U.S. patent application number 15/664733 was filed with the patent office on 2017-11-16 for therapeutic agent for pain.
This patent application is currently assigned to ASTELLAS PHARMA INC.. The applicant listed for this patent is ASTELLAS PHARMA INC.. Invention is credited to Tetsuo KISO, Mina TSUKAMOTO.
Application Number | 20170327474 15/664733 |
Document ID | / |
Family ID | 45810669 |
Filed Date | 2017-11-16 |
United States Patent
Application |
20170327474 |
Kind Code |
A1 |
KISO; Tetsuo ; et
al. |
November 16, 2017 |
THERAPEUTIC AGENT FOR PAIN
Abstract
[Problem] Provided is a pharmaceutical, in particular, a
pharmaceutical composition which is useful for the treatment of
pain. [Means for Solution] The present inventors have made
extensive studies using model animals with pain for the purpose of
providing a therapeutic agent for pain. As a result, they have
found that 11.beta.-hydroxydehydrogenase type 1 (11.beta.-HSD1)
inhibitor, in particular, a triazole compound having a cyclic group
at the 3-position (or 5-position) of a triazole ring has a good
effect of ameliorating chronic pain. That is, according to the
present invention, a pharmaceutical composition comprising an
11.beta.-HSD1 inhibitor, in particular, the triazole compound of
the present invention, as an active ingredient, is useful for the
treatment of pain (particularly, neuropathic pain or
fibromyalgia).
Inventors: |
KISO; Tetsuo; (Tokyo,
JP) ; TSUKAMOTO; Mina; (Tokyo, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ASTELLAS PHARMA INC. |
Tokyo |
|
JP |
|
|
Assignee: |
ASTELLAS PHARMA INC.
Tokyo
JP
|
Family ID: |
45810669 |
Appl. No.: |
15/664733 |
Filed: |
July 31, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13820873 |
Mar 5, 2013 |
9765040 |
|
|
PCT/JP2011/070205 |
Sep 6, 2011 |
|
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15664733 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/04 20180101;
A61P 29/00 20180101; C07D 413/12 20130101; A61P 21/00 20180101;
C07D 403/04 20130101; A61P 25/00 20180101; C07D 249/08 20130101;
A61K 31/4196 20130101 |
International
Class: |
C07D 249/08 20060101
C07D249/08; A61K 31/4196 20060101 A61K031/4196; C07D 403/04
20060101 C07D403/04; C07D 413/12 20060101 C07D413/12 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 7, 2010 |
JP |
2010-200305 |
Claims
1. (canceled)
2. A method for treating fibromyalgia, comprising administering, to
a subject in need thereof, an effective amount of a compound
selected from the group consisting of:
3-(2-chloro-4-fluorophenyl)-4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenox-
y)ethyl]-4H-1,2,4-triazole,
3-[1-(4-chloro-2,6-difluorophenoxy)-1-methylethyl]-5-(2-chlorophenyl)-4-m-
ethyl-4H-1,2,4-triazole,
4-{5-[1-(4-chloro-2,6-difluorophenoxy)-1-methylethyl]-4-ethyl-4H-1,2,4-tr-
iazol-3-yl}benzamide,
4-{5-[1-(4-chloro-2,6-difluorophenoxy)-1-methylethyl]-4-methyl-4H-1,2,4-t-
riazol-3-yl}-3-fluorobenzamide,
4-{4-cyclopropyl-5-[1-(2,4-difluorophenoxy)-1-methylethyl]-4H-1,2,4-triaz-
ol-3-yl}-3-fluorobenzamide, and
3-fluoro-4-{4-isopropyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1-
,2,4-triazol-3-yl}benzamide, or a pharmaceutically acceptable salt
thereof.
3. The method according to claim 2, wherein said compound is
3-(2-chloro-4-fluorophenyl)-4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenox-
y)ethyl]-4H-1,2,4-triazole or a pharmaceutically acceptable salt
thereof.
4. The method according to claim 2, wherein said compound is
3-[1-(4-chloro-2,6-difluorophenoxy)-1-methylethyl]-5-(2-chlorophenyl)-4-m-
ethyl-4H-1,2,4-triazole or a pharmaceutically acceptable salt
thereof.
5. The method according to claim 2, wherein said compound is
4-{5-[1-(4-chloro-2,6-difluorophenoxy)-1-methylethyl]-4-ethyl-4H-1,2,4-tr-
iazol-3-yl}benzamide or a pharmaceutically acceptable salt
thereof.
6. The method according to claim 2, wherein said compound is
4-{5-[1-(4-chloro-2,6-difluorophenoxy)-1-methylethyl]-4-methyl-4H-1,2,4-t-
riazol-3-yl-3-fluorobenzamide or a pharmaceutically acceptable salt
thereof.
7. The method according to claim 2, wherein said compound is
4-4-cyclopropyl-5-[1-(2,4-difluorophenoxy)-1-methylethyl]-4H-1,2,4-triazo-
l-3-yl}-3-fluorobenzamide or a pharmaceutically acceptable salt
thereof.
8. The method according to claim 2, wherein said compound is
3-fluoro-4-{4-isopropyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1-
,2,4-triazol-3-yl}benzamide or a pharmaceutically acceptable salt
thereof.
Description
[0001] This is a divisional of U.S. application Ser. No.
13/820,873, filed Mar. 5, 2013, which is the National Stage of
International Application no. PCT/JP2011/070205, filed Sep. 6,
2011, which claimed priority to Japanese Patent Application no.
2010-200305, filed Sep. 7, 2010, of which all of the disclosures
are incorporated herein by reference in their entireties.
TECHNICAL FIELD
[0002] The present invention relates to a pharmaceutical
composition which is useful as a therapeutic agent for pain, in
particular, neuropathic pain or fibromyalgia.
BACKGROUND ART
[0003] There are various classifications of pain, but in terms of
the duration or nature, they may be classified into acute pain
which plays a role as a biological alert system and chronic pain in
which a duration taken for curing the diseases is exceeded usually
but complaints of pain continue. According to the causes, pain can
be classified into three main types, that is, nociceptive pain,
neuropathic pain, and psychogenic pain. Neuropathic pain refers to
intractable chronic pain which occurs as a result of dysfunction of
the peripheral or central nervous system. Typical examples of
neuropathic pain include pain associated with diabetic neuropathy,
postherpetic neuralgia, low back pain and leg pain, trigeminal
neuralgia, cancer pain, post-operative or post-traumatic prolonged
pain, pain induced by spinal cord injury, thalamic pain, multiple
sclerosis-derived pain, a complex regional pain syndrome (CRPS),
phantom limb pain, HIV-related neuropathic pain, and the like.
There are many unclear points about the onset mechanism of the
disease, but believed to be induced by persistent abnormal firing
of sensory nerves or the like. Typical examples of neuropathic pain
include allodynia, hyperalgesia, hyperesthesia, and the like. These
symptoms exhibit characteristic pain which is expressed by
"burning", "pins and needles", "electric shock-like", or the
like.
[0004] It is known that non-steroidal anti-inflammatory analgesics
which are effective for common nociceptive pain are ineffective for
neuropathic pain, and even narcotic analgesics such as morphine and
the like do not work well for neuropathic pain (Non-Patent Document
1). As a treatment method for neuropathic pain, neurosurgical
treatments such as nerve block, electrical stimulation of spinal
epidural, and the like, an antidepressant (Non-Patent Document 2),
an antiepileptic (Non-Patent Document 3), and the like have been
used, but a safe and effective treatment method has not been
established. In recent years, new drugs such as pregabalin which is
a ligand for an .alpha.2.delta. subunit of a voltage-dependent
calcium channel have been launched commercially, but their efficacy
rates are not so high and there are problems in side effects such
as sleepiness, dizziness, and the like. Since a safe and effective
treatment method for neuropathic pain has not been still
established, there is a strong demand for development of a superior
therapeutic agent having fewer side effects with sufficient
efficacy.
[0005] Fibromyalgia has a core symptom of unbearable chronic pain
throughout the whole body, and is a chronic pain disease
accompanied by a variety of associated symptoms such as insomnia,
systemic fatigue, depressive symptoms, and the like. The symptoms
of fibromyalgia are very diverse. The pain symptoms of fibromyalgia
are characterized by being accompanied by chronic pain in deep
tissues such as muscle tissues, and pain during finger pressure
massage. Further, fibromyalgia is often associated with allodynia
such as touch allodynia and cold allodynia, or thermal
hyperalgesia. Further, as compared with patients with other pain
diseases (neuropathic pain, rheumatoid arthritis, osteoarthritis,
acute pain after operation, and the like), patients with
fibromyalgia have higher rates of being associated with
accompanying symptoms including affective disorders such as
depression, anxiety, and the like, feeling of fatigue, sleep
disorders, irritable bowel syndrome, and the like. For other pain
diseases, organic disorder or functional disorder which causes pain
are clear to certain degrees, whereas for the patients with
fibromyalgia, the causes accounting for pain are not clear. In
accordance with the American College of Rheumatology, diagnostic
criteria for fibromyalgia is defined as history of widespread pain
lasting for at least three months, and pain being present in at
least 11 of 18 tender point sites in the whole body (ligaments,
tendon, muscles, and the like in contact with the bones)
(Non-Patent Document 4). These diagnostic criteria are clearly
different from those of other pain diseases. That is, fibromyalgia
is a chronic disease which is independently present and clearly
different from other pain diseases from the viewpoints of symptoms,
causes of pain, diagnostic criteria, and the like.
[0006] In recent years, agents including pregabalin (Non-Patent
Document 5), duloxetine which is an SNRI (serotonin- and
noradrenaline-reuptake inhibitor) (Non-Patent Document 6),
pramipexole which is a dopamine agonist (Non-Patent Document 7),
and the like have been reported to statistically significantly
reduce the pain symptom scores of patients with fibromyalgia, as
compared with a placebo group, but the effects of these agents are
limited. A safe and effective treatment method for fibromyalgia has
yet to be established, and therefore, there is a strong demand for
development of a superior therapeutic agent having fewer side
effects with sufficient efficacy.
[0007] Glucocorticoid is a hormone which causes metabolic disorders
such as hyperglycemia, insulin resistance, obesity, hyperlipidemia,
hypertension and the like, and is not only produced from adrenal
glands but also converted from the inactive form into the active
form at the tissue level, and acts via its receptor.
[0008] 11.beta.-Hydroxysteroid dehydrogenase (11.beta.-HSD) is an
enzyme which catalyzes this conversion and the presence of two
subtypes thereof is known. 11.beta.-Hydroxysteroid dehydrogenase
type 1 (11.beta.-HSD1) is an enzyme which converts the inactive
form into the active form and highly expressed in the liver, and
11.beta.-hydroxysteroid dehydrogenase type 2 (11.beta.-HSD2) is an
enzyme which converts the active form into the inactive form and
highly expressed in the kidney. 11.beta.-HSD1 has a wide range of
substrate specificity (Non-Patent Document 8), but the relation
thereof with glucocorticoid is most well-known. Since it has been
reported, for example, that an 11.beta.-HSD1 knockout mouse
exhibits improved glucose tolerance, lowered blood triglyceride,
and increased HDL-cholesterol (Non-Patent Document 9) and a
non-selective 11.beta.-HSD inhibitor, carbenoxolone, improves the
lowering of insulin secretion in mouse pancreatic .beta.-cell
caused by the addition of inactive-form glucocorticoid (Non-Patent
Document 10), it is expected that an 11.beta.-HSD1 selective
inhibitor inhibits the conversion into active-form glucocorticoid,
and thus inhibits the glucocorticoid action in the tissues, and as
a result, metabolic abnormalities such as hyperglycemia, insulin
resistance, obesity, hyperlipidemia, hypertension, and the like
induced by glucocorticoid, are cured (Patent Document 1).
[0009] 11.beta.-HSD1 is also expressed in the central nervous
system such as the brain and the spinal cord (Non-Patent Documents
11 and 12). Since an action of improving language memory by
administering a nonselective 11.beta.-HSD inhibitor to a patient
with type II diabetes (Non-Patent Document 12), and an action of
ameliorating cognition disorders in aged 11.beta.-HSD1 knockout
mice (Non-Patent Document 13), and the like have been reported, it
is expected that the 11.beta.-HSD1-selective inhibitor inhibits the
action of glucocorticoid in the brain through the inhibition of
conversion into an active-form glucocorticoid, and as a result,
cognition disorders induced by glucocorticoid is cured (Patent
Document 1). The 11.beta.-HSD1 inhibitor is also expected to have
an effect to ameliorate, in addition to dementia, diseases in the
central nervous system, such as schizophrenia, depression, anxiety,
post-traumatic stress disorder (PTSD), attention
deficit/hyperactivity disorder (AD/HD), panic disorder, somnipathy,
and the like, which are greatly related to stress and in which an
HPA axis disorder, an increase in cortisol in the blood plasma, or
the like is recognized.
[0010] As for other diseases in which 11.beta.-HSD1 is involved,
osteoporosis and glaucoma are known, and the ameliorating effects
by the 11.beta.-HSD1 inhibitor on these diseases are expected.
[0011] While the involvement of 11.beta.-HSD1 is known in a number
of these diseases, the involvement of 11.beta.-HSD1 in pain has not
been clearly known, and in addition, the therapeutic effect of the
11.beta.-HSD1 inhibitor for pain has been unexplained thus far.
[0012] As the 11.beta.-HSD1 inhibitor, for example, there are
reports of Patent Documents 1 to 11.
[0013] In Patent Document 1, it is described that a triazole
compound represented by the following general formula (A) has an
11.beta.-HSD1 inhibitory action and is useful for the treatment of
diseases such as diabetes, hyperglycemia, insulin resistance,
obesity, hyperlipidemia, hypertension, osteoporosis, glaucoma,
dimentia, schizophrenia, depression, and the like. However, there
is no description of usefulness for the treatment of pain.
##STR00001##
[0014] (Refer to this publication for the symbols in the
formula.)
[0015] In Patent Document 2, it is described that a triazole
compound represented by the following general formula (B) has an
11.beta.-HSD1 inhibitory action and is useful for the treatment of
diseases such as diabetes, hyperglycemia, obesity, insulin
resistance, dyslipidemia, hyperlipidemia, hypertension, a metabolic
syndrome, and the like. However, there is no description of
usefulness for the treatment of pain.
##STR00002##
[0016] (Refer to this publication for the symbols in the
formula)
[0017] In Patent Documents 3 and 4, it is described that a triazole
compound represented by the following general formula (C) has an
11.beta.-HSD1 inhibitory action and is useful for the treatment of
diseases such as diabetes, hyperglycemia, hypertension, obesity,
insulin resistance, dyslipidemia, hyperlipidemia, hypertension, an
X syndrome, and the like. However, there is no description of
usefulness for the treatment of pain.
##STR00003##
[0018] (Refer to this publication for the symbols in the
formula.)
[0019] In Patent Document 5, it is described that a triazole
compound represented by the following general formula (D) has an
11.beta.-HSD1 inhibitory action and is useful for the treatment of
diseases such as diabetes, obesity, and a metabolic syndrome.
However, there is no description of usefulness for the treatment of
pain.
##STR00004##
[0020] (Z in the formula represents --(CH(R.sup.14))p-,
--(CH(R.sup.14))p-N(R.sup.16)--(CH(R.sup.15))q-, or
##STR00005##
Refer to this publication for other symbols.)
[0021] In Patent Document 6, it is described that a triazole
compound represented by the following general formula (E) has an
11.beta.-HSD1 inhibitory action and is useful for the treatment of
diseases such as diabetes, hyperglycemia, insulin resistance,
obesity, hyperlipidemia, hypertension, osteoporosis, glaucoma,
lowering of cognitive function, and the like. However, there is no
description of usefulness for the treatment of pain.
##STR00006##
[0022] (Refer to this publication for other symbols in the
formula.)
[0023] In Patent Document 7, it is described that a triazole
compound represented by the following general formula (F) has an
11.beta.-HSD1 inhibitory action and is useful for the treatment of
diseases such as diabetes, hyperglycemia, insulin resistance,
obesity, hyperlipidemia, hypertension, osteoporosis, glaucoma,
lowering of cognitive function, and the like. However, there is no
description of usefulness for the treatment of pain.
##STR00007##
[0024] (In the formula, R.sup.1 represents a heterocyclic group or
--N(R.sup.0)--R.sup.4, and A and B represent lower alkyl, or a
cycloalkyl ring formed by the combination with carbon atoms to
which these are bonded. Refer to this publication for other
symbols.)
[0025] In Patent Document 8, it is described that a compound
represented by the following general formula (G) has an
11.beta.-HSD1 inhibitory action and is useful for the treatment of
diabetes, metabolic syndrome, insulin resistance, obesity,
glaucoma, hyperglycemia, hyperinsulinemia, osteoporosis,
tuberculosis, atherosclerosis, dementia, depression, virus
diseases, inflammatory disease, and diseases in which the liver is
a target organ. Further, there is a description of pain for lots of
diseases exemplified as an inflammatory disease, but there is no
description of neuropathic pain.
##STR00008##
[0026] (Refer to this publication for other symbols in the
formula.)
[0027] In Patent Document 9, it is described that a compound
represented by the following general formula (H) has an
11.beta.-HSD1 inhibitory action and is useful for the treatment of
diabetes, metabolic syndrome, insulin resistance, obesity,
glaucoma, hyperglycemia, hyperinsulinemia, osteoporosis,
atherosclerosis, dementia, depression, virus disease, inflammatory
disease, and diseases in which the liver is a target organ.
Further, there is a description of pain for lots of diseases
exemplified as an inflammatory disease, but there is no description
of neuropathic pain.
##STR00009##
[0028] (Refer to this publication for other symbols in the
formula.)
[0029] In Patent Document 10, it is described that a compound
represented by the following general formula (J) has an
11.beta.-HSD1 inhibitory action and is useful for the treatment of
diabetes, metabolic syndrome, insulin resistance, obesity,
glaucoma, hyperglycemia, hyperinsulinemia, osteoporosis,
atherosclerosis dementia, depression, virus disease, inflammatory
disease, and diseases in which the liver is a target organ.
Further, there is a description of pain for lots of diseases
exemplified as an inflammatory disease, but there is no description
of neuropathic pain.
##STR00010##
[0030] (Refer to this publication for other symbols in the
formula.)
[0031] In Patent Document 11 which has been published after the
priority date of the present application, it is described that an
11.beta.-HSD1 inhibitor such as a compound represented by the
following general formula (K) and the like is useful for the
treatment of inflammation, chronic inflammation, pain, rheumatoid
arthritis (RA), or osteoarthritis (OA), and as specific examples of
the pain, pain associated with neuropathic pain and fibromyalgia,
and the like are described. However, in Patent Document 11, a test
method for neuropathic pain is described, but there is no
disclosure of any test results for neuropathic pain and pain
accompanied by fibromyalgia is described only in one line.
##STR00011##
[0032] (Refer to this publication for other symbols in the
formula.)
RELATED ART
Patent Documents
[0033] Patent Document 1: Pamphlet of International Publication WO
2010/001946 [0034] Patent Document 2: Specification of U. S.
Publication No. 2004/0133011 [0035] Patent Document 3: Pamphlet of
International Publication WO 03/104207 [0036] Patent Document 4:
Pamphlet of International Publication WO 03/104208 [0037] Patent
Document 5: Pamphlet of International Publication WO 2005/044192
[0038] Patent Document 6: Pamphlet of International Publication WO
2006/030805 [0039] Patent Document 7: Pamphlet of International
Publication WO 2007/105753 [0040] Patent Document 8: Pamphlet of
International Publication WO 2005/060963 [0041] Patent Document 9:
Pamphlet of International Publication WO 2006/134467 Patent
Document 10: Pamphlet of International Publication WO 2006/134481
Patent Document 11: Pamphlet of International Publication WO
2011/068927
Non-Patent Documents
[0041] [0042] Non-Patent Document 1: Lancet, 1999, Vol. 353, p.
1959-1966 [0043] Non-Patent Document 2: Basic & Clinical
Pharmacology & Toxicology, 2005, Vol. 96, p. 399-409 [0044]
Non-Patent Document 3: Clinical Therapeutics, 2003, Vol. 25, p.
2506-2538 [0045] Non-Patent Document 4: Arthritis & Rheumatism,
1990, Vol. 33, p. 160-172 [0046] Non-Patent Document 5: Journal of
Rheumatology, 2008, Vol. 35, p. 502-514 [0047] Non-Patent Document
6: Pain, 2008, Vol. 136, p. 432-444 [0048] Non-Patent Document 7:
Arthritis & Rheumatism, 2005, Vol. 52, p. 2495-2505 [0049]
Non-Patent Document 8: Journal of Steroid Biochemistry &
Molecular Biology, 2010, 119, p. 1-13 [0050] Non-Patent Document 9:
Journal of Biological Chemistry, 2001, Vol. 276, p. 41293-41300
[0051] Non-Patent Document 10: Journal of Biological Chemistry,
2000, Vol. 275, p. 34841-34844 [0052] Non-Patent Document 11:
Endocrinology, 1990, Vol. 127, p. 1450-1455 [0053] Non-Patent
Document 12: Proceeding of the National Academy of Science, 2004,
Vol. 101, p. 6734-6739 [0054] Non-Patent Document 13: Proceeding of
the National Academy of Science, 2001, Vol. 98, p. 4716-4721
DISCLOSURE OF INVENTION
Problems to be Solved by the Invention
[0055] An object of the present invention is to provide medicine
which is useful for the treatment of pain (in particular,
neuropathic pain or fibromyalgia).
Means for Solving the Problems
[0056] The present inventors have made extensive studies using
model animals with pain for the purpose of providing a therapeutic
agent for pain. As a result, they have found that a compound having
an 11.beta.-HSD1 inhibitory activity, in particular, a triazole
compound having a cyclic group at the 3-position (or 5-position) of
a triazole ring has a good chronic pain-ameliorating effect,
thereby completing the present invention.
[0057] That is, the present invention relates to:
[0058] (1) a therapeutic agent for pain comprising a compound
represented by the formula (I-a) or a pharmaceutically acceptable
salt thereof as an active ingredient:
##STR00012##
[0059] [the symbols in the formula have the following meanings:
[0060] Ring A: aryl, heterocyclic group, or cycloalkyl, each of
which may be substituted,
[0061] R.sup.1a: aryl or heterocyclic group each of which may be
substituted, or lower alkylene-cycloalkyl,
[0062] R.sup.2a: lower alkyl,
[0063] R.sup.1a: --H or lower alkyl, or
[0064] R.sup.2a and R.sup.1a are combined with each other to form
C.sub.2-6 alkylene, and
[0065] R.sup.4: lower alkyl, halogeno-lower alkyl, lower
alkylene-O-lower alkyl, cycloalkyl, lower alkylene-S-lower alkyl,
lower alkylene-S(O)-lower alkyl, lower alkylene-S(O).sub.2-lower
alkyl, or lower alkylene-cycloalkyl (the same shall apply
hereinafter)];
[0066] (2) the therapeutic agent for pain as set forth in (1),
wherein the pain is neuropathic pain; and
[0067] (3) the therapeutic agent for pain as set forth in (1),
wherein the pain is fibromyalgia.
[0068] The present invention further relates to use of the compound
of the formula (I-a) or a pharmaceutically acceptable salt thereof
for the manufacture of a pharmaceutical composition for preventing
or treating pain (in particular, neuropathic pain or fibromyalgia),
the compound of the formula (I-a) or a salt thereof used for the
treatment of pain (in particular, neuropathic pain or
fibromyalgia), and a method for treating pain, including a step of
administering an effective amount of the compound of the formula
(I-a) or a salt thereof to a subject.
[0069] That is, the present invention relates to:
[0070] (4) use of the compound represented by the formula (I-a) or
a pharmaceutically acceptable salt thereof for the manufacture of a
therapeutic agent for pain;
[0071] (5) use of the compound represented by the formula (I-a) or
a pharmaceutically acceptable salt thereof for the treatment of
pain;
[0072] (6) the compound represented by the formula (I-a) or a
pharmaceutically acceptable salt thereof for the treatment of pain;
and
[0073] (7) a method for treating pain, comprising a step of
administering a therapeutically effective amount of the compound
represented by the formula (I-a) or a pharmaceutically acceptable
salt thereof to a patient.
[0074] The present invention further relates to:
[0075] (8) a therapeutic agent for fibromyalgia comprising an
11.beta.-HSD1 inhibitor as an active ingredient.
EMBODIMENTS FOR CARRYING OUT THE INVENTION
[0076] Hereinafter, the present invention will be described in
detail.
[0077] The "lower alkyl" is preferably linear or branched alkyl
having 1 to 6 carbon atoms (hereinafter abbreviated as C.sub.1-6),
specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl, n-pentyl, n-hexyl, or the like, more
preferably C.sub.1-4 alkyl, and particularly preferably methyl,
ethyl, n-propyl, or isopropyl.
[0078] The "lower alkylene" is preferably linear or branched
C.sub.1-6 alkylene, specifically, methylene, ethylene,
trimethylene, tetramethylene, pentamethylene, hexamethylene,
propylene, methylmethylene, ethylethylene, 1,2-dimethylethylene,
1,1,2,2-tetramethylethylene, or the like, more preferably,
C.sub.1-4 alkylene, and particularly preferably methylene,
ethylene, or trimethylene.
[0079] The "halogen" means F, Cl, Br, or I.
[0080] The "halogeno-lower alkyl" is lower alkyl substituted with
one or more halogen atoms, preferably lower alkyl substituted with
1 to 7 halogen atoms, more preferably lower alkyl substituted with
1 to 5 halogen atoms, and still more preferably fluoromethyl,
difluoromethyl, or trifluoromethyl.
[0081] The "halogen-lower alkylene" is lower alkylene substituted
with one or more halogen atoms, preferably lower alkylene
substituted with 1 to 7 halogen atoms, and more preferably
fluoromethylene, difluoromethylene, trifluoromethylmethylene, or
bistrifluoromethylmethylene.
[0082] The "cycloalkyl" is a C.sub.3-10 saturated hydrocarbon ring
group, which may have a bridge, specifically, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
adamantyl, or the like, preferably C.sub.3-8 cycloalkyl, and more
preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
[0083] The "cycloalkenyl" is C.sub.3-15 cycloalkenyl, which may
have a bridge and includes a cyclic group fused with a benzene ring
in a moiety with a double bond, specifically, a cyclopentenyl,
cyclopentadienyl, cyclohexenyl, cyclohexadienyl,
1-tetrahydronaphthyl, 1-indenyl, 9-fluorenyl, or the like, more
preferably C.sub.5-10 cycloalkenyl, and particularly preferably
cyclopentenyl or cyclohexenyl.
[0084] The "aryl" is a C.sub.6-14 monocyclic to tricyclic aromatic
hydrocarbon ring group, preferably phenyl or naphthyl, and more
preferably phenyl.
[0085] The "heterocyclic" group means a cyclic group of i) a
monocyclic 3- to 8-membered (preferably 5- to 7-membered)
heterocycle having 1 to 4 hetero atoms selected from O, S, and N,
or ii) a bicyclic 8- to 14-membered (preferably 9- to 11-membered)
heterocycle or a tricyclic 11- to 20-membered (preferably 12- to
15-membered) heterocycle having 1 to 5 hetero atoms selected from
O, S, and N, which is formed by the ring fusion of the monocyclic
heterocycle with one or two rings selected from the group
consisting of a monocyclic heterocycle, a benzene ring, a C.sub.5-8
cycloalkane, and a C.sub.5-8 cycloalkene. The ring atom, S or N,
may be oxidized to form an oxide or a dioxide. The "heterocyclic"
group is preferably aziridinyl, azetidyl, pyrrolidinyl,
piperidinyl, piperazinyl, homopiperazinyl, oxiranyl, oxetanyl,
tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, homomorpholinyl,
tetrahydrothiopyranyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,
tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl,
oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,
thiadiazolyl, indolyl, isoindolinyl, indazolyl, indolizinyl,
benzimidazolyl, imidazo[1,2-a]pyridinyl, quinoxalinyl, quinolyl,
isoquinolyl, quinazolyl, cinnonyl, phthalazyl, benzofuranyl,
benzothienyl, benzoxazolyl, benzothiazolyl, benzotriazolyl,
4,5,6,7-tetrahydroindazolyl,
4,5,6,7-tetrahydropyrazolo[4,3-c]pyridinyl,
4,5,6,7-tetrahydrobenzimidazolyl, carbazolyl, or quinuclidinyl,
more preferably a monocyclic heterocyclic group, and still more
preferably pyrrolidinyl, piperidinyl, piperadinyl, morpholinyl,
pyridyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl, or
thiazolyl.
[0086] The "heteroaryl" means an aromatic heterocyclic ring among
the "heterocyclic" groups above, specifically, pyrrolyl, pyrazolyl,
imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl,
furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,
isothiazolyl, thiadiazolyl, indolyl, indazolyl, benzimidazolyl,
imidazo[1,2-a]pyridinyl, quinoxalinyl, quinolyl, isoquinolyl,
quinazolyl, cinnonyl, phthalazyl, benzofuranyl, benzothienyl,
benzoxazolyl, benzothiazolyl, benzotriazolyl, or carbazolyl, and
preferably monocyclic heteroaryl, more preferably pyridyl, furyl,
thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,
isothiazolyl, or thiadiazolyl.
[0087] The expression "which may be substituted" means
"unsubstituted" or "having 1 to 5 substituents which may be the
same as or different from one another". The term "substituted"
means "having 1 to 5 substituents which may be the same as or
different from one another". In addition, in a case where a
plurality of substituents is present, the substituents may be the
same as or different from one another.
[0088] The substituent in the "aryl" and the "heterocyclic group",
each of which may be substituted, in R.sup.1a is preferably a group
selected from the following Group G.sup.1 (in which R.sup.0 means
--H or lower alkyl; and the same shall apply hereinafter), and more
preferably halogen, lower alkyl, halogeno-lower alkyl, --O-lower
alkyl, --O-halogeno-lower alkyl, --C(O)NH.sub.2 or heteroaryl, and
still more preferably halogen, halogeno-lower alkyl, or
--C(O)NH.sub.2.
[0089] Group G.sup.1: halogen, cyano, lower alkyl, halogeno-lower
alkyl, lower alkylene-OR.sup.0, lower)alkylene-N(R.sup.0).sub.2,
lower)alkylene-N(R.sup.0)C(O)R.sup.0,
lower)alkylene-N(R.sup.0)S(O).sub.2-lower alkyl, --OR.sup.0,
--O-halogen-lower alkyl, --O-cycloalkyl, --O-aryl, --O-heterocyclic
group, --C(O)R.sup.0, --CO.sub.2R.sup.0, --C(O)NH.sub.2,
--C(O)N(R.sup.0)-(lower alkyl which may be substituted with
--OR.sup.0 or --CO.sub.2R.sup.0), --C(O)N(R.sup.0)-lower
alkylene-OR.sup.0,
--C(O)N(R.sup.0)-lower)alkylene-N(R.sup.0).sub.2,
--C(O)N(R.sup.0)-lower alkylene-S-lower alkyl,
--C(O)N(R.sup.0)-lower alkylene-S(O)-lower alkyl,
--C(O)N(R.sup.0)-lower alkylene-S(O).sub.2-lower alkyl,
--C(O)N(R.sup.0)-lower alkylene-C(O)N(R.sup.0).sub.2,
--C(O)N(R.sup.0)-lower)alkylene-C(O)N(R.sup.0)-cycloalkyl,
--C(O)N(R.sup.0)-lower alkylene-heterocyclic group,
--C(O)N(R.sup.0)-cycloalkyl, --C(O)N(R.sup.0)-heterocyclic group,
--C(O)N(R.sup.0)N(R.sup.0).sub.2,
--C(O)N(R.sup.0)N(R.sup.0)C(O)R.sup.0,
--C(O)N(R.sup.0)S(O).sub.2-lower alkyl, --C(O)-heterocyclic group,
--C(.dbd.NOR.sup.0)--N(R.sup.0).sub.2, --S-lower alkyl,
--S(O)-lower alkyl, --S(O).sub.2-lower alkyl, oxo, and a
heterocyclic group.
[0090] In this case, the aryl and the heterocyclic group in Group
G.sup.1 may be substituted with a group selected from the following
Group G.sup.2.
[0091] Group G.sup.2: halogen, cyano, lower alkyl, halogeno-lower
alkyl, --OR.sup.0, --O-halogeno-lower alkyl, --CO.sub.2R.sup.0,
--C(O)N(R.sup.0).sub.2, --C(O)N(R.sup.0)S(O).sub.2-lower alkyl,
--C(O)N(R.sup.0)S(O).sub.2N(R.sup.0).sub.2, cycloalkyl, and a
heterocyclic group.
[0092] The substituent in the "aryl", "heterocyclic group", and
"cycloalkyl", each of which may be substituted, in Ring A is
preferably a group selected from the following Group G.sup.3, more
preferably halogen, lower alkyl, halogen-lower alkyl, --O-lower
alkyl, --O-halogeno-lower alkyl, or --C(O)NH.sub.2, and still more
preferably halogen, halogeno-lower alkyl, or --C(O)NH.sub.2.
[0093] Group G.sup.3: halogen, cyano, lower alkyl, halogeno-lower
alkyl, lower alkylene-OR.sup.0, halogeno-lower alkylene-OR.sup.0,
lower)alkylene-N(R.sup.0).sub.2, lower alkylene-aryl, --OR.sup.0,
--O-halogeno-lower alkyl, --O-lower alkylene-OR.sup.0,
--O-lower)alkylene-N(R.sup.0).sub.2, --O-lower
alkylene-CO.sub.2R.sup.0, --O-lower)alkylene-C(O)N(R.sup.0).sub.2,
--O-lower alkylene-aryl, --O-aryl, --C(O)R.sup.0,
--CO.sub.2R.sup.0, --CON(R.sup.0).sub.2, --CON(R.sup.0)-lower
alkylene-OR.sup.0, --N(R.sup.0).sub.2, --N(R.sup.0)C(O)R.sup.0,
--S-lower alkyl, --S(O)-lower alkyl, --S(O).sub.2-lower alkyl,
--S(O).sub.2-aryl, oxo, cycloalkyl, aryl, and a heterocyclic
group.
[0094] In this case, the aryl and heterocyclic group in Group
G.sup.3 may be substituted with halogen, lower alkyl,
halogeno-lower alkyl, --OR.sup.0, --O-halogeno-lower alkyl,
--CO.sub.2R.sup.0, or --CON(R.sup.0).sub.2.
[0095] The substituent in the "aryl" which may be substituted in
R.sup.ib is preferably halogen, lower alkyl, halogeno-lower alkyl,
--O-lower alkyl, or --O-halogeno-lower alkyl, and more preferably
halogen.
[0096] The substituent in the "aryl" and the "heteroaryl", each of
which may be substituted, in Ring A.sup.b is preferably halogen,
lower alkyl, halogeno-lower alkyl, --O-lower alkyl,
--O-halogeno-lower alkyl or --C(O)NH.sub.2, and still more
preferably halogen, halogeno-lower alkyl, or --C(O)NH.sub.2.
[0097] The "11.beta.-HSD1 inhibitor" is a compound inhibiting the
enzyme activity of an 11.beta.-HSD1, and not particularly limited
as long as it is effective for pains. Preferably, the 11.beta.-HSD1
inhibitor is a compound having an IC.sub.50 value of 10 .mu.M or
less, more preferably 3 .mu.M or less, and still more preferably 1
.mu.M or less in the measurement test on the rat 1113-HSD1
inhibitory activity according to the test method described in
Example 1 described later.
[0098] The "pain" is preferably neuropathic pain. Further, in other
embodiments, it is preferably fibromyalgia.
[0099] Preferred embodiments of the compound represented by the
formula (I-a), which is an active ingredient for the pharmaceutical
of the present invention, are shown below.
[0100] (1) A compound represented by the formula (I-b):
##STR00013##
[0101] [the symbols in the formula denote the following
meanings:
[0102] R.sup.1b: aryl which may be substituted,
[0103] R.sup.2b: lower alkyl,
[0104] R.sup.3b: lower alkyl,
[0105] R.sup.4b: lower alkyl or cycloalkyl,
[0106] Ring A.sup.b: aryl or heteroaryl, each of which may be
substituted, and
[0107] the other symbols have the same meanings].
[0108] (2) A compound represented by the formula (I-c):
##STR00014##
[0109] [the symbols in the formula denote the following
meanings:
[0110] R.sup.1c: phenyl substituted with halogen,
[0111] R.sup.4c: methyl, ethyl, isopropyl, or cyclopropyl, and
[0112] Ring A.sup.c: phenyl substituted with halogen or
--C(O)NH.sub.2].
[0113] (3) The compound as set forth in (2), wherein Ring A.sup.c
is phenyl, which is substituted with --C(O)NH.sub.2 at the
4-position and may be further substituted with halogen.
[0114] (4) The compound as set forth in (2), wherein Ring A.sup.c
is phenyl substituted with halogen.
[0115] (5) A compound selected from the group consisting of: [0116]
3-(2-bromo-4-fluorophenyl)-4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy-
)ethyl]-4H-1,2,4-triazole, [0117]
3-(2-chloro-4-fluorophenyl)-4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenox-
y)ethyl]-4H-1,2,4-triazole, [0118]
3-(2-chlorophenyl)-4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]--
4H-1,2,4-triazole, [0119]
3-[1-(4-chloro-2,6-difluorophenoxy)-1-methylethyl]-5-(2-chlorophenyl)-4-m-
ethyl-4H-1,2,4-triazole, [0120]
3-[1-(4-chloro-2,6-difluorophenoxy)-1-methylethyl]-5-(2-chloro-4-fluoroph-
enyl)-4-methyl-4H-1,2,4-triazole, [0121]
3-(2-fluorophenyl)-4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]--
4H-1,2,4-triazole, [0122]
4-methyl-3-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-5-[3-(trifluorometh-
yl)-1H-pyrazol-4-yl]-4H-1,2,4-triazole, [0123]
4-{5-[1-(4-chloro-2,6-difluorophenoxy)-1-methylethyl]-4-ethyl-4H-1,2,4-tr-
iazol-3-yl}benzamide, [0124]
4-{4-isopropyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1,2,4-tria-
zol-3-yl}benzamide, [0125]
4-{5-[1-(4-chloro-2,6-difluorophenoxy)-1-methylethyl]-4-methyl-4H-1,2,4-t-
riazol-3-yl}-3-fluorobenzamide, [0126]
4-{4-cyclopropyl-5-[1-(2,4-difluorophenoxy)-1-methylethyl]-4H-1,2,4-triaz-
ol-3-yl}-3-fluorobenzamide, [0127]
3-fluoro-4-{4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1,2,-
4-triazol-3-yl}benzamide, [0128]
4-{5-[1-(4-chloro-2,6-difluorophenoxy)-1-methylethyl]-4-isopropyl-4H-1,2,-
4-triazol-3-yl}benzamide, [0129]
3-chloro-4-{4-cyclopropyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-
-1,2,4-triazol-3-yl}benzamide, and [0130]
3-fluoro-4-{4-isopropyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1-
,2,4-triazol-3-yl}benzamide.
[0131] Other preferred embodiments of the compound of the formula
(I-a) which is an active ingredient for the pharmaceutical of the
present invention are shown below.
[0132] (a) R.sup.1a is preferably aryl which may be substituted,
more preferably phenyl which may be substituted, still more
preferably phenyl substituted with halogen, and even still more
preferably phenyl substituted with halogens at the 2- and
4-positions, or phenyl substituted with halogens at the 2-, 4-, and
6-positions.
[0133] (b) R.sup.2a is preferably lower alkyl, and more preferably
methyl.
[0134] (c) R.sup.1a is preferably lower alkyl, and more preferably
methyl.
[0135] (d) R.sup.4 is preferably lower alkyl or cycloalkyl, and
more preferably methyl, ethyl, isopropyl, or cyclopropyl.
[0136] (e) Ring A is preferably aryl or heteroaryl, each of which
may be substituted, more preferably aryl which may be substituted,
still more preferably phenyl which may be substituted, even still
more preferably phenyl substituted with halogen or --C(O)NH.sub.2,
even still more preferably phenyl substituted with halogen,
particularly preferably phenyl substituted with halogen at the
2-position, or phenyl substituted with halogens at the 2- and
4-positions. In another embodiment, Ring A is preferably phenyl
which is substituted with --C(O)NH.sub.2 and may be further
substituted with halogen, more preferably phenyl which is
substituted with --C(O)NH.sub.2 at the 4-position and may be
further substituted with halogen. Further, in a further embodiment,
Ring A is preferably phenyl or pyrrole, each of which is
substituted with a group selected from halogen, halogeno-lower
alkyl, and --C(O)NH.sub.2.
[0137] (f) The compound formed by two or more combination of the
groups described in (a) to (e) above.
[0138] The compound of the formula (I-a) which is an active
ingredient for the pharmaceutical of the present invention may
exist in the form of tautomers or geometrical isomers depending on
the kind of substituents. In the present specification, the
compound of the formula (I-a) shall be described in only one form
of isomer, but the active ingredient for the pharmaceutical of the
present invention includes other isomers, isolated forms of the
isomers, or a mixture thereof.
[0139] In addition, the compound of the formula (I-a) which is an
active ingredient for the pharmaceutical of the present invention
may have asymmetric carbon atoms or axial chirality in some cases,
and correspondingly, it may exist in the form of optical isomers.
The active ingredient for the pharmaceutical of the present
invention includes both an isolated form of the optical isomers or
a mixture thereof.
[0140] Furthermore, the compound of the formula (I-a) which is an
active ingredient for the pharmaceutical of the present invention
also includes a pharmaceutically acceptable prodrug thereof. The
pharmaceutically acceptable prodrug is a compound having a group
that can be converted into an amino group, a hydroxyl group, a
carboxyl group, or the like through solvolysis or under
physiological conditions. Examples of the group forming the prodrug
include the groups described in Prog. Med., 5, 2157-2161 (1985) and
"Iyakuhin no Kaihatsu (Pharmaceutical Research and Development)"
(Hirokawa Publishing Company, 1990), Vol. 7, Bunshi Sekkei
(Molecular Design), 163-198.
[0141] Moreover, the compound of the formula (I-a) which is an
active ingredient for the pharmaceutical of the present invention
may form an acid addition salt or a salt with a base depending on
the kind of substituents. Specific examples thereof include acid
addition salts with inorganic acids such as hydrochloric acid,
hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid,
phosphoric acid, and the like, and with organic acids such as
formic acid, acetic acid, propionic acid, oxalic acid, malonic
acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic
acid, mandelic acid, tartaric acid, dibenzoyltartaric acid,
ditoluoyltartaric acid, citric acid, methanesulfonic acid,
ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
aspartic acid, glutamic acid, and the like, and salts with
inorganic bases such as sodium, potassium, magnesium, calcium,
aluminum, and the like, or organic bases such as methylamine,
ethylamine, ethanolamine, lysine, ornithine, and the like, salts
with various amino acids or amino acid derivatives such as
acetylleucine and the like, ammonium salts, etc.
[0142] Moreover, the compound of the formula (I-a) which is an
active ingredient for the pharmaceutical of the present invention
also includes various hydrates or solvates, and crystal polymorphs.
In addition, the compound of the formula (I-a) which is an active
ingredient for the pharmaceutical of the present invention also
includes compounds labeled with various radioactive or
non-radioactive isotopes.
[0143] (Preparation Methods)
[0144] The compound of the formula (I-a) and a salt thereof, which
are active ingredients for the pharmaceutical of the present
invention, can be prepared using the characteristics based on the
basic structure or the type of substituent and by applying various
known synthesis methods. During the preparation, replacement of the
relevant functional group with a suitable protective group (a group
that can be easily converted into the relevant functional group) at
the stage from starting material to an intermediate may be
effective depending on the type of the functional group in the
production technology in some cases. The protective group for such
a functional group may include, for example, the protective groups
described in "Greene's Protective Groups in Organic Synthesis
(4.sup.th Ed, 2006)" written by P. G M. Wuts and T. W. Greene, and
one of these should only be selected and used as necessary
depending on reaction conditions. In such a method, a desired
compound can be obtained by introducing the protective group, by
carrying out a reaction and by eliminating the protective group as
necessary.
[0145] In addition, the prodrug of the compound of the formula
(I-a) can be produced by introducing a specific group at the stage
from a starting material to an intermediate or by carrying out the
reaction using the obtained compound of the formula (I-a), just as
in the case of the above-mentioned protective group. The reaction
can be carried out using methods known to those skilled in the art,
such as ordinary esterification, amidation, dehydration, and the
like.
[0146] Hereinbelow, typical preparation methods for the compound of
the formula (I-a) will be described. Each of the production
processes may also be carried out with reference to the References
appended in the present description. Further, the preparation
methods of the present invention are not limited to the examples
shown below.
##STR00015##
[0147] (In the formula, L.sup.1 represents a leaving group. The
same shall apply hereinafter.)
[0148] The present production process is a method for preparing the
compound (I-a) which is an active ingredient for the pharmaceutical
of the present invention by cyclization of a compound (1) with a
compound (2). Examples of the leaving group of L.sup.1 include
chloro, bromo, methoxy, methylsulfanyl, and the like. The reaction
can be carried out in a solvent, for example, such as ethers such
as tetrahydrofuran (THF), 1,4-dioxane, diglyme, and the like;
alcohols such as methanol, ethanol, propanol, butanol, and the
like; aprotic polar solvents such as N,N-dimethylformamide (DMF),
N-methylpyrrolidin-2-one (NMP), dimethylimidazolidinone,
dimethylacetamide (DMA), dimethylsulfoxide (DMSO), and the like;
aromatic hydrocarbons such as benzene, toluene, xylene, and the
like; halogenated hydrocarbons such as dichloromethane, chloroform,
1,2-dichloroethane, and the like; etc., at room temperature or
under heating conditions. Depending on the compound, it may be
advantageous in some cases to carry out the reaction in the
presence of an acid, for example, an organic acid such as acetic
acid, p-toluenesulfonic acid, and the like; a mineral acid such as
sulfuric acid, hydrochloric acid, and the like; etc., or in the
presence of an organic base such as triethylamine,
N,N-diisopropylethylamine, and the like; or an inorganic base such
as sodium hydrogen carbonate, potassium carbonate, and the like.
Depending on the compound, it may be advantageous in some cases to
carry out the reaction in the presence of a phase transfer catalyst
such as tetra-n-butylammonium iodide and the like.
##STR00016##
[0149] The present preparation process is a method for obtaining
the compound (I-a) which is an active ingredient for the
pharmaceutical of the present invention by reacting a compound (3)
with a compound (4).
[0150] The reaction can be carried out using the compound (3) and
the compound (4) in equivalent amounts, or with either thereof in
an excess amount in a solvent inert to the reaction, for example,
alcohols, aromatic hydrocarbons such as benzene, toluene, xylene,
and the like, acetic acid, or the like, or in the absence of a
solvent, under room temperature to heating, preferably under
heating. Depending on the compound, it may be advantageous in some
cases to carry out the reaction in the presence of an acid, for
example, an organic acid such as acetic acid, p-toluenesulfonic
acid, trifluoroacetic acid, and the like; a mineral acid such as
sulfuric acid, hydrochloric acid, and the like; etc. Also, it is
advantageous in some cases to carry out the reaction using a
microwave.
##STR00017##
[0151] (In the formula, R.sup.1z is aryl or heteroaryl, each of
which may be substituted, and L.sup.2 represents a leaving group.
The same shall apply hereinafter.)
[0152] The present preparation process is a method for obtaining
the compound (I-a-1) which is an active ingredient for the
pharmaceutical of the present invention, by O-arylation of a
compound (5). Examples of the leaving group of L.sup.2 include
halogen such as fluoro, chloro, bromo and the like.
[0153] The arylation reaction can be carried out using a compound
(5) and a compound (6) in equivalent amounts, or with either
thereof in an excess amount, under cooling to heating with
refluxing, in the presence of a base, in a solvent inert to the
reaction, such as an aprotic polar solvent such as DMF, DMSO, and
the like; ethers; etc. Examples of the base include sodium hydride,
potassium hydride, butyl lithium, potassium carbonate and the
like.
##STR00018##
[0154] The present preparation process is a method for preparing
the compound (I-a) which is an active ingredient for the
pharmaceutical of the present invention by cyclization reaction of
a compound (7) with a compound (8).
[0155] The cyclization reaction can be carried out in the same
manner as in the Production Process 1.
##STR00019##
[0156] The present preparation process is a method for obtaining
the compound (I-a) which is an active ingredient for the
pharmaceutical of the present invention by cyclization of a
compound (9).
[0157] The cyclization reaction can be carried out in a solvent
such as ethers, aromatic hydrocarbons, halogenated hydrocarbons,
and the like, at room temperature or under heating conditions.
Depending on the compound, it may be advantageous in some cases for
the progress of the reaction that the reaction is carried out in
the presence of an acid such as an organic acid such as acetic
acid, p-toluenesulfonic acid, and the like, or a mineral acid such
as sulfuric acid, hydrochloric acid, and the like, etc.
[0158] Furthermore, several compounds represented by the formula
(I-a) can also be prepared from the compound (I-a) which is an
active ingredient for the pharmaceutical of the present invention
obtained as above by optionally combining processes commonly
adoptable by those skilled in the art, such as known alkylation,
acylation, substitution reaction, oxidation, reduction, hydrolysis,
and the like.
[0159] The starting materials for use in the preparation of the
compound (I-a) which is an active ingredient for the pharmaceutical
of the present invention can be prepared by applying the methods
described below, the methods described in Preparation Examples to
be mentioned below, known methods or methods obvious to those
skilled in the art, or modified methods thereof.
##STR00020##
[0160] (In the formula, L.sup.3 represents a leaving group. The
same shall apply hereinafter.)
[0161] The compound (3) can be prepared by cyclization of compound
(11) obtained by amidation of the compound (1) and a compound (10).
Here, examples of the leaving group of L.sup.3 include chloro,
bromo, hydroxy, and the like.
[0162] The amidation reaction can be carried out using the compound
(1) and the compound (10) in equivalent amounts, or with either
thereof in an excess amount, in a solvent such as halogenated
hydrocarbons, aprotic polar solvents, and the like, under room
temperature to heating conditions. Depending on the compounds, it
is advantageous for the smooth progress of the reaction in some
cases to carry out the reaction in the presence of an organic base
such as triethylamine, N,N-diisopropylethylamine, pyridine, and the
like, or an inorganic base such as potassium carbonate, sodium
carbonate, and the like.
[0163] In the case where the leaving group of L.sup.3 is hydroxy,
it is preferable that the reaction be carried out in the presence
of a condensing agent such as
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC),
dicyclohexylcarbodiimide (DCC), 1,1'-carbonyldiimidazole (CDI),
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumhexafluorophosphate
(HBTU), and the like. In addition, it is preferable in some cases
that an additive (for example, 1-hydroxybenzotriazole (HOBt),
1-hydroxy-7-azabenzotriazole (HOAt), and the like) is used.
[0164] The cyclization reaction can be carried out by reacting the
compound (11) with a dehydrating agent such as phosphorus
oxychloride, trifluoromethanesulfonic anhydride, a reagent prepared
from triphenylphosphine and carbon tetrabromide, and the like in a
solvent such as an aprotic polar solvent such as halogenated
hydrocarbons and the like. Depending on the compound, it is
advantageous for the smooth progress of the reaction in some cases
to carry out the reaction in the presence of an organic base such
as triethylamine, N,N-diisopropylethylamine, pyridine, and the
like, or an inorganic base such as potassium carbonate, sodium
carbonate, and the like.
##STR00021##
[0165] The compound (5) can be prepared from a compound (12) and
the compound (2) in the same manner as in the Preparation Process
1.
##STR00022##
[0166] (In the formula, R represents lower alkyl and L.sup.4
represents a leaving group. The same shall apply hereinafter.)
[0167] In addition, the compound (3) can also be prepared by
cyclization of the compound (1) with a compound (13). Here,
examples of the leaving group of L.sup.4 include chloro, bromo, and
the like.
[0168] The reaction can be carried out in the same manner as in the
Preparation Process 1.
##STR00023##
[0169] The compound (9) can be prepared by the amidation reaction
of a compound (14) and a compound (15).
[0170] The amidation reaction can be carried out in the same
condition as in the amidation of the first step of the starting
material synthesis 1.
[0171] The compound of the formula (I-a) is isolated and purified
as a free compound or a salt, a hydrate, a solvate, or a crystal
polymorph thereof. The salt of the compound of the formula (I-a)
can also be prepared using a conventional salt formation
reaction.
[0172] Isolation and purification are carried out by applying
common chemical operations such as extraction, fractional
crystallization, various types of fractional chromatography, and
the like.
[0173] A variety of isomers can be prepared by selecting suitable
starting compounds or separated using differences in the
physicochemical properties between the isomers. For example,
optical isomers are obtained by a general optical resolution method
of racemic forms (for example, fractional crystallization in which
the racemic form is converted into diastereomer salts with an
optically active base or acid, chromatography using a chiral column
and the like, and the like), or can also be prepared from suitable
starting compounds which are optically active.
[0174] A pharmaceutical composition for treating pain of the
present invention, including one or two or more kinds of the
compound of the formula (I-a) as an active ingredient, can be
prepared using excipients that are usually used in the art, that
is, excipients for pharmaceutical preparation, carriers for
pharmaceutical preparation, and the like, according to the methods
usually used.
[0175] Administration can be accomplished either by oral
administration via tablets, pills, capsules, granules, powders,
solutions, and the like, or parenteral administration via
injections, such as intraarticular, intravenous, or intramuscular
injections, and the like, suppositories, eye drops, eye ointments,
transdermal liquid preparations, ointments, transdermal patches,
transmucosal liquid preparations, transmucosal patches, inhalers,
and the like.
[0176] As a solid composition for oral administration, tablets,
powders, granules, and the like are used. In such a solid
composition, one or two or more kinds of the active ingredient(s)
are mixed with at least one inactive excipient. In a conventional
method, the composition may contain inactive additives, such as a
lubricant, a disintegrating agent, a stabilizer, or a
solubilization assisting agent. If necessary, tablets or pills may
be coated with sugar or with a film of a gastric or enteric coating
substance.
[0177] The liquid composition for oral administration includes
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, elixirs, or the like, and also includes generally used
inert diluents, for example, purified water or ethanol. In addition
to the inert diluent, the liquid composition may also include
auxiliary agents such as a solubilization assisting agent, a
moistening agent, and a suspending agent, sweeteners, flavors,
aromatics, and antiseptics.
[0178] The injections for parenteral administration include sterile
aqueous or non-aqueous solution preparations, suspensions, or
emulsions. The aqueous solvent includes, for example, distilled
water for injection and physiological saline. Examples of the
non-aqueous solvent include alcohols such as ethanol. Such a
composition may further include a tonicity agent, an antiseptic, a
moistening agent, an emulsifying agent, a dispersing agent, a
stabilizing agent, or a solubilizing assisting agent. These are
sterilized, for example, by filtration through a bacteria retaining
filter, blending of a bactericide, or irradiation. In addition,
these can also be used by preparing a sterile solid composition,
and dissolving or suspending it in sterile water or a sterile
solvent for injection prior to its use.
[0179] The agent for external use includes ointments, plasters,
creams, jellies, patches, sprays, lotions, eye drops, eye
ointments, and the like. The agents include generally used ointment
bases, lotion bases, aqueous or non-aqueous liquid preparations,
suspensions, emulsions, and the like.
[0180] The transmucosal agents such as an inhaler, a transnasal
agent, and the like, those in the form of a solid, liquid, or
semi-solid state are used, can be prepared in accordance with a
conventionally known method. For example, a known excipient, and
also a pH adjusting agent, an antiseptic, a surfactant, a
lubricant, a stabilizing agent, a thickening agent, or the like may
be appropriately added thereto. For their administration, an
appropriate device for inhalation or blowing can be used. For
example, a compound may be administered alone or as a powder of
formulated mixture, or as a solution or suspension in combination
with a pharmaceutically acceptable carrier, using a conventionally
known device such as a measured administration inhalation device,
and the like, or sprayer. A dry powder inhaler or the like may be
for single or multiple administration use, and a dry powder or a
powder-containing capsule may be used. Alternatively, this may be
in a form such as a pressurized aerosol spray which uses an
appropriate ejection agent, for example, a suitable gas such as
chlorofluoroalkane, carbon dioxide, and the like, or other
forms.
[0181] Usually, in the case of oral administration, the daily dose
is from about 0.001 to 100 mg/kg, preferably from 0.1 to 30 mg/kg,
and more preferably from 0.1 to 10 mg/kg, per body weight,
administered in one portion or in 2 to 4 divided portions. In the
case of intravenous administration, the daily dose is suitably
administered from about 0.0001 to 10 mg/kg per body weight, once a
day or two or more times a day. In addition, a transmucosal agent
is administered at a dose from about 0.001 to 100 mg/kg per body
weight, once or plural times a day. The dose is appropriately
decided in response to the individual case by taking the symptoms,
the age, and the gender, and the like into consideration.
[0182] A therapeutic agent for pain including the compound of the
formula (I-a) or a pharmaceutically acceptable salt thereof as an
active ingredient may be used in combination with other therapeutic
agents for pain. Such the combined preparations may be administered
simultaneously, or separately and continuously, or at a desired
time interval. The preparations to be co-administered may be a
blend, or may be prepared individually.
EXAMPLES
[0183] Hereinafter, the present invention will be described in
detail with reference to Examples, but these do not restrict the
scope of the present invention.
Example 1: Measurement Test for Rat 11.beta.-HSD1 Inhibitory
Activity
[0184] The procedure for measuring the 11.beta.-HSD1-inhibitory
activity is as follows. The enzyme reaction and the measurement
were carried out using a 384-well plate. The enzyme was prepared in
accordance with Journal of Biological Chemistry, 2001, Vol. 276, p.
21343-21350. The reaction was carried out by adding a test compound
at various concentrations to a reaction liquid consisting of a 5 mM
phosphate buffer (pH 6.6), 200 nM cortisone, 40 .mu.M reduced
nicotinamide adenine dinucleotide phosphate (NADPH), and rat
recombinant 113-HSD1, followed by incubating at room temperature
for one hour (10 .mu.l/well). The test compound was prepared by
dissolving in dimethyl sulfoxide (DMSO) such that a DMSO
concentration reached 1% in the reaction liquid. After the enzyme
reaction was completed, the enzyme inhibitory action was measured
by detecting cortisol using a homogeneous time-resolved
fluorescence (HTRF) method. Each of a d2-labeled cortisol
containing 400 .mu.M carbenoxolone and a cryptate-labeled cortisol
antibody (CIS Bio International Co., Ltd.) was added at 5 ml/well,
followed by incubating at room temperature for 2 hours, and then
the fluorescence intensity was measured using a fluorophotometer
(trade name: ARVO HTS 1420, Perkin Elmer/Wallac), and the enzyme
inhibitory activity was calculated from the fluorescence intensity
ratio of two wavelengths (665 nm/620 nm).
[0185] The measurement results were calculated by averaging the
values of 3 wells of the same condition. The ratio when DMSO was
added instead of the test compound was taken as 0% and the ratio
when 11.beta.-HSD1 was not added was taken as 100%, thereby
calculating the 50% inhibition concentration of the test compound
as IC.sub.50 of the compound inhibitory activity.
[0186] The IC.sub.50 values of the typical compounds with respect
to the active ingredients for the pharmaceutical of the present
invention are shown in Table 1 below. Further, Cpd represents
Compound No. (the same shall apply hereinafter).
TABLE-US-00001 TABLE 1 Cpd IC.sub.50 (nM) 1 35 2 52 3 24 4 32 5 263
6 322 7 32 8 70 9 26 10 135 11 64 12 182 13 68 14 16 15 23
Example 2: Test of Spinal Nerve Ligation Model
[0187] The test was carried out in accordance with Pain, 1992, Vol.
50, p. 355-363. The lumbar skin and muscle of a rat (SD, male, 5-
to 6-week old) were incised under pentobarbital anesthesia and the
transverse processes of lumbar L6 were removed to expose lumbar
nerves. The L5 and L6 spinal nerves were ligated with silk thread
and then the wound was sutured. The treatment was performed on the
left side. However, in a case of a pseudo-operation, the wound was
sutured without carrying out the nerve ligation.
[0188] Drug efficacy evaluation was carried out by a von Frey hair
test 7 to 20 days after the operation. The withdrawal response
threshold was calculated in accordance with Journal of Neuroscience
Methods, 1994, Vol. 53, p. 55-63. The plantar of hindlimb was
stimulated using 8 kinds of von Frey filaments (0.41 to 15.14 g),
and 50% withdrawal response thresholds were determined by an
up-and-down method. The test was initiated from 2.04 g of the
filament, and a case where the withdrawal response of the limb was
observed was taken as presence of the response.
[0189] On the previous day of the drug efficacy evaluation, the
animals showing reduction in the thresholds according to a von Frey
hair test were preliminarily selected and grouped such that the
difference in the average values of the thresholds between the
respective groups was reduced.
[0190] The test substance was suspended in a 0.5% methylcellulose
solution and administered orally 2 hours before the drug efficacy
evaluation. The evaluation of the test substance was carried out by
determining the improvement rate of the group administered with the
test substance when the threshold of the limb on the treatment side
in the pseudo-operation animal group was taken as 100% and the
threshold of the limb on the treatment side in an operated animal
group administered with a solvent was taken as 0%.
[0191] The improvement rates of the typical compounds with respect
to the active ingredients for the pharmaceuticals of the present
invention are shown in Table 2 below.
TABLE-US-00002 TABLE 2 Improvement rate % Cpd (dose) 1 71 (0.3
mg/kg) 2 88 (0.3 mg/kg) 3 62 (0.3 mg/kg) 4 85 (0.3 mg/kg) 5 65 (0.3
mg/kg) 6 52 (0.3 mg/kg) 7 73 (0.3 mg/kg) 8 87 (0.3 mg/kg) 9 78 (0.3
mg/kg) 10 81 (0.3 mg/kg) 11 82 (0.3 mg/kg) 12 54 (0.3 mg/kg) 13 53
(0.3 mg/kg) 14 73 (0.3 mg/kg) 15 86 (0.3 mg/kg)
Example 3: Test of Fibromyalgia Model Induced by Repeated
Administration of Reserpine
[0192] The test was carried out in accordance with Pain, 2009, Vol.
146, p. 26-33. Rats (SD, male, 7 weeks old) were used.
[0193] The threshold measurement for the muscle pressure pain was
carried out according to the method of Schafers et al. (Pain, 2003,
Vol. 104, p. 579-588). The pressure stimulus gradually increasing
up to 250 g was applied to the gastrocnemius muscle of the right
hindlimb of the rat. The magnitude of the minimum pressure stimulus
at which the rat showed a withdrawal response with respect to
pressure stimulus of the right hindlimb was measured as a muscle
pressure pain threshold (g). The measurements were carried out in
triplicate for each point of time and the average thereof was taken
as a measured value.
[0194] A solvent (0.5% acetic acid/water) or reserpine at 1 mg/kg
was subcutaneously administered on a dorsal subcutaneous part for 3
days once per day. The administration volume of the solvent or
reserpine was taken as 1 mL per kg of a body weight of an animal.
The muscle pressure pain thresholds of the respective rats were
measured at 6 days after the initiation of the administration of
the solvent or reserpine, and grouped such that the difference in
the average values of the thresholds between the respective groups
was reduced.
[0195] The drug efficacy evaluation was carried out the next day.
The test substance was suspended in a 0.5% methylcellulose solution
and the muscle pressure pain thresholds were measured 30, 60, and
120 minutes after oral administration. For the normal rats, drug
administration was not carried out, and only the measurement of the
muscle pressure pain thresholds was carried out. The measurement of
the drug effect was carried out by an experimenter who does not
know the drug treatment context to an animal. The evaluation of the
test substance was carried out by determining the maximal
improvement rate of the group administered with the test substance
among at time points of 30, 60, and 120 minutes after the
administration when the muscle pressure pain threshold of the
normal rat is taken as 100% and the muscle pressure pain threshold
of the rat treated with reserpine while administered with the
solvent is taken as 0%.
[0196] The improvement rates of the typical compounds with respect
to the active ingredients for the pharmaceuticals of the present
invention are shown in Table 3 below.
TABLE-US-00003 TABLE 3 Maximum improvement rate % Point for
calculation Cpd (dose) (min) 2 30 (1 mg/kg) 120 4 82 (1 mg/kg) 30 8
41 (1 mg/kg) 120 10 65 (1 mg/kg) 120 11 83 (1 mg/kg) 30 15 45 (1
mg/kg) 120
[0197] As the results of the tests above, it was confirmed that the
compound represented by the formula (I-a) is effective in various
pain models. Therefore, it is apparent that the compound
represented by the formula (I-a) which is an active ingredient for
the pharmaceutical of the present invention can be used for the
treatment of pain (in particular, neuropathic pain, fibromyalgia,
or the like).
[0198] The methods for preparing the compounds with respect to the
active ingredients for the pharmaceuticals of the present invention
are shown below.
[0199] All the compounds 1 to 15 described in Tables 4 to 6 below
are known compounds and can be prepared in the following
manner.
[0200] All the compounds 1 to 15 are described as Example compounds
in the pamphlet of International Publication WO 2010/001946, and
can be prepared by the method described in this publication. For
example, the compound 2 is described as Example 65 of this
publication.
[0201] The following abbreviations are used in Tables below.
[0202] Cpd: Compound No., Structure: Structural formula (in the
case where HCl is described in the structural formula, it denotes
that the compound is hydrochloride salt).
TABLE-US-00004 TABLE 4 Cpd Structure 1 ##STR00024## HCl 2
##STR00025## HCl 3 ##STR00026## HCl 4 ##STR00027## HCl 5
##STR00028## HCl 6 ##STR00029## HCl 7 ##STR00030##
TABLE-US-00005 TABLE 5 8 ##STR00031## HCl 9 ##STR00032## HCl 10
##STR00033## HCl 11 ##STR00034## 12 ##STR00035## HCl 13
##STR00036## HCl 14 ##STR00037##
TABLE-US-00006 TABLE 6 15 ##STR00038## HCl
INDUSTRIAL APPLICABILITY
[0203] An 11.beta.-HSD1 inhibitor which is an active ingredient for
the pharmaceutical of the present invention, in particular, the
compound of the formula (I-a), is useful for the treatment of pain
(in particular, neuropathic pain or fibromyalgia).
* * * * *