WO2002016319A1 - Novel thiourea compounds and the pharmaceutical compositions containing the same - Google Patents

Novel thiourea compounds and the pharmaceutical compositions containing the same Download PDF

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Publication number
WO2002016319A1
WO2002016319A1 PCT/KR2001/001408 KR0101408W WO0216319A1 WO 2002016319 A1 WO2002016319 A1 WO 2002016319A1 KR 0101408 W KR0101408 W KR 0101408W WO 0216319 A1 WO0216319 A1 WO 0216319A1
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WIPO (PCT)
Prior art keywords
pain
compound
group
compounds
mmol
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PCT/KR2001/001408
Other languages
French (fr)
Inventor
Young Ger Suh
Uh Taek Oh
Hee Doo Kim
Jee Woo Lee
Hyeung Geun Park
Young Ho Park
Jung Bum Yi
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Pacific Corporation
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Publication date
Application filed by Pacific Corporation filed Critical Pacific Corporation
Priority to AU2001280230A priority Critical patent/AU2001280230A1/en
Priority to DE60120421T priority patent/DE60120421T2/en
Priority to JP2002521195A priority patent/JP2004506714A/en
Priority to EP01958603A priority patent/EP1311478B1/en
Priority to US10/362,079 priority patent/US7067553B2/en
Publication of WO2002016319A1 publication Critical patent/WO2002016319A1/en

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/42—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms with nitro or nitroso radicals directly attached to ring carbon atoms
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
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    • C07C333/14—Dithiocarbamic acids; Derivatives thereof
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    • C07C335/04—Derivatives of thiourea
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    • C07C335/10—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
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    • C07C335/04—Derivatives of thiourea
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    • C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C335/20—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
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    • C07C335/24—Derivatives of thiourea containing any of the groups, X being a hetero atom, Y being any atom
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    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Definitions

  • Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is a main pungent component in
  • Nanilloid receptor (NR-1) has been recently cloned and its existence
  • noxious stimuli such as proton and thermal stimuli (Tominaga et al., 1998, Neuron 21,
  • vanilloid receptor functions as a
  • mice the mouse was found out to exhibit much reduced reaction to thermal stimuli and
  • pp43-444 act as the most likely endogenous ligand for the receptor and proton acts as a
  • a capsaicin-sensitive sensory nerve cell and a vanilloid receptor As such, a capsaicin-sensitive sensory nerve cell and a vanilloid receptor
  • neuropathic disease is suggested (WO 99/00125). Recently, attention has focused to
  • vanilloid receptor antagonist derived from
  • the present invention provides a novel
  • B represents 4-t-butylbenzyl, 3,4-dimethylphenylethyl
  • R represents hydrogen atom or a lower alkyl group having 1 to 5 carbon
  • IBS IBS syndrome
  • present mvention are preferably admimstered in an amount ranging from 0.001 to 100
  • Doses are administered from once to several portions per day. The
  • a mammalian subject such as rat, mouse, domestic animals, human being and the like
  • Step 4 Synthesis of (4-amino-3-methoxybenzyl)carbamic acid t-butyl ester (2-4)
  • Step 3 General method for synthesizing compound (3-3)
  • Step 4 General method for synthesizing compound (3-4)
  • NGF(Nerve Growth Factor) was added to final concentration of 200 ng/ml.
  • the resuspended cells were plated at a density of 1500-1700 neurons/well onto Terasaki
  • H-HBSS HEPES-buffered Ca 2+ , Mg 2+ -free HBSS
  • mice Male ICR mice (mean body weight 25 g) were maintained in a controlled environment.
  • vanilloid receptor antagonist can exhibit such potent analgesic effect, and the results suggests that vanilloid receptor antagonist has potential as an analgesic agent.
  • mice Male ICR mice(body weight 25-30g), 10 animals/group, were treated topically
  • diseases in particular, neurogenic inflammatory diseases.

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Abstract

The present invention relates to thiourea compounds and the pharmaceutical compositions containing the same, and particularly, to novel thiourea compounds as an antagonist against vanilloid receptor (VR) and the pharmaceutical compositions thereof. As diseases associated with the activity of vanilloid receptor, pain, acute pain, chronic pain, neuropathic pain, post-operative pain, migraine, arthralgia, neuropathies, nerve injury, diabetic neuropathy, neurodegeneration, neurotic skin disorder, stroke, urinary bladder hypersensitiveness, irritable bowel syndrome, a respiratory disorder such as asthma or chronic obstructive pulmonary disease, irritation of skin, eye or mucous membrane, fervescence, stomach-duodenal ulcer, inflammatory bowel disease and inflammatory diseases can be enumerated. The present invention provides a pharmaceutical composition for prevention or treatment of these diseases.

Description

Novel thiourea compounds and the pharmaceutical compositions containing the
same
Technical Field
The present invention relates to thiourea compounds and the pharmaceutical
compositions containing the same, and particularly, to thiourea compounds with
superior efficacy as an antagonist against vanilloid receptor (VR) and the
pharmaceutical compositions thereof.
Background Art
As diseases associated with the activity of vanilloid receptor, pain, acute pain,
chronic pain, neuropathic pain, post-operative pain, migraine, arthralgia, neuropathies,
nerve injury, diabetic neuropathy, neurodegeneration, neurotic skin disorder, stroke,
urinary bladder hypersensitiveness, irritable bowel syndrome, a respiratory disorder
such as asthma or chronic obstructive pulmonary disease, irritation of skin, eye or
mucous membrane, fervescence, stomach-duodenal ulcer, inflammatory bowel disease
and inflammatory diseases can be enumerated. The present invention provides
pharmaceutical compositions for prevention or treatment of these diseases. Yet, the diseases described above are only for enumeration, not to limit the scope of
clinical application of vanilloid receptor antagonist.
Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is a main pungent component in
hot peppers. Hot peppers have been used, for a long time, not only as a spice but also
as traditional medicine in the treatment of gastric disorders and when applied locally,
for the relief of pain and inflammation (Szallasi and Blumberg, 1999, Pharm, Rev. 51,
ppl59-211). Capsaicin has a wide spectrum of biological actions, and not only
exhibits effects on the cardiovascular and respiratory systems but also induces pain and
irritancy on local application. Capsaicin, however, after such induction of pain,
induces desensitization, both to capsaicin itself and also to other noxious stimuli to
make the pain stopped. Based on this property, capsaicin and its analogues such as
olvanil, nuvanil, DA-5018, SDZ-249482, resiniferatoxin are either used as analgesic
agent, therapeutic agent for incontinentia urinae or skin disorder, or under development
(Wriggleworth and Walpole, 1998, Drugs of the Future 23, pp 531-538).
Transmissions of mechanical, thermal and chemical noxious stimuli are mainly
occurred by primary afferent nerve fibers of fine unrnyelinated nerve (C-fϊber) and thin
myelinated nerve (A- fiber), and main reaction site of capsaicin and its analog called vanilloid is present at the nerve fiber transmitting the noxious stimuli. Capsaicin acts
at the receptor existing on these neurons to induce potent stimuli by causing potent
inflow of mono-and di-valent cations such as calcium and sodium, then exhibits potent
analgesic effect by blocking the nervous function (Wood et al, 1988, J. Neurosci, 8,
pp3208-3220). Nanilloid receptor (NR-1) has been recently cloned and its existence
becomes clear(Caterina et al., 1997, Nature 389, pp816-824). It was clarified that this
receptor transmits not only stimuli by capsaicin anlogues(vanilloid) but also various
noxious stimuli such as proton and thermal stimuli (Tominaga et al., 1998, Neuron 21,
pp531-543). Based on this, it is considered that vanilloid receptor functions as a
integrative modulator against various noxious stimuli and carries out critical role in
transmissions of pain and noxious stimuli. Recently, knock-out mouse in which gene
encoding for vanilloid receptor was deleted was prepared (Caterina et al., 2000, Science
288, ρρ306-313; Davis et al, 2000, Nature 405, ρpl83-187). Compared to normal
mice, the mouse was found out to exhibit much reduced reaction to thermal stimuli and
thermal pain, while exhibiting no difference in general behavior, reconfirming the
importance of the receptor in transmission of noxious signal. However, except proton,
no other endogenous ligand, not exogenous ligand such as capsaicin, actually involved
in transmission of noxious stimuli at vanilloid receptor was known. It is considered
that leucotriene metabolite represented by 12-hydroperoxyeicosatetraenoic acid (12-HPETE) (Hwang et al., 2000, PNAS 11, pp6155-6160) and arachidonic aicd
derivatives such as anandamide (Zygmunt et al., 2000, Trends Pharmocol. Sci. 21,
pp43-44) act as the most likely endogenous ligand for the receptor and proton acts as a
cofactor with receptor-stimulating activity, rather than as a direct ligand.
As such, a capsaicin-sensitive sensory nerve cell and a vanilloid receptor
existing in the cell are distributed over the entire body and play basic function in
transmission of noxious stimuli and pain, further act as crucial factor in expression of
neurogenic inflammation, thereby to have close relation with the cause of neuropathies,
nerve injury, stroke, asthma, chronic obstructive pulmonary diseases, urinary bladder
hypersensitiveness, irritable bowel syndrome, inflammatory bowel disease, fervescence,
skin disorder and inflammatory disease. Lately, their correlation even with
neuropathic disease is suggested (WO 99/00125). Recently, attention has focused to
the role of afferent sensory nerve responding to capsaicin in gastrointestinal injury, and
it was proposed that the afferent nerve might have a dual character that it exhibits
protective action against gastric damage by improving gastric microcirculation through
releasing peripheral neuropeptide such as CGRP (calcitonin gene-related peptide), while
inducing gastric injury by stimulating sympathetic nervous system (Ren et al., 2000,
Dig. Dis. Sci. 45, pp830-836). It is determined that vanilloid receptor antagonist has very high potential to be used for prevention or treatment of the said various diseases by
blocking the vanilloid receptor conducting such varied functions.
Though it may be, theoretically, anticipated that antagonist for this receptor
would exhibit substantial degree of inhibitory action against pain and neurogenic
inflammation, it was found out that the competitive antagonist for this receptor,
capsazepine, almost the only one known until now, failed to exhibit significant
analgesic and anti-inflammatory effects (Perkins and Campbell, 1992, Br. J. Pharmacol.
107, pp329-333). Therefore, not much progress was made on this field. However,
recently, there has been a report on significant results for analgesic action of
capsazepine in animal studies (Kwak et al., 1998, Neurosci. 86, pp619-626; Santos and
calixto, 1997, Neurosci. Lett. 235, pp73-76), in particular, the inventors of the present
invention clearly demonstrated through animal studies the analgesic and
anti-inflammatory effects of the strong vanilloid receptor antagonists which were
identified through experiments in laboratory, and based on this, strongly suggested the
development potential of vanilloid receptor antagonist as an analgesic and
anti-inflammatory agent. Yet, though the vanilloid receptor antagonist derived from
the present studies will mainly act based on the antagonistic activity of itself, even a
possibility that it could exhibit the pharmacological activity through transformation into
agonist via metabolism after absorption into body is not to be excluded. To resolve the problems described above, the present invention is to provide
novel compounds which are selectively antagonistic to vanilloid receptor and exhibit
analgesic and anti-inflammatory effects while causing no irritancy, and pharmaceutical
compositions containing the same.
Disclosure of the Invention
In order to attain the above objects, the present invention provides a novel
compound of formula (I):
Figure imgf000007_0001
wherein
X represents a sulfur atom or an oxygen atom;
Rt represents a lower alkyl sulfonyl group having 1 to 5 carbon atoms, an aryl
sulfonyl group or a lower alkyl carbonyl group having 1 to 5 carbon atoms, wliich may
be unsubstituted or substituted with halogen atom;
R2 represents a hydrogen atom, a methoxy group or a halogen;
Figure imgf000008_0001
when A is -NHCH2-, B represents (wherein, n is 0
or 1), or when A is -CH2-, B represents 4-t-butylbenzyl, 3,4-dimethylphenylethyl,
Figure imgf000008_0002
or an oleyl group;
Y represents -CH2- or -CH2CH2-;
R represents hydrogen atom or a lower alkyl group having 1 to 5 carbon
atoms; and
A represents a lower alkyl group having 1 to 5 carbon atoms or phenyl group.
The present invention also provides a pharmaceutical composition comprising a
compound of formula (I) or a pharmaceutically acceptable salt thereof as an active
ingredient.
The compounds according to the present invention can chemically be
synthesized by the following reaction schemes. However, these are given only for
illustration of the invention and are not intended to limit to them. [SCHEME 1]
Figure imgf000009_0001
1 -1 1-2
Figure imgf000009_0002
As depicted in the above Scheme 1, a compound 1-1 was synthesized by
selectively protecting 4-aminobenzylamine with Boc(t-butoxycarbonyl) group. Amine
of formula 1-1 was reacted with various kinds of agents, e.g., sulfonylchlori.de or acyl
chloride to synthesize a compound 1-2, Boc group was removed from the compound
1-2 under acidic conditions, and then various kinds of isotbiocyanate-based compounds
were reacted therewith to prepare compounds l-4a ~ l-4h.
[SCHEME 2]
Figure imgf000010_0001
2-1, RB=OCH3 2-2, RB=OCH3 2-3, Rg=0CH3
Figure imgf000010_0002
As depicted in the above Scheme 2, azide group was introduced into
3-methoxy-4-nitrobenzyl chloride, reduced, and then protected with Boc group to
synthesize a compound 2-3. Nitro group of the compound 2-3 was reduced to produce
an amine compound 2-4, methanesulfonylammo group (mesyl group) was introduced
thereinto to synthesize a compound 2-5, and then Boc group was removed therefrom to synthesize an amine compound 2-7. The amine compound 2-7 was treated with
l,l-thio-lH-carbonyl-di-2-pyridone to synthesize an isothiocyanate compound 2-9 as a
main intermediate. The azide compounds previously prepared was reacted with the
compound 2-9 to prepare compounds 2-13 ~ 2-16.
In case RB is H, a compound 2-8 was synthesized in accordance with the above
process except that 4-nitrobenzylchloride was used as a starting material, and the
compound 2-8 was reacted with azide compound to produce compounds 2-10 ~ 2-12,
2-17 and 2-18.
[SCHEME 3]
Figure imgf000011_0001
3-7, R3= 3,4-dimethyl 3-8, R3= 4-t-Bu As depicted in the above Scheme 3, amine salt 3-6 was synthesized by using a
compound 3-1 as a starting material according to a general method, and then the amine
salt 3-6 was reacted with an isocyanate compound 2-8 to produce compounds 3-7 and
3-8.
[SCHEME 4]
Figure imgf000012_0001
Compounds 4-1 ~ 4-4 were produced by condensing pentafluorophenyl ester of
4-methanesulfonylaminophenylacetic acid with the known amines.
The compound of formula (I) according to the present invention can be
provided as a pharmaceutical composition containing pharmaceutically acceptable
carriers, adjuvants, or diluents. For instance, the compounds of the present invention can be dissolved in oils, propylene glycol or other solvents which are commonly used to
produce an injection. Suitable examples of the carriers include, physiological saline,
polyethylene glycol, ethanol, vegetable oils, isopropyl myristate, etc., but are not limited
to them. For topical administration, the compounds of the present invention can be
formulated in the form of ointments and creams.
The pharmaceutical composition containing the compound of the present
invention as an active ingredient can be used for treating acute, chronic, inflammatory
or neuropathic pains; treating urinary bladder hypersensitiveness or irritable bowel
syndrome (IBS); treating asthma; preventing or treating neurodegenerative diseases; or
preventing or treating neurotic skin disorder, or irritation of skin, eye or mucous
membrane.
Hereinafter, the formulating methods and kinds of excipients will be described,
but the present invention is not limited to them.
The compound according to the present invention may also be used in the forms
of pharmaceutically acceptable salts thereof, and may be used either alone or in
combination or in admixture with other pharmaceutically active compounds.
The compounds of the present invention may be formulated into injections by dissolving, suspending or emulsifying in water-soluble solvent such as saline and 5%
dextrose, or in water-insoluble solvents such as vegetable oils, synthetic fatty acid
glyceride, higher fatty acid esters and propylene glycol. The formulations of the
invention may include any of conventional additives such as dissolving agents, isotonic
agents, suspending agents, emulsifiers, stabilizers and preservatives.
The preferable dose level of the compounds according to the present mvention
depends upon a variety of factors including the condition and body weight of the patient,
severity of the particular disease, dosage form, and route and period of administration,
but may appropriately be chosen by those skilled in the art. The compounds of the
present mvention are preferably admimstered in an amount ranging from 0.001 to 100
mg/kg of body weight per day, and more preferably from 0.01 to 30 mg/kg of body
weight per day. Doses are administered from once to several portions per day. The
compounds of the present invention must be present in a pharmaceutical composition in
an amount of 0.0001 ~ 10% by weight, and preferably 0.001 ~ 1% by weight, based on
the total amount of the composition.
The pharmaceutical composition of the present invention can be administered
to a mammalian subject such as rat, mouse, domestic animals, human being and the like
via various routes. The methods of administration which may easily be expected include oral and rectal administration; intravenous, intramuscular, subcutaneous,
intrauterine, duramatral and intracerebro ventricular injections.
Best Mode for Carrying Out the Invention
The present invention is more specifically explained by the following examples.
However, it should be understood that the present invention is not limited to these
examples in any manner.
Examples 1 ~ 8
The Examples 1 — 8 are divided into three steps (step 1, 2 and 3), and the
general methods for synthesizing the respective compounds are as follows.
Step 1 : General method for synthesizing compound (1-2)
Compound 1-1 (5.3 mmol) was dissolved in pyridine (10 mL), cooled to 0°C,
and then acyl chloride (6.34 mmol) was slowly added thereto. The resulting reaction
mixture was stirred at room temperature for 24 hours. The mixture was neutralized
with aqueous IM hydrochloric acid, diluted with water, and then extracted several times with dichloromethane. The extracted organic layers were collected, washed
successively with water and saturated aqueous sodium chloride solution, dried over
anhydrous magnesium sulfate, and then concentrated under reduced pressure. The
resulting residue was purified by column chromatography (eluent: hexane/ethyl acetate
= 1/1) to yield the title compound 1-2.
NHBoc
Figure imgf000016_0001
1-2
Figure imgf000016_0002
Figure imgf000017_0002
Step 2: General method for synthesizing compound (1-3)
Compound 1-2 (4.8 mmol) was dissolved in dichloromethane (20 mL), cooled
to 0°C, and trifluoroacetic acid (5 mL) was slowly added thereto. The resulting
mixture was stirred at 0°C for an hour and 30 minutes. The solvent was evaporated
under reduced pressure to obtain a flame-colored residue. The obtained residue was
washed with ethyl ether and filtered to yield the title compound 1-3.
Figure imgf000017_0001
1-3
Figure imgf000017_0003
Figure imgf000018_0001
Step 3: General method for synthesizing compound (1-4)
The compound 1-3 (0.38 mmol) was dissolved in DMF (1 mL), and
triethylamine (0.38 mmol) was added thereto. The mixture was stirred at room
temperature under nitrogen for 1 hour. To the mixture was added
2,2-dimethyl-propionic acid 3-(3,4-dimethylphenyl)-2-isothiocyanatomethylpropyl ester
(0.38 mmol), and the resulting mixture was stirred for 24 hours. The reaction mixture
was diluted with water, extracted several times with ethyl acetate. The collected organic
layer was washed successively with water and saturated aqueous sodium chloride
solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a residue. The obtained residue was purified by column
chromatography (eluent: hexane/ethyl acetate = 3/2) to yield the compound 1-4.
Figure imgf000019_0001
1-4
Figure imgf000019_0002
Figure imgf000020_0002
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000021_0002
Figure imgf000021_0003
Figure imgf000021_0004
Figure imgf000022_0001
l-4g NHCOCH3
Figure imgf000022_0002
NHCOiPr
Figure imgf000022_0003
Examples 9~17
Step 1: Synthesis of 4-chloromethyl-2-methoxy-l -nitrobenzene (2-1)
(3-methoxy-4-nitrophenyl)methanol (4.43 mmol) was dissolved in
dichloromethane (10 mL), and then triethylamine (13.3 mmol) was added thereto.
After the reaction mixture was cooled to 0°C, methanesulfonyl chloride (6.64 mmol) was slowly added thereto. The resulting mixture was stirred at room temperature
under nitrogen for 24 hours. To the mixture was added ammonium chloride solution
to terminate the reaction, diluted with water, and then extracted several times with
dichloromethane. The collected organic layer was washed with water and brine, dried
over anhydrous magnesium sulfate, and concentrated under reduced pressure. The
resulting residue thus obtained was purified by column chromatography (eluent:
hexane/ethyl acetate = 4/1) to yield the title compound 2-1 (yield: 93%) as a yellow
solid.
1H NMR (CDC13) δ 7.86 (d, IH), 7.05 (s, IH), 6.98 (d, IH), 4.56 (s, 2H), 3.99 (s, 3H)
Step 2: Synthesis of 4-azidomethyl-2-memoxy-l-nitro-benzene (2-2)
A solution of the compound 2-1 (4.12 mmol) and sodium azide (16.5 mmol) in
dimethylformamide (3 mL) was stirred at room temperature under nitrogen for 1 hour.
The reaction mixture was diluted with water, extracted several times with ethyl acetate,
and then the organic layer was collected. The collected organic layer was washed
successively with water and saturated aqueous sodium chloride solution, dried over
anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting
residue was purified by column chromatography (eluent: hexane/ethyl acetate = 3/1) to yield the title compound 2-2 (yield: 95%) as a yellow solid.
1H NMR (CDC13) δ 7.87 (d, IH), 7.05 (s, IH), 6.99 (d, IH), 4.45 (s, 2H), 3.99 (s, 3H)
Step 3: Synthesis of (3-methoxy-4-nitro-benzyl)-carbamic acid t-butyl ester (2-3)
A solution of the compound 2-2 (3.91 mmol), triphenyl p osphine (7.83 mmol)
and water (7.83 mmol) in THF (30 mL) was stirred at room temperature for 24 hours.
The reaction mixture was concentrated under reduced pressure. The residue thus
obtained was dissolved in ethanol (20 mL), and Boc2O (1.71 g) was added thereto.
The resulting mixture was stirred at room temperature for 2 hours. After the reaction
mixture was concentrated under reduced pressure, the resulting residue was purified by
column chromatography (eluent: hexane/ethyl acetate = 2/1) to yield the title compound
2-3 (yield: 86%) as a yellow liquid.
1H NMR (CDCI3)) δ 7.83 (d, IH), 7.02 (s, IH), 6.93 (d, IH), 5.01 (brs, IH), 4.35 (d,
2H), 3.95 (s, 3H), 1.47 (s, 9H)
Step 4: Synthesis of (4-amino-3-methoxybenzyl)carbamic acid t-butyl ester (2-4)
The compound 2-3 (3.13 mmol) was dissolved in methanol (20 mL), and then 10% palladium/carbon catalyst (85 mg) was added thereto. The resulting mixture was
stirred at room temperature under hydrogen for 1 hour. After the reaction mixture was
filtered, the filtrate was concentrated under reduced pressure to yield the title compound
2-4 (yield: 90%) as a brown liquid.
1H NMR (CDCI3) δ 6.6-6.7 (m, 3H), 4.19 (d, 2H), 3.88 (s, 3H), 1.46 (s, 9H)
Step 5: Synthesis of (4-methanesulfonylamino-3-methoxybenzyl)carbamic acid t-butyl
ester (2-5)
The title compound 2-5 was obtained as a pink solid in a yield of 67%
according to the same procedure as synthesizing method of compound l-2a, except that
the compound 2-4 (3.13 mmol) was used as a starting material.
1H NMR (CDCI3) δ 7.47 (d, IH), 6.86 (m, 2H), 6.74 (s, IH), 4.88 (bs, IH), 3.88 (s,
3H), 2.94 (s, 3H), 1.47 (s, 9H)
Step 6: Synthesis of 4-methaiiesulfonylamino-3-methoxybenzylammonium
trifluoroacetate (2-7)
The title compound 2-7 was obtained as a green solid in a yield of 87% according to the same procedure as synthesizing method of compound l-3a, except that
the compound 2-5 (2.1 mmol) was used as a starting material.
1H NMR (DMSO) δ 8.16 (bs, 3H), 7.29 (d, IH), 7.20 (s, IH), 6.99 (d, IH), 4.00 (s,
2H), 3.82 (s, 3H), 2.95 (s, 3H)
Step 7: General method for synthesizing compounds (2-8 and 2-9)
The compound 2-6 or 2-7 (12 mmol) was dissolved in DMF (lmL), and then
triethylamine (12 mmol) was added thereto. The resulting mixture was stirred at room
temperature under nitrogen for 1 hour. To the mixture was added
l,l-thio-lH-2-carbonyl-di-2-pyridone (12 mmol), and stirred for 24 hours. The
reaction mixture was diluted with water, extracted several times with ethyl acetate, and
then the organic layer was collected. The collected organic layer was washed with
water and then with saturated aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. The resulting residue
was purified by column chromatography (eluent: hexane/ethyl acetate = 3/2) to yield the
title compounds 2-8 or 2-9.
Figure imgf000027_0001
2-8, 2-9
Figure imgf000027_0002
Step 8: General method for synthesizing compounds (2-10 ~ 2-18)
A solution of azide compound (0.5 mmol) prepared in accordance with the
well-known method, Lindlers catalyst (50 mmol) and the compound 2-8 in ethanol (5
mL) was subjected to hydrogenization reaction under hydrogen atmosphere for 2 hours.
After the reaction mixture was filtered, the filtrate was concentrated under reduced
pressure. The concentrate was purified by column chromatography (eluent: ethyl
acetate/hexane = 1/1) to yield the title compounds 2-10 ~ 2-18
Figure imgf000028_0001
2-10-2-18
Figure imgf000028_0002
Figure imgf000029_0002
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000030_0002
Figure imgf000030_0003
Figure imgf000030_0004
Figure imgf000031_0001
Figure imgf000031_0002
Figure imgf000031_0003
Figure imgf000031_0004
Examples 18-19 Step 1 : General method for synthesizing compound (3-1)
N-(diphenylmethyleneglycine)ethyl ester (1.83 mmol) was dissolved in
dichloromethane (5mL), and then 50%> aqueous sodium hydroxide solution (3.66 mmol),
tetrabutylammonium bromide (1.83 mmol) and alkyl halide (2.50 mmol) were added
thereto. The reaction mixture was stirred at room temperature for 24 hours,
neutralized with 6N aqueous hydrochloric acid, diluted with water, and then extracted
several times with dichloromethane. After the obtained organic layer was dried over
anhydrous magnesium sulfate and filtered, the filtrate was concentrated under reduced
pressure. The concentrate was purified by column-chromatography (eluent:
hexane/ethyl acetate = 10/1) to yield the title compound 3-1.
Figure imgf000032_0001
Figure imgf000032_0002
Step 2: General method for synthesizing compound (3-2)
After the compound 3-1 (1.18 mmol) was dissolved in THF (10 ml), the
solution was adjusted to a pH 4 with IN aqueous hydrochloric acid. The mixture was
stirred at room temperature for 30 minutes. To the mixture was added ethyl acetate
(10 mL) and water (10 mL). The formed aqueous layer was neutralized to a pH 9 with
IN aqueous sodium hydroxide solution, and then extracted several times with ethyl
acetate. After the organic layer thus obtained was dried over anhydrous magnesium
sulfate and filtered, the filtrate was concentrated under reduced pressure. The
concentrate was purified by column chromatography (eluent: hexane/ethyl acetate =
2/1) to yield the title compound 3-2.
Figure imgf000033_0001
Example- Compound step No. R3 Spectral data
Figure imgf000034_0002
Step 3: General method for synthesizing compound (3-3)
After the compound 3-2 (0.68 mmol) was dissolved in dichloromethane (3 mL),
the solution was cooled to 0°C and (Boc)2O (0.75 mmol) was added thereto. The
reaction mixture was stirred at room temperature for 24 hours. The mixture was
concentrated under reduced pressure. The resulting residue was purified by column
chromatography (eluent: hexane/ethyl acetate = 4/1) to yield the title compound 3-3.
Figure imgf000034_0001
Figure imgf000034_0003
Figure imgf000035_0002
Step 4: General method for synthesizing compound (3-4)
After lithium aluminum hydride (1.79 mmol) was suspended in diethyl ether (5
mL), the suspension was cooled to 0°C and a solution of the compound 3-3 (0.48
mmol) in diethyl ether (5 mL) was added thereto by dropping. After the reaction
mixture was stirred at room temperature for 5 hours, the mixture was cooled to 0°C
again. Water (700 fΛ), NaOH (1.4 mL) and water (2.1 mL) were added to the mixture
in succession, and stirred continuously. After the resulting mixture was washed with
ethyl acetate and filtered, the obtained filtrate was concentrated under reduced pressure.
The resulting residue was purified by column chromatography (eluent: ethyl
acetate/hexane = 4/1) to yield the title compound 3-4.
Figure imgf000035_0001
Figure imgf000036_0001
Step 5: General method for synthesizing compound (3-5)
A mixture of the compound 3-4 (0.71 mmol), triethylamine (2.8 mmol) and a
catalytic amount of 4-dimethylaminopyridine (DMAP) was dissolved in
dichloromethane (7 mL), cooled to 0°C, and then trimethylacetyl chloride (2.8 mmol)
was added thereto. The reaction mixture was stirred at room temperature for 1 hour.
The mixture was diluted with dichloromethane, washed with IN HC1, water and
saturated aqueous sodium chloride solution once in succession, dried over anhydrous
magnesium sulfate and filtered. The obtained filtrate was then concentrated under
reduced pressure. The resulting residue was purified by column chromatography
(eluent: ethyl acetate/hexane = 1/4) to yield the title compound 3-5.
Figure imgf000037_0001
Figure imgf000037_0002
Step 6: General method for synthesizing compound (3-6)
The compound 3-5 (0.71 mmol) was dissolved in dichloromethane (6 mL),
cooled to 0°C, and then trifluoroacetic acid (1.5 mL) was slowly added thereto. The
reaction mixture was stirred at room temperature for 3 hours. The mixture was
concentrated under reduced pressure to yield the unpurified title amine salt 3-6.
Figure imgf000038_0001
3-6
Figure imgf000038_0002
Step 7: Method for synthesizing compounds (3-7 and 3-8)
To a solution of compound 3-6 (0.46 mmol) in dimethylformamide (1 mL) was
added triethylamine (0.46 mmol). The resulting mixture was stirred at room
temperature under nitrogen for 30 minutes. To the mixture was added the compound
2-8 (0.46 mmol), and stirred at room temperature for 24 hours. The reaction mixture
was diluted with water, and extracted several times with ethyl acetate. The obtained
organic layer was washed with water and brine, dried over anhydrous magnesium
sulfate, and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (eluent: hexane/ethyl acetate = 1/1) to yield the title
compounds 3-7 or 3-8.
Figure imgf000039_0001
3-7 or 3-8
Figure imgf000039_0003
Figure imgf000039_0002
Figure imgf000040_0001
Examples 20-23
General method for synthesizing compounds (4-1 - 4-4)
A solution of amine compound (0.5 mmol) and
(4-methanesulfonylaminoρhenyl)acetic acid pentafluorophenyl ester (0.5 mmol) in
dichloromethane was stirred at room temperature for 24 hours. The reaction mixture
was concentrated under reduced pressure. The resulting residue was purified by
column chromatography (eluent: hexane/ethyl acetate = 1/2) to yield the title
compounds 4-1 - 4-4.
Figure imgf000040_0002
4-1 - 4-4
Figure imgf000041_0002
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000042_0002
Figure imgf000042_0003
hi the below, it is confirmed by calcium influx test that the compounds of the
present invention are antagonist to vanilloid receptor, further confirmed by analgesic
effect test that they exhibit strong analgesic effects while showing no irritation shown in
an agonist.
Experimental Example. Biological potency test
(1) 45 Ca influx test
1) Separation of spinal dorsal root ganglia (DRG) in newborn rats and primary culture thereof
Neonatal(2-day old or younger than 2-day old) SD rats were put in ice for 5
minutes to anesthetize and disinfected with 70% ethanol. DRG of all part of spinal
cord were dissected (Wood et al, 1988, J. Neurosci. 8, pp3208-3220) and collected in
DME/F12 medium to which 1.2 g/1 sodium bicarbonate, 50 mg 1 gentamycin were
added. The DRG were incubated sequentially at 37°C for 30 min in 200 U/ml
collagenase and 2.5 mg/ml trypsin, separately. The ganglia were washed twice with
DME/F12 medium supplemented with 10% horse serum, triturated through a
fire-polished Pasteur pipette, filtered through Nitex 40 membrane to obtain single cell
suspension. This was subjected to centrifugation, then re-suspended in cell culture
medium at certain level of cell density. As the cell culture medium, DME/F12
medium supplemented with 10%> horse serum, diluted 1:1 with identical medium
conditioned by C6 glioma cells (2 days on a confluent monolayer) was used, and
NGF(Nerve Growth Factor) was added to final concentration of 200 ng/ml. After the
cells were grown 2 days in medium where cytosine arabinoside (Ara-C, 100 μM) was
added to kill dividing nonneuronal cells, medium was changed to one without Ara-C.
The resuspended cells were plated at a density of 1500-1700 neurons/well onto Terasaki
plates previously coated with 10 μg/ml poly-D-ornithine. 2) 45 Ca influx experiments
DRG nerve cells from the primary culture of 2-3 days were equilibrated by washing 4
times with HEPES (lOmM, pH 7.4)-buffered Ca 2+, Mg2+-free HBSS (H-HBSS). The
solution in each well was removed from the individual well. Medium containing the test
compound plus capsaicin (final concentration 0.5 μM) and 45Ca (final concentration 10
μCi/ml) in H-HBSS was added to each well and incubated at room temperature for 10
min. Terasaki plates were washed six times with H-HBSS and dried in an oven. To
each well, 0.3% SDS (10 μl) was added to elute 45Ca. After the addition of 2ml of
scintillation cocktail into each well, the amount of 5Ca influx into neuron was
measured by counting radioactivity. Antagonistic activities of test compounds against
vanilloid receptor were calculated as percent of the maximal response of capsaicin at a
concentration of 0.5 μM and results are given as IC50 (Table 1).
(2) Channel activity assay
Antagonistic activities of test compounds were assayed based on electrical
change of cation channel connected to vanilloid receptor and experiments were
conducted according to reference method (Oh et al., 1996, J. Neuroscience 16,
pp 1659- 1667) (Table 1). Table 1. Results of Calcium Influx and Patchclamp Test
Figure imgf000045_0001
NR: no response
+: antagonistic potency equal to capsazepine ++: antagonistic potency 10 times higher than capsazepine
(3) Analgesic activity test: Mouse writhing test by inducing with phenyl-p-quinone
Male ICR mice (mean body weight 25 g) were maintained in a controlled
lighting environment (12 h on/ 12 h off) for experiment. Animals received an
intraperitoneal injection of 0.3ml of the chemical irritant phenyl-p-quinone (dissolved in
saline containing 5% ethanol to be a dose of 4.5mg/kg) and 6 min later, the number of
abdominal constrictions was counted in the subsequent 6 min period. Animals (10
animals/group) received 0.2ml of test compounds solution in vehicle of ethanol Tween
80/saline (10/10/80) intraperitoneally 30 min before the injection of phenyl-p-quinone.
A reduction in the number of writhes responding to the test drug compound relative to
the number responding in saline control group was considered to be indicative of an
analgesic effect. Analgesic effect was calculated by % inhibition equation (%
inhibition:=(C-T)/C x 100), wherein C and T represent the number of writhes in control
and compound-treated group, respectively (Table 2).
The test results demonstrated that analgesic effect of the compounds used in
this experiment is potent, and in particular, it is significant to clarify that vanilloid
receptor antagonist can exhibit such potent analgesic effect, and the results suggests that vanilloid receptor antagonist has potential as an analgesic agent.
Table 2. Test result of analgesic activity for writhing by phenyl-p-quinone
Figure imgf000047_0001
(4) Antimflammatory activity test: TPA(12-O-tetradecanoylphorbol 13-acetate)-induced
mouse ear edema test
Male ICR mice(body weight 25-30g), 10 animals/group, were treated topically
on the right ear with 30 μl of TPA (2.5 μg) solution in acetone and after 15 min, 30 μl
of acetone or test compound solution in acetone was applied topically. After six hours,
an identical treatment was applied again. After twenty four hours following the
treatment of TPA, the animals were sacrificed and ear tissue was dissected using 6
mm-diameter punch. Ear tissue dissected were weighed to the nearest 0.1 mg on an
electrobalance. The increased weight of the tissue compared to control group was
considered as an index of inflammation. The percent inhibition is defined by the
following equation: % inhibition =(C-T)/C x 100, wherein C and T represent an increase of ear
weight in TPA-treated and TPA+drug-treated group, respectively.
The above experiment shows that vanilloid receptor antagonist exhibits
significant anti-inflammatory effects. This phenomenon can be understood by
connecting with the action of vanilloid receptor in neurogenic inflammation, and
suggests potential applicability of vanilloid receptor antagonist in various inflammatory
diseases, in particular, neurogenic inflammatory diseases.
Table 3. TPA-induced mice ear edema test
Figure imgf000048_0001
Industrial Applicability
The compounds according to the present invention are useful in the prevention
or treatment of pain, acute pain, chronic pain, neuropathic pain, post-operative pain,
migraine, arthralgia, neuropathies, nerve injury, diabetic neuropathy, neurodegeneration, neurotic skin disorder, stroke, urinary bladder hypersensitiveness, irritable bowel
syndrome, a respiratory disorder such as asthma and chronic obstructive pulmonary
diseases, irritation in skin, eye or mucous membrane, stomach-duodenal ulcer,
inflammatory bowel disease, inflammatory disease, etc.

Claims

1. A compound of formula I:
Figure imgf000050_0001
or a pharmaceutically acceptable salt thereof,
wherein,
X represents a sulfur atom or an oxygen atom;
R1 represents a lower alkyl sulfonyl group having 1 to 5 carbon atoms, an aryl
sulfonyl group or a lower alkyl carbonyl group having 1 to 5 carbon atoms, which may
be unsubstituted or substituted with halogen atom;
R2 represents a hydrogen atom, a methoxy group or a halogen;
Figure imgf000051_0001
when A is -NHCH -, B represents (wherein, n is 0 or
1), or when A is -CH2-, B represents 4-t-butylbenzyl, 3,4-dimethylphenylethyl,
Figure imgf000051_0002
or an oleyl group;
Y represents -CH2- or -CH2CH2-;
R3 represents a hydrogen atom or a lower alkyl group having 1 to 5 carbon
atoms; and
j represents a lower alkyl group having 1 to 5 carbon atoms or phenyl group.
2. A pharmaceutical composition comprising the compound of formula I
according to claim 1 or a pharmaceutically acceptable salt thereof as an active
ingredient together with a pharmaceutically acceptable carrier.
3. The pharmaceutical composition according to claim 2, wherein the compound of formula I according to claim 1 or a pharmaceutically acceptable salt
thereof as an active ingredient together with an acceptable carrier are present in an
effective amount for preventing or treating pain, acute pain, chronic pain, neuropathic
pain, post-operative pain, migraine, arthralgia, neuropathies, nerve injury, diabetic
neuropathy, neurodegeneration, neurotic skin disorder, stroke, urinary bladder
hypersensitiveness, irritable bowel syndrome, a respiratory disorder such as asthma or
chronic obstructive pulmonary disease, irritation of skin, eye or mucous membrane,
fervescence, stomach-duodenal ulcer, inflammatory bowel disease or inflammatory
diseases.
4. A method for preventing or treating pain, acute pain, chronic pain,
neuropathic pain, post-operative pain, migraine, arthralgia, neuropathies, nerve injury,
diabetic neuropathy, neurodegeneration, neurotic skin disorder, stroke, urinary bladder
hypersensitiveness, irritable bowel syndrome, a respiratory disorder such as asthma or
chronic obstructive pulmonary disease, irritation of skin, eye or mucous membrane,
fervescence, stomach-duodenal ulcer, inflammatory bowel disease or inflammatory
diseases, wherein the method comprises administering a therapeutically effective
amount of the compounds selected from the group consisting of compounds of formula
I or pharmaceutically acceptable salts thereof.
5. The use of compounds selected from the group consisting of compounds of
formula I or pharmaceutical acceptable salts thereof as antagonists of vanilloid
receptors.
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