PT1506167E - Hydroxy tetrahydro-naphthalenylurea derivatives - Google Patents

Description

DESCRIPTION " HYDROXY-TETRA-HYDRO-NAFTALENILUREIA DERIVATIVES "

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD The present invention relates to hydroxy-tetrahydro-naphthalenylurea derivatives which are useful as an active ingredient of pharmaceutical preparations. The hydroxy-tetrahydro-naphthalenylurea derivatives of the present invention have vanilloid receptor (VR) antagonist activity and can be used for the prophylaxis and treatment of diseases associated with VR1 activity, in particular, for the treatment of urinary incontinence of urgency, overactive bladder, chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritis pain, neuralgia, neuropathies, algesia, nerve damage, ischemia, neurodegeneration, stroke, incontinence and / or inflammatory disorders such as asthma and chronic obstructive pulmonary disease (COPD). Urinary incontinence (UI) is the involuntary loss of urine. Urge incontinence (UUI) is one of the most common types of UI in conjunction with stress urinary incontinence (SUI), which is usually caused by a defect in the urethral closure mechanism. UUI is often associated with disorders or neurological diseases that cause neuronal damage, such as dementia, Parkinson's disease, multiple sclerosis, stroke and diabetes, although it also occurs in individuals without these disorders. One of the normal causes of UUI is overactive bladder (OAB), which is a medical condition that refers to the symptoms of frequency and urgency derived from abnormal contractions and instability of the detrusor muscle.

Currently, there are several medicines for urinary incontinence on the market, mainly to assist in the treatment of UUI. OAB therapy is focused on drugs that affect peripheral neuronal control mechanisms or those that act directly on bladder detrusor smooth muscle contraction, with greater emphasis on the development of anticholinergic agents. These agents may inhibit parasympathetic nerves that control bladder emptying or may exert a direct spasmolytic effect on the detrusor bladder muscle. This results in a decrease in intravesical pressure, an increase in capacity and a reduction in the frequency of bladder contraction. Active oral anticholinergic drugs such as propantheline (ProBanthine), tolterodine tartrate (Detrol) and oxybutynin (Ditropan) are the most commonly prescribed drugs. However, its most serious disadvantages are unacceptable side effects, such as dry mouth, abnormal vision, constipation and central nervous system disorders. These side effects lead to poor compliance by patients. Only the dry mouth symptoms are responsible for a patient's failure rate of 70% with oxybutynin. The shortcomings of the present therapies highlight the need for new effective, safe and orally available new drugs which have fewer side effects. 2

BACKGROUND TECHNIQUE

Vanyloid compounds are characterized by the presence of a vanillyl group or a functionally equivalent group. Examples of various vanilloid compounds or vanilloid receptor modulators are vanillin (4-hydroxy-3-methoxybenzaldehyde), guaiacol (2-methoxyphenol), zingerone (4-4-hydroxy-3-methoxyphenyl) -2-butanone ), eugenol- (2-methoxy4- / 2-propenyl / phenol) and capsaicin (8-methyl-N-vanillyl-6-nonene-amide).

Among others, capsaicin, the most potent main ingredient in hot peppers, is a specific neurotoxin that desensitizes afferent neurons by C fibers. Capsaicin interacts with vanyloid receptors (VIR), which are predominantly expressed in bodies dendritic cell ganglia (DRG) or nerve endings of afferent sensory fibers, including nerve endings of C fibers [Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, Raumann BE, Basbaum AI, Julius D : The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron. 21: 531-543, 1998]. The VR1 receptor was recently cloned [Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D: Nature 389: 816-824, (1997)] and identified with a non-selective cation channel with six transmembrane domains that is structurally related to the family of TRP (transient potential receptor) channels. The binding of capsaicin to the RVR allows the reduction of the concentration gradients of the sodium, calcium and possibly potassium ions, causing the initial depolarization and release of the neurotransmitters from the nerve terminals. VR1 can therefore be regarded as a molecular member of the chemical and physical stimulus that induces neuronal signals in diseases or disease states.

There is much evidence, either direct or indirect, that demonstrates the relationship between IRR activity and diseases, such as pain, ischemia and inflammation (e.g., WO 99/00115 and 00/50387). In addition, it has been shown that VRl translates the reflex signals that are involved in the overactive bladder of patients who have abnormal or damaged spinal reflex pathways [De Groat WC: A neurologic basis for the overactive bladder. Urology 50 (Suppl 6A): 36-52, 1997]. Desensitization of afferent nerves by neurotransmitter depletion using RVR agonists such as capsaicin has been shown to provide promising results in the treatment of bladder dysfunction associated with spinal cord injury and multiple sclerosis (Maggi CA: Therapeutic potential of capsaicin- (Molecular Biology and Molecular Biology, University of California, Los Angeles, California, USA) and (DeRidder D, Chandiramani V, Dasgupta P, VanPoppel H, Baert L, Fowler CJ: Intravesical capsaicin as a treatment for refractory detrusor hyperreflexia: A dual center study with long-term followup J. Urol 158: 2087-2092 (1997)].

VR1 receptor antagonism is predicted to result in blocking the release of neurotransmitters, resulting in the prophylaxis and treatment of the pathology and diseases associated with the RVR activity. It is thus expected that the VR1 receptor antagonists may be used for the prophylaxis and treatment of pathology and diseases, including chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritis type pain, neuralgia, neuropathies, algesia , nerve damage, ischemia, neurodegeneration, stroke, incontinence, inflammatory disorders such as asthma and CODP, urinary incontinence (UI), such as urge urinary incontinence (UUI) and / or overactive bladder. WO 00/50387 discloses the compounds having a vanilloid agonist activity represented by the general formula:

on what; XP is an oxygen or sulfur atom; AP is -nhch2- or -ch2-;

Ra is a substituted or unsubstituted C 1-4 alkyl group, or Ral CO-; on what

Ral is an alkyl group having 1 to 18 carbon atoms, an alkenyl group having 2 to 18 carbon atoms or a substituted or unsubstituted aryl group having 6 to 10 carbon atoms;

Rb is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms or a halogen atom;

Rc is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aminoalkyl, a diacid monoester or α-alkyl acid; and the asterisk * denotes a chiral carbon atom, and pharmaceutically acceptable salts thereof. WO 2000/61581 discloses amine derivatives represented by the general formula:

R "

NH

(CF3, H) or (iPr, iPr) as useful agents for diabetes, hyperlipemia, arteriosclerosis and cancer. WO 00/75106 discloses the compounds represented by the general formula:

NH N-Z, 90

in which Z represents

O

7 or

In which R 90 is hydrogen, C 1-2 alkyl, C 3-8 cycloalkyl or the like, and R 91 is amino C 1-6 alkyl, aminocarbonyl-C 1-6 alkyl or hydroxyaminocarbonylC 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; as useful agents for the treatment of MMP-mediated diseases in mammals. WO 00/55152 discloses the compounds represented by the general formula:

X

In what

An is heterocycle; 8 is tetrahydronaphthyl; and

Ar 2 L and Q are defined in this description; as useful agents for the treatment of inflammation, related immune disease, pain and diabetes.

However, none of these references disclose single hydroxy-tetrahydronaphthenylurea derivatives with IRR antagonist activity. The development of a compound which exhibits effective RVR antagonist activity and may be used for the prophylaxis and treatment of diseases associated with RVR activity, in particular, for the treatment of urinary incontinence, urge incontinence, overactive bladder, as well as pain and / or inflammatory diseases such as asthma and COPD.

SUMMARY OF THE INVENTION

This invention provides a hydroxy-tetrahydro-naphthalenylurea derivative of the formula (I), its tautomeric and stereoisomeric form and salts thereof: wherein

or in which: Y represents a direct bond,

R1, R2 and R3 are independently hydrogen, halogen, hydroxy, nitro, carboxyl, amino, C1-6 alkylamino, di (C1-6 alkyl) amino, C3-8 cycloalkylamino, C1-6 alkoxycarbonyl, phenyl, benzyl, sulfonamide, C1-6 alkanoyl, C1-6 alkanoylamino, carbamoyl, C1-6 alkylcarbamoyl, cyano C 1-6 alkyl optionally substituted with cyano, C 1-6 alkoxycarbonyl or mono-, di- or trihalogen, C 1-6 alkoxy optionally substituted with mono-, di- or trihalogen, phenoxy optionally substituted with halo or C 1-6 alkyl or optionally substituted C 1-6 alkylthio substituted with mono-, di- or tri-halogen; R4, R5, R6 and R7 independently represent C1-6 alkyl or phenyl; Z 1 represents hydrogen or C 1-6 alkyl; and Z 2 represents hydrogen, halogen or C 1-6 alkyl

The hydroxy-tetrahydro-naphthalenylurea derivatives of formula (I), their tautomeric and stereoisomeric form and their salts, surprisingly exhibit excellent VR1 antagonist activity. They are therefore especially suitable for the prophylaxis and treatment of diseases associated with VR1 activity, in particular, for the treatment of urge urinary incontinence and / or overactive bladder.

Preferably, the hydroxy-tetrahydro-naphthalenyl urea derivatives of formula (I) are those wherein X represents

or wherein Y represents a direct bond, or

R1, R2 and R3 are independently hydrogen, halogen, hydroxy, nitro, carboxyl, amino, C1 -C6 alkylamino, di (C1 -C6 alkyl) amino, C3 -C8 cycloalkylamino, C1-6 alkoxycarbonyl, phenyl, benzyl, sulfonamide, C1-6 alkanoyl, alkanoylC1-6 alkoxy, carbamoyl, C1-6 alkylcarbamoyl , cyano, C1-6 alkyl optionally substituted with cyano, C1-6 alkoxycarbonyl or mono-, di- or trihalogen, C1-6 alkoxy optionally substituted with mono-, di- or trihalogen, phenoxy optionally substituted with halogen or C1-6 alkyl or C1-6 alkylthio optionally substituted with mono -, di- or tri-halogen; R 4 and R 5 independently represent hydrogen or C 1-6 alkyl, and Z 1 and Z 2 each represent hydrogen.

In another embodiment, the hydroxy-tetrahydro-naphthalenylurea derivatives of formula (I) may be those wherein

X represents

or in which Y represents a direct or

R1, R2 and R3 independently represent hydrogen, halogen, hydroxy, nitro, carboxyl, amino, C1-6 alkylamino, di (C1-5 alkyl) amino, C3-8 cycloalkylamino, C1-6 alkoxycarbonyl, phenyl, benzyl, sulfonamide, C1-6 alkanoyl, C1-6 alkanoylamino, carbamoyl, C1-6 alkylcarbamoyl, cyano, Optionally substituted with cyano, C 1-6 alkoxycarbonyl or mono-, di- or trihalogen, C 1-6 alkoxy optionally substituted with mono-, di- or trihalogen, phenoxy optionally substituted by halogen or C 1-6 alkyl or C 1-6 alkylthio optionally substituted with mono-, di - or tri-halogen; R 4 and R 5 each represent hydrogen; and Z 1 and Z 2 each represent hydrogen.

In another embodiment, the hydroxy-tetrahydro-naphthalenylurea derivatives of formula (I) may be those wherein

X represents

in which Y represents a direct or

R4, R4, R4, R4, R4, R4, R4, R4, R4, R3, R4 and R5 each represent hydrogen; and Z1 and Ζ2 each represent hydrogen.

In another embodiment, the hydroxy-tetrahydro-naphthalenylurea derivatives of formula (I) may be those wherein X represents

in which Y represents a direct bond or R 5 R 4 in which R 1 and R 2 are independently hydrogen, chlorine, bromine, fluoro, cyclopentylamino, trifluoromethyl or trifluoromethoxy; R3, R4 and R5 each represent hydrogen; and Z 1 and Z 2 each represent hydrogen. 15

More preferably, said hydroxy-tetrahydro-naphthalenylurea derivative of the formula (I) is selected from the group consisting of: N- [4-chloro-3- (trifluoromethyl) phenyl] -β- (7- hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea; N- (3-chlorophenyl) -N '- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea; N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -3 '- [3- (trifluoromethyl) phenyl] urea; N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -3 '- [4- (trifluoromethyl) phenyl] urea; Ethyl 3 - ({[(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) amino] carbonyl} amino) benzoate; N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '- (1-naphthyl) urea; N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '- (2-naphthyl) urea; N- (3,4-dichlorophenyl) -N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea; N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '- (4-isopropylphenyl) urea; 16β- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) - (4-phenoxyphenyl) urea. N- [4-chloro-3- (trifluoromethyl) phenyl] -β- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] urea; (trifluoromethyl) phenyl] - [(7S) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] urea: N- [4-chloro-3- (trifluoromethyl) phenyl] [(7R) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] urea: N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -1-phenylurea N - (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea; N- (7-hydroxy-5,6,7,8- tetrahydro-1-naphthalenyl) -N '- [2- (trifluoromethyl) phenyl] urea; N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) 4- (trifluoromethyl) phenyl] urea; N- (3,4-dichlorophenyl) -N '- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea; -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '- [4- (trifluoromethoxy) phenyl] urea; naphthalenyl) -N- [4- (trifluoromethoxy) benzyl] urea; 17β- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) 4,6-trimethoxybenzyl) urea; N- (2,6-difluorobenzyl) -N '- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea; - [(7R) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] -3 '- [4- (trifluoromethyl) benzyl] urea; N - [(7S) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] -N '- [4- (trifluoromethyl) benzyl] urea; N - [(7R) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] -3 '- [4- (trifluoromethoxy) benzyl] urea; N - [(7S) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] -3 '- [4- (trifluoromethoxy) benzyl] urea; N- [2- (4-chlorophenyl) ethyl] -N '- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea; and N- [3-fluoro-4- (trifluoromethyl) benzyl] -N '- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea.

In the context of the present invention, the substituents, unless otherwise noted, generally have the following meanings: Alkyl per se and " alc " and " alkyl " alkylaminocarbonyl, alkylaminosulfonyl, alkylsulfonylamino, alkoxycarbonyl, alkoxycarbonylamino and alkanoylamino groups represent a linear or branched alkyl radical with generally 1 to 6, preferably 1 to 4, and, in a preferred manner, particularly preferred, 1 to 3 carbon atoms, illustratively and preferably, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl. The alkoxy represents, in an illustrative and preferred manner, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy. The alkanoyl represents, in an illustrative and preferred manner, acetyl and propanoyl. The alkylamino represents an alkylamino radical containing one or two (independently selected) alkyl substituents, in an illustrative and preferred manner, representing methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N , N-dimethylamino, N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, N-isopropyl-Nn-propylamino, Nt -butyl-N-methylamino, N-ethyl-Nn-pentylamino and N-hexyl-N-methylamino. The alkylaminocarbonyl or alkylcarbamoyl radicals represent an alkylaminocarbonyl radical having one or two (independently selected) alkyl substituents, illustratively and preferably methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n- N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N-propylaminocarbonyl, N-isopropyl-N-propylaminocarbonyl, N-butyl-N-methylaminocarbonyl, N-ethyl- N-pentylaminocarbonyl and N-hexyl-N-methylaminocarbonyl. The alkoxycarbonyl represents, in an illustrative and preferred manner, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexyloxycarbonyl. The alkoxycarbonylamino represents, in an illustrative and preferred manner, methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, tert-butoxycarbonylamino, n-pentoxycarbonylamino and n-hexyloxycarbonylamino. The alkanoylamino represents, in an illustrative and preferred manner, acetylamino and ethylcarbonylamino. The cycloalkyl per se and in cycloalkylamino and in cycloalkylcarbonyl represents a cycloalkyl group with generally 3 to 8 and preferably 5 to 7 carbon atoms, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclo cyclohexyl and cycloheptyl. The cycloalkylamino represents a cycloalkylamino radical with one or two (independently selected) cycloalkyl substituents representing, preferably cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino and cycloheptylamino. The halogen represents fluorine, chlorine, bromine and iodine. 20

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

The hydroxy-tetrahydro-naphthalenylurea derivatives of the formula (I), their tautomeric and stereoisomeric form and their salts are effective for the treatment or prevention of a disease selected from the group consisting of urge urinary incontinence, overactive bladder, pain chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritis pain, neuralgia, neuropathies, algesia, nerve damage, ischemia, neurodegeneration and / or stroke, as well as inflammatory diseases such as asthma and COPD, since the diseases are also related to the RVR activity.

The compounds are further useful in the treatment and prophylaxis of neuropathic pain, which is a form of pain, often associated with herpes zoster and post-herpes neuralgia, painful diabetic neuropathy, neuropathic low back pain, post-traumatic and postoperative neuralgia , neuralgia due to nerve compression and other neuralgia, phantom pain, complex regional pain syndromes, infectious or para-infectious neuropathies such as those associated with HIV infection, pain associated with central nervous system disorders such as multiple sclerosis or disease of Parkinson's disease or spinal cord injury or traumatic brain injury and post-stroke pain.

In addition, the compounds are useful for the treatment of musculoskeletal pain, a form of pain often associated with osteoarthritis or rheumatoid arthritis or other forms of arthritis and back pain. 21

In addition, the compounds of the present invention are useful for the treatment of pain associated with cancer, including visceral or neuropathic pain associated with cancer or treatment of cancer.

The compounds are furthermore useful for the treatment of visceral pain, e.g. pain associated with obstruction of hollow viscera such as biliary colic, pain associated with irritable bowel syndrome, pelvic pain, vulvodynia, orchitis, or prostatodynia.

The compounds are also useful for the treatment of pain associated with inflammatory lesions of the joints, skin, muscles or nerves.

The compounds are of use for the treatment of orofacial pain and migraine, e.g. headache or tension-type migraine.

The compound of the formula (I) of the present invention may be, but is not limited to, the preparation of the compounds [A], [B], [C], [D], [E], [F] or [G] below. In some embodiments, one or more of the substituents, such as amino group, carboxyl group and hydroxyl group of the compounds used as starting materials or intermediates, are advantageously protected by a protecting group known to those skilled in the art. Examples of the protecting groups are described in " Protective Groups in Organic Synthesis 22 (3rd Edition) " by Greene and Wuts, John Wiley and Sons, New York 1999.

[Method A]

The compound of formula (I) (wherein X, Z 1 and Z 2 are as defined above) may be prepared by the reaction of the compound of formula (II) (wherein Z 1 and Z 2 are as defined above) and isocyanato ) (wherein X is as defined above). The reaction may be carried out in a solvent, including, for example, halogenated hydrocarbons, such as dichloromethane, chloroform and 1,2-dichloroethane; ethers, such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons, such as benzene, toluene and xylene; nitriles, such as acetonitrile; amides, such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP); urea, such as 1,3-dimethyl-2-imidazolidinone (DMI); sulfoxides, such as dimethylsulfoxide (DMSO); and others. Optionally, two or more of the solvents selected from the above list may be mixed and used. The reaction may be carried out in the presence of organic base, such as pyridine or triethylamine. The reaction temperature may optionally be set depending on the compounds to be reacted. The reaction temperature is usually but not limited to at about room temperature to 100 ° C. The reaction may be effected for usually 30 minutes to 48 hours, and preferably 1 to 24 hours. The compound of formula (II) and isocyanate (III) are commercially available or can be prepared by known techniques.

[Method B]

phosgene, diphosgene, + triphosgene, + CDI or CDT h2n (IV)

The compound of formula (I) (wherein X, Z 1 and Z 2 are as defined above) can be prepared by reacting the compound of formula (II) (wherein Z 1 and Z 2 are as defined above) with phosgene, diphosgene , triphosgene, 1,1-carbonyldiimidazole (CDI) or 1,1'-carbonyldi (1,2,4-triazole) (CDT), and then addition of the compound of formula (IV) (wherein X is such as defined above) to the reaction mixture. The reaction may be carried out in a solvent, including, for example, halogenated hydrocarbons, such as dichloromethane, chloroform and 1,2-dichloroethane; ethers, such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons, such as benzene, toluene and xylene; nitriles, such as acetonitrile; amides, such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP); urea, such as 1,3-dimethyl-2-imidazolidinone (DMI); and others. Optionally, two or more of the solvents selected from the above list may be mixed and used. The reaction temperature may be optionally set depending on the compounds to be reacted. The reaction temperature is usually, but not limited to, about 20 ° C to 50 ° C. The reaction may be effected for usually 30 minutes to 10 hours, and preferably 1 to 24 hours. Phosgene, diphosgene, triphosgene, CDI, CDT are commercially available and the compound of formula (IV) is commercially available or can be prepared by the use of known techniques. 25 [Method C]

The compound of formula (I) (wherein X, Z 1 and Z 2 are as defined above) can be prepared by the reaction of the compound of formula (II) (wherein Z 1 and Z 2 are as defined above) and the compound of formula formula (V) (wherein Li represents a halogen atom such as chlorine, bromine or iodine), and then the compound of formula (IV) (wherein X is as defined above) is added to the reaction mixture. The reaction may be carried out in a solvent, including, for example, halogenated hydrocarbons, such as dichloromethane, chloroform and 1,2-dichloroethane; ethers, such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons, such as benzene, toluene and xylene; nitriles, such as acetonitrile; amides, such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP); urea, such as 1,3-dimethyl-2-imidazolidinone (DMI); and others. Optionally, two or more of the solvents selected from the above list may be mixed and used. The reaction temperature may be optionally set depending on the compounds to be reacted. The reaction temperature is usually, but not limited to, about 30 ° C to 120 ° C. The reaction may be effected for, usually 1 hour to 48 hours, and preferably 2 to 24 hours. The reaction may advantageously be carried out in the presence of a base including, for example, organic amines, such as pyridine, triethylamine and N, N-diisopropylethylamine, dimethylaniline, diethylaniline, 4-dimethylaminopyridine and the like. Compound (V) is commercially available or can be prepared by the use of known techniques.

[Method D]

The compound of formula (I) (wherein X, Z 1 and Z 2 are as defined above) may be prepared by reacting the compound of formula (IV) (wherein X is as defined above) with phosgene, diphosgene, triphosgene , 1,1-carbonyldiimidazole 27 (GDI) or 1,1'-carbonyldi (1,2,4-triazole) (CDT) and then added the compound of formula (II) (wherein Z 1 and Z 2 are as defined above) defined above) to the reaction mixture. The reaction may be carried out in a solvent, including, for example, halogenated hydrocarbons, such as dichloromethane, chloroform and 1,2-dichloroethane; ethers, such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons, such as benzene, toluene and xylene; nitriles, such as acetonitrile; amides, such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP); urea, such as 1,3-dimethyl-2-imidazolidinone (DMI); sulfoxides, such as dimethylsulfoxide (DMSO); and others. Optionally, two or more of the solvents selected from the above list may be mixed and used. The reaction temperature may optionally be set depending on the compounds to be reacted. The reaction temperature is usually, but not limited to, about 30 ° C to 100 ° C. The reaction may be effected for usually 30 minutes to 40 hours, and preferably 1 to 24 hours. 28 [Method E] NH 2 h 2n

(Wherein X, Z 1 and Z 2 are as defined above) can be prepared by the reaction of the compound of formula (IV) (wherein X is as defined above) defined above) and the compound of formula (V) (wherein L x represents a halogen atom, such as a chlorine, bromine or iodine atom), and then the compound of formula (II) (wherein z 1 and z 2 are as defined above) to the reaction mixture. The reaction may be carried out in a solvent, including, for example, halogenated hydrocarbons, such as dichloromethane, chloroform and 1,2-dichloroethane; ethers, such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons, such as benzene, toluene and xylene; nitriles, such as acetonitrile; amides, such as N, N-dimethylformamide (DMF), Ν, Ν-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP); urea, such as 1,3-dimethyl-2-imidazolidinone (DMI); and others. Optionally, two or more of the solvents selected from the above list may be mixed and used. The reaction temperature may optionally be set depending on the compounds to be reacted. The reaction temperature is usually, but not limited to, about 30 ° C to 120 ° C. The reaction may be effected for usually 1 hour to 48 hours, and preferably 2 to 24 hours. The reaction may advantageously be carried out in the presence of a base including, for example, organic amines, such as pyridine, triethylamine and N, N-diisopropylethylamine, dimethylaniline, diethylaniline, 4-dimethylaminopyridine and the like.

[Method F]

Step F-1 The procedure similar to that described in Method [λ] [E], using (VI) instead of (II)

Step F-2

(VIII) (0

Step F-4

HC Z

The compound of formula (I ') (wherein X and Z 2 are as defined above) can be prepared by the following processes;

In Step F, the compound of formula (VII) (wherein X and Z 2 are as defined above) can be prepared, similarly to that described in Method [A], [B], [C], [D] or [E] for the preparation of the compound of formula (I), by use of a compound of formula (VI) (wherein Z 2 is as defined above) instead of a compound of formula (II).

In Step F-2, the compound of formula (VIII) (wherein X and Z 2 are as defined above) can be prepared by reacting the compound of formula (VII) (wherein X and Z 2 are as defined above) with an acid, such as hydrochloric acid. The reaction may be carried out in a solvent including, for example, halogenated hydrocarbons, such as dichloromethane, chloroform and 1,2-dichloroethane; ethers, such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; alcohols, such as methanol, ethanol; water and others. Optionally, two or more solvents selected from the above list may be mixed and used. The reaction temperature may optionally be set depending on the compounds to be reacted. The reaction temperature is customary, but not limited to, about 20 ° C to 100 ° C. The reaction may be effected for usually 30 minutes to 10 hours, and preferably 1 to 24 hours. 31

In Step F-3, the compound of formula (I ') (wherein X and Z 2 are as defined above) can be prepared by the reaction of the compound of formula (VIII) (wherein X and Z 2 are as defined above ) with reducing agent such as sodium borohydride or lithium aluminum hydride. The reaction may be carried out in a solvent, including, for example, ethers, such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (thf) and 1,2-dimethoxyethane; alcohols, such as methanol, ethanol, isopropanol and the like. Optionally, two or more solvents selected from the above list may be mixed and used. The reaction temperature may be optionally set depending on the compounds to be reacted. The reaction temperature is usually, but not limited to, about -20 ° C to 50 ° C. The reaction may be effected for usually 30 minutes to 10 hours, and preferably 1 to 24 hours. The compound of formula (I ") (wherein X and Z 2 are as defined above and Z 1 is C 1-6 alkyl) may be prepared by the following processes, in two steps.

In Step F-4, the compound of formula (IX) (wherein X and Z 2 are as defined above and Z 3 is hydrogen or C 1-5 alkyl) may be prepared by reaction of the compound of formula (VIII) (wherein X and Z 2 are as defined above) with tri (C1-6 alkyl) oxosulfonium salt, such as trimethyloxosulfonium iodide. The reaction can be carried out in a solvent, including, for example, ethers, such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aliphatic hydrocarbons, such as n-hexane, cyclohexane; aromatic hydrocarbons, such as benzene, toluene and xylene; and others. Optionally, two or more solvents selected from the above list may be mixed and used. The reaction temperature may be optionally set depending on the compounds to be reacted. The reaction temperature is usually, but not limited to, about -20 ° C to 50 ° C. The reaction may be effected for usually 30 minutes to 10 hours, and preferably 1 to 24 hours.

In Step F-5, the compound of formula (I ") (wherein X and Z 2 are as defined above and Z 1 is C 1-6 alkyl) may be prepared by reacting the compound of formula (IX) (wherein X is Z 2 are as defined above and Z 3 is hydrogen or C 1-5 alkyl) with reducing agent such as sodium borohydride or lithium aluminum hydride. The reaction may be carried out in a solvent, including, for example, ethers, such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aliphatic hydrocarbons, such as n-hexane, cyclohexane; aromatic hydrocarbons, such as benzene, toluene and xylene; and others. Optionally, two or more solvents selected from the above list may be mixed and used. The reaction temperature may optionally be set depending on the compounds to be reacted. The reaction temperature is usually, but not limited to, about 20 ° C to 50 ° C. The reaction may be effected for usually 30 minutes to 10 hours, and preferably 1 to 24 hours. The compound (VI) is commercially available or can be prepared by the use of known techniques.

[Method G]

A procedure similar to that described in Method [A] - [Ξ], using (II-a ') instead of (II) -> ) instead of (II) ->

The stereoisomeric form of the compound (I), form R (Ia) form R (Ia) (wherein X, Z 2 and Z 2 are as defined above) may be prepared, in a manner similar to that described in Method [A], [B ], [C], [D] or [E] for the preparation of the compound of formula (I), using a compound of formula (II-a) (wherein Z 1 and Z 2 are as defined above) of formula (II). The stereoisomeric form of the compound (I), form S (i-a ') (wherein X, Z 1 and Z 2 are as defined above) can be prepared, in a manner similar to that described in Method [A], [B], [C], [D] or [E] for the preparation of the compound of formula (I), by use of a compound of formula (ii-a ') (wherein Z 1 and Z 2 are as defined above) compound of formula (II). The compound (II-a) or (II-a ') may be prepared by the use of known techniques.

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

Typical salts of the compound represented by formula (I) include salts prepared by the reaction of the compounds of the present invention with an organic or mineral acid, or an organic or inorganic base. Such salts are known as acid addition and base addition salts, respectively.

Acids for forming acid addition salts include inorganic acids such as, without limitation, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid and the like and organic acids, such as, without limitation, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like.

The base addition salts include those derived from inorganic bases, such as, without limitation, ammonium hydroxide, alkali metal hydroxide, alkaline earth metal hydroxides, carbonates, bicarbonates and the like, and organic bases, such as, without limitation, ethanolamine, triethylamine, tris (hydroxymethyl) aminomethane and the like. Examples of inorganic bases include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate and the like. The compound of the present invention or a salt thereof, depending on the substituents thereof, may be modified to form lower alkyl esters or other known esters; and / or hydrates or other solvates. Such esters, hydrates and solvates are included within the scope of the present invention. The compound of the present invention may be administered in oral forms, such as, without limitation, normal or enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solution, suspensions, syrups, solid and liquid aerosols and emulsions. It may also be administered in parenteral forms, such as, without limitation, intravenously, intraperitoneally, subcutaneously, intramuscularly and the like, well known to those skilled in the pharmaceutical art. The compounds of the present invention may be administered in intranasal form via topical use of suitable intranasal vehicles or through transdermal routes using transdermal delivery systems well known to those skilled in the art. The dosage regimen with the use of the compounds of the present invention is selected by a person skilled in the art, taking into account various factors including, without limitation, age, weight, sex and medical condition of the recipient, severity of the condition being treated, the route of administration, the level of metabolic function and excretion of the receptor, the dosage form employed, the particular compound and its salt employed.

The compounds of the present invention are preferably formulated prior to administration in combination with one or more pharmaceutically acceptable excipients. Excipients are inert substances such as, but not limited to, vehicles, diluents, flavoring agents, sweeteners, lubricants, solubilizers, suspending agents, binders, tablet disintegrating agents and encapsulating material.

Yet another embodiment of the present invention is the pharmaceutical formulation comprising a compound of the invention and one or more pharmaceutically acceptable excipients which are compatible with the other ingredients of the formulation and are not detrimental to its recipient. The pharmaceutical formulations of the invention are prepared by combining a therapeutically effective amount of the compounds of the invention together with one or more of these pharmaceutically acceptable excipients. In preparing the compositions of the present invention, the active ingredient may be mixed with a diluent or encapsulated within a carrier which may be in the form of a capsule, sachet, paper or other receptor. The carrier may function as a diluent, which may be a solid, semi-solid or liquid material which acts as a carrier or may be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, containing, for example, up to 10% by weight of the active compound, hard and soft gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

For oral administration, the active ingredient may be combined with an oral and non-toxic pharmaceutically acceptable carrier, such as, without limitation, lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, methylcellulose and the like; together with, optionally, disintegrating agents, such as, without limitation, corn, starch, methylcellulose, agar, bentonite, xanthan gum, alginic acid and the like; and optionally binding agents, for example, without limitation, gelatin, natural sugars, beta-lactose, corn sweeteners, natural and synthetic gums, acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like; and optionally lubricating agents, for example, without limitation, magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate, sodium acetate, sodium chloride, talc and the like.

In the powder forms, the carrier may be a finely divided solid which is mixed with the finely divided active ingredient. The active ingredient may be mixed with a carrier having binding properties, in suitable proportions, and compacted in the desired shape and size, to produce tablets. The powders and tablets preferably contain from about 1 to about 99 percent by weight of the active ingredient which is the novel composition of the present invention. Suitable solid carriers are magnesium carboxymethylcellulose, low melting waxes and cocoa butter.

Sterile liquid formulations include suspensions, emulsions, syrups and elixirs. The active ingredient may be dissolved or suspended in pharmaceutically active carriers, such as sterile water, sterile organic solvent or a mixture of both, sterile water and sterile organic solvent. The active ingredient may also be dissolved in a suitable organic solvent, for example, aqueous propylene glycol. Other compositions may be prepared by dispersing the finely divided active ingredient in aqueous starch or sodium carboxymethylcellulose solution or in a suitable oil. The formulation may be in unit dosage form, which is a physically discrete unit containing a single dose, suitable for administration to humans or other mammals. A unit dosage form may be a capsule or tablets or several capsules or tablets. A " unit dose " is a predetermined amount of the active compound of the present invention, calculated to produce the desired therapeutic effect, in association with one or more excipients. The amount of the active ingredient in a unit dose can be varied or adjusted from about 0.1 to about 1000 milligrams or more, according to the particular treatment involved.

Typical oral dosages of the present invention, when used for the indicated effects, will range from about 0.01 mg / kg / day to about 100 mg / kg / day, preferably from 0.1 mg / kg / day to 30 mg / kg / day, and most preferably from about 0.5 mg / kg / day to about 10 mg / kg / day. In the case of parenteral administration, it has generally been found to be advantageous to administer an amount of about 0.001 to 100 mg / kg / day, preferably from 0.01 mg / kg / day to 1 mg / kg / day. The compounds of the present invention may be administered in a single daily dose or the total daily dose may be administered in divided doses two, three or more times per day. When the delivery is via transdermal forms, of course, administration is continuous.

EXAMPLES The present invention will be described in the form of examples, but should not be understood in any way as defining objectives and limits of the present invention.

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

Mass spectra were obtained using electrospray ionization (ES) techniques (micromass Platform LC). The melting points are not corrected. Liquid Chromatography Mass Spectroscopy (LC-MS) data were recorded on a Micromass Platform LC with Shimadzu Phenomenex ODS column (4.6 ιηιηφ X 30 mm) eluting with a mixture of acetonitrile-water (9: 1 to 1: 9) at 1 mL / min of flow rate. TLC was performed on a precoated silica plate (Merck silica gel 60 F-254). Silica gel (WAKO-gel C-200 (75-150 Âμm)) was used for all separations by column chromatography. All chemicals were reagent grade and were purchased from Sigma-Aldrich, Wako pure Chemical Industries, Ltd., Tokyo-kasei kogyo Co., Ltd., Arch Corporation. 40

All starting materials are commercially available or can be prepared using methods cited in the literature. The effect of the present compounds was evaluated by the following pharmacological tests and tests.

[Determination of capsaicin-induced Ca2 + influx in the human VR1 transfected CHO cell line] (Assay 1) (1) Establishment of the human VR1-CH01uc9aeq cell line

Human vanilloid receptor cDNA (hVR1) was cloned from axotomized dorsal root ganglion libraries (WO 00/29577). The cloned hVR1 cDNA was constructed with pcDNA3 vector and transfected into a CH01uc9aq cell line. The cell line contains reporter genes from aequorin and CRE-luciferase as read signals. Transfected 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 pg / ml streptomycin, 2 mM glutamine, non-essential amino acids and 2 mg / ml G418). The Ca2 + influx was evaluated in the capsaicin-stimulated clones. A high response clone was selected and used for other experiments in the project. Human VR1-CH01uc9aq cells were maintained in the selection medium and passed every 3-4 days at 1 - 2.5 x 10 5 cells / vial (75 mm 2). 41 (2) Determination of the Ca 2+ influx using FDSS-3000

Human VR1-CH01uc9aq cells were suspended in a culture medium which is the same as the selection medium except for G418 and seeded at a density of 1000 cells per well in 384-well black walled clear-base / Nalge Nunc International ). After culture for 48 hours, the medium was changed to 2 μM Fluo-3 AM (Molecular Probes) and 0.02% Puronic F-127 in assay buffer (Hank Balanced Salt Solution (HESS), 17 mM HEPES (pH 7.4), 1 mM Probenecid, 0.1% BSA) and the cells were incubated for 60 min at 25 ° C. After washing twice with the assay buffer, the cells were incubated with a test compound or vehicle for 20 min at 25 ° C. Mobilization of cytoplasmic Ca2 + was determined by FDSS-3000 (λΘΧ = 488 nm, νma = 540 nm / Hamamatsu Photonics) for 60 sec after the stimulation with 10 nM capsaicin. The Integral R was calculated and compared to the controls.

[Determination of capsaicin-induced Ca2 + influx in rat primary dorsal root ganglion neurons] (Assay 2) (1) Preparation of rat dorsal root ganglion neurons

Newborn Wister rats (5-11 days) were sacrificed and the dorsal root ganglion (DRG) was removed. The DRG was incubated with 0.1% trypsin (Gibco BRL) in PBS (-) (Gibco BRL) for 30 min at 37 ° C, then half the volume of fetal bovine serum (FCS) was added and the cells were centrifuged . DRG neuronal cells were resuspended in 42

Ham F12 / 5% FCS / 5% horse serum (Gibco BRL) and dispersed by repetitive pipetting and passing through a 70 pm mesh network (Falcon). The culture dish was incubated for 3 hours at 37 ° C to remove Schwann cells from contamination. Non-adherent cells were recovered and then cultured in laminin-coated 384 wells (Nunc) at 1 x 104 cells / 50 μl / well for 2 days in the presence of 50 ng / ml recombinant mouse NGF (Sigma) and 50 pM 5-fluorodeoxyuridine (Sigma). (2) Ca2 + mobilization assay

The drg neuronal cells were washed twice with HBSS supplemented with 17 mM HEPES (pH 7.4) and 0.1% BSA. After incubation with 2 ÂμM fluo-3AM (Molecular Probe), 0.02% PF127 (Gibco BRL) and 1 mM probenecid (Sigma) for 40 min at 37Â ° C, the cells were washed 3 times. Cells were incubated with RVR or vehicle (dimethylsulfoxide) antagonists and then with 1 pM capsaicin on FDSS-6000 (Aex = 480 nm, λmax = 520 nm / Hamamatsu

Photonics). Changes in fluorescence at 480 nm were monitored for 2.5 min. The integral R was calculated and compared to the controls.

[Organ bath assay to determine capsaicin-induced bladder contraction] (Assay 3)

Male Wistar rats (10 weeks old) were anesthetized with ether and sacrificed by displacement of the necks. The whole bladder was removed and placed in oxygenated Modified Krebs-Henseleit solution (pH 7.4) with the following composition (112 mM NaCl, 5.9 mM KCl, 1.2 mM MgCl2, 1.2 mM NaH2 PO4, 2 mM CaCl2, 2.5 mM NaHC03, 12 mM glucose). Urinary bladder contraction responses were studied as previously described [Maggi CA et al .: Br.J.Pharmacol. 108: 801-805, 1993]. The isometric tension was recorded under a load of 1 g using longitudinal strips of rat detrusor muscle. The bladder strips were equilibrated for 60 min before each stimulation. The contraction response at 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 assess maximal response to capsaicin. The effects of the compounds were investigated by incubating the strips with the compounds for 30 min prior to stimulation with 1 μ capsaicin (vehicle: 80% saline, 10% EtOH and 10% Tween 80). One of the preparations obtained from the same animal served as a control, while the others were used to evaluate the compounds. The ratio of each capsaicin-induced contraction to the internal standard (i.e., KC1 induced contraction) was calculated and the effects of the test compounds on capsaicin-induced contraction were evaluated.

[Determination of Ca2 + influx in human P2X1 transfected CHO cell line] (1) Preparation of human P2X1 transfected CH01uc9aeq cell line The human P2x1 transfected CH01uc9aeq 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, 44 100 pg / ml streptomycin, 2 mM glutamine (Gibco BRL) and 0.5 Units / mL of apyrase (grade I, Sigma). Suspension cells were seeded into each well of the 384-well black bottom plates (Nalge Nunc International) at 3 x 103/50 μl / well. Cells were cultured for 48 hours to adhere to the plates. (2) Determination of intracellular levels of Ca2 +

P2X1 receptor agonist-mediated increases in cytosolic Ca2 + levels were determined using a Fluo-3 AM fluorescent Ca 2+ chelating dye (Molecular Probes). The cells attached to the plates were washed twice with wash buffer (HBSS, 17 mM HEPES-KOH (pH 7.4), 0.1% BSA and 0.5 units / ml of apyrase) and incubated in 40 æl of the loading buffer (1 μM Fluo-3 AM, 1 mM probenecid, 1 μM cyclosporin A, 0.01% pluronic (Molecular Probes) in wash buffer) for 1 hour in a dark place. The plates were washed twice with 40 μl of wash buffer and 35 μl of wash buffer were added to each well with 5 μl of the test compounds or 2 ', 3'-o- (2,4- , 6-trinitrophenyl) adenosine (Molecular Probes) as a reference. After another incubation for 10 minutes in the dark, 200 nM β-methylene ATP agonist was added to initiate Ca2 + mobilization. The fluorescence intensity was determined by FDSS-6000 (Àex = -410 nm, Aem = 510 nm / Hamamatsu Photonics) at 250 msec intervals. The integral proportions were calculated from the data and compared with those obtained from a control. 45 [Determination 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) Implantation of the catheter

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, an incision was made in the inguinal region and a polyethylene catheter (Hibiki, size 5) filled with 2u / ml heparin (Novo Heparin, Aventis Pharma) in saline solution (Otsuka) was inserted into a common iliac artery. (3) Cystometric Investigation The bladder catheter was connected via a T-tube to a pressure translator (Viggo-Spectramed Pte Ltd, DT-XXAD) and a micro-injection pump (TERUMO). The saline solution was infused at room temperature into the bladder at a rate of 2.4 mL / hr. The intravesical pressure was continuously recorded on a graphic pen recorder (Yokogawa). At least three reproducible micturition cycles, corresponding to a period of 20 minutes, were recorded prior to administration of the test compound and used as baseline values. (4) Administration of test compounds and bladder stimulation with capsaicin Saline infusion was discontinued prior to administration of the compounds. A test compound dissolved in the ethanol mixture, Tween 80 (ICN Biomedicals Inc.) and saline (1: 1: 8, v / v / v) at 10 mg / kg was administered intraarterially. 10æg of capsaicin (Nacalai Tesque) dissolved in ethanol was administered intra-arterially 2 min after administration of the compound. (5) Analysis of cystometric parameters

Relative increases in intravesical pressure induced by capsaicin from cystometry data were analyzed. Capsaicin-induced pressures in the bladder were compared to maximal bladder pressure during urination without capsaicin stimulation. Inhibition mediated by test compounds at increased pressures in the bladder were evaluated using Student's t-test. A level of probability of less than 5% was accepted as significant difference. 47 [Determination of overactive bladder in anesthetized cystic rats] (Assay 5) (1) Animals

Female Sprague-Dawley rats (180 ~ 250 g / Charles River Japan) were used. Cyclophosphamide (CYP) dissolved in saline at 150 mg / kg was administered intraperitoneally 48 hours prior to the experiment. (2) Implantation of the catheter

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, an incision was made in the inguinal region and a polyethylene catheter (BECTON DICKINSON, PE50) filled with saline solution (Otsuka) was inserted into the femoral vein. After the bladder was empty, the mice were allowed 1 hour to recover from the operation. (3) Cystometric Investigation The bladder catheter was connected via a T-tube to a pressure translator (Viggo-Spectramed Pte Ltd, DT-XXAD) and a micro-injection pump (TERUMO). Infusion was administered saline at room temperature in the bladder at a rate of 3.6 mL / hr for 20 min. The intravesicular pressure was continuously recorded on a graphical pen recording apparatus 48 (Yokogawa). At least three reproducible urination cycles were recorded, corresponding to a period of 20 minutes, prior to administration of a test compound. (4) Administration of Test Compounds

A test compound dissolved in the ethanol mixture, Tween 80 (ICN Biomedicals Inc.) and saline (1: 1: 8, v / v / v), was administered intravenously at 0.05 mg / kg, 5 mg / kg or 5 mg / kg. 3 min after compound administration, was administered by infusing saline solution (Nacalai Tesque) at room temperature into the bladder at a rate of 3.6 mL / hr. (5) Analysis of cystometric parameters

Cystometric parameters were analyzed as described previously [Lecci A et al .: Eur. J. Pharmacol. 259: 129-135, 1994]. The frequency of urination calculated from a micturition interval and the capacity of the bladder calculated from a volume of saline solution infused up to the first micturition were analyzed from cystometry data. Inhibition of the test compound-mediated frequency and increase in bladder capacity mediated by test compounds were assessed using the unpaired Student's t-test. A probability level of less than 5% was accepted as a significant difference. Data were analyzed as mean ± SEM of 4-7 rats. 49 [Determination of Acute Pain] Acute pain is determined on a hot plate, especially in rats. Two variants of the hot plate test are used: In the classical variant, the animals are placed on a warm surface (52 to 56 ° C) and the latency time is determined until the animals demonstrate nociceptive behavior, such as raising or licking the paw . The other variant is an increase in the temperature of the hot plate, where animals of the experiment are placed on a surface of neutral temperature. Subsequently, this surface is heated continuously, but slowly, until the animals begin to lick the hind paw. The temperature that is reached when the animal begins to lick the hind paw is a measure of the pain threshold.

The compounds are tested against a vehicle treated control group. Application of the substance is effected at different time points via different routes of application (i.v., i.p., p.o., i.t., i.c.v., s.c., intradermal, transdermal) prior to the pain test.

[Persistent Pain Determination] Persistent pain is determined with the formalin or capsaicin test, especially in rats. A 1 to 5% formalin solution or 10 to 100æg capsaicin is injected into one of the hind paws of the experiment animal. After application of formalin or capsaicin, the animals demonstrated nociceptive reactions such as tremors, licking and biting the affected paw. The number of nociceptive reactions within a time frame of up to 90 minutes is a measure of the intensity of the pain. 50

The compounds are tested against a vehicle treated control group. The application of the substance is carried out at different time points via different routes of application (i.v., i.p., p.o., i.t., i.c.v., s.c., intradermal, transdermal) prior to formalin or capsaicin administration.

[Determination of Neuropathic Pain] Neuropathic pain is induced through different variants of unilateral sciatic nerve injury, especially in rats. The operation is performed under anesthesia. The first variant of sciatic nerve injury is produced by placing constrictive ligatures loosely around the common sciatic nerve (Bennett and Xie, Pain 33 (1988): 87-107). The second variant is the tight bond of about half the diameter of the common sciatic nerve (Seltzer et al., Pain 43 (1990): 205-218).

In the other variant, a group of models is used, in which the connections are made or tight transections of the L5 and L6 nerves of the spinal cord or only the L5 nerve of the spinal cord (KIM SH; CHUNG JM, 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 (common tibial and peroneal nerves) leaving the remaining sural nerve intact, whereas the latter variant comprises axotomy of only the tibial branch, leaving the nerves, sural and common , not damaged. Control animals are treated with a simulated operation. 51 Post-operation, animals with nerve damage develop chronic mechanical allodynia, cold allodynia, as well as thermal hyperalgesia. Mechanical allodynia is determined by a pressure translator (von Frey Electronic Anesthesiometer, IITC Inc.-Life Science Instruments, Woodland Hills, SA, USA, Electronic von Frey System, Somedic Sales AB, Herrby, Sweden). Thermal hyperalgesia is determined by a radiant heat source (Plantar Test, Ugo Basile, Comerio, Italy) or by a cold plate at 5 to 10 ° C where the nocifensive reactions of the affected hind paw are counted as a measure of the intensity of pain. Another test for cold induced pain is the counting of reactions or duration of nocifensive responses following plantar administration of acetone to the affected hind limb. Chronic pain is usually assessed by recording the circadian rhythms in the activity (Surjo and Arndt, Universitát zu Kõln, Cologne, Germany) and by differences in foot print patterns (FOOTPRINTS program, Klapdor et al., 1997. A Low-Cost Method for Analyzing Footprint Patterns, J. Neurosci, Methods 75, 49-54).

The compounds are tested against vehicle-treated control groups and mock operation groups. The application of the substance is carried out at different time points via different routes of application (i.v., i.p., p.o., i.t., i.c.v., s.c., intradermal, transdermal) prior to the pain test.

[Determination of Inflammatory Pain] Inflammatory pain is induced, especially in rats, by injection of 0.75 mg carrageenan or complete Freund's adjuvant into a hind paw. The animals developed edema with mechanical allodynia as well as thermal hyperalgesia. Mechanical allodynia is determined by a pressure translator (von Frey Electronic Anesthesiometer, IITC Inc.-Life Science Instruments, Woodland Hills, SA, USA). Thermal hyperalgesia is determined by a radiant heat source (Plantar Test, Ugo Basile, Comerio, Italy, Paw thermal stimulator, G. Ozaki, University of California, USA). Two methods are used to determine edema. In the first method, the animals are sacrificed and the affected hind legs sectioned and weighed. The second method comprises differences in paw volume by determining the water displacement in a plethysmometer (Ugo Basile, Comerio, Italy).

The compounds are tested against vehicle-treated control groups or non-inflamed groups. Application of the substance is effected at different time points via different routes of administration (i.v., i.p., p.o., i.t., i.c.v., s.c., intradermal, transdermal) prior to the pain test.

[Determination of Diabetic Neuropathic Pain]

Rats treated with a single intraperitoneal injection of 50 to 80 mg / kg streptozotocin, develop deep hyperglycemia and mechanical allodynia over the period of 1 to 3 weeks. Mechanical allodynia is determined by a pressure translator (von Frey Electronic Anesthesiometer, IITC Inc.-Life Science Instruments, Woodland Hills, SA, USA). The compounds are tested against vehicle-treated diabetic and non-diabetic control groups. Application of the substance is effected at different time points via different routes of administration (i.v., i.p., p.o., i.t., i.c.v., s.c., intradermal, transdermal) prior to the pain test.

The IC50 results of capsaicin-induced Ca2 + influx in the human VR1 transfected CHO cell line are presented in the Examples and tables of the Examples below. The data correspond to the compounds as provided by the solid phase synthesis and thus at purity levels of about 40 to 90%. For practical reasons, the compounds are grouped into four classes of activity as follows:

IC50 = A (<or =) 0.1 μΜ <Β (<or =) 0.5 μM <C (<or =) 1 pM <D

The compounds of the present invention also exhibit excellent selectivity and strong activity in other (2) - (5) assays described above. Method of preparation of the starting compounds [Starting compound A]

To a stirred solution of 8-amino-2-naphthol (50.0 g, 314 mmol) in tetrahydrofuran (1000 mL) was added di-t-butyldicarbonate (68.6 g, 314 mmol). The mixture was stirred at 70 ° C for 18 hours. After the mixture cooled to room temperature, the solvent was removed under reduced pressure. To the residue, ethyl acetate was added and washed with saturated aqueous sodium carbonate solution and then with water. The extracted organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. To the obtained residue was added diisopropyl ether and the precipitate was filtered and dried to provide N-t-butoxycarbonyl-8-amino-2-naphthol (64.2 g, yield 79%). NMR (DMSO-d6) δ 1.48 (s, 9H), 7.07 (dd, J = 2.2 Hz and 8.85 Hz, 1H) , 7.20 (t, J = 7.9 Hz, 1H), 7.24 (d, J = 2.2 Hz, 1H), 7.36 (d, J = 7.25 Hz, 1H) , 7.60 (d, J = 8.2 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 8.92 (s, 1H).

Then, to a mixture of Nt-butoxycarbonyl-8-amino-2-naphthol (64.0 g, 247 mmol) and cesium carbonate (161 g, 493 mmol) in 300 mL of anhydrous DMF was added iodoethane , 3 g, 272 mmol) at room temperature. The mixture was stirred at 60 ° C for 2 hours. Water was added to the mixture and the product was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure. To the obtained residue was added diisopropyl ether and the precipitate was collected and dried to afford (7-ethoxy-1-naphthalen-1-yl) -carbamic acid t-butyl ester (47.9 g, 67.5% yield) . 1 H NMR (DMSO-d 6) δ 1.41 (t, J = 6.95 Hz, 3H), 1.50 (s, 9H), 4.16 (m, q, J = 6.95 Hz, 2H), 7.15 (dd, J = 2.5,5 and 8.8 Hz, 1H), 7.28 (t, J = 8.8 Hz, 1H), 7 , 36 (d, J = 2.2 Hz, 1H), 7.54 (d, J = 7.25 Hz, 1H), 7.6. 1 (d, J = 8.2, Hz, 1H), 7.80 (d, J = 8, 85 Hz, 1H), 9.12 (s, 1H).

Then, to a solution of (7-ethoxy-1-naphthalen-1-yl) -carbamic acid t-butyl ester (47.9 g, 167 mmol) in 100 mL of anhydrous 1,4-dioxane was added HCl 4 N in 1,4-dioxane (100 mL) at 0 ° C. The mixture was stirred at room temperature for 2 hours. Diisopropyl ether was added to the reaction mixture and the precipitate was filtered. To the obtained solid was added saturated sodium bicarbonate and the product was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford (7-ethoxy-1-naphthyl) amine (27.0 g, 86.3% yield). NMR (DMSO-d 6) [delta] 1.39 (t, J = 11.3 Hz, 3H), 4.15 (q, J = 11.3 Hz, 2H ), 5.52 (s (br), 2H), 6.64 (dd, J = 3.75 and 10.05 Hz, 1H), 7.01-7.07 (m, 3H), 7.39 (d, J = 3.8 Hz, 1H), 7.63 (d, J = 14.45 Hz, 1H).

Thereafter, liquid ammonia (300 mL) was collected at -78 ° C into a flask containing a mixture of 7-ethoxy-1-naphthalen-1-ylamine (1.80 g, 9.61 mmol) and t-butanol ( 2.13 g, 28.8 mmol) in tetrahydrofuran (20 mL). To the mixture, lithium (0, 200 g, 28.8 mmol) was added over 30 minutes and stirred at -78 ° C for 1 hour. Methanol and water were added and the mixture was stirred at room temperature for 16 hours to allow evaporation of the ammonia. To the obtained residue was added ethyl acetate. The organic layer was washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure to provide 7-ethoxy-5,8-dihydronaphthalene-1-ylamine (1.37 g, 76% yield).

[Starting compound B]

To a stirred solution of 7-ethoxy-5,8-dihydronaphthalen-1-ylamine (1.07 g, 5.65 mmol) in tetrahydrofuran (30 mL) was added an aqueous solution of 2N HCl ( 10 mL) and stirred at 40 ° C for 1 hour. The mixture was neutralized with addition of sodium bicarbonate and the product was extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure to provide 8-amino-3,4-dihydro-1H-naphthalen-2-one (0.71 g, yield 78% ). MS (ESI) m / z 162 [M + H] + 1 H NMR (CDCl 3) δ 2.62-2.65 (m, 2H), 3.07 (t, J = 7.25 Hz, 2H), J = 7.85, 1H), 6.70 (d, J = 7.25 Hz, 1H), 7.07 (t, J = 7, 55 Hz, 1H). 57

Then 8-amino-3,4-dihydro-1H-naphthalen-2-one (0.050 g, 0.318 mmol) in methanol (10 mL) was added sodium borohydride (0.030 g, 0.175 mmol ) at 0 ° C and the mixture was stirred for 1 hour. The mixture was poured into water and the product was extracted with ethyl acetate. The organic layer was dried over Na 2 SO 4, filtered and concentrated under reduced pressure to provide 8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol (0.037 g, 71% yield). MS (ESI) m / z 163 [M] + 1 H NMR (DMSO- d 6) δ 1.53-1.57 (m, 1H), 1.81-1.85 (m, 1H) 16 (dd, J = 7.7 and 16.4 Hz, 1H), 2.61-2.74 (m, 3H), 3.89-3.90 (m, 1H), 4.65 (s 2H), 4.72 (d, J = 4.1Hz, 1H), 6.28 (d, J = 7.45Hz, 1H), 6.28 (d, J = 7.45Hz, 1H) ), 6.41 (d, J = 7.7 Hz, 1H), 6.76 (t, J = 7.55 Hz, 1H).

[Starting compound C]

A stirred solution of benzene (II) chloride dimer (3.10 mg, 0.006 mmol) and (1S, 2R) - (-) - cis-1-amino-2-indanol (3.7 mg, 0.025 mmol) in degassed isopropanol was heated at 80 ° C for 20 minutes under argon. The mixture was added to the solution of 8-amino-3,4-dihydro-1H-naphthalen-2-one (50 mg, 0.310 mmol) in isopropanol (3 mL) at ambient temperature. A solution of potassium hydroxide (3.48 mg, 0.062 mmol) in isopropanol (1 mL) was added and the mixture was stirred at 45 ° C for 1 hour. The mixture was passed through silica gel and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the chiral enantiomer 8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol (33.0 mg, yield 65%). MS (ESI) m / z 163 [M] + NMR of (DMSOd 6) δ 1.53-1.57 (m, 1H), 1.81-1.85 (m, 1H), 2.16 (m, dd, J = 7.7 and 16.4 Hz, 1H), 2.61-2.74 (m, 3H), 3.89-3.90 (m, 1H), 4.65 (s, 2H) , 4.72 (d, J = 4.1Hz, 1H), 6.28 (d, J = 7.45Hz, 1H), 6.28 (d, J = 7.45Hz, 1H), 6 , 41 (d, J = 7.7 Hz, 1 H), 6.76 (t, J = 7.55 Hz, 1 H).

[Starting compound D]

A stirred solution of benzenorhutene (II) chloride dimer (1.55 g) and (1S, 2R) - (-) - cis-1-amino-2-indanol (1.85 g) in degasified isopropanol (500 mL ) was heated at 80 ° C for 20 minutes under argon and then cooled to room temperature. The mixture was added to the solution of 8-amino-3,4-dihydro-1H-naphthalen-2-one (25.0 g) in isopropanol (700 mL) at room temperature followed by potassium hydroxide solution (1.74 g) in 300 ml of isopropanol (pre-prepared at 45 ° C to dissolve and then cooled to room temperature). After stirring at 45 ° C for 30 minutes, the mixture was cooled to room temperature and passed through a pad of silica gel and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the solid obtained dissolved in dichloromethane and treated with activated charcoal for 10 minutes. After filtration through a pad of silica gel, the mixture was concentrated under reduced pressure. The product obtained was recrystallized from dichloromethane to give (R) -8-amino-1,2,3,4-tetrahydronaphthalen-2-ol red crystals (14 g, 56% yield). MS (ESI) m / z 163 1 H-NMR (DMSO-d 6) δ 1.53-1.57 (m, 1H), 1.81-1.85 (m, 1H), 2.16 (m, 3H), 3.89-3.90 (m, 1H), 4.65 (s, 3H) 2H), 4.72 (d, J = 4.1Hz, 1H), 6.28 (d, J = 7.45Hz, 1H), 6.28 (d, J = 7.45Hz, 1H) , 6.41 (d, J = 7.7 Hz, 1H), 6.76 (t, J = 7.55 Hz, 1H). The use of (1R, 2S) - (+) - cis-1-amino-2-indanol resulted in (S) -8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol.

Then the solution of (R) -8-amino-1,2,3,4-tetrahydronaphthalen-2-ol (36.2 g) and pyridine (18.8 mL) in THF (850 mL) cooled to 0 ° C was added phenyl chloroformate (28.8 mL). The mixture was stirred for 3 hours at room temperature and then poured into ethyl acetate. The mixture was washed with aqueous NH 4 Cl and then, with water, the organic layer was dried over Na 2 SO 4, filtered and concentrated under reduced pressure. To the obtained residue was added acetonitrile and the precipitates were collected and washed with a mixture of acetonitrile and diisopropyl ether (2: 3) to give {(R) -7-hydroxy-5,6,7,8- tetrahydro-naphthalen-1-yl} -carbamic acid tert-butyl ester (33.0 g). NMR (DMSO-d 6) δ 1.59-1.64 (m, 1H), 1.83-1.89 (m, 1H) , 2.68-2.99 (m, 4H), 3.90-3.92 (m, 1H), 4.84 (dd, J = 3.8 Hz and 29.9 Hz, 1H), J = 7.9 Hz, 1H), 7.07-7.25 (m, 6H), 7.42 (t, J = 7.85 Hz, 1H), 9.29 (d, s, 1H);

Example 1-1 N- [4-chloro-3- (trifluoromethyl) phenyl] -Î ± - (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea

This example was performed according to general method F. To a stirred solution of 7-ethoxy-5,8-dihydronaphthalen-1-ylamine (0.16 g, 0.84 mmol) in tetrahydrofuran (15 mL ), 4-chloro-3-trifluoromethylphenylisocyanate (0.22 g, 61.0 mmol) was added. The mixture was stirred at room temperature for 1.5 hours and poured into water. The product was extracted with ethyl acetate and the organic layer was dried over Na 2 SO 4, filtered and concentrated under reduced pressure to provide N- (4-chloro-3-trifluoromethyl-phenyl) -α- (7-ethoxy- 8-dihydro-naphthalen-1-yl) urea (0.31 g, 89% yield). Then to a solution of N- (4-chloro-3-trifluoromethyl-phenyl) -α- (7-ethoxy-5,8-dihydro-naphthalen-1-yl) -urea (0.21 g , 0.51 mmol) in tetrahydrofuran (20 mL) was added 1N aqueous hydrochloric acid solution (5 mL) and the mixture was stirred at 40 ° C for 45 minutes. The mixture was neutralized with the addition of 10% aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over Na 2 SO 4, filtered and concentrated under reduced pressure to provide N- (4-chloro-3-trifluoromethylphenyl) -N '- (7-oxo-5,6,7,8-tetrahydro-naphthalen- 1-yl) urea (0.16 g, 85% yield). Then, N- (4-chloro-3-trifluoromethylphenyl) -Î ± - (7-oxo-5,6,7,8-tetrahydro-naphthalen-1-yl) urea (0.07 g, , 18 mmol) in methanol (10 mL) was added sodium borohydride (0.04 g, 0.09 mmol) at 0 ° C and the mixture was stirred for 30 minutes. The mixture was poured into water and the product was extracted with ethyl acetate. The organic layer was dried over Na 2 SO 4, filtered and concentrated under reduced pressure and the product obtained was recrystallized from a mixture of ethyl acetate / hexane (1/2) solution, to give N- [4-chloro-3- (trifluoromethyl) phenyl] -N '- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea (41 mg, 59% yield) 1 H-NMR (DMSO- d 6) δ 1 (M, 1H), 2.36-2.42 (m, 1H), 2.63-2.76 (m, 1H) , 2.83-2.87 (m, 2H), 3.91-3.96 (m, 1H), 4.87 (d, J = 4.1Hz, 1H), 6.82 (d, J = = 7.6 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 7.6 Hz, 6H), 7.61-7.62 ( m, 2H), 7.93 (s, 1H), 8.09 (s, 1H), 9.47 (s, 1H).

Molecular weight: 384.8 MS (M + H): 384 mp: 227-228 ° C

In vitro activity class: A

Example 1-2 N- [4-chloro-3- (trifluoromethyl) phenyl] -N - {(R) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl} urea

A racemic mixture of N- [4-chloro-3-

(trifluoromethyl) phenyl] -N '- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea (30.0 mg) was separated by chiral HPLC (Daicel OD column, n-hexane : 2-propanol = 98: 2) in the corresponding R-isomer (8.3 mg). The R-isomer was detected by chiral HPLC (ChiralCel OD column 0.49 cm x 25 cm, n-hexane / ethanol = 97/3, 1.5 mL / min flow) at 20.1 minutes. 63

Molecular weight: 384.8 MS (M + H): 384

Example 1-3 N- [4-chloro-3- (trifluoromethyl) phenyl] -N '- {(S) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl} urea

F

F

A racemic mixture of N- [4-chloro-3-

(trifluoromethyl) phenyl] -N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea (30.0 mg) was separated by chiral HPLC (Daicel OD column, n- hexane: 2-propanol = 98: 2) in the corresponding S-isomer (2.2 mg). S-isomer was detected by chiral HPLC (ChiralCel OD column 0.49 cm x 25 cm, n-hexane / ethanol = 97/3, 1.5 mL / min flow) at 17.6 minutes.

Molecular weight: 384.8 MS (M + H): 384 64

Example 2-1 N-Phenyl-N '- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea

This example was carried out according to general method A. To a solution of 8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol (20.0 mg, 0.123 mmol) in 1,4 (1.0 mL) was added phenyl isocyanate (14.6 mg, 0.123 mmol) at room temperature. The mixture was stirred for 16 hours and then diisopropyl ether and hexane added. The precipitate was filtered and dried to provide N-phenyl-N '- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea (17.8 mg, 51% yield).

Molecular weight: 282.3 MS (M + H): 283

mp: 198-199 ° C

Activity class: C

The compounds in Example 2-2 to 2-41 were synthesized and tested using the starting material B and according to similar procedures to examples 2-1 above. 65

Table 1

Ex n ° MOLECULAR STRUCTURE PM IN PF activity class 2-2 N X0 X0 316.79024 317 197-199 B 2-3 A rAo XÒ 316.79024 317 216-218 A 2-4. A No. 316,79024 317,229-231 A LO 1 A A 04 x 312.3717 313 187-189 B 66 (Continued)

Ex n ° MOLECULAR STRUCTURE PM IN PF activity class 2-6 XX N OO XÒ 312.3717 313 213-215 D 2-7; λ0 N N N OO Xó 350.34359 351 217-219 C 2-8 Λ F XO 350.34359 351 227-228 A 2-9 N o X 350.34359 351 222-224 A 67 (Continued)

Ex n ° MOLECULAR STRUCTURE PM IN PF activity class 2-10 ° C 354,40934 355 178-180 D 2-11 Λ 0 tò 354,40934 355 176-178 A 2-12 XO, 354, 40934 355 204-206 A 2-13 x 332,40575 333 250-252 A 68 (Continued)

Ex n ° MOLECULAR STRUCTURE PM IN PF activity class 2-14 X0 332,40575 333 212-214 A 2-15 XX 'lOo X 300.33564 301 214-216 B 2-16 xr N O O x 361,24124 362 237-239 A 2-17 XX No. 35 352.23527 352 234-235 A 69 (Continued)

Ex n ° MOLECULAR STRUCTURE PM IN PF activity class 2-18 Λ XÓ 296,3723 297 198-200 B 2-19 Xo Oò 324,42648 325 186-188 A 2-20 iXo XÓ 374,44339 375 188-190 A 2-21 hXo X6 325.41406 326 206-207 D 2-22 Xo 296.3723 297 198-200 B 70 (Continued)

Ex n ° MOLECULAR STRUCTURE PM IN PF activity class 2-23 OH, £ 0 X 310.39939 311 224-226 B 2-24 H0n, 0? 310.39939 311 194-196 B 2-26 AO, X6 310.39939 311 230-232 A 2-27 hon X0 314.36273 315 184-187 B 2-28 XC X 314.36273 315 193-194 B 71 (Continued)

Ex n ° PM MOLECULAR STRUCTURE IN PF activity class 2-29 &quot; o &quot; 0. 314.36273 315 218-221 A 2-30 X0 330.81733 331 213-215 B 2-31 xo, X0 '326.39879 327 209-211 B 2-32 xo 1A0 Xo 310.39939 311 161-163 c 2-33 N CH CH, Λ wYy Λ / 234.30061 235 216-217 D 72 (Continued)

Ex. N ° MOLECULAR STRUCTURE PM IN PF activity class 2-34 .X) N α O X 282.34521 283 198-199 C 2-35% N x0 X 316.79024 317 197-199 B 2-36 XC% 330.81733 331> 180Z A 2-37 1 X X 342.39819 343> 150Z A 2-38 Br 463.68465 464 234-235 A 73 (Continued)

Ex. N ° MOLECULAR STRUCTURE PM IN PF activity class 2-39 ° C, 398.81 399 219-220 A 2-40% haA0 Ff &quot; OÒ 398.81571 399 136-137 B 2-41 Ί0Ο 398.81571 399 213 B

Example 3-1

Chiral enantiomer N- (4-chloro-3- (trifluoromethyl) phenyl) -N '- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea

This example was performed according to general method G. To a solution of 8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol enantiomer (33.0 mg, 0.202 mmol) in 1 , 4-dioxane (3.0 mL) was added 4-chloro-3-trifluoromethyl-phenylisocyanate (44.8 mg, 0.202 mmol) at room temperature. The mixture was stirred for 16 hours and then diisopropyl ether and hexane added. The precipitate was filtered and dried to provide chiral N- (4-chloro-3- (trifluoromethyl) phenyl) -β- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) (54.0 mg, 69% yield). The enantiomeric excess (% ee) was determined using Chiral Cel OD column (15% isopropanol in hexane as eluent, with 1 mL per minute). Molecular weight: 384.8

MS (M + H): 384 mp: 227-228 ° C

In vitro activity class: A

Example 4-1 N- (7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) -α- (4-trifluoromethoxybenzyl) urea

This example was carried out according to general method C.

A mixture of 7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) -carbamic acid phenyl ester (30.0 mg, 0.11 mmol) and 4-trifluoromethoxybenzylamine (21 , 3 mg, 0.11 mmol) in DMSO (1.0 mL) was stirred at 100 ° C for 17 hours. The reaction mixture was cooled to room temperature and water was added. The precipitates were filtered and washed with water and then with acetonitrile to give N- (7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) -N '- (4-trifluoromethoxy benzyl) -urea (6.70 mg, 17% yield). 1 H-NMR (DMSOd 6) δ 1.54-1.65 (m, 1H), 1.81-1.92 (m, 1H), 2.25-2.38 (m, 1H), 2.68 (M, 1H), 4.32 (d, J = 6.0 Hz, 2H), 4.85 (d, J = 4.1 J = 7.5 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 7.06 (t, J = 6.0 Hz, 7.43 (d, J = 8.3 Hz, 2 H), 7.63 (d, J = 7.5 Hz, 1 H) , 7.5 (s, 1H). Molecular weight: 380.36 MS (M + H): 381

mp: 213 ° C

In vitro activity class: A Example 4-2 N - {(R) -7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl} -Î ± - (4-trifluoromethoxybenzyl) - urea

O

76

This example was carried out according to general method C.

A mixture of (R) -7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) -carbamic acid phenyl ester (147.3 mg, 0.52 mmol) and 4-trifluoromethoxy (99.4 mg, 0.52 mmol) in DMSO (1.5 mL) was stirred at 150 ° C for 1.5 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The extracted organic layer was washed with water and then brine, dried over Na2 SO4, filtered, and concentrated under reduced pressure. The obtained residue was triturated with dichloromethane and hexane to give N - {(R) -7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl} -N '- (4-trifluoromethoxy-benzyl) - urea (168.0 mg, 85% yield). NMR (DMSO-d6) δ1.54-1.65 (m, 1H), 1.81-1.92 (m, 1H), 2.25-2.38 (m, 1H), 2. (D, J = 6.0 Hz, 2H), 4.85 (d, J = 6.0 Hz, 2H), 4.86-3.98 J = 7.5 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 7.06 (t, J = (D, J = 8.3 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 5 Hz, 1H), 7.45 (s, 1H). Molecular Weight: 380.36 MS (M + H): 381

Class of in vitro activity: The R-isomer was detected by chiral HPLC (ChiralCel AD column 0.49 cm x 25 cm, n-hexane / ethanol = 90/10, 1.5 ml / min flow) at 17.7 minutes . 77

Example 4-3 N - ((S) -7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) -N '- (4-trifluoromethoxybenzyl) urea

This example was carried out according to general method C.

A mixture of (S) -7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) -carbamic acid phenyl ester (85.0 mg, 0.30 mmol) and 4-trifluoromethoxy (57.4 mg, 0.30 mmol) in DMSO (1.0 mL) was stirred at 150 ° C for 1.5 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The extracted organic layer was washed with water and then brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was triturated with dichloromethane and hexane to give N - {(S) -7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl} -N '- (4-trifluoromethoxy-benzyl) - urea (95.0 mg, yield 83%). 1 H-NMR (DMSOd 6) δ 1.54-1.65 (m, 1H), 1.81-1.92 (m, 1H), 2.25-2.38 (m, 1H) (D, J = 6.0 Hz, 2H), 4.85 (d, J = 4, 1Hz, 1H), 6.72 (d, J = 7.5Hz, 1H), 6.98 (t, J = 7.5Hz, 1H), 7.06 (t, J = 6.0Hz , 7.63 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 7.5 Hz, 1H), 7.5 (s, 1H).

Molecular weight: 380.36 MS (M + H): 381

Class of in vitro activity: The S-isomer was detected by chiral HPLC (ChiralCel ad 0.49 cm x 25 cm column, n-hexane / ethanol = 90/10, 1.5 mL / min flow) at 13.2 minutes .

Example 4-4 N - {(R) -7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl} -N '- (4-trifluoromethylbenzyl) urea

This example was carried out according to general method C.

A mixture of (R) -7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) -carbamic acid phenyl ester (150.0 mg,

0.53 mmol) and 4-trifluoromethyl-benzylamine (92.7 mg, 0.53 mmol) in DMSO (2.0 mL) was stirred at 100 ° C for 1.5 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The extracted organic layer was washed with water and then brine, dried over Na2 SO4, filtered, and concentrated under reduced pressure. The residue obtained was triturated with dichloromethane and hexane to give N - {(R) -7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl} -N '- (4-trifluoromethyl-benzyl) (156 mg, 81% yield). NMR (DMSO-d 6) δ1.58-1.59 (m, 1H), 1.85-1.86 (m, 1H), 2.33-2.85 (m, 4H) (D, J = 5.7 Hz, 2H), 4.84 (d, J = 4.1 Hz, 1H), 6.72 (d, J = = 7.25 Hz, 1H), 6.98 (t, J = 7.9 Hz, 1H), 7.12 (t, J = 6.0 Hz, 1H), 7.51-7.71 , 6H).

Molecular weight: 364.37 MS (M + H): 366

mp: 204.3 ° C

Class of in vitro activity: The R-isomer was detected by chiral HPLC (ChiralCel AD column 0.49 cm x 25 cm, n-hexane / ethanol = 90/10, 1.5 ml / min flow) at 16.2 minutes . 80

Example 4-5 N - {(S) -7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) -N '- (4-trifluoromethylbenzyl) urea

This example was carried out according to general method C.

A mixture of (S) -7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) -carbamic acid phenyl ester (100.0 mg, 0.35 mmol) and 4-trifluoromethyl (61.8 mg, 0.35 mmol) in DMSO (1.5 mL) was stirred at 100 ° C for 1.5 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The extracted organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was triturated with dichloromethane and diisopropyl ether to give N - {(S) -7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl} - [4- (4-trifluoromethyl-benzyl) 1 H NMR (DMSO-d 6) δ1.59 - 1.59 (m, 1H), 1.85-1.86 (m, 1H) 2.33-2.85 (m, 4H), 3.91-3.92 (m, 1H), 4.39 (d, J = 5.7 Hz, 2H) 4.84 (d, J = 4) (D, J = 7, 25 Hz, 1H), 6.98 (t, J = 7.9 Hz, 1H), 7.12 (t, J = 6.0 Hz , 1H), 7.51-7.71 (m, 6H).

Molecular weight: 364.37 MS (M + H): 366

Class of in vitro activity: The S-isomer was detected by chiral HPLC (ChiralCel AD column 0.49 cm x 25 cm, n-hexane / ethanol = 90/10, 1.5 ml / min flow) at 11.7 minutes.

In a similar manner, according to Example 4-1, 4-2, 4-3, 4-4 and 4-5 above, the compounds of Example 4-6 to 4-54 were synthesized. 82

Table 2

No. MOLECULAR STRUCTURE PM MS (M + H) PF activity class 4-6 XO x 296.3723 297 198-200 B 4-7 XX X 375.26833 376 220.5-222 A 1 co R / F 1 F xw OH 364.37068 365 186-187 A 4-9 XU.J OH 330.81733 331 235 ZA 4-10 x 364.37068 365 169.9 A 83 (Continued)

No. MOLECULAR STRUCTURE MW MS (M + H) PF activity class 4-11 0 · 0 · X6 326.39879 327 196 B 4-12 x a; 332.35316 333 193, 4 A 4-13 / -V ^ [ΎΥ CH, xó "&quot; 326.39879 327 171.3 B 4-14 x CR X X 330.81733 331 188.7 A 4-15 N / A N / A X 365.26236 366 212.7 A 84 (Continued)

No. MOLECULAR STRUCTURE PM MS (M + H) PF activity class 4-16 xoxo ** 352.48066 353 199.9 A 4-17 ΧΟχ X0 380.37008 381 213 A 4-18 x0: X3 365.26236 366 201.4 A 4-19 X 364.37068 365 218.6 A 4-20. XÓ &quot; 356.42528 357 212 B 85 (Continued)

No. MOLECULAR STRUCTURE PM MS (M + H) PF activity class 4-21 X0 &quot; t 375.26833 376 206.4 A 4-22 XV x 354,40934 355 210.9 A 4-23 O &quot; 01 *; ^ 1Λ0 x0 386,45117 387 175.4 C 4-24 XO * VÒ 375.26833 376 164.2 A 4-25 .XX * CO 3 341.36983 342 216.3 A 86 PM NO MOLECULAR STRUCTURE (M + H) PF class of activity 4-26 X + 432.36906 433 200.3 A 4-27 (M + H) xó &quot; 356.42528 357 219.7 C 4-28? N? O 332.35316 333 140.2 C 4-29 aQX? 380.37008 381 149 A 4-30? -X? 340.38225 341 278.5 c 87 (Continued)

No. MOLECULAR STRUCTURE PM MS (M + H) PF activity class 4-31 XO, X 311.38697 312 223 C 4-32 NH4 Xa X0 311.38697 312 132.5 C 4-33 ΧΠΤ Α &gt; Χ 36 368.43643 369 209.5 B 4-34 x 11 339.44115 340 197.7-199.5 A 4-35 0 x Γ F 398.81571 399 187.5 A 4-36 344.84442 345 &gt; 200 A 88 (Continued)

No. MOLECULAR STRUCTURE PM MS (M + H) PF activity class 4-37 0x W 382.36111 383 174 A 4-38xm, HNO O &quot; CO 388.47048 389 181-183 A 4-39 jnx HN-O-X0 408.88842 409 199-201 A 4-40 JUCrV · Xo '366,34299 367 198-200 A 4-41 CH3 &quot; CO 328,38982 329 163-164 B 89 (Continued)

No. MOLECULAR STRUCTURE PM MS (M + H) PF activity class 4-42 CH3 HN3 O X6 389.29542 389-391 174 A 4-43 m H 2 X 3 372.47108 373 205- 206 C 4-44 358.87151 359 140-141 B 1 CH 3 ΗΝ 4 X 4 4-45 a.a. &gt; 396.43468 397 209.1 A 4-46 nN-vV hiA4 X6 346.43284 347 221, 1 A 90 (Continued)

No. MOLECULAR STRUCTURE PM MS (M + H) PF activity class 4-47 JX '· HNO O XO 321.38218 322 147 decomp. B 4-48 ch3 xo &quot; ○ 310.39039 311 169.6 B 4-49 CH, HN ΙΙΊ hiA02 X3 360.45993 361 137.4 A 4-50 -toH 375.44977 376 &gt; 200 decomp. c 4-51 0 1 Λ Λ η ° ν / ΑΗ yA / 11 kA) q / NH f 447.50486 448 159 A 91 (Continued)

No. MOLECULAR STRUCTURE PM MS (M + H) PF activity class 4-52 (M + H) IR (KBr): 483.96583 448 83 A 4-53 HN + O 344, 84442 345 173.9 A 4-54% NaHCO 3 344.84442 345 159.3 A

Example 4-48 N - [(7R) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] -N '- {2- [4- (trifluoromethyl) phenyl] ethyl] urea

92

This example was carried out according to general method C.

A mixture of 7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) -carbamic acid phenyl ester (100.0 mg, 0.35 mmol) and 2- (4-trifluoromethyl- phenyl) ethylamine (66.7 mg, 0.35 mmol) in DMSO (1.0 mL) was stirred at 60 ° C for 3 hours. The reaction mixture was cooled to room temperature and the mixture partitioned between water and ethyl acetate. The organic layer was dried over Na 2 SO 4 and evaporated to dryness. The crude material was stirred with diethyl ether and the precipitate was filtered and dried in vacuo to provide N - [(7R) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] -N- '- {2- [4- (trifluoromethyl) phenyl] ethyl} urea (125 mg, 94% yield). 1 H NMR (DMSOd 6) δ 1.45-1.68 (dd, 1H), 2.65-2.93 (m, 5H), 3.88 (d, 1H), 6.57 ( t, 1H), 7.42-7.75 (m, 6 H). Molecular weight: 378.39 (m, 1H), 1.78-1.93 (m, 1H), 2.29 (dt, 2H), 3.80-4.00 (m, 1H) (D, 1H), 6.98 (t, 1H), MS (M + H): 379

Example 4-49 N - [(7R) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] -N '- {2- [4- (trifluoromethoxy) phenyl] ethyl} urea

This example was carried out according to general method C.

A mixture of 7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) -carbamic acid phenyl ester (100 mg, 0.35 mmol) and 2- (4-trifluoromethoxy-phenyl) ethylamine (72.4 mg, 0.35 mmol) in DMSO (1.0 mL) was stirred at 60 ° C for 2.5 hours. The reaction mixture was cooled to room temperature and the mixture partitioned between water and ethyl acetate. The organic layer was dried over Na2 SO4 and evaporated to dryness. The starting material was stirred with diethyl ether and the precipitate was filtered and dried in vacuo to afford N - [(7R) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] -N'- {2- [4- (trifluoromethoxy) phenyl] ethyl] urea (109 mg, yield 79%). 1 H-NMR (DMSOd 6) δ 1.50-1.65 (m, 1H), 1.80-1.91 (m, 1H), 2.30 (dd, 1H), 2.60-2, (M, 5H), 3.34 (dt, 2H), 3.85-3.97 (m, 1H), 4.81 (d, 1H), 6.55 (t, 1H), 6.70 (d, 1H), 6.98 (t, 1H), 7.30 (d, 2H), 7.38 (d, 2H), 7.50 (s, 1H) .

Molecular weight: 394.39 94 MS (M + H): 395

Table 3

MOLECULAR STRUCTURE PM EM (M + H) PF activity class CN 1 LO H ° 0 ΓΊ Λ (/ γ xA F \ Ast? 300.336 301 C 5-3 AA X 300.336 301 204-205 B 1 LO H0n * 361,241 362 196-197 B LO 1 LO ΑΛ X 361,241 362 A 95 (continued)

No. MOLECULAR STRUCTURE PM MS (M + H) PF activity class 5-6 x 10 X 296,372 297 223 C 5-7 x 296,372 297 B oo 1 LOx 324.426 325 A C3 H3 LO, W &quot; X0 338,454 339 A 5-10 ΛΑ x 374,443 375 194-195 A 96 (Continued)

No. MOLECULAR STRUCTURE PM MS (M + H) PF activity class 5-11 aA XÒ &quot; 0 -F 366,343 367 203-204 A 5-12 0 ^ A-dy XÒ 380.37 381 A 5-13 X> N-OXO N 408,242 409 226-228 A 5-14 (γ-γ0s / * 1) Î »326,399 327> 192Z A 5-15 XX> 328,371 329> 82Z C97 (Continued)

No. MOLECULAR STRUCTURE PM MS (M + H) PF activity class 5-16 x F- X 328,436 329> 186Z B 5-17 XXX NOR O 330,362 331> 185Z A 5-18 XO 34 343 333 343 203 -212 B 5-19 XX fOo X6 346,817 347> 200Z A 5-20 XT f Xo 298,348 299> 202Z C 98 (Continued)

No. MOLECULAR STRUCTURE PM MS (M + H) PF activity class 5-21 A Λ X0 310,399 311> 223Z A 5-22 xc Λ X0 310,399 311> 197Z A 5-23 aA Λ X 310,399 311> 142Z A 5-24 χχ; Λ X 314,363 315> 197Z A 99

Example 5-1 N- (7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) - (4-trifluoromethoxyphenyl) urea

This example was carried out according to the general method E.

A mixture of 8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol (32.6 mg, 0.20 mmol) and (4-trifluoromethoxy-phenyl) -carbamic acid phenyl ester 59.5 mg, 0.20 mmol) in DMSO (1.0 mL) was stirred at 100 ° C for 1.5 hours. The mixture was concentrated under reduced pressure and then purified by preparative HPLC to obtain N- (7-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl) -N '- (4-trifluoromethoxy -phenyl) -urea (15.5 mg, yield 21%). 1 H-NMR (DMSO-d 6) δ 1.61 (m, 1H), 1.40 (m, 1H), 2.40 (m, 1H), 2.85 (m, 2H), 3.96 1H), 4.88 (d, J = 4.2 Hz, 1H), 6.80 (d, J = 7.2 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H) (D, J = 7.2 Hz, 1H), 7.65 (d, J = 9 Hz, 2H) 85 (s, 1H), 9.24 (s, 1H). Molecular weight: 366.34 MS (M + H): 367 100

mp: 198-200 ° C

Class of in vitro activity: A.

In a similar manner, according to Example 5-1 above, the compounds of Example 5-2 to 5-24 were synthesized.

Lisbon, November 27, 2007 101

Claims (21)

Hydroxy-tetrahydro-naphthalenyl urea derivative of formula (I), its tautomeric or stereoisomeric form or a salt thereof: wherein X represents C 1-6 alkyl; in which: Y represents a direct bond, 1 R5 R4 R5 R7 R 'or R 1, R 2 and R 3 independently represent hydrogen, halogen, hydroxy, nitro, carboxy, amino, C 1-6 alkylamino, di (C 1-6 alkyl) amino, C 3-8 cycloalkylamino, C 1-6 alkoxycarbonyl, phenyl, benzyl, sulfonamide, C 1-6 alkanoyl, C 1-6 alkanoylamino, carbamoyl, C 1-6 alkyl optionally substituted with cyano, C 1-6 alkoxycarbonyl or mono-, di- or trihalogen, C 1-6 alkoxy optionally substituted with mono-, di- or trihalogen, phenoxy optionally substituted with halogen or C 1-6 alkyl or optionally substituted alkylC 1-6 alkyl substituted by mono-, di- or tri-halogen; R4, R5, R6 and R7 independently represent C1-6 alkyl or phenyl; Z 1 represents hydrogen or C 1-6 alkyl; and Z 2 represents hydrogen, halogen or C 1-6 alkyl A hydroxy-tetrahydro-naphthalenylurea derivative of the formula (I), its tautomeric or stereoisomeric form or a salt thereof as claimed in claim 1, wherein X represents or in which Y represents a direct bond, or R4, R4 and R4 independently represent hydrogen, halogen, hydroxy, nitro, carboxyl, amino, C1-6 alkylamino, di (C1-6 alkyl) amino, C3-8 cycloalkylamino, C1-6 alkoxycarbonyl, phenyl, benzyl, sulfonamide, C1-6 alkanoyl, carbamoyl, C1-6 alkylcarbamoyl, cyano, C1-6 alkyl optionally substituted with cyano, C1-6 alkoxycarbonyl or mono-, di- or trihalogen, C1-6 alkoxy optionally substituted with mono-, di- or trihalogen, phenoxy optionally substituted with halogen or C1-6 alkyl or optionally substituted C1-6 alkylthio substituted by mono-, di- or tri-halogen; R 4 and R 5 are independently hydrogen or C 1-6 alkyl; and Z 1 and Z 2 each represent hydrogen. A hydroxy-tetrahydro-naphthalenylurea derivative of formula (I), its tautomeric or stereoisomeric form or salt thereof as claimed in claim 1, wherein X represents or in which Y represents a direct or Wherein R 1 and R 2 are independently hydrogen, chlorine, bromine, fluoro, cyclopentylamino, trifluoromethyl or trifluoromethoxy; R3, R4 and R5 each represent hydrogen; and Z 1 and Z 2 each represent hydrogen. A hydroxy-tetrahydro-naphthalenylurea derivative of the formula (I), its tautomeric or stereoisomeric form or a salt thereof as claimed in claim 1, wherein X represents in which Y represents a direct bond or R 5 R 2 and R 3 independently represent hydrogen, halogen, hydroxy, nitro, carboxy, amino, C 1-6 alkylamino, C 3-8 cycloalkylamino, di (C 1-6 alkyl) amino, C 1-6 alkoxycarbonyl, phenyl, 4-benzyl, sulfonamide, C 1-6 alkanoyl, alkanoylC 1-6 alkoxy, carbamoyl , C1-6 alkylcarbamoyl, cyano, C1-6 alkyl optionally substituted with cyano, C1-6 alkoxycarbonyl or mono-, di- or trihalogen, C1-6 alkoxy optionally substituted with mono-, di- or trihalogen, phenoxy optionally substituted with halogen or C1-6 alkyl or C1-6 alkyl -thio optionally substituted by mono-, di- or tri-halogen; R4 and R5 each represent hydrogen; and Z 1 and Z 2 each represent hydrogen. A hydroxy-tetrahydro-naphthalenylurea derivative of the formula (I), its tautomeric or stereoisomeric form or a salt thereof as claimed in claim 1, wherein X represents in which Y represents a direct bond or in which R 1 and R 2 are independently hydrogen, chlorine, bromine, fluoro, cyclopentylamino, trifluoromethyl or trifluoromethoxy; R3, R4 and R5 each represent hydrogen; and Z 1 and Z 2 each represent hydrogen. A hydroxy-tetrahydro-naphthalenylurea derivative of the formula (I), its tautomeric or stereoisomeric form or a salt thereof as claimed in claim 1, wherein said hydroxy-tetrahydro-naphthalenyl urea derivative of formula (I) is selected from the group consisting of: N- [4-chloro-3- (trifluoromethyl) phenyl] -3 '- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea; N- (3-chlorophenyl) -N '- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea; N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -3 '- [3- (trifluoromethyl) phenyl] urea; N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -3 '- [4- (trifluoromethyl) phenyl] urea; Ethyl 3 - ({[(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) amino] carbonyl} amino) benzoate; N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '- (1-naphthyl) urea; N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '- (2-naphthyl) urea; N- (3,4-dichlorophenyl) -N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea; N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '- (4-isopropylphenyl) urea; N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N '- (4-phenoxyphenyl) urea. N- (4-chloro-3- (trifluoromethyl) phenyl] -β- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea; N- (7- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N'-phenylurea; N- (4-chlorophenyl) naphthalenyl) urea: N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) - [2- (trifluoromethyl) phenyl] urea; , 6,7,8-tetrahydro-1-naphthalenyl) -N '- [4- (trifluoromethyl) phenyl] urea; N- (3,4-dichlorophenyl) -N' - (7-hydroxy-5,6 N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N- [4- (trifluoromethoxy) phenyl] N- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) -N- [4- (trifluoromethoxy) benzyl] urea; N- (7-hydroxy-5,6,7- Tetrahydro-1-naphthalenyl) -N '- (2,4,6-trimethoxybenzyl) urea; N- (2,6-difluorobenzyl) -N' - (7-hydroxy-5,6,7,8- N- [7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] -N '- [4- (trifluoromethyl) benzyl] urea; N- [7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] - [4- (trifluoromethoxy) benzyl] urea; N- [2- (4-chlorophenyl) and til] -α '- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea; and N- [3-fluoro-4- (trifluoromethyl) benzyl] -N '- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) urea. A hydroxy-tetrahydro-naphthalenylurea derivative of the formula (I) as claimed in any one of claims 1 to 6, wherein said hydroxy-tetrahydro-naphthalenyl urea derivative of formula (I) is selected from the group consisting of of: N- [4-chloro-3- (trifluoromethyl) phenyl] -3 '- [(7S) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] urea; N- [4-chloro-3- (trifluoromethyl) phenyl] -N '- [(7R) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] urea; N - [(7R) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] - [4- (trifluoromethyl) benzyl] urea; N - [(7S) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] -N '- [4- (trifluoromethyl) benzyl] urea; N - [(7R) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] -N '- [4- (trifluoromethoxy) benzyl] urea; and N - [(7S) -7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl] -3 '- [4- (trifluoromethoxy) benzyl] urea. A medicament comprising a hydroxy-tetrahydro-naphthalenylurea derivative of formula (I), its tautomeric or stereoisomeric form or a pharmaceutically acceptable salt thereof as claimed in claim 1 as an active ingredient. A medicament as claimed in claim 8, also comprising one or more pharmaceutically acceptable excipients. A medicament as claimed in claim 8, wherein said hydroxy-tetrahydro-naphthalenylurea derivative of formula (I), its tautomeric or stereoisomeric form or a pharmaceutically acceptable salt thereof is a VR1 antagonist. A medicament as claimed in claim 8 for the treatment and / or prevention of a urological disorder or disease. A medicament as claimed in claim 11, wherein said urologic disorder or disorder is urinary incontinence or overactive bladder. A medicament as claimed in claim 8 for the treatment and / or prevention of pain. A medicament as claimed in claim 13, wherein said pain is chronic pain, neuropathic pain, postoperative pain or pain of rheumatoid arthritis. A medicament as claimed in claim 8, for the treatment and / or prevention of a pain related disorder or disease. A medicament as claimed in claim 15, wherein said pain related disorder or disease is neuralgia, neuropathies, algesia, nerve damage, ischemia, neurodegeneration or stroke. 11 A medicament as claimed in claim 8, for the treatment and / or prevention of an inflammatory disorder or disease. A medicament as claimed in claim 17, wherein said inflammatory disorder or disease is asthma or COPD. Use of compounds according to claim 1 for the preparation of a medicament for the treatment and / or prevention of a urological disorder or disease. The use of compounds according to claim 1 for the preparation of a medicament for the treatment and / or prevention of pain. Use of compounds according to claim 1 for the preparation of a medicament for the treatment and / or prevention of an inflammatory disorder or disease. Lisbon, November 27, 2007 12