U.S. patent application number 11/974130 was filed with the patent office on 2008-05-01 for n-dihydroxyalkyl-substituted 2-oxo-imidazole derivatives.
Invention is credited to Masaya Hashimoto, Yoshikazu Iwasawa, Hiroshi Kawamoto, Hisashi Ohta, Satoshi Ozaki, Takeshi Sagara, Hiroki Sakoh, Atsushi Satoh.
Application Number | 20080103178 11/974130 |
Document ID | / |
Family ID | 37662398 |
Filed Date | 2008-05-01 |
United States Patent
Application |
20080103178 |
Kind Code |
A1 |
Hashimoto; Masaya ; et
al. |
May 1, 2008 |
N-dihydroxyalkyl-substituted 2-oxo-imidazole derivatives
Abstract
The invention provides the compounds represented by the formula
(I) ##STR1## in which, R stands for a dihydroxy-substituted
C.sub.1-C.sub.6 alkyl group, and Cy stands for an optionally
substituted C.sub.6-C.sub.10 bi- or tri-cyclic aliphatic
carbocyclic group. These compounds act as nociceptin receptor
antagonist, and are useful, for example, as relievers against
tolerance to narcotic analgesic, dependence on narcotic analgesic
or addiction; analgesic enhancers; antiobestic or appetite
suppressors; treating or prophylactic agents for cognitive
impairment and dementia/amnesia; agents for treating developmental
cognitive abnormality; remedy for schizophrenia; agents for
treating neurodegenerative diseases; anti-depressant or treating
agents for affective disorder; treating or prophylactic agents for
diabetes insipidus; treating or prophylactic agents for polyuria;
and remedy for hypotension and the like.
Inventors: |
Hashimoto; Masaya;
(Tsukuba-shi, JP) ; Iwasawa; Yoshikazu;
(Tsukuba-shi, JP) ; Kawamoto; Hiroshi;
(Tsuchiura-shi, JP) ; Ohta; Hisashi; (Tsukuba-shi,
JP) ; Ozaki; Satoshi; (Tsukuba-shi, JP) ;
Sagara; Takeshi; (Tsukuba-shi, JP) ; Sakoh;
Hiroki; (Tsukuba-shi, JP) ; Satoh; Atsushi;
(Tsukuba-shi, JP) |
Correspondence
Address: |
MERCK AND CO., INC
P O BOX 2000
RAHWAY
NJ
07065-0907
US
|
Family ID: |
37662398 |
Appl. No.: |
11/974130 |
Filed: |
October 11, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11484203 |
Jul 11, 2006 |
7300947 |
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11974130 |
Oct 11, 2007 |
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60700770 |
Jul 20, 2005 |
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Current U.S.
Class: |
514/323 |
Current CPC
Class: |
C07D 403/04 20130101;
A61P 25/00 20180101 |
Class at
Publication: |
514/323 |
International
Class: |
A61K 31/454 20060101
A61K031/454; A61P 25/00 20060101 A61P025/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 13, 2005 |
JP |
JP2005-204264 |
Claims
1-15. (canceled)
16. A method for treating a disease or disorder involving the
nociceptin receptor ORL1 (Opioid receptor-like-1 receptor) by
inhibiting the binding of nociceptin to the nociceptin receptor
ORL1 in a human patient in need thereof which comprises
administering to the patient a compound of the formula (I):
##STR8## wherein: R is a di-hydroxy-substituted C.sub.3-C.sub.4
alkyl group, and Cy is selected from the group consisting of:
spiro[4.5]dec-6-yl; spiro[2.5]oct-4-yl; spiro[3.5]non-5-yl;
bicyclo[2.2.1]hept-2-yl; and
1-spiro(bicyclo[2.2.1]heptane-2,1'-cyclopropan)-3-yl, which is
unsubstituted or substituted with a substituent selected from:
halogen and C.sub.1-C.sub.6 alkyl; or a pharmaceutically acceptable
salt thereof.
17. The method of claim 16 wherein the compound of formula (I): R
is selected from the group consisting of:
2-hydroxy-1-(hydroxymethyl)ethyl; 2,3-dihydroxypropyl;
2,3-dihydroxy-2-methylpropyl; 2,3-dihydroxybutyl;
2,4-dihydroxybutyl; 3,4-dihydroxybutyl;
2,3-dihydroxy-1-methylpropyl; 2-hydroxy-1-(hydroxymethyl)propyl;
3-hydroxy-1-(hydroxymethyl)propyl; and
3-hydroxy-2-(hydroxymethyl)propyl.
18. The method of claim 16 wherein the compound of formula (I): R
is selected from the group consisting of: 2,3-dihydroxypropyl;
2-hydroxy-1-(hydroxymethyl)ethyl; and
2,3-dihydroxy-2-methylpropyl.
19. The method of claim 16 wherein the compound of formula (I): Cy
is selected from the group consisting of: spiro[4.5]dec-6-yl;
spiro[2.5]oct-4-yl; spiro[3.5]non-5-yl;
3,3-dimethylbicyclo[2.2.1]hept-2-yl; and
1-spiro(bicyclo[2.2.1]-heptane-2,1'-cyclopropan)-3-yl.
20. The method of claim 16 wherein the compound of formula (I): Cy
is unsubstituted.
21. The method of claim 16 wherein the compound of formula (I): Cy
is substituted with a C.sub.1-C.sub.4 alkyl group.
22. The method of claim 16 wherein the compound is selected from
the group consisting of:
1-(2,3-dihydroxypropyl)-3-[1-(spiro[4.5]dec-6-ylmethyl)-piperidin-4-yl]-1-
,3-dihydro-2H-benzimidazol-2-one;
1-(2,3-dihydroxypropyl)-3-[1-(spiro[2.5]oct-4-ylmethyl)-piperidin-4-yl]-1-
,3-dihydro-2H-benzimidazol-2-one;
1-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-[1-(spiro[bicyclo-[2.2.1]heptane-2-
,1'-cyclopropan]-3-ylmethyl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2--
one;
1-(2,3-dihydroxy-2-methylpropyl)-3-[1-(spiro[2.5]oct-4-ylmethyl)pipe-
ridin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one; and
1-(2,3-dihydroxypropyl)-3-[1(spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropan-
]3-ylmethyl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, or a
pharmaceutically acceptable salt thereof.
23. The method of claim 16 wherein the compound is
1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(spiro[4.5]dec-6-ylmethyl)piperidin-4--
yl}-1,3-dihydro-2H-benzimidazol-2-one, or a pharmaceutically
acceptable salt thereof.
24. The method of claim 16 wherein the compound is
1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(4S)-spiro[2.5]oct-4-ylmethyl]piperidi-
n-4-yl}-1,3-dihydro-2H-benzimidazol-2-one, or a pharmaceutically
acceptable salt thereof.
25. The method of claim 16 wherein the compound is
1-[2-hydroxy-1-(hydroxymethyl)-ethyl]-3-{1-[(1R,3S,4S)-spiro[bicyclo[2.2.-
1]heptane-2,1'-cyclopropan-3-ylmethyl]-piperidin-4-yl}-1,3-dihydro-2H-benz-
imidazol-2-one, or a pharmaceutically acceptable salt thereof.
26. The method of claim 16 wherein the compound is
1-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-{1-[(1R,3S,4S)-spiro[bicyclo[2.2.1-
]heptane-2,1'-cyclopropan-3-ylmethyl]-piperidin-4-yl}-1,3-dihydro-2H-benzi-
midazol-2-one hydrochloride.
27. The method of claim 16 wherein the compound is
1-[2,3-dihydroxy-2-methylpropyl]-3-{1-[(4S)-spiro[2.5]oct-4-ylmethyl]pipe-
ridin-4-yl}-1,3-dihydro-2H-benzimidzol-2-one, or a pharmaceutically
acceptable salt thereof.
28. The method of claim 16 wherein the compound is
1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(1R,3S,4S)-spiro[bicyclo-[2.2.1]heptan-
e-2,1'-cyclopropan]-3-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-
-2-one, or a pharmaceutically acceptable salt thereof.
29. The method of claim 16 wherein the compound is
1-[(2R)-2,3-dihydroxy-propyl]-3-{1-[(1R,3S,4S)-spiro[bicyclo-[2.2.1]hepta-
ne-2,1'-cyclopropan]-3-ylmethyl]-piperidin-4-yl}-1,3-dihydro-2H-benzimidaz-
ol-2-one hydrochloride.
30. The method of claim 16 wherein the disease or disorder is
selected from the group consisting of: pain, cancerous pain,
postoperative pain, migraine, gout, chronic rheumatism, chronic
pain, neuralgia, addiction, tolerance to narcotic analgesics,
dependence on narcotic analgesics, analgesic enhancement, obesity,
suppressing appetite, cognitive impairment, dementia in aging,
amnesia in aging, cerebrovascular disease, Alzheimer's disease,
attention deficit hyperactivity disorder, learning disability,
schizophrenia, neurodegenerative disease, Parkinson's disease,
chorea, depression, affective disorder, diabetes insipidus,
polyuria, and hypotension.
Description
TECHNICAL FIELD
[0001] This invention relates to substances which exhibit an
antagonism to binding of nociceptin to nociceptin receptor ORL1
(Opioid receptor-like-1 receptor).
[0002] Compounds which inhibit binding of nociceptin to nociceptin
receptor ORL1 are useful as analgesic against diseases accompanied
with pain such as cancerous pain, postoperative pain, migraine,
gout, chronic rheumatism, chronic pain and neuralgia; relievers
against tolerance to narcotic analgesic represented by morphine;
relievers against dependence on narcotic analgesic represented by
morphine or against addiction; analgesic enhancers; antiobestic or
appetite suppressors; treating or prophylactic agents for cognitive
impairment and dementia/amnesia in aging, cerebrovascular diseases
and Alzheimer's disease; agents for treating developmental
cognitive abnormality in attention deficit, hyperactivity disorder
and learning disability; remedy for schizophrenia; agents for
treating neurodegenerative diseases represented by Parkinsonism and
chorea; anti-depressant or treating agents for affective disorder;
treating or prophylactic agents for diabetes insipidus; treating or
prophylactic agents for polyuria; and remedy for hypotension and
the like.
BACKGROUND ART
[0003] Nociceptin (the same substance as orphanin FQ) is a peptide
consisting of 17 amino acid units having a similar structure to
that of opioid peptide. Nociceptin has an activity on reactivity
against nociceptive stimulation, appetite stimulating activity,
activity for reducing space learning ability, antagonism against
analgesic action of classic opiate agonists, dopamine release
inhibitory action, water diuresis action, vasodilative action and
systemic blood pressure-lowering action, and it is considered to
take part in intracerebral controlling of pain, appetite and memory
learning through a nociceptin receptor ORL1 [cf. Nature, 377, 532
(1995); Society for Neuroscience, 22, 455 (1996); NeuroReport, 8,
423 (1997); Eur. J. Neuroscience, 9, 194 (1997); Neuroscience, 75,
1 (1996); ibid., 333 (1996); Life Sciences, 60 PL15 (1997); ibid.,
PL141 (1997); Proceedings for National Academy of Sciences, 94,
14858 (1997)].
[0004] Further, it is known that morphine tolerance is reduced or
memory and learning ability are improved in knockout mice in which
expression of nociceptin receptor ORL1 is inhibited [cf.
Neuroscience Letters, 237, 136 (1997); Nature, 394, 577
(1998)].
[0005] It has also been reported that nociceptin itself induces
symptoms resembling withdrawal symptoms observed with morphine
addicts, and that non-peptide nociceptin receptor antagonist
improves morphine tolerance, dependence and symptoms resembling
withdrawal symptoms [cf. Psychopharmacology, 151, 344-350 (2000);
Journal of Neuroscience, 20, 7640 (2000)].
[0006] On the other hand, nociceptin protein precursor-defective
mice are reported to show behaviors resembling anxiety and changes
in stress response [cf. Proceedings for National Academy of
Sciences, 96, 10444 (1999)].
[0007] Hence the substances which specifically inhibit binding of
nociceptin to nociceptin receptor ORL1 are useful as analgesic
against diseases accompanied with pain such as cancerous pain,
postoperative pain, migraine, gout, chronic rheumatism, chronic
pain and neuralgia; relievers against tolerance to narcotic
analgesic represented by morphine; relievers against dependence on
narcotic analgesic represented by morphine or against addiction;
analgesic enhancers; antiobestic or appetite suppressors; treating
or prophylactic agents for cognitive impairment and
dementia/amnesia in aging, cerebrovascular diseases and Alzheimer's
disease; agents for treating developmental cognitive abnormality in
attention deficit, hyperactivity disorder and learning disability;
remedy for schizophrenia; agents for treating neurodegenerative
diseases represented by Parkinsonism and chorea; anti-depressant or
treating agents for affective disorder; treating or prophylactic
agents for diabetes insipidus; treating or prophylactic agents for
polyuria; and remedy for hypotension and the like.
[0008] International Publication WO98/54168 or J. Med. Chem.
5061-5063 (1999) disclose compounds having antagonism to binding of
nociceptin to nociceptin receptor ORL1. In particular, the compound
of the following formula (A) ##STR2## (hereinafter referred to as
"Compound A") is disclosed as having excellent selective antagonism
to binding of nociceptin to nociceptin receptor. Patent literature
1: International Publication WO98/54168. Non-patent literature 1:
J. Med. Chem., 1999, 5061-5063
DISCLOSURE OF THE INVENTION
[0009] We have investigated on compounds of analogous structures to
that of Compound A in search for compounds which exhibit
antagonistic activity to binding of nociceptin to nociceptin
receptor ORL1, to discover that those compounds having bi- or
tri-cyclic aliphatic carbocyclic group of specific carbon numbers
in place of the cyclooctyl group and also having dihydroxyalkyl
substituent group on the nitrogen atom possess well balanced
activities of not only selectively inhibiting binding of nociceptin
to nociceptin receptor but also exhibiting excellent in vivo
metabolic properties, and can be the compounds particularly
suitable for application to human being. The present invention is
completed based on that discovery.
[0010] Thus, the present invention provides (1) 2-oxoimidazole
derivatives represented by the formula (I) ##STR3##
[0011] in which R stands for a dihydroxy-substituted
C.sub.1-C.sub.6 alkyl group, and Cy stands for an optionally
substituted C.sub.6-C.sub.10 bi- or tri-cyclic aliphatic
carbocyclic group or their pharmaceutically acceptable salts.
[0012] The invention furthermore provides
(2) pharmaceutical preparations comprising pharmaceutically
acceptable adjuvants and an effective amount of a compound as
described in (1) above or a pharmaceutically acceptable salt
thereof; and
[0013] (3) analgesic; relievers against tolerance to narcotic
analgesic represented by morphine; relievers against dependence on
narcotic analgesic represented by morphine or against addiction;
analgesic enhancers; antiobestic or appetite suppressors; treating
or prophylactic agents for cognitive impairment and
dementia/amnesia in aging, cerebrovascular diseases and Alzheimer's
disease; agents for treating developmental cognitive abnormality in
attention deficit, hyperactivity disorder and learning disability;
remedy for schizophrenia; agents for treating neurodegenerative
diseases represented by Parkinsonism and chorea; anti-depressant or
treating agents for affective disorder; treating or prophylactic
agents for diabetes insipidus; treating or prophylactic agents for
polyuria; and remedy for hypotension; which comprise a compound as
described in (1) above or a pharmaceutically acceptable salt
thereof as the active ingredient.
[0014] Hereinafter the invention is explained in details, referring
to specific examples.
[0015] In the formula (I), R stands for a C.sub.1-C.sub.6 alkyl
group having two hydroxyl groups, specific examples including
2-hydroxy-1-(hydroxymethyl)ethyl, 2,3-dihydroxypropyl,
2,3-dihydroxy-2-methylpropyl, 2,3-dihydroxybutyl,
2,4-dihydroxybutyl, 3,4-dihydroxybutyl,
2,3-dihydroxy-1-methylpropyl, 2-hydroxy-1-(hydroxymethyl)propyl,
3-hydroxy-1-(hydroxymethyl)propyl,
3-hydroxy-2-(hydroxymethyl)propyl, 2,3-dihydroxypentyl,
2,4-dihydroxypentyl, 2,5-dihydroxypentyl, 3,4-dihydroxypentyl,
3,5-dihydroxypentyl, 4,5-dihydroxypentyl,
2,3-dihydroxy-1-methylbutyl, 2,4-dihydroxy-1-methylbutyl,
3,4-dihydroxy-1-methylbutyl, 2-hydroxy-1-(hydroxymethyl)butyl,
3-hydroxy-1-(hydroxymethyl)butyl, 4-hydroxy-1-(hydroxymethyl)butyl,
2,3-dihydroxy-2-methylbutyl, 2,4-dihydroxy-2-methylbutyl,
3,4-dihydroxy-2-methylbutyl, 2-hydroxy-2-(hydroxymethyl)butyl,
3-hydroxy-2-(hydroxymethyl)butyl, 4-hydroxy-2-(hydroxymethyl)butyl,
2,3-dihydroxy-3-methylbutyl, 2,4-dihydroxy-3-methylbutyl,
3,4-dihydroxy-3-methylbutyl, 4-hydroxy-3-(hydroxymethyl)butyl,
2,3-dihydroxy-1,1-dimethylpropyl,
2-hydroxy-1-(hydroxymethyl)-1-methylpropyl,
3-hydroxy-1-(hydroxymethyl)-1-methylpropyl,
1,1-bis(hydroxymethyl)propyl, 2,3-dihydroxy-1,2-dimethylpropyl,
2-hydroxy-1-(hydroxymethyl)-2-methylpropyl,
3-hydroxy-2-(hydroxymethyl)-2-methylpropyl,
2,3-dihydroxy-1-ethylpropyl, 2-hydroxy-1-(2-hydroxyethyl)propyl,
2-hydroxy-1-(1-hydroxyethyl)propyl,
3-hydroxy-1-(2-hydroxyethyl)propyl, 2,3-dihydroxyhexyl,
2,4-dihydroxyhexyl, 2,5-dihydroxyhexyl, 2,6-dihydroxyhexyl,
3,4-dihydroxyhexyl, 3,5-dihydroxyhexyl, 3,6-dihydroxyhexyl,
4,5-dihydroxyhexyl and 4,6-dihydroxyhexyl. Preferred examples are
C.sub.3-C.sub.4 alkyl groups having two hydroxyl group and, in
particular, 2,3-dihydroxypropyl, 2-hydroxy-1-(hydroxymethyl)ethyl
and 2,3-dihydroxy-2-methylpropyl groups are recommended.
[0016] Cy stands for an optionally substituted C.sub.6-C.sub.10 bi-
or tri-cyclic aliphatic carbocyclic group.
[0017] As the "substituent" in "optionally substituted
C.sub.6-C.sub.10 bi- or tri-cyclic aliphatic carbocyclic group",
for example, halogen such as fluorine, chlorine and the like and
C.sub.1-C.sub.6 alkyl groups such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, n-penty and the like can be named. Preferably,
C.sub.1-C.sub.4 alkyl groups are recommended.
[0018] "C.sub.6-C.sub.10 bi- or tri-cyclic aliphatic carbocyclic
groups" signify saturated aliphatic carbocyclic groups which are
bi- or tri-cyclic groups. For example, spiro[2.5]oct-4-yl,
spiro[2.5]oct-5-yl, spiro[2.5]oct-6-yl, spiro[3.5]non-5-yl,
spiro[3.5]non-6-yl, spiro[3.5]non-7-yl, spiro[4.5]dec-6-yl,
spiro[4.5]dec-7-yl, spiro[4.5]dec-8-yl, bicyclo[2.2.1]hept-2-yl,
bicyclo[2.2.2]oct-2-yl,
1-spiro(bicyclo[2.2.1]heptane-2,1'-cyclopropan)-3-yl,
1-spiro(bicyclo[2.2.1]heptane-2,1'-cyclopropan)-5-yl,
1-spiro(bicyclo[2.2.1]-heptane-2,1'-cyclopropan)-6-yl and the like
are named.
[0019] As specific examples of Cy, spiro[2.5]oct-4-yl,
spiro[2.5]oct-5-yl, spiro-[2.5]oct-6-yl, spiro[3.5]non-5-yl,
spiro[3.5]non-6-yl, spiro[3.5]non-7-yl, spiro[4.5]dec-6-yl,
spiro[4.5]dec-7-yl, spiro[4.5]dec-8-yl, bicyclo[2.2.1]hept-2-yl,
3,3-dimethylbicyclo[2.2.1]hept-2-yl,
3,3-dimethylbicyclo[2.2.1]hept-5-yl,
3,3-dimethylbicyclo[2.2.1]hept-6-yl, bicyclo[2.2.2]oct-2-yl,
1-spiro(bicyclo[2.2.1]heptane-2,1'-cyclopropan)-3-yl,
1-spiro(bicyclo[2.2.1]-heptane-2,1'-cyclopropan)-5-yl,
1-spiro(bicyclo[2.2.1]heptane-2,1'-cyclopropan)-6-yl and the like
can be named. Preferably, spiro[4.5]dec-6-yl, spiro[2.5]oct-4-yl,
spiro[3.5]non-5-yl, 3,3-dimethylbicyclo[2.2.1]hept-2-yl,
1-spiro(bicyclo[2.2.1]heptane-2,1'-cyclopropan)-3-yl and the like
are recommended.
[0020] According to the invention, by the adoption of those
2-oxoimidazole derivatives having on its 1-position nitrogen atom a
dihydroxyalkyl group and furthermore having as Cy an optionally
substituted C.sub.6-C.sub.10 bi- or tri-cyclic aliphatic
carbocyclic group, compounds having very well balanced
physiological activity of excellent antagonism to nociceptin
receptor and also excellent metabolic stability can be
provided.
[0021] As specific examples of the compounds represented by the
formula (I), the following can be named: [0022] 1)
1-(2,3-dihydroxypropyl)-3-[1-spiro[4.5]-dec-6-ylmethyl]-piperidin-4-yl]-1-
,3-dihydro-2H-benzimidazol-2-one, [0023] 2)
1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(6S)-spiro[4.5]dec-6-ylmethyl]piperidi-
n-4-yl}-1,3-dihydro-2H-benzimidazol-2-one, [0024] 3)
1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(6R)-spiro[4.5]dec-6-ylmethyl]piperidi-
n-4-yl}-1,3-dihydro-2H-benzimidazol-2-one, [0025] 4)
1-[(2S)-2,3-dihydroxypropyl]-3-{1-[(6S)spiro[4.5]dec-6-ylmethyl]piperidin-
-4-yl}-1,3-dihydro-2H-benzimidazol-2-one, [0026] 5)
1-[(2S)-2,3-dihydroxypropyl]-3-{1-[(6R)-spiro[4.5]dec-6-ylmethyl]piperidi-
n-4-yl}-1,3-dihydro-2H-benzimidazol-2-one, [0027] 6)
1-(2,3-dihydroxypropyl)-3-[1-(spiro-[3.5]non-5-ylmethyl)-piperidin-4-yl]--
1,3-dihydro-2H-benzimidazol-2-one, [0028] 7)
1-[(2R-2,3-dihydroxypropyl]-3-{1-[(5S)spiro[3.5]non-5-ylmethyl]piperidin--
4-yl}-1,3-dihydro-2H-benzmidazol-2-one, [0029] 8)
1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(5R)-spiro[3.5]non-5-ylmethyl]piperidi-
n-4-yl}-1,3-dihydro-2H-benzimidazol-2-one, [0030] 9)
1-[(2S)-2,3-dihydroxypropyl]-3-{1-[(5S)spiro[3.5]non-5-ylmethyl]piperidin-
-4-yl}-1,3-dihydro-2H-benzimidazol-2-one, [0031] 10)
1-[(2S)-2,3-dihydroxypropyl]-3-{1-[(5R)-spiro[3.5]non-5-ylmethyl]piperidi-
n-4-yl}-1,3-dihydro-2H-benzimidazol-2-one, [0032] 11)
1-(2,3-dihydroxypropyl)-3-{1-[(3,3-dimethylbicyclo[2.2.1]-hept-2-yl)methy-
l]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one,
[0033] 12)
1-[(2R)-2,3-dihydroxypropyl]-3-(1-{[(1S,2S,4R)-3,3-dimethylbicyclo[2.2.1]-
hept-2-yl]methyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,
[0034] 13)
1-[(2R)-2,3-dihydroxypropyl]-3-(1-{[(1S,2R,4R>3,3-dimethylbicyclo[2.2.-
1]hept-2-yl]methyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,
[0035] 14)
1-[(2R)-2,3-dihydroxypropyl]-3-(1-{[(1R,2R,4S)-3,3-dimethylbicyclo[2.2.1]-
hept-2-yl]methyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,
[0036] 15)
1-[(2R)-2,3-dihydroxypropyl]-3-(1-{[(1R,2S,4S)-3,3-dimethylbicyclo[2.2.1]-
hept-2-yl]methyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,
[0037] 16)
1-[(2S)-2,3-dihydroxypropyl]-3-(1-{[(1S,2S,4R)-3,3-dimethylbicyclo[2.2.1]-
hept-2-yl]methyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,
[0038] 17)
1-[(2S)-2,3-dihydroxypropyl]-3-(1-{[(1S,2R,4R)-3,3-dimethylbicyclo[2.2.1]-
hept-2-yl]methyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,
[0039] 18)
1-[(2S-2,3-dihydroxypropyl]-3-(1-{[(1R,2R,4S)-3,3-dimethylbicyclo[2.2.1]h-
ept-2-yl]methyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,
[0040] 19)
1-[(2S)-2,3-dihydroxypropyl]-3-(1-{[(1R,2S,4S)-3,3-dimethylbicyclo[2-
.2.1]hept-2-yl]methyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one,
[0041] 20)
1-(2,3-dihydroxypropyl)-3-[1-(spiro[2.5]oct-4-ylmethyl)-piperidin-4-yl]-1-
,3-dihydro-2H-benzimidazol-2-one, [0042] 21)
1-[(2R-2,3-dihydroxypropyl]-3-{1-[(4S)-spiro[2.5]oct-4-ylmethyl]piperidin-
-4-yl}-1,3-dihydro-2H-benzimidazol-2-one, [0043] 22)
1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(4R)spiro[2.5]oct-4-ylmethyl]piperidin-
-4-yl}-1,3-dihydro-2H-benzimidazol-2-one, [0044] 23)
1-[(2S)-2,3-dihydroxypropyl]-3-{1-[(4S)-spiro[2.5]oct-4-ylmethyl]piperidi-
n-4-yl}-1,3-dihydro-2H-benzimidazol-2-one, [0045] 24)
1-[(2S)-2,3-dihydroxypropyl]-3-{1-[(4R)-spiro[2.5]oct-4-ylmethyl]piperidi-
n-4-yl}-1,3-dihydro-2H-benzimidazol-2-one, [0046] 25)
1-(2,3-dihydroxypropyl)-3-[1-(spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropa-
n]-3-ylmethyl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,
[0047] 26)
1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(1R,3S,4S)-spiro[bicyclo[2.2.1]hep-
tane-2,1'-cyclopropan]-3-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimida-
zol-2-one, [0048] 27)
1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(1R,3R,4S)-spiro-[bicyclo[2.2.1]heptan-
e-2,1'-cyclopropan]-3-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-
-2-one, [0049] 28)
1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(1S,3R,4R)-spiro-[bicyclo[2.2.1]heptan-
e-2,1'-cyclopropan]-3-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-
-2-one, [0050] 29)
1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(1S,3S,4R)-spiro-bicyclo[2.2.1]heptane-
-2,1'-cyclopropan]-3-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol--
2-one, [0051] 30)
1-[(2S)-2,3-dihydroxypropyl]-3-{1-[(1R,3S,4S)-spiro-[bicyclo[2.2.1]heptan-
e-2,1'-cyclopropane]-3-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazo-
l-2-one, [0052] 31)
1-[(2S)-2,3-dihydroxypropyl]-3-{1-[(1R,3R,4S)-spiro-[bicyclo[2.2.1]heptan-
e-2,1'-cyclopropan]-3-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-
-2-one, [0053] 32)
1-[(2S)-2,3-dihydroxypropyl]-3-{1-[(1S,3R,4R)-spiro-[bicyclo[2.2.1]heptan-
e-2,1'-cyclopropan]-3-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-
-2-one, [0054] 33)
1-[(2S)-2,3-dihydroxypropyl]-3-{1-[(1S,3S,4R)-spiro-[bicyclo[2.2.1]heptan-
e-2,1'-cyclopropan]-3-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-
-2-one, [0055] 34)
1-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-[1-(spiro[2.5]-oct-4-ylmethyl)pipe-
ridin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, [0056] 35)
1-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-{1-[(4R)-spiro-[2.5]oct-4-ylmethyl-
]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one, [0057] 36)
1-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-{1-[(4S)-spiro[2.5]-oct-4-ylmethyl-
]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one, [0058] 37)
1-[2-hydroxy-1-(hydroxymethyl)ethyl-3-[1-(spiro[bicyclo-[2.2.1]heptane-2,-
1'-cyclopropan]-3-ylmethyl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-o-
ne, 38)
1-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-{1-[(1R,3S,4S)-spiro[bicycl-
o[2.2.1]heptane-2,1'-cyclopropan]-3-ylmethyl]piperidin-4-yl}-1,3-dihydro-2-
H-benzimidazol-2-one, [0059] 39)
1-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-{1-[(1R,3R,4S)-spiro[bicyclo[2.2.1-
]heptane-2,1'-cyclopropan]-3-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzi-
midazol-2-one, [0060] 40)
1-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-{1-[(1S,3R,4R)-spiro[bicyclo[2.2.1-
]heptane-2,1'-cyclopropan]-3-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzi-
midazol-2-one, [0061] 41)
1-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-{1-[(1S,3S,4R)-spiro[bicyclo[2.2.1-
]heptane-2,1'-cyclopropan]-3-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzi-
midazol-2-one, [0062] 42)
1-(2,3-dihydroxy-2-methylpropyl)-3-[1-(spiro[2.5]oct-4-ylmethyl)piperidin-
-4-yl]-1,3-dihydro-2H-benzimidazol-2-one, [0063] 43)
1-[(2R)-2,3-dihydroxy-2-methylpropyl]-3-{1-[(4S)spiro[2.5]-oct-4-ylmethyl-
]piperidin-4-yl})-1,3-dihydro-2H-benzimidazol-2-one, [0064] 44)
1-[(2R-2,3-dihydroxy-2-methylpropyl]-3-{1-[(4R)-spiro[2.5]-oct-4-ylmethyl-
]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one, [0065] 45)
1-[(2S)-2,3-dihydroxy-2-methylpropyl]-3-{1-[(4S)-spiro[2.5]-oct-4-ylmethy-
l]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one, and [0066] 46)
1-[(2S)-2,3-dihydroxy-2-methylpropyl]-3-{1-[(4R)-spiro[2.5]-oct-4-ylmethy-
l]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one. Preferably,
[0067]
1-[(2R)-2,3-dihydroxypropyl]-3-{(1R,3S,4S)spiro[bicyclo-[2.2.1]heptane-2,-
1'-cyclopropan]-3-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-o-
ne, [0068] 1-[(2S or
2R-2,3-dihydroxy-2-methylpropyl-3-{1-[(4S)-spiro[2.5]oct-4-ylmethyl]piper-
idin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one, [0069]
1-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-{1-[(1R,3S,4S)spiro-[bicyclo[2.2.1-
]heptane-2,1'-cyclopropan]-3-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzi-
midazol-2-one, [0070]
1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(4S)-spiro[2.5]oct-4-ylmethyl]piperidi-
n-4-yl}-1,3-dihydro-2H-benzimidazol-2-one and [0071]
1-[(2R)-2,3-dihydroxypropyl]-3-[1-[(6S or
6R)-spiro[4.5]dec-6-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol--
2-one are recommended. Production Processes of the Compounds
Represented by the Formula (I)
[0072] Those compounds represented by the formula (I) can be
prepared by following production processes or also by the processes
as described in WO98/54168.
Production Process 1
[0073] Production process I uses
1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one which is a
known compound, and provides compounds of the formula (I) through
three- or four-stage steps. ##STR4##
[0074] in which, R.sup.p stands for a lower alkyl group having two
protected hydroxyl groups, L stands for a leaving group, Cy* stands
for an optically active Cy, and Cy and R have the same
significations as defined earlier.
[0075] A compound of the formula (II) and a compound of the formula
(III) are subjected to a reductive alkylation reaction in an
organic solvent in the presence of a reducing agent, to provide a
compound of the formula (IV).
[0076] As the use rate of the compounds of the formulae (II) and
(III), respectively, they are normally used in equimolar amounts,
or either one of them is used in slight molar excess.
[0077] As the reducing agent, for example, sodium cyanoborohydride,
sodium triacetoxyborohydride, zinc biscyanoborohydride, nickel
biscyanoborohydride and the like can be named.
[0078] As the use rate of the reducing agent, it may be a mol to
molar excess, preferably 1-5 mols, per mol of the compound
represented by the formula (II).
[0079] The reaction is normally carried out in organic solvent.
Examples of useful solvent include alcohols such as methanol,
ethanol and propanol; ethers such as diethyl ether, tetrahydrofuran
("THF") and dioxane; halogenated hydrocarbons such as methylene
chloride, chloroform and dichloroethane; aromatic hydrocarbons such
as benzene, toluene, chlorobenzene and xylene; and aprotic polar
solvents such as dimethylformamide ("DMF"), acetonitrile and
hexamethylphosphorictriamide, or mixed solvents of the
foregoing.
[0080] Exemplary reaction temperature normally ranges -20.degree.
C.-100.degree. C., preferably 0.degree. C.--room temperature, and
the reaction time ranges normally from 5 minutes to 7 days,
preferably 1-6 hours.
[0081] As the compounds represented by the formula (III), for
example, the following compounds can be used. ##STR5##
[0082] Then the compound of the formula (IV) is condensed with a
compound of the formula (V) in an organic solvent in the presence
of a base, to provide a compound of the formula (VI).
[0083] As the use rate of the compound of the formula (V), it may
range from a mol to molar excess, preferably 1-5 mols, per mol of
the compound of the formula (IV).
[0084] Examples of useful base include sodium hydride, potassium
hydride, lithium hexamethyldisilazide, sodium hexamethyldisilazide,
potassium hexamethyldisilazide, potassium carbonate and sodium
carbonate. Preferably, sodium hydride and potassium hydride are
recommended.
[0085] As the use rate of such a base, for example, it may range
from a mol to molar excess, preferably 1-5 mols, per mol of the
compound of the formula (V).
[0086] An alkali metal halide such as sodium iodide, potassium
iodide or the like may be added to the reaction system for
promoting the reaction. As the use rate in such an occasion, for
example, 0.1 mol--molar excess of an alkali metal halide per mol of
the compound of the formula (IV) can be used.
[0087] As the organic solvent, for example, DMF, THF,
hexamethylphosphorictriamide and the like can be named.
[0088] Exemplary reaction temperature normally ranges 0.degree.
C.-150.degree. C., preferably room temperature--130.degree. C.
being recommended. The reaction time normally ranges 5 minutes to 7
days, preferably an hour--12 hours.
[0089] In the compound of the formula (V), L stands for a leaving
group which can be, for example, benzenesulfonyloxy,
p-toluenesulfonyloxy, methanesulfonyloxy, fluorine, chlorine or
bromine.
[0090] Specific examples of the compounds represented by the
formula (V) include the following. ##STR6##
[0091] Successively the compound of the formula (V) is optically
resolved with optically active column, where necessary, to provide
an optically active compound of the formula (Ia), and then the
protective groups of the hydroxyl groups in the compound of the
formula (Ia) are removed to provide a compound of the formula
(I).
[0092] Such hydroxyl-protective groups are subject to no particular
limitation, so long as they have the required function. For
example, such groups as tert-butyl; alkylsilyl, e.g.,
trimethylsilyl, tert-butyldimethylsilyl and
tert-butyldiphenylsilyl; methoxymethyl; tetrahydropyranyl;
trimethylsilylethoxymethyl; aralkyl, e.g., benzyl, p-methoxybenzyl,
2,3-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl and trityl; and
acyl, e.g., formyl and acetyl can be named, among which
methoxymethyl, tetrahydropyranyl, trityl,
trimethylsilylethoxymethyl, tert-butyldimethylsilyl and acetyl are
particularly preferred.
[0093] In particular, as protective groups of 1,2- or 1,3-diols,
for example, methyleneketal, ethylideneacetal,
phenylethylideneacetal, 4-methoxyphenylethylideneacetal,
isopropylideneketal and benzylideneacetal can be named.
[0094] Means for removing protective groups differ depending on
kind of protective groups and stability of individual compounds
represented by formula [Ia]. For example, the removal is conducted
following those methods describe in literature [cf. Protective
Groups in Organic Synthesis, T. W. Greene, John Wiley & Sons
Co., (1981)] or those analogous thereto, by solvolysis using acid
or base, i.e., a method of having, for example, from 0.01 mol to a
large molar excess of acid, preferably trifulroacetic acid, formic
acid, hydrochloric acid or the like; or from equimolar to a large
molar excess of base, preferably potassium hydroxide, calcium
hydroxide or the like, act on the object compound; chemical
reduction using hydrogenated metal complex or by catalytic
reduction using palladium-on-carbon catalyst or Raney nickel
catalyst.
[0095] In case of diol-protective groups such as ketal, acetal and
the like, the deprotection can be effected by hydrolyzing the
compound of the formula (V) using hydrochloric acid, in a solvent
such as THF, dioxane or the like, at room temperature--100.degree.
C.
[0096] Where necessary, the compound of the formula (V) can be
optically resolved by means of chromatography using optically
active column, to provide an optically active compound of the
formula (Ia).
[0097] As the optically active column, for example CHIRALPAK.RTM.
AD, CHIRALPAK.RTM. AD-H, CHIRAL CELL.RTM. OD and CHIRAL CELL.RTM.
OD-H (Daicel Co., Ltd.) can be named.
[0098] As the eluent solvent in that occasion, mixed solvents such
as hexane/2-propanol/diethylamine=1900/100/2-800/200/1 by volume,
or hexane/ethanol/diethylamine=1900/100/2-800/200/1 by volume can
be used.
[0099] As the detection means of the compounds in such occasion,
for example, ultraviolet rays in the wavelength region near 280 nm
may be used.
Production Process 2
[0100] Production process 2 is one for making compounds of the
formula (I), using the formula (IV) compounds as the starting
material. ##STR7##
[0101] in which, Ms stands for methanesulfonyl group, TEA stands
for triethylamine, and Cy, Cy*, R.sup.p, L and R have the same
significations as previously defined.
[0102] A compound of the formula (IV) is mesylated by a means known
per se, to be converted to a compound of the formula (VII) which is
successively optically resolved according to the production process
1 to provide a compound of the formula (VIIa). Further, mesyl group
in a compound of the formula (VIIa) is removed using
tetra-n-butylammonium fluoride (TBAF) to provide a compound of the
formula (VIIb) which is reacted with the compound of the formula
(V) according to the production process 1 to provide the compound
of the formula (Ia) which is further converted to the compound of
the formula (I) by deprotection.
[0103] So obtained compound of the formula (I) can be easily
isolated and purified by ordinary separation means, for example,
solvent extraction, recrystallization, column chromatography,
preparative thin layer chromatography or the like.
[0104] These compounds can be converted to pharmaceutically
acceptable salts according to accepted practice. Conversely,
conversion from salts to free compounds can also be conducted by
conventionally practiced means.
[0105] As examples of salts of compounds of the formula (I), acid
addition salts at the piperidinyl group can be named.
[0106] As examples of such acid addition salts, inorganic acid
salts such as hydrochloride, sulfate, nitrate, phosphate,
perchlorate and the like; carboxylic acid salts such as maleate,
fumarate, tartrate, citrate, ascorbate, trifluoroacetate and the
like; and sulfonates such as methanesulfonate, isethionate,
benzenesulfonate, p-toluenesulfonate and the like can be named.
[0107] Action of compounds of the present invention as nociceptin
receptor antagonist is shown, for example, by the following
pharmacological test examples.
PHARMACOLOGICAL TEST EXAMPLE 1
Nociceptin Receptor Binding Inhibition Assay
[0108] cDNA which codes a human nociceptin receptor gene was
integrated with an expression vector pCR3 (Invitrogen) to prepare
pCR3/ORL1. Next, pCR3 ORL1 was transfected in CHO cells using a
transfectam (Nippongene) to obtain a stable expression strain
(CHO/ORL1 cells) having resistance against 1 mg/ml G418. Membrane
fractions were prepared from this stable expression strain to carry
out a receptor binding assay. The membrane of 11 .mu.g, 50 pM
[.sup.125 I] Tyr.sup.14-Nociceptin (Amersham Pharmacia), 1 mg
Wheatgerm agglutinin SPA beads (PVT based; Amersham Pharmacia) and
each test compound were suspended in an NC buffer (50 mM Hepes, 10
mM sodium chloride, 1 mM magnesium chloride, 2.5 mM calcium
chloride, 0.1% BSA, 0.025% bacitracin, pH 7.4) and incubated at
37.degree. C. for 60 minutes, and then the radioactivity was
determined. The binding activity to the nociceptin receptor was
indicated by the 50% inhibition concentration (IC.sub.50 value) of
[.sup.125I] Tyr.sup.14-Nociceptin binding of each test compound.
The results were as shown in Table 1. TABLE-US-00001 TABLE 1
Compound IC.sub.50 value (nM) Example 1 1.6 Example 2 5.1 Example 3
8.7 Example 4 1.9 Example 5 2.8
PHARMACOLOGICAL TEST EXAMPLE 2
Antagonism Against Nociceptin-Elicited G Protein Activation
[0109] CHO cells which stably represented nociceptin receptor ORL1
were used to investigate the action of each test compound against
nociceptin-elicited G protein activation. A membrane prepared from
the CHO/ORL1 cells, 50 nM nociceptin, 200 pM GTP.gamma.[.sup.35S]
(NEN), 1.5 mg Wheatgerm agglutinin SPA beads (Amersham Pharmacia)
and each of the test compounds were mixed in a GDP buffer (20 mM
Hepes, 100 mM sodium chloride, 10 mM magnesium chloride, 1 mM EDTA,
5 .mu.M GDP, pH 7.4) and incubated at 25.degree. C. for 150
minutes, and then the radioactivity was determined. The antagonism
against nociceptin-elicited G protein activation was shown by the
50% inhibition concentration (IC.sub.50 value) of each test
compound against GTP.gamma.[.sup.35S] binding. The results were as
shown in Table 2. TABLE-US-00002 TABLE 2 Compound 50% value (nM)
Example 1 3.9 Example 2 8.6 Example 3 18.0 Example 4 6.0 Example 5
4.5
PHARMACOLOGICAL TEST EXAMPLE 3
Metabolic Stability Test
[0110] Metabolic stability of test compounds was examined using
human liver microsome. A 100 mM potassium phosphate buffer (pH 7.4)
comprising 10 mM G-6-P, 1.0 mM NADP.sup.+, 10 units/mL G-6-P DH,
3.0 mM MgCl.sub.2 and 0.25 mg protein/mL of human liver microsome
was prepared, each 392 .mu.L of which was poured into plural
vessels and preincubated at 37.degree. C. for 5 minutes. Then 8
.mu.L each of 50 .mu.M test compound (50% acetonitrile solution)
was added to initiate the reaction (final test compound
concentration: 1 .mu.M). At the initiation time and 30 minutes
thereafter of the reaction, 150 .mu.L of each reaction solution was
added to 450 .mu.L of ethanol to suspend the reaction, followed by
centrifugal separation (12,000 g, 12 minutes, 4.degree. C.).
Resulting supernatant was analyzed with LC/MS/MS. Based on the peak
area of the test compound in each sample at the initiating time of
the reaction as 100%, the test compound's residual ratio in the
sample after 30 minutes' reaction was calculated. The results were
as shown in Table 3. Residual ratio(%)=[peak area(after 30 minutes'
reaction)/peak area(0 minute's reaction)].times.100. TABLE-US-00003
TABLE 3 Compound Residual Ratio (%) Example 2 82 Example 4 72
Example 5 65
Pharmaceutical Preparations Comprising Compounds Represented by the
Formula (I)
[0111] The compounds of the present invention can be administered
orally or parenterally and, as formulated into preparation forms
suitable for such administration routes, can be used as analgesic
against diseases accompanied by pain such as cancerous pain,
postoperative pain, migraine, gout, chronic rheumatism, chronic
pain and neuralgia; relievers against tolerance to narcotic
analgesic represented by morphine; relievers against dependence on
narcotic analgesic represented by morphine or against addiction;
analgesic enhancer; antiobestic or appetite suppressors; treating
or prophylactic agents for cognitive impairment and
dementia/amnesia in aging, cerebrovascular diseases and Alzheimer's
disease; agents for treating developmental cognitive abnormality in
attention deficit, hyperactivity disorder and learning disability;
remedy for schizophrenia; agents for treating neurodegenerative
diseases represented by Parkinsonism and chorea; anti-depressants
or treating agents for affective disorder; treating or prophylactic
agents for diabetes insipidus; treating or prophylactic agents for
polyuria; remedy for hypotension, and the like.
[0112] In actually using the compounds of the present invention
clinically, they can normally be formulated into various
preparation forms suitable for individual mode of administration,
with pharmaceutically acceptable adjuvants. As the adjuvants,
various additives customarily used in the field of medical
preparations can be used, examples of which including gelatin,
lactose, sucrose, titanium oxide, starch, crystalline cellulose,
hydroxypropylmethyl cellulose, carboxymethyl cellulose, corn
starch, microcrystalline wax, white petrolatum, magnesium aluminate
metasilicate, anhydrous calcium phosphate, citric acid, trisodium
citrate, hydroxypropyl cellulose, sorbitol, sorbitan fatty acid
ester, polysorbate, sucrose fatty acid ester, polyoxyethylene,
hardened castor oil, polyvinylpyrrolidone, magnesium stearate,
light silicic anhydride, talc, vegetable oil, benzyl alcohol,
acacia, propylene glycol, polyalkylene glycol, cyclodextrin or
hydroxypropyl cyclodextrin and the like.
[0113] As the forms of preparations formulated as pharmaceutical
compositions using these adjuvants, solid preparations such as
tablets, capsules, granules, powders and suppositories; liquid
preparations such as syrups, elixirs and injections can be named.
These preparations can be formulated according to conventional
methods used in the field of pharmaceutics. Liquid preparations may
be in a form which is dissolved or suspended in water or other
suitable medium immediately prior to use. In particular, injections
may be in the form of a solution or suspension in physiological
saline solution or a glucose solution, to which a buffer agent, a
preservative or the like may be added.
[0114] These preparations can contain a compound or compounds of
the present invention at the ratios of 1-100 wt %, preferably 1-60
wt %, based on the total pharmaceutical preparation. These
preparations may further contain other therapeutically active
compounds.
[0115] Where the compounds of the present invention are used as
analgesic against diseases accompanied with pain such as cancerous
pain, postoperative pain, migraine, gout, chronic rheumatism,
chronic pain and neuralgia; relievers against tolerance to narcotic
analgesic represented by morphine; relievers against dependence on
narcotic analgesic represented by morphine or against addiction;
analgesic enhancer; antiobestic or appetite suppressors; treating
or prophylactic agents for cognitive impairment and
dementia/amnesia in aging, cerebrovascular diseases and Alzheimer's
disease; agents for treating developmental cognitive abnormality in
attention deficit, hyperactivity disorder and learning disability;
remedy for schizophrenia; agents for treating neurodegenerative
diseases represented by Parkinsonism and chorea; anti-depressants
or treating agents for affective disorder; treating or prophylactic
agents for diabetes insipidus; treating or prophylactic agents for
polyuria; or remedy for hypotension; their administration dosage or
frequency can be varied depending on gender, age, body weight,
degree of symptoms of individual patients and kind and extent of
intended therapeutic effect. In general terms, the dose can
normally range from 0.001 to 50 mg per day per kilogram of body
weight, which can be administered at a time or by plural times.
Preferably the dose is within a range of from about 0.01 to about
25 mg/kg per day, in particular, from about 0.05 to about 10 mg/kg
per day.
EXAMPLES
[0116] Hereinafter the present invention is explained more
specifically, referring to working Examples, it being understood
that the invention is not limited to those working Examples. Unless
otherwise specified, those various reagents used in the working
Examples were those available on the market, and, H-NMR values were
measured, using tetramethylsilane as the reference material, using
AL-400-2(400 MHz, JEOL Co). Also the mass spectra were measured
with Micromass ZQ (Waters Co.), by electro spray ionizing method
(ESI) or atmospheric pressure chemical ionization method
(APCI).
Production Example 1
Production of spiro[4.5]decane-6-carbaldehyde
1) Spiro[4.5]decane-6-one
[0117] Cyclohexanone (3.0 mL) was dissolved in toluene (60 mL), and
cooled to 0.degree. C. in nitrogen atmosphere. Potassium
tert-butoxide (6.86 g) was added to the reaction liquid at
0.degree. C. and stirred for 30 minutes. To the resulting
suspension, 1,4-dibromomethane (3.65 mL) was added, and then the
reaction liquid was stirred at 150.degree. C. for 6 hours. Cooling
the reaction liquid to room temperature, water was added thereto,
followed by extraction with ethyl acetate. The extract was dried
over anhydrous magnesium sulfate, removed of the solvent by
distillation, and the resulting residue was purified on silica gel
column chromatography (hexane/ethyl acetate=50/1) to provide 690.0
mg of the title compound as a colorless, oily substance.
2) Spiro[4.5]decane-6-carbaldehyde
[0118] A solution of diethyl(isocyanomethyl)phosphonate (410 .mu.L)
in diethyl ether (5 mL) was cooled to -78.degree. C. in nitrogen
atmosphere. After addition of 1.54M n-butyl lithium solution in
hexane (1.7 mL) to the reaction liquid at -78.degree. C., the
temperature was raised to 0.degree. C. and stirred for 15 minutes.
To the resulting solution spiro[4.5]decane-6-one (300 mg) was added
at 0.degree. C., and the temperature was raised to room temperature
under stirring. An hour thereafter, conc. hydrochloric acid (5 mL)
was added to the reaction liquid at room temperature, followed by
further 10 hours' stirring. The resulting solution was diluted with
water and extracted with diethyl ether. The extract was dried over
anhydrous magnesium sulfate, and from which the solvent was
distilled off to provide the title compound in crude, unpurified
form, as a colorless oily substance.
Production Example 2
Preparation of spiro[3.5]nonane-5-carbaldehyde
1) Ethyl 1,4-dioxaspiro[4.5]decane-6-carboxylate
[0119] Ethyl 2-oxocyclohexane carboxylate (11.3 g) and ethylene
glycol (11 mL) were dissolved in toluene (100 mL). To the reaction
liquid camphorsulfonic acid (1.03 g) was added and refluxed for 8
hours with Dean-Stark apparatus. The reaction liquid was cooled to
room temperature, diluted with diethyl ether and washed with
saturated aqueous sodium hydrogencarbonate solution. The extract
was washed with saturated brine, dried over anhydrous magnesium
sulfate, and from which the solvent was distilled off to provide a
crude product of the title compound.
2) 1,4-Dioxaspiro[4.5]dec-6-ylmethanol
[0120] The compound as obtained in 1) was dissolved in
tetrahydrofuran (120 mL) and cooled to 0.degree. C. in nitrogen
atmosphere. To the reaction liquid lithium aluminum hydride (3.06
g) was added at 0.degree. C., and then the temperature was raised
to room temperature, followed by an overnight stirring. The
reaction liquid was again cooled to 0.degree. C., to which sodium
sulfate decahydrate was added and stirred for an hour, followed by
drying by addition of anhydrous magnesium sulfate and filtering the
insoluble matter off. Distilling off the solvent in the filterate,
9.80 g of a crude product of the title compound was obtained.
3) 6-[(Benzyloxy)methyl]-1,4-dioxaspiro[4.5]decane
[0121] The compound (9.80 g) as obtained in 2) was dissolved in
tetrahydrofuran (100 mL) and cooled to 0.degree. C. in nitrogen
atmosphere. To the reaction liquid 60-72% sodium hydride (in the
form of an oil dispersion) (3.34 g) was added at 0.degree. C.,
followed by 30 minutes' stirring. To the resulting reaction liquid,
benzyl bromide (8.4 mL) was added at 0.degree. C., the temperature
was raised to room temperature, and the system was stirred for 3
hours. The reaction liquid was diluted with diethyl ether, and
washed first with water and successively, with saturated brine. The
organic layer was dried over anhydrous magnesium sulfate, the
solvent was distilled off, and the resulting residue was purified
on silica gel column chromatography (hexane/ethyl acetate=19/1) to
provide 7.24 g of the title compound.
4) 2-[(Benzloxy)methyl]cyclohexanone
[0122] The compound (3.37 g) as obtained in 3) was dissolved in
tetrahydrofuran (30 mL), to which 10% hydrochloric acid (10 mL) was
added at room temperature, followed by 3 hours' stirring. The
reaction liquid was diluted with diethyl ether and washed first
with water, successively with saturated aqueous sodium
hydrogencarbonate solution and then with saturated brine. The
organic layer was dried over anhydrous magnesium sulfate, the
solvent was distilled off, and 2.94 g of a crude product of the
title compound was obtained.
5)
2-[(Benzyloxy)methyl]-1-[1-(phenylthio)cyclopropyl]cyclohexanol
[0123] A cyclopropyl phenyl sulfide (2.33 mL) solution in
tetrahydrofuran (50 mL) was cooled to 0.degree. C. in nitrogen
atmosphere. To the reaction liquid, 1.0 M n-butyl lithium hexane
solution (16 mL) was added at 0.degree. C., followed by an hour's
stirring. The reaction liquid was cooled to -78.degree. C., and to
which a tetrahydrofuran solution (10 mL) of the compound (2.94 g)
as obtained in 4) was added at -78.degree. C., followed by stirring
at -78.degree. C. for 30 minutes and then at 0.degree. C. for an
hour. Water was added to the reaction liquid which then was
extracted with diethyl ether. The extract was washed first with
water and then with saturated brine, dried over anhydrous magnesium
sulfate, removed of the solvent by distillation, and the resulting
residue was purified on silica gel column chromatography
(hexane/ethyl acetate=19/1) to provide 3.04 g of the title
compound.
6) 5-[(Benzyloxy)methyl]spiro[3.5]nonane-1-one
[0124] The compound (3.04 g) as obtained in 5) was dissolved in
toluene (40 mL), to which p-toluenesulfonic acid monohydrate (1.60
g) and water (0.15 mL) were added and stirred at 90.degree. C. for
5 hours. The reaction liquid was diluted with diethyl ether and
washed with water, 10% aqueous sodium hydroxide solution and
saturated brine, by the order stated. The organic layer was dried
over anhydrous magnesium sulfate, removed of the solvent by
distillation, and the resulting residue was purified on silica gel
column chromatography (hexane/ethyl acetate=19/1) to provide 670 mg
of the title compound.
7) 5-[(Benzyloxy)methyl]spiro[3.5]nonane
[0125] The compound (670 mg) as obtained in 6) was dissolved in
diethylene glycol (3 mL), to which hydrazine monohydrate (1.5 mL)
and potassium carbonate (838 mg) were added, followed by stirring
under heating at 150.degree. C. for 3 hours and at 200.degree. C.
for 5 hours. The reaction liquid was cooled to room temperature,
diluted with diethyl ether, and then washed with 10% hydrochloric
acid and then with saturated brine. The organic layer was dried
over anhydrous magnesium sulfate and removed of the solvent by
distillation, to provide 224 mg of a crude title compound.
8) Spiro[3.5]non-5-ylmethanol
[0126] The compound (224 mg) as obtained in 7) was dissolved in
methanol (5 mL), to which a catalytic amount of activated
carbon-carried palladium hydroxide was added, and the system was
stirred at room temperature for 4 hours in hydrogen atmosphere of
one atmospheric pressure. Filtering off the insoluble matter with
Celite.RTM., the filtrate was condensed to provide 151 mg of crude
title compound.
9) Spiro[3.5]nonane-5-carbaldehyde
[0127] The compound (151 mg) as obtained in 8) was dissolved in
dimethylsulfoxide (5 mL) and to which triethylamine (2 mL) and
anhydrous sulfurylic acid-pyridine complex (1.17 g) were added,
followed by an hour's stirring at room temperature. The reaction
liquid was diluted with diethyl ether and washed successively with
water, 10% hydrochloric acid, saturated aqueous sodium
hydrogen-carbonate solution and saturated brine. The organic layer
was dried over anhydrous magnesium sulfate and distilled off of the
solvent to provide 120 mg of crude title compound.
Production Example 3
Preparation of spiro[2.5]octane-4-carbaldehyde
1) Ethyl 1,4-dioxaspiro[4.5]dec-6-yl acetate
[0128] Ethyl (2-oxocyclohexyl)acetate (50.05 g) and ethylene glycol
(45.5 mL) were dissolved in toluene (200 mL). p-Toluenesulfonic
acid monohydrate (7.75 g) was added to the reaction liquid which
then was refluxed for 5 hours using Dean-Stark apparatus. The
reaction liquid was cooled to room temperature and saturated
aqueous sodium hydrogencarbonate solution was added thereto,
followed by extraction with ethyl acetate. The extract was washed
with saturated brine, dried over anhydrous magnesium sulfate and
removed of the solvent by distillation to provide 76.54 g of crude
title compound as a pale, yellowish brown oily substance.
2) 2-(1,4-Dioxaspiro[4.5]-dec-6-yl)ethanol
[0129] The compound (76.54 g) as obtained in 1) was dissolved in
tetrahydrofuran (350 mL) and cooled to 0.degree. C. in nitrogen
atmosphere. To the reaction liquid lithium aluminum hydride (10.36
g) was added at 0.degree. C., followed by 3 hours' stirring. To the
resulting reaction liquid sodium sulfate decahydrate (51.85 g) was
added and stirred at room temperature for an overnight. The
insoluble matter in the solution was filtered off with Celite.RTM.,
and the filtrate was condensed to provide crude title compound
(63.77 g) as a pale yellow, oily substance.
3) 2-(2-Chloroethyl)cyclohexanone
[0130] The compound (63.77 g) as obtained in 2) was dissolved in
acetonitrile (40 mL) and added to conc. hydrochloric acid (250 mL)
which had been cooled to 0.degree. C. The reaction liquid's
temperature was raised to room temperature, followed by 1.5 hours'
heating under reflux. The reaction liquid was cooled to room
temperature, diluted with water and extracted with hexane. The
extract was successively washed with water and then with saturated
aqueous sodium hydrogencarbonate solution, dried over anhydrous
sodium sulfate and removed of the solvent by distillation to
provide crude title compound (46.15 g) as a pale yellow, oily
substance.
4) Spiro[2.5]octane-4-one
[0131] The compound (46.15 g) as obtained in 3) was dissolved in
ethanol (100 mL) and cooled to 0.degree. C. To the reaction liquid
powdery potassium hydroxide (19.97 g) was added at 0.degree. C. and
the temperature was raised to room temperature, followed by 3
hours' stirring. Potassium chloride as precipitated was filtered
off, and the filterate was used in the subsequent reaction as an
ethanol solution of the title compound.
5) Spiro[2.5]octane-4-carbonitrile
[0132] Potassium tert-butoxide (158.0 g) was suspended in
dimethylsulfoxide (370 mL), and into which p-toluenesulfonylethyl
isocyanide (60.60 g) was added under cooling with ice, followed by
15 minutes' stirring at 0.degree. C. Into the resulting
brown-colored reaction liquid, an ethanol solution of the
spiro[2.5]octane-4-one as obtained in 4) was added at 0.degree. C.,
heated to room temperature and stirred for 3 hours. To the reaction
liquid, water (300 mL) and hexane (300 mL) were added, followed by
addition of 10% hydrochloric acid (400 mL). The reaction liquid was
extracted with hexane, and the extract was washed with water and
saturated aqueous solution of sodium hydrogencarbonate. The organic
layer was dried over anhydrous sodium sulfate, from which the
solvent was distilled off, and the resulting residue was purified
on silica gel column chromatography (hexane/ethyl acetate=3/1) to
provide 39.95 g of the title compound as an yellowish brown, oily
substance.
6) Spiro[2.5]octane-4-carbaldehyde
[0133] The compound (39.95 g) as obtained in 5) was dissolved in
hexane (250 mL), and cooled to 0.degree. C. in nitrogen atmosphere.
To the reaction liquid, 0.95 M diisobutylaluminum hydride-in-hexane
solution (400 mL) was dropped at 0.degree. C. After the end of
dropping, the reaction liquid was heated to room temperature and
stirred for 3 hours. The resulting reaction liquid was again cooled
to 0.degree. C. and into which 10% hydrochloric acid (300 mL) was
dropped, followed by an hour's stirring at room temperature. The
reaction liquid was extracted with hexane, and to the hexane
extract first water (1.5 L) and then sodium hydrogensulfite (500 g)
were added, followed by violent stirring at room temperature to
extract the title compound as its hydrogen sulfite adduct in a
water layer. The aqueous layer as extracted was separated, and to
which methyl tert-butyl ether (IL) was added, followed by addition
of sodium hydroxide (280 g) and violent stirring at room
temperature. Separating the ether layer, the aqueous layer was
again extracted with methyl tert-butyl ether. The resulting ether
layers were combined and dried over anhydrous magnesium sulfate,
and from which the solvent was distilled off to provide 20.04 g of
the title compound as a pale yellow, oily substance.
Production Example 4
Preparation of
spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-carbaldehyde
1) Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-one
[0134] Zinc powder (15.10 g) was suspended in diethyl ether (70 mL)
and to which cuprous chloride (2.29 g) was added at room
temperature, followed by 30 minutes' refluxing in nitrogen
atmosphere. The suspension was cooled to 0.degree. C. and to which
3-methylenebicyclo[2.2.1]heptan-2-one (7.0 mL) was added at
0.degree. C. Into the reaction liquid, methane diiodide (7.0 mL)
was slowly dropped at 0.degree. C. and after the end of the
dropping, the reaction liquid was refluxed for 30 hours in nitrogen
atmosphere. Cooling the reaction liquid to room temperature, the
insoluble matter was filtered off with Celite.RTM. and the
filterate was washed twice with 5% aqueous sodium thiosulfate
solution. The organic layer was dried over anhydrous magnesium
sulfate, removed of the solvent by distillation, and the resulting
residue was purified on silica gel column chromatography
(hexane/ethyl acetate=100/1-7/1) to provide 4.89 g of the title
compound as a colorless oily substance.
2)Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-carbaldehyde
[0135] Methoxymethyltriphenylphosphonium chloride (6.41 g) was
suspended in tetrahydrofuran (80 mL) and cooled to 0.degree. C. in
nitrogen atmosphere. After adding 1.56 M n-butyl lithium-in-hexane
solution (36.2 mL) at 0.degree. C., the reaction liquid was stirred
for an hour. Into the resulting deep red-colored solution, a
spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropane]-3-one (6.41 g)
solution in tetrahydrofuran (10 mL) was dropped at 0.degree. C.,
and thereafter the temperature was raised to room temperature,
followed by an overnight's stirring. To the reaction liquid, 5M
hydrochloric acid (50 mL) was added at room temperature and stirred
for further 3 hours. The reaction liquid was diluted with water and
extracted with diethyl ether. The extract was washed with saturated
brine, dried over anhydrous sodium sulfate, removed of the solvent
by distillation and the resulting residue was purified on silica
gel column chromatography (hexane/ethyl acetate=99/1-97/3) to
provide 5.04 g of the title compound as a colorless oily
substance.
Production Example 5
Preparation of 2,2-dimethyl-1,3-dioxolan-5-yl methanesulfonate
1) 2,2-Dimethyl-1,3-dioxolan-5-ol
[0136] A 2,2-dimethyl-1,3-dioxolan-5-one (930 mg) solution in
tetrahydrofuran (10 mL) was cooled to 0.degree. C. in nitrogen
atmosphere. To the reaction liquid lithium aluminium hydride (293
mg) was added at 0.degree. C., followed by 30 minutes' stirring.
After adding sodium sulfate decahydrate (3 g) to the reaction
liquid at 0.degree. C., the temperature was raised to room
temperature, followed by further 2 hours' stirring. The insoluble
matter was filtered off and the filterate was condensed. The
resulting residue was purified on silica gel column chromatography
(hexane/ethyl acetate=3/2) to provide 743 mg of the title compound
as a colorless, oily substance.
2) 2,2-Dimethyl-1,3-dioxolan-5-yl methanesulfonate
[0137] A 2,2-dimethyl-1,3-dioxolan-5-ol (743 mg) solution in
tetrahydrofuran (10 mL) was cooled to 0.degree. C. in nitrogen
atmosphere. To the reaction liquid, triethylamine (1.87 mL) and
methanesulfonyl chloride (520 .mu.L) were successively added at
0.degree. C., followed by 30 minutes' stirring. After addition of
saturated aqueous ammonium chloride solution, the reaction liquid
was extracted with ethyl acetate. The extract was washed with
saturated brine, dried over anhydrous magnesium sulfate and removed
of the solvent by distillation to provide 837 mg of crude title
compound as a colorless solid.
Production Example 6
Preparation of [(4R or 4S)-2,2,4-trimethyl-1,3-dioxolan-4-yl]methyl
4-methylbenzenesulfonate
[0138] Two kinds of optical isomers of
(2,2,4-trimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate
(976 mg) which is a per se known substance, was separated using
CHIRALPAK.RTM. AD (Daicel Co., Ltd., 2 cm.phi..times.25 cm;
hexane/ethanol=9/1), to provide as the first eluate 478 mg of (4S
or 4R) body of the title compound, and as the second eluate, 477 mg
of (4R or 4S) body of the title compound.
Example 1
Preparation of 1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(6S or
6R)-spiro[4.5]dec-6-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol--
2-one
1)
3-[(1-(spiro[4.5]dec-6-ylmethyl)piperidin-4-yl)-1,3-dihydro-2H-benzimid-
azol-2-one
[0139] To a 1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one (360
mg) solution in dichloromethane (15 mL), the compound (250 mg) as
obtained in Production Example 1 was added at room temperature,
followed by addition of sodium triacetoxyborohydride (380 mg) at
room temperature. The mixed solution was stirred at room
temperature for 3 hours, 1M aqueous sodium hydroxide solution was
added, and the reaction liquid was extracted with chloroform. The
extract was washed with saturated brine, dried over anhydrous
magnesium sulfate, removed of the solvent by distillation, and the
resulting residue was purified on silica gel column chromatography
(chloroform/methanol=50/1-30/1) to provide 179.5 mg of the title
compound as a colorless solid.
2)
1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-3-[1-(spiro[4.5]-dec-6--
ylmethyl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one
[0140] The compound (90 mg) as obtained in 1) was dissolved in
dimethylformamide (3 mL), and to the solution 60-72% sodium hydride
(oil dispersion) (20 mg) was added at room temperature, followed by
30 minutes' stirring. After addition of
[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl
4-methylbenzene-sulfonate (140 mg) and potassium iodide (20 mg),
the reaction liquid was stirred at 60.degree. C. for 14 hours. The
reaction liquid was cooled to room temperature, to which 1M aqueous
sodium hydroxide solution was added, followed by extraction with
ethyl acetate. The extract was washed with saturated brine, dried
over anhydrous magnesium sulfate, removed of the solvent by
distillation, and the resulting residue was purified on silica gel
column chromatography (hexane/ethyl acetate=5/1-2/1) to provide
100.2 mg of the title compound as a pale yellow, oily
substance.
3) 1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-3-{1-[(6S or
6R)-spiro[4.5]-dec-6-ylmethyl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-
-2-one
[0141] The two kinds of diastereomers of the compound (100.2 mg) as
obtained in 2) were separated using CHIRALPAK.RTM. AD (Daicel Co.,
Ltd.; 2 cm.phi..times.25 cm,
hexane/2-propanol/diethylamine=6/1/0.007), to provide as the first
eluate 44.1 mg of (6S or 6R) body of the title compound.
4) 1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(6S or
6R)-spiro[4.5]dec-6-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol--
2-one
[0142] The compound (44 mg) as obtained in 3) was dissolved in
tetrahydrofuran (2 mL), to which 5M hydrochloric acid (2 mL) was
added at room temperature and stirred for an hour. The resulting
reaction solution was cooled to 0.degree. C., neutralized with 1M
aqueous sodium hydroxide solution and extracted with ethyl acetate.
The extract was washed with saturated brine, dried over anhydrous
magnesium sulfate, removed of the solvent by distillation and the
resulting residue was purified on silica gel preparative thin layer
chromatography (chloroform/methanol=20/1) to provide 28.8 mg of the
title compound as a colorless oily substance.
[0143] .sup.1H-NMR (CDCl.sub.3) .delta.=1.14-1.85 (19H, m),
1.88-1.99 (1H, m),
[0144] 2.14-2.55 (5H, m), 2.90-2.99 (1H, m), 3.05-3.14 (1H, m),
[0145] 3.55-3.62 (2H, m), 3.96-4.10 (3H, m), 4.26-4.40 (1H, m),
[0146] 7.07-7.15 (3H, m), 7.28-7.34 (1H, m)
[0147] ESI-MS (+20 eV) m/z 442.2
Example 2
Preparation of
1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(4S)-spiro[2.5]oct-4-ylmethyl]piperidi-
n-4-yl}-1,3-dihydro-2H-benzimidazol-2-one
1)
3-[1-(spiro[2.5]oct-4-ylmethyl)piperidin-4-yl]-1,3-dihydro-2H-benzimida-
zol-2-one
[0148] To 1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one (4.00
g) solution in tetrahydrofuran (150 mL), the compound (3.02 g) as
obtained in Production Example 3 was added at room temperature, and
successively, sodium triacetoxyborohydride (4.68 g), at room
temperature. The mixed solution was stirred at room temperature for
2 hours, followed by addition of 1.5M aqueous sodium hydroxide
solution and extraction with chloroform. The extract was dried over
anhydrous magnesium sulfate and removed of the solvent by
distillation to provide 4.98 g of crude title compound as a pale,
yellowish brown solid.
2)
1-(Methylsulfonyl)-3-[1-(spiro[2.5]oct-4-ylmethyl)piperidin-4-yl]-1,3-d-
ihydro-2H-benzimidazol-2-one
[0149] The compound (4.98 g) as obtained in 1) was dissolved in
chloroform (150 mL). To the solution triethylamine (7 mL) and
methanesulfonyl chloride (1.94 mL) were added at room temperature,
followed by 2 hours' stirring at room temperature. The reaction
liquid was diluted with chloroform and washed with saturated
aqueous sodium hydrogencarbonate solution. The organic layer was
dried over anhydrous magnesium sulfate, removed of the solvent by
distillation and the resulting residue was purified on silica gel
column chromatography (chloroform/methanol=100/1-15/1) to provide
5.47 g of the title compound as a pale yellow, oily substance.
3)
1-(Methylsulfonyl)-3-{1-[(4S)-spiro[2.5]oct-4-ylmethyl)piperidin-4-yl}--
1,3-dihydro-2H-benzimidazol-2-one
[0150] The two kinds of diastereomers of the compound (5.47 g) as
obtained in 2) were separated using CHIRALPAK.RTM. AD (Daicel Co.,
Ltd.; 2 cm.phi..times.25 cm, hexane/ethanol/diethylamine=4/1/0.005)
to provide as the first eluate 2.15 g of (4S) body of the title
compound.
4)
3-{1-[(4S)-spiro[2.5]oct-4-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benz-
imidazol-2-one
[0151] The compound (2.15 g) as obtained in 3) was dissolved in
tetrahydrofuran (70 mL), to which 1M tetra-n-butylammonium
fluoride-in-tetrahydrofuran solution (9.5 mL) was added at room
temperature and stirred for 3 hours. Saturated aqueous sodium
hydrogencarbonate solution was added to the reaction liquid which
then was extracted with ethyl acetate. The extract was washed with
saturated brine, dried over anhydrous magnesium sulfate, removed of
the solvent by distillation and the resulting residue was purified
on N basic silica gel column chromatography (hexane/ethyl
acetate=1/1-1/2) to provide 1.56 g of the title compound as a
colorless solid.
5)
1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-3-{1-[(4S)-spiro-[2.5]--
oct-4-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one
[0152]
3-{1-[(4S)-spiro[2.5]oct-4-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-
-benzimidazol-2-one (2.94 g) was dissolved in dimethylformamide (60
mL), and to which 60-72% sodium hydride (oil dispersion) (706.6 mg)
was added at room temperature and stirred for 30 minutes. To the
reaction liquid, [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl
4-methylbenzene-sulfonate (7.25 g) was added and stirred at
80.degree. C. for 7 hours. After cooling the reaction liquid to
room temperature, water was added, followed by extraction with
ethyl acetate. The extract was washed with saturated brine, dried
over anhydrous magnesium sulfate, removed of the solvent by
distillation and the resulting residue was purified on silica gel
column chromatography (hexane/ethyl acetate=2/1-1/2) to provide
3.43 g of the title compound as a pale yellow, oily substance.
[0153] 6)
1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(4S)-spiro[2.5]oct-4-ylmethy-
l]-piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one
hydrochloride
[0154] The compound (2.71 g) as obtained in 5) was dissolved in
methanol (15 mL), to which 10% hydrogen chloride/methanol solution
(65 mL) was added and stirred for an overnight at room temperature.
The reaction liquid was condensed, and the resulting solid was
washed with ethanol to provide 1.60 g of the title compound as a
colorless solid.
[0155] .sup.1H-NMR (CDCl.sub.3) .delta.=0.31-0.42 (2H, m),
0.42-0.58 (2H, m),
[0156] 0.76-0.86 (1H, m), 1.40-1.75 (4H, m), 1.75-2.10 (4H, m),
[0157] 2.72-3.00 (4H, m), 3.22-3.42 (3H, m), 3.52-3.64 (3H, m),
[0158] 3.65-3.78 (2H, m), 4.00-4.08 (3H, m), 4.65-4.80 (1H, m),
[0159] 7.10-7.20 (3H, m), 8.02-8.08 (1H, m), 12.60 (1H, brs)
[0160] ESI-MS (+20 eV) m/z 414.4
Example 3
Preparation of
1-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-{1-[(1R,3S,4S)-spiro[bicyclo[2.2.1-
]heptane-2,1'-cyclopropan-3-ylmethyl]-piperidin-4-yl}-1,3-dihydro-2H-benzi-
midazol-2-one
[0161] 1)
3-[1-(Spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropan]-3-ylmethyl)-
-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one
[0162] To 1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one (1.5
g) solution in tetrahydrofuran (15 mL), the compound (1.2 g) as
obtained in Production Example 4 was added at room temperature, and
successively sodium triacetoxyborohydride (2.0 g) was added and
stirred for 2 days at room temperature. To the reaction liquid 1M
aqueous sodium hydroxide solution was added, followed by extraction
with ethyl acetate. The extract was dried over anhydrous magnesium
sulfate, then the solvent was distilled off and the resulting
residue was purified on silica gel column chromatography
(chloroform/methanol=100/1-10/1) to provide 1.53 g of the title
compound as a pale orange-colored solid.
2)
1-(Methylsulfonyl)-3-[1-(spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropan]--
3-ylmethyl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one
[0163] The compound (1.53 g) as obtained in 1) was dissolved in
chloroform (15 mL) and cooled to 0.degree. C. To the solution first
triethylamine (1.2 mL) and successively methanesulfonyl chloride
(512 .mu.L) were added at 0.degree. C., followed by an hour's
stirring at 0.degree. C. The reaction liquid was diluted with ethyl
acetate and washed with 1M aqueous sodium hydroxide solution. The
organic layer was dried over anhydrous magnesium sulfate and
removed of the solvent by distillation. The resulting residue was
purified on silica gel column chromatography
(chloroform/methanol=200/1-20/1) to provide 1.90 g of the title
compound as a pale yellow, oily substance.
3)
1-(Methylsulfonyl)-3-{1-[(1R,3S,4S)-spiro[bicyclo[2.2.1]heptane-2,1'-cy-
clopropan]-3-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one
[0164] The four kinds of optical isomers of the compound (1.90 g)
as obtained in 2) were separated using CHIRALPAK.RTM. AD (Daicel
Co., Ltd.; 2 cm.phi..times.25 cm,
hexane/ethanol/diethylamine=9/1/0.01), to provide as the third
eluate 420 mg of the title compound (1R,3S,4S) bodies.
4)
3-{1-[(1R,3S,4S)-spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropan]-3-ylmeth-
yl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one
[0165] The third eluate (420 mg) as obtained in 3) was dissolved in
tetrahydrofuran (5 mL), and to which 1M tetra-n-butylammonium
fluoride solution in tetrahydrofuran (1.5 mL) was added at room
temperature and stirred for an overnight. After distilling off the
solvent from the reaction liquid, the resulting residue was
purified on silica gel column chromatography
(chloroform/methanol=100/1-10/1) to provide 294 mg of the title
compound as a colorless solid.
5)
1-(2,2-Dimethyl-1,3-dioxolan-5-yl)-3-{1-[(1R,3S,4S)-spiro-[bicyclo[2.2.-
1]heptane-2,1'-cyclopropan]-3-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benz-
imidazol-2-one
[0166] The compound (294 mg) as obtained in 4) above was dissolved
in dimethylformamide (5 mL), and to which 60-72% sodium hydride (an
oil dispersion) (100 mg) was added at room temperature and stirred
for 30 minutes. To the resulting reaction liquid the compound (353
mg) as obtained in Production Example 5 was added and stirred at
120.degree. C. for 2 hours. Thereafter 60-72% sodium hydride (an
oil dispersion) (100 mg) and the compound (353 mg) as obtained in
Production Example 5 was added to the reaction liquid twice at an
interval of an hour. The reaction liquid was cooled to room
temperature, to which 1M aqueous sodium hydroxide solution was
added and extracted with ethyl acetate. The extract was washed with
saturated brine, dried over anhydrous magnesium sulfate, removed of
the solvent by distillation and the resulting residue was purified
on silica gel column chromatography
(chloroform/methanol=400/1-20/1) to provide 132 mg of the title
compound as a pale yellow, oily substance.
6)
1-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-{1-[(1R,3S,4S)-spiro-bicyclo[2.2-
.1]heptane-2,1'-cyclopropan]-3-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-ben-
zimidazol-2-one hydrochloride
[0167] The compound (132 mg) as obtained in 5) was dissolved in
methanol (5 mL), to which 6M hydrochloric acid (100 .mu.L) was
added at room temperature and stirred for 3 hours. Distilling the
solvent off from the reaction liquid, the resulting solid was
washed with ethyl acetate to provide 128 mg of the title compound
as a colorless solid.
[0168] .sup.1H-NMR (CD.sub.3OD) .delta.0.29-0.39 (2H, m), 0.46-0.55
(1H, m),
[0169] 0.66-0.74 (1H, m), 1.46-1.68 (6H, m), 1.79-1.86 (1H, m),
[0170] 2.00-2.12 (2H, m), 2.28-2.37 (1H, m), 2.53-2.59 (1H, m),
[0171] 2.74-3.26 (5H, m), 3.49-3.62 (1H, m), 3.71-3.82 (2H, m),
[0172] 3.94 (2H, dd, J=5.3, 11.6 Hz), 4.08 (2H, dd, J=8.1, 11.6
Hz),
[0173] 4.45-4.65 (2H, m), 7.06-7.14 (2H, m), 7.28-7.41 (2H, m)
[0174] ESI-MS (+20 eV) m/z 426.2
Example 4
Preparation of 1-[(2S or
2R)-2,3-dihydroxy-2-methylpropyl]-3-{1-[(4S)-spiro[2.5]oct-4-ylmethyl]pip-
eridin-4-yl}-1,3-dihydro-2H-benzimidzol-2-one
(2R,3R)-3-carboxy-2,3-dihydroxypropionic acid salt
1) 1-{1-[(4S)-spiro[2.5]oct-4-ylmethyl]piperidin-4-yl}-3-{[(4S or
4R)-2,2,4-trimethyl-1,3-dioxolan-4-yl]methyl}-1,3-dihydro-2H-benzimidazol-
-2-one
[0175]
3-{1-[(4S)spiro[2.5]oct-4-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H--
benzimidazol-2-one (753 mg) as obtained in Example 2-4) and
potassium iodide (372 mg) were dissolved in dimethylformamide (100
mL), and to which 60-72% sodium hydride (an oil dispersion) (428
mg) was added at room temperature and stirred for 30 minutes. To
the resulting reaction liquid, a solution of the (4R or
4S)-2,2,4-trimethyl-1,3-dioxolan-4-yl]methyl
4-methylbenzenesulfonate (1.99 g), as obtained in Production
Example 6 as the second eluate, in dimethylformamide (30 mL) was
added at room temperature and stirred at 120.degree. C. for an
overnight. To the reaction liquid saturated aqueous ammonium
chloride solution was added, followed by extraction with ethyl
acetate. The extract was washed with saturated aqueous sodium
hydrogen-carbonate solution, dried over anhydrous magnesium
sulfate, removed of the solvent by distillation and the resulting
residue was purified on basic silica gel column chromatography
(hexane/ethyl acetate=10/1-5/1) to provide 1.27 g of the title
compound as a pale yellow, oily substance.
2) 1-[(2S or
2R)-2,3-dihydroxy-2-methylpropyl]-3-{1-[(4S)-spiro-[2.5]oct-4-ylmethyl]pi-
peridin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one
(2R,3R)-3-carboxy-2,3-dihydroxypropionic acid salt
[0176] The compound (1.27 g) as obtained in 1) was dissolved in
tetrahydrofuran (20 mL), and to which 1M hydrochloric acid (20 mL)
was added at room temperature and stirred for an overnight. The
resulting reaction liquid was cooled to 0.degree. C., and to which
saturated aqueous sodium hydrogencarbonate solution was added,
followed by extraction with chloroform. The extract was dried over
anhydrous magnesium sulfate, removed of the solvent by distillation
and the resulting residue was purified on silica gel column
chromatography (chloroform/methanol=30/1-4/1) to provide 1.09 g of
free amine body of the title compound. This free amine body (33.2
mg) and (2R,3R) -tartaric acid (11.6 mg) were dissolved in methanol
(3 mL), and the solvent was distilled off. The resulting solid was
washed with ethyl acetate to provide 44.8 mg of the title compound
as a colorless solid.
[0177] .sup.1H-NMR (CD.sub.3OD) .delta.=0.35 (2H, brs), 0.45 (2H,
brs),0.84 (1H, m),
[0178] 1.14 (1H, d, J=6.2 Hz), 1.20 (3H, s), 1.41-1.82 (8H, m),
2.01 (2H, m),
[0179] 2.78-3.25 (5H, m), 3.30-3.51 (2H, m), 3.69 (2H, m), 3.92
(2H, s),
[0180] 4.43 (2H, s), 4.60 (1H, m), 7.12 (2H, m), 7.36 (2H, m)
[0181] ESI-MS (+20 eV) m/z 428.3
Example 5
Preparation of
1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(1R,3S,4S)-spiro[bicyclo-[2.2.1]heptan-
e-2,1'-cyclopropan]-3-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-
-2-one hydrochloride
1)
1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-3-{1-[(1R,3S,4S)-spiro[-
bicyclo[2.2.1]heptane-2,1'-cyclopropan]-3-ylmethyl]piperidin-4-yl}-1,3-dih-
ydro-2H-benzimidazol-2-one
[0182]
3-{1-[(1R,3S,4S)-spiro[bicyclo[2.2.1]heptane-2,1'-cyclopropan]-3-y-
lmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one (1.47 g)
as obtained in 4) of Example 3 was dissolved in dimethylformamide
(25 mL), and to which 60-72% sodium hydride
[0183] (an oil dispersion) (418 mg) was added at room temperature
and stirred for 15 minutes. To the resulting reaction liquid, a
[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl
4-methylbenzenesulfonate (2.39 g) solution in dimethylformamide (5
mL) was added at room temperature, and stirred at 80.degree. C. for
5 hours. The reaction liquid was cooled to room temperature, to
which phosphate buffer (pH 6.5) was added, followed by extraction
with ethyl acetate. The extract was washed with water, dried over
anhydrous sodium sulfate, removed of the solvent by distillation
and the resulting residue was purified on silica gel column
chromatography (hexane/ethyl acetate=9/1-1/1) to provide 1.80 g of
the title compound as a colorless, oily substance.
2)
1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(1R,3S,4S)-spiro[bicyclo[2.2.1]hepta-
ne-2,1'-cyclopropan]-3-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazo-
l-2-one hydrochloride
[0184] The compound (1.75 g) as obtained in 1) was dissolved in
tetrahydrofuran (57 mL), to which 1M hydrochloric acid (19 mL) was
added at room temperature and stirred for 30 hours. The reaction
liquid was neutralized by addition of aqueous sodium
hydrogencarbonate solution at 0.degree. C., followed by extraction
with ethyl acetate. The extract was washed with saturated brine,
dried over anhydrous sodium sulfate, removed of the solvent by
distillation and the resulting residue was purified on silica gel
column chromatography (chloroform/methanol=1/0-95/5) to provide
1.42 g of free amine body of the title compound. The amine body was
dissolved in diethyl ether, to which 4M hydrogen chloride solution
in dioxane (0.92 mL) was added at room temperature. Distilling the
solvent off from the resulting suspension, the remaining solid was
washed with ethanol/ethyl acetate (1/1) mixture to provide 1.06 g
of the title compound as a colorless solid.
[0185] .sup.1H-NMR (CD.sub.3OD) .delta.=0.27-0.38 (2H, m),
0.43-0.57 (1H, m),
[0186] 0.63-0.73 (1H, m), 1.40-1.69 (6H, m), 1.78-1.87 (1H, m),
[0187] 1.96-2.09 (2H, m), 2.27-2.37 (1H, m), 2.52-2.60 (1H, m),
[0188] 2.70-3.27 (6H, m), 3.51-3.60 (2H, m), 3.65-3.80 (2H, m),
[0189] 3.87-4.03 (3H, m), 4.52-4.67 (1H, m), 7.08-7.16 (2H, m),
[0190] 7.22-7.29 (1H, m), 7.32-7.41 (1H, m)
[0191] ESI-MS (+20 eV) m/z 426.2
INDUSTRIAL APPLICABILITY
[0192] Those compounds of the invention have the action to inhibit
binding of nociceptin to nociceptin receptor ORL1 and are useful as
analgesic against diseases accompanied with pain such as cancerous
pain, postoperative pain, migraine, gout, chronic rheumatism,
chronic pain and neuralgia; relievers against tolerance to narcotic
analgesic represented by morphine; relievers against dependence on
narcotic analgesic represented by morphine or against addiction;
analgesic enhancers; antiobestic or appetite suppressors; treating
or prophylactic agents for cognitive impairment and
dementia/amnesia in aging, cerebrovascular diseases and Alzheimer's
disease; agents for treating developmental cognitive abnormality in
attention deficit, hyperactivity disorder and learning disability;
remedy for schizophrenia; agents for treating neurodegenerative
diseases represented by Parkinsonism and chorea; anti-depressant or
treating agents for affective disorder; treating or prophylactic
agents for diabetes insipidus; treating or prophylactic agents for
polyuria; and remedy for hypotension and the like.
* * * * *