membered ring optionally containing at least one heteroatom
selected from N, O, and S; and m is the integer 2; [0066] (AD)
R.sup.1 is an isopropyl group; R.sup.2 is a hydrogen atom; R.sup.3
is a carboxy group or a tetrazolyl group; A is ##STR15## and m is
the integer 2; [0067] (AE) R.sup.1 is an isopropyl group; R.sup.2
is a hydrogen atom, a fluorine atom or a hydroxy group; R.sup.3 is
a carboxy group; A is alkylene group having 1 to 2 carbon atoms,
said alkylene group being substituted with 2 substituents
independently selected from the group consisting of a halogen atom,
an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group
having to 4 carbon atoms and an alkoxy-alkyl group having 2 to 6
carbon atoms, wherein any 2 non-halogen substituents can be taken
together with the carbon atoms to which they are attached to form a
3 to 4-membered ring optionally containing at least one heteroatom
selected from N, O, and S; and m is the integer 2; [0068] (AF)
R.sup.1 is an isopropyl group; R.sup.2 is a hydrogen atom, a
fluorine atom or a hydroxy group; R.sup.3 is a carboxy group; A is
##STR16## and m is the integer 2; [0069] (AG) R.sup.1 is an
isopropyl group, R.sup.2 is a hydrogen atom, a fluorine atom or a
hydroxy group, R.sup.3 is a carboxy group, A is ##STR17## and m is
the integer 2; or [0070] (AH) R.sup.1 is an isopropyl group;
R.sup.2 is a hydrogen atom; R.sup.3 is a carboxy group or a
tetrazolyl group; A is ##STR18## and m is the integer 2.
[0071] One embodiment of the invention provides a compound selected
from the group consisting of: [0072]
4-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]ami-
no}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic
acid; [0073]
1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carb-
onyl]amino}methyl)piperidin-1-yl]methyl}cyclohexanecarboxylic acid;
[0074]
1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carb-
onyl]amino}methyl)piperidin-1-yl]methyl}cyclopentanecarboxylic
acid; [0075]
1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carb-
onyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylic
acid; [0076]
1-{[4-hydroxy-4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-
-1-yl)carbonyl]amino}methyl)piperidin-1-yl]methyl}cyclohexanecarboxylic
acid; [0077]
1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]ami-
no}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid; and a
pharmaceutically acceptable salt or solvate thereof.
[0078] One embodiment of the invention provides a compound from the
group consisting of: [0079]
4-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]ami-
no}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic
acid; [0080]
1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carb-
onyl]amino}methyl)piperidin-1-yl]methyl}cyclohexanecarboxylic acid;
and a pharmaceutically acceptable salt and solvate thereof.
[0081] One embodiment of the invention provides a compound from the
group consisting of: [0082]
1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]ami-
no}methyl)piperidin-1-yl]methyl}cyclopentanecarboxylic acid; and a
pharmaceutically acceptable salt and solvate thereof.
[0083] One embodiment of the invention provides a compound from the
group consisting of: [0084]
1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]ami-
no}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylic acid; [0085]
1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]ami-
no}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid; and a
pharmaceutically acceptable salt and solvate thereof.
[0086] Pharmaceutically acceptable salts of a compound of formula
(I) include the acid addition and base salts (including disalts)
thereof.
[0087] Suitable acid addition salts are formed from acids which
form non-toxic salts. Examples include the acetate, aspartate,
benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate,
borate, camsylate, citrate, edisylate, esylate, formate, fumarate,
gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate,
hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide,
isethionate, lactate, malate, maleate, malonate, mesylate,
methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate,
orotate, oxalate, palmitate, pamoate, phosphate/hydrogen
phosphate/dihydrogen phosphate, saccharate, stearate, succinate,
tartrate, tosylate and trifluoroacetate salts.
[0088] Suitable base salts are formed from bases which form
non-toxic salts. Examples include the aluminium, arginine,
benzathine, calcium, choline, diethylamine, diolamine, glycine,
lysine, magnesium, meglumine, olamine, potassium, sodium,
tromethamine and zinc salts.
[0089] For a review on suitable salts, see "Handbook of
Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and
Wermuth (Wiley-VCH, Weinheim, Germany, 2002). A pharmaceutically
acceptable salt of a compound of formula (I) may be readily
prepared by mixing together solutions of the compound of formula
(I) and the desired acid or base, as appropriate. The salt may
precipitate from solution and be collected by filtration or may be
recovered by evaporation of the solvent. The degree of ionisation
in the salt may vary from completely ionised to almost
non-ionised.
[0090] The compounds of the invention may exist in both unsolvated
and solvated forms. The term `solvate` is used herein to describe a
molecular complex comprising a compound of the invention and one or
more pharmaceutically acceptable solvent molecules, for example,
ethanol. The term `hydrate` is employed when said solvent is
water.
[0091] Pharmaceutically acceptable solvates in accordance with the
invention include hydrates and solvates wherein the solvent of
crystallization may be isotopically substituted, e.g. D.sub.2O,
d.sub.6-acetone, d.sub.6-DMSO
[0092] Included within the scope of the invention are complexes
such as clathrates, drug-host inclusion complexes wherein, in
contrast to the aforementioned solvates, the drug and host are
present in stoichiometric or non-stoichiometric amounts. Also
included are complexes of the drug containing two or more organic
and/or inorganic components which may be in stoichiometric or
non-stoichiometric amounts. The resulting complexes may be ionised,
partially ionised, or non-ionised. For a review of such complexes,
see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).
[0093] Hereinafter all references to a compound of formula (I)
include references to salts, solvates and complexes thereof and to
solvates and complexes of salts thereof.
[0094] The term "compound of the invention" or "compounds of the
invention" refers to, unless indicated otherwise, a compound of
formula (I) as hereinbefore defined, polymorphs, prodrugs, and
isomers thereof (including optical, geometric and tautomeric
isomers) as hereinafter defined and isotopically-labeled compounds
of formula (I).
[0095] Also within the scope of the invention are so-called
`prodrugs` of the compounds of formula (I). Thus certain
derivatives of compounds of formula (I) which may have little or no
pharmacological activity themselves can, when administered into or
onto the body, be converted into compounds of formula (I) having
the desired activity, for example, by hydrolytic cleavage. Such
derivatives are referred to as `prodrugs`. Further information on
the use of prodrugs may be found in `Pro-drugs as Novel Delivery
Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and
`Bioreversible Carriers in Drug Design`, Pergamon Press, 1987 (ed.
E B Roche, American Pharmaceutical Association).
[0096] Prodrugs in accordance with the invention can, for example,
be produced by replacing appropriate functionalities present in the
compounds of formula (I) with certain moieties known to those
skilled in the art as `pro-moieties` as described, for example, in
"Design of Prodrugs" by H Bundgaard (Elsevier, 1985). Some examples
of prodrugs in accordance with the invention include:
(i) where the compound of formula (I) contains a carboxylic acid
functionality (--COOH), an ester thereof, for example, replacement
of the hydrogen with (C.sub.1-C.sub.8)alkyl;
(ii) where the compound of formula (I) contains an alcohol
functionality (--OH), an ether thereof, for example, replacement of
the hydrogen with (C.sub.1-C.sub.6)alkanoyloxymethyl; and
(iii) where the compound of formula (I) contains a primary or
secondary amino functionality (--NH.sub.2 or --NHR where
R.noteq.H), an amide thereof for example, replacement of one or
both hydrogens with (C.sub.1-C.sub.10)alkanoyl.
[0097] Further examples of replacement groups in accordance with
the foregoing examples and examples of other prodrug types may be
found in the aforementioned references.
[0098] Finally, certain compounds of formula (I) may themselves act
as prodrugs of other compounds of formula (I).
[0099] Compounds of formula (I) containing one or more asymmetric
carbon atoms can exist as two or more stereoisomers. Where a
compound of formula (I) contains an alkenyl or alkenylene group,
geometric cis/trans (or Z/E) isomers are possible. Where the
compound contains, for example, a keto or oxime group or an
aromatic moiety, tautomeric isomerism (`tautomerism`) can occur. It
follows that a single compound may exhibit more than one type of
isomerism.
[0100] Included within the scope of the present invention are all
stereoisomers, geometric isomers and tautomeric forms of the
compounds of formula (I), including compounds exhibiting more than
one type of isomerism, and mixtures of one or more thereof. Also
included are acid addition or base salts wherein the counterion is
optically active, for example, O-lactate or L-lysine, or racemic,
for example, DL-tartrate or DL-arginine.
[0101] Cis/trans isomers may be separated by conventional
techniques well known to those skilled in the art, for example,
chromatography and fractional crystallization.
[0102] Conventional techniques for the preparation/isolation of
individual enantiomers include chiral synthesis from a suitable
optically pure precursor or resolution of the racemate (or the
racemate of a salt or derivative) using, for example, chiral high
pressure liquid chromatography (HPLC).
[0103] Alternatively, the racemate (or a racemic precursor) may be
reacted with a suitable optically active compound, for example, an
alcohol, or, in the case where the compound of formula (I) contains
an acidic or basic moiety, an acid or base such as tartaric acid or
1-phenylethylamine. The resulting diastereomeric mixture may be
separated by chromatography and/or fractional crystallization and
one or both of the diastereoisomers converted to the corresponding
pure enantiomer(s) by means well known to a skilled person.
[0104] Chiral compounds of the invention (and chiral precursors
thereof) may be obtained in enantiomerically-enriched form using
chromatography, typically HPLC, on an asymmetric resin with a
mobile phase consisting of a hydrocarbon, typically heptane or
hexane, containing from 0 to 50% isopropanol, typically from 2 to
20%, and from 0 to 5% of an alkylamine, typically 0.1%
diethylamine. Concentration of the eluate affords the enriched
mixture.
[0105] Stereoisomeric conglomerates may be separated by
conventional techniques known to those skilled in the art--see, for
example, "Stereochemistry of Organic Compounds" by E L Eliel
(Wiley, New York, 1994).
[0106] The present invention includes all pharmaceutically
acceptable isotopically-labelled compounds of formula (I) wherein
one or more atoms are replaced by atoms having the same atomic
number, but an atomic mass or mass number different from the atomic
mass or mass number usually found in nature.
[0107] Examples of isotopes suitable for inclusion in the compounds
of the invention include isotopes of hydrogen, such as .sup.2H and
.sup.3H, carbon, such as .sup.11C, .sup.13C and .sup.14C, chlorine,
such as .sup.36Cl, fluorine, such as .sup.18F, iodine, such as
.sup.123I and .sup.125I, nitrogen, such as .sup.13N and .sup.15N,
oxygen, such as .sup.15O, .sup.17O and .sup.18O, phosphorus, such
as .sup.32P, and sulphur, such as .sup.35S.
[0108] Certain isotopically-labelled compounds of formula (I), for
example, those incorporating a radioactive isotope, are useful in
drug and/or substrate tissue distribution studies. The radioactive
isotopes tritium, i.e. .sup.3H, and carbon-14, i.e. .sup.14C, are
particularly useful for this purpose in view of their ease of
incorporation and ready means of detection.
[0109] Substitution with heavier isotopes such as deuterium, i.e.
2H, may afford certain therapeutic advantages resulting from
greater metabolic stability, for example, increased in vivo
half-life or reduced dosage requirements, and hence may be
preferred in some circumstances.
[0110] Substitution with positron emitting isotopes, such as
.sup.11C, .sup.18F, .sup.15O and .sup.13N, can be useful in
Positron Emission Topography (PET) studies for examining substrate
receptor occupancy.
[0111] Isotopically-labeled compounds of formula (I) can generally
be prepared by conventional techniques known to those skilled in
the art or by processes analogous to those described in the
accompanying Examples and Preparations using an appropriate
isotopically-labeled reagents in place of the non-labeled reagent
previously employed.
[0112] All of the compounds of the formula (I) can be prepared by
the procedures described in the general methods presented below or
by the specific methods described in the Examples section and the
Preparations section, or by routine modifications thereof. The
present invention also encompasses any one or more of these
processes for preparing the compounds of formula (I), in addition
to any novel intermediates used therein.
General Synthesis
[0113] The compounds of the present invention may be prepared by a
variety of processes well known for the preparation of compounds of
this type, for example as shown in the following Methods A to
G.
[0114] The following Methods A and B illustrate the preparation of
compounds of formula (I). Methods C through G illustrate the
preparation of various intermediates.
[0115] Unless otherwise indicated, R.sup.1, R.sup.2, R.sup.3, m and
A in the following Methods are as defined above. The term
"protecting group", as used hereinafter, means a hydroxy, carboxy
or amino-protecting group which is selected from typical hydroxy,
carboxy or amino-protecting groups described in Protective Groups
in Organic Synthesis edited by T. W. Greene et al. (John Wiley
& Sons, 1999). All starting materials in the following general
syntheses may be commercially available or obtained by conventional
methods known to those skilled in the art, such as European Journal
of Medicinal Chemistry, 12(1), 87-91; 1977 and the disclosures of
which are incorporated herein by reference.
Method A
[0116] This illustrates the preparation of compounds of formula
(I). ##STR19##
[0117] In Reaction Scheme A, R.sup.3a is R.sup.3 as defined above
or a group of formula --C(.dbd.O)--R.sup.4, wherein R.sup.4 is a
carboxy-protecting group.
[0118] The term "carboxy-protecting group", as used herein,
signifies a protecting group capable of being cleaved by chemical
means, such as hydrogenolysis, hydrolysis, electrolysis or
photolysis, and such carboxy-protecting groups are described in
Protective Groups in Organic Synthesis edited by T. W. Greene et
al. (John Wiley & Sons, 1999). Typical carboxy-protecting
groups include, but are not limited to: methoxy, ethoxy,
t-butyloxy, methoxymethoxy, 2,2,2-trichloroethoxy, benzyloxy,
diphenylmethoxy, trimethylsilyloxy, t-butyldimethylsilyloxy and
allyloxy. Of these groups, t-butyloxy, methoxy or ethoxy is
preferred.
Step A1
[0119] In this step, the desired compound of formula (I) of the
present invention is prepared by carbonylation of the compound of
formula (II) with the compound of formula (II). The compound of
formula (II) is commercially available. The compound of formula
(III) can be prepared according to Method C set forth below.
[0120] The reaction is normally and preferably effected in the
presence of solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or the reagents involved and that it
can dissolve reagents, at least to some extent. Examples of
suitable solvents include, but are not limited to: halogenated
hydrocarbons, such as dichloromethane, chloroform, carbon
tetrachloride and 1,2-dichloroethane; aromatic hydrocarbons, such
as benzene, toluene and nitrobenzene; ethers, such as diethyl
ether, diisopropyl ether, tetrahydrofuran and dioxane; and amides,
such as N,N-dimethylformamide and N,N-dimethylacetamide. Of these
solvents, dichloromethane is preferred.
[0121] There is likewise no particular restriction on the nature of
the carbonylating agents used, and any carbonylating agent commonly
used in reactions of this type may equally be used here. Examples
of such carbonylating agents include, but are not limited to: an
imidazole derivative such as N,N'-carbonyldiimidazole (CDI); a
chloroformate such as trichloromethyl chloroformate and
4-nitrophenyl chloroformate; urea; and triphosgene. Of these,
4-nitrophenyl chloroformate is preferred.
[0122] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
materials. However, in general, it is convenient to carry out the
reaction at a temperature of from about -78.degree. C. to about
120.degree. C. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature
and the nature of the starting materials and solvent employed.
However, provided that the reaction is effected under the preferred
conditions outlined above, a period of from about 5 minutes to
about 24 hours will usually suffice.
[0123] In the case where R.sup.3a is a group of formula
--C(.dbd.O)--R.sup.4, the deprotection reaction will follow to
yield a carboxy group. This reaction is described in detail by T.
W. Greene et al., Protective Groups in Organic Synthesis, 369-453,
(1999), the disclosures of which are incorporated herein by
reference. The following exemplifies a typical reaction involving
the protecting group t-butyl.
[0124] The deprotection reaction is normally and preferably
effected in the presence of solvent. There is no particular
restriction on the nature of the solvent to be employed, provided
that it has no adverse effect on the reaction or the reagents
involved and that it can dissolve reagents, at least to some
extent. Examples of suitable solvents include, but are not limited
to: halogenated hydrocarbons, such as dichloromethane, chloroform,
carbon tetrachloride and 1,2-dichloroethane; and aromatic
hydrocarbons, such as benzene, toluene and nitrobenzene. Of these
solvents, halogenated hydrocarbons are preferred.
[0125] The deprotection reaction is carried out in the presence of
an acid. There is likewise no particular restriction on the nature
of the acids used, and any acid commonly used in reactions of this
type may equally be used here. Examples of such acids include, but
are not limited to: acids, such as hydrochloric acid, acetic acid
p-toluenesulfonic acid or trifluoroacetic acid. Of these,
trifluoroacetic acid is preferred.
[0126] The deprotection reaction may be carried out in the presence
of a radical scavenger. There is likewise no particular restriction
on the nature of the radical scavenger used, and any radical
scavenger commonly used in reactions of this type may equally be
used here. Examples of such radical scavengers include, but are not
limited to: HBr, dimethylsulfoxide or (CH.sub.3CH.sub.2).sub.3SiH.
Of these, (CH.sub.3CH.sub.2).sub.3SiH is preferred.
[0127] The deprotection reaction can take place over a wide range
of temperatures, and the precise reaction temperature is not
critical to the invention. The preferred reaction temperature will
depend upon such factors as the nature of the solvent, and the
starting materials. However, in general, it is convenient to carry
out the reaction at a temperature of from about 0.degree. C. to
about 100.degree. C., more preferably from about 0.degree. C. to
about 50.degree. C. The time required for the reaction may also
vary widely, depending on many factors, notably the reaction
temperature and the nature of the starting materials and solvent
employed. However, provided that the reaction is effected under the
preferred conditions outlined above, a period of from about 5
minutes to about 24 hours, more preferably from about 1 hour to
about 24 hours, will usually suffice.
Method B
[0128] This illustrates an alternative preparation of the desired
compound of formula (I). ##STR20##
[0129] In Reaction Scheme B, R.sup.3a is as defined above; R.sup.5
is an amino-protecting group; A.sup.a is A as defined above or an
alkylene group having from 1 to 3 carbon atoms, said alkylene group
being unsubstituted or substituted with 1 to 4 substituents
independently selected from the group consisting of a halogen atom,
an alkyl group having from 1 to 4 carbon atoms, a hydroxy-alkyl
group having 1 to 4 carbon atoms and an alkoxy-alkyl group having 2
to 6 carbon atoms, wherein 2 of said substituents may optionally be
taken together with the carbon atom(s) form a 3 to 6 membered ring;
and X is a halogen atom such as an iodine atom, a chlorine atom or
a bromine atom.
[0130] The term "amino-protecting group", as used herein, signifies
a protecting group capable of being cleaved by chemical means, such
as hydrogenolysis, hydrolysis, electrolysis or photolysis and such
amino-protecting groups are described in Protective Groups in
Organic Synthesis edited by T. W. Greene et al. (John Wiley &
Sons, 1999). Typical amino-protecting groups include, but are not
limited to, benzyl, C.sub.2H.sub.5O(C.dbd.O)--,
CH.sub.3(C.dbd.O)--, t-butyldimethylsilyl, t-butyldiphenylsilyl,
benzyloxycarbonyl and t-buthoxycarbonyl. Of these groups,
t-buthoxycarbonyl is preferred.
Step B1
[0131] In this step, the compound of formula (V) is prepared by the
deprotection of the compound of formula (IV), which may be
prepared, for example, by a method similar to that described in
Method A for the preparation of the compound of formula (I) from a
compound of formula (II). This deprotection method is described in
detail by T. W. Greene et al [Protective Groups in Organic
Synthesis, 494-653, (1999)], the disclosures of which are
incorporated herein by reference. The following exemplifies a
typical method involving the protecting group
t-buthoxycarbonyl.
[0132] The reaction is normally and preferably effected in the
presence of solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or the reagents involved and that it
can dissolve reagents, at least to some extent. Examples of
suitable solvents include, but are not limited to: halogenated
hydrocarbons, such as dichloromethane, chloroform, carbon
tetrachloride and 1,2-dichloroethane; and alcohols, such as
methanol, ethanol, propanol, 2-propanol and butanol. Of these
solvents, alcohols are preferred.
[0133] The reaction is carried out in the presence of excess amount
of an acid. There is likewise no particular restriction on the
nature of the acids used, and any acid commonly used in reactions
of this type may equally be used here. Examples of such acids
include, but are not limited to: acids, such as hydrochloric acid,
or trifluoroacetic acid. Of these, hydrochloric acid is
preferred.
[0134] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
materials. However, in general, it is convenient to carry out the
reaction at a temperature of from about 0.degree. C. to about
100.degree. C. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature
and the nature of the starting materials and solvent employed.
However, provided that the reaction is effected under the preferred
conditions outlined above, a period of from about 5 minutes to
about 24 hours, will usually suffice.
Step B2
[0135] In this step, the desired compound of formula (I) is
prepared by the coupling (B2-a) of the compound of formula (V)
prepared as described in Step B1 with the compound of formula (VI)
or by the reductive amination (B2-b) of the compound of formula (V)
with the compound of formula (VII).
(B2-a) Coupling with the Compound of Formula (V):
[0136] The reaction is normally and preferably effected in the
presence of solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or the reagents involved and that it
can dissolve reagents, at least to some extent. Examples of
suitable solvents include, but are not limited to: halogenated
hydrocarbons, such as dichloromethane, chloroform, carbon
tetrachloride and 1,2-dichloroethane; ethers, such as diethyl
ether, diisopropyl ether, tetrahydrofuran and dioxane; amines, such
as N-methylmorpholine, triethylamine, tripropylamine,
tributylamine, diisopropylethylamine, dicyclohexylamine,
N-methylpiperidine, N-methylpyrrolidine, pyridine,
4-pyrrolidinopyridine, N,N-dimethylaniline and N,N-diethylaniline;
and amides, such as N,N-dimethylformamide and
N,N-dimethylacetamide. Of these, N,N-dimethylformamide or
N-methylpyrrolidine is preferred.
[0137] The reaction is carried out in the presence of a base. There
is likewise no particular restriction on the nature of the base
used, and any base commonly used in reactions of this type may
equally be used here. Examples of such bases include, but are not
limited to amines, such as N-methylmorpholine, triethylamine,
tripropylamine, tributylamine, diisopropylethylamine,
dicyclohexylamine, N-methylpiperidine, pyridine,
4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine,
2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline,
N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
1,4-diazabicyclo[2.2.2]octane (DABCO) and
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); alkali metal hydrides,
such as lithium hydride, sodium hydride and potassium hydride; and
alkali metal alkoxides, such as sodium methoxide, sodium ethoxide,
potassium t-butoxide. Of these, diisopropylethylamine is
preferred.
[0138] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
materials. However, in general, it is convenient to carry out the
reaction at a temperature of from about 0.degree. C. to about
120.degree. C. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature
and the nature of the starting materials and solvent employed.
However, provided that the reaction is effected under the preferred
conditions outlined above, a period of from about 5 minutes to
about 48 hours will usually suffice.
(B2-b) Reductive Amination:
[0139] The reaction is normally and preferably effected in the
presence of solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or the reagents involved and that it
can dissolve reagents, at least to some extent. Examples of
suitable solvents include, but are not limited to: halogenated
hydrocarbons, such as dichloromethane, chloroform, carbon
tetrachloride and 1,2-dichloroethane; ethers, such as diethyl
ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran and
dioxane; alcohols, such as methanol, ethanol, propanol, 2-propanol
and butanol; acetic acid; and water. Of these solvents, halogenated
hydrocarbons are preferred.
[0140] The reaction is carried out in the presence of a reducing
reagent. There is likewise no particular restriction on the nature
of the reducing reagents used, and any reducing reagent commonly
used in reactions of this type may equally be used here. Examples
of such reducing reagent include, but are not limited to: sodium
borohydride, sodium cyanoborohydride and sodium
triacetoxyborohydride. Of these, sodium triacetoxyborohydride is
preferred. The quantity of the reducing reagent required for the
reaction may also vary widely, depending on many factors, notably
the reaction temperature and the nature of the starting materials
and solvent employed. However, that the reaction is effected under
preferred conditions, a chemical equivalent ratio of 1 to 3 of the
reducing reagent to the starting material will usually suffice.
[0141] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
materials. However, in general, it is convenient to carry out the
reaction at a temperature of from about -20.degree. C. to about
60.degree. C. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature
and the nature of the starting materials and solvent employed.
However, provided that the reaction is effected under the preferred
conditions outlined above, a period of from about 5 minutes to
about 24 hours, will usually suffice.
[0142] In the case where R.sup.3a is a group of formula
--C(.dbd.O)--R.sup.4, the deprotection reaction will follow to
yield a carboxy group. The reaction may be carried out under the
same conditions as described in Step A1 of Method A.
Method C
[0143] This illustrates the preparation of the compound of formula
(III). ##STR21##
[0144] In Reaction Scheme C, X, A, A.sup.a, and R.sup.3a, R.sup.6
and are each as defined above. Therefore, when R.sup.3a is
--C(.dbd.O)--R.sup.4, the above compound of formula (IX) is as
follows. ##STR22## Step C1
[0145] In this step, the compound of formula (IX) is prepared by
the coupling of the compound of formula (VIII) with a compound of
formula (VI) or by the reductive amination of the compound of
formula (VIII) with the compound of formula (VII). The compound of
formula (VIII) can be prepared according to Methods F and G set
forth below or is commercially available.
Step C2
[0146] In this step, the compound of formula (III) is prepared by
the deprotection of the compound of formula (IX) prepared as
described in Step C1. The reaction may be carried out under the
same conditions as described in Step B1 of Method B.
Method D
[0147] This illustrates the preparation of the compound of formula
(IIIa). ##STR23##
[0148] In Reaction Scheme D, R.sup.3a, R.sup.4, R.sup.6 and Y are
each as defined above and R.sup.7 is a silyl group such as
t-butyldimethylsilyl, t-butyldiphenylsilyl, triethylsilyl or
trimethylsilyl, preferably trimethylsilyl; R.sup.8 and R.sup.9
independently represent a halogen atom, an alkyl group having 1 to
4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms
and an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein
R.sup.8 and R.sup.9 may optionally be taken together with the
carbon atom to which they are attached to form a 3 to 6 membered
ring; A.sup.b is A as defined above with proviso a methylene group
and a substituted methylene group are excluded.
Step D1
[0149] In this step, the compound of formula (XI) is prepared by
condensation of the compound of formula (VIII) with the compound of
formula (X) in the presence of paraformaldehyde. A compound of
formula (VIII) can be prepared according to Method F and G or is
commercially available.
[0150] In the case that Y is not an alkoxy group, the reaction is
normally and preferably effected in the presence of solvent. There
is no particular restriction on the nature of the solvent to be
employed, provided that it has no adverse effect on the reaction or
the reagents involved and that it can dissolve reagents, at least
to some extent. Examples of suitable solvents include, but are not
limited to: halogenated hydrocarbons, such as dichloromethane,
chloroform, carbon tetrachloride and 1,2-dichloroethane; and
alcohols, such as methanol, ethanol, propanol, 2-propanol and
butanol; Of these, dichloromethane or ethanol is preferred.
[0151] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
materials. However, in general, it is convenient to carry out the
reaction at a temperature of from about 0.degree. C. to about
120.degree. C. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature
and the nature of the starting materials and solvent employed.
However, provided that the reaction is effected under the preferred
conditions outlined above, a period of from about 5 minutes to
about 48 hours, will usually suffice.
Step D2
[0152] In this step, the compound of formula (IIIa) is prepared by
Mannnich reaction of the compound of formula (XI) with the compound
of formula (XII).
[0153] The reaction is normally and preferably effected in the
presence of solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or the reagents involved and that it
can dissolve reagents, at least to some extent. Examples of
suitable solvents include, but are not limited to: halogenated
hydrocarbons, such as dichloromethane, chloroform, carbon
tetrachloride and 1,2-dichloroethane; ethers, such as diethyl
ether, diisopropyl ether, tetrahydrofuran and dioxane; nitrites,
such as acetonitrile and benzonitrile; and amides, such as
formamide, N,N-dimethylformamide, N,N-dimethylacetamide and
hexamethylphosphoric triamide. Of these solvents, dichloromethane
is preferred.
[0154] The reaction is carried out in the presence of a Lewis acid.
There is likewise no particular restriction on the nature of the
Lewis acids used, and any Lewis acid commonly used in reactions of
this type may equally be used here. Examples of such Lewis acid
include, but are not limited to: BF.sub.3, AlCl.sub.3, FeCl.sub.3,
MgCl.sub.2, AgCl, Fe(NO.sub.3).sub.3,
CF.sub.3SO.sub.3Si(CH.sub.3).sub.3, Yb(CF.sub.3SO.sub.3).sub.3 and
SnCl.sub.4. Of these, Yb(CF.sub.3 SO.sub.3).sub.3, MgCl.sub.2, or
CF.sub.3SO.sub.3Si(CH.sub.3).sub.3 is preferred.
[0155] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
materials. However, in general, it is convenient to carry out the
reaction at a temperature of from about 0.degree. C. to about
100.degree. C. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature
and the nature of the starting materials and solvent employed.
However, provided that the reaction is effected under the preferred
conditions outlined above, a period of from about 5 minutes to
about 24 hours, will usually suffice.
Method E
[0156] This illustrates the preparation of the compound of formula
(III) wherein R.sup.2 is a hydrogen atom and A is A.sup.b.
##STR24##
[0157] In Reaction Scheme E, A.sup.a, A.sup.b and R.sup.3a are each
as defined above; each of R and R' is an alkyl group having 1 to 4
carbon atoms, preferably a methyl group, or an aralkyl group such
as a benzyl or phenethyl group, preferably a benzyl group.
Step E1
[0158] In this step, the compound of formula (XIV) is prepared by
reduction of the cyano group of the compound of formula (XIII),
which is commercially available.
[0159] The reaction is normally and preferably effected in the
presence of solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or the reagents involved and that it
can dissolve reagents, at least to some extent. Examples of
suitable solvents include, but are not limited to: ethers, such as
diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane;
aromatic hydrocarbons, such as benzene, toluene and nitrobenzene;
and alcohols, such as methanol, ethanol, propanol, 2-propanol and
butanol. Of these, methanol is preferred.
[0160] The reaction is carried out in the presence of a reducing
agent. There is likewise no particular restriction on the nature of
the reducing agents used, and any reducing agent commonly used in
reactions of this type may equally be used here. Examples of such
reducing agents include, but are not limited to: metal borohydrides
such as sodium borohydride and sodium cyanoborohydride;
combinations of hydrogen gas and a catalyst such as
palladium-carbon, platinum and Raney nickel; and hydride compounds
such as lithium aluminum hydride, and diisobutyl aluminum hydride.
Of these, Raney nickel is preferred.
[0161] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
materials. However, in general, it is convenient to carry out the
reaction at a temperature of from about 0.degree. C. to about
100.degree. C. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature
and the nature of the starting materials and solvent employed.
However, provided that the reaction is effected under the preferred
conditions outlined above, a period of from about 5 minutes to
about 24 hours, will usually suffice.
Step E2
[0162] In this step, the compound of formula (XVI) is prepared by
reacting a compound of formula (XV), which is commercially
available, with a compound of formula (XIV).
[0163] The reaction is normally and preferably effected in the
presence of solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or the reagents involved and that it
can dissolve reagents, at least to some extent. Examples of
suitable solvents include, but are not limited to: water; and
alcohols, such as methanol, ethanol, propanol, 2-propanol and
butanol. Of these, a mixture of water and ethanol is preferred.
[0164] The reaction is carried out in the presence of a base. There
is likewise no particular restriction on the nature of the base
used, and any base commonly used in reactions of this type may
equally be used here. Examples of such bases include, but are not
limited to: alkali metal hydroxides, such as lithium hydroxide,
sodium hydroxide and potassium hydroxide; alkali metal alkoxides,
such as sodium methoxide, sodium ethoxide, potassium t-butoxide;
and alkali metal carbonates, such as lithium carbonate, sodium
carbonate and potassium carbonate. Of these, potassium carbonate is
preferred.
[0165] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
materials. However, in general, it is convenient to carry out the
reaction at a temperature of from about 0.degree. C. to about
120.degree. C. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature
and the nature of the starting materials and solvent employed,
However, provided that the reaction is effected under the preferred
conditions outlined above, a period of from about 5 minutes to
about 24 hours, will usually suffice.
Step E3
[0166] In this step, the compound of formula (XVII) is prepared by
converting the carbonyl group of the compound of formula (XVI) to a
cyano group in the presence of p-toluenesulfonylmethyl
isocyanide.
[0167] The reaction is normally and preferably effected in the
presence of solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or the reagents involved and that it
can dissolve reagents, at least to some extent. Examples of
suitable solvents include, but are not limited to: ethers, such as
diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether,
tetrahydrofuran and dioxane; and alcohols, such as methanol,
ethanol, propanol, 2-propanol and butanol. Of these, a mixture of
ethylene glycol dimethyl ether and ethanol is preferred.
[0168] The reaction is carried out in the presence of a base. There
is likewise no particular restriction on the nature of the base
used, and any base commonly used in reactions of this type may
equally be used here. Examples of such bases include, but are not
limited to: alkali metal alkoxides, such as sodium methoxide,
sodium ethoxide and potassium t-butoxide. Of these, potassium
t-butoxide is preferred.
[0169] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
materials. However, in general, it is convenient to carry out the
reaction at a temperature of from about 0.degree. C. to about
100.degree. C. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature
and the nature of the starting materials and solvent employed.
However, provided that the reaction is effected under the preferred
conditions outlined above, a period of from about 5 minutes to
about 24 hours, will usually suffice.
Step E4
[0170] In this step, the compound of formula (IIIb) is prepared by
reduction of the cyano group of the compound of formula (XVII). The
reaction may be carried out under the same conditions as described
in Step E1 of Method E.
Method F
[0171] This illustrates the preparation of compounds of formula
(VIII) wherein R.sup.2 is a halogen atom. ##STR25##
[0172] In Reaction Scheme F, R.sup.2a is a halogen atom; R.sup.6 is
as defined above; and R.sup.10 is an amino-protecting group,
preferably a benzoyl group.
Step F1
[0173] In this step, the compound of formula (XIX) is prepared by
converting the carbonyl group of the compound of formula (XVIII)
into the epoxide group.
[0174] The reaction is normally and preferably effected in the
presence of solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or the reagents involved and that it
can dissolve reagents, at least to some extent. Examples of
suitable solvents include, but are not limited to: amides, such as
formamide, N,N-dimethylformamide, N,N-dimethylacetamide and
hexamethylphosphoric triamide; sulfoxide such as dimethyl sulfoxide
or sulfolane. Of these solvents, dimethyl sulfoxide is
preferred.
[0175] The reaction is carried out in the presence of a base. There
is likewise no particular restriction on the nature of the base
used, and any base commonly used in reactions of this type may
equally be used here. Examples of such bases include, but are not
limited to: alkali metal alkoxides, such as sodium methoxide,
sodium ethoxide and potassium t-butoxide; and alkali metal
carbonates, such as lithium carbonate, sodium carbonate and
potassium carbonate. Of these, potassium t-butoxide is
preferred.
[0176] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
materials. However, in general, it is convenient to carry out the
reaction at a temperature of from about 0.degree. C. to about
100.degree. C., more preferably from about 10.degree. C. to about
50.degree. C. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature
and the nature of the starting materials and solvent employed.
However, provided that the reaction is effected under the preferred
conditions outlined above, a period of from about 5 minutes to
about 24 hours, more preferably from about 60 minutes to about 12
hours, will usually suffice.
Step F2
[0177] In this step, the compound of formula (XX) is prepared by
reacting a hydrogen halide with the compound of formula (XIX).
[0178] The reaction is normally and preferably effected in the
presence of solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or the reagents involved and that it
can dissolve reagents, at least to some extent. Examples of
suitable solvents include, but are not limited to, ethers, such as
diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane;
amides, such as formamide, N,N-dimethylformamide,
N,N-dimethylacetamide and hexamethylphosphoric triamide. Of these
solvents, tetrahydrofuran is preferred.
[0179] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
materials. However, in general, it is convenient to carry out the
reaction at a temperature of from about 0.degree. C. to about
100.degree. C., more preferably from about 10.degree. C. to about
50.degree. C. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature
and the nature of the starting materials and solvent employed.
However, provided that the reaction is effected under the preferred
conditions outlined above, a period of from about 5 minutes to
about 24 hours, more preferably from about 60 minutes to about 12
hours, will usually suffice.
Step F3
[0180] In this step, the compound of formula (XXI) is prepared by
reaction of the compound of formula (XX) with sodium azide (F3-a)
followed by the reduction of the azide group (F3-b).
(F3-a) Reaction with Sodium Azide:
[0181] The reaction is normally and preferably effected in the
presence of solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or the reagents involved and that it
can dissolve reagents, at least to some extent. Examples of
suitable solvents include, but are not limited to: halogenated
hydrocarbons, such as dichloromethane, chloroform, carbon
tetrachloride and 1,2-dichloroethane; ethers, such as diethyl
ether, diisopropyl ether, tetrahydrofuran and dioxane; amides, such
as formamide, N,N-dimethylformamide, N,N-dimethylacetamide and
hexamethylphosphoric triamide; and sulfoxide such as dimethyl
sulfoxide and sulfolane. Of these solvents, N,N-dimethylformamide
is preferred.
[0182] Before adding sodium azide, the hydroxy group is converted
to a leaving group, such as a methylsulfonyl group, a
trifluoromethylsulfonyl group and 4-methyl phenylsulfonyl group by
adding reagents, such as trifluoromethanelsulfonylchloride, mesyl
chloride and tosyl chloride. Of these reagents, mesyl chloride is
preferred.
[0183] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
materials. However, in general, it is convenient to carry out the
reaction at a temperature of from about 0.degree. C. to about
120.degree. C. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature
and the nature of the starting materials and solvent employed.
However, provided that the reaction is effected under the preferred
conditions outlined above, a period of from about 5 minutes to
about 24 hours, will usually suffice.
(F3-b) Reduction:
[0184] The reaction may be carried out under the same conditions as
described in Step E1 of Method E.
Step F4
[0185] In this step, the compound of formula (VIIIa) is prepared by
introducing the amino-protecting group R.sup.6 to the primary amino
group (F4-a) and selectively deprotecting the amino-protecting
group R.sup.10 of the secondary amino group (F4-b).
(F4-a) Introduction of the Amino-Protecting Group:
[0186] This reaction is described in detail by T. W. Greene et al
[Protective Groups in Organic Synthesis, 494-653, (1999)], the
disclosures of which are incorporated herein by reference. The
following exemplifies a typical reaction involving the protecting
group t-buthoxycarbonyl.
[0187] The reaction is normally and preferably effected in the
presence of solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or the reagents involved and that it
can dissolve reagents, at least to some extent. Examples of
suitable solvents include, but are not limited to: water; ethers,
such as diethyl ether, diisopropyl ether, tetrahydrofuran and
dioxane; and sulfoxide such as dimethyl sulfoxide and sulfolane. Of
these solvents, tetrahydrofuran is preferred.
[0188] The reaction is carried out in the presence of reagent.
There is likewise no particular restriction on the nature of the
reagents used, and any reagent commonly used in reactions of this
type may equally be used here. Examples of such reagents include,
but are not limited to: di-t-butyl carbonate and
1-(t-butoxycarbonyl)benztriazole. Of these, di-t-butyl carbonate is
preferred.
[0189] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
materials. However, in general, it is convenient to carry out the
reaction at a temperature of from about 0.degree. C. to about
120.degree. C., more preferably from about 20.degree. C. to about
80.degree. C. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature
and the nature of the starting materials and solvent employed.
However, provided that the reaction is effected under the preferred
conditions outlined above, a period of from about 5 minutes to
about 24 hours, more preferably from about 60 minutes to about 12
hours, will usually suffice.
(F4-b) Deprotection:
[0190] This method is described in detail by T. W. Greene et al,
Protective Groups in Organic Synthesis, 494-653, (1999), the
disclosures of which are incorporated herein by reference. The
following exemplifies a typical method involving the benzoyl
protecting group in the presence of combinations of hydrogen gas
and a catalyst such as palladium-carbon or platinum.
[0191] The reaction is normally and preferably effected in the
presence of solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or the reagents involved and that it
can dissolve reagents, at least to some extent. Examples of
suitable solvents include, but are not limited to: halogenated
hydrocarbons, such as dichloromethane, chloroform, carbon
tetrachloride and 1,2-dichloroethane; alcohols, such as methanol,
ethanol, propanol, 2-propanol and butanol; and ethers, such as
diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane. Of
these solvents, methanol is preferred.
[0192] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
materials. However, in general, it is convenient to carry out the
reaction at a temperature of from about 0.degree. C. to about
120.degree. C. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature
and the nature of the starting materials and solvent employed.
However, provided that the reaction is effected under the preferred
conditions outlined above, a period of from about 5 minutes to
about 24 hours, will usually suffice.
Method G
[0193] This illustrates the preparation of compounds of formula
(VIII) wherein R.sup.2 is a hydroxy group. ##STR26##
[0194] In Reaction Scheme G. R.sup.6 and R.sup.10 are each as
defined above.
Step G1
[0195] In this step, the compound of formula (XXII) is prepared by
reacting the carbonyl group of the compound of formula (XVIII),
which is commercially available, with trimethylsilyl cyanide.
[0196] The reaction is normally and preferably effected in the
presence of solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or the reagents involved and that it
can dissolve reagents, at least to some extent. Examples of
suitable solvents include, but are not limited to: aromatic
hydrocarbons, such as benzene, toluene and nitrobenzene;
halogenated hydrocarbons, such as dichloromethane, chloroform,
carbon tetrachloride and 1,2-dichloroethane; ethers, such as
diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether,
tetrahydrofuran and dioxane; nitriles, such as acetonitrile and
benzonitrile; and alcohols, such as methanol, ethanol, propanol,
2-propanol and butanol. Of these, toluene is preferred.
[0197] The reaction is carried out in the presence of a reagent.
There is likewise no particular restriction on the nature of the
reagents used, and any reagent commonly used in reactions of this
type may equally be used here. Examples of such reagent include,
but are not limited to: Lewis acids, such as BF.sub.3, AlCl.sub.3,
FeCl.sub.3, AgCl, ZnI.sub.2, Fe(NO.sub.3).sub.3,
CF.sub.3SO.sub.3Si(CH.sub.3).sub.3, Yb(CF.sub.3SO.sub.3).sub.3 and
SnCl.sub.4; bases, such as CaO; ethers, such as 18-crown-6; acids,
such as Amberlite XAD-4 resin. Of these, ZnI.sub.2 is
preferred.
[0198] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
materials. However, in general, it is convenient to carry out the
reaction at a temperature of from about 0.degree. C. to about
100.degree. C. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature
and the nature of the starting materials and solvent employed.
However, provided that the reaction is effected under the preferred
conditions outlined above, a period of from about 5 minutes to
about 24 hours, will usually suffice.
Step G2
[0199] In this step, the compound of formula (XXIII) is prepared by
converting the cyano group of the compound of formula (XXII) to an
amino group followed by deprotection of the amino-protecting group
R.sup.10. The reaction may be carried out under the same conditions
as described in Step E1 of Method E and Step F4 of Method F.
Step G3
[0200] In this step, the compound of formula (VIIIb) is prepared by
protecting and deprotecting the amino groups of the compound of
formula (XXIII). The reaction may be carried out under the same
conditions as described in Step F4 of Method F.
[0201] The compounds of formula (I), and the intermediates
above-mentioned preparation methods can be isolated and purified by
conventional procedures, such as distillation, recrystallization or
chromatographic purification.
[0202] Compounds of the invention intended for pharmaceutical use
may be administered as crystalline or amorphous products. They may
be obtained, for example, as solid plugs, powders, or films by
methods such as precipitation, crystallization, freeze drying,
spray drying, or evaporative drying. Microwave or radio frequency
drying may be used for this purpose.
[0203] They may be administered alone or in combination with one or
more other compounds of the invention or in combination with one or
more other drugs (or as any combination thereof). Generally, they
will be administered as a pharmaceutical composition or formulation
in association with one or more pharmaceutically acceptable
carriers or excipients. The term "carrier" or "excipient" is used
herein to describe any ingredient other than the compound(s) of the
invention. The choice of carrier or excipient will to a large
extent depend on factors such as the particular mode of
administration, the effect of the excipient on solubility and
stability, and the nature of the dosage form.
[0204] Pharmaceutical compositions suitable for the delivery of
compounds of the present invention and methods for their
preparation will be readily apparent to those skilled in the art.
Such compositions and methods for their preparation may be found,
for example, in `Remington's Pharmaceutical Sciences`, 19th Edition
(Mack Publishing Company, 1995).
Oral Administration
[0205] The compounds of the invention may be administered orally.
Oral administration may involve swallowing, so that the compound
enters the gastrointestinal tract, or buccal or sublingual
administration may be employed by which the compound enters the
blood stream directly from the mouth.
[0206] Formulations suitable for oral administration include solid
formulations such as, for example, tablets, capsules containing
particulates, liquids, or powders, lozenges (including
liquid-filled), chews, multi- and nano-particulates, gels, solid
solution, liposome, films (including muco-adhesive), ovules, sprays
and liquid formulations.
[0207] Liquid formulations include, for example, suspensions,
solutions, syrups and elixirs. Such formulations may be employed as
fillers in soft or hard capsules and typically comprise a carrier,
for example, water, ethanol, polyethylene glycol, propylene glycol,
methylcellulose, or a suitable oil, and one or more emulsifying
agents and/or suspending agents. Liquid formulations may also be
prepared by the reconstitution of a solid, for example, from a
sachet.
[0208] The compounds of the invention may also be used in
fast-dissolving, fast-disintegrating dosage forms such as those
described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986
by Liang and Chen (2001).
[0209] For tablet dosage forms, depending on dose, the drug may
make up from about 1 wt % to about 80 wt % of the dosage form, more
typically from about 5 wt % to about 60 wt % of the dosage form. In
addition to the drug, tablets generally contain a disintegrant.
Examples of disintegrants include sodium starch glycolate, sodium
carboxymethyl cellulose, calcium carboxymethyl cellulose,
croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl
cellulose, microcrystalline cellulose, lower alkyl-substituted
hydroxypropyl cellulose, starch, pregelatinised starch and sodium
alginate. Generally, the disintegrant will comprise from about 1 wt
% to about 25 wt %, preferably from about 5 wt % to about 20 wt %
of the dosage form.
[0210] Binders are generally used to impart cohesive qualities to a
tablet formulation. Suitable binders include microcrystalline
cellulose, gelatin, sugars, polyethylene glycol, natural and
synthetic gums, polyvinylpyrrolidone, pregelatinised starch,
hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets
may also contain diluents, such as lactose (monohydrate,
spray-dried monohydrate, anhydrous and the like), mannitol,
xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose,
starch and dibasic calcium phosphate dehydrate.
[0211] Tablets may also optionally comprise surface active agents,
such as sodium lauryl sulfate and polysorbate 80, and glidants such
as silicon dioxide and talc. When present, surface active agents
may comprise from about 0.2 wt % to about 5 wt % of the tablet, and
glidants may comprise from about 0.2 wt % to about 1 wt % of the
tablet.
[0212] Tablets also generally contain lubricants such as magnesium
stearate, calcium stearate, zinc stearate, sodium stearyl fumarate,
and mixtures of magnesium stearate with sodium lauryl sulphate.
Lubricants generally comprise from about 0.25 wt % to about 10 wt
%, preferably from about 0.5 wt % to about 3 wt % of the
tablet.
[0213] Other possible ingredients include anti-oxidants,
colourants, flavouring agents, preservatives and taste-masking
agents.
[0214] Exemplary tablets contain up to about 80% drug, from about
10 wt % to about 90 wt % binder, from about 0 wt % to about 85 wt %
diluent, from about 2 wt % to about 10 wt % disintegrant, and from
about 0.25 wt % to about 10 wt % lubricant.
[0215] Tablet blends may be compressed directly or by roller to
form tablets. Tablet blends or portions of blends may alternatively
be wet-, dry-, or melt-granulated, melt congealed, or extruded
before tabletting. The final formulation may comprise one or more
layers and may be coated or uncoated, it may even be
encapsulated.
[0216] The formulation of tablets is discussed in "Pharmaceutical
Dosage Forms: Tablets, Vol. 1", by H. Lieberman and L. Lachman,
Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X).
[0217] Solid formulations for oral administration may be formulated
to be immediate and/or modified release. Modified release
formulations include delayed-, sustained-, pulsed-, controlled-,
targeted and programmed release.
[0218] Suitable modified release formulations for the purposes of
the invention are described in U.S. Pat. No. 6,106,864. Details of
other suitable release technologies such as high energy dispersions
and osmotic and coated particles are to be found in Verma et al,
Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of
chewing gum to achieve controlled release is described in WO
00/35298.
Parenteral Administration
[0219] The compounds of the invention may also be administered
directly into the blood stream, into muscle, or into an internal
organ. Suitable means for parenteral administration include
intravenous, intraarterial, intraperitoneal, intrathecal,
intraventricular, intraurethral, intrasternal, intracranial,
intramuscular and subcutaneous. Suitable devices for parenteral
administration include needle (including microneedle) injectors,
needle-free injectors and infusion techniques.
[0220] Parenteral formulations are typically aqueous solutions
which may contain excipients such as salts, carbohydrates and
buffering agents (preferably to a pH of from about 3 to about 9),
but, for some applications, they may be more suitably formulated as
a sterile non-aqueous solution or as a dried form to be used in
conjunction with a suitable vehicle such as sterile, pyrogen-free
water.
[0221] The preparation of parenteral formulations under sterile
conditions, for example, by lyophilisation, may readily be
accomplished using standard pharmaceutical techniques well known to
those skilled in the art.
[0222] The solubility of compounds of formula (I) used in the
preparation of parenteral solutions may be increased by the use of
appropriate formulation techniques, such as the incorporation of
solubility-enhancing agents.
[0223] Formulations for parenteral administration may be formulated
to be immediate and/or modified release. Modified release
formulations include delayed-, sustained-, pulsed-, controlled-,
targeted and programmed release. Thus compounds of the invention
may be formulated as a solid, semi-solid, or thixotropic liquid for
administration as an implanted depot providing modified release of
the active compound. Examples of such formulations include
drug-coated stents and PGLA microspheres.
Topical Administration
[0224] The compounds of the invention may also be administered
topically to the skin or mucosa, that is, dermally or
transdermally. Typical formulations for this purpose include gels,
hydrogels, lotions, solutions, creams, ointments, dusting powders,
dressings, foams, films, skin patches, wafers, implants, sponges,
fibres, bandages and microemulsions. Liposomes may also be used.
Typical carriers include alcohol, water, mineral oil, liquid
petrolatum, white petrolatum, glycerin, polyethylene glycol and
propylene glycol. Penetration enhancers may be incorporated--see,
for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan
(October 1999).
[0225] Other means of topical administration include delivery by
electroporation, iontophoresis, phonophoresis, sonophoresis and
microneedle or needle-free (e.g. Powderject.TM., Bioject.TM., etc.)
injection.
[0226] Formulations for topical administration may be formulated to
be immediate and/or modified release. Modified release formulations
include delayed-, sustained-, pulsed-, controlled-, targeted and
programmed release.
Inhaled/Intranasal Administration
[0227] The compounds of the invention can also be administered
intranasally or by inhalation, typically in the form of a dry
powder (either alone, as a mixture, for example, in a dry blend
with lactose, or as a mixed component particle, for example, mixed
with phospholipids, such as phosphatidylcholine) from a dry powder
inhaler or as an aerosol spray from a pressurized container, pump,
spray, atomiser (preferably an atomiser using electrohydrodynamics
to produce a fine mist), or nebuliser, with or without the use of a
suitable propellant, such as 1,1,1,2-tetrafluoroethane or
1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder
may comprise a bioadhesive agent, for example, chitosan or
cyclodextrin.
[0228] The pressurized container, pump, spray, atomizer, or
nebuliser contains a solution or suspension of the compound(s) of
the invention comprising, for example, ethanol, aqueous ethanol, or
a suitable alternative agent for dispersing, solubilising, or
extending release of the active, a propellant(s) as solvent and an
optional surfactant, such as sorbitan trioleate, oleic acid, or an
oligolactic acid.
[0229] Prior to use in a dry powder or suspension formulation, the
drug product is micronised to a size suitable for delivery by
inhalation (typically less than 5 microns). This may be achieved by
any appropriate comminuting method, such as spiral jet milling,
fluid bed jet milling, supercritical fluid processing to form
nanoparticles, high pressure homogenization, or spray drying.
[0230] Capsules (made, for example, from gelatin or HPMC), blisters
and cartridges for use in an inhaler or insufflator may be
formulated to contain a powder mix of the compound of the
invention, a suitable powder base such as lactose or starch and a
performance modifier such as i-leucine, mannitol, or magnesium
stearate. The lactose may be anhydrous or in the form of the
monohydrate, preferably the latter. Other suitable excipients
include dextran, glucose, maltose, sorbitol, xylitol, fructose,
sucrose and trehalose.
[0231] A suitable solution formulation for use in an atomiser using
electrohydrodynamics to produce a fine mist may contain from about
1 .mu.g to about 20 mg of the compound of the invention per
actuation and the actuation volume may vary from about 1 .mu.l to
about 100 .mu.l. A typical formulation may comprise a compound of
formula (I), propylene glycol, sterile water, ethanol and sodium
chloride. Alternative solvents which may be used instead of
propylene glycol include glycerol and polyethylene glycol.
[0232] Suitable flavours, such as menthol and levomenthol, or
sweeteners, such as saccharin or saccharin sodium, may be added to
those formulations of the invention intended for inhaled/intranasal
administration. Formulations for inhaled/intranasal administration
may be formulated to be immediate and/or modified release using,
for example, poly(DL-lactic-coglycolic acid (PGLA). Modified
release formulations include delayed-, sustained-, pulsed-,
controlled-, targeted and programmed release.
[0233] In the case of dry powder inhalers and aerosols, the dosage
unit is determined by means of a valve which delivers a metered
amount. Units in accordance with the invention are typically
arranged to administer a metered dose or "puff" containing from
about 1 to about 100 .mu.g of the compound of formula (I). The
overall daily dose will typically be in the range about 50 .mu.g to
about 20 mg which may be administered in a single dose or, more
usually, as divided doses throughout the day.
Rectal/Intravaginal Administration
[0234] The compounds of the invention may be administered rectally
or vaginally, for example, in the form of a suppository, pessary,
or enema. Cocoa butter is a traditional suppository base, but
various alternatives may be used as appropriate.
[0235] Formulations for rectal/vaginal administration may be
formulated to be immediate and/or modified release. Modified
release formulations include delayed-, sustained-, pulsed-,
controlled-, targeted and programmed release.
Ocular/Aural Administration
[0236] The compounds of the invention may also be administered
directly to the eye or ear, typically in the form of drops of a
micronised suspension or solution in isotonic, pH-adjusted, sterile
saline. Other formulations suitable for ocular and aural
administration include ointments, biodegradable (e.g. absorbable
gel sponges, collagen) and non-biodegradable (e.g. silicone)
implants, wafers, lenses and particulate or vesicular systems, such
as niosomes or liposomes. A polymer such as crossed-linked
polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic
polymer, for example, hydroxypropylmethylcellulose,
hydroxyethylcellulose, or methyl cellulose, or a
heteropolysaccharide polymer, for example, gelan gum, may be
incorporated together with a preservative, such as benzalkonium
chloride. Such formulations may also be delivered by
iontophoresis.
[0237] Formulations for ocular/aural administration may be
formulated to be immediate and/or modified release. Modified
release formulations include delayed-, sustained-, pulsed-,
controlled-, targeted, or programmed release.
Other Technologies
[0238] The compounds of the invention may be combined with soluble
macromolecular entities, such as cyclodextrin and suitable
derivatives thereof or polyethylene glycol-containing polymers, in
order to improve their solubility, dissolution rate, taste-masking,
bioavailability and/or stability for use in any of the
aforementioned modes of administration.
[0239] Drug-cyclodextrin complexes, for example, are found to be
generally useful for most dosage forms and administration routes.
Both inclusion and non-inclusion complexes may be used. As an
alternative to direct complexation with the drug, the cyclodextrin
may be used as an auxiliary additive, i.e. as a carrier, diluent,
or solubiliser. Most commonly used for these purposes are alpha-,
beta- and gamma-cyclodextrins, examples of which may be found in
International Patent Applications Nos. WO 91/11172, WO 94/02518 and
WO 98/55148.
Kit-of-Parts
[0240] Inasmuch as it may be desirable to administer a combination
of active compounds, for example, for the purpose of treating a
particular disease or condition, it is within the scope of the
present invention that two or more pharmaceutical compositions, at
least one of which contains a compound in accordance with the
invention, may conveniently be combined in the form of a kit
suitable for coadministration of the compositions,
[0241] Thus the kit of the invention comprises two or more separate
pharmaceutical compositions, at least one of which contains a
compound of formula (I) in accordance with the invention, and means
for separately retaining said compositions, such as a container,
divided bottle, or divided foil packet. An example of such a kit is
the familiar blister pack used for the packaging of tablets,
capsules and the like.
[0242] The kit of the invention is particularly suitable for
administering different dosage forms, for example, oral and
parenteral, for administering the separate compositions at
different dosage intervals, or for titrating the separate
compositions against one another. To assist compliance, the kit
typically comprises directions for administration and may be
provided with a so-called memory aid.
Dosage
[0243] For administration to human patients, the total daily dose
of the compounds of the invention is typically in the range of
about 0.05 mg to about 100 mg depending, of course, on the mode of
administration, preferred in the range of about 0.1 mg to about 50
mg and more preferred in the range of about 0.5 mg to about 20 mg.
For example, oral administration may require a total daily dose of
from about 1 mg to about 20 mg, while an intravenous dose may only
require from about 0.5 mg to about 10 mg. The total daily dose may
be administered in single or divided doses.
[0244] These dosages are based on an average human subject having a
weight of about 65 kg to about 70 kg. The physician will readily be
able to determine doses for subjects whose weight falls outside
this range, such as infants and the elderly.
Combination
[0245] As discussed above, a compound of the invention exhibits
5-HT.sub.4 agonist activity. A 5-HT.sub.4 agonist of the present
invention may be usefully combined with at least one other
pharmacologically active agent or compound, particularly in the
treatment of gastroesophageal reflux disease. For example, a
5-HT.sub.4 agonist, particularly a compound of the formula (I), or
a pharmaceutically acceptable salt or solvate thereof, as defined
above, may be administered simultaneously, sequentially or
separately in combination with one or more pharmacologically active
agents selected from: [0246] (i) histamine H.sub.2 receptor
antagonists, e.g. ranitidine, lafutidine, nizatidine, cimetidine,
famotidine and roxatidine; [0247] (ii) proton pump inhibitors, e.g.
omeprazole, esomeprazole, pantoprazole, rabeprazole, tenatoprazole,
ilaprazole and lansoprazole; [0248] (iii) Acid pump antagonists,
e.g. soraprazan, revaprazan (YH-1885), AZD-0865, CS-526, AU-2064
and YJA-203798; [0249] (iv) oral antacid mixtures, e.g.
Maalox.RTM., Aludrox.RTM. and Gaviscon.RTM.; [0250] (v) mucosal
protective agents, e.g. polaprezinc, ecabet sodium, rebamipide,
teprenone, cetraxate, sucralfate, chloropylline-copper and
plaunotol; [0251] (vi) GAB.sub.8 agonists, e.g. baclofen and
AZD-3355; [0252] (vii) .alpha.2 agonists, e.g. clonidine,
medetomidine; lofexidine, moxonidine, tizanidine, guanfacine,
guanabenz, talipexole and dexmedetomidine; [0253] (viii) Xanthin
derivatives, e.g. Theophylline, aminophylline and doxofylline;
[0254] (ix) calcium channel blockers, e.g. aranidipine, lacidipine,
falodipine, azelnidipine, clinidipine, lomerizine, diltiazem,
gallopamil, efonidipine, nisoldipine, amlodipine, lercanidipine,
bevantolol, nicardipine, isradipine, benidipine, verapamil,
nitrendipine, barnidipine, propafenone, manidipine, bepridil,
nifedipine, nilvadipine, nimodipine, and fasudil; [0255] (x)
benzodiazepine agonists, e.g. diazepam, zaleplon, zolpidem,
haloxazolam, clonazepam, prazepam, quazepam, flutazolam, triazolam,
lormetazepam, midazolam, tofisopam, clobazam, flunitrazepam and
flutoprazepam; [0256] (xi) prostaglandin analogues, e.g.
Prostaglandin, misoprostol, treprostinil, esoprostenol,
latanoprost, iloprost, beraprost, enprostil, ibudilast and ozagrel;
[0257] (xii) histamine H.sub.3 agonists, e.g.
R-alpha-methylhistamine and BP-294; [0258] (xiii) anti-gastric
agents, e.g. Anti-gastrin vaccine, itriglumide and Z-360; [0259]
(xiv) 5-HT.sub.3 antagonists, e.g. dolasetron, palonosetron,
alosetron, azasetron, ramosetron, mitrazapine, granisetron,
tropisetron, E-3620, ondansetron and indisetron; [0260] (xv)
tricyclic antidepressants, e.g. imipramine, amitriptyline,
clomipramine, amoxapine and lofepramine; [0261] (xvi) GABA
agonists, e.g. gabapentin, topiramate, cinolazepam, clonazepam,
progabide, brotizolam, zopiclone, pregabalin and eszopiclone;
[0262] (xvii) opioid analgesics, e.g. morphine, heroin,
hydromorphone, oxymorphone, levorphanol, levallorphan, methadone,
meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone,
hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone,
naltrexone, buprenorphine, butorphanol, nalbuphine and pentazocine;
[0263] (xviii) somatostatin analogues, e.g. octreotide, AN-238 and
PTR-3173. [0264] (xix) C.sub.1-Channel activator: e.g.
lubiprostone; [0265] (xx) selective serotonin reuptake inhibitors,
e.g. sertraline, escitalopram, fluoxetine, nefazodone, fluvoxamine,
citalopram, milnacipran, paroxetine, venlafaxine, tramadol,
sibutramine, duloxetine, desvenlafaxine and dapoxetine; [0266]
(xxi) anticholinergics, e.g. dicyclomine and hyoscyamine; [0267]
(xxii) laxatives, e.g. Trifyba.RTM., Fybogel.RTM., Konsyl.RTM.,
Isogel.RTM., Regulan.RTM., Celevac.RTM. and Normacol.RTM.; [0268]
(xxiii) fiber products, e.g. Metamucil.RTM.; [0269] (xxiv)
antispasmodics, e.g.: mebeverine; [0270] (xxv) dopamine
antagonists, e.g. metoclopramide, domperidone and levosulpiride;
[0271] (xxvi) cholinergics, e.g. neostigmine [0272] (xxvii) AChE
inhibitors, e.g. galantamine, metrifonate, rivastigmine, itopride
and donepezil; [0273] (xxviii) Tachykinin (NK) antagonists,
particularly NK-3, NK-2 and NK-1 antagonists e.g. nepadutant,
saredutant, talnetant,
(.alpha.R,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-m-
ethyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthridine-6-13-di-
one (TAK-637),
5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorop-
henyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one
(MK-869), lanepitant, dapitant and
3-[[2-methoxy-5-(trifluoromethoxy)phenyl]methylamino]-2-phenyl-piperidine
(2S,3S). Method for Assessing Biological Activities:
[0274] The 5-HT.sub.4 receptor binding affinities of the compounds
of this invention are determined by the following procedures.
Human 5-HT.sub.4 Binding(1)
[0275] Human 5-HT.sub.4(d) transfected HEK293 cells were prepared
and grown in-house. The collected cells were suspended in 50 mM
HEPES (pH 7.4 at 4.degree. C.) supplemented with protease inhibitor
cocktail (Boehringer, 1:1000 dilution) and homogenized using a hand
held Polytron PT 1200 disruptor set at full power for 30 sec on
ice. The homogenates were centrifuged at 40,000.times.g at
4.degree. C. for 30 min. The pellets were then resuspended in 50 mM
HEPES (pH 7.4 at 4.degree. C.) and centrifuged once more in the
same manner. The final pellets were resuspended in an appropriate
volume of 50 mM HEPES (pH 7.4 at 25.degree. C.), homogenized,
aliquoted and stored at -80.degree. C. until use. An aliquot of
membrane fractions was used for protein concentration determination
using BCA protein assay kit (PIERCE) and ARVOsx plate reader
(Wallac).
[0276] For the binding experiments, 25 .mu.l of test compounds were
incubated with 25 .mu.l of [.sup.3H]-GR113808 (Amersham, final 0.2
nM) and 150 .mu.l of membrane homogenate and WGA-SPA beads
(Amersham) suspension solutions (10 .mu.g protein and 1 mg SPA
beads/well) for 60 minutes at room temperature. Nonspecific binding
was determined by 1 .mu.M GR113808 (Tocris) at the final
concentration. Incubation was terminated by centrifugation at 1000
rpm.
[0277] Receptor-bound radioactivity was quantified by counting with
MicroBeta plate counter (Wallac). [0278] All compounds of Examples
showed 5HT.sub.4 receptor affinity. Human 5-HT.sub.4 Binding(2)
[0279] Human 5-HT.sub.4(d) transfected HEK293 cells were prepared
and grown in-house. The collected cells were suspended in 50 mM
Tris buffer (pH 7.4 at 4.degree. C.) supplemented with protease
inhibitor cocktail (Boehringer, 1:1000 dilution) and homogenized
using a hand held Polytron PT 1200 disruptor set at full power for
30 sec on ice. The homogenates were centrifuged at 40,000.times.g
at 4.degree. C. for 10 min. The pellets were then resuspended in 50
mM Tris buffer (pH 7.4 at 4.degree. C.) and centrifuged once more
in the same manner. The final pellets were resuspended in an
appropriate volume of 50 mM Tris buffer (pH 7.4 at 25.degree. C.)
containing 10 mM MgCl.sub.2, homogenized, aliquoted and stored at
-80.degree. C. until use. An aliquot of membrane fractions was used
for protein concentration determination using BCA protein assay kit
(PIERCE) and ARVOsx plate reader (Wallac).
[0280] For the binding experiments, 50 .mu.l of test compounds were
incubated with 50 .mu.l of [.sup.3H] 5-HT (Amersham, final 8.0 nM)
and 400 .mu.l of membrane homogenate (300 .mu.g protein/tube) for
60 minutes at room temperature. Nonspecific binding was determined
by 50 .mu.M GR113808 (Tocris) at the final concentration. All
incubations were terminated by rapid vacuum filtration over 0.2%
PEI soaked glass fiber filter papers using BRANDEL harvester
followed by three washes with 50 mM Tris buffer (pH 7.4 at
25.degree. C.). Receptor-bound radioactivity was quantified by
liquid scintillation counting using Packard LS counter. [0281] All
compounds of Examples showed 5HT.sub.4 receptor affinity.
Agonist-Induced Camp Elevation in Human 5-HT.sub.4(d) Transfected
HEK293 Cells
[0282] Human 5-HT.sub.4(d) transfected HEK293 cells were
established in-house. The cells were grown at 37.degree. C. and 5%
CO.sub.2 in DMEM supplemented with 10% FCS, 20 mM HEPES (pH 7.4),
200 .mu.g/ml hygromycin B (Gibco), 100 units/ml penicillin and 100
.mu.g/ml streptomycin.
The cells were grown to 60-80% confluence. On the previous day
before treatment with compounds dialyzed FCS (Gibco) was
substituted for normal and the cells were incubated overnight.
[0283] Compounds were prepared in 96-well plates (12.5 .mu.l/well).
The cells were harvested with PBS/1 mM EDTA, centrifuged and washed
with PBS. At the beginning of the assay, cell pellet was
resuspended in DMEM supplemented with 20 mM HEPES, 10 .mu.M
pargyline (Sigma) and 1 mM 3-isobutyl-1-methylxanthine (Sigma) at
the concentration of 1.6.times.10.sup.5 cells/ml and left for 15
minutes at room temperature. The reaction was initiated by addition
of the cells into plates (12.5 .mu.l/well). After incubation for 15
minutes at room temperature, 1% Triton X-100 was added to stop the
reaction (25 .mu.l/well) and the plates were left for 30 minutes at
room temperature. Homogenous time-resolved fluorescence-based cAMP
(Schering) detection was made according to the manufacturer's
instruction. ARVOsx multilabel counter (Wallac) was used to measure
HTRF (excitation 320 nm, emission 665 nm/620 nm, delay time 50
.mu.s, window time 400 .mu.s). Data was analyzed based on the ratio
of fluorescence intensity of each well at 620 nm and 665 nm
followed by CAMP quantification using CAMP standard curve.
Enhancement of CAMP production elicited by each compound was
normalized to the amount of CAMP produced by 1000 nM serotonin
(Sigma). [0284] All compounds of Examples showed 5HT.sub.4 receptor
agonistic activity. Human Dofetilide Binding
[0285] Human HERG transfected HEK293S cells were prepared and grown
in-house. The collected cells were suspended in 50 mM Tris-HCl (pH
7.4 at 4.degree. C.) and homogenized using a hand held Polytron PT
1200 disruptor set at full power for 20 sec on ice. The homogenates
were centrifuged at 48,000.times.g at 4.degree. C. for 20 min. The
pellets were then resuspended, homogenized, and centrifuged once
more in the same manner. The final pellets were resuspended in an
appropriate volume of 50 mM Tris-HCl, 10 mM KCl, 1 mM MgCl.sub.2
(pH 7.4 at 4.degree. C.), homogenized, aliquoted and stored at
-80.degree. C. until use. An aliquot of membrane fractions was used
for protein concentration determination using BCA protein assay kit
(PIERCE) and ARVOsx plate reader (Wallac).
[0286] Binding assays were conducted in a total volume of 200 .mu.l
in 96-well plates. Twenty .mu.l of test compounds were incubated
with 20 .mu.l of [.sup.3H]-dofetilide (Amersham, final 5 nM) and
160 .mu.l of membrane homogenate (25 .mu.g protein) for 60 minutes
at room temperature. Nonspecific binding was determined by 10 .mu.M
dofetilide at the final concentration. Incubation was terminated by
rapid vacuum filtration over 0.5% presoaked GF/B Betaplate filter
using Skatron cell harvester with 50 mM Tris-HCl, 10 mM KCl, 1 mM
MgCl.sub.2, pH 7.4 at 4.degree. C. The filters were dried, put into
sample bags and filled with Betaplate Scint. Radioactivity bound to
filter was counted with Wallac Betaplate counter.
Caco-2 Permeability
[0287] Caco-2 permeability was measured according to the method
described in Shiyin Yee, Pharmaceutical Research, 763 (1997).
[0288] Caco-2 cells were grown on filter supports (Falcon HTS
multiwell insert system) for 14 days. Culture medium was removed
from both the apical and basolateral compartments and the
monolayers were preincubated with pre-warmed 0.3 ml apical buffer
and 1.0 ml basolateral buffer for 0.5 hour at 37.degree. C. in a
shaker water bath at 50 cycles/min. The apical buffer consisted of
Hanks Balanced Salt Solution, 25 mM D-glucose monohydrate, 20 mM
MES Biological Buffer, 1.25 mM CaCl.sub.2 and 0.5 mM MgCl.sub.2 (pH
6.5). The basolateral buffer consisted of Hanks Balanced Salt
Solution, 25 mM D-glucose monohydrate, 20 mM HEPES Biological
Buffer, 1.25 mM CaCl.sub.2 and 0.5 mM MgCl.sub.2 (pH 7.4). At the
end of the preincubation, the media was removed and test compound
solution (10 .mu.M) in buffer was added to the apical compartment.
The inserts were moved to wells containing fresh basolateral buffer
at 1 hr. Drug concentration in the buffer was measured by LC/MS
analysis.
[0289] Flux rate (F, mass/time) was calculated from the slope of
cumulative appearance of substrate on the receiver side and
apparent permeability coefficient (P.sub.app) was calculated from
the following equation. P.sub.app(cm/sec)=(F*VD)/(SA*MD)
[0290] where SA is surface area for transport (0.3 cm.sup.2), VD is
the donor volume (0.3 ml), MD is the total amount of drug on the
donor side at t=0. All data represent the mean of 2 inserts.
Monolayer integrity was determined by Lucifer Yellow transport.
Half-Life in Human Liver Microsomes (HLM)
[0291] Test compounds (1 .mu.M) were incubated with 3.3 mM
MgCl.sub.2 and 0.78 mg/mL HLM (HL101) in 100 mM potassium phosphate
buffer (pH 7.4) at 37.degree. C. on the 96-deep well plate. The
reaction mixture was split into two groups, a non-P450 and a P450
group. NADPH was only added to the reaction mixture of the P450
group. An aliquot of samples of P450 group was collected at 0, 10,
30, and 60 min time point, where 0 min time point indicated the
time when NADPH was added into the reaction mixture of P450 group.
An aliquot of samples of non-P450 group was collected at -10 and 65
min time point. Collected aliquots were extracted with acetonitrile
solution containing an internal standard. The precipitated protein
was spun down in centrifuge (2000 rpm, 15 min). The compound
concentration in supernatant was measured by LC/MS/MS system.
[0292] The half-life value was obtained by plotting the natural
logarithm of the peak area ratio of compounds/internal standard
versus time. The slope of the line of best fit through the points
yields the rate of metabolism (k). This was converted to a
half-life value using following equations: Half-life=In2/k
EXAMPLES
[0293] The invention is illustrated in the following non-limiting
examples in which, unless stated otherwise: all reagents are
commercially available, all operations were carried out at room or
ambient temperature, that is, in the range of about 18-25.degree.
C.; evaporation of solvent was carried out using a rotary
evaporator under reduced pressure with a bath temperature of up to
about 60.degree. C.; reactions were monitored by thin layer
chromatography (tlc) and reaction times are given for illustration
only; melting points (m.p.) given are uncorrected (polymorphism may
result in different melting points); the structure and purity of
all isolated compounds were assured by at least one of the
following techniques: tlc (Merck silica gel 60 F.sub.254 precoated
TLC plates or Merck NH.sub.2 F.sub.254s, precoated HPTLC plates),
mass spectrometry, nuclear magnetic resonance (NMR), infrared red
absorption spectra (IR) or microanalysis. Yields are given for
illustrative purposes only. Flash column chromatography was carried
out using Merck silica gel 60 (230-400 mesh ASTM) or Fuji Silysia
Chromatorex.RTM. DU3050 (Amino Type, 30-50 .mu.m). Low-resolution
mass spectral data (EI) were obtained on a Integrity (Waters) mass
spectrometer or a Automass 120 (JEOL) mass spectrometer.
Low-resolution mass spectral data (ESI) were obtained on a ZMD2
(Waters) mass spectrometer or a Quattro II (Micromass) mass
spectrometer. NMR data was determined at 270 MHz (JEOL JNM-LA 270
spectrometer) or 300 MHz (JEOL JNM-LA300) using deuterated
chloroform (99.8% D) or dimethylsulfoxide (99.9% D) as solvent
unless indicated otherwise, relative to tetramethylsilane (TMS) as
internal standard in parts per million (ppm); conventional
abbreviations used are: s=singlet, d=doublet, t=triplet, q=quartet,
m=multiplet, br.=broad, etc. IR spectra were measured by a Shimazu
infrared spectrometer (IR-470). Optical rotations were measured
using a JASCO DIP-370 Digital Polarimeter (Japan Spectroscopic Co.,
Ltd.). Chemical symbols have their usual meanings; b.p. (boiling
point), m.p. (melting point), l (liter(s)), mL (milliliter(s)), g
(gram(s)), mg (milligram(s)), mol (moles), mmol (millimoles), eq.
(equivalent(s)). The powder X-ray diffraction (PXRD) pattern was
determined using a Rigaku RINT-TTR powder X-ray diffractometer
fitted with an automatic sample changer, a 2 theta-theta
goniometer, beam divergence slits, a secondary monochromator and a
scintillation counter. The sample was prepared for analysis by
packing the powder on to an aluminum sample holder. The specimen
was rotated by 60.00 rpm and scanned by 4.degree./min at room
temperature with Cu-K.alpha. radiation.
Example 1
4-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amin-
o}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic
acid
[0294] ##STR27##
Step 1. tert-butyl 4-cyanotetrahydro-2H-pyran-4-carboxylate
[0295] To a stirred suspension of NaH (17.7 g, 0.443 mol) in DMF
(200 mL) was added dropwise tert-butyl cyanoacetate (25.0 g, 0.177
mol) in DMF (100 mL) at 0.degree. C. under N.sub.2. The mixture was
allowed to warm to ambient temperature, and stirred for 1 hour.
Then, bis(2-bromoethyl)ether (49.3 g, 0.177 mol) was added to the
mixture, and the resulting mixture was stirred at 90.degree. C. for
24 h. After cooling to 0.degree. C., the mixture was quenched with
water (100 mL). The volatile components were removed by evaporation
and the residue was precipitated with a mixture of EtOAc-Toluene
(1:2, 500 mL) and water (500 mL). The organic phase was washed with
water (500 mL) for three times, dried over Na.sub.2SO.sub.4,
filtered and evaporated. The solid was washed with Hexane and dried
in vacuo to give 19.0 g (57%) of the title compound as a white
crystal.
[0296] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.96 (2H, dt, J=3.9 Hz,
12.3 Hz), 3.73 (2H, dt, J=2.6 Hz, 12.3 Hz), 2.20-1.94 (4H, m), 1.52
(9H, s).
Step 2. tert-butyl
4-(aminomethyl)tetrahydro-2H-pyran-4-carboxylate
[0297] A mixture of tert-butyl
4-cyanotetrahydro-2H-pyran-4-carboxylate (18.95 g, 0.0897 mol, step
1) and Raney Ni (1.00 g) in methanol (200 mL) was hydrogenated (3
atm) at room temperature for 12 h. Then, the mixture was filtered
through a pad of Celite, and the filtrate was concentrated in vacuo
to give 16.01 g (83%) of the title compound as a yellow syrup.
[0298] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.86 (2H, dt, J=4.1 Hz,
11.4 Hz), 3.48 (2H, dt, J=2.5 Hz, 11.5 Hz), 2.75 (2H, s), 2.03 (2H,
br d, J=10.7 Hz), 1.55-1.35 (13H, m, including 9H, s, 1.49
ppm).
Step 3. tert-butyl
4-[(4-oxopiperidin-1-yl)methyl]tetrahydro-2H-pyran-4-carboxylate
[0299] To a refluxing mixture of tert-butyl
4-(aminomethyl)tetrahydro-2H-pyran-4-carboxylate (8.00 g, 0.0372
mol, step 2) and K.sub.2CO.sub.3 (0.51 g, 0.0372 mol) in
EtOH--H.sub.2O (2:1, 240 mL) was added dropwise
1-ethyl-1-methyl-4-oxopiperidinium iodide (12.0 g, 0.0445 mol, J.
Org. Chem. 1995, 60, 4324-4330) in EtOH--H.sub.2O (2:1, 150 mL),
and the resulting mixture was stirred at the same temperature
(reflux) for 1 h. After cooling to room temperature, the solvent
was removed in vacuo. The residue was poured into sat. NaHCO.sub.3
aq. (200 mL), and the mixture was extracted with CH.sub.2Cl.sub.2
(200 mLx three times). The extracts were dried over
Na.sub.2SO.sub.4 and concentrated. The residue was chromatographed
on a column of silica gel eluting with hexane/ethyl acetate (3:1 to
2:1) to give 10.77 g (98%) of the title compound as a colorless
syrup.
[0300] MS (ESI) m/z: 298 (M+H).sup.+.
[0301] .sup.1H NMR (CDCl.sub.3) .delta. 3.84 (2H, br d, J=11.4 Hz),
3.50 (2H, dt, J=2.0 Hz, 11.7 Hz), 2.85 (4H, t, J=5.9 Hz), 2.61 (2H,
s), 2.39 (4H, t, J=6.1 Hz), 2.06 (2H, d, J=11.5 Hz), 1.75-1.45
(11H, m, including 9H, s, 1.49 ppm).
Step 4. tert-butyl
4-[(4-cyanopiperidin-1-yl)methyl]tetrahydro-2H-pyran-4-carboxylate
[0302] To a stirred solution of tert-butyl
4-[(4-oxopiperidin-1-yl)methyl]tetrahydro-2H-pyran-4-carboxylate
(8.77 g, 0.0295 mol, step 3) in 1,2-dimethoxyethane (250 mL) was
added p-toluenesulfonylmethyl isocyanide (11.51 g, 0.0590 mol),
EtOH (3.96 mL, 0.0678 mol) and t-BuOK (11.58 g, 0.1032 mol) at
0.degree. C. The resulting mixture was stirred at 50.degree. C. for
16 h. After cooling, the reaction mixture was poured into sat.
NaHCO.sub.3 aq. (200 mL), and the mixture was extracted with
CH.sub.2Cl.sub.2 (200 mL.times.3 times). The extracts were dried
over Na.sub.2SO.sub.4 and concentrated. The residue was
chromatographed on a column of silica gel eluting with hexane/ethyl
acetate (2:1) to give 5.76 g (63%) of the title compound as a
yellow syrup.
[0303] MS (ESI) m/z: 309 (M+H.sup.+).
[0304] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.81 (2H, dt, J=3.1 Hz,
11.0 Hz), 3.48 (2H, dt, J=2.1 Hz, 11.7 Hz), 2.76-2.64 (2H, m),
2.64-2.52 (1H, m), 2.50-2.35 (4H, m, including 2H, s, 2.46 ppm),
1.98 (2H, br d, J=1.9 Hz), 1.92-1.70 (4H, m), 1.65-1.40 (11H, m,
including 9H, s, 1.47 ppm).
Step 5. tert-butyl
4-{[4-(aminomethyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylat-
e
[0305] A mixture of tert-butyl
4-[(4-cyanopiperidin-1-yl)methyl]tetrahydro-2H-pyran-4-carboxylate
(5.76 g, 0.0187 mol, step 4) and Raney Ni (3.00 g) in methanol (100
mL) was hydrogenated (3 atm) at room temperature for 12 h. Then,
the mixture was filtered through a pad of Celite, and the filtrate
was concentrated in vacuo to give 5.72 g (98%) of the title
compound as a yellow syrup.
[0306] MS (ESI) m/z: 313 (M+H.sup.+).
[0307] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.80 (2H, dt, J=3.1 Hz,
11.5 Hz), 3.49 (2H, dt, J=2.1 Hz, 12.2 Hz), 2.80 (2H, br d, J=11.5
Hz), 2.58-2.40 (4H, m, including 2H, s, 2.43 ppm), 2.15 (2H, br t,
J=7.3 Hz), 1.98 (2H, br d, J=13.7 Hz), 1.70-1.40 (16H, m, including
9H, s, 1.47 ppm), 1.30-1.10 (2H, m).
Step 6. tert-butyl
4-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]ami-
no}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylate
[0308] A mixture of p-nitrophenylchloroformate (4.14 g, 0.0205
mol), 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one (3.62 g, 0.0205
mol, J. Med. Chem. 1999, 42, 2870-2880) and Et.sub.3N (7.81 mL,
0.0560 mol) in CH.sub.2Cl.sub.2 (100 mL) was stirred at room
temperature for 4 h. Then, tert-butyl
4-([4-(aminomethyl)piperidin-1-yl]methyltetrahydro-2H-pyran-4-carboxylate
(5.72 g, 0.0187 mol, step 5) was added, and the resulting mixture
was stirred at room temperature for 24 h. The reaction mixture was
diluted with sat. NaHCO.sub.3 aq. (300 mL), extracted with
CH.sub.2Cl.sub.2 (300 mL) for three times. The combined extract was
dried over Na.sub.2SO.sub.4 and concentrated. The residue was
chromatographed on a column of NH-silica gel eluting with
hexane/ethyl acetate (1:1) to give 9.83 g (100%) of the title
compound as a yellow syrup.
[0309] MS (ESI) m/z: 515 (M+H).sup.+.
[0310] .sup.1H NMR (CDCl.sub.3) .delta. 8.90 (1H, t, J=4.9 Hz),
8.31-8.21 (1H, m), 7.25-7.10 (3H, m), 4.80-4.60 (1H, m), 3.80 (2H,
dt, J=3.1 Hz, 11.5 Hz), 3.49 (2H, dt, J=1.7 Hz, 11.4 Hz), 3.28 (2H,
t, J=6.4 Hz), 2.81 (2H, br d, J=10.4 Hz), 2.44 (2H, s), 2.16 (2H,
t, J=10.4 Hz), 1.98 (2H, d, J=12.4 Hz), 1.81-1.20 (22H, m,
including 6H, d, J=7.1 Hz, 1.56 ppm and 9H, s, 1.47 ppm).
Step 7.
4-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbo-
nyl]amino}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic
acid
[0311] To a stirred solution of tert-butyl
4-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]ami-
no}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylate
(3.67 g, 7.13 mmol, step 6) in THF (80 mL) was added conc. HCl (40
mL) at 0.degree. C. and the resulting mixture was stirred for 20 h
at room temperature. The mixture was concentrated to remove the
solvent and the residue was poured into sat. NaHCO.sub.3 aq. The
mixture was extracted with CH.sub.2Cl.sub.2 for three times and the
organic layer was dried over Na.sub.2SO.sub.4. Removal of the
solvent gave a residue, which was chromatographed on a column of
silica gel eluting MeOH/CH.sub.2Cl.sub.2 (1:10) to give 3.01 g
(92%) of the title compound. The product was recrystallized from
THF to give the titled compound (0.893 g) as white crystals.
[0312] MS (ESI) m/z: 459 (M+H).sup.+.
[0313] .sup.1H NMR (CDCl.sub.3) .delta.8.99 (1H, t, J=5.6 Hz),
8.30-8.15 (1H, m), 7.25-7.105 (3H, m), 4.80-4.60 (1H, m), 3.95-3.70
(4H, m), 3.34 (2H, t, J=6.3 Hz), 3.14 (2H, br d, J=12.0 Hz),
2.65-2.45 (4H, m, including 2H, s, 2.59 ppm), 1.92 (4H, t, J=13.8
Hz), 1.85-1.40 (11H, m, including 6H, d, J=6.9 Hz, 1.57 ppm).
[0314] m.p.: 176.degree. C.
[0315] IR (KBr) v: 3281, 2947, 1720, 1688, 1611, 1595, 1547, 1481,
1447, 1375, 1200, 1159, 1136, 1105, 760 cm.sup.-1.
[0316] Anal. calcd. for C.sub.24H.sub.34N.sub.4O.sub.5: C, 62.86;
H, 7.47; N, 12.22. Found: C, 62.77; H, 7.42; N, 12.16.
Alternative route to synthesize
4-{[4-({[(3-Isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]ami-
no}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic
acid is described below.
Step 8. tert-Butyl
{[1-(ethoxymethyl)piperidin-4-yl]methyl}carbamate
[0317] To a stirred solution of tert-butyl
(piperidin-4-ylmethyl)carbamate (7.0 g, 33 mmol) in ethanol (19
mL), paraformaldehyde (1.2 g, 39 mmol) and potassium carbonate (5.4
g, 39 mmol) were added at ambient temperature. The mixture was
stirred at ambient temperature for 4 h. The mixture was filtered
and the filter cake was washed with ethanol (50 mL). The volatile
components were removed by evaporation to give the title compound
8.9 g (quant.) as a white powder.
[0318] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.60 (1H, brs), 4.07 (2H,
s), 3.49 (2H, q, J=7.1 Hz), 3.08-2.83 (4H, m), 2.50-2.36 (2H, m),
1.75-1.60 (2H, m), 1.44 (9H, s), 1.52-1.35 (1H, m), 1.19 (3H, t,
J=7.1 Hz), 1.31-1.12 (2H, m).
Step 9.
[Methoxy(tetrahydro-4H-pyran-4-ylidene)methoxy](trimethyl)silane
[0319] To a stirred solution of diisopropylamine (1.6 g, 0.016 mol)
in tetrahydrofuran (4 mL) was added dropwise n-butyllithium (1.59 M
in hexane, 9.2 mL, 0.014 mol) at 0.degree. C. under nitrogen, and
stirred for 20 min. Then, the reaction mixture was cooled to
40.degree. C., methyl tetrahydro-2H-pyran-4-carboxylate (1.9 g,
0.013 mol) and trimethylsilyl chloride (2.0 mL, 0.015 mol) in
tetrahydrofuran (1 mL) was added, and the resulting mixture was
gradually warmed to room temperature over 3 h. The volatile
components were removed by evaporation and the residue was filtered
through a pad of celite washing with hexane. The filtrate was dried
in vacuo to give 2.9 g (quant.) of the title compound as a clear
yellow oil.
[0320] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.64-3.59 (4H, m), 3.52
(3H, s), 2.24 (2H, t, J=5.2 Hz), 2.15 (2H, t, J=5.3 Hz), 0.22 (9H,
s).
Step 10.
4-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]t-
etrahydro-2H-pyran-4-carboxylate
[0321] To a stirred solution of tert-butyl
{[1-(ethoxymethyl)piperidin-4-yl]methyl}carbamate (4 g, 14 mmol,
Step 8) and
[methoxy(tetrahydro-4H-pyran-4-ylidene)methoxy](trimethyl)silane
(2.9 g, 13 mmol, Step 9) in dichloromethane (30 mL) was added
dropwise trimethylsilyl trifluoromethanesulfonate (0.24 mL, 1.3
mmol) at 0.degree. C., and the resulting mixture was stirred at
room temperature for 12 h. The reaction mixture was quenched with
saturated aqueous sodium bicarbonate (150 mL), extracted with
dichloromethane (30 mL.times.2), and the combined organic layer was
dried over sodium sulfate. Removal of the solvent gave a residue,
which was chromatographed on a column of silica gel eluting with
ethyl acetate/hexane (1:1) to give 6.3 g (64%) of the title
compound as a clear colorless oil.
[0322] MS (ESI) m/z: 371 (M+H).sup.+.
[0323] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.57 (1H, br s), 3.84-3.78
(2H, m), 3.70 (3H, s), 3.49-3.41 (2H, m), 2.99-2.95 (2H, m),
2.73-2.68 (2H, m), 2.47 (2H, s), 2.19-2.11 (2H, m), 2.06-2.01 (2H,
m), 1.61-1.51 (5H, m), 1.44 (9H, s), 1.24-1.11 (2H, m).
Step 11.
4-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]t-
etrahydro-2H-pyran-4-carboxylic acid
[0324] To a solution of Methyl
4-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]tetrahydr-
o-2H-pyran-4-carboxylate (6.47 g, 17.5 mmol, Step 10) in MeOH (32
mL), 5 N NaOH aq (10 mL) was added at room temperature
(exothermic). The resulting solution was stirred at 60.degree. C.
for 7 h, then cooled to 5-10.degree. C. in ice-cold bath. To this
solution, 5 N HCl aq (10 mL) was added and the resulting solution
(pH value was ca.6) was concentrated. To the residue, 2-propanol
(80 mL) was added. This solution was concentrated. To the residue,
2-propanol (80 mL) was added and it was concentrated again. The
residue was diluted with EtOH (80 mL) and the mixture was stirred
at room temperature for 2 h. It was filtered through a celite pad
(5.0 g) to remove NaCl. The Celite pad was washed with EtOH (20 mL)
and the combined filtrate was concentrated. To the residue,
CH.sub.3CN (40 mL) was added and it was concentrated. During this
procedure, the formation of white precipitate was noticed. To the
residue CH.sub.3CN (40 mL) was added and the resulting suspension
was stirred at room temperature for 2 h. This mixture was filtered
and obtained solid was washed with CH.sub.3CN (10 mL), then dried
under reduced pressure to give 4.1 g (65%) of the titled compound
as white powder.
[0325] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 4.66 (1H, m),
3.93-3.82 (3H, m), 3.15-2.99 (4H, m), 2.58 (2H, s), 2.58-2.45 (2H,
m), 1.98-1.76 (4H, m), 1.55-1.35 (6H, m), 1.44 (9H, s)
[0326] mp 129.degree. C.
Step 12.
4-{[4-(aminomethyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-ca-
rboxylic acid 4-methylbenzenesulfonate
[0327] In a 300 mL, 3-necked round bottom flask under N.sub.2,
4-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]tetrahydr-
o-2H-pyran-4-carboxylic acid (10 g, 28 mmol, Step 11) was placed
and a solution of p-TsOH H.sub.2O (16 g, 84 mmol) in IPA (150 mL)
was poured at room temperature. The resulting mixture was stirred
at 60.degree. C. for 7 h under N.sub.2 and Et.sub.3N (8.6 mL, 62
mmol) was added dropwise slowly during the period of 2 hr with
seeding. The white precipitate was formed during the addition of
Et.sub.3N. The resulting white suspension was stirred at 60.degree.
C. for 3 h, at 50.degree. C. for 5 h and at room temperature for 10
h. The suspension was filtered and the obtained solid was washed
with IPA (100 mL), dried at 50.degree. C. for 5 h to give 10.5 g
(87%) of the titled compound as white powder.
[0328] .sup.1H-NMR (D.sub.2O) .delta. 7.54 (2H, d, J=7.4 Hz), 7.22
(2H, J=7.4 Hz), 3.80-3.65 (2H, m), 3.55-3.40 (4H, m), 3.20-2.75
(6H, m), 2.24 (3H, s), 1.90-1.80 (6H, m), 1.55-1.35 (4H, m)
[0329] mp 247.degree. C.
Step 13.
4-{[4-({[(3-Isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carb-
onyl]amino}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic
acid
[0330] A mixture of 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one
(1.0 g, 5.7 mmol) and chloroformic acid 4-nitrophenyl ester (1.14
g, 5.7 mmol) in CH.sub.2Cl.sub.2 (20 mL) was stirred at room
temperature for 5 min under N.sub.2. To this mixture, Et.sub.3N
(1.7 mL, 12.5 mmol) was added slowly and this generated mixture was
added to a mixture of
4-{[4-(aminomethyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic
acid 4-methylbenzenesulfonate (2.4 g, 5.7 mmol, Step 12) in
CH.sub.2Cl.sub.2 (15 mL) at rt. The resulting mixture was stirred
at room temperature for 2 hrs. This mixture was washed with 0.5 N
HCl aq (100 mL) and the organic layer was washed with saturated
NaHCO.sub.3 aq (75 ml) then the organic layer was concentrated. The
residue was diluted with EtOAc (75 mL) and it was concentrated
until ca 15 mL. After seeding of the product, this mixture was
stirred at room temperature for 30 min. During this procedure, the
solid was formed and this mixture was filtered. Obtained solid was
washed with EtOAc (10 mL), dried at 50.degree. C. under vacuum to
give 1.9 g (73%) of the titled compound as white solid.
Step 14.
4-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carb-
onyl]amino}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic
acid benzenesulfonate
[0331] To a suspension of
4-{[4-({[(3-Isopropyl-2-oxo-2,3-dihydro'-1H-benzimidazol-1-yl)carbonyl]am-
ino}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic
acid (750 mg, Step 13) in CH.sub.3CN (5 mL), a solution of
benzenesulfonic acid monohydrate (288 mg) in CH.sub.3CN (5 mL) was
added at room temperature. The resulting mixture was stirred at
room temperature for 2 days and it was concentrated. The residue
was dried to afford 909 mg (90%) of the titled compound as a
solid.
[0332] .sup.1H-NMR (CD.sub.3OD) .delta.9.10 (1H, t, J=5.7 Hz), 8.11
(1H, dt, J=8.0, 0.8 Hz), 7.88-7.76 (2H, m), 7.46-7.36 (3H, m), 7.32
(1H, dt, J=8.0, 0.8 Hz), 7.22 (1H, td, J=7.8, 1.4 Hz), 7.13 (1H,
td, J=7.8, 1.4 Hz), 4.70 (1H, sextet, J=6.9 Hz), 3.85-3.55 (5H, m),
3.50-3.38 (4H, m), 3.23-3.05 (2H, m), 2.15-1.90 (5H, m), 1.78-1.58
(5H, m), 1.55 (6H, d, J=6.9 Hz)
[0333] mp 223.degree. C.
[0334] Anal. calcd. for C.sub.30H.sub.40N.sub.4O.sub.8S: C, 58.42;
H, 6.54; N, 9.08. Found: C, 58.50; H, 6.51; N, 9.11.
[0335] PXRD (2.theta.(+/-0.1): 5.3, 12.6, 21.4, 21.9)
Example 2
1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amin-
o}methyl)piperidin-1-yl]methyl}cyclohexanecarboxylic acid
[0336] ##STR28##
Step 1. tert-butyl 4-cyanocyclohexanecarboxylate
[0337] The title compound was prepared by a method similar to that
shown in the Step 1 of Example 1 by using 1,5-dibromopentane.
[0338] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.07 (2H, d, J=13.0 Hz),
1.85-1.57 (7H, m), 1.50 (9H, s), 1.35-1.15 (1H, m).
Step 2. tert-butyl 1-(aminomethyl)cyclohexanecarboxylate
[0339] The title compound was prepared by a method similar to that
shown in the Step 2 of Example 1.
[0340] MS (ESI) m/z: 214 (M+H).sup.+.
[0341] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.69 (2H, s), 2.02 (2H, d,
J=13.2 Hz), 1.65-1.05 (19H, m, including 9H, s, 1.47 ppm).
Step 3. tert-butyl
1-[(4-oxopiperidin-1-yl)methyl]cyclohexanecarboxylate
[0342] The title compound was prepared by a method similar to that
shown in the Step 3 of Example 1.
[0343] MS (ESI) m/z: 296 (M+H).sup.+.
[0344] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.84 (4H, t, J=6.1 Hz)
2.57 (2H, s), 2.38 (4H, t, J=6.1 Hz), 2.04 (2H, d, J=12.2 Hz),
1.65-1.15 (17H, m, including 9H, s, 1.47 ppm).
Step 4. tert-butyl
1-[(4-cyanopiperidin-1-yl)methyl]cyclohexanecarboxylate
[0345] The title compound was prepared by a method similar to that
shown in the Step 4 of Example 1.
[0346] MS (ESI) m/z: 307 (M+H).sup.+.
[0347] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.53-2.66 (2H, m),
2.53-2.48 (1H, m), 2.48-2.30 (4H, m, including 2H, s, 2.41 ppm),
1.97 (2H, d, J=2.5 Hz), 1.92-1.70 (4H, m), 1.65-1.10 (19H, m,
including 9H, s, 1.45 ppm).
Step 5. tert-butyl
1-{[4-(aminomethyl)piperidin-1-yl]methyl}cyclohexanecarboxylate
[0348] The title compound was prepared by a method similar to that
shown in the Step 5 of Example 1.
[0349] MS (ESI) m/z: 311 (M+H.sup.+).
[0350] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.81 (2H, d, J=11.37 Hz),
2.55 (2H, d, J=5.8 Hz), 2.39 (2H, s), 2.11 (2H, t, J=11.0 Hz),
2.03-1.85 (5H, m), 1.65-1.10 (21H, m, including 9H, s, 1.45
ppm).
Step 6. tert-butyl
1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]ami-
no}methyl)piperidin-1-yl]methyl}cyclohexanecarboxylate
[0351] The title compound was prepared by a method similar to that
shown in the Step 6 of Example 1.
[0352] MS (ESI) m/z: 513 (M+H).sup.+.
[0353] .sup.1H NMR (CDCl.sub.3) .delta. 8.89 (1H, t, J=5.3 Hz),
8.33-8.20 (1H, m), 7.23-7.10 (3H, m), 4.80-4.60 (1H, m), 3.27 (2H,
t, J=6.3 Hz), 2.82 (2H, d, J=11.5 Hz), 2.39 (2H, s), 2.12 (2H, t,
J=11.4 Hz), 1.97 (2H, d, J=13.2 Hz), 1.73-1.10 (28H, m, including
6H, d, J=6.9 Hz, 1.56 ppm and 9H, s, 1.45 ppm).
Step 7.
1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbo-
nyl]amino}methyl)piperidin-1-yl]methyl}cyclohexanecarboxylic
acid
[0354] The title compound was prepared by a method similar to that
shown in the Step 7 of Example 1.
[0355] MS (ESI) m/z: 457 (M+H).sup.+.
[0356] .sup.1H NMR (CDCl.sub.3) .delta. 8.98 (1H, t, J=5.8 Hz),
8.28-8.18 (1H, m), 7.25-7.10 (3H, m), 4.80-4.60 (1H, m), 3.34 (2H,
t, J=6.3 Hz), 3.11 (2H, d, J=11.9 Hz), 2.61 (2H, s), 2.48 (2H, t,
J=12.2 Hz), 2.05-1.20 (21H, m, including 6H, d, J=6.9 Hz, 1.57
ppm).
[0357] m.p.: 151.degree. C.
[0358] IR (KBr) v: 3291, 2930, 1732, 1690, 1545, 1481, 1373, 1298,
1202, 1134, 762 cm.sup.-1.
[0359] Anal. calcd. for C.sub.25H.sub.36N.sub.4O.sub.4: C, 65.76;
H, 7.95; N, 12.27. Found: C, 65.41; H, 8.18; N, 12.18.
Example 3
1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amin-
o}methyl)piperidin-1-yl]methyl}cyclopentanecarboxylic acid
[0360] ##STR29##
Step 1. Methyl 1-(iodomethyl)cyclopentanecarboxylate
[0361] To a stirred solution of HN(iPr).sub.2 (1.31 mL, 9.36 mmol)
in THF (5 mL) was added n-BuLi (1.58 M in hexane, 5.43 mL, 8.58
mmol) with keeping -10.degree. C. under N.sub.2, and the mixture
was stirred at -10.degree. C. for 1 h. Then, to this mixture was
added a solution of methyl cyclopentanecarboxylate (1.00 g, 7.80
mmol) in THF (3 mL) dropwise at 0.degree. C., and the mixture was
stirred at 0.degree. C. for 2 h. Finally, to this mixture was added
CH.sub.2I.sub.2 (0.628 mL, 7.80 mmol) at 0.degree. C., and the
resulting mixture was stirred at room temperature for 16 h. The
reaction mixture was quenched with sat. NH.sub.4Cl aq. (50 mL),
extracted with Et.sub.2O (75 mL) for two times, and the combined
organic layer was washed with brine (75 mL). The organic layer was
dried over Na.sub.2SO.sub.4, filtered and concentrated. Removal of
the solvent gave a residue, which was chromatographed on a column
of silica gel eluting with EtOAc/hexane (1:20.fwdarw.1:10) to give
1.085 g (52%) of title compound as a colorless oil.
[0362] .sup.1H-NMR (CDCl.sub.3) .delta. 3.73 (3H, s), 3.42 (2H, s),
2.30-2.15 (2H, m), 1.80-1.55 (6H, m).
Step 2. Methyl
1-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidine-1-yl)methyl]cyclopen-
tanecarboxylate
[0363] A mixture of Methyl 1-(iodomethyl)cyclopentanecarboxylate
(5.52 g, 0.0206 mol. Step 1), tert-butyl
(piperidin-4-ylmethyl)carbamate (8.83 g, 0.0412 mol) and
iPr.sub.2NEt (10.76 mL, 0.0618 mol) in N-methylpyrrolidone (70 mL)
was stirred at 120.degree. C. for 24 h. After cooling, the reaction
mixture was diluted with sat. NaHCO.sub.3 aq. (200 mL), extracted
with AcOEt (200 mL) for three times, and the combined organic layer
was washed with water (200 mL) and brine (200 mL). The organic
layer was dried over Na.sub.2SO.sub.4, filtered and concentrated.
Removal of the solvent gave a residue, which was chromatographed on
a column of silica gel eluting with EtOAc/hexane (1:1) to give 4.91
g (67%) of title compound as a yellow syrup.
[0364] MS (ESI) m/z: 355 (M+H).sup.+.
[0365] .sup.1H-NMR (CDCl.sub.3) .delta. 4.58 (1H, br s), 3.66 (3H,
s), 2.97 (2H, t, J=6.3 Hz), 2.77 (2H, br d, J=11.5 Hz), 2.55 (2H,
s), 1.70-1.50 (9H, m), 1.44 (9H, s), 1.25-1.08 (2H, m).
Step 3. Methyl
1-{[4-(aminomethyl)piperidin-1-yl]methyl}cyclopentanecarboxylate
[0366] A solution of methyl
1-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidine-1-yl)methyl]cyclopen-
tanecarboxylate (1.16 g, 3.27 mmol, Step 2) in CH.sub.2Cl.sub.2 (25
mL) and trifluoroacetic acid (5 mL) was stirred at room temperature
for 1.5 h. The reaction mixture was then concentrated and basified
with sat. NaHCO.sub.3 aq. (100 mL), extracted with CHCl.sub.3 (100
mL) for five times. The combined extract was dried and concentrated
to give 0.831 g (100%) of title compound as yellow syrup.
[0367] MS (ESI) m/z: 255 (M+H).sup.+.
[0368] .sup.1H-NMR (CDCl.sub.3) .delta. 3.66 (3H, s), 2.78 (2H, d,
J=11.5 Hz), 2.62-2.50 (4H, m), 2.15-1.98 (4H, m), 1.80-1.40 (9H,
m), 1.30-1.05 (2H, m).
Step 4. Methyl
1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]ami-
no}methyl)piperidin-1-yl]methyl}cyclopentanecarboxylate
[0369] The title compound was prepared by a method similar to that
shown in the Step 6 of Example 1. MS (ESI) m/z: 457
(M+H).sup.+.
[0370] .sup.1H NMR (CDCl.sub.3) .delta. 8.94 (1H, t, J=5.7 Hz),
8.28-8.20 (7.25-7.10 (3H, m), 4.80-4.60 (1H, m), 3.66 (3H, s), 3.27
(2H, t, J=6.4 Hz), 2.84 (2H, d, J=11.6 Hz), 2.62 (2H, s), 2.20-2.00
(4H, m), 1.75-1.50 (15H, m, including 6H, d, J=7.0 Hz, 1.56 ppm),
1.40-1.20 (2H, m).
Step 5.
1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbo-
nyl]amino}methyl)piperidin-1-yl]methyl}cyclopentanecarboxylic
acid
[0371] A mixture of Methyl
1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]ami-
no}methyl)piperidin-1-yl]methyl}cyclopentanecarboxylate (1.33 g,
2.90 mmol, Step 4) in 4N--HCl (6 mL) and acetic acid (6 mL) was
stirred at reflux for 18 h. After cooling, the reaction mixture was
concentrated and basified with sat. NaHCO.sub.3 aq. (100 mL),
extracted with CH.sub.2Cl.sub.2 (150 mL) for three times. The
combined extracts were dried over Na.sub.2SO.sub.4, filtered and
concentrated. The residue was chromatographed on a column of silica
gel eluted with MeOH/CH.sub.2Cl.sub.2 (1:10) to give 1.12 g (85%)
of title compound as white solid. The crude compound was
recrystallized from EtOAc.times.2 and dried in vacuo at 50.degree.
C. for 2 days to give 610 mg of title compound as white
crystal.
[0372] MS (ESI) m/z: 443 (M+H).sup.+.
[0373] m.p.: 165.degree. C.
[0374] IR (KBr) v: 3271, 2934, 1736, 1684, 1607, 1558, 1483, 1454,
1379, 1358, 1298, 1209, 1167, 1097, 758 cm.sup.-1.
[0375] .sup.1H NMR (CDCl.sub.3) .delta. 9.00 (1H, t, J=5.5 Hz),
8.30-8.18 (1H, m), 7.25-7.10 (3H, m), 4.80-4.60 (1H, m), 3.34 (2H,
t, J=11.0 Hz), 2.32-2.17 (2H, m), 2.00-1.30 (17H, m, including 6H,
d, 7.0 Hz, 1.57 ppm).
[0376] Anal. calcd. for C.sub.24H.sub.34N.sub.4O.sub.4.0.2H.sub.2O:
C, 64.61; H, 7.77; N, 12.56. Found: C, 64.34; H, 7.79; N,
12.48.
Alternative route to synthesize
1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]ami-
no}methyl)piperidin-1-yl]methyl}cyclopentanecarboxylic acid is
described below.
Step 6. Methyl
1-[(4-{[(tert-butoxycarbonyl)amino]methyl}Piperidine-1-yl)methyl]cyclopen-
tanecarboxylate
[0377] The title compound was prepared according to the procedure
described in the Step 10 of the Example 1 using
[cyclopentylidene(methoxy)methoxy](trimethyl)silane (Synthesis,
1982, 1, 58-60) instead of
[methoxy(tetrahydro-4H-pyran-4-ylidene)methoxy](trimethyl)silane.
[0378] MS (ESI) m/z: 355 (M+H).sup.+.
[0379] .sup.1H-NMR (CDCl.sub.3) .delta. 4.58 (1H, br s), 3.66 (3H,
s), 2.97 (2H, t, J=6.3 Hz), 2.77 (2H, br d, J=11.5 Hz), 2.55 (2H,
s), 2.18-1.95 (4H, m), 1.70-1.50 (9H, m), 1.44 (9H, s), 1.25-1.08
(2H, m).
Step 7.
1-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]cy-
clopentanecarboxylic acid
[0380] To a solution of Methyl
1-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]cyclopent-
anecarboxylate (2.8 g, 8.0 mmol, Step 6) in MeOH (11 mL), 2 N
aqueous NaOH solution (6 mL) was added at room temperature
(exothermic). The resulting solution was stirred at 70.degree. C.
for 4 h, then cooled to 5.about.10.degree. C. in ice-cold water
bath. To the solution, 5 N HCl aq (6 mL) was added dropwise. The
resulting solution (pH value was ca.6) was concentrated and to the
residue, 2-propanol (40 mL) was added. This solution was
concentrated and to the residue, CH.sub.3CN (40 mL) was added. The
resulting mixture was stirred at room temperature for 2 h and it
was filtered through a Celite pad (5.0 g) to remove NaCl. The
filtrate was concentrated to give 2.4 g (quant) of the titled
compound as white solid.
[0381] .sup.1H NMR (300 MHz, DMSO-d6) .delta. 6.90-6.75 (1H, m),
2.95-2.80 (2H, m), 2.79 (2H, t, J=6.4 Hz), 2.58 (2H, s), 2.25-2.05
(2H, m), 2.05-1.85 (2H, m), 1.65-1.50 (6H, m), 1.50-1.25 (3H, m),
1.37 (9H, s), 1.20-0.95 (2H, m).
[0382] mp 150.degree. C.
Step 8.
1-{[4-(aminomethyl)piperidin-1-yl]methyl}cyclopentanecarboxylic
acid 4-methylbenzenesulfonate
[0383] In a 100 mL, 2-necked round bottom flask, to a mixture of
1-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]cyclopent-
anecarboxylic acid (5 g, 14.7 mmol, Step 7) in THF (25 mL), a
solution of p-TsOH H.sub.2O (8.4 g, 44 mmol) in THF (25 mL) was
added at room temperature. The resulting mixture was stirred at
70.degree. C. for 3 h under N.sub.2 and it was cooled down to room
temperature. To this solution, Et.sub.3N (6 mL, 44 mmol) was added
dropwise slowly. The white precipitate was formed during the
addition of Et.sub.3N and the resulting mixture was stirred at room
temperature for 14 h. The suspension was filtered and the obtained
solid was washed with THF (10 mL), dried at 50.degree. C. for 5 h
to give 5.9 g (97%) of the titled compound as a white solid.
[0384] .sup.1H-NMR (D.sub.2O) .delta.7.51 (2H, J=8.2 Hz), 7.19 (2H,
J=8.2 Hz), 3.38 (2H, d, J=11.0 Hz), 3.09 (2H d, J=2.6 Hz), 2.88
(2H, t, J=12.1 Hz), 2.79 (2H, t, J=6.6 Hz), 2.21 (3H, s), 1.94-1.75
(5H, m), 1.61-1.27 (9H, m)
Step 9.
1-{[4-({[(3-Isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbo-
nyl]amino}methyl)piperidin-1-yl]methyl}cyclopentanecarboxylic
acid
[0385] A mixture of 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one
(10 g, 56.8 mmol) and chloroformic acid 4-nitrophenyl ester (11.4
g, 56.8 mmol) in CH.sub.2Cl.sub.2 (150 mL) was stirred at room
temperature for 5 min. To this mixture, Et.sub.3N (17.4 mL, 125
mmol) was added slowly and the resulting mixture was added to a
mixture of
1-{([4-(aminomethyl)piperidin-1-yl]methyl}cyclopentanecarboxylic
acid 4-methylbenzene sulfonate (23.4 g, 56.8 mmol, Step 8) in
CH.sub.2Cl.sub.2 (75 mL) at room temperature. After stirring for 10
min, Et.sub.3N (7.9 mL, 56.8 mmol) was added and the resulting
mixture was stirred at room temperature for 2 hr. This mixture was
washed with 1 N HCl aq (100 mL). Organic layer was concentrated at
50.degree. C. until ca 5 vol and it was replaced by acetone (50
mL.times.3) at 80.degree. C. until ca 5 vol. To this mixture,
H.sub.2O (100 mL) was added at 80.degree. C. and the resulting
mixture was concentrated at 100.degree. C. After cooling down to
50.degree. C., 20% N,N-dimethylaminoethanol aqueous solution (100
mL) was added to this mixture and the solid was observed. The
resulting mixture was cooled in ice cold bath and it was stirred
for 18 hrs at that temperature. This mixture was filtered and the
obtained solid was washed with H.sub.2O (100 mL), dried at
50.degree. C. under vacuum to afford 17.9 g (71%) of the titled
compound as white solid.
[0386] mp. 166.degree. C.
[0387] PXRD (2.theta.(+/-0.1): 4.4, 8.8, 13.2, 17.6)
Example 4
1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amin-
o}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylic acid
hydrochloride
[0388] ##STR30##
Step 1. tert-butyl
1-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidine-1-yl)methyl]cyclopro-
panecarboxylate
[0389] Tert-butyl 1-(iodomethyl)cyclopropanecarboxylate (including
starting material, 3:2 mixture) was prepared according to the
procedure described of Step 1 in the Example 3 using tert-butyl
cyclopropanecarboxylate (J. Organomet. Chem., 1983, 252, 267-274)
instead of methyl cyclopentanecarboxylate. This was used for the
next step without further purification.
[0390] The title compound was prepared by a method similar to that
shown in the Step 2 of Example 3.
[0391] MS (ESI) m/z: 369 (M+H).sup.+.
[0392] .sup.1H NMR (CDCl.sub.3) .delta. 4.59 (1H, br s), 2.99 (2H,
d, J=5.9 Hz), 2.89 (2H, br d, J=11.5 Hz), 2.57 (2H, s), 2.00 (2H,
t, J=11.7 Hz), 1.62 (2H, d, J=12.9 Hz), 1.55-1.35 (1H, m), 1.44
(9H, s), 1.42 (9H, s), 1.30-1.15 (2H, m), 1.13 (2H, dd, J=3.8 Hz,
6.6 Hz), 0.74 (2H, dd, J=3.5 Hz, 6.3 Hz).
Step 2. tert-butyl
1-{[4-(aminomethyl)piperidin-1-yl]methyl}cyclopropanecarboxylate
[0393] The title compound was prepared by a method similar to that
shown in the Step 3 of Example 3.
[0394] MS (ESI) m/z: 269 (M+H).sup.+.
[0395] .sup.1H NMR (CDCl.sub.3) .delta. 2.96 (2H, br d, J=11.5 Hz),
2.60-2.50 (4H, m), 2.00 (2H, t, J=11.4 Hz), 1.75-1.35 (14H, m,
including 2H, br d, J=9.6 Hz, 1.66 ppm and 9H, s, 1.43 ppm),
1.33-1.16 (2H, m), 1.13 (2H, dd, J=4.0 Hz, 6.9 Hz), 0.74 (2H, dd,
J=3.8 Hz, 6.6 Hz).
Step 3. tert-butyl
1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]ami-
no}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylate
[0396] The title compound was prepared by a method similar to that
shown in the Step 4 of Example 3.
[0397] MS (ESI) m/z: 471 (M+H).sup.+.
[0398] .sup.1H NMR (CDCl.sub.3) .delta. 8.91 (1H, br t, J=5.5 Hz),
8.32-8.20 (1H, m), 7.25-7.10 (3H, m), 4.80-4.60 (1H, m), 3.30 (2H,
t, J=6.4 Hz), 2.91 (2H, br d, J=11.6 Hz), 2.57 (2H, s), 2.01 (2H,
br t, J=9.5 Hz), 1.73 (2H, br d, J=12.1 Hz), 1.67-1.50 (10H, m,
including 6H, d, J=7.0 Hz, 1.56 ppm), 1.43 (9H, s), 1.34-1.20 (2H,
m), 1.12 (2H, dd, J=4.0 Hz, 7.0 Hz), 0.73 (2H, dd, J=3.9 Hz, 6.8
Hz).
Step 4.
1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbo-
nyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylic acid
hydrochloride
[0399] The title compound was prepared by a method similar to that
shown in the Step 7 of Example 1.
[0400] MS (ESI) m/z: 415 (M+H).sup.+.
[0401] m.p.: 206.degree. C.
[0402] IR (KBr) v: 2936, 2700, 1732, 1688, 1556, 1485, 1383, 1359,
1182, 1164, 758 cm.sup.-1.
[0403] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.86 (1H, t, J=6.3 Hz),
8.07 (1H, dd, J=1.0 Hz, 7.8 Hz), 7.45 (1H, d, J=7.1 Hz), 7.22 (1H,
dt, J=1.3 Hz, 7.6 Hz), 7.15 (1H, dt, J=1.2 Hz, 7.7 Hz), 4.95-4.60
(1H, m), 3.70-3.10 (6H, m), 3.10-2.90 (2H, m), 1.86 (3H, m,
including 2H, d, J=11.2 Hz, 1.86 ppm), 1.70-1.53 (2H, m), 1.49 (6H,
d, J=6.9 Hz), 1.35-1.15 (4H, m).
[0404] Anal. calcd. for
C.sub.22H.sub.30N.sub.4O.sub.4.HCl.0.2H.sub.2O: C, 58.13; H, 6.96;
N, 12.33. Found: C, 57.93; H, 6.97; N, 12.18.
Example 5
3-[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amino-
}methyl)piperidin-1-yl]propanoic acid hydrochloride
[0405] ##STR31##
Step 1. tert-Butyl
4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amino}m-
ethyl)piperidine-1-carboxylate
[0406] To a stirred solution of
1-isopropyl-1,3-dihydro-2H-benzimidazol-2one (J. Med. Chem. 1999,
42, 2870-2880) (3.00 g, 17.02 mmol) and triethylamine (7.12 ml,
51.06 mmol) in 70 ml tetrahydrofuran was added triphosgene (5.15 g,
17.02 mmol) in 14 ml tetrahydrofuran at room temperature. The
reaction mixture was refluxed for 19 hours. The mixture was then
cooled to room temperature, tert-butyl
4-(aminomethyl)piperidine-1-carboxylate (J. Prugh, L. A.
Birchenough and M. S. Egbertson, Synth. Commun., 1992, 22, 2357-60)
(3.28 g, 15.32 mmol) in 10 ml tetrahydrofuran was added. The
reaction mixture was refluxed for another 24 hours. Then cooled and
basified with aqueous saturated NaHCO.sub.3 50 ml, and extracted
with ethyl acetate 100 ml for three times. The combined extract was
washed with brine, dried over MgSO.sub.4 and concentrated. Flash
chromatography of the residue (elutent: hexane/ethyl acetate=5/1 to
1/2) afforded a colorless oil 3.99 g (62%) as the titled
compound.
[0407] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.04-8.88 (1H, m),
8.83-8.20 (1H, m), 7.26-7.10 (3H, m), 4.80-4.60 (1H, m), 4.28-4.02
(2H, m), 3.32 (2H, t, J=6.1 Hz), 2.82-2.60 (2H, m), 1.94-1.10 (5H,
m), 1.57 (6H, d, J=7.1 Hz), 1.45 (9H, s).
Step 2.
3-Isopropyl-2-oxo-N-(piperidin-4-ylmethyl)-2,3-dihydro-1H-benzimid-
azole-1-carboxamide
[0408] A solution of tert-butyl
4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amino}m-
ethyl)piperidine-1-carboxylate (3.992 g, 9.58 mmol) in 50 ml 10%
hydrochloric acid in methanol and 10 ml concentrated hydrochloric
acid was stirred at room temperature for 18 hours. The mixture was
then concentrated and basified with aqueous Na.sub.2CO.sub.3,
extracted with CHCl.sub.3 (100 ml) for 3 times. The combined
extract was dried and concentrated. Flash chromatography of the
residue (NH-silica gel, elutent: CH.sub.2Cl.sub.2/methanol=100/1)
afforded a colorless oil 2.272 g (75%) as the title compound.
[0409] MS (ESI) m/z: 317 (M+H).sup.+.
[0410] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.93 (1H, br), 8.32-8.22
(.sup.1H, m), 7.24-7.02 (3H, m), 4.80-4.61 (.sup.1H, m), 3.31 (2H,
t, J=6.0 Hz), 3.20-3.05 (2H, m), 2.79-2.54 (2H, m), 1.84-1.52 (3H,
m), 1.57 (6H, d, J=6.9 Hz), 1.36-1.13 (2H, m).
Step 3. tert-butyl
3-[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amin-
o}methyl)piperidin-1-yl]propanoate
[0411] A mixture of
3-isopropyl-2-oxo-N-(piperidin-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-
-carboxamide (0.50 g, 1.58 mmol, Step 2), tert-butyl acrylate
(0.340 mL, 2.37 mmol) and iPrNEt (0.275 mL, 2.37 mmol) in THF (20
mL) was refluxed for 18 h. After cooling, the reaction mixture was
diluted with sat. NaHCO.sub.3 aq. (100 mL), extracted with
CH.sub.2Cl.sub.2 (100 mL) for three times. The combined extracts
were dried over Na.sub.2SO.sub.4, filtered and concentrated. The
residue was chromatographed on a column of silica get eluted with
MeOH/CH.sub.2Cl.sub.2 (1:20-1:10) and then NH-silica gel eluted
with EtOAc/hexane (1:5.fwdarw.1:2) to give 0.111 g (16%) of title
compound as colorless syrup.
[0412] MS (ESI) m/z: 445 (M+H).sup.+.
[0413] .sup.1H NMR (CDCl.sub.3) .delta. 8.94 (1H, br s), 8.30-8.20
(1H, m), 7.25-7.11 (3H, m), 7.11-7.00 (1H, m), 4.80-4.62 (1H, m),
3.31 (2H, t, J=6.2 Hz), 2.95 (2H, br t, J=11.6 Hz), 2.68 (2H, t,
J=7.2 Hz), 2.43 (2H, t, J=7.7 Hz), 2.03 (2H, br t, J=11.4 Hz),
1.98-1.82 (1H, m), 1.79 (2H, d, J=12.1 Hz), 1.56 (6H, d, J=7.2 Hz),
1.50-1.30 (11H, m, including 9H, s, 1.44 ppm).
Step 4.
3-[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbon-
yl]amino}methyl)piperidin-1-yl]propanoic acid hydrochloride
[0414] The title compound was prepared by a method similar to that
shown in the Step 7 of Example 1.
[0415] MS (ESI) m/z: 389 (M+H).sup.+.
[0416] IR (KBr) v: 2939, 2637, 1724, 1682, 1542, 1466, 1373, 1217,
1194, 953, 762 cm.sup.-1.
[0417] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.86 (1H, t, J=5.9 Hz),
8.07 (1H, dd, J=0.8 Hz, 7.7 Hz), 7.49 (1H, d, J=7.6 Hz), 7.22 (1H,
dt, J=1.3 Hz, 7.6 Hz), 7.15 (1H, dt, J=1.0 Hz, 7.6 Hz), 4.75-4.60
(1H, m), 3.70-3.10 (6H, m), 2.93 (2H, br t, J=11.2 Hz), 2.85-2.70
(2H, m), 1.95-1.75 (3H, m, including 2H, d, J=11.5 Hz, 1.87 ppm),
1.65-1.40 (8H, m, including 6H, d, J=7.1 Hz, 1.49 ppm).
[0418] Anal. calcd. for C.sub.20H.sub.28N.sub.4O.sub.4.HCl.0.8
H.sub.2O: C, 54.68; H, 7.02; N, 12.75. Found: C, 54.67; H, 6.88; N,
12.70.
Example 6
1-{[4-hydroxy-4-(4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-
carbonyl]amino}methyl)piperidin-1-yl]methyl}cyclohexanecarboxylic
acid
[0419] ##STR32##
Step 1. methyl 1-(iodomethyl)cyclohexanecarboxylate
[0420] The title compound was prepared by a method similar to that
shown in the Step 1 of Example 3 by using Methyl
cyclohexanecarboxylate.
[0421] .sup.1H NMR (CDCl.sub.3) .delta. 3.73 (3H, s), 3.32 (2H, s),
2.20-2.05 (2H, m), 1.70-1.20 (8H, m).
Step 2. Methyl
1-[(4-{[(tert-butoxycarbonyl)amino]methyl}-4-hydroxypiperidine-1-yl)methy-
l]cyclohexanecarboxylate
[0422] The title compound was prepared by a method similar to that
shown in the Step 2 of Example 3 by using tert-butyl
[(4-hydroxypiperidin-4-yl)methyl]carbamate (Chem. Pharm. Bull.,
2002, 50 (9) 1187-1194) and methyl
1-(iodomethyl)cyclohexanecarboxylate (Step 1 of Example 6).
[0423] MS (ESI) m/z: 385 (M+H).sup.+.
[0424] .sup.1H NMR (CDCl.sub.3) .delta. 4.86 (1H, br s), 3.66 (3H,
s), 3.11 (2H, d, J=6.3 Hz), 2.55-2.45 (6H, m), 2.03 (2H, br d,
J=10.4 Hz), 1.70-1.15 (18H, m, including 9H, s, 1.44 ppm).
Step 3. Methyl
1-{[4-(aminomethyl)-4-hydroxypiperidin-1-yl]methyl}cyclohexanecarboxylate
[0425] The title compound was prepared by a method similar to that
shown in the Step 3 of Example 3.
[0426] MS (ESI) m/z: 285 (M+H).sup.+.
[0427] .sup.1H NMR (CDCl.sub.3) .delta. 3.66 (3H, s), 2.61 (1H, br
s), 2.57-2.45 (5H, m), 2.35-2.11 (3H, m), 2.04 (2H, br d, J=11.5
Hz), 1.65-1.45 (6H, m), 1.45-1.20 (4H, m).
Step 4. Methyl
1-{[4-hydroxy-4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)ca-
rbonyl]amino}methyl)piperidin-1-yl]methyl}cyclohexanecarboxylate
[0428] The title compound was prepared by a method similar to that
shown in the Step 4 of Example 3.
[0429] MS (ESI) m/z: 487 (M+H).sup.+.
[0430] .sup.1H NMR (CDCl.sub.3) .delta. 9.12 (1H, t, J=5.6 Hz),
8.30-8.20 (1H, m), 7.25-7.10 (3H, m), 4.80-4.65 (1H, m), 3.66 (3H,
s), 3.54 (2H, d, J=5.9 Hz), 2.60-2.45 (6H, m), 2.03 (2H, br d,
J=9.1 Hz), 1.75-1.47 (12H, m), 1.47-1.15 (6H, m).
Step 5.
1-{[4-hydroxy-4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol--
1-yl
carbonyl]amino}methyl)piperidin-1-yl]methyl}cyclohexanecarboxylic
acid
[0431] The title compound was prepared by a method similar to that
shown in the Step 5 of Example 3.
[0432] MS (ESI) m/z: 473 (M+H).sup.+.
[0433] m.p.: 184.degree. C.
[0434] IR (KBr) v: 3437, 3273, 2943, 1732, 1688, 1601, 1533, 1479,
1452, 1371, 1134, 978, 762 cm.sup.-1.
[0435] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.94 (1H, t, J=5.6 Hz),
8.09 (1H, d, J=7.7 Hz), 7.43 (1H, d, J=7.7 Hz), 7.22 (1H, t, J=7.8
Hz), 7.14 (1H, t, J=7.4 Hz), 4.75-4.58 (1H, m), 4.59 (1H, s), 2.47
(2H, s), 4.00-3.00 (6H, m), 1.86 (2H, d, J=11.4 Hz), 1.60-1.10
(18H, m, including 6H, d, J=6.9 Hz, 1.49 ppm).
[0436] Anal. calcd. for C.sub.25H.sub.36N.sub.4O.sub.5.0.5H.sub.2O:
C, 62.35; H, 7.74; N, 11.63. Found: C, 62.52; H, 7.70; N,
11.66.
Example 7
1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amin-
o}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid
[0437] ##STR33##
Step 1. methyl
1-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]cyclobuta-
necarboxylate
[0438] To a stirred mixture of tert-butyl
(piperidin-4-ylmethyl)carbamate (12.8 g, 60 mmol) and methyl
1-formylcyclobutanecarboxylate (2.13 g, 15 mmol, Davis, Charles R.;
Swenson, Dale C.; Burton, Donald J., J. Org. Chem., 1993, 58, 6843)
in tetrahydrofuran was added acetic acid (8.6 mL, 150 mmol) at
ambient temperature. After 30 min, sodium triacetoxyborohydride
(12.7 g, 60 mmol) was added to the mixture. Then, the mixture was
heated to 60.degree. C. for 2 h.
[0439] After cooling, the reaction mixture was poured into sat.
NaHCO.sub.3 aq. The aqueous layer was extracted with
dichloromethane for 3 times. The combined organic phase was washed
with brine, dried over MgSO.sub.4 and concentrated. The residue was
chromatographed on a column of silica gel eluting with hexane/ethyl
acetate (1:1) to give 4.25 g (83%) of the title compound as a white
solid.
[0440] MS (ESI) m/z: 341 (M+H.sup.+).
[0441] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.69 (3H, s), 2.96 (2H, t,
J=6.2 Hz), 2.75 (2H, d, J=11.4 Hz), 2.67 (2H, s), 2.37-2.46 (2H,
m), 1.78-2.05 (6H, m), 1.45-1.65 (2H, m), 1.43 (9H, s), 1.09-1.21
(2H, m),
Step 2. methyl
1-{[4-(aminomethyl)piperidin-1-yl]methyl}cyclobutanecarboxylate
[0442] The title compound was prepared according to the procedure
described in Step 3 of Example 3 from methyl
1-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]cyclobuta-
necarboxylate (step 1 of Example 7).
[0443] MS (ESI) m/z: 241 (M+H.sup.+).
[0444] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.67 (3H, s), 2.72-2.78
(2H, m), 2.66 (2H, s), 2.54 (2H, d, J=6.2 Hz), 2.34-2.47 (2H, m),
1.79-2.04 (8H, m), 1.54-1.64 (2H, m), 1.05-1.35 (3H, m).
Step 3. Methyl
1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]ami-
no}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylate
[0445] The title compound was prepared according to the procedure
described in Step 6 of Example 1 from
1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and methyl
1-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]cyclobuta-
necarboxylate (step 2 of Example 7).
[0446] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.92-8.86 (1H, m),
8.28-8.24 (1H, m), 7.20-7.12 (3H, m), 4.75-4.62 (1H, m), 3.70 (3H,
s), 3.27 (2H, t, J=6.4 Hz), 2.85-2.72 (2H, m), 2.68 (2H, s),
2.47-2.35 (2H, m), 2.05-1.92 (4H, m), 1.92-1.76 (2H, m), 1.71-1.61
(2H, m), 1.56 (6H, d, J=7.0 Hz), 1.32-1.17 (2H, m),
[0447] MS (ESI) m/z: 443 (M+H.sup.+).
Step 4.
1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbo-
nyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic
acid
[0448] The title compound was prepared according to the procedure
described in Step 5 of Example 3 from Methyl
1-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]ami-
no}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylate (step 3 of
Example 7).
[0449] IR (KBr) v: 3293, 2979, 2937, 2875, 1732, 1687, 1610, 1548,
1479, 1375, 1298, 1203, 1099, 761, 704 cm.sup.-1
[0450] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.02-8.95 (1H, m),
8.26-8.22 (1H, m), 7.22-7.12 (3H, m), 4.76-4.62 (1H, m), 3.33 (2H,
t, J=6.2 Hz), 3.10-3.00 (2H, m), 2.77 (2H, s), 2.58-2.48 (2H, m),
2.44-2.24 (2H, m), 1.92-1.79 (2H, s), 1.99-1.80 (5H, m), 1.56 (6H,
d, J=7.0 Hz), 1.50-1.33 (3H, m).
[0451] MS (ESI) m/z: 429 (M+H.sup.+).
[0452] Anal. Calcd. for C.sub.23H.sub.32N.sub.4O.sub.4: C, 64.46;
H, 7.53; N, 13.07. Found: C, 64.47; H, 7.43; N, 12.93.
Alternative route to synthesize
1-{[4-({[(3-Isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]ami-
no}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid is
described below.
Step 5. Ethyl
1-4[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]cyclobut-
anecarboxylate
[0453] The title compound was prepared according to the procedure
described in the Step 10 of the Example 1 using
[cyclobutylidene(ethoxy)methoxy](trimethyl)silane (Chem. Commun.,
1971, 136-137) instead of
[methoxy(tetrahydro-4H-pyran-4-ylidene)methoxy](trimethyl)silane.
[0454] MS (ESI) m/z: 355 (M+H).sup.+.
[0455] .sup.1H-NMR (CDCl.sub.3) .delta. 4.55 (1H, br), 4.17 (2H, q,
J=7.1 Hz), 2.96 (2H, t, J=6.3 Hz), 2.76 (2H, d, J=11.4 Hz),
2.48-2.33 (2H, m), 2.05-1.80 (6H, m), 1.43 (9H, s), 1.25 (3H, q,
J=7.1 Hz), 1.40-1.05 (7H, m).
Step 6.
1-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]cy-
clobutanecarboxylic acid
[0456] A mixture of Ethyl
1-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]cyclobuta-
necarboxylate (4.2 g, 11.9 mmol, Step 5), 2N NaOH (18 mL) and EtOH
(12 mL) was heated at 50.degree. C. for 4 hrs. The resulting
solution was cooled in ice bath and 2N HCl (ca 19 mL) was added
until pH of the mixture was ca 5-6. The whole was extracted with
CH.sub.2Cl.sub.2/.sup.iPrOH (3:1, 30 mL.times.3). Combined organic
layer was dried (Na.sub.2SO.sub.4) and filtered. The filtrate was
concentrated to give 3.8 g (98%) of the titled compound as yellow
solid.
[0457] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 4.08 (1H, m),
3.20-3.10 (2H, m), 3.08-2.99 (2H, m), 2.91 (2H, s), 2.60-2.38 (4H,
m), 2.35-2.16 (2H, m), 2.05-1.76 (6H, m), 1.65 (1H, m), 1.44 (9H,
s).
[0458] mp 160.degree. C.
Step 7.
1-{[4-(aminomethyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid
4-methyl benzenesulfonate
[0459] In a 500 mL, 3-necked round bottom flask under N.sub.2, a
mixture of
1-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]cyclob-
utane carboxylic acid (30 g, 92 mmol, Step 6) in THF (150 mL) was
stirred at room temperature for 10 min. To this suspension, a
solution of p-TsOH H.sub.2O (52.4 g, 276 mmol) in THF (150 mL) was
added at room temperature. After stirring at that temp for 10 min,
the resulting solution was heated under reflux condition for 3 hrs.
After cooling down to room temperature, Et.sub.3N (28.1 mL, 202
mmol) was added very slowly during the period of 1 h with seeding.
The white precipitate was formed during the addition of Et.sub.3N.
The resulting white suspension was stirred at room temperature for
6 h and it was filtered and the obtained solid was washed with THF
(100 mL.times.2), dried at 50.degree. C. for 5 h to give 35 g (96%)
of the titled compound as white powder
[0460] .sup.1H-NMR (D.sub.2O) .delta. 7.40 (2H, d, J=7.2 Hz), 7.07
(2H, d, J=7.2 Hz), 3.28-3.00 (4H, m), 2.80-2.57 (4H, m), 2.09 (3H,
s), 2.18-1.97 (2H, m), 1.85-1.58 (8H, m), 1.36-1.12 (2H, m)
[0461] mp: 210.degree. C.
Step 8.
1-{[4-({[(3-Isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbo-
nyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic
acid
[0462] A mixture of 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one
(486 mg, 2.8 mmol) and chloroformic acid 4-nitrophenyl ester (556
mg, 2.8 mmol) in CH.sub.2Cl.sub.2 (10 mL) was stirred at room
temperature for 5 min. To this mixture, Et.sub.3N (0.84 mL, 6.1
mmol) was added slowly and this mixture became a solution. This
solution was added to a mixture of
1-{([4-(aminomethyl)piperidin-1-yl]methyl}cyclobutanecarboxylic
acid 4-methylbenzene sulfonate (1.1 g, 2.8 mmol, Step 7) in
CH.sub.2Cl.sub.2 (5 mL) at room temperature. After stirring for 10
min, Et.sub.3N (0.38 mL, 2.8 mmol) was added and the resulting
mixture was stirred at room temperature for 2 hr. This mixture was
washed with 0.5 N HCl aq (10 mL) and saturated NaHCO.sub.3 aq (10
mL) then the organic layer was concentrated. To the residue,
saturated NaHCO.sub.3 aq (15 mL) and heptane (15 mL) was added at
room temperature and it was stirred for 6 hrs at that temperature.
Solid was observed and this mixture was filtered. The obtained
solid was washed with H.sub.2O and heptane. After drying, crude
material was obtained (1.0 g, 82%) as white solid. This crude
material (4.0 g) was purified by recrystallization from toluene (36
mL) to give 2.6 g of the titled compound (66%) as white solid.
[0463] mp. 173.degree. C.
[0464] PXRD (2e(+/-0.1): 10.8, 16.9, 18.9, 26.5)
Example 8
N-({1-(2-oxycarbonyl-2-methylpropyl)piperidin-4-yl}methyl)-3-isopropyl-2-o-
xo-2,3-dihydro-1H-benzimidazole-1-carboxamide
[0465] ##STR34##
Step 1. tert-Butyl
[{1-(2-benzyloxycarbonyl-2-methylpropyl)piperidin-4-yl}methyl]carbamate
[0466] To a stirred solution of tert-butyl
(piperidin-4-ylmethyl)carbamate (38.8 g, 181 mmol) in
N,N-dimethylformamide (100 mL) was added benzyl 3-chloropivalate
(14.2 g, 124 mmol, prepared from 3-chloropivaloyl chloride (25.6 g,
165 mmol) and benzyl alcohol (19.6 g, 181 mmol),
ethyldiisopropylamine (64.0 g, 495 mmol) and sodium iodide (27.1 g,
181 mmol) at ambient temperature. The resulting mixture was stirred
at 120.degree. C. for 14 h. The volatile components were removed by
evaporation and the resulting residue was chromatographed on a
column of silica gel eluting with hexane/ethyl acetate (1:1) to
give 640 mg (1%) of the title compound as a pale yellow oil.
[0467] MS (ESI) m/z: 405 (M+H.sup.+).
[0468] .sup.1H NMR (CDCl.sub.3) .delta. 7.43-7.23 (5H, m), 5.10
(2H, s), 4.58 (1H, br t), 2.95 (2H, m), 2.71 (2H, m), 2.46 (2H, br
s), 2.06 (2H, m), 1.57-1.36 (3H, m), 1.44 (9H, s), 1.12 (2H, m),
1.17 (6H, s).
Step 2.
N-({1-(2-benzyloxycarbonyl-2-methylpropyl)piperidin-4-yl}methyl)-3-
-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide
[0469] To a stirred mixture of
1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one (J. Med. Chem. 1999,
42, 2870-2880) (411 mg, 2.33 mmol) and triethylamine (1.00 mL, 7.17
mmol) in dichloromethane (20.0 mL) was added 4-nitrophenyl
chloroformate (470 mg, 2.33 mmol) at room temperature. The
resulting mixture was stirred for 2 h at room temperature. To the
mixture was added a suspension of
1-(2-benzyloxycarbonyl-2-methylpropyl)-4-aminomethylpiperidine
hydrochloride [prepared from concentration of a mixture of
tert-butyl
[{1-(2-benzyloxycarbonyl-2-methylpropyl)piperidin-4-yl}methyl]carbamate
(step 1 of Example 1) (640 mg, 1.49 mmol) and 10% HCl in MeOH (20.0
mL)] and triethylamine (1.00 mL, 7.17 mmol) in dichloromethane
(5.00 mL). The resulting mixture was stirred for 13 h at room
temperature and 0.5 M NaOH aq. was added to the mixture. The
mixture was extracted with dichloromethane. The extracts were
washed with 0.5 M NaOH aq. and brine, dried over MgSO.sub.4 and
concentrated in vacuo. The residue was purified by preparative thin
layer chromatography (silica gel, eluting with
dichloromethane/methanol (10:1)) to give 508 mg (63%) of the title
compound as a pale yellow oil.
[0470] MS (ESI) m/z: 507 (M+H.sup.+).
[0471] .sup.1H NMR (CDCl.sub.3) .delta. 8.89 (1H, br t, J=5.7 Hz),
8.26 (1H, m), 7.43-7.05 (8H, m), 5.10 (2H, s), 4.70 (1H, septet,
J=7.0 Hz), 3.26 (2H, m), 2.75 (2H, m), 2.48 (2H, br s), 2.11 (2H,
m), 1.61 (2H, m), 1.56 (6H, d, J=7.0 Hz), 1.52 (1H, m), 1.26 (2H,
m), 1.18 (6H, s).
Step 3.
N-({1-(2-oxycarbonyl-2-methylpropyl)piperidin-4-yl}methyl)-3-isopr-
opyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide
[0472] A mixture of
N-({1-(2-benzyloxycarbonyl-2-methylpropyl)piperidin-4-yl}methyl)-3-isopro-
pyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide (step 2 of
Example z) (418 mg, 0.825 mmol) and 20% Pd(OH).sub.2/C (58.0 mg) in
methanol (80 mL) was stirred under an atmosphere of hydrogen gas at
room temperature for 12 h. The catalyst was filtered off on a pad
of Celite, and the filtrate was evaporated under reduced pressure.
Recrystallization of the resulting solid with
hexane-CH.sub.2Cl.sub.2 afforded a colorless solid 285 mg (84%) as
the titled compound.
[0473] MS (ESI) m/z: 417 (M+H).sup.+.
[0474] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.80 (1H, br t, J=5.8
Hz), 8.05 (1H, m), 7.42 (1H, m), 7.20 (1H, m), 7.12 (1H, m), 4.65
(1H, septet, J=7.0 Hz), 3.20 (2H, m), 2.85 (2H, m), 2.44 (2H, br
s), 2.18 (2H, m), 1.61 (2H, m), 1.50 (1H, m), 1.47 (6H, d, J=7.0
Hz), 1.20 (2H, m), 1.04 (6H, s). The signal which correspond to
carboxylic acid was not observed.
[0475] Anal. calcd. for C.sub.22H.sub.32N.sub.4O.sub.4.0.1H.sub.2O:
C, 63.17; H, 7.76; N, 13.39. Found: C, 62.78; H, 7.74; N,
13.11.
Example 9
N-({1-(2-tetrazole-2-methylpropyl)piperidin-4-yl}methyl)-3-isopropyl-2-oxo-
-2,3-dihydro-1H-benzimidazole-1-carboxamide
[0476] ##STR35##
Step 1. 2-benzyl-.alpha.,.alpha.-dimethyl-2H-tetrazole-5-acetic
acid, ethyl ester
[0477] To a stirred mixture of
.alpha.,.alpha.-dimethyltetrazole-5-acetic acid, ethyl ester (J.
Med. Chem. 1996, 39, 2354-2366.) (6.87 g, 37.3 mmol) and
K.sub.2CO.sub.3 (12.3 g, 89.0 mmol) in acetone (200 mL) was added
benzyl bromide (4.45 mL, 37.4 mmol) at ambient temperature. The
resulting mixture was stirred at 50.degree. C. for 18 h and
concentrated under reduced pressure. The resulting residue was
chromatographed on a column of silica gel eluting with hexane/ethyl
acetate (10:1) to give 6.14 g (60%) of the title compound as a
colorless oil.
[0478] MS (ESI) m/z: 275 (M+H.sup.+).
[0479] .sup.1H NMR (CDCl.sub.3) .delta. 7.45-7.23 (5H, m), 5.73
(2H, s), 4.11 (2H, q, J=7.2 Hz), 1.70 (6H, s), 1.13 (3H, t, J=7.2
Hz).
Step 2.
2-benzyl-.alpha.,.alpha.-dimethyl-2H-tetrazole-5-acetaldehyde
[0480] To a stirred mixture of
2-benzyl-.alpha.,.alpha.-dimethyl-2H-tetrazole-5-acetic acid, ethyl
ester acetaldehyde (step 1 of Example 9) (6.14 g, 22.4 mmol) in
dichloromethane (100 mL) at -78.degree. C. was added DIBAL (1.0 M
in toluene, 50.0 mL, 50.0 mmol). The resulting mixture was stirred
at -78.degree. C. for 4 h. To the reaction mixture was added DIBAL
(1.0 M in toluene, 25.0 mL, 25.0 mmol) and the resulting mixture
was stirred at -78.degree. C. for 8 h. To the mixture were added 2
M aqueous HCl (100 mL) and saturated aqueous NH.sub.4Cl (20 mL).
The organic layer was separated, dried over magnesium sulfate, and
concentrated under reduced pressure. The resulting residue was
chromatographed on a column of silica gel eluting with hexane/ethyl
acetate (10:1) to give 3.45 g (67%) of the title compound as a
colorless oil.
[0481] MS (ESI) m/z: 231 (M+H.sup.+).
[0482] .sup.1H NMR (CDCl.sub.3) .delta. 9.68 (1H, s), 7.45-7.23
(5H, m), 5.74 (2H, s), 1.56 (6H, s).
Step 3. tert-Butyl
[{1-(2-(2-benzyltetrazole)-2-methylpropyl)piperidin-4-yl}methyl]carbamate
[0483] To a stirred solution of
2-benzyl-.alpha.,.alpha.-dimethyl-2H-tetrazole-5-acetaldehyde (step
2 of Example 9) (1.28 g, 5.56 mmol) and tert-butyl
(piperidin-4-ylmethyl)carbamate (2.40 g, 11.2 mmol) in
tetrahyrdofuran (300 mL) were added NaBH(OAc).sub.3 (5.90 g, 27.8
mmol) and AcOH (1.67 g, 27.8 mmol). The resulting mixture was
stirred at 60.degree. C. for 9 h and concentrated under reduced
pressure. To the stirred residual oil and solid were added
saturated aqueous NaHCO.sub.3 and dichloromethane. The organic
layer was separated, dried over magnesium sulfate, and concentrated
under reduced pressure. The resulting residue was chromatographed
on a column of silica gel eluting with hexane/ethyl acetate (1:1)
to give 830 mg (35%) of the title compound as a colorless oil.
[0484] MS (ESI) m/z: 429 (M+H).sup.+.
[0485] .sup.1H NMR (CDCl.sub.3) .delta. 7.43-7.23 (5H, m), 5.72
(2H, s), 4.50 (1H, br t), 2.91 (2H, m), 2.58 (2H, br s), 2.49 (2H,
m), 2.05 (2H, m), 1.68-1.14 (3H, m), 1.44 (9H, s), 1.38 (6H, s),
1.00 (2H, m).
Step 4.
N-({1-(2-(2-benzyltetrazole)-2-methylpropyl)piperidin-4-yl}methyl)-
-3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide
[0486] The title compound was prepared according to the procedure
described in step 2 of Example 8 from
1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and tert-Butyl
[{1-(2-(2-benzyltetrazole)-2-methylpropyl)piperidin-4-yl}methyl]carbamate
(step 3 of Example 9).
[0487] MS (ESI) m/z: 531 (M+H.sup.+).
[0488] .sup.1H NMR (CDCl.sub.3) .delta. 8.86 (1H, br t, J=5.7 Hz),
8.26 (1H, m), 7.43-7.08 (8H, m), 5.72 (2H, s), 4.70 (1H, septet,
J=7.0 Hz), 3.21 (2H, m), 2.59 (2H, br s), 2.51 (2H, m), 2.07 (2H,
m), 1.65-1.32 (3H, m), 1.56 (6H, d, J=7.0 Hz), 1.38 (6H, s), 1.10
(2H, m).
[0489] Step 5.
N-({1-(2-methyl-2-tetrazolepropyl)piperidin-4-yl}methyl)-3-isopropyl-2-ox-
o-2,3-dihydro-1H-benzimidazole-1-carboxamide
[0490] The title compound was prepared according to the procedure
described in Step 3 of Example 8 from
N-({1-(2-(2-benzyltetrazole)-2-methylpropyl)piperidin-4-yl}methyl)-3-isop-
ropyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide (step 4 of
Example 9).
[0491] MS (ESI) m/z: 441 (M+H).sup.+.
[0492] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.77 (1H, br t, J=5.9
Hz), 8.04 (1H, m), 7.40 (1H, m), 7.18 (1H, m), 7.11 (1H, m), 4.63
(1H, septet, J=7.0 Hz), 3.15 (2H, m), 2.54 (2H, br s), 2.43 (2H,
m), 2.10 (2H, m), 1.60-1.25 (3H, m), 1.45 (6H, d, J=7.0 Hz), 1.32
(6H, s), 1.14 (2H, m). The signal which correspond to tetrazole was
not observed.
[0493] Anal. calcd. for
C.sub.22H.sub.32N.sub.8O.sub.4.0.95H.sub.2O: C, 57.74; H, 7.47; N,
24.48. Found: C, 58.03; H, 7.43; N, 24.10.
Example 10
N-({1-(2-cyclopentyl-2-tetrazoleethyl)piperidin-4-yl}methyl)-3-isopropyl-2-
-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide
[0494] ##STR36##
Step 1. .alpha.-cyclopentyltetrazole-5-acetic acid, ethyl ester
[0495] To a stirred solution of 1-cyano-1-cyclopentanecarboxylic
acid, ethyl ester (Bioorg. Med. Chem. Lett. 1999, 9, 369-374.)
(6.19 g, 37.0 mmol) in 1,4-dioxane (100 mL) was added
.sup.nBu.sub.3SnN.sub.3 (12.3 g, 37.0 mmol) at ambient temperature.
The resulting mixture was refluxed for 15 h and concentrated under
reduced pressure. To the resulting residue was added 4 M HCl in
1,4-dioxane (50 mL) and concentrated under reduced pressure. The
resulting oil was washed twice with hexane to give crude product of
the title compound as a yellow oil, which was used for the next
step without further purification.
Step 2. 2-benzyl-.alpha.-cyclopentyl-2H-tetrazole-5-acetic acid,
ethyl ester
[0496] The title compound was prepared according to the procedure
described in Step 1 of Example 9 from
.alpha.-cyclopentyltetrazole-5-acetic acid, ethyl ester (step 1 of
Example 10).
[0497] MS (ESI) m/z: 301 (M+H.sup.+).
[0498] .sup.1H NMR (CDCl.sub.3) .delta. 7.45-7.23 (5H, m), 5.73
(2H, s), 4.11 (2H, q, J=7.1 Hz), 2.55-2.35 (4H, m), 1.88-1.56 (4H,
m), 1.12 (3H, t, J=7.1 Hz).
Step 3.
2-benzyl-.alpha.-cyclopentyl-2H-tetrazole-5-acetaldehyde
[0499] The title compound was prepared according to the procedure
described in Step 2 of Example 9 from
2-benzyl-.alpha.-cyclopentyl-2H-tetrazole-5-acetic acid, ethyl
ester (step 2 of Example 10).
[0500] MS (ESI) m/z: 257 (M+H.sup.+).
[0501] .sup.1H NMR (CDCl.sub.3) .delta. 9.71 (1H, s), 7.50-7.30
(5H, m), 5.74 (2H, s), 2.45-2.18 (4H, m), 1.85-1.66 (4H, m).
Step 4. tert-Butyl
[{1-(2-(2-benzyltetrazole)-2-cyclopentylethyl)piperidin-4-yl}methyl]carba-
mate
[0502] The title compound was prepared according to the procedure
described in Step 3 of Example 9 from
2-benzyl-.alpha.-cyclopentyl-2H-tetrazole-5-acetaldehyde (step 3 of
Example 10).
[0503] MS (ESI) m/z: 455 (M+H).sup.+.
[0504] .sup.1H NMR (CDCl.sub.3) .delta. 7.43-7.23 (5H, m), 5.72
(2H, s), 4.67 (1H, br t), 2.88 (2H, m), 2.66 (2H, br s), 2.48 (2H,
m), 2.24 (2H, m), 1.93 (2H, m), 1.83 (2H, m), 1.78-1.48 (4H, m),
1.43 (9H, s), 1.37 (2H, m), 1.23 (1H, m), 0.94 (2H, m).
Step 5.
N-({1-(2-(2-benzyltetrazole)-2-cyclopentylethyl)piperidin-4-yl}met-
hyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide
[0505] The title compound was prepared according to the procedure
described in step 2 of Example 8 from
1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and tert-Butyl
[{1-(2-(2-benzyltetrazole)-2-cyclopentylethyl)piperidin-4-yl}methyl]carba-
mate (step 4 of Example 10).
[0506] MS (ESI) m/z: 557 (M+H.sup.+).
[0507] .sup.1H NMR (CDCl.sub.3) .delta. 8.85 (1H, br t, J=5.5 Hz),
8.26 (1H, m), 7.43-7.08 (8H, m), 5.73 (2H, s), 4.70 (1H, septet,
J=7.0 Hz), 3.19 (2H, m), 2.70 (2H, br s), 2.53 (2H, m), 2.25 (2H,
m), 2.15-1.35 (11H, m), 1.56 (6H, d, J=7.0 Hz), 1.07 (2H, m).
Step 6.
N-({1-(2-cyclopentyl-2-tetrazoleethyl)piperidin-4-yl}methyl)-3-iso-
propyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide
[0508] The title compound was prepared according to the procedure
described in Step 3 of Example 8 from
N-({1-(2-(2-benzyltetrazole)-2-cyclopentylethyl)piperidin-4-yl}methyl)-3--
isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide (step 5
of Example 10).
[0509] MS (ESI) m/z: 467 (M+H).sup.+.
[0510] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.76 (1H, br t, J=5.9
Hz), 8.04 (1H, m), 7.40 (1H, m), 7.18 (1H, m), 7.11 (1H, m), 4.64
(1H, septet, J=7.0 Hz), 3.14 (2H, m), 2.63 (2H, br s), 2.54 (2H,
m), 2.08 (2H, m), 2.00 (2H, m), 1.76 (2H, m), 1.68-0.96 (9H, m),
1.46 (6H, d, J=7.0 Hz). The signal which correspond to tetrazole
was not observed.
[0511] Anal. calcd. for
C.sub.24H.sub.34N.sub.8O.sub.4.1.0H.sub.2O.0.5 CH.sub.2Cl.sub.2: C,
55.83; H, 7.08; N, 21.26. Found: C, 55.71; H. 7.48; N, 20.86.
Example 11
N-({1-(2-cyclohexyl-2-tetrazoleethyl)piperidin-4-yl}methyl)-3-isopropyl-2--
oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide
[0512] ##STR37##
Step 1. .alpha.-cyclohexyltetrazole-5-acetic acid, ethyl ester
[0513] The title compound was prepared according to the procedure
described in Step 1 of Example 10 from
1-cyano-1-cyclohexanecarboxylic acid, ethyl ester (Bioorg. Med.
Chem. Lett. 1999, 9, 369-374.).
Step 2. 2-benzyl-.alpha.-cyclohexyl-2H-tetrazole-5-acetic acid,
ethyl ester
[0514] The title compound was prepared according to the procedure
described in Step 1 of Example 9 from
.alpha.-cyclohexyltetrazole-5-acetic acid, ethyl ester (step 1 of
Example 11).
[0515] MS (ESI) m/z: 315 (M+H.sup.+).
[0516] .sup.1H NMR (CDCl.sub.3) .delta. 7.45-7.23 (5H, m), 6.75
(2H, s), 4.11 (2H, q, J=7.1 Hz), 2.36-2.16 (4H, m), 1.70-1.44 (6H,
m), 1.12 (3H, t, J=7.1 Hz).
Step 3. 2-benzyl-.alpha.-cyclohexyl-2H-tetrazole-5-acetaldehyde
[0517] The title compound was prepared according to the procedure
described in Step 2 of Example 9 from
2-benzyl-.alpha.-cyclohexyl-2H-tetrazole-5-acetic acid, ethyl ester
(step 2 of Example 11).
[0518] MS (ESI) m/z: 271 (M+H.sup.+).
[0519] .sup.1H NMR (CDCl.sub.3) .delta. 9.55 (1H, s), 7.45-7.25
(5H, m), 5.75 (2H, s), 2.34-2.16 (2H, m), 2.14-1.94 (2H, m),
1.70-1.32 (6H, m).
Step 4. tert-Butyl
[{1-(2-(2-benzyltetrazole)-2-cyclohexylethyl)piperidin-4-yl}methyl]carbam-
ate
[0520] The title compound was prepared according to the procedure
described in Step 3 of Example 9 from
2-benzyl-.alpha.-cyclohexyl-2H-tetrazole-5-acetaldehyde (step 3 of
Example 11).
[0521] MS (ESI) m/z: 469 (M+H).sup.+.
[0522] .sup.1H NMR (CDCl.sub.3) .delta. 7.43-7.23 (5H, m), 5.74
(2H, s), 4.55 (1H, br t), 2.87 (2H, m), 2.62-1.05 (17H, m), 2.49
(2H, br s), 1.43 (9H, s), 0.93 (2H, m).
Step 5.
N-({1-(2-(2-benzyltetrazole)-2-cyclohexylethyl)piperidin-4-yl}meth-
yl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide
[0523] The title compound was prepared according to the procedure
described in step 2 of Example 8 from
1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and tert-Butyl
[{1-(2-(2-benzyltetrazole)-2-cyclohexylethyl)piperidin-4-yl}methyl]carbam-
ate (step 4 of Example 11).
[0524] MS (ESI) m/z: 571 (M+H.sup.+).
[0525] .sup.1H NMR (CDCl.sub.3) .delta. 8.86 (1H, br t, J=5.7 Hz),
8.26 (1H, m), 7.43-7.08 (8H, m), 5.73 (2H, s), 4.70 (1H, septet,
J=7.0 Hz), 3.18 (2H, m), 2.51 (2H, br s), 2.45-1.15 (17H, m), 1.56
(6H, d, J=7.0 Hz), 1.04 (2H, m).
Step 6.
N-({1-(2-cyclohexyl-2-tetrazoleethyl)piperidin-4-yl}methyl)-3-isop-
ropyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide
[0526] The title compound was prepared according to the procedure
described in Step 3 of Example 8 from
N-({1-(2-(2-benzyltetrazole)-2-cyclohexylethyl)piperidin-4-yl}methyl)-3-i-
sopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide (step 5
of Example 11).
[0527] MS (ESI) m/z: 481 (M+H).sup.+.
[0528] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.76 (1H, br t, J=5.9
Hz), 8.04 (1H, m), 7.41 (1H, m), 7.18 (1H, m), 7.12 (1H, m), 4.64
(1H, septet, J=7.0 Hz), 3.14 (2H, m), 2.38 (2H, br s), 2.33-2.10
(4H, m), 1.98 (2H, m), 1.65-0.96 (13H, m), 1.46 (6H, d, J=7.0 Hz).
The signal which correspond to tetrazole was not observed.
Example 12
1-[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amino-
}methyl)piperidin-1-yl]cyclohexanecarboxylic acid hydrochloride
[0529] ##STR38##
Step 1. tert-butyl
1-(4-oxopiperidin-1-yl)cyclohexanecarboxylate
[0530] The title compound was prepared by a method similar to that
shown in the Step 3 of Example 1 by using tert-butyl
1-aminocyclohexanecarboxylate (Kenner et al., J. Chem. Soc., 1965,
6239, 6243.).
[0531] MS (ESI) m/z: 282 (M+H.sup.+).
[0532] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.92 (4H, t, J=5.9 Hz),
2.41 (4H, t, J=6.0 Hz), 2.01-1.89 (2H, m), 1.76-1.62 (4H, m), 1.45
(9H, s), 1.53-1.33 (4H, m).
Step 2. tert-butyl
1-(4-cyanopiperidin-1-yl)cyclohexanecarboxylate
[0533] The title compound was prepared by a method similar to that
shown in the Step 4 of Example I by using tert-butyl
1-(4-oxopiperidin-1-yl)cyclohexanecarboxylate.
[0534] MS (ESI) m/z: 293 (M+H.sup.+).
[0535] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.94-2.85 (2H, m),
2.67-2.56 (1H, m), 2.55-2.42 (2H, m), 1.96-1.72 (6H, m), 1.70-1.23
(8H, m), 1.48 (9H, s).
Step 3. tert-butyl
1-[4-(aminomethyl)piperidin-1-yl]cyclohexanecarboxylate
[0536] The title compound was prepared by a method similar to that
shown in the Step 5 of Example 1 by using tert-butyl
1-(4-cyanopiperidin-1-yl)cyclohexanecarboxylate.
[0537] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.07-3.18 (2H, m), 2.55
(2H, d, J=6.4 Hz), 2.15-1.94 (4H, m), 1.47 (9H, s), 1.76-1.19 (13H,
m), 1.19-1.03 (2H, m).
[0538] MS (ESI) m/z: 297 (M+H.sup.+).
Step 4. tert-butyl
1-[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amin-
o}methyl)piperidin-1-yl]cyclohexanecarboxylate
[0539] The title compound was prepared by a method similar to that
shown in the Step 6 of Example I by using
1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and tert-butyl
1-(4-cyanopiperidin-1-yl)cyclohexanecarboxylate.
[0540] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.97-8.86 (1H, m),
8.29-8.24 (1H, m), 7.21-7.11 (3H, m), 4.78-4.64 (1H, m), 3.29 (2H,
t, J=6.2 Hz), 3.19-3.09 (2H, m), 2.16-2.05 (2H, m), 2.04-1.93 (2H,
m), 1.83-1.73 (2H, m), 1.56 (6H, d, J=7.0 Hz), 1.46 (9H, s),
1.70-1.39 (2H, m), 1.38-1.16 (7H, m).
[0541] MS (ESI) m/z: 499 (M+H.sup.+).
Step 5.
1-[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbon-
yl]amino}methyl)piperidin-1-yl]cyclohexanecarboxylic acid
hydrochloride
[0542] To a stirred solution of tert-butyl
1-[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amin-
o}methyl)piperidin-1-yl]cyclohexanecarboxylate (400 mg, 0.802 mmol)
in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL,
65.2 mmol) at room temperature. After 12 h, the volatile components
were removed under reduced pressure. To the residue was added 4N
HCl in dioxane (5.0 mL) was added and stirred for 10 min. Then, the
volatile was removed under reduced pressure.
[0543] The residue was precipitated in diethylether/ethanol to give
370 mg of the titled compound as a colorless powder.
[0544] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.94-8.82 (1H, m), 7.45
(1H, d, J=7.9 Hz), 7.27-7.10 (2H, m), 4.73-4.61 (1H, m), 3.71-3.19
(7H, m), 2.98-2.81 (2H, m), 2.38-2.26 (2H, m), 1.98-1.53 (10H, m),
1.49 (6H, d, J=7.0 Hz), 1.38-1.03 (2H, m),
[0545] MS (ESI) m/z: 443 (M+H.sup.+).
[0546] Anal. Calcd. for C.sub.24H.sub.35N.sub.4O.sub.4.2H2O: C,
55.97; H, 7.63; N, 10.88. Found: C, 55.61; H, 7.51; N, 10.48.
Example 13
2-ethyl-2-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbo-
nyl]amino}methyl)piperidin-1-yl]methyl}butanoic acid
[0547] ##STR39##
Step 1. Methyl
2-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]-2-ethylb-
utanoate
[0548] The title compound was prepared by a method similar to that
shown in the Step 1 of Example 7 by using methyl
2-ethyl-2-formylbutanoate (Okano, K.; Morimoto, T.; Sekiya, M.
Journal of the Chemical Society, Chemical Communications, 1985, 3,
119)
[0549] .sup.1H-NMR (CDCl.sub.3) .delta.: 4.62-4.48 (1H, br), 3.65
(3H, s), 3.01-2.93 (2H, m), 2.73-2.65 (2H, m), 2.46 (2H, s),
2.13-2.02 (2H, m), 1.73-1.50 (6H, m), 1.44 (9H, s), 1.28-1.10 (3H,
m), 0.76 (6H, t, J=7.5 Hz)
[0550] MS (ESI) m/z: 357 (M+H.sup.+).
Step 2. Methyl
2-ethyl-2-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carb-
onyl]amino}methyl)piperidin-1-yl]methyl}butanoate
[0551] The title compound was prepared according to the procedure
described in Step 2 of Example 8 from
1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and Methyl
2-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]-2-ethylb-
utanoate (step 1 of Example 13).
[0552] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.92-8.86 (1H, m),
8.28-8.23 (1H, m), 7.20-7.12 (3H, m), 4.77-4.61 (1H, m), 3.65 (3H,
s), 3.27 (2H, t, J=6.4 Hz), 2.75-2.66 (2H, m), 2.47 (2H, s),
2.16-2.05 (2H, m), 1.72-1.49 (10H, m), 1.38-1.21 (5H, m), 0.76 (6H,
d, J=7.5 Hz)
[0553] MS (ESI) m/z: 459 (M+H.sup.+).
Step 3.
2-ethyl-2-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1--
yl)carbonyl]amino}methyl)piperidin-1-yl]methyl}butanoic acid
[0554] The title compound was prepared according to the procedure
described in Step 5 of Example 3 from Methyl
2-ethyl-2-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carb-
onyl]amino}methyl)piperidin-1-yl]methyl}butanoate (step 3 of
Example 13).
[0555] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.03-8.94 (1H, m),
8.27-8.21 (1H, m), 7.20-7.12 (3H, m), 4.76-4.63 (1H, m), 3.34 (2H,
t, J=6.2 Hz), 3.16-3.05 (2H, m), 2.60 (2H, s), 2.55-2.38 (2H, m),
1.94-1.38 (2H, m), 1.80-1.38 (15H, m), 0.88 (6H, d, J=7.5 Hz)
[0556] MS (ESI) m/z: 445 (M+H.sup.+).
[0557] Anal. Calcd. for C24H37N4O4Cl.0.2H2O: C, 59.48; H, 7.78; N,
11.56. Found: C, 59.38; H, 7.74; N, 11.29.
Example 14
1-[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amino-
}methyl)piperidin-1-yl]cyclopentanecarboxylic acid
hydrochloride
[0558] ##STR40##
Step 1. tert-butyl
1-(4-oxopiperidin-1-yl)cyclopentanecarboxylate
[0559] The title compound was prepared by a method similar to that
shown in the Step 3 of Example 1 by using tert-butyl
1-aminocyclopentanecarboxylate (WO 9105796)
[0560] MS (ESI) m/z: 268 (M+H.sup.+).
[0561] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.93 (4H, t, J=5.9 Hz),
2.41 (4H, t, J=6.0 Hz), 2.39-2.26 (2H, m), 1.85-1.54 (8H, m), 1.46
(9H, s).
Step 2. tert-butyl
1-(4-cyanopiperidin-1-yl)cyclopentanecarboxylate
[0562] The title compound was prepared by a method similar to that
shown in the Step 4 of Example 1 by using tert-butyl
1-(4-oxopiperidin-1-yl)cyclopentanecarboxylate.
[0563] MS (ESI) m/z: 279 (M+H.sup.+).
[0564] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.94-2.82 (2H, m),
2.67-2.49 (3H, m), 2.33-2.21 (2H, m), 1.96-1.72 (5H, m), 1.70-1.40
(6H, m), 1.48 (9H, s).
Step 3. tert-butyl
1-[4-(aminomethyl)piperidin-1-yl]cyclopentanecarboxylate
[0565] The title compound was prepared by a method similar to that
shown in the Step 5 of Example 1 by using tert-butyl
1-(4-cyanopiperidin-1-yl)cyclopentanecarboxylate.
[0566] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.07-2.95 (2H, m),
2.60-2.52 (2H, m), 2.41-1.19 (4H, m), 1.76-1.62 (4H, m), 1.61-1.40
(12H, m), 1.19-1.03 (2H, m).
[0567] MS (ESI) m/z: 283 (M+H.sup.+).
Step 4. tert-butyl
1-[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amin-
o}methyl)piperidin-1-yl]cyclopentanecarboxylate
[0568] The title compound was prepared by a method similar to that
shown in the Step 6 of Example 1 by using
1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and tert-butyl
1-[4-(aminomethyl)piperidin-1-yl]cyclopentanecarboxylate.
[0569] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.96-8.84 (1H, m),
8.29-8.22 (1H, m), 7.21-7.11 (3H, m), 4.77-4.56 (1H, m), 3.29 (2H,
t, J=6.2 Hz), 3.07-2.94 (2H, m), 2.37-2.17 (4H, m), 1.82-1.63 (6H,
m), 1.56 (6H, d, J=7.1 Hz), 1.46 (9H, s), 1.61-1.49 (2H, m),
1.38-1.16 (3H, m).
[0570] MS (ESI) m/z: 485 (M+H.sup.+).
Step 5.
1-[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbon-
yl]amino}methyl)piperidin-1-yl]cyclopentanecarboxylic acid
hydrochloride
[0571] The title compound was prepared by a method similar to that
shown in the Step 5 of Example 12 by using tert-butyl
1-[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amin-
o}methyl)piperidin-1-yl]cyclopentanecarboxylate.
[0572] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.91-8.82 (1H, m), 8.07
(1H, d, J=7.5 Hz), 7.45 (1H, d, J=7.7 Hz), 7.26-7.09 (2H, m),
4.74-4.56 (1H, m), 3.60-3.00 (6H, m), 2.26-2.10 (4H, m), 1.96-1.57
(9H, m), 1.49 (6H, d, J=7.0 Hz).
[0573] MS (ESI) m/z: 429 (M+H.sup.+).
[0574] Anal. Calcd. for C23H33N4O4Cl: C, 59.41; H, 7.15; N, 12.05.
Found: C, 59.14; H, 7.22; N, 11.82.
Example 15
N-({1-[(4-Oxycarbonyltetrahydro-2H-pyran-4-yl)methyl]-4-fluoropiperidin-4--
yl}methyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide
[0575] ##STR41##
Step 1. Benzyl tetrahydropyran-4-yl-carboxylate
[0576] A mixture of tetrahydropyran-4-yl-carboxylic acid (910 mg,
6.99 mmol) and SOCl.sub.2 (5.0 mL) was stirred for 1 h at
60.degree. C. and concentrated in vacuo. To the residue were added
benzyl alcohol (1.52 g, 14.1 mmol) and tetrahydrofuran (5.0 mL) at
ambient temperature. The resulting mixture was stirred for 13 h at
ambient temperature and concentrated in vacuo. The residue was
purified by preparative thin layer chromatography (silica gel,
eluting with hexane/ethyl acetate (2:1)) to give 1.08 g (70%) of
the title compound as a pale yellow oil.
[0577] .sup.1H NMR (CDCl.sub.3) .delta. 7.45-7.25 (5H, m), 5.13
(2H, s), 3.95 (2H, m), 3.42 (2H, m), 2.59 (1H, m), 1.94-1.68 (4H,
m).
Step 2. Benzyl 4-iodomethyltetrahydropyran-4-yl-carboxylate
[0578] The title compound was prepared according to the procedure
described in step 1 of Example 3 from benzyl
tetrahydropyran-4-yl-carboxylate (step 1 of Example 15).
[0579] .sup.1H NMR (CDCl.sub.3) .delta. 7.45-7.25 (5H, m), 5.19
(2H, s), 3.80 (2H, m), 3.47 (2H, m), 3.31 (2H, s), 2.18 (2H, m),
1.56 (2H, m).
Step 3.
N-benzoyl-4-tert-butoxycarbonylaminomethyl-4-fluoropiperidine
[0580] A mixture of N-benzoyl-4-aminomethyl-4-fluoropiperidine (J.
Med. Chem. 1999, 42, 1648-1660.) (3.54 g, 15.0 mmol) and
di-tert-butyl dicarbonate (4.91 g, 22.5 mmol) in methanol (80 mL)
was stirred at room temperature for 15 h and concentrated in vacuo.
The resulting residue was chromatographed on a column of silica gel
eluting with hexane/ethyl acetate (1:1) to give 4.52 g (89%) of the
title compound as a colorless oil.
[0581] MS (ESI) m/z: 337 (M+H).sup.+.
[0582] .sup.1H NMR (CDCl.sub.3) .delta. 7.55-7.25 (5H, m), 5.16
(1H, br t, J=63 Hz), 4.51 (1H, m), 3.62 (1H, m), 3.55-3.00 (4H, m),
2.10-1.25 (4H, m), 1.43 (9H, s).
Step 4. 4-tert-Butoxycarbonylaminomethyl-4-fluoropiperidine
[0583] A mixture of
N-benzoyl-4-tert-butoxycarbonylaminomethyl-4-fluoropiperidine (step
3 of Example 15) (4.42 g, 13.1 mmol), NaOH (2.62 g, 65.5 mmol),
H.sub.2O (9.00 mL) and ethanol (90.0 mL) was refluxed for 15 h and
concentrated in vacuo. To the resulting residue were added water
and chloroform. The organic layer was separated, dried over
magnesium sulfate, and concentrated under reduced pressure.
Recrystallization of the resulting solid with
hexane-CH.sub.2Cl.sub.2 afforded a colorless solid 1.77 g (58%) as
the titled compound.
[0584] MS (ESI) m/z: 233 (M+H).sup.+.
[0585] .sup.1H NMR (CDCl.sub.3) .delta. 4.93 (1H, m), 3.30 (2H, dd,
J=21.5, 6.3 Hz), 2.91 (4H, m), 1.88-1.34 (4H, m), 1.45 (9H, s), The
signal which correspond to amino group was not observed.
Step 5. tert-Butyl
({1-[(4-benzyloxycarbonyltetrahydro-2H-pyran-4-yl)methyl]-4-fluoropiperid-
in-4-yl}methyl)carbamate
[0586] The title compound was prepared according to the procedure
described in step 2 of Example 3 from
4-tert-butoxycarbonylaminomethyl-4-fluoropiperidine (step 4 of
Example 15) and benzyl 4-iodomethyltetrahydropyran-4-yl-carboxylate
(step 2 of Example 15).
[0587] MS (ESI) m/z: 465 (M+H).sup.+.
[0588] .sup.1H NMR (CDCl.sub.3) .delta. 7.45-7.25 (5H, m), 5.16
(2H, s), 4.78 (1H, br t), 3.80 (2H, m), 3.46 (2H, m), 3.23 (2H, dd,
J=21.9, 6.3 Hz), 2.64-2.32 (4H, m), 2.52 (2H, s), 2.08 (2H, m),
1.90-1.35 (6H, m), 1.45 (9H, s).
Step 6.
N-({1-[(4-Benzyloxycarbonyltetrahydro-2H-pyran-4-yl)methyl]-4-fluo-
ropiperidin-4-yl}methyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-1--
carboxamide
[0589] The title compound was prepared according to the procedure
described in step 6 of Example 1 from
1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and tert-Butyl
({1-[(4-benzyloxycarbonyltetrahydro-2H-pyran-4-yl)methyl]-4-fluoropiperid-
in-4-yl}methyl)carbamate (step 5 of Example 15).
[0590] MS (ESI) m/z: 567 (M+H.sup.+).
[0591] .sup.1H NMR (CDCl.sub.3) .delta. 9.08 (1H, br t, J=6.0 Hz),
8.25 (1H, m), 7.46-7.06 (8H, m), 5.16 (2H, s), 4.71 (1H, septet,
J=7.0 Hz), 3.80 (2H, m), 3.54 (2H, dd, J=20.9, 6.0 Hz), 3.46 (2H,
m), 2.65-2.36 (4H, m), 2.53 (2H, br s), 2.08 (2H, m), 1.88-1.44
(6H, m), 1.56 (6H, d, J=7.0 Hz).
Step 7.
N-({1-[(4-Oxycarbonyltetrahydro-2H-pyran-4-yl)methyl]-4-fluoropipe-
ridin-4-yl}methyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carbox-
amide
[0592] The title compound was prepared according to the procedure
described in Step 3 of Example 1 from
N-({1-[(4-benzyloxycarbonyltetrahydro-2H-pyran-4-yl)methyl]-4-fluoropiper-
idin-4-yl}methyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxa-
mide (step 6 of Example 15).
[0593] MS (ESI) m/z: 477 (M+H).sup.+.
[0594] .sup.1H NMR (CD.sub.3OD) .delta. 7.93 (1H, m), 7.12 (1H, m),
7.02 (1H, m), 6.93 (1H, m), 4.49 (1H, septet, J=7.0 Hz), 3.65-3.36
(6H, m), 3.15-2.82 (4H, m), 2.80 (2H, br s), 1.98-1.70 (6H, m),
1.35 (6H, d, J=7.0 Hz), 1.34 (2H, m). The signals which correspond
to amide and carboxylic acid were not observed.
[0595] All publications, including but not limited to, issued
patents, patent applications, and journal articles, cited in this
application are each herein incorporated by reference in their
entirety.
[0596] Although the invention has been described above with
reference to the disclosed embodiments, those skilled in the art
will readily appreciate that the specific experiments detailed are
only illustrative of the invention. It should be understood that
various modifications can be made without departing from the spirit
of the invention. Accordingly, the invention is limited only by the
following claims.
* * * * *