Bicyclic Amide, Carbamate or Urea Derivatives as Vanilloid Receptor Modulators

Abstract

This invention relates to bicyclic amide, carbamate or urea derivatives and salts thereof which are useful as active ingredients of pharmaceutical preparations. The bicyclic amide, carbamate or urea derivative of the present invention has vanilloid receptor (VR1) antagonistic activity, and can be used for the prophylaxis and treatment of diseases associated with VR1 activity, in particular for the treatment of urological diseases or disorders, such as detrusor overactivity (overactive bladder), urinary incontinence, neurogenic detrusor oeractivity (detrusor hyperflexia), idiopathic detrusor overactivity (detrusor instability), benign prostatic hyperplasia, and lower urinary tract symptoms; chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, neuralgia, neuropathies, algesia, nerve injury, ischaemia, neurodegeneration, stroke, and inflammatory disorders such as asthma and chronic obstructive pulmonary (or airways) disease (COPD).

Description

EXAMPLES

The present invention will be described as a form of examples, but they should by no means be construed as defining the metes and bounds of the present invention.

In the examples below, all quantitative data, if not stated otherwise, relate to percentages by weight.

Mass spectra were obtained using electrospray (ES) ionization techniques (micromass platform LC). Melting points are uncorrected. Liquid Chromatography-Mass spectroscopy (LC-MS) data were recorded on a Micromass platform LC with Shimadzu Phenomenex ODS column(4.6 mmΦ×30 mm) flushing a mixture of acetonitrile-water (9:1 to 1:9) at 1 ml/min of the flow rate. TLC was performed on a precoated silica gel plate (Merck silica gel 60 F-254). Silica gel (WAKO-gel C-200 (75-150 μm)) was used for all column chromatography separations. All chemicals were reagent grade and were purchased from Sigma-Aldrich, Wako pure chemical industries, Ltd., Great Britain, Tokyo kasei kogyo Co., Ltd., Nacalai tesque, Inc., Watanabe Chemical Ind. Ltd., Maybridge p1c, Lancaster Synthesis Ltd., Merck KgaA, Germany, Kanto Chemical Co., Ltd.

¹H NMR spectra were recorded using either Bruker DRX -300 (300 MHz for ¹H) spectrometer or Brucker 500 UltraShieled™ (500 MHz for 1H). Chemical shifts are reported in parts per million (ppm) with tetramethylsilane (TMS) as an internal standard at zero ppm. Coupling constant (J) are given in hertz and the abbreviations s, d, t, q, m, and br refer to singlet, doblet, triplet, quartet, multiplet, and broad, respectively. The mass determinations were carried out by MAT95 (Finnigan MAT).

All starting materials are commercially available or can be prepared using methods cited in the literature.

The effect of the present compounds was examined by the following assays and pharmacological tests.

[Measurement of Capsaicin-Induced Ca²⁺ Influx in the Human VR1-Transfected CHO Cell Line] (Assay 1)

(1) Establishment of the human VR1-CHOluc9aeq cell line

• • Human vanilloid receptor (hVR1) cDNA was cloned from libraries of axotomized dorsal root ganglia (WO 00/29577). The cloned hVR1 cDNA was constructed with pcDNA3 vector and transfected into a CHOluc9aeq cell line. The cell line contains aequorin and CRE-luciferase reporter genes as read-out signals. The transfectants were cloned by limiting dilution in selection medium (DMEM/F12 medium (Gibco BRL) supplemented with 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, non-essential amino acids and 2 mg/ml G418). Ca²⁺ influx was examined in the capsaicin-stimulated clones. A high responder clone was selected and used for further experiments in the project. The human VR1-CHOluc9aeq cells were maintained in the selection medium and passaged every 3-4 days at 1-2.5×10⁵ cells/flask (75 mm²).

(2) Measurement of Ca²⁺ influx using FDSS-3000

• • Human VR1-CHOluc9aeq cells were suspended in a culture medium which is the same as the selection medium except for G418 and seeded at a density of 1,000 cells per well into 384-well plates (black walled clear-base/Nalge Nunc International). Following the culture for 48 hrs the medium was changed to 2 μM Fluo-3 AM (Molecular Probes) and 0.02% Puronic F-127 in assay buffer (Hank's balanced salt solution (HBSS), 17 mM HEPES (pH7.4), 1 mM Probenecid, 0.1% BSA) and the cells were incubated for 60 min at 25° C. After washing twice with assay buffer the cells were incubated with a test compound or vehicle for 20 min at 25° C. Mobilization of cytoplasmic Ca²⁺ was measured by FDSS-3000 (λ_ex=488 nm, λ_em=540 nm/Hamamatsu Photonics) for 60 sec after the stimulation with 10 nM capsaicin. Integral R was calculated and compared with controls.

[Measurement of the Capsaicin-Induced Ca²⁺ Influx in Primary Cultured Rat Dorsal Root Ganglia Neurons] (Assay 2)

(1) Preparation of rat dorsal root ganglia neurons

• • New born Wister rats (5-11 days) were sacrificed and dorsal root ganglia (DRG) was removed. DRG was incubated with 0.1% trypsin (Gibco BRL) in PBS(-) (Gibco BRL) for 30 min at 37° C., then a half volume of fetal calf serum FCS) was added and the cells were spun down. The DRG neuron cells were resuspended in Ham F12/5% FCS/5% horse serum (Gibco BRL) and dispersed by repeated pipetting and passing through 70 μm mesh (Falcon). The culture plate was incubated for 3 hours at 37° C. to remove contaminating Schwann cells. Non-adherent cells were recovered and further cultured in laminin-coated 384 well plates (Nunc) at 1×10⁴ cells/50 μl/well for 2 days in the presence of 50 ng/ml recombinant rat NGF (Sigma) and 50 μM 5-fluorodeoxyuridine (Sigma).

(2) Ca²⁺ mobilization assay

• • DRG neuron cells were washed twice with HBSS supplemented with 17 mM HEPES (pH 7.4) and 0.1% BSA. After incubating with 2 μM fluo-3AM (Molecular Probe), 0.02% PF127 (Gibco BRL) and 1 mM probenecid (Sigma) for 40 min at 37° C., cells were washed 3 times. The cells were incubated with VR1 antagonists or vehicle (dimethylsulfoxide) and then with 1 μM capsaicin in FDSS-6000 (λ_ex480 nm, λ_em=520 mn/Hamamatsu Photonics). The fluorescence changes at 480 nm were monitored for 2.5 min. Integral R was calculated and compared with controls.

[Organ Bath Assay to Measure the Capsaicin-Induced Bladder Contraction] (Assay 3)

• • Male Wistar rats (10 week old) were anesthetized with ether and sacrificed by dislocating the necks. The whole urinary bladder was excised and placed in oxygenated Modified Krebs-Henseleit solution (pH 7.4) of the following composition (112 mM NaCl, 5.9 mM KCl, 1.2 mM MgCl₂, 1.2 mM NaH₂PO₄, 2 mM CaCl₂, 2.5 mM NaHCO₃, 12 mM glucose). Contractile responses of the urinary bladder were studied as described previously [Maggi CA et al. Br. J. Pharmacol. 108: 801-805, 1993]. Isometric tension was recorded under a load of 1 g using longitudinal strips of rat detrusor muscle. Bladder strips were equilibrated for 60 min before each stimulation. Contractile response to 80 mM KCl was determined at 15 min intervals until reproducible responses were obtained. The response to KCl was used as an internal standard to evaluate the maximal response to capsaicin. The effects of the compounds were investigated by incubating the strips with compounds for 30 min prior to the stimulation with 1 μM capsaicin (vehicle: 80% saline, 10% EtOH, and 10% Tween 80). One of the preparations made from the same animal was served as a control while the others were used for evaluating compounds. Ratio of each capsaicin-induced contraction to the internal standard (i.e. KCL-induced contraction) was calculated and the effects of the test compounds on the capsaicin-induced contraction were evaluated.

[Measurement of Ca²⁺ Influx in the Human P2X1-Transfected CHO Cell Line]

(1) Preparation of the human P2X1-transfected CHOluc9aeq cell line

• • Human P2X1-transfected CHOluc9aeq cell line was established and maintained in Dulbecco's modified Eagle's medium (DMEM/F12 ) supplemented with 7.5% FCS, 20 mM HEPES-KOH (pH 7.4), 1.4 mM sodium pyruvate, 100 U/ml penicillin, 100 μg/ml streptomycin, 2 mM glutamine (Gibco BRL) and 0.5 Units/ml apyrase (grade I, Sigma). The suspended cells were seeded in each well of 384-well optical bottom black plates
  • (Nalge Nunc International) at 3×10³ /50 μl/well. The cells were cultured for following 48 hrs to adhere to the plates.(2) Measurement of the intracellular Ca²⁺ levels P12X1 receptor agonist-mediated increases in cytosolic Ca²³⁰ levels were measured using a fluorescent Ca²⁺ chelating dye, Fluo-3 AM (Molecular Probes). The plate-attached cells were washed twice with washing buffer (HBSS, 17 mM HEPES-KOH (pH 7.4), 0.1% BSA and 0.5 units/ml apyrase), and incubated in 40 μl of loading buffer (1 μM Fluo-3 AM, 1 mM probenecid, 1 μM cyclosporin A, 0.01% μluronic (Molecular Probes)in washing buffer) for 1 hour in a dark place. The plates were washed twice with 40 μl washing buffer and 35 μl of washing buffer were added in each well with 5 μl of test compounds or 2′,3′-o-(2,4,6-trinitrophenyl) adenosine 5′-triphosphate Molecular Probes) as a reference. After further incubation for 10 minutes in dark 200 nM α, β-methylene ATP agonist was added to initiate the Ca²⁺ mobilization. Fluorescence intensity was measured by FDSS-6000 (λ_ex=410 nm, λ_em510 mn/Hamamatsu Photonics) at 250 msec intervals. Integral ratios were calculated from the data and compared with that of a control.

[Measurement of Capsaicin-Induced Bladder Contraction in Anesthetized Rats] (Assay 4)

(1) Animals

• • Female Sprague-Dawley rats (200-250 g/Charles River Japan) were used.

(2) Catheter implantation

• • Rats were anesthetized by intraperitoneal administration of urethane (Sigma) at 1.2 g/kg. The abdomen was opened through a midline incision, and a polyethylene catheter (BECTON DICKINSON, PE50) was implanted into the bladder through the dome. In parallel, the inguinal region was incised, and a polyethylene catheter (Hibiki, size 5) filled with 2 IU/ml of heparin (Novo Heparin, Aventis Pharma) in saline (Otsuka) was inserted into a common iliac artery.

(3) Cystometric investigation

• • The bladder catheter was connected via T-tube to a pressure transducer (Viggo-Spectramed Pte Ltd, DT-XXAD) and a microinjection pump TERUMO). Saline was infused at room temperature into the bladder at a rate of 2.4 ml/hr. Intravesical pressure was recorded continuously on a chart pen recorder (Yokogawa). At least three reproducible micturition cycles, corresponding to a 20 -minute period, were recorded before a test compound administration and used as baseline values.

(4) Administration of test compounds and stimulation of bladder with capsaicin

• • The saline infusion was stopped before administrating compounds. A testing compound dissolved in the mixture of ethanol, Tween 80 (ICN Biomedicals Inc.) and saline (1:1:8, v/v/v) was administered intraarterially at 10 mg/kg. 2 min after the administration of the compound 10 μg of capsaicin (Nacalai Tesque) dissolved in ethanol was administered intraarterially.

(5) Analysis of cystometry parameters

• • Relative increases in the capsaicin-induced intravesical pressure were analyzed from the cystometry data. The capsaicin-induced bladder pressures were compared with the maximum bladder pressure during micturition without the capsaicin stimulation. The testing compounds-mediated inhibition of the increased bladder pressures was evaluated using Student's t-test. A probability level less than 5% was accepted as significant difference.

[Measurement of Over Active Bladder in Anesthetized Cystitis Rats] (Assay 5)

(1) Animals

• • Female Sprague-Dawley rats (180-250 g/Charles River Japan) were used. Cyclophosphamide (CYP) dissolved in saline was administered intraperitoneally at 150 mg/kg 48 hours before experiment.

(2) Catheter implantation

• • Rats were anesthetized by intraperitoneal administration of urethane (Sigma) at 1.25 g/kg. The abdomen was opened through a midline incision, and a polyethylene catheter (BECTON DICKINSON, PE50) was implanted into the bladder through the dome. In parallel, the inguinal region was incised, and a polyethylene catheter (BECTON DICKINSON, PE50) filled with saline (Otsuka) was inserted into a femoral vein. After the bladder was emptied, the rats were left for 1 hour for recovery from the operation.

(3) Cystometric investigation

• • The bladder catheter was connected via T-tube to a pressure transducer (Viggo-Spectramed Pte Ltd, DT-XXAD) and a microinjection pump (TERUMO). Saline was infused at room temperature into the bladder at a rate of 3.6 ml/hr for 20 min. Intravesical pressure was recorded continuously on a chart pen recorder (Yokogawa). At least three reproducible micturition cycles, corresponding to a 20 -minute period, were recorded before a test compound administration.

(4) Administration of test compounds

• • A testing compound dissolved in the mixture of ethanol, Tween 80 (ICN Biomedicals Inc.) and saline (1:1:8, v/v/v) was administered intravenously at 0.05 mg/kg, 0.5 mg/kg or 5 mg/kg. 3 min after the administration of the compound, saline (Nacalai Tesque) was infused at room temperature into the bladder at a rate of 3.6 ml/hr.

(5) Analysis of cystometry parameters

• • The cystometry parameters were analyzed as described previously [ Lecci A et al: Eur. J. Pharmacol. 259: 129-135, 1994]. The micturition frequency calculated from micturition interval and the bladder capacity calculated from a volume of infused saline until the first micturition were analyzed from the cystometry data. The testing compounds-mediated inhibition of the frequency and the testing compounds-mediated increase of bladder capacity were evaluated using unpaired Student's t-test. A probability levels less than 5% was accepted as significant difference. Data were analyzed as the mean ± SEM from 4-7 rats.

[Measurement of Acute Pain]

• • Acute pain is measured on a hot plate mainly in rats. Two variants of hot plate testing are used: In the classical variant animals are put on a hot surface (52 to 56 ° C.) and the latency time is measured until the animals show nociceptive behavior, such as stepping or foot licking. The other variant is an increasing temperature hot plate where the experimental animals are put on a surface of neutral temperature. Subsequently this surface is slowly but constantly heated until the animals begin to lick a hind paw. The temperature which is reached when hind paw licking begins is a measure for pain threshold.
  • Compounds are tested against a vehicle treated control group. Substance application is performed at different time points via different application routes (i.v., i.p., p.o., i.t., i.c.v., s.c., intradermal, transdermal) prior to pain testing.

[Measurement of Persistent Pain]

• • Persistent pain is measured with the formalin or capsaicin test, mainly in rats. A solution of 1 to 5% formalin or 10 to 100 μg capsaicin is injected into one hind paw of the experimental animal. After formalin or capsaicin application the animals show nociceptive reactions like flinching, licking and biting of the affected paw. The number of nociceptive reactions within a time frame of up to 90 minutes is a measure for intensity of pain.
  • Compounds are tested against a vehicle treated control group. Substance application is performed at different time points via different application routes (iv., i.p., p.o., i.t, i.c.v., s.c., intradermal, transdermal) prior to formalin or capsaicin administration.

[Measurement of Neuropathic Pain]

• • Neuropathic pain is induced by different variants of unilateral sciatic nerve injury mainly in rats. The operation is performed under anesthesia. The first variant of sciatic nerve injury is produced by placing loosely constrictive ligatures around the common sciatic nerve (Bennett and Xie, Pain 33 (1988): 87-107). The second variant is the tight ligation of about the half of the diameter of the common sciatic nerve (Seltzer et al., Pain 43 (1990): 205-218). In the next variant, a group of models is used in which tight ligations or transections are made of either the L5 and L6 spinal nerves, or the L5 spinal nerve only (KIM SH; CHUNG J M, AN EXPERIMENTAL-MODEL FOR PERIPHERAL NEUROPATHY PRODUCED BY SEGMENTAL SPINAL NERVE LIGATION IN THE RA, PAIN 50 (3) (1992): 355-363). The fourth variant involves an axotomy of two of the three terminal branches of the sciatic nerve (tibial and common peroneal nerves) leaving the remaining sural nerve intact whereas the last variant comprises the axotomy of only the tibial branch leaving the sural and common nerves uninjured. Control animals are treated with a sham operation.
  • Postoperatively, the nerve injured animals develop a chronic mechanical allodynia, cold allodynia, as well as a thermal hyperalgesia. Mechanical allodynia is measured by means of a pressure transducer (electronic von Frey Anesthesiometer, IITC Inc.-Life Science Instnnents, Woodland Hills, SA, USA; Electronic von Frey System, Somedic Sales AB, Hörby, Sweden). Thermal hyperalgesia is measured by means of a radiant heat source (Plantar Test, Ugo Basile, Comerio, Italy), or by means of a cold plate of 5 to 10° C. where the nocifensive reactions of the affected hind paw are counted as a measure of pain intensity. A further test for cold induced pain is the counting of nocifensive reactions, or duration of nocifensive responses after plantar administration of acetone to the affected hind limb. Chronic pain in general is assessed by registering the circadanian rhytins in activity (Surjo and Arndt, Universität zu Köln, Cologne, Germany), and by scoring differences in gait (foot print patterns; FOOTPRINTS program, Klapdor et al., 1997. A low cost method to analyse footprint patterns. J. Neurosci. Methods 75, 49-54).
  • Compounds are tested against sham operated and vehicle treated control groups. Substance application is performed at different time points via different application routes (i.v., i.p., p.o., i.t., i.c.v., s.c., intradermal, transdermal) prior to pain testing.

[Measurement of Inflammatory Pain]

• • Inflammatory pain is induced mainly in rats by injection of 0.75 mg carrageenan or complete Freund's adjuvant into one hind paw. The animals develop an edema with mechanical allodynia as well as thermal hyperalgesia. Mechanical allodynia is measured by means of a pressure transducer (electronic von Frey Anesthesiometer, IITC Inc.-Life Science Instruments, Woodland Hills, SA, USA). Thermal hyperalgesia is measured by means of a radiant heat source (Plantar Test, Ugo Basile, Comerio, Italy, Paw thermal stimulator, G. Ozaki, University of California, USA). For edema measurement two methods are being used. In the first method, the animals are sacrificed and the affected hindpaws sectioned and weighed. The second method comprises differences in paw volume by measuring water displacement in a plethysmometer (Ugo Basile, Comerio, Italy).
  • Compounds are tested against uninflamed as well as vehicle treated control groups. Substance application is performed at different time points via different application routes (i.v., i.p., p.o., i.t, i.c.v., s.c., intradermal, transdermal) prior to pain testing.

[Measurement of Diabetic Neuropathic Pain]

• • Rats treated with a single intraperitoneal injection of 50 to 80 mg/kg streptozotocin develop a profound hyperglycemia and mechanical allodynia within 1 to 3 weeks. Mechanical allodynia is measured by means of a pressure transducer (electronic von Frey Anesthesiometer, IITC Inc.-Life Science Instruments, Woodland Hills, SA, USA).
  • Compounds are tested against diabetic and non-diabetic vehicle treated control groups. Substance application is performed at different time points via different application routes (i.v., i.p., p.o., i.t., i.c.v., s.c., intradermal, transdermal) prior to pain testing.

Results in capsaicin-induced Ca²⁺ influx assay in the human VR1-transfected CHO cell line (Assay 1) are shown in Examples and tables of the Examples below: For practical reasons, the compounds are grouped in four classes based on activity as follows:

IC ₅₀ =A (<or=)0.1 μM<B(<or =)0.5 μM<C(<or=)1 μM<D

The compounds of the present invention also show excellent selectivity, and strong activity in other assays 2-5 and assays for pain described above.

Preparation of Starting Compounds

[Starting compound A]

7-amino-1,2,3,4tetrahydronaphthalen-2-ol

A mixture of 2,7-dihydroxynaphthalene (3.24 g, 20.2 mmol), sodium bisulfite (2.38 g, 22.9 mmol), and 28% aq. ammonia solution (50 mL) in sealed stainless-steel reactor was heated at 150° C. for 4.5 hours. After cooled to ambient temperature, a mixture of ethylacetate and acetonitrile was added and then extracted aqueous in sodium hydroxide solution. The aqueous layer was acidified to pH 1, and the mixture was extracted with ethylacetate. The mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethylacetate/hexane=1/3) to provide 7-amino-2-naphthol (0.54 g).

MS (ESI) m/z 160 [M+H]⁺

• ¹H NMR (CDCl3-d) δ3.80 (brs, 2H), 4.82 (s, 1H), 6.78 (d, J=8.5 Hz, 1H), 7.26=6.83 (m, 2H), 6.90 (s, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H).

Next, a mixture of 7-amino-2-naphthol (0.54 g, 3.39 mmol) and di-t-butylcarbonate (0.74g, 3.39 mmol) in tetrahydrofuran (30 mL) was stirred at room temperature for 16 hours. To the mixture was added water and extracted with ethylacetate. The organic layer was dried over MgSO₄, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: ethylacetate/hexane=1/2) to afford tert-butyl (7-hydroxy-2-naphthyl)carbamate (615 mg).

MS (ESI) m/z 204 [M+H]⁺

• ¹H NMR (CDCl3-d) δ1.53 (s, 9H), 5.22 (s, 1H), 6.59 (brs, 1H), 6.98 (dd, J=2.5, 8.8 Hz, 1H), 7.05 (d, J=2.5 Hz, 1H), 7.14 (dd, J=2.1, 8.8 Hz, 1H), 7.64 (d, J=8.7 Hz, 1H), 7.66 (d, J=8.7 Hz, 1H), 7.84 (s, 1H).

Next, a mixture of tert-butyl (7-hydroxy-2-naphthyl)carbamate (61o mg, 2.35 mmol), ethyliodide (734 mg, 4.70 mmol), and potassium carbonate (650 mg, 4.70 mmol) in acetone (50 mL) was stirred at refluxing temperature for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel columnn chromatography (eluent: ethylacetate/hexane=1/2) to give tert-butyl (7-ethoxy-2-naphthyl)-carbamate (440 mg).

MS (ESI) m/z 232 [M+H]⁺

• ¹H NMR (CDCl3-d) δ1.46 (t, J=7.0 Hz, 3H), 1.55 (s, 9H), 4.12 (q, J=7.0 Hz, 2H), 6.58 (s, 1H), 7.02 (dd, J=2.5, 8.9 Hz, 1H), 7.06 (d, J=2.3 Hz, 1H), 7.12 (dd, J=2.3, 8.9 Hz, 1H), 7.63 (d, J=8.9 Hz, 1H), 7.65 (d, J=8.9 Hz, 1H), 7.92 (s, 1H).

Next, in a flask containing tert-butyl (7-ethoxy-2-naphthyl)carbamate (530 mg, 1.84 mmol) and t- buthanol (0.53 mL) in tetrahydrofuran (25 mL) was collected liquid ammonia (150 mL) at −78° C. Lithium (38.4 mg) was added, and the mixture was stirred for 1 hour. After raising to room temperature, the mixture was concentrated under reduced pressure then water was added. The mixture was extracted with ethylacetate, and the organic layer was washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure. To the obtained residue was added a mixture of tetrahydrofuran (38 mL) and aqueous in solution of hydrochloric acid (12 mL) and stirred at 45° C. for 45 minutes. The mixture was concentrated under reduced temperature and then ethylacetate was added. The organic layer was dried over MgSO₄, filtered, and concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography (eluent: ethylacetate/hexane=1/4) to provide tert-butyl (7-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)carbamate (177 mg).

MS (ESI) m/z 206 [M+H]⁺

¹H NMR (CDCl3-d) δ1.52 (s, 9H), 2.53 (t, J=6.9 Hz, 2H), 3.00 (t, J=6.9 Hz, 2H), 3.56 (s, 2H), 4.30 (brs, 1H), 6.41 (brs, 1H), 7.10−7.15 (m, 2H).

Next, to a solution of tert-butyl (7-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)carbamate (177 mg, 0.68 mmol) in methanol (10 mL) was added sodium borohydride (25.6 mg, 0.68 mml) at 0° C. After stirred for 1 hour, water was added and the mixture was concentrated under reduced pressure. To the resulting residue was added 4N hydrochloric acid in 1,4-dioxane solution, and the mixture was stirred for 3.5 hours. After neutralized with saturated aqueous solution of sodium bicarbonate, the mixture was extracted with chloroform. The organic layer was dried over MgSO₄, filtered, and concentrated under reduced pressure. The obtained residue was recrystallized from diethylether to afford 7-amino-1,2,3,4-tetrahydronaphthalen-2-ol (78.1 mg).

MS (ESI) m/z 164 [M+H]⁺

• ¹H NMR (acetone-d6) δ1.69-1.75 (m, 2H), 2.64-2.95 (m, 5H), 3.60-3.80 (m, 1H), 4.02 (brs, 1H), 6.39 (d, J=6.0 Hz, 1H), 6.41 (dd, J=6.0, 8.0 Hz, 1H), 6.96 (d,J=8.0 Hz, 1H).

[Starting Compound B]

7-Amino-1,2,3,4-tetrahydro-naphthalen-2-ol (enantiomer)

To a stirred solution of benzeneruthenium(II) chloride dimer and (1S, 2R)-(-)-cis-2-amino-2-indanol in degaussed isopropanol was heated at 80° C. for 20 minutes under argon. The mixture was added to the solution of 7-amino-3,4-dihydro-1H-naphthalen-2-one in isopropanol at room temperature. A solution of potassium hydroxide in isopropanol was added, and the mixture was stirred at 45° C. for 1 hour. The mixture was passed through silica gel and washed with ethylacetate. The filtrate was concentrated under reduced pressure to afford 7-amino-1,2,3,4-tetra-hydro-naphthalen-2-ol enantiomer.

The other enantiomer of 7-amino-1,2,3,4tetrahydronaphthalen-2-ol was obtained in the same fashion replacing (1S,2R)-(-)-cis-1-amino-2-indanol with (1R,2S)-(+)-cis-1-amino-2-indanol.

[Starting Compound C]

(7-hydroxy-5,6,7,8tetrahydro-naphthalen-2-yl)-carbamic acid phenyl ester

To a stirred solution of 7-amino-1,2,3,4-tetrahydro-naphthalen-2-ol and pyridine in THF was added phenyl chloroformate, and the mixture was stirred for 1 hour at room temperature. To the product mixture was added water and extracted with ethylacetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The obtained residue was triturated with ethylacetate and hexane to afford (7-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-carbamic acid phenyl ester.

Example 1-1

N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)urea

A mixture of 7-amino-1,2,3,4-tetrahydronaphthalen-2-ol (70.0 mg, 0.43 mmol) and 4-chloro-3-trifluoromethylphenyl isocyanate (95.0 mg, 0.43 mmol) in N,N-dimethylformide (10 mL) was stirred at 50° C. for 2 hours. After the mixture was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent: ethylacetate/hexane=2.5/1) to provide N-[4-chloro-3-trifluoromethyl)phenyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)urea (49.9 mg).

MS (ESI) m/z 385 [M+H]⁺

• ¹H NMR (DMSO-d6) δ1.59-1.63 (m, 1H), 1.80-1.88 (m, 1H), 2.56 (dd, J=7.9, 16.1 Hz, 1H), 2.65 (dq, J=9.5, 16.7 Hz, 1H), 2.78 (dt, J=5.4, 16.7 Hz, 1H), 2.89 (dd, J=5.4, 16.1 Hz, 1H), 3.89 (m, 1H), 4.73 (d,J=6.0 Hz, 1H), 5.97 (d,J=8.2 Hz, 1H), 7.13 (dd, J=2.3, 8.2 Hz, 1H), 7.16 (d, J=2.3, 1H), 7.58-7.62 (m, 2H), 8.10 (d, J=2.0 Hz, 1H), 8.62 (s, 1H), 9.06 (s, 1H).

Also, the following compounds are prepared in a similar manner.

Example	A	m	p	—X—	Y	—R
1-2		0	0	bond	N
1-3		1	0	bond	C
1-4		0	1	bond	C
1-5		0	1	—O—	C
1-6		0	0	—O—	C
1-7		0	2	—NH—	C
1-8		0	2	—NH—	N
1-9		0	0	bond	C
1-10		0	0	bond	C
1-11		0	0	—O—	N
1-12		0	2	—O—	N
1-13		0	1	—NH—	N
1-14		1	1	bond	N
1-15		1	2	bond	N
1-16		1	2	bond	N
1-17		1	2	bond	C
1-18		0	1	bond	C
1-19		0	1	—O—	C
1-20		0	2	—O—	C
1-21		0	0	—NH—	C
1-22		1	1	bond	N
1-23		1	1	bond	N

Claims

1. A bicyclic amide, carbamate or urea derivative of formula (I), its tautomeric or stereoisomeric form, or a salt thereof:

2. The bicyclic amide, carbamate or urea derivative of formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1,

3. The bicyclic amide, carbamate or urea derivative of formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1,

4. The bicyclic amide, carbamate or urea derivative of formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1,

5. The bicyclic amide, carbamate or urea derivative of formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1,

6. The bicyclic amide, carbamate or urea derivative of formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1,

7. The bicyclic amide, carbamate or urea derivative of formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1,

8. The bicyclic amide, carbamate or urea derivative of formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1, wherein said bicyclic amide, carbamate or urea derivative of the formula (I) is selected from the group consisting of:

9. A pharmaceutical composition comprising a bicyclic amide, carbamate or urea derivative of formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof as claimed in claim 1 as an active ingredient.

10. The pharmaceutical composition as claimed in claim 9, further comprising one or more pharmaceutically acceptable excipients.

11. The pharmaceutical composition as claimed in claim 9, wherein said bicyclic amide, carbamate or urea derivative of formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof is a VR1 antagonist.

12. A method for the treatment and/or prevention of an urological disorder or disease comprising administering to a subject in need thereof a therapeutically effective amount of at least one bicyclic amide carbamate or urea derivative of formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof as claimed in claim 1.

13. The method as claimed in claim 12, wherein said urological disorder or disease is urge urinary incontinence or overactive bladder.

14. A method for the treatment and/or prevention of pain comprising administering to a subject in need thereof a therapeutically effective amount of at least one bicyclic amide, carbamate or urea derivative of formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof as claimed in claim 1.

15. The method as claimed in claim 14, wherein said pain is chronic pain, neuropathic pain, postoperative pain, or rheumatoid arthritic pain.

16. A method for the treatment and/or prevention of a disorder or disease related to pain comprising administering to a subject in need thereof a therapeutically effective amount of at least one bicyclic amide, carbamate or urea derivative of formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof as claimed in claim 1.

17. The method as claimed in claim 16, wherein said disorder or disease related to pain is neuralgia, neuropathies, algesia, nerve injury, ischaemia, neurodegeneration, or stroke.

18. A method for the treatment and/or prevention of an inflammatory disorder or disease comprising administering to a subject in need thereof a therapeutically effective amount of at least one bicyclic amide, carbamate or urea derivative of formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof as claimed in claim 1.

19. The method as claimed in claim 18, wherein said inflammatory disorder or disease is asthma or COPD.

20. (canceled)

21. (canceled)

22. (canceled)

23. (canceled)

24. (canceled)

25. (canceled)