JP2003192673A - Piperazinecarboxamide derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine having excellent activities as a vanilloid recep tor (VR1) antagonist, and useful for prevention and treatment of a disease associated with VR1 activities, especially treatment of impending incontinence, bladder overactivity, chronic pain, nervous disorder pain, postoperative pain, rheumatoid arthritis pain, neuralgia, neuropathy, hyperpselaphesia, nerve injury, ischemia, neurodegeneration, apoplexy, incontinence and/or inflammatory disease. <P>SOLUTION: This piperazinecarboxamide derivative is represented by formula (I) (wherein, R<SP>1</SP>and R<SP>2</SP>are each a substituted phenyl, pyridyl, quinolyl or naphthyl) or a salt thereof. The medicine contains the derivative as an active ingredient. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a piperazine carboxamide derivative useful as an active ingredient of a pharmaceutical preparation. The piperazine carboxamide derivative of the present invention is
Prevention and treatment of diseases that have vanilloid receptor (VR1) antagonistic activity and VR1 activity is involved, especially urinary incontinence, bladder overactivity, chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritis pain, neuralgia , Neuropathy, hyperalgesia, nerve injury, ischemia, neurodegeneration, stroke, incontinence and / or inflammatory disease.

[0002]

Vanilloid compounds are characterized by the presence of vanillyl groups or functionally identical groups. Some examples of vanilloid compounds or vanilloid receptor modulators are vanillin (4-hydroxy-3-methoxy-benzaldehyde), guaiacol (2-methoxy-phenol), zingerone (4- / 4-hydroxy-3-methoxyphenyl / -2-butanone), eugenol (2-methoxy 4- / 2-propenyl / phenol), and capsaicin (8-methyl-N-vanillyl-6-nonenamide).

Among them, capsaicin, which is the main stimulating component of pepper, is a specific neurotoxin that desensitizes C-fiber afferent neurons. Capsaicin interacts with vanilloid receptor (VR1), and VR1 is mainly expressed in the intracellular body of dorsal root ganglion (DRG) or in nerve endings of afferent sensory fibers including C-fiber nerve endings. [Tominag
a M, Caterina MJ, Malmberg AB, Rosen TA, Gilbe
rt H, Skinner K, Raumann BE, Basbaum AI, Juliu
s D: The cloned capsaicin Receptor integrates mul
tiple pain-producing stimuli. Neuron. 21: 531-54
3, 1998]. VR1 was recently cloned [Caterina M
J, Schumacher MA, Tominaga M, Rosen TA, Levine
JD, Juius D: Nature 389: 816-824 (1997)] and was identified as a nonselective cation channel with six transmembrane domains structurally related to the TRP (transient receptor potential) channel family. . Binding of VR1 to capsaicin causes sodium, calcium, and possibly potassium ions to flow to their lower concentrations, depolarizing first, and releasing neurotransmitters from nerve endings. For this reason, VR1 is considered a molecular integrator of chemical or physical stimulators that induce neuronal signals during pathological conditions or diseases.

There is a great deal of direct or indirect evidence of a relationship between VR1 activity and diseases such as pain, ischemia, and inflammation (eg WO 99/00115 and 0).
0/50387). In addition, VR1 has been demonstrated to transduce reflex signals associated with bladder hyperactivity in patients with damaged or abnormal spinal reflex pathways [De Groat WC: A neurologic basis for the overac
Urtive 50 (6A Suppl): 36-52, 199
7]. Desensitization of afferent nerves by depletion of neurotransmitters using VR1 agonists such as capsaicin has been shown to be significantly effective in treating bladder dysfunction associated with spinal cord injury and multiple sclerosis [(Maggi CA: Therape
utic potential of capsaicin-like molecules-Studi
es in animals and humans. Life Sciences 51: 1777-1
781, 1992) and (DeRidder D; Chandiramani V; Da
sgupta P; VanPoppel H; Baert L; Fowler CJ: Intrav
esical capsaicin as a treatment for refractory det
rusor hyperreflexia: Adual center study with long
-term followup. J. Urol. 158: 2087-2092, 1997)].

[0006] VR1 receptor antagonism is expected to inhibit the release of neurotransmitters and lead to the prevention or treatment of symptoms and diseases associated with VR1 activity.

Therefore, VR1 receptor antagonists include chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritis pain, neuralgia, neuropathy, hyperalgesia, nerve injury, ischemia, neurodegeneration, stroke, incontinence, It is believed to be useful in the prevention and treatment of conditions and illnesses including inflammatory diseases, urge incontinence (UUI), and / or bladder overactivity.

WO 2000/50387 discloses compounds having vanilloid agonist activity represented by the following general formula or a pharmaceutically acceptable salt thereof.

[Chemical 3] Wherein; X ^P is an oxygen or sulfur atom, A ^P is -NHC
H ₂ — or —CH ₂ — and ^Ra is a substituted or unsubstituted C
_1-4 alkyl group, or R ^al CO-, wherein R
^al is an alkyl group having 1 to 18 carbon atoms, 2
An alkenyl group having from 18 to 18 carbon atoms, or 6
A substituted or unsubstituted aryl group having 10 to 10 carbon atoms, R ^b represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, 1 to A haloalkyl group having 6 carbon atoms, or a halogen atom, R ^c represents a hydrogen atom, 1
To alkyl groups having 4 to 4 carbon atoms, aminoalkyl groups, diacid monoesters or α-alkyl acids, and the asterisk * are chiral carbon atoms.

[0008] WO 2000/61581 discloses an amine derivative represented by the following general formula as a drug useful for diabetes, hyperlipidemia, arteriosclerosis, or cancer.

[Chemical 4] In the formula, (R ', R'') is (F, F), (CF ₃ , H) or (iP
r, iPr).

WO 2000/75106 discloses compounds represented by the following general formula as substances useful for the treatment of MMP-mediated mammalian diseases.

[Chemical 5] Where Z is

[Chemical 6] In the formula, R ⁹⁰ is hydrogen, C _1-12 alkyl, C _3-8 cycloalkyl, etc., and R ⁹¹ is amino-C _1-6 alkyl, aminocarbonyl-C _1-6 alkyl, or hydroxyaminocarbonyl-C. _1-6 alkyl; and R ⁹⁰ and R ⁹¹ are
Independently selected from the group consisting of H, C _1-6 alkyl, C _1-6 alkylthio, C _1-6 alkoxy, fluoro, chloro, bromo, iodo and nitro.

[0010]

However, none of these documents disclose a simple piperazine carboxamide derivative having a pharmaceutically active property.

It has been desired to develop compounds having effective VR1 antagonistic activity and which can be used for the prevention and treatment of diseases associated with VR1 activity, in particular for the treatment of urge incontinence and / or bladder overactivity.

[0012]

The present invention provides the above formula (I).
And a tautomer or stereoisomer thereof, or a salt thereof.

[Chemical 7] Wherein, -R ¹ is optionally R ^11, R ^12, phenyl substituted with R ^13, pyridyl optionally substituted with R ^11, R ^12, R ^13, optionally R ^11, R ^12, R ¹³ Optionally substituted with pyrimidyl
Represents quinolyl substituted with R ¹¹ , R ¹² , R ¹³ or naphthyl optionally substituted with R ¹¹ , R ¹² , R ¹³ , where R ¹¹ , R ¹² , and R ¹³ are each independently Hydrogen, halogen, straight-chain or branched C _1-6 alkyl, mono-, di-, or tri-halogen-substituted straight-chain or branched C _1-6 alkyl, nitro, cyano, straight-chain or branched C _1-6 alkoxy, hydroxy, straight or branched C _1-6 alkylcarbamoyl, carbamoyl, carboxyl, amino, straight or branched C _1-6 alkylamino, di (straight-chain or branched C _1-6 alkyl) amino, straight-chain or Branched C _1-6 alkoxycarbonyl, phenyl, benzyl, phenoxy, halogen-substituted phenoxy, straight-chain or branched C _{1-6
Alkylthio} , straight chain or branched C _1-6 alkanoyl,
Straight-chain or branched C _1-6 alkanoylamino, hydroxy-substituted straight-chain or branched C _1-6 alkyl, mono-, di-, or trihalogen-substituted straight-chain or branched C _1-6 alkoxy, R ² is optionally R ^21, R ^22, and phenyl substituted with R ^23, optionally R ^21, R ^22, and pyridyl substituted with R ^23, optionally substituted with R ^21, R ^22, and R ²³ pyrimidyl optionally R ^21, R ^22, and represents quinolyl which is substituted with R ^23, or optionally R ^{2 1,} R ^22, and naphthyl substituted with R ^23, wherein, R ^21, R ^22, and R ²³ are each independently hydrogen, halogen, straight chain or branched C _1-6
Alkyl, mono-, di-, or trihalogen-substituted linear or branched C _1-6 alkyl, nitro, cyano, linear or branched C _1-6 alkoxy, hydroxy, linear or branched C _1-6 alkylcarbamoyl, carbamoyl, carboxyl, amino, straight or branched C _1-6 alkylamino, di (straight-chain or branched C _1-6 alkyl) amino, straight or branched C _1-6 alkoxycarbonyl, phenyl,
Benzyl, phenoxy, halogen-substituted phenoxy, straight-chain or branched C _1-6 alkylthio, straight-chain or branched C
_1-6 alkanoyl, straight-chain or branched C _1-6 alkanoylamino, hydroxy-substituted straight-chain or branched C _1-6 alkyl, mono-, di-, or trihalogen-substituted straight-chain or branched C _1-6 alkoxy .

The piperazinecarboxamide derivative of the above formula (1), its tautomers and stereoisomers, and salts thereof exhibit extremely excellent VR1 antagonistic activity. They are therefore suitable for the prevention and treatment of illnesses associated with VR1 activity, in particular for the treatment of urge incontinence and / or bladder overactivity.

Preferably, the pipette of the above formula (I) of the present invention
The azine carboxamide derivative has the formula —R¹Is arbitrary
To R¹¹, R¹², R¹³Phenyl substituted with, optionally R¹¹, R
¹², R¹³Pyridyl, optionally with R¹¹, R¹², R¹³so
A substituted pyrimidyl, optionally R¹¹, R¹², R¹³Replaced by
Quinolyl, or optionally R¹¹, R¹², R¹³Replace with
Represents naphthyl, where R¹¹, R¹², And R¹³
Are each independently hydrogen, halogen, straight chain or branched
C_1-6Direct substitution with alkyl, mono, di, or trihalogen
Chain or branch C_1-6Alkyl, nitro, cyano, straight chain
Or branch C_1-6Alkoxy or hydroxy
Representation; and R²Is arbitrarily R^{twenty one}, R^{twenty two}, And R^{twenty three}Replace with
Phenyl, optionally R^{twenty one}, R^{twenty two}, And R^{twenty three}Replaced by
Pyridyl, optionally R^{twenty one}, R^{twenty two}, And R^{twenty three}Replaced by
Pyrimidyl, optionally R^{twenty one}, R^{twenty two}, And R^{twenty three}Replaced by
Quinolyl, or optionally R^{2 1}, R^{twenty two}, And R^{twenty three}Set in
Represents a substituted naphthyl, where R^{twenty one}, R^{twenty two}, And R
^{twenty three}Are each independently hydrogen, halogen, straight chain or
Branch C_1-6Alkyl, mono-, di-, or trihalogen substitution
Straight or branched C_1-6Alkyl, nitro, cyano, straight
Chain or branch C_1-6Alkoxy or hydroxy
Represent

In another embodiment, the pipera of formula (I) above
The gincarboxamide derivative has the formula —R¹Is arbitrarily
R¹¹, R¹², R¹³Phenyl substituted with, optionally R¹¹,
R¹², R¹³Pyridyl, optionally with R¹¹, R¹², R¹³
Pyrimidyl substituted with, optionally R ¹¹, R¹², R¹³Replace with
Quinolyl, or optionally R¹¹, R¹², R¹³Set in
It may be a derivative representing a substituted naphthyl, wherein R¹¹
And R¹²Are independently hydrogen, halogen, straight chain
Branch C_{1 -6}Alkyl, mono, di, or trihalo
Gen-substituted linear or branched C_1-6Alkyl, nitro, shea
No, linear or branched C_1-6Alkoxy or high
Represents Droxy, and R¹³Represents hydrogen. Yet another
In an embodiment, the piperazinecarboxyl of formula (I) above.
The amide derivative is represented by R²Is

[Chemical 8] Can be a derivative of

More preferably, the described piperazine carboxamide derivative of formula (1) is selected from the group consisting of: 4- (2-chlorophenyl) -N-
[4-chloro-3- (trifluoromethyl) phenyl]
-1-Piperazine Carboxyamid; N- [4-chloro-
3- (Trifluoromethyl) phenyl] -4- [3-
(Trifluoromethyl) -2-pyridinyl] -1-piperazinecarboxamide; N- [4-chloro-3- (trifluoromethyl) phenyl] -4- (2-fluorophenyl) -1-piperazinecarboxamide; N -[4-chloro-3- (trifluoromethyl) phenyl] -4-phenyl-1-piperazinecarboxamide; N- [4-chloro-3- (trifluoromethyl) phenyl] -4-
(3,5-Dichloro-4-pyridinyl) -1-piperazinecarboxamide; N- (7-hydroxy-1-naphthyl) -4- [3- (trifluoromethyl) -2-pyridinyl] -1-piperazinecarboxamide 4- (2-
Chlorophenyl) -N- (7-hydroxy-1-naphthyl) -1-piperazinecarboxamide; and 4-
(3,4-Dimethylphenyl) -N- (7-hydroxy-
1-naphthyl) -1-piperazinecarboxamide.

Preferably, the medicament of the present invention further comprises one or more pharmaceutically acceptable carriers and / or additives.

The piperazinecarboxamide derivative of the above formula (I), its tautomer or stereoisomer, or a salt thereof is used for urinary incontinence, bladder overactivity, chronic pain, neuropathic pain, postoperative pain, It is useful for treating rheumatoid arthritis pain, neuralgia, neuropathy, hyperalgesia, nerve injury, ischemia, neurodegeneration, stroke, incontinence and / or inflammatory disease. These are because of diseases related to VR1 activity.

[0019]

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the above formula (I) of the present invention can be produced by the following method [A] or [B], but is not limited to these methods.
In some embodiments, it is advantageous to protect one or more substituents such as amino groups, carboxyl groups and hydroxyl groups in the compounds used as starting materials or intermediates with protecting groups known to those skilled in the art. . Examples of such protecting groups are "Protective Groups in Organ" by Greene and Wuts.
It is described in ^{ic Synthesis (2 nd Edition) "} .

[Method A]

[Chemical 9]

In the above compounds, R ¹ and R ² are as defined above. These compounds can be prepared by reaction with a substituted piperazine and an isocyanate. This reaction is carried out, for example, by halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as dioxane and tetrahydrafuran; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; dimethylformamide (DM).
F) and amides such as dimethylacetamide; sulfoxides such as dimethylsulfoxide, and other solvents. The reaction can be carried out in the presence of an organic base such as triethylamine. The reaction temperature is arbitrarily set depending on the compound to be reacted. The reaction temperature is not limited, but is usually room temperature to about 100 ° C. The reaction is usually performed for 30 minutes to 48 hours, preferably for 1 hour to 24 hours. Substituted piperazine and isocyanates can be obtained by commercial routes or prepared by use of known techniques.

[Method B]

[Chemical 10] In said compound, R ¹ is as defined above.
These compounds are (1) naphthylamine and 1, 1 '
-Carbonyldi (1,2,4-triazole) (CDT)
It can be prepared by adding allylpiperazine having a substituent to the reaction mixture with (2) and the reaction mixture. The reaction (1) includes, for example, ethers such as dioxane and tetrahydrafuran; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as dimethylformamide (DMF) and dimethylacetamide; It can be carried out in sulfoxide or other solvent. The reaction temperature is arbitrarily set depending on the compound to be reacted. The reaction temperature is not limited, but is usually about 20 ° C.
To 50 ° C. The reaction is usually performed for 30 minutes to 10 hours, preferably 1 hour to 24 hours.

When the compound represented by the above formula (I) or a salt thereof has tautomers or stereoisomers (eg geometrical isomers and conformers), each of the separated isomers and Mixtures are also within the scope of the invention.

When the compound of formula (I) or a salt thereof has an asymmetric carbon in its structure, its optically active form and racemic mixture are also included in the scope of the present invention.

Representative salts of the compounds of formula (I) include salts prepared by reacting the compounds of this invention with a mineral or organic acid, or an organic or inorganic base. Such salts are known as acid addition salts and base addition salts, respectively.

The acid forming the acid addition salt is not particularly limited, but is not limited to inorganic acids such as sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid, and p-toluenesulfonic acid, but is not particularly limited. It includes organic acids such as methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid.

The base addition salt is not particularly limited, but is not limited to inorganic bases such as ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, carbonates and hydrogen carbonates, and ethanol is not particularly limited. It includes salts derived from organic bases such as amines, triethylamine, tris (hydroxymethyl) aminomethane. Examples of the inorganic base include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, calcium hydroxide, calcium carbonate and the like.

The compounds of the invention or salts thereof may be modified, depending on the substituents, to form lower alkyl esters or other known esters, and / or hydrates or other solvates. . Those esters, hydrates, and solvates are included in the scope of the present invention.

The compound of the present invention is not particularly limited,
It may be administered in the form of oral preparations such as conventional and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups, solid or liquid aerosols, and emulsions. . In addition, the compound of the present invention is not particularly limited, but may be parenterally administered in a form well known to those skilled in the field of pharmacy such as intravenous administration, intraperitoneal administration, subcutaneous administration, and intramuscular administration. Is also good. The compounds of the present invention are administered in intranasal form via topical use of suitable nasal vehicles or via transdermal routes using transdermal delivery systems well known to those skilled in the art. sell.

The administration schedule for the use of the compound of the present invention is not particularly limited, but includes age, weight, sex, medical condition of patient, medical condition, administration route, level of metabolic / excretory function of patient, dosage form used. It will be selected by one of ordinary skill in the art having regard to various factors, including the particular compound to be administered and its salts.

The compounds of the invention are preferably formulated with one or more pharmaceutically acceptable additives prior to administration. The additives are inert substances such as, but not limited to, carriers, diluents, flavors, sweeteners, lubricants, solubilizers, suspending agents, binders, tablet disintegrating agents, and encapsulating materials. .

Yet another embodiment of the present invention is a compound of the present invention, together with one or more pharmaceutically acceptable additives which are compatible with the other ingredients of the formulation and which are not harmful to the patient. It is a pharmaceutical preparation consisting of The pharmaceutical formulations of the invention are prepared by combining a therapeutically effective amount of a compound of the invention with one or more pharmaceutically acceptable additives. To make the formulations of the present invention, the active agent may be mixed with a diluent or enclosed in a carrier, which may be in the form of capsules, sachets, paper or other containers. The carrier may also serve as diluent, solid, semi-solid, liquid acting as vehicle, or for example tablets, pills, powders, lozenges, elixirs containing up to 10% by weight of active compound.
Suspensions, emulsions, solutions, syrups, aerosols, ointments,
It can be in the form of soft or hard gelatin capsules, suppositories, sterile injectable solutions and packaged sterile powders.

For oral administration, the active ingredient may be an oral, non-toxic, pharmaceutically acceptable carrier such as, but not limited to, lactose, starch, sucrose, glucose,
Sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, methylcellulose, etc.) and, if necessary, a disintegrant (including, but not limited to, corn flour, starch, methylcellulose, agar, bentonite, xanthan gum, alginic acid). And, optionally, a binder (including, but not limited to, gelatin, natural sugar, beta-lactose, corn sweetener, natural and synthetic gums, gum arabic, gum tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, wax, etc.), And, if necessary, a lubricant (including, but not limited to, magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate, sodium acetate). Um, salt, may be mixed with talc).

In powders, the carrier can be a finely divided solid, which is in admixture with the finely divided active ingredient. The active ingredient may be mixed with a carrier having binding strength in suitable proportions and compressed into tablets of the desired shape and size into tablets. The powders and tablets preferably contain from about 1 to about 99% by weight of the novel composition of the present invention, the active ingredient. Suitable solid carriers are carboxymethyl cellulose magnesium, low melting waxes and cocoa butter.

Sterile solution formulations include suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or mixtures thereof.

The active ingredient can also be dissolved in a suitable organic solvent, for example an aqueous propylene glycol solution. Another formulation is a finely ground active ingredient in starch solution,
It can be prepared by dispersing in an aqueous solution of sodium CMC (carboxymethyl cellulose) or a suitable oil.

The formulations may also be in unit dosage form, ie, physically divided units containing a unit dose suitable for administration to humans or other mammals. The unit dosage form can be a single capsule or tablet, or multiple capsules or tablets. A "unit dose" is a predetermined amount of active compound of the invention, mixed with one or more additives, calculated to produce the desired therapeutic effect. The amount of active ingredient in a unit dose will be about 0.1, depending on the particular treatment involved.
Can be varied or adjusted from about 1000 mg or more.

A typical oral dose of the present invention, when used for the indicated effect, is about 0.01 mg / kg / kg.
From about 100 mg / kg / day, preferably 0.1 mg
/ Kg / day to 30 mg / kg / day, and most preferably about 0.5 mg / kg / day to about 10 mg / kg / day. For parenteral administration, approximately 0.001 mg / kg /
From day to about 100 mg / kg / day, preferably 0.01 m
It has proven to be generally advantageous to administer doses of g / kg / day to 1 mg / kg / day. The compounds of the invention may be administered only once a day or the total daily dose may be administered twice, three times or more times daily in divided doses. Of course, administration is continuous when via the transdermal form.

[0039]

EXAMPLES The present invention will be described below in the form of examples.
They should not be construed as limiting the scope or scope of the invention in any way. In the examples below, all values are in weight percent unless otherwise stated.
Mass spectra are based on electrospray (ES) ionization (micr
omass Platform LC). Melting points are uncorrected values. Liquid chromatography mass spectrum (Liq
uid Chromatography-Mass spectroscopy, LC-MS)
Data are for Shimadzu Phenomenex ODS columns (4.6 mm X
30 mm) equipped with Micromass PlatformLC, and mixed solvent of acetonitrile and water (9: 1 to 1: 9) with 1
The flow rate was recorded at m 1 / min. TLC is a pre-coated silica gel plate (Merck silica gel
60F-254). For all column chromatography separations, use silica gel (WAKO-gel C-200 (75-150
(m)) was used. All chemicals are reagent grade and S
igma-Aldrich, purchased from Wako Pure Chemical Industries, Ltd., Tokyo Chemical Industry Co., Ltd., Arch corporation.

The efficacy of the compounds of this invention was tested in the following assays and pharmacological tests.

[Measurement of capsacin-induced Ca ²⁺ influx in VR1-transfected CHO cell line] (Assay 1) (1) Establishment of human VR1-CHOluc9aeq cell line Human vanilloid receptor (hVR1) cDNA was axotomized. Cloned with a library of dorsal root ganglia (W
O2000 / 29577). The cloned hVR
1 cDNA was constructed with pcDNA3 vector and transfected into CHOluc9aeq cell line. The cell line carries the aequorin and CRE-luciferase reporter genes as decoding signals. The transfected cells were 10% FCS, 1.4 mM sodium pyruvate, 20 mM HEPES, 0.15% sodium bicarbonate, 100 U / ml penicillin, 100.
μg / ml streptomycin, 2 mM glutamine,
Cloning was performed by the limiting dilution method in a selective medium (DMEM / F12 medium, Gibco BRL) containing non-essential amino acids and 2 mg / ml G418. Ca ²⁺ influx was tested on capsaicin stimulated clones. High response clones were selected and used for further experiments in this project. The human VR1-CHOluc9ae
q cells are maintained in the selective medium and are from 1 to 2.5 x 10
^Five cells / flask (75 mm ² ) were passaged once every 3-4 days.

(2) Ca using FDSS-3000
Measurement of ²⁺ influx Human VR1-CHOluc9aeq cells were suspended in medium without G418 from the selection medium and plated at 384-well plate (bla) at a density of 1,000 cells per well.
ck walled clear-base / Nalge Nunc International). After culturing for 48 hours, the medium was added with 2 μM Fl.
uo-3 AM (Molecular Probes) and 0.02%
Assay buffer containing Puronic F-127 (Hank's balanced salt solution (HBSS), 17 mM
HEPES (pH 7.4), 1 mM probenecid,
0.1% BSA) and the cells were incubated at 25 ° C for 6
Incubated for 0 minutes. After washing twice with assay buffer, the cells are treated with test compound or vehicle for 25
Incubated for 20 minutes at 0 ° C. C in the cytoplasm
The movement of a ²⁺ is FDSS-3000 (λ _ex = 488n
m, λ _em = 540 nm / Hamamatsu Photonics) and measured 60 seconds after stimulation with 10 nM capsaicin. Integral ratios were calculated and compared to controls.

[Measurement of Ca ²⁺ influx induction by capsaicin using primary cultured neurons of rat dorsal root ganglia] (Assay 2) (1) Preparation of rat dorsal root ganglion neurons Newborn rat of Wistar rat (postnatal 5 to 11 days) were killed and the dorsal root ganglion (DRG) was removed. DRG is PB
0.1% trypsin in S (-) (Gibco BRL) (Gibco BR
L) and incubate for 30 minutes at 37 ° C, then
Half the volume of fetal calf serum (FCS) was added and the cells were pelleted by centrifugation. The DRG nerve cells are H
am F12 / 5% FCS / 5% horse serum (Gibco B
RL) and repeat pipetting and 7
Dispersed by passage through a 0 μm mesh (Falcon). Culture plates were incubated at 37 ° C for 3 hours to remove contaminating Schwann cells. Non-adherent cells are
Harvested and laminin-coated 384-well plate (N
unc), 50 ng / ml recombinant rat NGF (Sigma)
And 50 μM 5-fluorodeoxyuridine (Sigm
In the presence of a), the cells were further cultured at 1 × 10 ⁴ cells / 50 μl / well for 2 days. (2) Ca ²⁺ migration assay DRG neurons were cultured in 17 mM HEPES (pH 7.
4) and HBSS containing 0.1% BSA twice. 2 μM fluo-3M (Molecular Probe),
After incubating with 0.02% PF127 (Gibco BRL) and 1 mM probenecid (Sigma) for 40 minutes at 37 ° C., the cells were washed 3 times. The cells are V
FDSS-60 with R1 antagonist or solvent (dimethyl sulfoxide), followed by 1 μM capsaicin
00 (λ _ex = 480 nm, λ _em = 520 nm / Hamama
tsu Photonics) incubated. The change in fluorescence at 480 nm was followed for 2.5 minutes. Calculate the integral ratio,
Compared to control.

[Magnus Assay for Measuring Capsaicin-Induced Bladder Contraction] (Assay 3) Male Wistar rats (10 weeks old) were anesthetized with ether and killed by cervical fracture. Remove the entire bladder,
Modified Krebs-Henseleit solution (pH 7.
4) The solution is 112 mM NaCl,
5.9 mM KCl, 1.2 mM MgCl ₂ , 1.2
mM NaH ₂ PO ₄ , 2 mM CaCl ₂ , 2.5 mM
It has a composition of NaHCO ₃ , 12 mM glucose. The contractile response of the bladder was studied as previously described [Maggi CA et al: BR.J.Pharmacol. 10
8: 801-805, 1993]. Isometric tension was recorded using a longitudinal strip of rat detrusor muscle at a load of 1 g. The bladder strips were allowed to equilibrate for 60 minutes prior to each stimulation. 80 mM
Contractile response to KCl was measured at 15 minute intervals until a repeatable response was obtained. The response to KCl was used as an internal standard to evaluate the maximum response value to capsaicin. The effect of the compound is to stimulate the strip with 1 μM capsaicin (vehicle: 80).
% Saline, 10% Ethanol, and 10%
Tween 80) was examined by incubating the compounds for 30 minutes. One of the samples made from the same animal served as a control and the other was used for the compound to be evaluated. Each capsaicin-induced contraction to the internal standard (ie KCl-induced contraction) was calculated and the effect of test compound on the capsaicin-induced contraction was evaluated.

[Measurement of Ca ²⁺ entry into human P2X1 transfected CHO cell line] (1) Preparation of human P2X1 transfected CHOluc9aeq cell line Human P2X1 transfected CHOluc9aeq cell line was established and 7.5% FCS, 20 mM. HEPES-KO
H (pH 7.4), 1.4 mM sodium pyruvate, 100 U / ml penicillin, 100 μg / ml
Streptomycin, 2 mM glutamine (Gibco BRL)
And 0.5 unit / ml apyrase (first grade, Sigm
Dulbecco's modified Eagle medium containing a) (DMEM /
Hold in F12). Resuspend the cells in 384-well o
ptical bottom black plates (Nalge Nunc Internation
To each well of al), it was seeded at ³ × 10 3 / 50μl / well. The cells were subsequently cultured for 48 hours and allowed to adhere to the plates. (2) Ca ²⁺ in the cytoplasm measurement P2X1 receptor agonist of intracellular Ca ²⁺ level mediated
Elevated levels are due to the fluorescent Ca ²⁺ chelating dye Fluo-
3 AM (Molecular Probes) was used for measurement. The cells adhered to the plate were washed with a washing buffer (HBSS, 17 m
M HEPES-KOH (pH 7.4), 0.1% B
Washed twice with SA and 0.5 units / ml apyrase) and 40 μl of loading solution (1 μM F in wash buffer)
luo-3 AM, 1 mM probenecid, 1 μM
Cyclosporine A, 0.01% pluronic (Molecular
Probes)) and incubated for 1 hour in the dark. The plate was washed twice with 40 μl wash buffer and washed 3 times.
5 μl of wash buffer was added to each well 5 μl of test compound or 2 ′, 3′-o- (2,
4,6-Trinitrophenyl) adenosine 5'-triphosphate (Molecular Probes) was added. 10 in the dark
After a 2 minute incubation, 200 nM α, β-methylene ATP agonist was added to initiate Ca ²⁺ migration. The fluorescence intensity is FDSS-6000 (λ _ex = 410
nm, λ _em = 510 nm / Hamamatsu Photonics) at 250 msec intervals. The integral ratio was calculated from the data and compared to the control.

[Measurement of Capsaicin-Induced Bladder Contraction in Rats Under Anesthesia] (Assay 4) (1) Animal Female Sprague-Dawley rat (200-250 g / Charle)
s River Japan) was used. (2) A catheter-implanted rat was anesthetized by intraperitoneal administration of 1.2 g / kg of urethane (Sigma). An abdominal incision was made via a midline incision and a polyethylene catheter (BECTON DICKINSON, PE50) was implanted in the bladder through its top. On the other hand, a polyurethane catheter (Hibiki, size 5) filled with 2 IU / ml of heparin (Novo Heparin, Aventis Pharma) in physiological saline (Otsuka) was inserted into the common iliac artery. (3) Cytometric investigation The bladder catheter was connected to a pressure transducer (Viggo-SpectramedPte Ltd, DT-XXAD) and a microinjection pump (TERUMO) through a T-tube. Saline was infused into the bladder at room temperature at a rate of 2.4 ml / hR. The pressure in the bladder is measured by the chart pen recorder (Yokog
awa) continuously recorded. At least 3 repeatable voiding cycles, corresponding to 20 minutes, were recorded prior to test compound administration and used as baseline values. (4) The injection of physiological saline was stopped before the administration of the test compound and the administration of the bladder stimulating compound by capsaicin. Test compounds dissolved in a mixture of ethanol, Tween 80 (ICN Biomedicals Inc.) and saline (1: 1: 8, v / v / v) were administered intraarterially at 10 mg / kg.
Two minutes after the administration of the compound, 10 μg of capsaicin (Nacalai Tesque) dissolved in ethanol was intraarterially administered. (5) Analysis of cystometry parameters Capsaicin-induced increase in intravesical pressure was analyzed from cystometry data. Capsaicin-induced bladder pressure was compared to maximal bladder pressure during voiding without capsaicin stimulation. Inhibition of test compound-mediated bladder pressure increase was assessed using the Student's t-test. 5%
A probability level less than was considered significant.

In the human VR1 transfected CHO cell line
Capsaicin-induced Ca²⁺Inflow IC ₅₀The result of the value is
Examples and Tables of Examples. Data is solid phase synthesis
Obtained by the method and therefore a purity level of about 40 to 9
Corresponds to the compound being 0%. For practical reasons,
The compounds were classified into the following four classes of activity. IC₅₀= A ≦ 0.1 μM <B ≦ 0.5 μM <C ≦ 1 μM
<D

The compounds of the present invention also show excellent selectivity and strong activity in the other assays (2) to (4) above.

Example 1-1 4- (2-chlorophenyl) -N- [4-chloro-3-
(Trifluoromethyl) phenyl] -1-piperazinecarboxamide

[Chemical 11]

This example was conducted according to General Method A above. 4-Chloro-3-trifluoromethylphenylisocyanate (80.0 mg, 0.36 mmol) in CH ₂ Cl
While stirring the ₂ (1.5 ml) solution, add 1-
(2-chlorophenyl) piperazine (79.0 mg,
A solution of 0.40 mmol of CH ₂ Cl ₂ (1.5 ml) was added at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. The solvent was removed under reduced pressure and the residue was washed with diethyl ether and 4- (2-chlorophenyl) -N- [4-chloro-3- (trifluoromethyl) phenyl] -1-piperazinecarboxamide (112. 0 mg, 67
%) Was obtained. Melting point: 175-176 ° C Molecular weight: 418.25 MS (M + H): 418 Activity: A

Example 1-2 4- (4-chlorophenyl) -N- [4-chloro-3-
(Trifluoromethyl) phenyl] -1-piperazinecarboxamide

[Chemical 12]

This example was conducted according to General Method A.
4-chlorophenylpiperazine hydrochloride (9
4.0 mg, 0.40 mmol) and triethylamine (0.062 ml, 0.44 mmol) in CH ₂ Cl ₂ (2.0 m
l) While stirring the solution, add 4-chloro-3-
Trifluoromethylphenyl isocyanate (80.0
mg, 0.36 mmol) was added at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. Add saturated NaHCO ₃ solution,
Then the reaction mixture was extracted with CH ₂ Cl ₂ . The organic layer is Na ₂ SO ₄
Dried in vacuo and then concentrated under reduced pressure. The residue was washed with diethyl ether, 4- (4-chlorophenyl)
-N- [4-chloro-3- (trifluoromethyl) phenyl] -1-piperazinecarboxamide (130.0 m
g, yield 78%). Melting point: 119 ° C Molecular weight: 418.24 MS (M + H): 418 Activity: B

The following compounds were synthesized and tested in the same manner as in Examples 1-1 and 1-2 above.

Table 1 (formula 13 to formula 24)

[Chemical 13]

[0055]

[Chemical 14]

[0056]

[Chemical 15]

[0057]

[Chemical 16]

[0058]

[Chemical 17]

[0059]

[Chemical 18]

[0060]

[Chemical 19]

[0061]

[Chemical 20]

[0062]

[Chemical 21]

[0063]

[Chemical formula 22]

[0064]

[Chemical formula 23]

[0065]

[Chemical formula 24]

Example 2-1 4- (4-hydroxyphenyl) -N- [4-chloro-3
-(Trifluoromethyl) phenyl] -1-piperazinecarboxamide

[Chemical 25]

This example was carried out according to the general method A and further modifying the phenyl moiety present as a substituent of piperazine. N- [4-chloro-3- (trifluoromethyl) phenyl] -4- (4-methoxyphenyl) -1
-Piperazinecarboxamide (100.0 mg, 0.
24 mmol) of CH ₂ Cl _{2 in} boron tribromide (1.0 M of CH 2
Solution in ₂ Cl ₂ ; 0.72 ml, 0.7 mmol) was added at 0 ° C. The mixture was stirred at room temperature for 5 hours. The reaction mixture was neutralized with saturated NaHCO ₃ solution and then extracted with CH ₂ Cl ₂ . Its residue was purified by preparative thin layer silica gel chromatography _{(CHC1 3: MeOH = 10:} 1) to give the desired compound (29mg, 30%). Melting point: 231-233 ° C Molecular weight: 399.80 MS (M + H): 400 Activity: C The following compounds were synthesized and tested according to the method of Example 2-1.

Table 2 (Chemical formula 26)

[Chemical formula 26]

Example 3 N- (7-Hydroxy-1-naphthyl) -4- [3- (trifluoromethyl) -2-pyridinyl] -1-piperazinecarboxamide

[Chemical 27]

This example was carried out according to General Method B.
8-Amino-2-naphthol (69.0 mg, 0.43
mmol) in THF (2 ml), 1,1′-carbonyldi (1,2,4-triazole) (71.0 mg, 0.4
3 mmol) was added and the mixture was stirred at room temperature for 2 hours. 1- [3-Trifluoromethyl] pyridin-2-yl] piperazine (100.0 mg, 0.43 mmol) was added and the mixture was stirred at 50 ° C. for 3 hours. Add water,
Then the mixture was extracted with AcOEt. The organic layer was dried over MgSO _4, and then concentrated under reduced pressure. The residue was washed with diethyl ether and N- (7-hydroxy-1-naphthyl) -4- [3- (trifluoromethyl) -2-pyridinyl] -1-piperazinecarboxamide (125.0
mg, 69%). Melting point: 202-204 ° C Molecular weight: 416.41 MS (M + H): 417 Activity: B The following compounds were synthesized and tested according to Example 3-1.

Table 3 (Formula 28)

[Chemical 28]

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 13/02 A61P 13/02 13/10 13/10 19/02 19/02 25/00 25/00 25 / 04 25/04 25/28 25/28 29/00 29/00 101 101 43/00 111 43/00 111 C07D 215/42 C07D 215/42 239/42 239/42 Z 295/20 295/20 A ( 72) Inventor Yuka Ikegami 942, Fushimi Gyosho, Nishifukugyo-cho, Fushimi-ku, Kyoto, Kyoto Prefecture (72) Inventor Tsutomu Masuda 3-15-6-6A (72) Inventor Toshio Kokubo Shinko, Nara-shi, Nara Prefecture 3-15-18B (72) Inventor Warburns Klaus 6-3-1-301 Kusunoka-cho, Nada-ku, Kobe-shi, Hyogo Prefecture (72) Inventor Nagahiro Yoshida 5-18-15 Sorakudai, Kizu-cho, Soraku-gun, Kyoto Prefecture (72) Inventor Makiko Marumoshi 4-9-307 Saidaiji Minamimachi, Nara City, Nara Prefecture (72) Invention Masahiro Shiro 1-3-17 Kanodainan, Ikoma-shi, Nara (72) Inventor Masaomi Tajimi 1-8-17 Sakuragaoka, Seika-cho, Soraku-gun, Kyoto (72) Keisuke Takeshita Nanajo-dori, Shimogyo-ku, Kyoto-shi, Kyoto Omiya Higashiiri Carpentry Town 118-405 (72) Inventor Toshiya Moriwaki 2-25-4 Kitayamato, Ikoma City, Nara Prefecture (72) Inventor Yasuhiro Tsukimi 2-10-1, Kukuchi, Amagasaki City, Hyogo Prefecture 4C031 LA03 4C055 AA01 BA02 BA03 BA52 BB02 CA01 CA02 CA03 CA06 CA13 CA39 DA01 DA52 DB02 4C086 AA01 AA02 AA03 BC50 MA01 MA02 MA03 MA04 MA05 NA14 ZA01 ZA08 ZA15 ZA20 ZA36 ZA81 ZB11 ZB15 ZC42

Claims (10)

[Claims] 1. A piperazinecarboxamide derivative of the following formula (I), a tautomer or stereoisomer thereof, or a salt thereof. [Chemical 1] Wherein, -R ¹ is, R ^11, R ^12, and phenyl substituted with R ^13, optionally R ^11, R ^12, and pyridyl substituted with R ^13, optionally R ^11, R ¹² optionally, and pyrimidyl substituted with R ^13, optionally R ^11, R ^12, and quinolyl substituted with R ¹³ or optionally R ^11, R ^12,, and represents a naphthyl substituted with R ^13, wherein, R ¹¹ , R ¹² , and R ¹³ are each independently hydrogen, halogen, linear or branched C _1-6 alkyl, mono.
Di- or trihalogen-substituted linear or branched C _1-6 alkyl, nitro, cyano, linear or branched C _1-6 alkoxy, hydroxy, linear or branched C _1-6 alkylcarbamoyl, carbamoyl, carboxyl, amino, straight or branched C _1-6 alkylamino, di (straight-chain or branched C _1-6 alkyl) amino, straight or branched C
_1-6 alkoxycarbonyl, phenyl, benzyl, phenoxy, halogen-substituted phenoxy, straight-chain or branched C
_1-6 alkylthio, linear or branched C _1-6 alkanoyl, linear or branched C _1-6 alkanoylamino, hydroxy-substituted linear or branched C _1-6 alkyl, mono-di-
Or it represents a tri-halogen-substituted linear or branched C _1-6 alkoxy, R ² is optionally substituted with R ^21, R ^22, and phenyl substituted with R ^23, optionally R ^21, R ^22, and R ²³ pyridyl, optionally R ^21, R ^22, and pyrimidyl substituted with R ^23, optionally R ^21, R ^22, and quinolyl substituted with R ²³ or optionally R ^21,, R ^22, and R ²³ Represents naphthyl substituted with, where R ²¹ , R ²² , and R ²³ are each independently hydrogen, halogen, straight-chain or branched C _1-6 alkyl, mono.
Di- or trihalogen-substituted linear or branched alkyl, nitro, cyano, linear or branched C _1-6 alkoxy, hydroxy, linear or branched C _1-6 alkylcarbamoyl, carbamoyl, carboxyl, amino, linear Or branched C _1-6 alkylamino, di (linear or branched C _1-6 alkyl) amino, linear or branched C _1-6 alkoxycarbonyl, phenyl, benzyl, phenoxy,
Halogen-substituted phenoxy, straight-chain or branched C _1-6 alkylthio, straight-chain or branched C _1-6 alkanoyl, straight-chain or branched C _1-6 alkanoylamino, hydroxy-substituted straight-chain or branched C _1-6 alkyl , Mono-, di-, or trihalogen-substituted linear or branched C _1-6 alkoxy. 2. The piperazine carboxamide derivative according to claim 1, a tautomer or stereoisomer thereof, or a salt thereof. However, -R ¹ is optional for R ¹¹ , R ¹² and
Phenyl substituted with R ^13, optionally R ^11, R ^12, and pyridyl substituted with R ^13, optionally R ^11, R ¹² and pyrimidyl substituted with R ^13, optionally R ^11, R ¹² and R ¹³ A quinolyl substituted with, or naphthyl optionally substituted with R ¹¹ , R ¹² and R ¹³ , wherein R ¹¹ , R ¹² and R ¹³ are each independently hydrogen,
Represents halogen, straight-chain or branched C _1-6 alkyl, mono-, di- or tri-halogen-substituted straight-chain or branched C _1-6 alkyl, nitro, cyano, straight-chain or branched C _1-6 alkoxy, or hydroxy. And R ² is optionally
Phenyl substituted with R ²¹ , R ²² , and R ²³ , optionally R
A pyridyl substituted with ²¹ , R ²² , and R ²³ , optionally
A pyrimidyl substituted with R ²¹ , R ²² , and R ²³ , optionally
Represents quinolyl substituted with R ²¹ , R ²² , and R ²³ or naphthyl optionally substituted with R ²¹ , R ²² , and R ²³ , provided that R ²¹ , R ²² , and R ²³ are each independently Hydrogen, halogen, linear or branched C _1-6 alkyl, mono
It represents a di- or tri-halogen-substituted straight-chain or branched C _1-6 alkyl, nitro, cyano, straight-chain or branched C _1-6 alkoxy, or hydroxy. 3. The piperazine resin according to claim 1 or 2.
Ruboxamide derivative, its tautomer or stereochemistry
Sex bodies or their salts. However, −R¹Is arbitrarily
R¹¹, R¹²And R¹³Phenyl substituted with, optionally R¹¹,
R¹²And R¹³Pyridyl, optionally with R¹¹, R¹²Oh
And R¹³Pyrimidyl substituted with, optionally R¹¹, R¹²And
And R¹³Quinolyl substituted with or optionally R ¹¹, R¹²
And R¹³Represents naphthyl substituted with Where R¹¹And R¹²Are independently hydrogen and halogen
Straight chain or branched C_1-6Alkyl, Mono, Di, Moshishi
Is a trihalogen-substituted linear or branched alkyl,
Nitro, cyano, linear or branched C_1-6Alkoxy,
Alternatively, represents hydroxy and R¹³Represents hydrogen. 4. The piperazine carboxamide derivative according to any one of claims 1 to 3, a tautomer or stereoisomer thereof, or a salt thereof. In the formula, R ² is Represents 5. The piperazine carboxamide derivative of the formula (1) is selected from the group consisting of the following substances:
The piperazine carboxamide derivative according to claim 1,
The tautomer or stereoisomer, or a salt thereof. Four
-(2-chlorophenyl) -N- [4-chloro-3- (trifluoromethyl) phenyl] -1-piperazinecarboxyamid; N- [4-chloro-3- (trifluoromethyl) phenyl] -4- [ 3- (trifluoromethyl)-
2-pyridinyl] -1-piperazinecarboxamide;
N- [4-chloro-3- (trifluoromethyl) phenyl] -4- (2-fluorophenyl) -1-piperazinecarboxamide; N- [4-chloro-3- (trifluoromethyl) phenyl] -4- Phenyl-1-piperazinecarboxamide; N- [4-chloro-3- (trifluoromethyl) phenyl] -4- (3,5-dichloro-4-
Pyridinyl) -1-piperazinecarboxamide; N-
(7-Hydroxy-1-naphthyl) -4- [3- (trifluoromethyl) -2-pyridinyl] -1-piperazinecarboxamide; 4- (2-chlorophenyl) -N-
(7-Hydroxy-1-naphthyl) -1-piperazinecarboxamide; and 4- (3,4-dimethylphenyl) -N- (7-hydroxy-1-naphthyl) -1-piperazinecarboxamide. 6. A piperazinecarboxamide derivative of the formula (1) according to any one of claims 1 to 3, a tautomer or stereoisomer thereof, or a compound for the treatment and / or prevention of a disease. Salt. 7. One or more pharmaceutically acceptable carriers and / or additives, and at least one compound according to claims 1 to 5, a tautomer or stereoisomer thereof, and a salt thereof. A medicament comprising a combination of. 8. The piperazine carboxamide derivative of formula (1), its tautomer or stereoisomer, and salts thereof are VR1 antagonists.
The medicine according to. 9. Urinary incontinence, bladder overactivity, chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritis pain, neuralgia, neuropathy, hyperalgesia, nerve injury, ischemia, neurodegeneration, stroke, incontinence. The medicament according to claim 7, which is useful for treating and / or preventing a disease selected from the group consisting of and an inflammatory disease. 10. Urinary incontinence, bladder overactivity, chronic pain,
Neuropathic pain, postoperative pain, rheumatoid arthritis pain, neuralgia,
A method for producing a medicament useful for treating and / or preventing a disease selected from the group consisting of neuropathy, hyperalgesia, nerve injury, ischemia, neurodegeneration, stroke, incontinence and inflammatory disease. Use of a compound according to any of 5.