DESCRIPTION
TITLE OF THE INVENTION
Cyclohexane Derivative and Pharmaceutical Use Thereof
TECHNICAL FIELD
[0001]
The present invention relates to a cyclohexane derivative and its medical use.
BACKGROUND ART
[0002]
Pain is an experience that is accompanied by an uncomfortable sense or
uncomfortable emotion, which occurs when a tissue is damaged or tissue may be
damaged. Pain is roughly divided into nociceptive pain and neuropathic pain
depending on its cause.
[0003]
The term "nociceptive pain" means a pain caused when a tissue of the body
was damaged or a nociceptive stimulus that may cause such damage was given to a
tissue of the body, and a nociceptive pain is caused through a nociceptor. Examples
of the nociceptive pain include physiological pains and inflammatory pains.
[0004]
The term "neuropathic pain" means a pathological pain due to a functional
abnormality of the peripheral nerve or the central nervous system itself, and a
neuropathic pain is caused by a direct damage to, or pressure on, a nerve without a
nociceptive stimulus to a nociceptor.
[0005]
Examples of therapeutic drugs of nociceptive pain include nonsteroidal anti-
inflammatory drugs (NSAIDs) and narcotic analgesics (e.g., opioid), and examples
of therapeutic drugs of neuropathic pain include anticonvulsants, antidepressants,
antianxiety agents, and antiepileptics such as gabapentin and pregabalin.
[0006]
Further, in recent years, it has been reported that a pyrazole derivative is
effective as an analgesic or a therapeutic drug for neuropathic pain (Patent Document
1) and that the cyclohexane derivative of the following Formula having sulfonyl on
an aromatic ring linked to a pyrazole ring has an analgesic effect on neuropathic pain
(Patent Document 2).

[0178]
The amount of the base to be used is preferably 0.8 to 5 moles, more
preferably 0.9 to 3 moles with respect to 1 mole of Compound (XII).
[0179]
The amount of Compound (LVI) or Compound (LVII) to be used is
preferably 0.8 to 5 moles, more preferably 0.9 to 3 moles with respect to 1 mole of
Compound (XII).
[0180]
The reaction temperature of the nucleophilic addition reaction is preferably -
78 to 150°C, more preferably 0 to 50°C.
[0181]
The reaction time of the nucleophilic addition reaction varies depending on
the reaction conditions, and is preferably 5 minutes to 72 hours, more preferably 30
minutes to 48 hours.
[0182]
(Step 26)
The oxidation reaction of Compound (XIII) is generally carried out by
allowing Compound (XIII) to react with an oxidizing agent in a solvent, and the
solvent is appropriately selected such that it does not inhibit the reaction. Examples
of the solvent which does not inhibit the reaction include trifluoroacetic acid,
pyridine, acetone, hydrocarbons such as octane, hexane, benzene and toluene;
halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride
and 1,2-dichloroethane; ethers such as tetrahydrofuran, 1,2-dimethoxyethane and
1,4-dioxane; and alkyl nitriles such as acetonitrile; and mixtures thereof may also be
used as the solvent.
[0183]
Examples of the oxidizing agent include commercially available reagents
such as manganese dioxide;" sulfur trioxide-pyridine; activated dimethyl sulfoxide;
and Dess-Martin reagent.
[0184]
The amount of the oxidizing agent to be used is preferably 0.5 to 3 moles,
more preferably 0.8 to 2 moles with respect to 1 mole of Compound (XIII).
[0185]
The reaction temperature of the oxidation reaction varies depending on the
type of the oxidizing agent, and is preferably -78 to 100°C, more preferably -78 to
40°C.
[0186]
The reaction time of the oxidation reaction varies depending on the reaction
conditions such as the type of the oxidizing agent and the reaction temperature, and
is preferably 5 minutes to 72 hours, more preferably 1 to 24 hours.
[0187]
(Production Method 17: Production Method of Intermediate Compound (SIIIa))
[wherein the symbols have the same meanings as those defined above.]
[0188]
Compound (SIIIa) can be obtained by alkylating Compound (XIV) with
Compound (LX) or acylating Compound (XVI) obtained from Compound (XIV)
with Compound (LXI), thereby obtaining Compound (XV), which is then cyclized.
Compound (XIV) and Compound (LX) can be synthesized according to methods
obvious to those skilled in the art. The Compound (LXI) may be one commercially
available, but it may also be synthesized according to a method obvious to those
skilled in the art.
[0189]
(Step 27)
The alkylation reaction of Compound (XIV) is generally carried out by
allowing Compound (XIV) to react with a halogenated alkyl in a solvent in the
presence of a base, and the solvent is appropriately selected such that it does not
inhibit the reaction. Examples of the solvent which does not inhibit the reaction
include ethers such as tetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl
ether; acetone; acetonitrile; and N,N-dimethylformamide; and mixtures thereof may
also be used as the solvent.
[0190]
Examples of the base include alkali metal hydrogen carbonates such as
sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal
carbonates such as potassium carbonate and cesium carbonate; amines such as
triethylamine, diisopropylethylamine and pyridine; potassium tert-butoxide; and '
sodium hydride.
[0191]
The amount of the base to be used is preferably 0.5 to 6 moles, more
preferably 0.8 to 3 moles with respect to 1 mole of Compound (XIV).
[0192]
The amount of the Compound (LX) to be used is preferably 0.5 to 5 moles,
more preferably 0.8 to 2 moles with respect to 1 mole of Compound (XIV).
[0193]
The reaction temperature of the alkylation reaction is preferably -78 to 200°C,
more preferably -20 to 100°C.
[0194]
The reaction time of the alkylation reaction varies depending on the reaction
conditions, and is preferably 5 minutes to 78 hours, more preferably 30 minutes to 48
hours.
[0195]
(Step 28)
Compound (XVI) can be synthesized from Compound (XIV) according to,
for example, a method using thionyl chloride, oxalyl chloride or the like, which
method is obvious to those skilled in the art.
[0196]
(Step 29)
The acylation reaction of Compound (LXI) with Compound (XVI) is
generally carried out in a solvent in the presence of a base, and the solvent is
appropriately selected such that it does not inhibit the reaction. Examples of the
solvent which does not inhibit the reaction include halogenated hydrocarbons such as
dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; and
ethers such as tetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane; and mixtures
thereof may also be used as the solvent.
[0197]
Examples of the base include pyridine, triethylamine, diisopropylethylamine
and N,N-dimethylaminopyridine.
[0198]
The amount of the base to be used is preferably 0.1 to 6 moles, more
preferably 0.8 to 3 moles with respect to 1 mole of Compound (XVI).
[0199]
The amount of Compound (LXI) to be used is 0.5 to 3 moles, more preferably
0.8 to 1.5 moles with respect to 1 mole of Compound (XVI).
[0200]
The reaction temperature of the acylation reaction is preferably -20 to 150°C,
more preferably 0 to 100°C.
[0201]
The reaction time of the acylation reaction varies depending on the reaction
conditions, and is preferably 5 minutes to 72 hours, more preferably 30 minutes to 48
hours.
[0202]
(Step 30)
The cyclization reaction of Compound (XV) is generally carried out in a
solvent in the presence of an ammonium salt, and the solvent is selected such that it
does not inhibit the reaction. Examples of the solvent which does not inhibit the
reaction include acetic acid and formic acid; and mixtures thereof may also be used
as the solvent.
[0203]
Examples of the ammonium salt include ammonium acetate, ammonium
formate and ammonium carbonate, which are commercially available reagents.
[0204]
The amount of the ammonium salt to be used is preferably 1 to 20 moles,
more preferably 2 to 15 moles with respect to 1 mole of Compound (XV).
[0205]
The reaction temperature of the cyclization reaction is preferably 0 to 200°C,
more preferably 0 to 120°C.
[0206]
The reaction time of the cyclization reaction varies depending on the reaction
conditions, and is preferably 5 minutes to 100 hours, more preferably 30 minutes to
48 hours.
[0207]
(Production Method 18: Production Method of Intermediate Compound (SIIIb))

[wherein the symbols have the same meanings as those defined above.]
[0208]
Compound (SIIIb) can be obtained by amidating Compound (XIV) and then
thioamidating the resulting Compound (XVII) to produce Compound (XVIII), which
is then cyclized using Compound (LX). Compound (XIV) can be synthesized
according to a method obvious to those skilled in the art. Compound (LX) can also
be synthesized according to a method obvious to those skilled in the art.
[0209]
(Step 31)
The amidation reaction of Compound (XIV) is generally carried out by
forming a mixed anhydride in a solvent in the presence of a base using a
chloroformic ester or the like, followed by allowing aqueous ammonia to react with
the mixed anhydride. The solvent is appropriately selected such that it does not
inhibit the reaction. Examples of the solvent which does not inhibit the reaction
include ethers such as tetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl
ether; halogenated hydrocarbons such as dichloromethane and chloroform; and N,N-
dimethylformamide; and mixtures thereof may also be used as the solvent.
[0210]
Examples of the chloroformic ester include methyl chloroformate, ethyl
chloroformate, isopropyl chloroformate and sec-butyl chloroformate.
[0211]
The amount of the chloroformic ester is preferably 0.5 to 4 moles, more
preferably 0.9 to 2 moles with respect to 1 mole of Compound (XIV).
[0212]
Examples of the base include inorganic bases such as sodium hydrogen
carbonate, sodium carbonate, potassium carbonate and cesium carbonate; and
organic bases such as triethylamine, diisopropylethylamine and pyridine.
[0213]
The amount of the base to be used is preferably 0.5 to 5 moles, more
preferably 0.9 to 2.5 moles with respect to 1 mole of Compound (XIV).
[0214]
The reaction temperature of the amidation reaction is preferably -78 to 200°C,
more preferably -20 to 100°C in terms of the formation of a mixed anhydride. In
terms of the reaction after addition aqueous ammonia, the temperature is preferably -
78 to 200°C, more preferably -20 to 100°C.
[0215]
The reaction time of the amidation reaction varies depending on the reaction
conditions, and is preferably 5 minutes to 48 hours, more preferably 30 minutes to 24
hours in terms of the formation of a mixed anhydride. In terms of the reaction after
addition aqueous ammonia, the reaction time is preferably 5 minutes to 72 hours,
more preferably 30 minutes to 48 hours
[0216]
(Step 32)
The thioamidation reaction of Compound (XVII) is generally carried out by
allowing Compound (XVII) to react with Lawesson's reagent or phosphorus
pentasulfide, which are commercially available reagents, in a solvent. The solvent
is appropriately selected such that it does not inhibit the reaction. Examples of the
solvent which does not inhibit the reaction include saturated hydrocarbons such as
benzene and toluene; halogenated solvents such as dichloromethane and chloroform;
and ethers such as tetrahydrofuran and 1,4-dioxane; and mixtures thereof may also be
used as the solvent.
[0217]
The amount of the Lawesson's reagent or phosphorus pentasulfide to be used
is preferably 0.3 to 4 moles, more preferably 0.4 to 2 moles with respect to 1 mole of
Compound (XVII).
[0218]
The reaction temperature of the thioamidation reaction is preferably -20 to
200°C, more preferably 0 to 120°C.
[0219]
The reaction time of the thioamidation reaction varies depending on the
reaction conditions, and is preferably 5 minutes to 72 hours, more preferably 30
minutes to 48 hours.
[0220]
(Step 33)
The cyclization reaction of Compound (XVIII) is generally carried out in a
solvent appropriately selected such that it does not inhibit the reaction. Examples
of the solvent which does not inhibit the reaction include alcohols such as methanol
and ethanol; ethers such as tetrahydrofuran and 1,4-dioxane; and acetonitrile; and
mixtures thereof may also be used as the solvent.
[0221]
The amount of Compound (LX) to be used is preferably 0.5 to 4 moles, more
preferably 0.9 to 1.5 moles with respect to 1 mole of Compound (XVIII).
[0222]
The reaction temperature of the cyclization reaction is preferably -20 to
200°C, more preferably 0 to 100°C.
[0223]
The reaction time of the cyclization reaction varies depending on the reaction
conditions, and is preferably 5 minutes to 72 hours, more preferably 30 minutes to 48
hours.
[0224]
In cases where Compound (I) was obtained as a free form, it may be
converted to a desired salt according to a known method or a method corresponding
thereto. Conversely, in cases where it was obtained as a salt, it may be converted to
a free form or another desired salt according to a known method or a method
corresponding thereto.
[0225]
Compound (I) may also be used as a prodrug, and examples of the prodrug of
Compound (I) include compounds which are converted to Compound (I) by reaction
by an enzyme, gastric acid or the like under physiological conditions in a living body,
that is, compounds that undergo enzymatic oxidation, reduction or hydrolysis to
change into Compound (I); and compounds that undergo hydrolysis by gastric acid
or the like to change into Compound (I) of the present invention, which compounds
correspond to those wherein a hydroxyl group of Compound (I) was acylated,
alkylated, phosphorylated or borated. Preferred particular examples of the prodrug
in cases where R5 or R6 of Compound (I) is a hydroxyl group are shown in Table 2,
but these examples do not restrict the present invention.
[0227]
The prodrug of Compound (I) can be synthesized according to a known
method from Compound (I) of the present invention. Further, the prodrug of
Compound (I) may be one that changes into Compound (I) under the physiological
conditions described in a known document ('Iyakuhin no Kaihatsu' (Development of
Drugs), Hirokawa Shoten, 1990, vol. 7, pp. 163-198; Prog. Med. 5,1985, pp. 2157-
2161). By using Compound (I) as a prodrug, its solubility and/or absorbability may
be improved.
[0228]
The excellent analgesic effect, or therapeutic effect on neuropathic pain or
therapeutic action against diabetic neuropathic pain, of Compound (I) can be
evaluated using an appropriate animal model. Examples of the appropriate animal
model for nociceptive pain include mouse acetic acid writhing model, rat or mouse
formalin test, rat carrageenin-induced inflammation model, rat hot plate test ,and tail-
flick test for acute pain.
[0229]
Examples of the appropriate animal models for neuropathic pain include
mouse or rat partial sciatic nerve ligation model and mouse or rat spinal nerve
ligation model, and examples of the appropriate animal model for diabetic
neuropathic pain include mouse or rat streptozotocin (STZ)-induced diabetic
neuropathy model.
[0230]
Since Compound (I) has an excellent analgesic effect, or therapeutic effect on
neuropathic pain or therapeutic effect on diabetic neuropathic pain, the compound
can be used as a pharmaceutical, and is preferably used as an analgesic, therapeutic
drug for neuropathic pain, or therapeutic drug for diabetic neuropathic pain.
[0231]
In cases where Compound (I) is used as an analgesic, it is preferably used for
nociceptive pain. Examples of the nociceptive pain herein include pain due to
injuries such as fracture and incised wound; postoperative pain; sprain pain; bruise
pain; joint pain; low back pain; muscle pain; pain after tooth extraction; dental pain;
appendicitis; chronic rheumatoid arthritis; rheumatic fever; osteoarthritis; ankylosing
spondylitis; spondylosis deformans; cervicobrachial syndrome; periarthritis;
cellulitis; acute otitis media; prostatitis; alveolar periostitis; and pain due to
inflammatory diseases such as vaginitis. Further, the above-described nociceptive
pain include deep pain and visceral pain (e.g., headache; abdominal pain; back pain;
chronic pelvic pain syndrome; pain due to endometriosis; pain due to urolithiasis or
urethral calculus; colicky pain due to digestive organ disease, pelvic pain; and
urologic diseases pain). In cases where Compound (I) is used as an analgesic,
examples of more preferred target diseases include chronic rheumatoid arthritis,
osteoarthritis, postoperative pain, joint pain, low back pain, muscle pain and dental
pain.
[0232]
Compound (I) is used as a therapeutic drug for neuropathic pain, and also as a
therapeutic drug for diabetic neuropathic pain. Examples of the neuropathic pain
herein include cancer pain, herpes zoster pain, postherpetic neuralgia, AIDS-related
neuralgia and trigeminal neuralgia. The diabetic neuropathic pain herein means
pain due to diabetic neuralgia.
[0233]
Compound (I) is also useful for therapy of acute and chronic pain. Acute
pain usually continues for a short period of time, and examples thereof include
postoperative pain, pain after tooth extraction and trigeminal neuralgia. Chronic
pain is defined as pain that usually continues for 3 to 6 months. It includes
somatogenic pain and psychogenic pain, and examples thereof include chronic
rheumatoid arthritis, osteoarthritis and postherpetic neuralgia.
[0234]
A pharmaceutical containing Compound (I) shows an excellent analgesic
effect, or therapeutic effect on neuropathic pain or diabetic neuropathic pain, in cases
where it was administered to a mammal (e.g., mouse, rat, hamster, rabbit, cat, dog,
bovine, sheep, monkey or human), especially human.
[0235]
Further, Compound (I) may be used not only as an analgesic or a therapeutic
drug for neuropathic pain, but also in a therapeutic method for pain or neuropathic
pain, or in a therapeutic use for pain or neuropathic pain. Further, Compound (I)
may be used in a therapeutic method or therapeutic use for diabetic neuropathic pain.
[0236]
The dosage form of Compound (I) may be oral or parenteral administration of
Compound (I) as it is or after blending of a pharmaceutically acceptable carrier
thereto.
[0237]
Examples of the dosage form of the drug product containing Compound (I) in
cases where it is orally administered include tablets (e.g., sugar-coated tablets and
film-coated tablets), pills, granules, powders, capsules (e.g., soft capsules and
microcapsules), syrups, emulsions and suspensions; examples of the dosage form in
cases where it is parenterally administered include injections, impregnating agents,
drops and suppositories. It is also effective to formulate the drug into a sustained-
release preparation by combining the drug with an appropriate base (e.g., polymer of
butyric acid, polymer of glycolic acid, copolymer of butyric acid-glycolic acid,
mixture of a polymer of butyric acid and a polymer of glycolic acid, or polyglycerol
fatty acid ester).
[0238]
Preparation of the drug product containing Compound (I) into the above-
described dosage form can be carried out according to a known method commonly
used in the field of drug formulation. In such a case, the formulation can be
produced by inclusion of an excipient, binder, lubricant, disintegrant, sweetener,
surfactant, suspending agent, emulsifier and/or the like, which are commonly used in
the field of drug formulation.
[0239]
Preparation of a tablet containing Compound (I) may be carried out by
inclusion of an excipient, binder, disintegrant, lubricant and/or the like; and
preparation of a pill or granule may be carried out by inclusion of an excipient,
binder, disintegrant and/or the like. Preparation of a powder or capsule may be
carried out by inclusion of an excipient and/or the like; preparation of a syrup may be
carried out by inclusion of a sweetener and/or the like; and preparation of an
emulsion or suspension be carried out by inclusion of a surfactant, suspending agent,
emulsifier and/or the like.
[0240]
Examples of the excipient include lactose, glucose, starch, sucrose,
microcrystalline cellulose, powdered glycyrrhiza, mannitol, sodium hydrogen
carbonate, calcium phosphate and calcium sulfate.
[0241]
Examples of the binder include starch paste solutions, gum arable solutions,
gelatin solutions, tragacanth solutions, carboxymethylcellulose solutions, sodium
alginate solutions and glycerin.
[0242]
Examples of the disintegrant include starch and calcium carbonate.
[0243]
Examples of the lubricant include magnesium stearate, stearic acid, calcium
stearate and purified talc.
[0244]
Examples of the sweetener include glucose, fructose, invert sugar, sorbitol,
xylitol, glycerin and simple syrup.
[0245]
Examples of the surfactant include sodium lauryl sulfate, polysorbate 80,
sorbitan monofatty acid ester and polyoxyl 40 stearate.
[0246]
Examples of the suspending agent include gum arabic, sodium alginate,
sodium carboxymethylcellulose, methyl cellulose and bentonite.
[0247]
Examples of the emulsifier include gum arabic, tragacanth, gelatin and
polysorbate 80.
[0248]
Further, in cases where the drug containing Compound (I) is formulated into
the above-described dosage form, a coloring agent, preservative, aromatic, corrigent,
stabilizer, thickener and/or the like, which are commonly used in the field of drug
formulation, may be added.
[0249]
The daily dose of the formulation varies depending on the conditions and the
body weight of the patient, type of the compound, administration route and the like,
and is preferably 1 mg to 1000 mg in the case of oral administration to an adult
(about 60 kg body weight), which is administered in one time or dividedly in several
times. In cases where the formulation is parenterally administered, the daily dose is
preferably 0.01 mg to 100 mg per 1 kg body weight, which is intravenously
administered.
[0250]
Compound (I) may also be used after blending with, or in combination with,
another drug in an appropriate amount in order to complement or enhance the
therapeutic or prophylactic effect, or to reduce the dose. Compound (I) may be
used in combination with, for example, the following drugs.
[0251]
Examples of antitussive agents, expectorants and antitussive expectorant
agents include dextromethorphan, benproperine, dimemorfan, clofedanol, ephedrine,
huscode, fominoben, methylephedrine, acetylcysteine, ambroxol, carbocisteine,
bromhexine, eprazinone, cherry bark extract, codeine, dihydrocodeine and tipepidine.
[0252]
Examples of bronchodilators include clenbuterol, cromoglycate, salbutamol,
salmeterol, tulobuterol, theophylline and procaterol.
[0253]
Examples of antipeptic ulcer drugs include azulene, aldioxa, irsogladine,
ecabet, omeprazole, ornoprostil, cimetidine, sucralfate, sulpiride, cetraxate and
famotidine.
[0254]
Examples of antibiotics include amoxicillin, azithromycin, erythromycin,
clarithromycin, tetracycline and doxycycline.
[0255]
Examples of narcotic analgesics include opium alkaloid, ethylmorphine,
oxycodone, morphine, cocaine, fentanyl and pethidine.
EXAMPLES
[0256]
The present invention will now be described in more detail with reference to
Reference Examples and Examples. However, the present invention is not limited
thereto.
[0257]
The names of solvents in the parentheses set forth in NMR data indicate the
solvents used for the measurements.
[0258]
JNM-AL400 type nuclear magnetic resonance apparatus manufactured by
JEOL LTD. was used for measuring 400 MHz NMR spectrum. Chemical shifts
were referenced to tetramethylsilane and expressed in 8 (unit: ppm). Each signal
was expressed in s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), sept
(septet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets),
ddd (doublet of doublet of doublets), dq (doublet of quartets), td (triplet of doublets)
or tt (triplet of triplets). IR spectrum was measured using FT/IR-410 manufactured
by JASCO Corporation, and ESI-MS spectrum was measured using Micromass
ZQ2K manufactured by Waters or 1200LC/MSD manufactured by Agilent
Technology. All the solvents used were commercially available. YFLC W-
prep2XY manufactured by Yamazen Corporation was used for flash chromatography.
[0259]
The raw materials of the compounds of the present invention and synthesis of
the intermediates are described as Reference Examples in the following. Among
the compounds used in the synthesis of the compounds of Reference Examples, for
the compounds whose synthesis method is not described, commercially available
compounds were used.
[0260]
(Reference Example 1)
8-Ethynyl-1,4-dioxaspiro[4.5]decan-8-ol

To a solution of trimethylsilylacetylene (27.1 mL, 0.192 mol) in
tetrahydrofuran (300 mL), 2.77 M n-butyllithium (solution in n-hexane, 69.3 mL,
0.192 mol) was added dropwise at -76°C for 30 minutes, and the obtained solution
was stirred at the same temperature for 30 minutes. A solution of 1,4-
dioxaspiro[4.5]decan-8-one (25.0 g, 0.160 mol) in tetrahydrofuran (100 mL) was
added dropwise at -74°C for 30 minutes, and the obtained solution was stirred at the
same temperature for 1 hour and 30 minutes. The reaction solution was poured into
saturated aqueous ammonium chloride solution and the resulting solution was
extracted with ethyl acetate. The organic layer was washed with brine, dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
[0261]
Methanol (320 mL) was added to the residue to dissolve it, and potassium
carbonate (55.3 g, 0.400 mol) was added thereto. The resulting solution was stirred
at room temperature for 2 hours and the obtained reaction solution was concentrated
under reduced pressure. Distilled water was added to the residue and the resultant
was extracted with ethyl acetate. The organic layer was washed with distilled water
and brine, dried over anhydrous sodium sulfate and concentrated under reduced
pressure. The residue was purified by flash chromatography (silica gel, n-
hexane/ethyl acetate) to obtain the captioned compound (29.1 g, 0.160 mol, 100%) as
white solid.
1H-NMR (400 MHz, CDCl3) :d 1.75-2.03 (9H, m), 2.49 (1H, m), 3.95 (4H, s).
ESI-MS: m/z = 165 (M-OH)+
[0262]
(Reference Example 2)
1 -(3-Hydroxy-3-(p-tolyl)propyn-1-yl)cyclohexanol

To a solution of 1-ethynylcyclohexanol (500 mg, 4.02 mmol) in
tetrahydrofuran (20 mL), 2.77 M n-butyllithium (solution in n-hexane, 3.6 mL, 9.90
mmol) was added dropwise at -78°C, and the obtained solution was stirred at the
same temperature for 1 hour. To the reaction solution, p-tolualdehyde (0.52 mL,
4.40 mmol) was added at -78°C, and the obtained solution was allowed to warm
gradually to room temperature with stirring. To the reaction solution, distilled
water and 1 M hydrochloric acid were added to make the mixture acidic, and the
resultant was extracted with ethyl acetate. The organic layer was dried over
anhydrous magnesium sulfate and concentrated under reduced pressure. The
residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to
obtain the captioned compound (598 mg, 2.44 mmol, 61%) as a pale yellow solid.
1H-NMR (400 MHz, CDCl3) :d 1.18-1.30 (1H, m), 1.47-1.74 (7H, m), 1.89-1.98 (2H,
m), 2.08 (1H, brs), 2.22 (1H, brs), 2.36 (3H, s), 5.47 (1H, s), 7.19 (2H, d, J= 8.0 Hz),
7.43 (2H,d, J=8.0 Hz).
ESI-MS: m/z = 227 (M-OH)+
[0263]
(Reference Example 3)
8-(3-Hydroxy-3-(p-tolyl)propyn-l-yl)-l,4-dioxaspiro[4.5]decan-8-ol

To a solution of 8-ethynyl-l,4-dioxaspiro[4.5]decan-8-ol (Reference Example
1) (15.0 g, 82.3 mmol) in tetrahydrofuran (165 mL), 2.77 M n-butyllithium (solution
in n-hexane, 62.4 mL, 172.9 mmol) was added dropwise at -72°C for 25 minutes,
and the obtained solution was stirred at the same temperature for 30 minutes.
Thereafter, p-tolualdehyde (10.2 mL, 86.4 mmol) was added dropwise at -72°C for 5
minutes, and the obtained solution was stirred at the same temperature for 30 minutes.
The reaction solution was allowed to warm to room temperature and poured into
saturated aqueous ammonium chloride solution. The reaction solution was
extracted with ethyl acetate. The organic layer was washed with brine, dried over
anhydrous sodium sulfate and concentrated under reduced pressure. The residue
was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain
the captioned compound (17.7 g, 58.5 mmol, 71%) as an amorphous product.
1H-NMR (400 MHz, CDCl3) d: 1.72-1.85 (4H, m), 1.90-2.04 (4H, m), 2.35 (3H, s),
2.55 (1H, s), 2.78 (1H, d, J= 6.0 Hz), 3.93 (4H, s), 5.44 (1H, d, J= 6.0 Hz), 7.17 (2H,
d, J= 8.0 Hz), 7.40 (2H, d, J= 8.0 Hz).
ESI-MS: m/z = 285 (M-OH)+
[0264]
(Reference Example 4)
8-(3-Hydroxy-3-(4-methoxyphenyl)propyn-l-yl)-l,4-dioxaspiro[4.5]decan-8-ol

To a solution of 8-ethynyl-l,4-dioxaspiro[4.5]decan-8-ol (Reference Example
1) (5.02 g, 27.6 mmol) in tetrahydrofuran (100 mL), 2.63 M n-butyllithium (solution
in n-hexane, 22.0 mL, 57.9 mmol) was added dropwise at -72°C for 15 minutes, and
the obtained solution was stirred at the same temperature for 60 minutes.
Thereafter, 4-methoxyaldehyde (3.52 mL, 28.9 mmol) was added dropwise at -72°C
for 10 minutes, and the obtained solution was stirred at the same temperature for 60
minutes. The reaction solution was allowed to warm to room temperature and
poured into saturated aqueous ammonium chloride solution. The reaction solution
was extracted with ethyl acetate. The organic layer was washed with brine, dried
over anhydrous sodium sulfate and concentrated under reduced pressure. The
residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to
obtain the captioned compound (7.46 g, 23.4 mmol, 85%) as an amorphous product.
1H-NMR (400 MHz, CDCl3) d: 1.73-1.85 (4H, m), 1.91-2.04 (4H, m), 2.32 (1H, s),
2.52 (1H, d, J= 6.1 Hz), 3.81 (3H, s), 3.94 (4H, s), 5.44 (1H, d, J= 6.1 Hz), 6.89 (2H,
d, J= 8.5 Hz), 7.44 (2H, d, J= 8.5 Hz).
[0265]
(Reference Example 5)
8-(3-(4-Chlorophenyl)-3-hydroxypropyn-l-yl)-l,4-dioxaspiro[4.5]decan-8-ol

To a solution of 8-ethynyl-l,4-dioxaspiro[4.5]decan-8-ol (Reference Example
1) (5.03 g, 27.6 mmol) in tetrahydrofuran (100 mL), 2.63 M n-butyllithium (solution
in n-hexane, 22.1 mL, 57.9 mmol) was added dropwise at -72°C for 15 minutes, and
the obtained solution was stirred at the same temperature for 60 minutes.
Thereafter, 4-chlorobenzaldehyde (4.06 g, 28.9 mmol) was added dropwise at -72°C
for 10 minutes, and the obtained solution was stirred at the same temperature for 60
minutes. The reaction solution was allowed to warm to room temperature and
poured into saturated aqueous ammonium chloride solution. The reaction solution
was extracted with ethyl acetate. The organic layer was washed with brine, dried
over anhydrous sodium sulfate and concentrated under reduced pressure. The
residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to
obtain the captioned compound (8.13 g, 25.2 mmol, 91%) as an amorphous product.
1H-NMR (400 MHz, CDCl3) d:1.68-1.81 (4H, m), 1.86-1.90 (4H, m), 3.55 (1H, s),
3.90 (4H, s), 4.03 (1H, d, J= 4.2 Hz), 5.41 (1H, d, J= 4.2 Hz), 7.28 (2H, d, J= 8.3
Hz),7.41(2H,d,J=8.3Hz).
[0266]
The following compounds were prepared in the same manner as described
above.
[0269]
(Reference Example 14)
3 -(1 -Hydroxycyclohexyl)-1-(p-tolyl)-2-propyn-1 -one

To a solution of l-(3-hydroxy-3-(p-tolyl)propyn-l-yl)cyclohexanol
(Reference Example 2) (593 mg, 2.42 mmol) in dichloromethane (20 mL),
manganese dioxide (1.15 g, 13.2 mmol) was added, and the obtained solution was
stirred at room temperature for 5 hours. The reaction solution was filtered through
Celite and the filtrate was concentrated under reduced pressure. The residue was
purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the
captioned compound (534 mg, 2.20 mmol, 91%) as a light yellow oily product.
1H-NMR (400 MHz, CDCl3) :d 1.28-1.39 (1H, m), 1.55-1.84 (7H, m), 2.02-2.11 (2H,
m), 2.23 (1H, brs), 2.43 (3H, s), 7.28 (2H, d, J= 8.0 Hz), 8.02 (2H, d, J= 8.0 Hz).
[0270]
(Reference Example 15)
3-(8-Hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-1-(p-tolyl)-2-propyn-1-one

To a solution of 8-(3-hydroxy-3-(p-tolyl)propyn-l-yl)-l,4-
dioxaspiro[4.5]decan-8-ol (Reference Example 3) (17.5 g, 57.9 mmol) in
dichloromethane (289 mL), manganese dioxide (29.6 g, 289 mmol) was added, and
the obtained solution was stirred at room temperature for 15 hours. The reaction
solution was filtered through Celite and the filtrate was concentrated under reduced
pressure. The residue was purified by flash chromatography (silica gel, n-
hexane/ethyl acetate) to obtain the captioned compound (14.3 g, 47.6 mmol, 82%) as
an oily product.
1H-NMR (400 MHz, CDCl3) d: 1.79-1.85 (2H, m), 1.87-1.93 (2H, m), 2.04-2.15 (4H,
m), 2.20 (1H, s), 2.43 (3H, s), 3.97 (4H, s), 7.28 (2H, d, J= 8.0 Hz), 8.00 (2H, d, J=
8.0 Hz).
ESI-MS: m/z = 284 (M-OH)+
[0271]
(Reference Example 16)
3-(8-Hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-1-(6-methylpyridin-3-yl)-2-propyn-1 -
one

To a solution of 8-ethynyl-1,4-dioxaspiro[4.5]decan-8-ol (Reference Example
1) (592 mg, 3.25 mmol) in tetrahydrofuran (6 mL), 2.63 M n-butyllithium (solution
in n-hexane, 2.6 mL, 6.82 mmol) was added dropwise at -78°C for 5 minutes, and the
obtained solution was stirred at the same temperature for 30 minutes. Thereafter, a
solution of N-methoxy-N-methyl-6-methylnicotinamide (614.5 mg, 3.41 mmol) in
tetrahydrofuran (5ml) was added dropwise at -78°C for 20 minutes, and the obtained
solution was stirred at the same temperature for 30 minutes. The reaction solution
was allowed to warm to room temperature and poured into saturated aqueous
ammonium chloride solution. The reaction solution was extracted with ethyl
acetate. The organic layer was washed with brine, dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The residue was purified by flash
chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned
compound (626.3 mg, 2.08 mmol, 65%) as a pale yellow solid.
1H-NMR (400 MHz, CDCl3) d: 1.76-1.83 (2H, m), 1.87-1.94 (2H, m), 2.04-2.10 (2H,
m), 2.12-2.19 (2H, m), 2.30 (1H, s), 2.66 (3H, s), 3.97 (4H, s), 7.29 (1H, d, J= 8.0
Hz), 8.22 (1H, dd, J= 2.4, 8.0 Hz), 9.21 (1H, d, J= 2.4 Hz).
ESI-MS: m/z = 284 (M-OH)+
[0272]
(Reference Example 17)
3-(8-Hydroxy-l,4-dioxaspiro[4.5]decan-8-yl)-1-(4-methoxyphenyl)-2-propyn-l-one

To a solution of 8-(3-hydroxy-3-(4-methoxyphenyl)propyn-1-yl)-1,4-
dioxaspiro[4.5]decan-8-ol (Reference Example 4) (7.10 g, 22.3 mmol) in
dichloromethane (100 mL), manganese dioxide (9.69 g, 112 mmol) was added, and
the obtained solution was stirred at room temperature for 18 hours. The reaction
solution was filtered through Celite and the filtrate was concentrated under reduced
pressure. The residue was purified by flash chromatography (silica gel, n-
hexane/ethyl acetate) to obtain the captioned compound (5.45 g, 17.2 mmol, 77%) as
an oily product.
1H-NMR (400 MHz, CDCl3) d: 1.78-1.93 (4H, m), 2.03-2.17 (4H, m), 2.27 (1H, s),
3.89 (3H, s), 3.97 (4H, s), 6.95 (2H, d, J= 9.0 Hz), 8.08 (2H, d, J= 9.0 Hz).
ESI-MS: m/z = 299 (M-OH)+
[0273]
(Reference Example 18)
1-(4-Chlorophenyl)-3-(8-hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-2-propyn-l-one

To a solution of 8-(3-(4-chlorophenyl)-3-hydroxypropyn-l-yl)-l,4-
dioxaspiro[4.5]decan-8-ol (Reference Example 5) (7.70 g, 23.9 mmol) in
dichloromethane (120 mL), manganese dioxide (10.4 g, 119 mmol) was added, and
the obtained solution was stirred at room temperature for 18 hours. The reaction
solution was filtered through Celite and the filtrate was concentrated under reduced
pressure. The residue was purified by flash chromatography (silica gel, n-
hexane/ethyl acetate) to obtain the captioned compound (5.45 g, 17.0 mmol, 71%) as
an oily product.
1H-NMR (400 MHz, CDCl3) :d 1.77-1.94 (4H, m), 2.04-2.19 (4H, m), 2.15 (1H, s),
3.98 (4H, s), 7.47 (2H, d, J= 8.5 Hz), 8.04 (2H, d, J= 8.5 Hz).
ESI-MS: m/z = 303 (M-OH)+
[0274]
The following compounds were prepared in the same manner as described
above.
[0277]
(Reference Example 30)
8-(1-(4-Methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-l,4-dioxaspiro[4.5]decan-8-ol

To a solution of 4-methoxyphenylhydrazine hydrochloride (7.35 g, 42.1
mmol) in ethanol (76.6 mL), triethylamine (5.87 mL, 42.1 mmol) was added
dropwise, and the obtained solution was stirred at room temperature for 30 minutes.
To the reaction solution, a solution of 3-(8-hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-
1-(p-tolyl)-2-propyn-1-one (Reference Example 15) (11.5 g, 38.3 mmol) in ethanol
(76.6 mL) was added dropwise, and the obtained solution was stirred at room
temperature for 15 hours. Thereafter, the reaction solution was concentrated under
reduced pressure. Water was added to the residue and the resultant was extracted
with ethyl acetate. The organic layer was washed with 1 M hydrochloric acid,
distilled water and brine, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. The residue was purified by flash chromatography (silica
gel, n-hexane/ethyl acetate) to obtain the captioned compound (14.7 g, 35.0 mmol,
91%) as an amorphous product.
1H-NMR (400 MHz, CDCl3) :d 1.71-1.74 (2H, m), 1.99-2.25 (6H, m), 2.33 (3H, s),
2.71 (1H, s), 3.81 (3H, s), 3.96-4.01 (4H, m), 6.39 (1H, s), 6.84 (2H, d, J= 8.0 Hz),
7.09 (4H, s), 7.21 (2H, d,J= 8.0 Hz).
ESI-MS: m/z = 421 (M+H)+
[0278]
(Reference Example 31)
8-(1-(4-Methoxyphenyl)- 5-(6-methylpyridin-3 -yl)-1H-pyrazol-3-yl)-1,4-
dioxaspiro[4.5]decan-8-ol

To a solution of 4-methoxyphenylhydrazine hydrochloride (359 mg, 2.06
mmol) in ethanol (4 mL), triethylamine (286 µL, 2.06 mmol) was added dropwise,
and the obtained solution was stirred at room temperature for 30 minutes. To the
reaction solution, a solution of 3-(8-hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-1-(6-
methylpyridin-3-yl)-2-propyn-1-one (Reference Example 16) (563.7 mg, 1.87 mmol)
in ethanol (5.4 mL) was added dropwise, and the obtained solution was stirred at
room temperature for 22 hours. Thereafter, the reaction solution was concentrated
under reduced pressure. Water was added to the residue and the resultant was
extracted with ethyl acetate. The organic layer was washed with distilled water and
brine, dried over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by flash chromatography (silica gel, n-
hexane/ethyl acetate) to obtain the captioned compound (177 mg, 0.42 mmol, 22%)
as an amorphous product.
1H-NMR (400 MHz, CDCl3) d: 1.72-1.75 (2H, m), 2.00-2.03 (2H, m), 2.07-2.14 (2H,
m), 2.19-2.26 (2H, m), 2.55 (3H, s), 2.65 (1H, s), 3.81 (3H, s), 3.96-4.03 (4H, m),
6.47 (1H, s), 6.86 (2H, d, J= 8.8 Hz), 7.06 (1H, d, J= 8.0 Hz), 7.20 (2H, d, J= 8.8
Hz), 7.33 (1H, dd, J= 2.2, 8.0 Hz), 8.40 (1H, d, J= 2.2 Hz).
ESI-MS: m/z = 422 (M+H)+
[0279]
(Reference Example 32)
8-(l,5-Bis(4-methoxyphenyl)-1H-pyrazol-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol

To a solution of 3-(8-hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-1-(4-
methoxyphenyl)-2-propyn-1-one (Reference Example 17) (700 mg, 2.24 mmol) in
ethanol (4.5 mL), a solution of 4-methoxyphenylhydrazine hydrochloride (470 mg,
2.69 mmol) and triethylamine (0.74 mL, 5.41 mmol) in ethanol (4.5 mL) was added,
and the obtained solution was stirred at room temperature for 20 hours. The
reaction solution was concentrated under reduced pressure. Distilled water was
added to the residue and the resultant was extracted with ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by flash chromatography (silica gel, n-
hexane/ethyl acetate) to obtain the captioned compound (864 mg,1.98 mmol, 88%)
as a white amorphous product.
1H-NMR (400 MHz, CDCl3) :d 1.68-1.77 (2H, m), 1.96-2.26 (6H, m), 2.70 (1H, brs),
3.80 (3H, s), 3.81 (3H, s), 3.94-4.04 (4H, m), 6.37 (1H, s), 6.81 (2H, d, J= 8.8 Hz),
6.85 (2H, d, J= 8.8 Hz), 7.13 (2H, d, J= 8.8 Hz), 7.21 (2H, d, J= 8.8 Hz).
ESI-MS: m/z = 437 (M+H)+
[0280]
(Reference Example 33)
8-(5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl)-1,4-
dioxaspiro[4.5]decan-8-ol

To a solution of 4-methoxyphenylhydrazine hydrochloride (457 mg, 2.62
mmol) in ethanol (4.4 mL), triethylamine (0.730 mL, 5.24 mmol) was added
dropwise, and the obtained solution was stirred at room temperature for 30 minutes.
To the reaction solution, a solution of l-(4-chlorophenyl)-3-(8-hydroxy-1,4-
dioxaspiro[4.5]decan-8-yl)-2-propyn-1-one (Reference Example 18) (700 mg, 2.18
mmol) in ethanol (4.4 mL) was added dropwise, and the obtained solution was stirred
at room temperature for 14 hours. Thereafter, the reaction solution was
concentrated under reduced pressure. Water was added to the residue and the
resultant was extracted with ethyl acetate. The organic layer was washed with 1 M
hydrochloric acid, distilled water and brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified by flash
chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned
compound (756 mg, 1.71 mmol, 79%) as an amorphous product.
1H-NMR (400 MHz, CDCl3) d: 1.69-1.76 (2H, m), 1.97-2.25 (6H, m), 2.66 (1H, brs),
3.82 (3H, s), 3.94-4.03 (4H, m), 6.43 (1H, s), 6.85-6.87 (2H, m), 7.13 (2H, d, J= 8.4
Hz), 7.19 (2H, d, J= 8.4 Hz), 7.25-7.27 (2H, m).
ESI-MS: m/z = 441 (M+H)+
[0281]
(Reference Example 34)
8-(1-(4-Chlorophenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol

To a solution of 4-chlorophenylhydrazine hydrochloride (418 mg, 2.33
mmol) in ethanol (4.8 mL), triethylamine (5.87 mL, 42.1 mmol) was added dropwise,
and the obtained solution was stirred at room temperature for 30 minutes. To the
reaction solution, a solution of 3-(8-hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-1-(p-
tolyl)-2-propyn-1-one (Reference Example 15) (698 mg, 2.32 mmol) in ethanol (4.7
mL) was added dropwise, and the obtained solution was stirred at room temperature
for 14 hours. Thereafter, the reaction solution was concentrated under reduced
pressure. Water was added to the residue and the resultant was extracted with ethyl
acetate. The organic layer was washed with distilled water and brine, dried over
anhydrous sodium sulfate and concentrated under reduced pressure. The residue
was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain
the captioned compound (948 mg, 2.23 mmol, yield: 96%) as an amorphous product.
1H-NMR (400 MHz, CDCl3) d: 1.71-1.75 (2H, m), 1.98-2.14 (4H, m), 2.17-2.25
(2H,m), 2.36 (3H, s), 2.62 (1H, s), 3.96-4.03 (4H, m), 6.41 (1H, s), 7.09 (2H, d, J=
8.0 Hz), 7.13 (2H, d, J= 8.0 Hz), 7.22-7.30 (4H, m).
ESI-MS: m/z = 407 (M-OH)+
[0282]
The following compounds were prepared in the same manner as described
above.
[0290]
The following compounds were prepared in the same manner as in Examples
37-41 described below.
[0294]
(Reference Example 78)
1 -(1 -(4-Methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cyclohexane-cis-1,4-diyl
diacetate

To a suspension of l-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-
yl)cyclohexane-cis-1,4-diol (Example 2-B) (300 mg, 0.793 mmol) in
dichloromethane (2.6 mL), acetic anhydride (0.187 mL, 1.98 mmol), pyridine (0.192
mL, 2.38 mmol) and 4-dimethylaminopyridine (48.4 mg, 0.396 mmol) were added,
and the obtained solution was stirred at room temperature for 60 hours. Again, 4-
dimethylaminopyridine (48.4 mg, 0.396 mmol) was added and the resulting solution
was stirred at room temperature for an additional 6 hours. The reaction was
quenched by adding water to the reaction solution, and the resulting solution was
extracted with ethyl acetate. The organic layer was washed with brine, dried over
anhydrous sodium sulfate and concentrated under reduced pressure. The residue
was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain
the captioned compound (297 mg, 0.642 mmol, 81%) as a white solid.
1H-NMR (400 MHz, CDCl3) d: 1.74-1.82 (2H, m), 1.92-1.98 (2H, m), 2.01-2.08 (5H,
m), 2.10 (3H, s), 2.32 (3H, s), 2.70-2.77 (2H, m), 3.80 (3H, s), 4.80-4.89 (1H, m),
6.38 (1H, s), 6.83 (2H, d, J= 8.8 Hz), 7.08 (4H, s), 7.20 (2H, d, J= 8.8 Hz).
ESI-MS: m/z = 463 (M+H)+
[0295]
(Reference Example 79)
c-4-Methoxy-1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cyclohexan-r-1-
yl acetate

To a solution of c-4-hydroxy-1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-
pyrazol-3-yl)-cyclohexan-r-1-yl acetate (Comparative Example 26) (0.150 g, 0.357
mmol) in N,N-dimethylformamide (1.8 mL), 55% sodium hydride (23.4 mg, 0.535
mmol) and methyl iodide (29.0 µL, 0.464 mmol) were added with stirring under ice-
cooling, and the obtained solution was stirred at room temperature for 9 hours. The
reaction was quenched by adding water to the reaction solution with stirring under
ice-cooling, and the resulting solution was extracted with ethyl acetate. The organic
layer was washed with brine, dried over anhydrous sodium sulfate and concentrated
under reduced pressure. The residue was purified by flash chromatography (silica
gel, n-hexane/ethyl acetate) to obtain the captioned compound (124 mg, 0.284 mmol,
80%) as a white solid.
1H-NMR (400 MHz, CDCl3) d: 1.60-1.68 (2H, m), 1.94-2.03 (4H, m), 2.08 (3H, s),
2.32 (3H, s), 2.69-2.76 (2H, m), 3.24-3.33 (1H, m), 3.39 (3H, s), 3.80 (3H, s), 6.37
(1H, s), 6.83 (2H, d, J= 8.8 Hz), 7.08 (4H, s), 7.20 (2H, d, J= 8.8 Hz).
ESI-MS: m/z = 435 (M+H)+
[0296]
(Reference Example 80)
4-(4-Fluoro-1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-c-4-hydroxy-
cyclohexan-r-1-yl acetate

To a solution of c-4-hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-
pyrazol-3-yl)-cyclohexane-r-1-yl acetate (Example 57) (130 mg, 0.309 mmol) in
acetonitrile (3.09 mL), Selectfluor™ (120 mg, 0.340 mmol) was added, and the
obtained solution was stirred at room temperature for 3 hours. Saturated aqueous
sodium thiosulfate solution was added to the reaction solution, and the resulting
solution was extracted with ethyl acetate. The organic layer was washed with brine,
dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate)
to obtain the captioned compound (61 mg, 0.140 mmol, 45%) as a light yellow
amorphous product.
1H-NMR (400MHz, CDCl3) :d 1.89-2.15 (11H, m), 2.35 (3H, m), 2.73 (1H, s), 3.81
(3H, s), 4.82-4.89 (1H, m), 6.84-6.86 (2H, m), 7.10-7.18 (6H, m).
ESI-MS: m/z = 439 (M+H)+
[0297]
(Reference Example 81)
1-(1-(4-Methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-4-oxo-cyclohexan-1-yl acetate

To a solution of c-4-hydroxy-1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-
pyrazol-3-yl)-cyclohexan-r-1-yl acetate (Comparative Example 26) (142 mg, 0.338
mmol) in dichloromethane (3.38 mL), Dess-Martin reagent (172 mg, 0.405 mmol)
was added, and the obtained solution was stirred at 0°C for 2 hours. The reaction
solution was filtered through Celite and the residue was purified by flash
chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned
compound (120 mg, 0.287 mmol, 85%) as a white amorphous product.
1H-NMR (400 MHz, CDCl3) d: 2.13 (3H, s), 2.33 (3H, s), 2.44-2.52 (4H, m), 2.59-
2.65 (2H, m), 2.93-2.96 (2H, m), 3.81 (3H, s), 6.45 (1H, s), 6.84 (2H, d, J= 8.8 Hz),
7.08 (4H, s), 7.20 (2H, d, J= 8.8 Hz).
ESI-MS: m/z = 419 (M+H)+
[0298]
(Reference Example 82)
c-4-Hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cis-cyclohexane-
r-1-carbaldehyde

To a solution of (methoxymethyl)triphenylphosphonium chloride (546.3 mg,
1.59 mmol) in tetrahydrofuran (1.3 mL), potassium tert-butoxide (178.7 mg, 1.59
mmol) was added at -40°C, and the obtained solution was stirred at the same
temperature for 60 minutes. To the reaction solution, a solution of 4-hydroxy-4-(1-
(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3 -yl)cyclohexan-1 -one (Example 37)
(200 mg, 0.53 mmol) in tetrahydrofuran (1.35 mL) was added dropwise at -40°C,
and the obtained solution was stirred at room temperature for 1.5 hours. To the
reaction solution, 6 M aqueous hydrochloric acid solution was added at 0°C, and the
obtained solution was stirred for 12 hours. Distilled water was added to the reaction
solution and the resulting solution was extracted with ethyl acetate. The organic
layer was washed with saturated aqueous sodium hydrogen carbonate solution and
brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate)
to obtain the captioned compound (87.5 mg, 0.23 mmol, 42%) as a colorless oily
product.
1H-NMR (400 MHz, CDCl3) d: 1.88-1.96 (6H, m), 2.09-2.11 (2H, m), 2.25-2.36 (5H,
m), 3.80 (3H, s), 6.39 (1H, s), 6.84 (2H, d, J= 8.8 Hz), 7.09-7.14 (4H, m), 7.20 (2H,
d, J= 8.8 Hz), 9.66 (1H, d, J= 2.0 Hz).
ESI-MS:m/z = 391(M+H)+
[0299]
(Reference Example 83)
Ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate

To a solution of ethyl 4-oxocyclohexanecarboxylate (10.0 g, 58.8 mmol) in
toluene (196 mL), ethylene glycol (3.6 mL, 64.6 mmol) and p-toluenesulfonic acid
monohydrate (1.12 g, 5.88 mmol) were added, and the obtained solution was heated
to reflux at 150°C. The resulting solution was stirred for 18 hours. The reaction
was quenched by adding a saturated sodium bicarbonate solution to the reaction
solution, and the resulting solution was extracted with ethyl acetate. The organic
layer was washed with brine, dried over anhydrous sodium sulfate and concentrated
under reduced pressure. The residue was purified by flash chromatography (silica
gel, n-hexane/ethyl acetate) to obtain the captioned compound (12.3 g, 57.4 mmol,
98%) as a colorless oily compound.
1H-NMR (400 MHz, CDCl3) d: 1.25 (3H, t, J= 7.2 Hz), 1.51-1.61 (2H, m), 1.75-1.86
(4H, m), 1.90-1.98 (2H, m), 2.29-2.38 (1H, s), 3.95 (4H, s), 4.13 (2H, q, J= 7.2 Hz).
ESI-MS: m/z = 215 (M+H)+
[0300]
(Reference Example 84)
Ethyl 8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate

To a solution of ethyl l,4-dioxaspiro[4.5]decane-8-carboxylate (Reference
Example 83) (500 mg, 2.33 mmol) in tetrahydrofuran (7.8 mL), 0.5 M potassium
bis(trimethylsilyl)amide (solution in toluene, 4.67 mL, 2.33 mmol) was added at -
78°C, and the obtained solution was stirred for 20 minutes. Thereafter,
benzylchloromethylether (0.379 mL, 2.45 mmol) was added, and the obtained
solution was stirred at -78°C for 30 minutes and at room temperature for 1.5 hours.
Saturated aqueous ammonium chloride solution was added to the reaction solution,
and the resulting solution was extracted with ethyl acetate. The organic layer was
dried over anhydrous sodium sulfate and concentrated under reduced pressure. To
the residue, 3 M aqueous sodium hydroxide solution (1.0 mL) was added, and the
obtained solution was stirred for 4 hours. The reaction solution was extracted with
ether and the organic layer was washed with brine, dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The residue was purified by flash
chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned
compound (279 mg, 0.834 mmol, 36%) as a colorless oily compound.
1H-NMR (400 MHz, CDCl3) d: 1.24 (3H, t, J= 7.2 Hz), 1.52-1.68 (6H, m), 2.16-2.23
(2H, m), 3.46 (2H, s), 3.88-3.96 (4H, m), 4.17 (2H, q, J= 7.2 Hz), 4.49 (2H, s), 7.25-
7.39 (5H, m).
ESI-MS: m/z = 335 (M+H)+
[0301]
(Reference Example 85)
(8-(Benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl)methanol

To a solution of ethyl 8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decane-8-
carboxylate (Reference Example 84) (279 mg, 0.834 mmol) in tetrahydrofuran (4.2
mL), lithium borohydride (91.0 mg, 4.17 mmol) was added with stirring under ice-
cooling, and the obtained solution was stirred at 70°C for 4 hours. The reaction was
quenched by adding saturated aqueous ammonium chloride solution to the reaction
solution, and the resulting solution was extracted with ethyl acetate. The organic
layer was washed with brine, dried over anhydrous sodium sulfate and concentrated
under reduced pressure. The residue was purified by flash chromatography (silica
gel, n-hexane/ethyl acetate) to obtain the captioned compound (183 mg, 0.625 mmol,
75%) as a colorless oily compound.
1H-NMR (400 MHz, CDCl3) :d 1.48-1.66 (8H, m), 2.76 (1H, t, J= 6.0 Hz), 3.43 (2H,
s), 3.60 (2H, d, J= 6.0 Hz), 3.91-3.95 (4H, m), 4.52 (2H, s), 7.27-7.38 (5H, m).
ESI-MS: m/z = 293 (M+H)+
[0302]
(Reference Example 86)
8-(Benzyloxymethyl)-1,4-dioxaspiro[4.5]decane-8-carbaldehyde

To a solution of (8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-
yl)methanol (Reference Example 85) (183 mg, 0.625 mmol) in dimethyl sulfoxide
(2.1 mL), 50% sulfur trioxide-pyridine complex (596 mg, 1.87 mmol) and
triethylamine (0.522 mL, 3.75 mmol) were added, and the obtained solution was
stirred at room temperature for 20 minutes. The reaction was quenched by adding
water to the reaction solution, and the resulting solution was extracted with ethyl
acetate. The organic layer was washed sequentially with 20% aqueous citric acid
solution, saturated sodium bicarbonate solution and brine, dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The residue was purified
by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned
compound (172 mg, 0.592 mmol, 95%) as a colorless oily compound.
1H-NMR (400 MHz, CDCl3) d: 1.55-1.67 (6H, m), 2.03-2.11 (2H, m), 3.45 (2H, s),
3.90-3.95 (4H, m), 4.47 (2H, s), 7.25-7.36 (5H, m), 9.60 (1H, s).
ESI-MS: m/z = 291 (M+H)+
[0303]
(Reference Example 87)
8-(Benzyloxymethyl)-8-ethynyl-1,4-dioxaspiro[4.5]decane

To a solution of 8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decane-8-
carbaldehyde (Reference Example 86) (100 mg, 0.344 mmol) in methanol (5.2 mL),
potassium carbonate (143 mg, 1.03 mmol) and dimethyl-1-diazo-2-
oxopropylphosphonate (165 mg, 0.861 mmol) were added with stirring under ice-
cooling, and the obtained solution was stirred at room temperature for 1 hour. The
reaction was quenched by adding water to the reaction solution, and the resulting
solution was extracted with ethyl acetate. The organic layer was washed with brine,
dried over anhydrous sodium sulfate and concentrated under reduced pressure. The
residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to
obtain the captioned compound (88.9 mg, 0.310 mmol, 90%) as a colorless oily
compound.
1H-NMR (400 MHz, CDCl3) d: 1.52-1.71 (4H, m), 1.77-1.85 (2H, m), 1.94-2.04 (2H,
m), 2.19 (1H, s), 3.38 (2H, s), 3.89-3.99 (4H, s), 4.61 (2H, s), 7.25-7.37 (5H, m).
ESI-MS: m/z = 287 (M+H)+
[0304]
(Reference Example 88)
3-(8-(Benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl)-1-(p-tolyl)propyn-1-ol

To a solution of 8-(benzyloxymethyl)-8-ethynyl-1,4-dioxaspiro[4.5]decane
(Reference Example 87) (393 mg, 1.37 mmol) in tetrahydrofuran (4.6 mL), 2.6 M n-
butyllithium (solution in hexane, 0.555 mL, 1.44 mmol) was added at -78°C, and the
obtained solution was stirred for 10 minutes. Further, 4-methylbenzaldehyde (0.178
mL, 1.51 mmol) was added, and the obtained solution was allowed to warm
gradually to room temperature and stirred for 1 hour. Saturated aqueous
ammonium chloride solution was added to the reaction solution, and the resulting
solution was extracted with ethyl acetate. The organic layer was washed with brine,
dried over anhydrous sodium sulfate and concentrated under reduced pressure. The
residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to
obtain the captioned compound (459 mg, 1.13 mmol, 82%) as a colorless oily
compound.
1H-NMR (400 MHz, CDCl3) d: 1.62-1.71 (4H, m), 1.79-1.86 (2H, m), 1.92-2.02 (2H,
m), 2.23 (1H, brs), 2.34 (3H, s), 3.41 (2H, s), 3.89-3.98 (4H, m), 4.59 (2H, m), 5.44
(1H, d, J= 5.2 Hz), 7.15 (2H, d, J= 8.0 Hz), 7.25-7.35 (5H, m), 7.43 (2H, d, J= 8.0
Hz).
ESI-MS: m/z = 407 (M+H)+
[0305]
(Reference Example 89)
3-(8-(Benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl)-1 -(p-tolyl)propyn-1 -one

To a solution of 3-(8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl)-1-(p-
tolyl)propyn-1-ol (Reference Example 88) (585 mg, 1.44 mmol) in dichloromethane
(7.2 mL), manganese dioxide (625 mg, 7.19 mmol) was added, and the obtained
solution was stirred at room temperature for 13 hours. The reaction solution was
filtered through Celite and the filtrate was concentrated under reduced pressure.
The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate)
to obtain the captioned compound (540 mg, 1.33 mmol, 93%) as a colorless oily
compound.
1H-NMR (400 MHz, CDCl3) d: 1.71-1.80 (4H, m), 1.97-2.03 (4H, m), 2.41 (3H, s),
3.52 (2H, s), 3.91-4.00 (4H, m), 4.63 (2H, m), 7.21 (2H, d, J- 8.0 Hz), 7.25-7.38
(5H, m), 8.03 (2H, d, J= 8.0 Hz).
ESI-MS: m/z = 405 (M+H)+
[0306]
(Reference Example 90)
3-(8-(Benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl)-1-(4-methoxyphenyl)-5-(p-
tolyl)-1H-pyrazole

To a solution of 4-methoxyphenylhydrazine hydrochloride (280 mg, 1.60
mmol) in ethanol (2.7 mL), triethylamine (0.447 mL, 3.20 mmol) was added
dropwise, and the obtained solution was stirred at room temperature for 30 minutes.
To the reaction solution, a solution of 3-(8-(benzyloxymethyl)-1,4-
dioxaspiro[4.5]decan-8-yl)-1-(p-tolyl)propyn-1-one (Reference Example 89) (540
mg, 1.33 mmol) in ethanol (2.7 mL) was added dropwise, and the obtained solution
was stirred at room temperature for 14 hours. Thereafter, the reaction solution was
concentrated under reduced pressure. Water was added to the residue and the
resultant was extracted with ethyl acetate. The organic layer was washed with 1 M
hydrochloric acid, distilled water and brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified by flash
chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned
compound (458 mg, 0.872 mmol, 65%) as a white amorphous product.
1H-NMR (400 MHz, CDCl3) :d 1.64-1.72 (2H, m), 1.76-1.85 (2H, m), 1.89-1.98 (2H,
m), 2.27-2.35 (5H, m), 3.50 (2H, s), 3.80 (3H, s), 3.90-3.99 (4H, m), 4.49 (2H, s),
6.38 (1H, s), 6.80-6.85 (2H, m), 7.06-7.31 (11H, m).
ESI-MS: m/z = 525 (M+H)+
[0307]
(Reference Example 91)
4-(Benzyloxymethyl)-4-( 1 -(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3 -
yl)cyclohexan-1 -one

To a solution of 3-(8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl)-1-(4-
methoxyphenyl)-5-(p-tolyl)-1H-pyrazole (Reference Example 90) (458 mg, 0.872
mmol) in tetrahydrofuran (2.2 mL), 6 M hydrochloric acid (4.4 mL) was added, and
the obtained solution was stirred at room temperature for 15 hours. The reaction
solution was cooled in ice and 50% aqueous sodium hydroxide solution was added
dropwise thereto at 0°C until basic. Thereafter, the resulting solution was extracted
with ethyl acetate. The organic layer was washed with brine, dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The residue was purified
by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned
compound (387 mg, 0.804 mmol, 92%) as a white amorphous product.
^-NMR (400 MHz, CDCl3) :d 2.11-2.21 (2H, m), 2.31-2.39 (5H, m), 2.52-2.68 (4H,
m), 3.57 (2H, s), 3.81 (3H, s), 4.51 (2H, s), 6.44 (1H, s), 6.83-6.88 (2H, m), 7.08-
7.34(llH,m).
ESI-MS: m/z = 481 (M+H)+
[0308]
(Reference Example 92)
8-(4,5-Bis(4-methoxyphenyl)oxazol)-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol

To a solution of 2-chloro-1,4-bis(4-methoxyphenyl)oxazole (1.01 g, 3.20
mmol), which was synthesized by the known production process (WO2007111323),
in tetrahydrofuran (32 mL), 1.09 M borane-tetrahydrofuran complex (4.0 mL, 4.36
mmol) was added at 0°C, and the obtained solution was stirred at the same
temperature for 1 hour. To the reaction solution, 2.66 M n-butyllithium (1.47 mL,
mmol) was added at -78°C, and the obtained solution was stirred at the same
temperature for 1 hour. To the reaction solution, 1,4-cyclohexanedione
monoethylene ketal (524 mg, 3.36 mmol) was added, and the obtained solution was
allowed to warm gradually to room temperature with stirring. To the reaction
solution, 1 M hydrochloric acid was added to make the mixture acidic, and the
resulting solution was extracted with ethyl acetate. The organic layer was dried
over anhydrous magnesium sulfate and concentrated under reduced pressure. The
residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to
obtain the captioned compound (844 mg, 1.92 mmol, 60%) as a light yellow
amorphous product.
1H-NMR (400 MHz, CDCl3) d: 1.71-1.80 (2H, m), 2.01-2.11 (4H, m), 2.30-2.41 (2H,
m), 2.76 (1H, s), 3.83 (3H, s), 3.84 (3H, s), 3.99 (4H, dd, J= Hz), 6.89 (2H, d, J=
8.8 Hz), 6.90 (2H, d, J= 8.8 Hz), 7.50 (2H, d, J= 8.8 Hz), 7.56 (2H, d, J= 8.8 Hz).
[0309]
(Reference Example 93)
l,4-Dioxaspiro[4.5]decane-8-carboxamide

To a solution of l,4-dioxaspiro[4.5]decane-8-carboxylic acid (823 mg, 4.42
mmol) in tetrahydrofuran (22 mL), triethylamine (5.87 mL, 42.1 mmol) and n-propyl
chloroformate were added at 0°C, and the obtained solution was stirred at the same
temperature for 1 hour. After adding dropwise, the obtained solution was stirred at
room temperature for 30 minutes. To the reaction solution, 28% aqueous ammonia
(1.5 mL) was added, and the obtained solution was stirred at room temperature for 1
hour. The organic layer was separated from the reaction solution, dried over
sodium sulfate and concentrated under reduced pressure. The residue was purified
by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned
compound (694 mg, 3.75 mmol, 85%) as a colorless amorphous product.
1H-NMR (400 MHz, CDCl3) :d 1.53-1.61 (2H, m), 1.72-1.86 (4H, m), 1.91-1.98 (2H,
m), 2.17-2.25 (1H, m), 3.95 (4H, s), 5.29 (1H, brs), 5.46 (1H, brs).
ESI-MS: m/z = 186 (M+H)+
[0310]
(Reference Example 94)
l,4-Dioxaspiro[4.5]decane-8-carbothioamide

To a solution of 1,4-dioxaspiro[4.5]decane-8-carboxamide (Reference
Example 93) (281 mg, 1.52 mmol) in toluene (5 mL), Lawson's reagent (337 mg,
0.834 mmol) was added, and the obtained solution was stirred at 100°C for 1 hour
before being cooled to room temperature. Methanol was added to the reaction
solution, and the obtained solution was concentrated under reduced pressure. The
residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to
obtain the captioned compound (147 mg, 0.730 mmol, 48%) as a white solid.
1H-NMR (400 MHz, CDCl3) d: 1.57-1.66 (2H, m), 1.79-1.90 (4H, m), 1.97-2.03 (2H,
m), 2.64-2.72 (1H, m), 3.96 (4H, s), 6.89 (1H, brs), 7.46 (1H, brs).
ESI-MS: m/z = 202 (M+H)+
[0311]
(Reference Example 95)
8-(4-(4-Methoxyphenyl)-5-(p-tolyl)thiazol-2-yl)-1,4-dioxaspiro[4.5]decane

A solution of l,4-dioxaspiro[4.5]decane-8-carbothioamide (Reference
Example 94) (389 mg, 1.93 mmol) and 2-bromo-1-(4-methoxyphenyl)-2-(p-
tolyl)ethanone (588 mg, 1.84 mmol) in acetonitrile (9.2 mL) was stirred at room
temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate solution
was added to the reaction solution, and the resulting solution was extracted with
ethyl acetate. The organic layer was washed with brine, dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The residue was purified
by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned
compound (630 mg, 1.49 mmol, 81%) as a colorless amorphous product.
1H-NMR (400 MHz, CDCl3) d: 1.68-1.76 (2H, m), 1.88-1.98 (4H, m), 2.18-2.24 (2H,
m), 2.35 (3H, s), 3.05-3.13 (1H, m), 3.80 (3H, s), 3.99 (4H, s), 6.79-6.82 (2H, m),
7.11 (2H, d, J= 8.0 Hz), 7.22 (2H, d, J= 8.0 Hz), 7.43-7.46 (2H, m).
ESI-MS: m/z = 422 (M+H)+
[0312]
(Reference Example 96)
8-(4-(4-Methoxyphenyl)-5-(p-tolyl)thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol

To a solution of 8-(4-(4-methoxyphenyl)-5-(p-tolyl)thiazol-2-yl)-1,4-
dioxaspiro[4.5]decane (Reference Example 95) (734 mg, 1.74 mmol) in
tetrahydrofuran (8.7 mL), 1.63 M n-butyllithium/solution in n-hexane (1.17 mL) was
added at -78°C, and the obtained solution was stirred at the same temperature for 1
hour. The reaction solution was added at -78°C to a solution of 3-phenyl-2-
(phenylsulfonyl)-l,2-oxaziridine (546 mg, 2.09 mmol) in tetrahydrofuran (8.7 mL),
and the obtained solution was allowed to warm gradually to room temperature with
stirring. Distilled water was added to the reaction solution, and the resulting
solution was extracted with ethyl acetate. The organic layer was washed with brine,
dried over sodium sulfate and concentrated under reduced pressure. The residue
was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain
the captioned compound (417 mg, 0.954 mmol, 55%) as a colorless amorphous
product.
1H-NMR (400 MHz, CDCl3) :d 1.73-1.79 (2H, m), 2.03-2.10 (4H, m), 2.32-2.39 (2H,
m), 2.37 (3H, s), 2.78 (1H, s), 3.84 (3H, s), 3.97-4.02 (4H, m), 6.88-6.92 (2H, m),
7.16 (2H, d, J= 8.4 Hz), 7.47 (2H, d, J= 8.4 Hz), 7.55-7.58 (2H, m).
ESI-MS: m/z = 438 (M+H)+
[0313]
(Reference Example 97)
4-Hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cis-cyclohexyl 2-
benzyloxycarbonylamino acetate

To a solution of l-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-
cyclohexane-cis-1,4-diol (Example 2-B) (76.0 mg, 0.201 mmol) in dichloromethane
(2.00 mL), triethylamine (0.084 mL, 0.60 mmol), 2-benzyloxycarbonylamino acetic
acid (46.2 mg, 0.241 mmol), l-ethyl-3-(3-dimethylaminopropyl) carbodiimide
hydrochloride (46.2 mg, 0.241 mmol) and 1-hydroxybenzotriazole (15.4 mg, 0.100
mmol) were added at room temperature, and the resulting solution was stirred for 20
hours. Distilled water was added to the reaction solution, and the resulting solution
was extracted with ethyl acetate. The organic layer was washed with brine, dried
over anhydrous sodium sulfate and concentrated under reduced pressure. The
residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to
obtain the captioned compound (33.2 mg, 0.058 mmol, 29%) as a colorless
amorphous product.
1H-NMR (400 MHz, CDCl3) d: 1.91-2.07 (8H, m), 2.33 (3H, s), 2.75 (1H, s), 3.80
(3H, s), 3.98-3.99 (2H, m), 4.89-4.94 (1H, m), 5.14 (2H, s), 5.33-5.35 (1H, m), 6.36
(1H, s), 6.82-6.86 (2H, m), 7.08-7.10 (4H, m), 7.17-7.21 (2H, m), 7.29-7.38 (5H, m).
ESI-MS: m/z = 552 (M-OH)+
[0314]
(Reference Example 98)
(5)-4-Hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-c/5-
cyclohexyl 2-(benzyloxycarbonylamino)-3-methylbutanoate was synthesized in the
same manner as in Reference Example 97.

1H-NMR (400 MHz, CDCl3) d: 0.92 (3H, d, J = 6.4Hz), 0.99 (3H, d, J = 6.
4 Hz), 1.89-2.10 (8H, m), 2.16-2.24 (1H, m), 2.34 (3H, s), 2.63 (1H, s), 3.81
(3H, s), 4.30-4.33 (1H, m), 4.88-4.95 (1H, m), 5.12 (2H, s), 5.28-5.30 (1H,
m), 6.36 (1H, s), 6.78-6.82 (2H, m), 7.09-7.10 (4H, m), 7.18-7.24 (2H, m), 7.
29-7.38 (5H, m).
ESI-MS: m/z = 594 (M-OH)+
[0315]
(Reference Example 99)
(5)-4-Hydroxy-4-(1 -(4-methoxyphenyl)-5 -(p-tolyl)-1H-pyrazol-3 -
yl)cyclohexyloxy)methyl2-(benzyloxycarbonylamino)-3-methylbutanoate

To a solution of l-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-
cyclohexane-cis-1,4-diol (Example 2-B) (199 mg, 0.506 mmol) in dichloromethane
(3.00 mL), molecular sieves 4A (300 mg) and diisopropyl ethylamine (0.210 mL,
1.21 mmol) were added at room temperature, and the resulting solution was cooled to
-50oC. Subsequently, (5)-iodomethyl 2-benzyloxycarbonylamino-3-
methylbutanoate (0.187 mL, 1.26 mmol) and silver trifluoromethanesulfonate (232
mg, 0.904 mmol) were added at the same temperature, and the obtained solution was
stirred for 2 hours. Thereafter, the resulting solution was stirred at -30°C for 14
hours. Saturated sodium bicarbonate solution was added to the reaction solution,
and the resulting solution was filtered through Celite. The filtrate was washed with
brine, and the organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was purified by flash
chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned
compound (123 mg, 0.192 mmol, 64%) as a colorless amorphous product.
1H-NMR (400 MHz, CDCl3) d: 0.92 (3H, d, J= 6.4 Hz), 1.01 (3H, d, J= 6.4 Hz),
1.88-1.99 (6H, m), 2.02-2.09 (2H, m), 2.20-2.26 (1H, m), 2.34 (3H, s), 2.50 (1H, s),
3.66-3.72 (1H, m), 3.81 (3H, s), 4.32-4.36 (1H, m), 5.12 (2H, s), 5.38 (1H, d, J= 6.4
Hz), 5.50 (1H, d, J= 6.4 Hz), 6.37 (1H, s), 6.83-6.87 (2H, m), 7.08-7.11 (4H, m),
7.18-7.24 (2H, m), 7.29-7.38 (5H, m).
ESI-MS: m/z = 624 (M-OH)+
[0316]
(Reference Example 100)
Dibenzyl 4-hydroxy-4-( 1 -(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3 -yl)-cis-cyclo
hexylphosphate

To a solution of l-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-
yl)cyclohexane-cis-1,4-diol (Example 2-B) (200 mg, 0.528 mmol) in tetrahydrofuran
(2.6 mL), 55% sodium hydride (55.3 mg, 1.27 mmol) and
tetrabenzylpyrophosphonate (370 mg, 0.687 mmol) were sequentially added with
stirring under ice-cooling, and the obtained solution was stirred at room temperature
for 15 hours. The reaction solution was cooled in ice and water was added thereto.
The resulting solution was extracted with ethyl acetate. The organic layer was
washed with brine, dried over anhydrous sodium sulfate and concentrated under
reduced pressure. The residue was purified by flash chromatography (silica gel, n-
hexane/ethyl acetate) to obtain the captioned compound (251 mg, 0.393 mmol, 74%)
as a colorless transparent oily compound.
1H-NMR (400 MHz, CDCl3) :d 1.87-2.11 (8H, m), 2.33 (3H, s), 3.79 (3H, s),
4.42-4.51 (1H, m), 5.00-5.12 (4H, m), 6.34 (1H, s), 6.81-6.87 (2H, m), 7.09
(4H, s), 7.16-7.23 (2H, m), 7.29-7.37 (10H, m).
ESI-MS: m/z = 639 (M+H)+
[0317]
With regard to the compounds of the present invention, the compounds of the
following Examples 1 to 71 and Comparative Examples 1 to 30 were synthesized.
As the compounds used for the syntheses of the compounds of Examples, for which a
synthesis method is not described, commercially available compounds were used.
[0318]
(Example 1)
1 -(1 -(4-Methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3 -yl)cyclohexanol

To a suspension of 4-methoxyphenylhydrazine (165 mg, 0.944 mmol) in
ethanol (5.0 mL), triethylamine (258 µL, 1.88 mmol) was added, and the obtained
solution was stirred at room temperature for 30 minutes. The resulting solution was
added to a solution of 3-(1-hydroxycyclohexyl)-1-(4-tolyl)-2-propyn-1-one
(Reference Example 14) (214 mg, 0.883 mmol) in ethanol (3.0 mL), and the resulting
mixture was stirred at room temperature for 20 hours. The reaction solution was
concentrated under reduced pressure, and distilled water was added to the residue.
The resulting solution was extracted with ethyl acetate. The organic layer was dried
over anhydrous magnesium sulfate, and concentrated under reduced pressure. The
residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to
obtain the title compound (141 mg, 0.389 mmol, 44%) as a yellow amorphous
product.
1H-NMR (400 MHz, CDCl3) :d 1.31-1.42 (1H, m), 1.54-2.03 (9H, m), 2.33 (3H, s),
2.52 (1H, brs), 3.81 (3H, s), 6.40 (1H, s), 6.84 (2H, d, J= 8.8 Hz), 7.09 (4H, s), 7.21
(2H,d,J=8.8Hz).
[0319]
(Example 2)
1 -(1 -(4-Methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)cyclohexan-trans-1,4-diol (2-
A)

l-(1-(4-Methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)cyclohexan-c/5'-1,4-diol(2-B)

To a solution of 4-hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-
3-yl)-cyclohexan-1-one (Example 37) (8.00 g, 21.3 mmol) in methanol (200 mL),
sodium borohydride (804 mg, 21.3 mmol) was added. The obtained solution was
stirred at room temperature for 2 hours, and then poured into 1 M hydrochloric acid.
The reaction solution was extracted with ethyl acetate. The organic layer was
washed with brine, dried over anhydrous sodium sulfate, and concentrated under
reduced pressure. The residue was purified by flash chromatography (silica gel, n-
hexane/ethyl acetate) to obtain the title compound 2-A (1.66 g, 4.39 mmol, 21%) as a
white solid, and the title compound 2-B (4.85 g, 12.8 mmol, 60%) as a white solid.
2-A: 1H-NMR (400 MHz, CDCl3) :d 1.36 (1H, d, J= 3.6 Hz), 1.64-1.72 (2H, m),
1.77-1.83 (2H, m), 2.04-2.12 (2H, m), 2.32-2.39 (5H, m), 2.56 (1H, s), 3.81 (3H, s),
4.03-4.06 (1H, m), 6.43 (1H, s), 6.85 (2H, d, J= 8.8 Hz), 7.10 (4H, s), 7.21 (2H, d, J
= 8.8 Hz).
IR(KBr, cm-1): 3344,2929,2875,1740,1516, 1443,1369,1251,1032,1001, 832.
ESI-MS: m/z = 379 (M+H)+
Mp 151-153°C
Anal. Calcd for C23H26N203: C, 72.99; H, 6.92; N, 7.40. found: C, 72.97; H, 6.92;
N, 7.34.
2-B: 1H-NMR (400 MHz, CDCl3) :d 1.44 (1H, s), 1.81-1.99 (6H, m), 2.04-2.12 (2H,
m), 2.33 (3H, s), 2.56 (1H, s), 3.70-3.77 (1H, m), 3.80 (3H, s), 6.37 (1H, s), 6.85 (2H,
d,J= 8.8 Hz), 7.09 (4H, s), 7.20 (2H, d, J= 8.8 Hz).
IR(KBr, cm-1): 3303,2918,1517,1442,1366, 1248,1063,1026, 837, 807.
ESI-MS: m/z = 379 (M+H)+
Mp 164-166°C
Anal. Calcd for C23H26N203: C, 72.99; H, 6.92; N, 7.40. found: C, 72.87; H, 6.86;
N, 7.22.
[0320]
(Example 3)
1 -(1 -(4-Methoxyphenyl)-5-(6-methylpyridin-3 -yl)-1H-pyrazol-3 -yl)cyclohexan-cis-
1,4-diol

To a solution of 4-hydroxy-4-(1-(4-methoxyphenyl)-5-(6-methylpyridin-3-
yl)-1H-pyrazol-3-yl)-cyclohexan-1-one (Example 38) (109.5 mg, 0.29 mmol) in
methanol (1.5 mL), sodium borohydride (12.1 mg, 0.32 mmol) was added. The
obtained solution was stirred at room temperature for 40 minutes, and 1 M
hydrochloric acid was then added thereto. The reaction solution was washed with
ethyl acetate, and the aqueous layer was basified with 1 M aqueous sodium
hydroxide solution, followed by extraction of the resulting mixture twice with ethyl
acetate. The organic layers were washed with brine, dried over anhydrous sodium
sulfate, and concentrated under reduced pressure. The residue was purified by flash
chromatography (silica gel, ethyl acetate) to obtain the title compound (30.6 mg, 0.81
mmol, 28%) as a white solid.
1H-NMR (400 MHz, CDCl3) :d 1.59 (1H, brs), 1.81-2.00 (6H, m), 2.05-2.08 (2H, m),
2.55 (3H, s), 2.61 (1H, s), 3.71-3.78 (1H, m), 3.81 (3H, s), 6.46 (1H, s), 6.86 (2H, d,
J= 8.8 Hz), 7.06 (1H, d, J= 8.0 Hz), 7.18 (2H, d, J= 8.8 Hz), 7.32 (1H, dd, J= 2.0,
8.0 Hz), 8.40 (1H, d, J- 2.0 Hz).
IR (KBr, cm-1): 3444,2933,2858,1516,1249,1067, 968, 839.
ESI-MS: m/z = 380 (M+H)+
[0321]
(Example 4)
1-(l,5-Bis(4-methoxyphenyl)-1H-pyrazol-3-yl)cyclohexan-trans-1,4-diol (4-A)

1-(1,5-Bis(4-methoxyphenyl)-1H-pyrazol-3-yl)cyclohexan-cis-1,4-diol(4-B)
To a solution of 4-(l,5-bis(4-methoxyphenyl)-1H-pyrazol-3-yl)-4-hydroxy-
cyclohexan-1-one (Example 39) (523 mg, 1.38 mmol) in methanol, sodium
borohydride (65 mg, 1.7 mmol) was added. The obtained solution was stirred at
room temperature for 1.5 hours, and concentrated under reduced pressure. Distilled
water was added to the residue, and the resulting solution was extracted with ethyl
acetate. The organic layer was dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue was purified by flash
chromatography to separate into low polar component and high polar component.
The low polar component was purified by recrystallization (ethyl acetate/n-hexane =
2/1) to obtain the title compound 4-A (79 mg, 0.20 mmol, 14%) as a white crystal.
The high polar component was purified by recrystallization (ethyl acetate/n-hexane =
2/1) to obtain the title compound 4-B (186 mg, 0.471 mmol, 34%) as a white crystal.
4-A: 1H-NMR (400 MHz, CDCl3) d: 1.33 (1H, d, J= 3.4 Hz), 1.63-1.73 (2H, m),
1.75-1.84 (2H, m), 2.03-2.13 (2H, m), 2.30-2.39 (2H, m), 2.55 (1H, s), 3.80 (3H, s),
3.81 (3H, s), 4.02-4.08 (1H, m), 6.40 (1H, s), 6.82 (2H, d, J= 8.8 Hz), 6.85 (2H, d, J
= 8.8 Hz), 7.14 (2H, d, J= 8.8 Hz), 7.21 (2H, d, J= 8.8 Hz).
IR (KBr, cm-1): 3379, 1613, 1517, 1503, 1251, 1180, 1032, 1001, 835.
ESI-MS: m/z = 395 (M+H)+
4-B: 1H-NMR (400 MHz, CDCl3) :d 1.41 (1H, d, J= 4.1 Hz), 1.79-2.55 (8H, m),
2.55 (1H, s), 3.69-3.78 (1H, m), 3.80 (3H, s), 3.81 (3H, s), 6.34 (1H, s), 6.81 (2H, d,
J= 8.8 Hz), 6.85 (2H, d, J= 8.8 Hz), 7.13 (2H, d, J= 8.8 Hz), 7.20 (2H, d, J= 8.8
Hz).
IR (KBr, cm-1): 3385,1613, 1517, 1503, 1250, 1064, 1031, 970, 835.
ESI-MS: m/z = 395 (M+H)+
[0322]
(Example 5)
1 -(5-(4-Chlorophenyl)-1 -(4-methoxyphenyl)-1H-pyrazol-3 -yl)cyclohexan-trans-1,4-
diol (5-A)

1 -(5-(4-Chlorophenyl)-1 -(4-methoxyphenyl)- 1H-pyrazol-3 -yl)cyclohexan-cis-1,4-
diol (5-B)

To a solution of 4-(5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3 -
yl)-4-hydroxy-cyclohexan-1-one (Example 40) (619 mg, 1.56 mmol) in methanol
(15.6 mL), sodium borohydride (59.0 mg, 1.56 mmol) was added. The obtained
solution was stirred at room temperature for 1 hour, and then poured into 1 M
hydrochloric acid. The reaction solution was extracted with ethyl acetate. The
organic layer was washed with brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified by flash
chromatography (silica gel, n-hexane/ethyl acetate) to obtain the title compound 5-A
(131 mg, 0.328 mmol, 21%) as a white solid, and the title compound 5-B (291 mg,
0.730 mmol, 47%) as a white solid.
5-A: 1H-NMR (400 MHz, CDCl3) d: 1.32 (1H, d, J= 3.2 Hz), 1.63-1.73 (2H, m),
1.76-1.84 (2H, m), 2.03-2.12 (2H, m), 2.30-2.39 (2H, m), 2.50 (1H, s), 3.82 (3H, s),
4.02-4.09 (1H, m), 6.46 (1H, s), 6.84-6.87 (2H, m), 7.14 (2H, d, J= 8.8 Hz), 7.19
(2H, d, J= 8.8 Hz), 7.26-7.28 (2H, m).
ESI-MS: m/z = 399 (M+H)+
5-B: 1H-NMR (400 MHz, CDCl3) d: 1.41 (1H, d, J= 5.2 Hz), 1.82-2.09 (8H, m),
2.49 (1H, s), 3.70-3.78 (1H, s), 3.82 (3H, s), 6.41 (1H, s), 6.85-6.87 (2H, m), 7.13
(2H, d, J= 8.4 Hz), 7.18 (2H, d, J= 8.4 Hz), 7.25-7.27 (2H, m).
ESI-MS: m/z = 399 (M+H)+
[0323]
(Example 6)
1 -(1 -(4-Chlorophenyl)-5-p-tolyl-1H-pyrazol-3-yl)cyclohexan-trans-1,4-diol (6-A)

1 -(1 -(4-Chlorophenyl)-5-p-tolyl-1H-pyrazol-3 -yl)cyclohexan-cis-1,4-diol (6-B)

To a solution of 4-hydroxy-4-(1-(4-chlorophenyl)-5-(p-tolyl)-1H-pyrazol-3-
yl)-cyclohexan-1-one (Example 41) (510 mg, 1.34 mmol) in methanol (13 mL),
sodium borohydride (53 mg, 1.40 mmol) was added, and the obtained solution was
stirred at room temperature for 2 hours. The reaction solution was concentrated
under reduced pressure, and then dissolved into ethyl acetate, and washed with
distilled water and brine. The organic layer was dried over anhydrous sodium
sulfate, and concentrated under reduced pressure. The residue was purified by flash
chromatography (silica gel, n-hexane/ethyl acetate) to obtain the title compound 6-A
(114 mg, 0.298 mmol, 22%) as a white solid, and the title compound 6-B (360 mg,
0.940 mmol, 70%) as a white solid.
6-A: 1H-NMR (400 MHz, CDCl3) d: 1.36 (1H, br), 1.65-1.72 (2H, m), 1.77-1.82 (2H,
m), 2.04-2.11 (2H, m), 2.31-2.38 (2H, m), 2.36 (3H, s), 2.51 (1H, s), 4.03-4.08 (1H,
m), 6.44 (1H, s), 7.10 (2H, d, J= 8.8 Hz), 7.13 (2H, d, J= 8.8 Hz), 7.22-7.30 (4H,
m).
IR(KBr, cm-1): 3349, 2918,1497,1440,1366,1240,1098,1007, 969, 833, 810.
ESI-MS: m/z = 383 (M+H)+
6-B: 1H-NMR (400 MHz, CDCl3) d: 1.45 (1H, br), 1.80-1.99 (6H, m), 2.03-2.07 (2H,
m), 2.35 (3H, s), 2.51 (1H, s), 3.70-3.80 (1H, m), 6.39 (1H, s), 7.09 (2H, d, J= 8.4
Hz), 7.13 (2H, d, J= 8.4 Hz), 7.21-7.24 (2H, m), 7.27-7.31 (2H, m).
IR (KBr, cm-1): 3365,2946,1496,1442,1368,1241,1095,1059,1014, 970, 887.
ESI-MS: m/z = 365 (M-OH)+
[0324]
The compounds of the following Examples were prepared by the same
procedure as described above.
[0332]
(Example 37)
4-Hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)cyclohexan-1-one

To a solution of 8-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-1,4-
dioxaspiro[4.5]decan-8-ol (Reference Example 30) (14.6 g, 34.7 mmol) in
tetrahydrofuran (69.4 mL), 6 M hydrochloric acid (138.9 mL) was added, and the
obtained solution was stirred at room temperature for 15 hours. The reaction
solution was cooled in ice, and 50% aqueous sodium hydroxide solution was added
dropwise thereto at 0°C until it became basic. Thereafter, the resulting solution was
extracted with ethyl acetate. The organic layer was washed with brine, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure. The residue
was purified by recrystallization (77-hexane/ethyl acetate, 70°C) to obtain the title
compound (10.5 g, 27.9 mmol, 80%) as a white solid.
1H-NMR (400 MHz, CDCl3) d: 2.33-2.43 (9H, m), 2.87-2.95 (3H, m), 3.82 (3H, s),
6.39 (1H, s), 6.86 (2H, d, J= 8.8 Hz), 7.10 (4H, s), 7.22 (2H, d, J= 8.8 Hz).
IR (KBr, cm4): 3321,2929,1712,1518,1463,1299,1249,1179,1114,1027, 961,
821.
ESI-MS: m/z = 377 (M+H)+
[0333]
(Example 38)
4-Hydroxy-4-(1-(4-methoxyphenyl)-5-(6-methylpyridin-3-yl)-1H-pyrazol-3-yl)-
cyclohexan-1-one

To a solution of 8-(1-(4-methoxyphenyl)-5-(6-methylpyridin-3-yl)-1H-
pyrazol-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol (Reference Example 31) (128.8 mg, 0.30
mmol) in tetrahydrofuran (0.6 mL), 6 M hydrochloric acid (1.2 mL) was added, and
the obtained solution was stirred at room temperature for 3 hours. The reaction
solution was cooled in ice, and 50% aqueous sodium hydroxide solution was added
dropwise thereto at 0°C until it became basic. Thereafter, the resulting solution was
extracted with ethyl acetate. The organic layer was washed with brine, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure. The residue
was purified by flash chromatography (silica gel, «-hexane/ethyl acetate) to obtain
the title compound (109.5 mg, 0.29 mmol, 96%) as an amorphous product.
1H-NMR (400 MHz, CDCl3) d:2.34-2.44 (6H, m), 2.55 (3H, s), 2.87-2.95 (2H, m),
3.18 (1H, s), 3.82 (3H, s), 6.49 (1H, s), 6.87 (2H, d, J- 8.8 Hz), 7.08 (1H, d, J= 8.1
Hz), 7.19 (2H, d, J= 8.8 Hz), 7.35 (1H, dd, J= 2.2, 8.1 Hz), 8.40 (1H, d, J= 2.2 Hz).
ESI-MS: m/z = 378 (M+H)+
[0334]
(Example 39)
4-( 1,5-Bis(4-methoxyphenyl)-1 i/-pyrazol-3 -yl)-4-hydroxy-cyclohexan-1 -one

To a solution of 8-(l,5-bis(4-methoxyphenyl)-1H-pyrazol-3-yl)-1,4-
dioxaspiro[4.5]decan-8-ol (Reference Example 32) (658 mg, 1.50 mmol) in
tetrahydrofuran (3.75 mL), 6 M hydrochloric acid (7.5 mL) was added at 0°C, and
the obtained solution was stirred at room temperature for 5 hours. The reaction
solution was neutralized by pouring it into ice-cooled 10% aqueous sodium
hydroxide solution. The resulting solution was basified by addition of saturated
sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer
was dried over anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by flash chromatography (silica gel, n-
hexane/ethyl acetate) to obtain the title compound (523 mg, 1.33 mmol, 89%) as an
amorphous product.
1H-NMR (400 MHz, CDCl3) d: 2.30-2.45 (6H, m), 2.86-2.96 (2H, m), 2.99 (1H, s),
3.80 (3H, s), 3.82 (3H, s), 6.36 (1H, s), 6.82 (2H, d, J= 8.8 Hz), 6.87 (2H, d, J= 8.8
Hz), 7.13 (2H, d, J= 8.8 Hz), 7.21 (2H, d, J= 8.8 Hz).
ESI-MS: m/z = 393 (M+H)+
[0335]
(Example 40)
4-(5-(4-Chlorophenyl)-1 -(4-methoxyphenyl)-1H-pyrazol-3 -yl)-4-hydroxy-
cyclohexan-1 -one

To a solution of 8-(5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-
yl)-1,4-dioxaspiro[4.5]decan-8-ol (Reference Example 33) (756 mg, 1.71 mmol) in
tetrahydrofuran (4.3 mL), 6 M hydrochloric acid (8.6 mL) was added, and the
obtained solution was stirred at room temperature for 15 hours. The reaction
solution was cooled in ice, and 50% aqueous sodium hydroxide solution was added
dropwise thereto at 0°C until it became basic. Thereafter, the resulting solution was
extracted with ethyl acetate. The organic layer was washed with brine, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure. The residue
was purified by flash chromatography (silica gel, w-hexane/ethyl acetate) to obtain
the title compound (619 mg, 1.56 mmol, 91%) as an amorphous product.
1H-NMR (400 MHz, CDCl3) d: 2.31-2.45 (6H, m), 2.85-2.98 (3H, m), 3.82 (3H, s),
6.43 (1H, s), 6.86-6.90 (2H, m), 7.14 (2H, d, J= 8.8 Hz), 7.19 (2H, d, J= 8.8 Hz),
7.26-7.29 (2H, m).
ESI-MS: m/z = 397 (M+H)+
[0336]
(Example 41)
4-Hydroxy-4-(1-(4-chlorophenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cyclohexan-1-one

To a solution of 8-(1-(4-chlorophenyl)-5-/?-tolyl-1H-pyrazol-3-yl)-1,4-
dioxaspiro[4.5]decan-8-ol (Reference Example 34) (931 mg, 2.19 mmol) in
tetrahydrofuran (5.5 mL), 6 M hydrochloric acid (11 mL) was added, and the
obtained solution was stirred at room temperature for 15 hours. The reaction
solution was basified by pouring it into saturated aqueous sodium hydrogen
carbonate solution, and the resulting solution was extracted with ethyl acetate. The
organic layer was washed with brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified by flash
chromatography (silica gel, H-hexane/ethyl acetate) to obtain the title compound (513
mg, 1.35 mmol, 61%) as a white solid.
1H-NMR (400 MHz, CDCl3) :d 2.32-2.36 (4H, m), 2.36 (3H, s), 2.38-2.44 (2H, m),
2.87-2.95 (2H, m), 2.90 (1H, s), 6.41 (1H, s), 7.10 (2H, d, J= 8.0 Hz), 7.14 (2H, d, J
= 8.0 Hz), 7.23 (2H, d, J= 8.8 Hz), 7.31 (2H, d, J= 8.8 Hz).
ESI-MS:w/z = 381(M+H)+
[0337]
The following compounds were prepared by the same procedure as described
above.
[0341]
(Example 57)
c-4-Hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cyclohexan-r-1-
yl acetate

To a suspension of l-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-
yl)cyclohexan-cw-1,4-diol (Example 2-B) (500 mg, 1.32 mmol) in dichloromethane
(4.4 mL), acetic anhydride (0.312 mL, 3.30 mmol), pyridine (0.267 mL, 3.30 mmol),
and 4-dimethylaminopyridine (16.1 mg, 0.132 mmol) were added, and the obtained
solution was stirred at room temperature for 45 minutes. Water was added to the
reaction solution to quench the reaction, and the resulting solution was extracted with
ethyl acetate. The organic layer was washed with brine, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure. The residue was purified
by flash chromatography (silica gel, w-hexane/ethyl acetate) to obtain the title
compound (556 mg, 1.32 mmol, quant.) as an amorphous product.
1H-NMR (400 MHz, CDCl3) d: 1.89-2.08 (11H, m), 2.34 (3H, s), 2.64 (1H, brs), 3.81
(3H, s), 4.80-4.88 (1H, m), 6.36 (1H, s), 6.85 (2H, d, J= 8.8 Hz), 7.00 (4H, s), 7.20
(2H,d,J-8.8Hz).
ESI-MS: m/z = 421 (M+H)+
[0342]
(Example 58)
4-(4-Chloro-1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-c-4-hydroxy-
cyclohexan-r-1-yl acetate

To a solution of c-4-hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-
pyrazol-3-yl)-cyclohexan-r-1-yl acetate (Example 57) (140 mg, 0.333 mmol) in
acetonitrile (1.66 mL), N-chlorosuccinimide (49 mg, 0.366 mmol) was added. The
obtained solution was stirred at 80°C for 15 hours, and cooled to room temperature.
Brine was added to the reaction solution, and the resulting solution was extracted
with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate,
and concentrated under reduced pressure. The residue was purified by flash
chromatography (silica gel, n-hexane/ethyl acetate) to obtain the title compound (67
mg, 0.147 mmol, 44%) as a white solid.
1H-NMR (400 MHz, CDCl3) d: 1.92-2.04 (6H, m), 2.28-2.36 (8H, m), 3.10 (1H, s),
3.79 (3H, s), 4.85-4.88 (1H, m), 6.80-6.82 (2H, m), 7.11-7.16 (6H, m).
[0343]
(Example 59)
1 -(4-Chloro-1 -(4-methoxyphenyl)-5-(p-tolyl)- 1H-pyrazol-3 -yl)cyclohexan-cis-1,4-
diol

To a solution of 4-(4-chloro-1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-
yl)-c-4-hydroxy-cyclohexan-r-1-yl acetate (Example 58) (67 mg, 0.147 mmol) in
methanol (1.5 mL), potassium carbonate (102 mg, 0.736 mmol) was added, and the
obtained solution was stirred at room temperature for 2 hours. Water was added to
the reaction solution to quench the reaction, and the resulting solution was extracted
with ethyl acetate. The organic layer was washed with brine, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure. The residue was purified
by flash chromatography (silica gel, H-hexane/ethyl acetate) to obtain the title
compound (58 mg, 0.140 mmol, 95%) as a white solid.
1H-NMR (400 MHz, CDCl3) d: 1.45 (1H, s), 1.83-2.05 (6H, m), 2.21-2.23 (2H, m),
2.36 (3H, s), 3.04 (1H, s), 3.76-3.79 (4H, m), 6.79-6.83 (2H, m), 7.11-7.16 (6H, m).
ESI-MS: m/z = 395, 397 (M-OH)+
[0344]
(Example 60)
?-4-Fluoro-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cyclohexan-r-1-ol

To a solution of c-4-hydroxy-4-(1-(4-methoxyphenyl)-5-p-tolyl-1H-pyrazol-
3-yl)-cyclohexan-r-1-yl acetate (Example 57) (100 mg, 0.238 mmol) in
dichloromethane (1.19 mL), Deoxofluor™ (48 µL, 0.262 mmol) was added, and the
obtained solution was stirred at room temperature for 15 minutes. To the reaction
solution, 1 M hydrochloric acid was added, and the resulting solution was extracted
with chloroform. The organic layer was washed with brine, and then dried over
anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the
residue.
[0345]
To a solution of the obtained residue in methanol (2.4 mL), potassium
carbonate (164 mg, 1.18 mmol) was added, and the obtained solution was stirred at
room temperature for 2 hours. Water was added to the reaction solution to quench
the reaction, and the resulting solution was extracted with ethyl acetate. The
organic layer was washed with brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified by flash
chromatography (silica gel, n-hexane/ethyl acetate) to obtain the title compound
(22.4 mg, 0.058 mmol, 25%) as a white solid.
1H-NMR (400 MHz, CDCl3) :d 1.37 (1H, m), 1.72-1.77 (2H, m), 2.02-2.14 (4H, m),
2.34 (3H, s), 2.38-2.49 (2H, m), 3.81 (3H, s), 4.11 (1H, m), 6.52 (1H, m), 6.84 (2H, d,
J= 8.8 Hz), 7.22 (2H, d, J= 8.8 Hz), 7.26 (4H, s).
ESI-MS:m/z = 381(M+H)+
[0346]
(Example 61)
4,4-Difluoro-1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3 -yl)cyclohexanol

To a solution of l-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-4-oxo-
cyclohexan-1-yl acetate (Reference Example 81) (110 mg, 0.263 mmol) in
dichloromethane (2.63 mL), (dimethylamino)sulfur trifluoride (DAST) (104 µL,
0.578 mmol) was added, and the obtained solution was stirred at room temperature
for 2 hours. To the reaction solution, 1 M hydrochloric acid was added, and the
resulting solution was extracted with chloroform. The organic layer was washed
with brine, and then dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure to obtain the residue.
[0347]
To a solution of the obtained residue in tetrahydrofuran (193 µL) and
methanol (386 uL), 4 M aqueous sodium hydroxide solution (193 µL, 0.772 mmol)
was added, and the obtained solution was stirred at room temperature for 6 hours.
Water was added to the reaction solution to quench the reaction, and the resulting
solution was extracted with ethyl acetate. The organic layer was washed with brine,
dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The
residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to
obtain the title compound (41.0 mg, 0.103 mmol, 39%) as a white solid.
1H-NMR (400 MHz, CDCl3) d: 2.01-2.31 (8H, m), 2.34 (3H, s), 2.77 (1H, s), 3.81
(3H, s), 6.37 (1H, s), 6.86 (2H, d, J= 8.8 Hz), 7.10 (4H, s), 7.21 (2H, d, J= 8.8 Hz).
ESI-MS: m/z = 399 (M+H)+
[0348]
(Example 62)
1-(1-(4-Methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-4-
(trifluoromethyl)cyclohexan-cis-1,4-diol

To a solution of 4-hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-
3-yl)cyclohexanone (Example 37) (620 mg, 1.65 mmol) in tetrahydrofuran (6.60 mL),
(trifluoromethyl)trimethylsilane (535 uL, 3.62 mmol) was added at 0°C. Thereafter,
tetra-n-butylammonium fluoride (TBAF, 1 M tetrahydrofuran solution) (362 uL,
0.36 mmol) was added dropwise thereto, and the obtained solution was stirred at
room temperature for 6 hours. To the reaction solution, tetra-n-butylammonium
fluoride (TBAF, 1 M tetrahydrofuran solution) (3.29 mL, 3.29 mmol) was added.
The obtained mixture was stirred at room temperature for 1 hour, and then poured
into 1 M hydrochloric acid. The reaction solution was extracted with diethyl ether.
The organic layer was washed with brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified by flash
chromatography (silica gel, n-hexane/ethyl acetate) to obtain the title compound (410
mg, 0.92 mmol, 56%) as a white solid.
1H-NMR (400 MHz, CDCl3) d: 1.60 (1H, s), 1.87-2.02 (4H, m), 2.09-2.02 (2H, m),
2.34-2.40 (6H, m), 3.82 (3H, s), 6.47 (1H, s), 6.86 (2H, d, J= 8.8 Hz), 7.08-7.11 (4H,
m),7.20(2H,d,J=8.8Hz).
IR(KBr, cm-1): 3402,2954,1517,1463,1305,1250,1249,1179,1121,1056,1024,
834.
ESI-MS: m/z = 447 (M+H)+
[0349]
(Example 63)
4-Methoxy-1 -(1 -(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)cyclohexanol

To a solution of c-4-methoxy-1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-
pyrazol-3-yl)-cyclohexan-r-1-yl acetate (Reference Example 79) (124 mg, 0.284
mmol) in methanol (2.8 mL), potassium carbonate (197 mg, 1.42 mmol) was added,
and the obtained solution was stirred at room temperature for 18 hours. Water was
added to the reaction solution to quench the reaction, and the resulting solution was
extracted with ethyl acetate. The organic layer was washed with brine, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure. The residue
was purified by flash chromatography (silica gel, H-hexane/ethyl acetate) to obtain
the title compound (102 mg, 0.260 mmol, 91%) as a white amorphous product.
1H-NMR (400 MHz, CDCl3) d: 1.78-1.88 (2H, m), 1.90-1.99 (4H, m), 2.03-2.09 (2H,
m), 2.33 (3H, s), 2.49 (1H, s), 3.24-3.32 (1H, m), 3.39 (3H, s), 3.81 (3H, s), 6.39 (1H,
s), 6.85 (2H, d, J= 8.8 Hz), 7.09 (4H, s), 7.20 (2H, d, J= 8.8 Hz).
IR(KBr, cm-1): 3425,2937,1516,1443,1369,1300,1249,1171,1099,1030, 968,
834,801.
ESI-MS: m/z = 393 (M+H)+
[0350]
(Example 64)
4-Hydroxy-4-(1-(4-methoxyphenyl)-5-p-tolyl-1H-pyrazol-3-yl)-cis-
cyclohexanecarboxylic acid

To a solution of c-4-hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-
pyrazol-3-yl)-cis-cyclohexan-r-1-carbaldehyde (Reference Example 82) (124.9 mg,
0.32 mmol) in f-butanol (2.4 ml), distilled water (0.8 ml) and 2-methyl-2-butene (101
µl, 0.96 mmol) were added, and the obtained solution was cooled in ice. At 0°C,
sodium dihydrogen phosphate (42.1 mg, 0.35 mmol) and sodium chlorite (72.3 mg,
0.80 mmol) were added thereto, and the obtained mixture was stirred for 5 minutes.
The mixture was warmed to room temperature, and stirred for 1 hour, and then
cooled to 0°C. Thereafter, aqueous sodium thiosulfate solution was added thereto,
and the resulting mixture was stirred. To the mixture, 1 M hydrochloric acid and
ethyl acetate were added, and the resulting solution was extracted. The organic
layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated
under reduced pressure. The residue was purified by flash chromatography (silica
gel, H-hexane/ethyl acetate) to obtain the title compound (116.6 mg, 0.29 mmol,
93%) as a white solid.
1H-NMR (400 MHz, CDCl3) d: 1.87-2.11 (9H, m), 2.33 (3H, s), 2.40-2.43 (1H, m),
3.81 (3H, s), 6.38 (1H, s), 6.84 (2H, d, J= 9.2 Hz), 7.09-7.09 (4H, m), 7.20 (2H, d, J
= 9.2 Hz).
IR(KBr, cm-1): 3523,2928,1706,1517,1252, 831.
ESI-MS: m/z = 407 (M+H)+
[0351]
(Example 65)
4-(Hydroxymethyl)-4-(1-(4-methoxyphenyl)-5-p-tolyl-1H-pyrazol-3-yl)-trans-1,4-
cyclohexanol (65-A)

4-(Hydroxymethyl)-4-(1-(4-methoxyphenyl)-5 -p-tolyl-1H-pyrazol-3 -yl)-cis-1,4-
cyclohexanol (65-B)

To a solution of 4-(benzyloxymethyl)-4-(1-(4-methoxyphenyl)-5-p-tolyl-1H-
pyrazol-3-yl)cyclohexan-l-one (Reference Example 91) (387 mg, 0.804 mmol) in
methanol (8.0 mL), sodium borohydride (30.4 mg, 0.804 mmol) was added. The
obtained solution was stirred at room temperature for 1 hour, and then poured into 1
M hydrochloric acid. The reaction solution was extracted with ethyl acetate. The
organic layer was washed with brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure to obtain the residue.
[0352]
To a solution of the obtained residue in methanol (8.0 mL), under hydrogen
atmosphere, 10% palladium carbon (86.0 mg, 0.080 mmol) was added, and the
obtained solution was stirred at room temperature for 3 hours. The reaction
solution was filtered through Celite, and concentrated under reduced pressure. The
residue was purified by flash chromatography (amine silica gel, n-hexane/ethyl
acetate) to obtain the title compound 65-A (51.6 mg, 0.131 mmol, 16%) as a white
solid, and the title compound 65-B (164 mg, 0.418 mmol, 52%) as a white
amorphous product.
65-A: 1H-NMR (400 MHz, CDCl3) :d 1.43 (1H, brs), 1.54-1.67 (2H, m), 1.83-1.91
(4H, m), 2.00-2.08 (2H, m), 2.34 (3H, s), 3.24-3.33 (1H, m), 3.78-3.86 (6H, m), 6.32
(1H, s), 6.84 (2H, d, J= 8.8 Hz), 7.10 (4H, s), 7.19 (2H, d, J= 8.8 Hz).
ESI-MS: m/z = 393 (M+H)+
65-B: 1H-NMR (400 MHz, CDCl3) d: 1.39 (1H, d, J= 4.8 Hz), 1.46-1.60 (4H, m),
1.85-1.95 (2H, m), 2.33-2.40 (5H, m), 2.71 (1H, t, J= 6.4 Hz), 3.55 (2H, d, J= 6.4
Hz), 3.71-3.83 (4H, m), 6.37 (1H, s), 6.85 (2H, d, J= 8.8 Hz), 7.10 (4H, s), 7.20 (2H,
d, J=8.8 Hz).
ESI-MS: m/z = 393 (M+H)+
[0353]
(Example 66)
4-(4,5-Bis(4-methoxyphenyl)oxazol-2-yl)-4-hydroxycyclohexanone

To a solution of 8-(4,5-bis(4-methoxyphenyl)oxazol-2-yl)-1,4-
dioxaspiro[4.5]decan-8-ol (Reference Example 92) (781 mg, 1.78 mmol) in
tetrahydrofuran (4.5 mL), 6 M hydrochloric acid (9.0 mL) was added at 0°C, and the
obtained solution was stirred at room temperature for 2 hours. The reaction
solution was cooled to 0°C, and alkalified by addition of 10% aqueous sodium
hydroxide solution and saturated sodium bicarbonate solution. The resulting
solution was extracted with ethyl acetate. The organic layer was dried over
anhydrous magnesium sulfate, and concentrated under reduced pressure. The
residue was purified by recrystallization (ethyl acetate/n-hexane) to obtain the title
compound (445 mg, 1.13 mmol, 63%) as a pale yellow solid.
1H-NMR (400 MHz, CDCl3) d: 2.32-2.54 (6H, m), 2.81-2.92 (2H, m), 3.17 (1H, m),
3.84 (6H, s), 6.90 (2H, d, J= 8.8 Hz), 6.91 (2H, d, J= 8.8 Hz), 7.49 (2H, d, J= 8.8
Hz), 7.56 (2H,d, J-8.8 Hz).
ESI-MS: m/z = 394 (M+H)+
[0354]
(Example 67)
4-(4,5-Bis(4-methoxyphenyl)oxazol-2-yl)cyclohexan-/trans-1,4-diol (67-A)

4-(4,5-Bis(4-methoxyphenyl)oxazol-2-yl)cyclohexan-cis-1,4-diol (67-B)

To a solution of 4-hydroxy-4-(4,5-bis(4-methoxyphenyl)oxazol-2-
yl)cyclohexan-1-one (Example 66) (395 mg, 1.00 mmol) in methanol (20 mL),
sodium borohydride (47 mg, 1.24 mmol) was added, and the obtained solution was
stirred at room temperature for 16 hours. The reaction solution was concentrated
under reduced pressure, and distilled water was added to the residue. The resulting
solution was extracted with ethyl acetate. The organic layer was dried over
anhydrous magnesium sulfate, and concentrated under reduced pressure. The
residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to
obtain the title compound 67-A (73 mg, 0.18 mmol, 18%) as a white solid, and the
title compound 67-B (207 mg, 0.523 mmol, 52%) as a white solid.
67-A: 1H-NMR (400 MHz, CDCl3) :d 1.63-1.75 (2H, m), 1.78-1.88 (2H, m), 2.01-
2.12 (2H, m), 2.44-2.53 (2H, m), 2.67 (1H, s), 4.00-4.07 (1H, m), 6.89 (2H, d, J= 8.8
Hz), 6.90 (2H, d, J= 8.8 Hz), 7.51 (2H, d, J= 8.8 Hz), 7.57 (2H, d, J= 8.8 Hz).
IR(KBr, cm-1): 3356,1613,1600,1520,1503,1254,1182,1033, 999,966, 834.
ESI-MS: m/z = 396 (M+H)+
67-B: 1H-NMR (400 MHz, CDCl3) d: 1.49 (1H, brs), 1.78-2.13 (8H, m), 2.76 (1H, s),
3.72-3.78 (1H, m), 3.83 (6H, s), 6.89 (2H, d, J= 8.8 Hz), 6.90 (2H, d, J= 8.8 Hz),
7.49 (2H, d, J= 8.8 Hz), 7.55 (2H, d, J= 8.8 Hz).
IR(KBr, cm-1): 3364,1615,1599,1520,1500,1302,1252,1176,1069,1053,1028,
965, 833.
ESI-MS: m/z = 396 (M+H)+
[0355]
(Example 68)
4-Hydroxy-4-(4-(4-methoxyphenyl)-5-(p-tolyl)thiazol-2-yl)cyclohexan-1-one

To a solution of 8-(4-(4-methoxyphenyl)-5-(p-tolyl)thiazol-2-yl)-1,4-
dioxaspiro[4.5]decan-8-ol (Reference Example 96) (469 mg, 1.07 mmol) in
tetrahydrofuran (5.4 mL), 6 M hydrochloric acid (5.4 mL) was added at 0°C, and the
obtained solution was stirred at room temperature for 14 hours. The reaction
solution was basified by pouring it into saturated aqueous sodium hydrogen
carbonate solution, and the resulting mixture was extracted with ethyl acetate. The
organic layer was washed with brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified by flash
chromatography (silica gel, n-hexane/ethyl acetate) to obtain the title compound (352
mg, 0.895 mmol, 83%) as a white solid.
1H-NMR (400 MHz, CDCl3) d: 2.33-2.51 (6H, m), 2.37 (3H, s), 2.86-2.95 (2H, m),
3.50 (1H, s), 3.81 (3H, s), 6.81-6.84 (2H, m), 7.14 (2H, d, J= 8.0 Hz), 7.24 (2H, d, J
= 8.0 Hz), 7.44-7.48 (2H, m).
ESI-MS: m/z = 394 (M+H)+
[0356]
(Example 69)
1 -(4-(4-Methoxyphenyl)-5-(p-tolyl)thiazol-2-yl)cyclohexan-trans-1,4-diol (69-A)

1 -(4-(4-Methoxyphenyl)-5-p-tolylthiazol-2-yl)cyclohexan-cis-1,4-diol (69-B)

To a solution of 4-hydroxy-4-(4-(4-methoxyphenyl)-5-(p-tolyl)thiazol-2-
yl)cyclohexan-1-one (Example 68) (186 mg, 0.471 mmol) in methanol (4.7 mL),
sodium borohydride (36 mg, 0.943 mmol) was added, and the obtained solution was
stirred at room temperature for 1 hour. The reaction solution was concentrated
under reduced pressure, and then dissolved into ethyl acetate, and washed with
distilled water and brine. The organic layer was dried over anhydrous sodium
sulfate, and concentrated under reduced pressure. The residue was purified by flash
chromatography (silica gel, n-hexane/ethyl acetate) to obtain the title compound 69-
A (42 mg, 0.106 mmol, 23%) as a white solid, and the title compound 69-B (136 mg,
0.344 mmol, 73%) as a white solid.
69-A: 1H-NMR (400 MHz, CDCl3) :d 1.53-1.57 (1H, m), 1.76-1.87 (4H, m), 2.05-
2.12 (2H, m), 2.35-2.42 (2H, m), 2.36 (3H, s), 3.15 (1H, br), 3.80 (3H, s), 4.10-4.14
(1H, m), 6.80-6.84 (2H, m), 7.13 (2H, d,J= 8.0 Hz), 7.24 (2H, d,J= 8.0 Hz), 7.45-
7.49 (2H, m).
IR (KBr, cm-1): 3409,2923,1613,1515,1252,1179,1004, 815.
ESI-MS: m/z = 396 (M+H)+
69-B: 1H-NMR (400 MHz, CDCl3) d: 1.48 (1H, d, J= 4.8 Hz), 1.82-1.89 (2H, m),
1.95-2.01 (2H, m), 2.05-2.09 (4H, m), 2.36 (3H, s), 3.01 (1H, s), 3.76-3.82 (1H, m),
3.80 (3H, s), 6.80-6.83 (2H, m), 7.13 (2H, d,J= 8.0 Hz), 7.22 (2H, d, J= 8.0 Hz),
7.43-7.47 (2H, m).
IR (KBr, cm-1): 3418,2938,1611,1515,1249,1177,1058, 816.
ESI-MS: m/z = 396 (M+H)+
[0357]
(Example 70)
1-(4-(4-Methoxyphenyl)-5-p-tolylthiazol-2-yl)-4-(trifluoromethyl)cyclohexan-trans-
1,4-diol(70-A)

1-(4-(4-Methoxyphenyl)-5-(p-tolyl)thiazol-2-yl)-4-(trifluoromethyl)cyclohexan-cis-
1,4-diol(70-B)

To a solution of 4-hydroxy-4-(4-(4-methoxyphenyl)-5-p-tolylthiazol-2-
yl)cyclohexan-1-one (Example 68) (199 mg, 0.506 mmol) and Ruppert's reagent
(0.187 mL, 1.26 mmol) in tetrahydrofuran (2.5 mL), 1.0 M tetrabutylammonium
fluoride/tetrahydrofuran solution (0.051 mL, 0.051 mmol) was added at room
temperature, and the obtained solution was stirred for 10 minutes. The reaction
solution was concentrated under reduced pressure, and dissolved into tetrahydrofuran
(3.0 mL). Distilled water (0.2 mL) and 1.0 M tetrabutylammonium
fluoride/tetrahydrofuran solution (1.02 mL, 1.02 mmol) were added thereto, and the
resulting mixture was stirred at room temperature for 30 minutes. Distilled water
was added to the reaction solution, and the resulting solution was extracted with
ethyl acetate, followed by washing with brine. The organic layer was dried over
anhydrous sodium sulfate, and concentrated under reduced pressure. The residue
was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain
the title compound 70-A (70 mg, 0.151 mmol, 30%) as a white solid, and the title
compound 70-A (132 mg, 0.285 mmol, 56%) as a white solid.
70-A: 1H-NMR (400 MHz, CDCl3) d: 1.79-1.84 (2H, m), 1.90 (1H, s), 1.96-2.01 (2H,
m), 2.21-2.33 (4H, m), 2.37 (3H, s), 3.28 (1H, s), 3.80 (3H, s), 6.80-6.84 (2H, m),
7.13 (2H, d, J= 8.0 Hz), 7.23 (2H, d, J= 8.0 Hz), 7.44-7.48 (2H, m).
IR(KBr, cm-1): 3460,2940,1610,1515,1494,1442,1310,1245,1175,1035,1005,
837,813
ESI-MS: m/z = 464 (M+H)+
70-B: 1H-NMR (400 MHz, CDCl3)d: 1.90-1.96 (2H, m), 1.97 (1H, br), 2.16-2.23
(2H, m), 2.28-2.36 (4H, m), 2.37 (3H, s), 2.81 (1H, br), 3.80 (3H, s), 6.80-6.83 (2H,
m), 7.14 (2H, d, J= 8.0 Hz), 7.26 (2H, d, J= 8.0 Hz), 7.44-7.48 (2H, m).
IR (KBr, cm-1): 3419,2940, 1611,1515, 1443, 1290, 1250, 1175, 1120, 1066, 993,
837, 814
ESI-MS: m/z = 464 (M+H)+
[0358]
(Example 71)
Ethyl 4-hydroxy-4-(1-(4-methoxyphenyl)-5-p-tolyl-1H-pyrazol-3-yl)-cis-
cyclohexanecarboxylate

To a solution of 4-hydroxy-4-(1-(4-memoxyphenyl)-5-p-tolyl-1H-pyrazol-3-
yl)-cis-cyclohexanecarboxylic acid (Example 64) (41.6 mg, 0.10 mmol) in DMF (1.0
ml), potassium carbonate (41.4 mg, 0.3 mmol) and ethyl iodide (24.8 µl, 0.3 mmol)
were added, and the obtained solution was stirred for 2 hours. Brine was added to
the reaction solution, and the resulting solution was extracted with ethyl acetate.
The organic layer was washed with brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified by flash column
chromatography (silica gel, n-hexane/ethyl acetate) to obtain the title compound
(44.1 mg, 0.10 mmol, 97%) as a white amorphous product.
1H-NMR (400 MHz, CDCl3) :d 1.27 (3H, t, J = 6.8 Hz), 1.85-2.09 (8H, m),
2.33 (3H, s), 2.34-2.41 (1H, m), 2.59 (1H, s), 3.80 (3H, s), 4.15 (2H, q, J =
6.8 Hz), 6.38 (1H, s), 6.84 (2H, d, J = 8.8 Hz), 7.09-7.09 (4H, m), 7.20 (2
H, d, J = 8.8 Hz).
ESI-MS: m/z = 435 (M+H)+
[0359]
The compounds of the following Comparative Examples 1 to 25 were
prepared by the same procedure as in the above Examples 2 to 6.
[0366]
(Comparative Example 26)
c-4-Hydroxy-1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cyclohexan-r-1-
yl acetate

To a solution of l-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-
cyclohexan-cis-1,4-diyl diacetate (Reference Example 78) (297 mg, 0.642 mmol) in
methanol (4.3 mL), potassium carbonate (89.0 mg, 0.642 mmol) was added, and the
obtained solution was stirred at room temperature for 4 hours. Water was added to
the reaction solution to quench the reaction, and the resulting solution was extracted
with ethyl acetate. The organic layer was washed with brine, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure. The residue was purified
by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the title
compound (213 mg, 0.507 mmol, 79%) as a white solid.
1H-NMR (400 MHz, CDCl3) d: 1.49 (1H, d, J= 4.4 Hz), 1.65-1.74 (2H, m), 1.90-
1.98 (4H, m), 2.10 (3H, s), 2.32 (3H, s), 2.71-2.78 (2H, m), 3.74-3.81 (4H, m), 6.37
(1H, s), 6.83 (2H, d, J= 9.2 Hz), 7.08 (4H, s), 7.20 (2H, d, J= 9.2 Hz).
ESI-MS: m/z = 421 (M+H)+
[0367]
(Comparative Example 27)
4-Methoxy-4-(1-(4-methoxyphenyl)-5 -p-tolyl-1H-pyrazol-3 -yl)cyclohexanol

To a solution of c-4-hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-
pyrazol-3-yl)-cyclohexan-r-1-yl acetate (Example 57) (200 mg, 0.476 mmol) in N,N-
dimethylformamide (2.4 mL), 55% sodium hydride (31.1 mg, 0.713 mmol) and
methyl iodide (39.0 µL, 0.618 mmol) were added with stirring under ice-cooling.
The obtained solution was stirred at room temperature for 60 hours. Water was
added to the reaction solution with stirring under ice-cooling, and the resulting
solution was stirred for 15 minutes, followed by extraction with ethyl acetate. The
organic layer was washed with brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified by flash
chromatography (silica gel, H-hexane/ethyl acetate) and further purified by
reprecipitation and washing (n-hexane/diethyl ether) to obtain the title compound
(60.5 mg, 0.139 mmol, 29%) as a white solid.
1H-NMR (400 MHz, CDCl3) :d 1.42 (1H, brs), 1.70-1.78 (2H, m), 1.84-1.95 (4H, m),
2.25-2.34 (5H, m), 3.18 (3H, s), 3.68-3.77 (1H, m), 3.81 (3H, s), 6.43 (1H, s), 6.84
(2H, d, J= 8.8 Hz), 7.10 (4H, s), 7.20 (2H, d, J= 8.8 Hz).
IR(KBr, cm-1): 3407,2937,1516,1457,1368,1298,1249,1185,1071,1035, 969,
833.
ESI-MS:m/z = 393(M+H)+
[0368]
(Comparative Example 28)
1 -(4-Fluoro-1 -(4-methoxyphenyl)-5-(p-tolyl)- 1H-pyrazol-3 -yl)cyclohexan-cis-1,4-
diol

To a solution of 4-(4-fluoro-1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-
yl)-c-4-hydroxy-cyclohexan-r-1-yl acetate (Reference Example 80) (90 mg, 0.205
mmol) in methanol (2.0 mL), potassium carbonate (142 mg, 1.03 mmol) was added,
and the obtained solution was stirred at room temperature for 2 hours. Water was
added to the reaction solution to quench the reaction, and the resulting solution was
extracted with ethyl acetate. The organic layer was washed with brine, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure. The residue
was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain
the title compound (62 mg, 0.156 mmol, 76%) as a white solid.
1H-NMR (400 MHz, CDCl3) :d 1.45 (1H, s), 1.83-1.95 (4H, m), 2.06-2.08 (4H, m),
2.36 (3H, s), 2.70 (1H, s), 3.77-3.81 (4H, m), 6.83-6.86 (2H, m), 7.12-7.19 (6H, m).
ESI-MS: m/z = 379 (M-OH)+
[0369]
(Comparative Example 29)
4-(4-Fluoro-1 -(4-methoxyphenyl)-5-(4-tolyl)-1H-pyrazol-3 -yl)-1 -(N-hydroxy-N-
methylcarbamoyl)-4-piperidinol

To a solution of 4-(4-fluoro-1-(4-methoxyphenyl)-5-(4-tolyl)-1H-pyrazol-3-
yl)-4-piperidinol (3.61 g, 9.46 mmol) in tetrahydrofuran (946 mL), triphosgene (1.12
g, 3.78 mmol) and triethylamine (1.65 mL, 11.8 mmol) were added at 0°C, and the
obtained solution was stirred at the same temperature for 40 minutes. To the
reaction solution, vV-methylhydroxylamine hydrochloride (988 mg, 11.8 mmol) and
triethylamine (3.43 mL, 24.6 mmol) were added, and the obtained mixture was
stirred at 80°C for 3 hours. The reaction solution was cooled to room temperature,
and distilled water was added to the reaction solution. The resulting solution was
extracted with ethyl acetate. The organic layer was washed with 1 M hydrochloric
acid, saturated sodium bicarbonate solution and brine, dried over anhydrous sodium
sulfate, and concentrated under reduced pressure. The residue was purified by
recrystallization (n-hexane/ethyl acetate, 80°C) to obtain the title compound (2.96 g,
6.51 mmol, 68%) as a pale yellow solid.
1H-NMR (400 MHz, CDCl3) d: 1.94-1.98 (2H, m), 2.23-2.31 (2H, m), 2.35 (3H, s),
2.86 (1H, s), 3.00 (3H, s), 3.50-3.56 (2H, m), 3.81 (3H, s), 3.92-3.95 (2H, m), 6.84-
6.87 (3H, m), 7.10-7.19 (6H, m).
IR(KBr, cm-1): 3382,1630,1513,1440,1251,1164,1108,1031, 836.
ESI-MS: m/z = 438 (M-OH)+
[0370]
(Comparative Example 30)
4-(3-Cyclohexyl-5-phenyl-1H-pyrazol-1-yl)-2-(hydroxymethyl)benzenesulfonamide

To a suspension of 4-hydrazinyl-2-(hydroxymethyl)benzenesulfonamide (224
mg, 0.884 mmol) in ethanol (4.0 mL), triethylamine (246 µL, 1.77 mmol) and 1-
cyclohexyl-3-phenylpropan-1,3-dione (185 mg, 0.803 mmol) were added, and the
obtained solution was stirred at 100°C for 72 hours. Water was added to the
reaction solution, and the resulting solution was extracted with ethyl acetate. The
organic layer was washed with brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified by flash
chromatography (silica gel, H-hexane/chloroform/acetone) to obtain the title
compound (51.5 mg, 0.125 mmol, 16%) as a white amorphous product.
1H-NMR (400 MHz, CDCl3) d: 1.18-1.89 (8H, m), 1.98-2.09 (2H, m), 2.69-2.79 (1H,
m), 3.28 (1H, br), 4.94 (2H, d, J= 5.2 Hz), 5.56-5.63 (2H, m), 6.35 (1H, s), 7.05-7.38
(6H, m), 7.48-7.54 (1H, m), 7.83 (1H, d, J= 8.8 Hz).
ESI-MS: m/z = 412 (M+H)+
[0371]
(Example 72)
Effect on Nociceptive Pain
Using a mouse acetic acid writhing model with which nociceptive pain can be
evaluated, the analgesic effect of Compound (I) was studied.
[0372]
1. Experimental Method
Male ddY mice of 5 to 6 weeks old were fasted for not less than 16 hours,
during which water was given ad libitum. Thereafter, the test compound solution or
its vehicle was orally administered (10 mL/kg). As the vehicle of the test
compound solution, dimethyl sulfoxide (hereinafter referred to as DMSO):Tween
80:distilled water (1:1:8) or 27% hydroxypropyl-P-cyclodextrin (hereinafter referred
to as HP-P-CD) was used. Forty five minutes after the administration of the vehicle
or test compound, 0.6% acetic acid solution (10 mL/kg) was intraperitoneally
administered to induce writhing responses (behaviors such as extending the body and
bending the body backward). The number of writhing responses occurred from 10
minutes after the administration of the acetic acid solution was counted for 10
minutes, and the number of writhing responses was used as an index of pain.
[0373]
The mean number of writhing responses obtained in the vehicle group was
defined as 100%, and the dose of the test compound with which 50% of the response
was suppressed was represented as the ED50 value.
[0374]
2. Results
Results are shown in Table 10.
Vehicle A=DMSO:Tween 80:distilled water (1:1:8), vehicle B=27% HP-ß-CD
[0376]
All the compounds of Examples 1, 2-A, 2-B, 3, 6-A, 28-31, 33, 35, 37, 57, 59,
60, 62-64, 65-A, 67-B, 69-A, 70-B and 71 described in Table 10 showed ED50
values of 0.41 to 9.92 mg/kg. In terms of Comparative Examples 1 to 28, the ED50
values were >10 mg/kg. These results indicate that Compound (I) has an excellent
analgesic effect. Further, the compound of Comparative Example 30 did not cause
significant reduction in the number of writhing responses even by administration of
10 mg/kg of the compound (t-test).
[0377]
(Example 73)
Effect in Mouse Sciatic Nerve-Ligation Model
Using a mouse sciatic nerve-ligation model (Seltzer model) with which
neuropathic pain can be evaluated, the analgesic effect of Compound (I) was studied.
[0378]
The neuropathic pain model was prepared according to the method by Seltzer
et al. Male ICR mice of 5 weeks old were anesthetized with sodium pentobarbital
(70 mg/kg, i.p.), and the sciatic nerve at the femoral region of the right hind limb was
exposed, followed by triply and tightly ligating the sciatic nerve under microscope
such that only half thickness thereof was pressed with silk suture of 8-0 (NATSUME
SEISAKUSHO), to provide Ligation group. A group wherein the sciatic nerve was
exposed but not ligated was provided as a control group (Sham). In terms of
evaluation of neuropathic pain (hereinafter referred to as von Frey test), mice were
kept in acrylic cages (NATSUME SEISAKUSHO) placed on nets for at least 1 hour
for habituation, and a filament (North Coast Medical Inc. CA, USA) which exerts a
pressure of 0.16 g was used to mechanically stimulate the both plantar hind paws by
pressing them with the filament 3 times for 3 seconds/time at intervals of 3 seconds.
The escape behavior occurred upon application of the mechanical stimulation was
scored (0: no response, 1: showed slow and slight escape behavior in response to the
stimulation, 2: showed quick escape behavior without flinching (behavior of shaking
legs quickly and continuously) or licking (leg-licking behavior), 3: showed quick
escape behavior with flinching or licking), and the total of the scores obtained in the
triplicate pressing trials was used as an index of pain. The von Frey test was carried
out 7 days after the sciatic nerve ligation operation to obtain the pre value before oral
administration of the test compound, and also carried out 1 hour, 2 hours and 3 hours
after the oral administration to obtain values to be used as indices of the analgesic
effect. To provide a positive control, gabapentin (30 mg/kg, oral administration)
was used.
[0379]
The results are shown in Figs. 1 to 4 and Table 11. In Figs. 1 to 4, the
ordinate indicates the total score of the von Frey test, and a higher value indicates a
stronger pain. The abscissa indicates the time (hr) after the administration of the
test compound. As the vehicle of the test compound solution, 27% HP-ß-CD was
used in the experiments of Fig. 1, Fig. 3 and Fig. 4, and DMSO:Tween 80:distilled
water (1:1:8) was used in the experiment of Fig. 2. The pharmacological effect was
evaluated by statistical analysis by multiple unpaired t-test corrected with Dunnett's
method using the vehicle group (Ligation+Vehicle) at each measurement time as a
control. The symbols "*" in the Figures indicate statistical significance (**: p<0.01,
***:p<0.001).
[0380]
Based on the results of the von Frey test with the compounds of Example 2-A
(Fig. 1), Example 2-B (Fig. 2), Example 62 (Fig. 3) and Comparative Example 29
(Fig. 4), gabapentin and the compound of Comparative Example 29, which were
positive controls, showed the strongest analgesic effect 1 hour after the oral
administration, and the analgesic effect drastically decreased 3 hours after the oral
administration. On the other hand, in the cases of oral administration of the
compound of Example 2-A in an amount of 0.3 mg/kg, and oral administration of the
compounds of Example 2-B and Example 62 in amounts of 0.3 and 1.0 mg/kg,
respectively, a strong analgesic effect was maintained even 3 hours after the oral
administration. From these results, it was revealed that Compound (I) having a
cyclohexane skeleton is continuously effective on neuropathic pain.
[0381]
As shown in Table 11, based on the results of the von Frey test carried out 1
hour after oral administration of the compounds of Example 4-B, Example 30,
Example 31, Example 59, Example 64 and Example 67-B, all of these compounds
significantly improved the von Frey total score compared to the vehicle group.
Thus, it was revealed that these compounds are effective on neuropathic pain.
[0382]

Vehicle A=DMSO:Tween 80:distilled water (1:1:8), vehicle B=27% HP-p-CD,
vehicle C=0.5% methyl cellulose
In the cases where vehicle A or B was used, the compound was administered as a test
compound solution, and in the cases where Vehicle C was used, the compound was
administered as a test compound suspension.
The score improvement rate was calculated as follows:
score improvement rate = 100 - (score of compound-administered group - score of
control group) / (score of vehicle group - score of control group) x 100.
The symbols "*" in the table indicate statistical significance (*: p<0.05, **: p<0.01,
***: p0.001) based on comparison with the vehicle group (multiple unpaired t-test
corrected with Dunnett's method).
[0383]
(Example 74)
Effect on Mouse Model Having Pain Due to Diabetic Neuralgia
Using a mouse model having pain due to streptozotocin (hereinafter referred
to as STZ)-induced diabetic neuralgia, with which diabetic neuropathic pain can be
evaluated, the analgesic effect of Compound (I) was studied.
[0384]
STZ (250 mg/kg) or physiological saline was intraperitoneally administered
to male ICR mice of 5 weeks old, to prepare mice having diabetes and a control
group thereof. The mice having diabetes herein means mice whose blood glucose
level at full feeding is not less than 350 mg/dL when a small amount of blood was
collected from the tail vein 6 days after administration of STZ and the blood glucose
level was measured using a blood glucose meter Precision Xceed and an electrode
for measurement of blood glucose Smartblue (Abbott).
[0385]
Seven days after the administration of STZ, the von Frey test was carried out
for the mice having diabetes as in the above-described case of evaluation of
neuropathic pain, and individuals showing a total score of 5 or higher were selected
as individuals having the diseased state of pain due to diabetic neuralgia. The
selected individuals were divided into groups such that the total score becomes even
among the groups, followed by oral administration of test compounds. One hour
after the oral administration, the von Frey test was further carried out, and the
obtained value was used as an index of the analgesic effect. As a positive control,
pregabalin (10 mg/kg, oral administration) was used.
[0386]
The results are shown in Fig. 5. In Fig. 5, the ordinate indicates the total
score of the von Frey test, and a higher value indicates a stronger pain. As the
vehicle of the test compound suspension, 0.5% methyl cellulose was used. The
pharmacological effect was evaluated by statistical analysis using the group of STZ
administration+vehicle administration as a control, by Wiiliams test for the Example
2-B-administered group and by unpaired t-test for the pregabalin-administered group.
The symbols "*" and "#" in the figure indicate statistical significance based on
comparison with the group of STZ administration+vehicle administration (*:
p<0.025, #: p<0.05).
[0387]
Based on the results of the von Frey test obtained with the compound of
Example 2-B, the oral administration of 1 and 10 mg/kg of the compound
significantly improved the total score of the von Frey test. It was revealed from
these test results that Compound (I) is effective for pain due to diabetic neuralgia.
[0388]
(Example 75)
Human and Mouse Liver Microsomal Stability Assay
A liver microsomal stability assay, which is known to be an in vitro assay for
evaluation of the stability of a compound against hepatic metabolism, was carried out
to evaluate the stability of Compound (I) against human and mouse hepatic
metabolism.
[0389]
A total of 4 times of experiments were carried out for the combinations of the
compound of Example 2-B or the compound of Comparative Example 29 as the test
compound and human liver microsomes (Xenotech) or mouse liver microsomes
(Xenotech) as the liver microsomes.
[0390]
The respective reagents to be used for the liver microsomal stability assay
were prepared as follows. That is, an appropriate amount of D-glucose 6-phosphate
disodium salt (hereinafter referred to as G6P) was dissolved in distilled water at 100
mmol/L, to prepare 100 mmol/L aqueous G6P solution. In 5 mL of distilled water,
1000 units of Glucose 6-phosphate dehydrogenase from Yeast (hereinafter referred
to as G6PDH) was dissolved, to prepare 200 units/mL aqueous G6PDH solution.
An appropriate amount of MgCl2 was dissolved in distilled water at 100 mmol/L, to
prepare 100 mmol/L aqueous MgCl2 solution. To 500 mL of 200 mmol/L aqueous
K2HPO4 solution, 200 mmol/L aqueous KH2PO4 solution (about 130 mL) was added,
and pH was adjusted to 7.4, to prepare 200 mmol/L KH2PO4/K2HPO4 buffer pH7.4
(hereinafter referred to as 200 mmol/L PB). ß-nicotinamide-adenine dinucleotide
phosphate, reduced form, tetrasodium salt (hereinafter referred to as (NADPH) was
dissolved in distilled water such that the NADPH content becomes 10 mmol/L based
on the purity (Purity NADPH) in the assay data described in the attached document,
to prepare 10 mmol/L aqueous NADPH solution.
[0391]
The liver microsomal stability assay was carried out according to the
following procedure. First, the reagents listed in Table 12 (excluding microsomes)
were mixed together to prepare a reaction mixture, and the reaction mixture was
aliquoted in 130 uL volumes to 4 wells (which play roles as the wells for the 0-
minute reaction, well for the 30-minute reaction, well for the 20-minute reaction and
well for the 10-minute reaction, respectively) in a 96-well tube plate (BM Equipment
Co., Ltd; hereinafter referred to as plate). The entire plate was covered with a
silicone cap, and the plate was subjected to preincubation by being soaked in a water
bath at 37°C for 10 minutes.
[0392]
After the preincubation, 3.75 µL of 20 mg/mL microsome suspension + 16.25
µL of distilled water (20 µL in total) were added to the well for the 30-minute
reaction, and the plate was covered with the cap, followed by soaking the plate in a
water bath at 37°C to initiate the reaction.
[0393]
Ten minutes after the beginning of the reaction, 3.75 µL of 20 mg/mL
microsome suspension + 16.25 µL of distilled water (20 µL in total) were added to
the well for the 20-minute reaction, and 20 minutes after the beginning of the
reaction, 3.75 µL of 20 mg/mL microsome suspension + 16.25 µL of distilled water
(20 µL in total) were added to the well for the 10-minute reaction. The reaction was
further continued by keeping the plate soaked in the water bath at 37°C.
[0394]
Thirty minutes after the beginning of the reaction, the plate was removed
from the water bath, and 120 µL of acetonitrile was added to each well, followed by
covering the plate with the cap, stirring the plate for 10 seconds with Direct Mixer,
and stopping the reaction by 10 minutes of ice cooling. After the reaction was
stopped, 3.75 µL of 20 mg/mL microsome suspension + 16.25 µL of distilled water
(20 µL in total) were added to the well for the 0-minute reaction.
[0395]
The reaction liquid in each well was centrifuged at 4°C at 2500 rpm for 10
minutes, and the supernatant was transferred to a glass-coated microplate (TOMSIC
Plate+) to begin LC/MS/MS analysis. The conditions for the LC/MS/MS analysis
were as follows.

[0396]
For the chromatogram of the reaction liquid in each well obtained by the
LC/MS/MS analysis, the peak area of the test compound was confirmed, and test
compound remaining rate (%) at each reaction time t (min.) was calculated taking the
peak area at the reaction time of 0 minute as 100%. The test compound remaining
rate was semi-logarithmically plotted against the reaction time and fitted to Equation
1 by the least squares method, thereby calculating the elimination rate constant k
(1/min.). Further, the obtained k was divided by the microsome protein
concentration, to calculate hepatic intrinsic clearance CLint (mL/min./mg) (Equation
2).
Substrate remaining rate = A x exp(-kt) ... Equation 1
CLint= k / microsome protein concentration... Equation 2
[0397]
The values of the hepatic intrinsic clearance obtained as a result of the total of
4 times of the liver microsomal stability assay are shown in Table 13 and Table 14.
A higher hepatic intrinsic clearance indicates faster metabolism of the compound in
liver microsomes.

[0398]
As shown in Table 13, the hepatic intrinsic clearance obtained by the liver
microsomal stability assay using the compound of Example 2-B as the test
compound was extremely smaller than that using the compound of Comparative
Example 29 as the test compound. From these test results, it was revealed that
Compound (I) having a cyclohexane skeleton remarkably improves the metabolic
stability in liver.
[0399]
Table 14 shows the results of the human liver microsomal stability assay.
When compared with Comparative Example 29 in Table 13, Examples 2-A, 4-B, 28,
30, 33, 35, 59, 62, 64 and 67-B showed smaller human hepatic intrinsic clearance,
indicating that the metabolic stability in liver was improved.

[0400]
(Example 76)
Pharmacokinetics (PK) Test
Example 2-B or Comparative Example 29 was orally administered to mice,
and the plasma level after the administration was measured to study the influence of
improvement of the metabolic stability in liver microsomes on the change in the
plasma level of the compound.
[0401]
Female CD1 (ICR) mice of 7 weeks old which had been fed ad libitum with
pellets (Oriental Yeast Co., Ltd.) and tap water were fasted for 17 hours before the
administration. Feeding to the mice was begun again 4 hours after the
administration.
[0402]
The compound of Example 2-B was dissolved in DMSO:Tween 80:distilled
water (1:1:8), or the compound of Comparative Example 29 was dissolved in 27%
aqueous HP-P-CD solution, to prepare each solution to be administered that
contained the compound at a concentration of 0.2 mg/mL.
[0403]
In the case of intravenous administration of the solution, the animal was fixed
in a holder, and the administration was carried out from the tail vein without
anesthesia, using a syringe with an injection needle (25 G) attached thereto. In the
case of oral administration, a syringe with a feeding needle attached thereto was used
without anesthesia to force the solution into the stomach.
[0404]
In terms of the mice to which the solution was intravenously administered,
blood was collected a total of 8 times from the jugular vein or heart 5, 15 and 30
minutes and 1, 2, 4, 8 and 24 hours after the intravenous administration. In terms of
the mice to which the solution was orally administered, blood was collected a total of
8 times from the jugular vein or heart 15, 30 and 45 minutes and 1, 2, 4, 8 and 24
hours after the oral administration. Further, from the jugular vein or heart of mice
to which the solution was not administered, blood was collected as a blank. The
collected blood was centrifuged at 4°C at 12000 rpm for 5 minutes, and the obtained
mouse plasma and blank plasma were stored at about -20°C until preparation of
samples for analysis.
[0405]
To 50 µL of a mouse plasma sample, or a mouse plasma sample appropriately
diluted with the blank plasma, an internal standard solution and 150 µL of methanol
were added, and the resulting mixture was stirred, followed by cooling the mixture at
4°C for 20 minutes. In terms of calibration curve samples, blank plasma to which a
standard solution for a calibration curve was added was prepared by the same process.
Each sample after the cooling was centrifuged (Hitachi Koki Co., Ltd.) at 4°C at
2000 rpm for 10 minutes, and the supernatant was transferred onto a 0.20 µm filter
plate (Whatman), followed by centrifugal filtration (Hitachi Koki Co., Ltd.) at 4°C at
2000 rpm for 10 minutes. The obtained filtrate was subjected to LC/MS/MS
analysis. The conditions for the LC/MS/MS analysis were the same as those in the
above-described human and mouse liver microsomal stability assay.
[0406]
From the results of the LC/MS/MS analysis, a calibration curve was prepared
using Analysis 1.4 (Applied Biosystems). Based on the LC/MS/MS analysis and
the prepared calibration curve, the concentration in each measurement sample was
calculated using Analysis 1.4. For 3 times each of the experiments by intravenous
administration and oral administration, the mean plasma level at each time point was
calculated, and PK analysis was carried out using the obtained values (Fig. 6 and Fig.
7; each plot indicates the mean plasma level at each time point and its ±standard
deviation; i.v. indicates test data by intravenous administration; and p.o. indicates test
data by oral administration). The PK parameter was calculated using WinNonlin
(Pharsight) by analysis independent of the models (intravenous administration:
Model 201, oral administration: Model 200). Further, the bioavailability (BA) was
calculated by normalization by dividing AUC0-24 hr from the time point of the
intravenous administration or oral administration to the time point of the final blood
collection by the dose.
[0407]
As shown in Fig. 6 and Fig. 7, the mean plasma level in the mice to which the
compound of Example 2-B was administered was higher than the mean plasma level
in the mice to which the compound of Comparative Example 29 was administered, at
all the time points. Further, BA, which indicates the ratio of oral absorption, was
88% for the compound of Example 2-B, but it was as low as 54% for the compound
of Comparative Example 29. Further, the total body clearance, which indicates the
rate of disappearance of a compound, was 971 mL/hr/kg for the compound of
Example 2-B, but it was as high as 5672 mL/hr/kg for the compound of Comparative
Example 29. From these test results, it was revealed that Compound (I) having a
cyclohexane skeleton remarkably improves the metabolic stability compared to
similar compounds having no cyclohexane skeleton.
[0408]
(Example 77)
Evaluation of Safety Using Mice
1. Experimental Method
Crlj:CDl (ICR) mice of 7 weeks old were subjected to repeated oral
administration of Example 2-B or Comparative Example 29 for 5 days, and
observation of clinical sign, measurement of body weight, hematology, blood
chemistry, gross autopsy, measurement of organ weight and histopathology were
carried out. Further, on Day 1 and Day 5 after the administration, TK measurement
was carried out. Exposure to the respective compounds was confirmed.
The doses of Example 2-B were 0, 40, 200 and 1000 mg/kg/day, and those of
Comparative Example 29 were 0, 30, 100 and 300 mg/kg/day. The solution to be
administered was prepared using 0.5% aqueous methyl cellulose solution as a vehicle,
such that the administration volume becomes 10 mL/kg.
[0409]
2. Results
In the animals to which Example 2-B was administered, possibilities of
induction of hepatotoxicity, effects on immune organs/tissues and induction of
gastrointestinal toxicity were suggested at 1000 mg/kg/day, and the no-observed-
adverse-effect-level was assumed to be 200 mg/kg/day.
On the other hand, in the animals to which Comparative Example 29 was
administered, possibilities of induction of hepatotoxicity and drug-induced
phospholipidosis were suggested at not less than 30 mg/kg/day, and the no-observed-
adverse-effect-level was assumed to be less than 30 mg/kg/day. From these results,
cyclohexane derivatives (I) represented by Example 2-B can be expected to be
superior to the compound described in Patent Document 1, in view of safety.
[0410]
(Example 78)
Prodrugs of Example 2-B were synthesized.
[0411]
4-Hydroxy-4-(1-(4-methoxyphenyl)-5-p-tolyl-1H-pyrazol-3-yl)-cis-cyclohexyl
dimethylcarbamate (78-A)

A solution of 1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-
yl)cyclohexane-cis-1,4-diol (Example 2-B) (230 mg, 0.60 mmol) in tetrahydrofuran
(6.0ml) was stirred on ice for 10 minutes. To the reaction liquid, sodium hydride
(26.4 mg, 0.66 mmol) was added, and the resulting mixture was stirred at the same
temperature for 20 minutes, followed by adding dimethylcarbamoyl chloride (84 µl,
0.9 mmol) dropwise thereto. The resulting mixture was stirred at room temperature
for 3 hours, and brine was added to the reaction liquid, followed by extraction with
ethyl acetate. The organic layer was washed with brine and dried over anhydrous
sodium sulfate, followed by concentration under reduced pressure. The residue was
purified by flash column chromatography (silica gel, n-hexane/ethyl acetate) to
obtain the captioned compound (95.6 mg, 0.21 mmol, 35%) as a pale yellow
amorphous product.
1H-NMR (400 MHz, CDCl3) d: 1.93-2.04 (8H, m), 2.33 (3H, s), 2.71 (1H, s), 2.92
(6H, s), 3.80 (3H, s), 4.73-4.79 (1H, m), 6.37 (1H, s), 6.84 (2H, d, J=8.8 Hz), 7.09-
7.09 (4H, m), 7.20 (2H, J=8.8 Hz).
ESI-MS: m/z= 450 (M+H)+
[0412]
Cyclohexyl 4-hydroxy-4-(1-(4-methoxyphenyl)-5-p-tolyl-1H-pyrazol-3-yl)-cis-
cyclohexyl carbonate (78-B)

A solution of 1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-
yl)cyclohexane-cis-1,4-diol (Example 2-B) (250 mg, 0.66 mmol) in tetrahydrofuran
(2.2 ml) was cooled on ice, and sodium hydride (63.4 mg, 1.45 mmol) was added
thereto, followed by stirring the resulting mixture at the same temperature for 10
minutes. Cyclohexyl 1 -iodoethyl carbonate (354 mg 1.18 mmol) was then added
to the mixture, and the resulting mixture was stirred at room temperature for 12 hours.
To the reaction liquid, brine was added, and the resulting mixture was extracted with
ethyl acetate. The organic layer was washed with brine and dried over anhydrous
sodium sulfate, followed by concentration under reduced pressure. The residue was
purified by flash column chromatography (silica gel, n-hexane/ethyl acetate) to
obtain the captioned compound (161 mg, 0.29 mmol, 44%) as a white amorphous
product.
1H-NMR (400 MHz, CDCl3) d: 1.23-1.28 (4H, m), 1.31-1.40 (2H, m), 1.44-1.56 (4H,
m), 1.70-1.79 (4H, m), 1.93-2.08 (4H, m), 2.32 (3H, s), 2.82 (1H, s), 3.79 (3H, s),
4.57-4.64 (1H, m), 4.67-4.71 (1H, m), 6.38 (1H, s), 6.84 (2H, d, J=8.4 Hz), 7.08-7.08
(4H,m),7.19(2H,J=8.4Hz).
ESI-MS: m/z= 505 (M+H)+
[0413]
By the same procedure as described above, the following compounds were
prepared.
[0414]

[0415]
Succinic acid mono-4-hydroxy-4-( 1 -(4-methoxyphenyl)-5 -p-tolyl-1H-pyrazol-3 -yl)-
cis-cyclohexyl ester (78-E)

To a solution of l-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-
yl)cyclohexane-cis-1,4-diol (Example 2-B) (250mg, 0.66mmol) in DMF (3.3 ml),
sodium hydride (63.4 mg, 1.45 mmol) was added, and the resulting mixture was
stirred for 30 minutes. Succinic anhydride (99 mg, 0.99 mmol) was then added
thereto, and the resulting mixture was stirred for 12 hours, followed by adding 1 M-
hydrochloric acid and ethyl acetate to the reaction liquid and extraction with ethyl
acetate. The organic layer was washed with brine and dried over anhydrous sodium
sulfate, followed by concentration under reduced pressure. The residue was
purified by flash column chromatography (silica gel, n-hexane/ethyl acetate) to
obtain the captioned compound (87.0 mg, 0.18 mmol, 28%) as a white amorphous
product.
1H-NMR (400 MHz, CDCl3) d: 1.86-1.88 (2H, m), 1.96-2.02 (4H, m), 2.08-2.11 (3H,
m), 2.32 (3H, s), 2.58-2.64 (4H, m), 3.81 (3H, s), 4.82-4.88 (1H, m), 6.38 (1H, s),
6.84 (2H, d, J=8.0 Hz), 7.09-7.09 (4H, m), 7.18 (2H, J=8.0 Hz).
ESI-MS: m/z= 479 (M+H)+
[0416]
Cyclohexyl (4-hydroxy-4-( 1 -(4-methoxyphenyl)-5-(p-tolyl)-1 H-pyrazol-3 -yl)-cis-
cyclohexyloxy)ethyl carbonate (78-F)

To a solution of 1-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-
yl)cyclohexane-cis-1,4-diol (Example 2-B) (400 mg, 1.05 mmol) in dichloroethane
(5.4 ml), cyclohexyl 1-iodoethyl carbonate (567 mg, 1.90 mmol),
diisopropylethylamine (460 µl, 2.64 mmol) and silver chloride (273 mg, 1.90 mmol)
were added, and the resulting mixture was stirred at 80°C for 12 hours, followed by
allowing the mixture to cool to room temperature and filtering the reaction liquid
through Celite. To the filtrate, 1 M-hydrochloric acid and ethyl acetate were added,
and the resulting mixture was extracted with ethyl acetate. The organic layer was
washed with brine and dried over anhydrous sodium sulfate, followed by
concentration under reduced pressure. The residue was purified by flash column
chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned
compound (31.9 mg, 0.058 mmol, 5.1%) as a white amorphous product.
1H-NMR (400 MHz, CDCl3) d: 1.15-1.34 (9H, m), 1.48-1.65 (4H, m), 1.83-1.98 (8H,
m), 2.33 (3H, s), 2.49 (1H, s), 3.52-3.58 (1H, m), 3.64-3.71 (1H, m), 3.81 (3H, s),
4.92 (1H, q, J=5.2 Hz), 6.39 (1H, s), 6.84 (2H, d, J=8.8 Hz), 7.09-7.09 (4H, m), 7.19
(2H, J=8.8 Hz).
ESI-MS: m/z= 549 (M+H)+
[0417]
By the same procedure as described above, the following compounds were
prepared.
[0418]

[0419]
4-Hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cis-cyclohexyl2-
aminoacetate (78-1)

To a solution of 4-hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-
3-yl)-cis-cyclohexyl 2-benzyloxycarbonylaminoacetate (Reference Example 97)
(33.2 mg, 0.058 mmol) in methanol (2.00 mL), 10% palladium/carbon (6.16 mg, 50
wt%) was added at room temperature, and the resulting mixture was stirred for 14
hours under hydrogen atmosphere. The reaction liquid was filtered through Celite,
and the filtrate was concentrated under reduced pressure. The residue was purified
by flash column chromatography (NH silica gel, chloroform/methanol) to obtain the
captioned compound (18.4 mg, 0.042 mmol, 73%) as a colorless amorphous product.
1H-NMR (400 MHz, CDCl3) d: 1.58-1.82 (2H, m), 1.88-2.12(9H, m), 2.33 (3H, s),
3.43 (2H, s), 3.81 (3H, s), 4.88-4.94 (1H, m), 6.37 (1H, s), 6.83-6.87 (2H, m), 7.09-
7.11 (4H, m), 7.18-7.22 (2H, m).
ESI-MS: m/z= 436 (M+H)+
[0420]
By the same procedure as described above, the following compound was
prepared.

[0421]
(S)-4-Hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)-cis-cyclohexyl
2-amino-3-methylbutanoate (78-K)

To a mixed solution of (S)-4-hydroxy-4-(1-(4-methoxyphenyl)-5-(p-tolyl)-
1 H-pyrazol-3 -yl)-cis-cyclohexyl 2-benzyloxycarbonylamino-3 -methylbutanoate
(Reference Example 99) (122 mg, 0.190 mmol) in dioxane/ethanol (2.00 mL/2.00
mL), 2,2'-bipyridyl (15.0 mg, 0.096 mmol) and 10% palladium/carbon (49.0 mg, 40
wt%) was added at room temperature, and the resulting mixture was stirred for 14
hours under hydrogen atmosphere. The reaction liquid was filtered through Celite,
and the filtrate was concentrated under reduced pressure. The residue was purified
by flash column chromatography (silica gel, chloroform/methanol) to obtain the
captioned compound (38.6 mg, 0.076 mmol, 40%) as a colorless amorphous product.
1H-NMR (400 MHz, CDCl3) :d 0.92 (3H, d, J=6.8 Hz), 1.02 (3H, d, J=6.8 Hz), 1.90-
2.12 (9H, m), 2.34 (3H, s), 3.32-3.34 (1H, m), 3.67-3.76 (1H, m), 3.81 (3H, s), 5.41
(1H, d, J=6.4 Hz), 5.47 (1H, d, J=6.4 Hz), 6.38, (1H, s), 6.83-6.87 (2H, m), 7.09-7.12
(4H,m), 7.18-7.22 (2H,m).
ESI-MS: m/z= 490 (M-OH)+
[0422]
4-Hydroxy-4-(l -(4-methoxyphenyl)-5-(p-tolyl)-1 H-pyrazol-3-yl)-cis-cyclohexyl
dihydrogen phosphate (78-L)

To a mixed solution of dibenzyl 4-hydroxy-4-(1-(4-methoxyphenyl)-5-(p-
tolyl)-1H-pyrazol-3-yl)-cis-cyclohexyl phosphate (Reference Example 100) (251 mg
0.393 mmol), methanol (2.6 mL) and ethyl acetate (2.6 mL), 10% palladium/carbon
(41.8 mg, 50 wt%) was added, and the resulting mixture was stirred under hydrogen
atmosphere at room temperature for 2.5 hours. The reaction liquid was filtered
through Celite, and the filtrate was concentrated under reduced pressure. The
residue was recrystallized from dichloromethane/diethyl ether to obtain the captioned
compound (97.2 mg, 0.212 mmol, 54%) as a white solid.
1H-NMR (400 MHz, DMSO-d6) d: 1.68-1.98 (8H, m), 2.28 (3H, s), 3.76 (3H, s), 4.13
(1H, br), 4.92 (1H, br), 6.53 (1H, s), 6.91-6.95 (2H, m), 7.08-7.17 (6H, m).
ESI-MS: m/z= 459 (M+H)+
INDUSTRIAL APPLICABILITY
[0423]
The cyclohexane derivative of the present invention or a pharmaceutically
acceptable salt thereof or a prodrug thereof can exert an analgesic action against
nociceptive pain, neuropathic pain and diabetic neuropathic pain, and has less side
effects, so that it may be used as a pharmaceutical for a wide range of pain symptoms.
We claim:
1. A cyclohexane derivative represented by General Formula (I):

(I)
[wherein
A represents a substituent represented by General Formula (IIa) or (IIb):

R1 and R2 each independently represent a hydrogen atom, chlorine atom, C1-
C3 haloalkyl, C1-C4 alkyl, C1-C4 alkoxy or cyano;
R3 represents a hydrogen atom or chlorine atom;
R4 represents a fluorine atom, hydroxymethyl or hydroxyl;
R5 and R6 each independently represent a hydrogen atom, fluorine atom, C1-
C3 haloalkyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, C1-C4 alkoxy, hydroxyl or
C2-C5 alkylcarbonyloxy, or R5 and R6 may together form an oxo group;
R7 and R8 each independently represent a hydrogen atom or fluorine atom;
Y represents an oxygen atom or sulfur atom; and
Z represents a nitrogen atom or methine]
or a pharmaceutically acceptable salt thereof or a prodrug thereof.
2. A cyclohexane derivative represented by General Formula (I):

[wherein
A represents a substituent represented by General Formula (IIc) or (IId):

R1 and R2 each independently represent a hydrogen atom, chlorine atom, C1-
C3 haloalkyl, C1-C4 alkyl or C1-C4 alkoxy;
R3 represents a hydrogen atom or chlorine atom;
R4 represents a fluorine atom, hydroxymethyl or hydroxyl;
R5 and R6 each independently represent a hydrogen atom, fluorine atom, C1-
C3 haloalkyl, carboxyl, C1-C4 alkoxy, hydroxyl or C2-C5 alkylcarbonyloxy, or R5 and
R6 may together form an oxo group;
Y represents an oxygen atom or sulfur atom; and
Z represents a nitrogen atom or methine]
or a pharmaceutically acceptable salt thereof or a prodrug thereof.
3. The cyclohexane derivative according to claim 1 or 2, or a pharmaceutically
acceptable salt thereof or a prodrug thereof, wherein R1 and R2 each independently
represent trifluoromethyl, methyl or methoxy.
4. The cyclohexane derivative according to any one of claims 1 to 3, or a
pharmaceutically acceptable salt thereof or a prodrug thereof, wherein R3 represents
a hydrogen atom.
5. The cyclohexane derivative according to any one of claims 1 to 4, or a
pharmaceutically acceptable salt thereof or a prodrug thereof, wherein R4 represents
hydroxymethyl or hydroxyl.
6. The cyclohexane derivative according to any one of claims 1 to 5, or a
pharmaceutically acceptable salt thereof or a prodrug thereof, wherein R5 and R6
each independently represent a hydrogen atom, fluorine atom, trifiuoromethyl,
carboxyl, methoxy, hydroxyl or acetyloxy, or R5 and R6 may together form an oxo
group.
7. A pharmaceutical comprising the cyclohexane derivative according to any
one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or a prodrug
thereof.
8. An analgesic comprising an effective amount of the cyclohexane derivative
according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or
a prodrug thereof.
9. A therapeutic drug for neuropathic pain and/or nociceptive pain, comprising
an effective amount of the cyclohexane derivative according to any one of claims 1
to 6 or a pharmaceutically acceptable salt thereof or a prodrug thereof.
10. A therapeutic drug for diabetic neuropathic pain, comprising an effective
amount of the cyclohexane derivative according to any one of claims 1 to 6 or a
pharmaceutically acceptable salt thereof or a prodrug thereof.

The present invention aims to provide a compound having a strong analgesic
action against both nociceptive pain and neuropathic pain and having less side effects,
and a medical use thereof. The present invention provides cyclohexane derivatives
represented by the following compound, or pharmaceutically acceptable salts thereof
or prodrugs thereof.