HK1082946B - Hydroxy tetrahydro-naphthalenylurea derivatives - Google Patents

Description

Hydroxytetrahydro-naphthalenylurea derivatives

Detailed Description

Technical Field

The present invention relates to hydroxy-tetrahydro-naphthalenylurea derivatives for use as active ingredients in pharmaceutical formulations. The hydroxy-tetrahydro-naphthylurea derivatives of the present invention have Vanilloid Receptor (VR) antagonistic activity and are useful for the prophylaxis and treatment of diseases which are associated with VR1 activity, in particular for the treatment of acute urinary incontinence, Overactive Bladder (Overactive blader), chronic pain, neuropathic pain, post-operative pain, rheumatoid arthritic pain, neuralgia, neuropathy, hyperesthesia, nerve injury, ischaemia, neurodegeneration, stroke, incontinence and/or inflammatory diseases such as asthma and Chronic Obstructive Pulmonary Disease (COPD).

Urinary Incontinence (UI) is involuntary enuresis. Acute urinary incontinence (UUI) is the most common type of UI with Stress Urinary Incontinence (SUI), which is usually caused by a defect in the urethral closing mechanism. UUI is often associated with neurological disorders or diseases that cause neuronal damage, such as dementia, parkinson's disease, multiple sclerosis, stroke, and diabetes, but individual patients without these diseases may also suffer from UUI. One of the common causes of UUI is overactive bladder (OAB), which refers to a medical condition of frequency and urgency symptoms caused by abnormal contraction and instability of the bladder detrusor.

Currently, there are several major urinary incontinence medications on the market that help treat UUI. Treatment of OAB has mainly employed drugs that affect peripheral nerve control mechanisms and those that act directly on bladder detrusor smooth muscle contractions, and emphasis has been placed primarily on the development of anticholinergic drugs. These drugs can inhibit parasympathetic nerves that control bladder micturition or can directly produce spasmolytic effects on bladder detrusor muscle. This results in a decrease in pressure within the bladder, an increase in volume and a decrease in the frequency of bladder contractions. Orally active anticholinergic drugs such as, for example, procaine (ProBanthine), tolterodine tartrate (Detrol) and oxybutynin (Ditropan) are the most commonly prescribed drugs. However, they have the greatest disadvantage of having unacceptable side effects, such as dry mouth, abnormal vision, constipation and central nervous system disorders. These side effects lead to poor compliance. Dry mouth alone results in 70% oral non-compliance with oxybutynin. The deficiencies of existing treatments indicate a need for new, effective, safe, orally effective drugs with fewer side effects.

Background

Vanillic acid (Vanilloid) compounds are characterized by having vanillyl groups or functionally equivalent groups. Examples of several vanillic acid compounds or modulators of the vanillic acid receptor are vanillin (4-hydroxy-3-methoxy-benzaldehyde), guaiacol (2-methoxy-phenol), zingerone (4-/4-hydroxy-3-methoxyphenyl/-2-butanone), eugenol (2-methoxy-4-/2-propenyl/phenol) and capsaicin (8-methyl-N-vanillyl-6-nonene-amide).

Among these, capsaicin (the major irritant component of "hot" red peppers) is a specific neurotoxin which desensitizes the transmission of C-fibers into neurons. Capsaicin interacts with vanilloid receptor (VR1), which is expressed primarily in the ganglion (DRG) cell bodies of the posterior root nerves or nerve endings (including C-fiber nerve endings) afferent to sensory nerve fibers [ Tominaga M, caterpillar MJ, malmbeg AB, Rosen TA, Gilbert H, Skinner K, Raumann BE, basbaume ai, Julius D: cloned capsaicin receptor and stimulation to produce multiple pain; neuron.21: 531-543, 1998]. The VR1 receptor has recently been cloned [ caterpillar MJ, SchumacherMA, Tominaga M, Rosen TA, Levine JD, Julius D: nature 389: 816, 824, (1997) and was confirmed to be a non-selective cation channel with 6 transmembrane domains structurally related to the TRP (transient receptor potential) channel family. Binding of capsaicin to VR1 causes sodium, calcium, and possibly potassium ions to spill out along their concentration gradient, causing initial depolarization and the release of neurotransmitters at the nerve terminals. Thus, VR1 can be viewed as a collection of molecules that produce chemical and physical stimuli of neuronal signals in a disorder or disease.

There is a great deal of direct or indirect evidence showing the relationship between VR1 activity and diseases such as pain, ischemia, and inflammatory diseases (e.g., WO 99/00115 and 00/50387). Furthermore, VR1 transducing reflex signals has been shown to be associated with overactive bladder in patients with impaired or abnormal spinal cord reflex pathways [ De Groat WC: one neurological basis for overactive bladder, Urology 50(6A Suppl): 36-52, 1997]. It has been shown that the use of VR1 agonists such as capsaicin reduces neurotransmitters, leading to desensitization of afferent nerves, which has promising results in the treatment of bladder dysfunction associated with spinal cord injury and multiple sclerosis [ (Maggi CA: therapeutic activity of capsaicin-like molecules-studies in animals and humans, Life sciences 51: 1777-1781, 1992) and (DeRidder D; Chandrimami V; Dasguppap; VanPoppel H, Baert L; Fowler CJ: treatment of refractory detrusor hyperreflexia with intracapsular capsaicin: a two-center long-term follow-up study, J.Urol.158: 2087-2092, 1997).

Antagonism of the VR1 receptor is expected to block neurotransmitter release, thereby preventing and treating conditions and diseases associated with VR1 activity.

Therefore, VR1 receptor antagonists are expected to be useful in the prevention and treatment of conditions and diseases that include: chronic pain, neuropathic pain, post-operative pain, rheumatoid arthritic pain, neuropathic pain, neuropathy, hyperesthesia, nerve injury, ischemia, neurodegeneration, stroke, incontinence, inflammatory diseases such as asthma and COPD, Urinary Incontinence (UI), such as acute urinary incontinence (UUI), and/or overactive bladder.

WO 00/50387 discloses compounds having vanilloid agonist activity represented by the general formula:

wherein:

X^Pis an oxygen atom or a sulfur atom;

A^pis-NHCH₂-or-CH₂-；

R^aIs substituted or unsubstituted C_1-4Alkyl, or R^alCO-；

Wherein

R^alIs 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;

R^bis 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;

R^cis hydrogen atom, alkyl containing 1-4 carbon atoms, aminoalkyl, diacid monoester or alpha-alkyl acid; and is

Star sign^*Represents a chiral carbon atom.

WO 2000/61581 discloses amine derivatives represented by the following general formula as effective drugs for the treatment of diabetes, hyperlipidemia, arteriosclerosis and cancer:

wherein:

(R ', R') represents (F, F), (CF)₃H) or (iPr ).

WO 00/75106 discloses compounds represented by the following general formula as effective drugs for treating MMP-mediated animal diseases:

wherein

Z represents

Wherein

R⁹⁰Is hydrogen, C_1-12Alkyl radical, C_3-8Cycloalkyl, etc., and R⁹¹Is amino-C_1-6Alkyl, aminocarbonyl-C_1-6Alkyl or hydroxyamino-carbonyl group C_1-6An alkyl group; and

R⁹⁰and R⁹¹Independently selected from H, C_1-6Alkyl radical, C_1-6Alkylthio radical, C_1-6Alkoxy, fluoro, chloro, bromo, iodo and nitro;

WO 00/55152 discloses compounds represented by the following general formula as effective drugs for the treatment of inflammation, immune-related diseases, pain and diabetes:

wherein

Ar₁Is a heterocycle;

Ar₂is tetrahydronaphthyl (tetrahydronapthy); and is

L and Q are defined in the description of the invention.

However, none of these references disclose simple hydroxy-tetrahydro-naphthyl-urea derivatives having VR1 antagonistic activity.

Accordingly, there is a need to develop compounds which have potent VR1 antagonistic activity and which are useful in the prevention and treatment of diseases associated with VR1 activity, in particular in the treatment of urinary incontinence, acute urinary incontinence, overactive bladder and pain and/or inflammatory diseases such as asthma and COPD.

Summary of The Invention

The present invention provides hydroxy-tetrahydro-naphthalenylurea derivatives of formula (I), tautomers and stereoisomers thereof, and salts thereof:

wherein X represents C_1-6Alkyl, aryl, heteroaryl, and heteroaryl,

Or

Wherein

Y represents a chemical bond,

Or

R¹、R²And R³Independently represent: hydrogen, halogen, hydroxy, nitro, carboxy, amino, C_1-6Alkylamino, di (C)_1-6Alkyl) amino, C_3-8Cycloalkylamino, C_1-6Alkoxycarbonyl, phenyl, benzyl, sulfamoyl (sulfonamide), C_1-6Alkanoyl radical, C_1-6Alkanoylamino, carbamoyl, C_1-6Alkylcarbamoyl, cyano, C optionally substituted by cyano_1-6Alkyl radical, C_1-6Alkoxycarbonyl or mono-, di-or tri-halogen, C optionally substituted by mono-, di-or tri-halogen_1-6Alkoxy, optionally substituted by halogen or C_1-6Alkyl-substituted phenoxy or C optionally substituted by mono-, di-or tri-halogen_1-6An alkylthio group;

R⁴、R⁵、R⁶and R⁷Independently represent: hydrogen, C_1-6Alkyl or phenyl;

Z¹represents: hydrogen or C_1-6An alkyl group; and is

Z²Represents: hydrogen, halogen or C_1-6An alkyl group.

Hydroxy-tetrahydro-naphthalenylurea derivatives of formula (I) and tautomers and stereoisomers thereof, and salts thereof unexpectedly exhibit excellent VR1 antagonistic activity. Thus. They are particularly suitable for the prophylaxis and treatment of diseases which are associated with VR1 activity, in particular for the treatment of acute urinary incontinence and/or overactive bladder.

Preferred hydroxy-tetrahydro-naphthalenylurea derivatives of formula (I) are those wherein

X represents

Or

Wherein

Y represents a bond, or

R¹、R²And R³Independently represent: hydrogen, halogen, hydroxy, nitro, carboxy, amino, C_1-6Alkylamino, di (C)_1-6Alkyl) amino, C_3-8Cycloalkylamino, C_1-6Alkoxycarbonyl, phenyl, benzyl, sulfamoyl, C_1-6Alkanoyl radical, C_1-6Alkanoylamino, carbamoyl, C_1-6Alkylcarbamoyl, cyano, C optionally substituted by cyano_1-6Alkyl radical, C_1-6Alkoxycarbonyl or mono-, di-or tri-halogen, C optionally substituted by mono-, di-or tri-halogen_1-6Alkoxy, optionally substituted by halogen or C_1-6Alkyl-substituted phenoxy or C optionally substituted by mono-, di-or tri-halogen_1-6An alkylthio group;

R⁴and R⁵Independently represent: hydrogen or C_1-6An alkyl group; and

Z¹and Z²Each represents hydrogen.

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

X represents

Or

Wherein

Y represents a bond, or

R¹、R²And R³Independently represent: hydrogen, halogen, di (C)_1-6Alkyl) amino, C_3-8Cycloalkylamino, C_1-6Alkoxycarbonyl, optionally cyano-substituted C_1-6Alkyl radical, C_1-6Alkoxycarbonyl or mono-, di-or tri-halogen, C optionally substituted by mono-, di-or tri-halogen_1-6Alkoxy, optionally substituted by halogen or C_1-6Alkyl-substituted phenoxy or C optionally substituted by mono-, di-or tri-halogen_1-6An alkylthio group;

R⁴and R⁵Each represents hydrogen; and

Z¹and Z²Each represents hydrogen.

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

X represents

Wherein

Y represents a bond, or

Wherein

R¹And R²Independently represent: hydrogen, chloro, bromo, fluoro, cyclopentylamino, trifluoromethyl or trifluoromethoxy;

R³、R⁴and R⁵Each represents hydrogen; and

Z¹and Z²Each represents hydrogen.

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

X represents

Wherein

Y represents a bond, or

Wherein

R¹And R²Independently represent: hydrogen, chloro, bromo, fluoro, cyclopentylamino, trifluoromethyl or trifluoromethoxy;

R³、R⁴and R⁵Each represents hydrogen; and

Z¹and Z²Each represents hydrogen.

More preferably, the hydroxy-tetrahydro-naphthalenylurea derivative of formula (I) is selected from:

1) n- [ 4-chloro-3- (trifluoromethyl) phenyl ] -N' - (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) urea;

2) n- (3-chlorophenyl) -N' - (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) urea;

3) n- (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) -N' - [3- (trifluoromethyl) phenyl ] urea;

4) n- (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) -N' - [4- (trifluoromethyl) phenyl ] urea;

5) ethyl 3- ({ [ (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthalenyl) amino ] carbonyl } amino) benzoate;

6) n- (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) -N' - (1-naphthyl) urea;

7) n- (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) -N' - (2-naphthyl) urea;

8) n- (3, 4-dichlorophenyl) -N' - (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) urea;

9) n- (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) -N' - (4-isopropylphenyl) urea;

10) n- (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) -N' - (4-phenoxyphenyl) urea;

11) n- [ 4-chloro-3- (trifluoromethyl) phenyl ] -N' - (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl ] urea;

12) n- [ 4-chloro-3- (trifluoromethyl) phenyl ] -N' - [ (7S) -7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl ] urea;

13) n- [ 4-chloro-3- (trifluoromethyl) phenyl ] -N' - [ (7R) -7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl ] urea;

14) n- (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) -N' -phenylurea;

15) n- (4-chlorophenyl) -N' - (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) urea;

16) n- (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) -N' - [2- (trifluoromethyl) phenyl ] urea;

17) n- (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) -N' - [4- (trifluoromethyl) phenyl ] urea;

18) n- (3, 4-dichlorophenyl) -N' - (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) urea;

19) n- (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) -N' - [4- (trifluoromethoxy) phenyl ] urea;

20) n- (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) -N' - [4- (trifluoromethoxy) benzyl ] urea;

21) n- (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) -N' - (2, 4, 6-trimethoxybenzyl) urea;

22) n- (2, 6-difluorobenzyl) -N' - (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) urea;

23) n- [ (7R) -7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl ] -N' - [4- (trifluoromethyl) benzyl ] urea;

24) n- [ (7S) -7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl ] -N' - [4- (trifluoromethyl) -benzyl ] urea;

25) n- [ (7R) -7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl ] -N' - [4- (trifluoromethoxy) -benzyl ] urea;

26) n- [ (7S) -7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl ] -N' - [4- (trifluoromethoxy) -benzyl ] urea;

27) n- [2- (4-chlorophenyl) ethyl ] -N' - (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) urea; and

28) n- [ 3-fluoro-4- (trifluoromethyl) benzyl ] -N' - (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) urea.

More preferably, the hydroxy-tetrahydro-naphthalenylurea derivative of formula (I) is selected from:

1) n- [ 4-chloro-3- (trifluoromethyl) phenyl ] -N' - [ (7S) -7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl ] urea;

2) n- [ 4-chloro-3- (trifluoromethyl) phenyl ] -N' - [ (7R) -7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl ] urea;

3) n- [ (7R) -7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl ] -N' - [4- (trifluoromethyl) benzyl ] urea;

4) n- [ (7S) -7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl ] -N' - [4- (trifluoromethyl) benzyl ] urea;

5) n- [ (7R) -7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl ] -N' - [4- (trifluoromethoxy) benzyl ] urea; and

6) n- [ (7S) -7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl ] -N' - [4- (trifluoromethoxy) benzyl ] urea.

In the context of the present invention, the substituents generally have the following meanings, if not indicated otherwise:

alkyl as such and in alkoxy, alkanoyl, alkylamino-carbonyl, alkylaminosulfonyl, alkylsulfonylamino, alkoxycarbonyl, alkoxycarbonylamino and alkanoylamino denotes straight-chain or branched alkyl groups, generally containing 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms and particularly preferably 1 to 3 carbon atoms, and represents, by way of example and preferably, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

Alkoxy represents by way of example and preferably methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkanoyl is exemplified and preferably denotes acetyl and propionyl.

Alkylamino represents alkylamino having one or two (independently selected) alkyl substituents, exemplified and preferred by methylamino, ethylamino, N-propylamino, isopropylamino, tert-butylamino, N-pentylamino, N-hexylamino, N-dimethylamino, N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-N-propylamino, N-isopropyl-N-N-propylamino, N-tert-butyl-N-methylamino, N-ethyl-N-N-pentylamino and N-N-hexyl-N-methylamino.

Alkylaminocarbonyl or alkylcarbamoyl denotes alkylaminocarbonyl containing one or more (independently selected) alkyl substituents, and is exemplified by and preferably denotes methylaminocarbonyl, ethylaminocarbonyl, N-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, N-pentylaminocarbonyl, N-hexylaminocarbonyl, N-dimethylaminocarbonyl, N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N-N-propylaminocarbonyl, N-isopropyl-N-N-propylaminocarbonyl, N-tert-butyl-N-methylaminocarbonyl, N-ethyl-N-N-pentylaminocarbonyl and N-N-hexyl-N-methylaminocarbonyl.

Alkoxycarbonyl is exemplified by and preferably represents methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl. Alkoxycarbonylamino represents by way of example and preferably methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, tert-butoxycarbonylamino, n-pentoxycarbonylamino and n-hexoxycarbonylamino.

Alkanoylamino exemplifies and preferably represents acetylamino and propionylamino.

Cycloalkyl as such and in cycloalkylamino and cycloalkylcarbonyl generally denotes cycloalkyl having 3 to 8 carbon atoms and preferably 5 to 7 carbon atoms, and is exemplified by and preferably denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Cycloalkylamino represents cycloalkylamino with one or 2 (independently selected) cycloalkyl substituents, exemplified and preferred to represent cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino and cycloheptylamino.

Halogen represents fluorine, chlorine, bromine and iodine.

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

Hydroxy-tetrahydro-naphthalenylurea derivatives of formula (I) and tautomers and stereoisomers thereof, and salts thereof, are effective for treating or preventing a disease associated with VR1 activity selected from the group consisting of: acute urinary incontinence, overactive bladder, chronic pain, neuropathic pain, post-operative pain, rheumatoid arthritic pain, neuralgia, neuropathy, hyperesthesia, nerve injury, ischemia, neurodegeneration and/or stroke, and inflammatory diseases such as asthma and COPD.

The compounds are useful for the treatment and prevention of disorders or diseases of the urinary system, such as acute urinary incontinence or overactive bladder. The compounds are also useful in the treatment and prevention of pain, and disorders or diseases in which pain is involved.

In addition, the compounds are useful for the treatment and prevention of neuropathic pain (a class of pain commonly associated with herpes zoster and post herpetic neuralgia), painful diabetic neuropathy, neuropathic lower back pain, post-traumatic and post-operative neuralgia, neuralgia induced by nerve compression and other neuralgia, phantom pain, complex regional pain syndromes, infectious or infectioid neuropathies such as those associated with HIV infection, pain associated with central nervous system disorders (e.g., multiple sclerosis, Parkinson's disease, spinal cord injury or traumatic brain injury), and post-stroke pain.

In addition, the compounds are useful in the treatment of musculoskeletal pain (a type of pain commonly associated with osteoarthritis or rheumatoid arthritis or other forms of arthritis) and back pain.

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

Furthermore, the compounds are useful for the treatment of visceral pain, for example pain associated with blockage of hollow organs such as biliary colic (coik), pain associated with irritable bowel syndrome, pelvic pain, vulvodynia, testicular pain or prostatodynia.

The compounds may also be used to treat pain associated with inflammatory injury of joints, skin, muscles or nerves.

The compounds are useful for the treatment of oromandibular facial pain and headaches such as migraine or tension-type headaches.

Modes for carrying out the invention

The compound of formula (I) of the present invention can be prepared by, but not limited to, the following [ A ], [ B ], [ C ], [ D ], [ E ], [ F ] or [ G ]. In some embodiments, one or more substituents of the compounds used as starting materials or intermediates, such as amino, carboxyl, and hydroxyl groups, are preferably protected with protecting groups well known to those skilled in the art. Examples of protecting Groups are described in "Protective Groups in Organic Synthesis (third edition)" (Greene and Wuts, John Wiley and Sons, New York, 1999).

[ method A ]

A compound of formula (I) (wherein X, Z¹And Z²As defined above) may be prepared from compounds of formula (II) (wherein Z is¹And Z²As defined above) and an isocyanate (III) (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, 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-Dimethylacetamide (DMAC), and N-methylpyrrolidone (NMP); ureas, such as 1, 3-dimethyl-imidazolidinone (DMI); sulfoxides, such as dimethyl sulfoxide (DMSO); and others. Mixtures of two or more of the above-listed solvents may optionally be used.

The reaction can be carried out in the presence of an organic base such as pyridine or triethylamine.

The reaction temperature of the reaction can be selectively set according to the compound to be reacted. The reaction temperature is typically, but not limited to, about room temperature to 100 ℃. The reaction may be carried out for generally 30 minutes to 48 hours, and preferably 1 to 24 hours.

The compounds of formula (II) and the isocyanates (III) are commercially available or can be prepared using known techniques.

[ method B ]

A compound of formula (I) (wherein X, Z¹And Z²As defined above) may be prepared from compounds of formula (II) (wherein Z is¹And Z²As defined above) with phosgene, diphosgene, triphosgene, 1-Carbonyldiimidazole (CDI) or 1, 1' -carbonylbis (1, 2, 4-triazole) (CDT) and then adding a compound of formula (IV) (wherein X is 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, 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-Dimethylacetamide (DMAC), and N-methylpyrrolidone (NMP); ureas, such as 1, 3-dimethyl-2-imidazolidinone (DMI); and others. Mixtures of two or more of the above-listed solvents may optionally be used.

The reaction temperature of the reaction can be selectively set according to the compound to be reacted. The reaction temperature is generally, but not limited to, about 20 ℃ to 50 ℃. The reaction may be carried out for generally 30 minutes to 10 hours, and preferably 1 to 24 hours.

Phosgene, diphosgene, triphosgene, CDI or CDT can be obtained commercially, and the compound of formula (IV) can be obtained commercially or prepared using known techniques.

[ method C ]

A compound of formula (I) (wherein X, Z¹And Z²As defined above) may be prepared from compounds of formula (II) (wherein Z is¹And Z²As defined above) and a compound of formula (V) (wherein L₁Representing a halogen atom such as a chlorine atom, a bromine atom or an iodine atom) and then adding a compound of the formula (IV) wherein X is 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, 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-Dimethylacetamide (DMAC), and N-methylpyrrolidone (NMP); ureas, such as 1, 3-dimethyl-2-imidazolidinone (DMI); and others. Mixtures of two or more of the above-listed solvents may optionally be used.

The reaction temperature of the reaction can be selectively set according to the compound to be reacted. The reaction temperature is generally, but not limited to, about 30 ℃ to 120 ℃. The reaction may be carried out for a period of time generally ranging from 1 hour to 48 hours, and preferably from 2 hours to 24 hours.

The reaction is preferably carried out in the presence of a base, which includes, for example, organic amines such as pyridine, triethylamine, N-diisopropylethylamine, dimethylaniline, diethylaniline, 4-dimethylaminopyridine and others.

The compounds of formula (V) are either commercially available or can be prepared using known techniques.

[ method D ]

A compound of formula (I) (wherein X, Z¹And Z²As defined above) can be prepared by reacting a compound of formula (IV) (wherein X is as defined above) with phosgene, diphosgene, triphosgene, 1-Carbonyldiimidazole (CDI) or 1, 1' -carbonylbis (1, 2, 4-triazole) (CDT) and then reacting a compound of formula (II) (wherein Z is¹And Z²As 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, 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-Dimethylacetamide (DMAC), and N-methylpyrrolidone (NMP); ureas, such as 1, 3-dimethyl-2-imidazolidinone (DMI); sulfoxides, such as dimethyl sulfoxide (DMSO); and others. Mixtures of two or more of the above-listed solvents may optionally be used.

The reaction temperature of the reaction can be selectively set according to the compound to be reacted. The reaction temperature is generally, but not limited to, about 30 ℃ to 100 ℃.

The reaction is generally carried out for 30 minutes to 40 hours, and preferably for 1 to 24 hours.

[ method E ]

A compound of formula (I) (wherein X, Z¹And Z²As defined above) may be prepared from compounds of formula (IV) wherein X is as defined above and compounds of formula (V) wherein L₁Representing a halogen atom, such as a chlorine atom, a bromine atom or an iodine atom), and then reacting a compound of formula (II) (wherein Z is¹And Z²As 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, 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-Dimethylacetamide (DMAC), and N-methylpyrrolidone (NMP); ureas, such as 1, 3-dimethyl-2-imidazolidinone (DMI); and others. Mixtures of two or more of the above-listed solvents may optionally be used.

The reaction temperature of the reaction can be selectively set according to the compound to be reacted. The reaction temperature is generally, but not limited to, about 30 ℃ to 120 ℃.

The reaction may be carried out for a period of time generally ranging from 1 hour to 48 hours, and preferably from 2 hours to 24 hours.

The reaction is preferably carried out in the presence of a base, which includes, for example, organic amines such as pyridine, triethylamine, N-diisopropylethylamine, dimethylaniline, diethylaniline, 4-dimethylaminopyridine and others.

[ method F ]

A compound of formula (I') (wherein X and Z²As defined above) can be passed throughThe preparation method comprises the following steps:

in step F-1, a compound of formula (VII) (wherein X and Z²As defined above) can be used as method [ A ]]、[B]、[C]、[D]Or [ E]Analogous processes for the preparation of the compounds of the formula (I) are described, in which compounds of the formula (VI) are used (in which Z²As defined above) in place of the compound of formula (II).

In step F-2, a compound of formula (VIII) (wherein X and Z²As defined above) can be prepared by reacting a compound of the formula (VII) wherein X and Z are²As 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, Tetrahydrofuran (THF) and 1, 2-dimethoxyethane; alcohols such as methanol, ethanol; water and others. Mixtures of two or more of the above-listed solvents may optionally be used.

The reaction temperature of the reaction can be selectively set according to the compound to be reacted. The reaction temperature is generally, but not limited to, about 20 ℃ to 100 ℃. The reaction may be carried out for generally 30 minutes to 10 hours, and preferably 1 to 24 hours.

In step F-3, a compound of formula (I') (wherein X and Z²As defined above) can be prepared by reacting a compound of the formula (VIII) (wherein X and Z are²As defined above) with a 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, Tetrahydrofuran (THF) and 1, 2-dimethoxyethane; aliphatic hydrocarbons such as n-hexane, cyclohexane; aromatic hydrocarbons such as benzene, toluene and xylene; alcohols such as methanol, ethanol, isopropanol, and others. Mixtures of two or more of the above-listed solvents may optionally be used.

The reaction temperature of the reaction can be selectively set according to the compound to be reacted. The reaction temperature is generally, but not limited to, about-20 ℃ to 50 ℃. The reaction may be carried out for generally 30 minutes to 10 hours, and preferably 1 to 24 hours.

A compound of formula (I') (wherein X and Z²Is as defined above, and Z¹Is C_1-6Alkyl) can be prepared in two steps by the following method:

in step F-4, a compound of formula (IX) (wherein X and Z²Is as defined above, and Z³Is hydrogen or C_1-5Alkyl) by a compound of the formula (VIII) (wherein X and Z²As defined above) and tri (C)_1-6Alkyl) oxosulfonium salts such as trimethyloxosulfonium iodide.

The reaction may be carried out in a solvent including, for example, ethers such as diethyl ether, isopropyl ether, dioxane, Tetrahydrofuran (THF) and 1, 2-dimethoxyethane; aliphatic hydrocarbons such as n-hexane, cyclohexane; aromatic hydrocarbons such as benzene, toluene and xylene; and others. Mixtures of two or more of the above-listed solvents may optionally be used.

The reaction temperature of the reaction can be selectively set according to the compound to be reacted. The reaction temperature is generally, but not limited to, about-20 ℃ to 50 ℃. The reaction may be carried out for generally 30 minutes to 10 hours, and preferably 1 to 24 hours.

In step F-5, a compound of formula (I') (wherein X and Z²Is as defined above, and Z¹Is C_1-6Alkyl) by a compound of the formula (IX) in which X and Z²Is as defined above, and Z³Is hydrogen or C_1-5Alkyl) with a 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, Tetrahydrofuran (THF) and 1, 2-dimethoxyethane; aliphatic hydrocarbons such as n-hexane, cyclohexane; aromatic hydrocarbons such as benzene, toluene and xylene; and others. Mixtures of two or more of the above-listed solvents may optionally be used.

The reaction temperature of the reaction can be selectively set according to the compound to be reacted. The reaction temperature is generally, but not limited to, about 20 ℃ to 50 ℃.

The reaction may be carried out for generally 30 minutes to 10 hours, and preferably 1 to 24 hours.

The compounds of formula (VI) are either commercially available or can be prepared using known techniques.

[ method G ]

Stereoisomer R form (I-a) (wherein X, Z is present) of Compound (I)¹And Z²As defined above) can be prepared by employing the method [ A ] for preparing the compound of the formula (I)]、[B]、[C]、[D]Or [ E]Analogously to the process described, wherein a compound of the formula (II-a) (wherein Z is¹And Z²As defined above) in place of the compound of formula (II).

Stereoisomer S form (I-a') of Compound (I) (wherein X, Z¹And Z²As defined above) can be obtained by a method [ A ] for preparing a compound of the formula (I)]、[B]、[C]、[D]Or [ E]By a similar process, wherein a compound of the formula (II-a') (wherein Z is¹And Z²As defined above) in place of the compound of formula (II).

The compounds of formula (II-a) or (II-a') may be prepared using known techniques.

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

Typical salts of the compounds of formula (I) include salts prepared by reaction of the compounds of the present invention with an inorganic or organic acid, or an inorganic or organic base. These salts are referred to as acid addition salts and base addition salts, respectively.

Acids which form acid addition salts include inorganic acids such as, but not limited to, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, and the like; and organic acids such as, but not limited to, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.

Base addition salts include those derived from inorganic bases such as, but not limited to, ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, carbonates, bicarbonates, and the like; such as, but not limited to, ethanolamine, triethylamine, tris (hydroxymethyl) methylamine, and the like. Examples of the inorganic base include sodium hydroxide, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, calcium hydroxide, calcium carbonate and the like.

The compound of the present invention or a salt thereof may be modified into a lower alkyl ester or other known ester depending on its substituent; and/or hydrates or other solvates. Such esters, hydrates and solvates are included within the scope of the present invention.

The compounds of the present invention may be administered in oral forms such as, but not limited to, plain and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups, solid and liquid aerosols and emulsions. They may also be administered parenterally, such as, but not limited to, intravenously, intraperitoneally, sublingually, intramuscularly, and the like, as is well known to those of ordinary skill in the pharmaceutical arts. The compounds of the present invention may be administered in intranasal form by topical administration of suitable intranasal vehicles, or by the transdermal route using transdermal delivery systems well known to those of ordinary skill in the art.

One of ordinary skill in the art can select a dosage regimen for use of a compound of the present invention based on a variety of factors including, but not limited to, age, body weight, sex, medical condition of the recipient, severity of the condition to be treated, route of administration, metabolic level and excretory function of the recipient, dosage form used, the particular compound used, and salts thereof.

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

Yet another embodiment of the invention is a pharmaceutical formulation comprising a compound of the invention and one or more pharmaceutically acceptable excipients that are compatible with the other components of the formulation and not deleterious to the recipient thereof. Pharmaceutical formulations of the invention may be prepared by combining a therapeutically effective amount of a compound of the invention with one or more pharmaceutically acceptable excipients. In preparing the compositions of the present invention, the active ingredient may be mixed with a diluent or may be contained in a carrier, which may be in the form of a capsule, sachet, paper or other container. The carrier may act as a diluent, may be a solid, semi-solid or liquid material as a medium, or may be in the form of: tablets, pills, troches, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example, up to 10% by weight of active compound, soft and hard 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, but not limited to, lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, methylcellulose, etc.; such disintegrating agents are, for example, but not limited to, corn, starch, methylcellulose, agar bentonite (agarbentonite), xanthan gum, alginic acid, and the like; such binders are, for example, but are not limited to, gelatin, natural sugars (natural sugars), beta-lactose, corn sweeteners, natural and synthetic gums, acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like; such lubricants are, for example, but not limited to, magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate, sodium acetate, sodium chloride, talc, and the like.

In powder form, the carrier may be a finely divided solid which is in admixture with the finely divided active component. The active ingredient may be mixed with the carrier having binding properties in suitable proportions and compressed into the shape and size desired for tableting. Preferably, powders and tablets contain from about 1% to about 99% 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 preparations include suspensions, emulsions, syrups and elixirs. The active ingredient may be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, a sterile organic solvent, or a mixed solvent of sterile water and a sterile organic solvent.

The active ingredient may also be dissolved in a suitable organic solvent such as aqueous propylene glycol. Other compositions can be prepared by dispersing the fine-particle active ingredient in aqueous starch or sodium carboxymethylcellulose solution or in a suitable oil.

The formulations may be in unit dosage form, being physically discrete units containing a unit dose, suitable for administration to humans or other mammals. The unit dosage form may be one capsule or tablet, or a plurality of capsules or tablets. By "unit dose" is meant a predetermined amount of an active compound of the present invention calculated to produce the desired therapeutic effect, together with one or more excipients. The amount of active ingredient in a unit dose may be varied or adjusted from about 0.1mg to about 1000mg or more depending upon the particular treatment involved.

Typical oral dosages for use in the present invention 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, when the indicated effect is to be achieved. In the case of parenteral administration, it has proven generally advantageous to administer an amount of from about 0.001 mg/kg/day to 100 mg/kg/day, preferably from 0.01 mg/kg/day to 1 mg/kg/day. The compounds of the invention may be administered in a daily dose of 1 time, or the daily dose may be administered in divided doses of 2, 3 or more times per day. Where delivery is in transdermal form, administration is, of course, continuous.

Examples

The present invention will be described in terms of embodiments, but they are not intended to define the metes and bounds of the invention.

In the examples below, all quantitative data are% by weight unless otherwise indicated.

Mass spectra were obtained using Electrospray (ES) ionization (micro Platform LC). Melting points were not corrected. Liquid chromatography-mass spectrometry (LC-MS) data were recorded on a Micromass Platform LC, Shimadzu Phenomenex ODS column (4.6 mm. phi. times.30 mm), eluent: acetonitrile-water (9: 1 to 1: 9) mixture, flow rate: 1 ml/min. TLC was performed on pre-formed silica gel plates (Merck silica gel 60F-254). Silica gel (WAKO-gel C-200(75-150 μm)) was used for all column chromatographies. All chemicals were reagent grade and purchased from Sigma-Aldrich, Wako pure chemical industries, Ltd., Tokyo Kasei Kogyo co.Ltd., Archicorporption.

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

The effects of the compounds of the present invention were determined by the following experiments and pharmacological tests.

[ measurement of capsaicin-induced Ca in human VR 1-transfected CHO cell line²⁺Inflow rate of fluid](experiment 1)

(1) Establishment of human VR1-CHO luc9aeq cell line

The human vanillic acid receptor (hVR1) cDNA (WO 00/29577) was cloned from a pool of axon-dissected dorsal root ganglia. The cloned hVR1 cDNA was constructed with pcDNA3 vector and transfected into the CHOluc9aeq cell line. The cell line contains aequorin and CRE-luciferase receptor genes as readout signals. In selective medium (with 10% FCS, 1.4mM sodium pyruvate, 20mM HEPES, 0.15% sodium bicarbonate, 100U/ml PenicilliumThe transfectants were cloned by limiting dilution in DMEM/F12 medium (Gibco BRL)) supplemented with biotin, 100. mu.g/ml streptomycin, 2mM glutamine, non-essential amino acids and 2mg/ml G418. Determination of Ca in capsaicin-stimulated clones²⁺The inflow amount. Highly responsive clones were selected and used further in the experiments of this protocol. Human VR1-CHO luc9aeq cells were maintained in selective medium at 1-2.5X 10 every 3-4 days⁵Cell/bottle (75 mm)²) At a speed of passage.

(2) Determination of Ca Using FDSS-3000²⁺Inflow rate of fluid

Human VR1-CHO luc9aeq cells were suspended in culture medium and plated at a density of 1,000 cells/well on 384-well plates (black wall clear matrix/Nalge Nunc International), the medium being identical to the selective medium except for G418. After 48 hours of incubation, the medium was changed to 2. mu.M Fluo-3AM (molecular Probe) and 0.02% Puronic F-127/assay buffer (Hank's Balanced salt solution (HBSS), 17mM HEPES (pH7.4), 1mM probenecid, 0.1% BSA) and the cells were incubated at 25 ℃ for 60 minutes. After washing twice with assay buffer, cells were incubated with test compound or medium for 20 minutes at 25 ℃. Stimulation with 10nM capsaicin for 60 seconds followed by FDSS-3000 (. lamda.) (_ex＝488nm，λ_em540nm/Hamamatsuphotonics) assay for cytoplasmic Ca²⁺And (6) moving. The Integral (Integral) R was calculated and compared to the control.

[ measurement of capsaicin-induced Ca in Primary cultured rat posterior root ganglion neurons²⁺Inflow rate of fluid](experiment 2)

(1) Preparation of rat posterior root ganglion neuron

Freshly born Wister rats (5-11 days) were sacrificed and the posterior root ganglia (DRG) were excised. DRG was incubated with 0.1% trypsin (Gibco BRL)/PBS (-) (Gibco BRL) at 37 ℃ for 30 minutes, then half the volume of Fetal Calf Serum (FCS) was added and the cells were spun down (spun down). DRG neuronal cells were resuspended in Ham F12/5% FCS/5% horse serum (Gibco BRL) and pipetted repeatedlyDispersed and then passed through a 70 μm mesh screen (Falcon). The plates were incubated at 37 ℃ for 3 hours to remove contaminating Schwann cells. Non-adherent cells were recovered and cultured in the presence of 50ng/ml recombinant rat NGF (Sigma) and 50 μm 5-fluorodeoxyuridine (Sigma) at 1X 10⁴Cells were cultured for an additional 2 days in 384 well plates coated with laminin (Nunc) at a density of 50. mu.l wells.

(2)Ca²⁺Determination of migration

DRG neuronal cells were washed twice with HBSS (supplemented with 17mM HEPES (pH7.4) and 0.1% BSA). After incubation for 40 min at 37 ℃ using 2. mu.M fluorine-3 AM (molecular probe), 0.02% PF127(GibcoBRL) and 1mM probenecid (Sigma), the cells were washed 3 times. Cells were incubated with VR1 antagonist or vehicle (dimethyl sulfoxide) followed by 1 μm capsaicin/FDSS-6000 (. lamda.) (L.)_ex＝480nm，λ_em520nm/Hamamatsu Photonics). The change in fluorescence was monitored at 480nm for 2.5 minutes. The integral R is calculated and compared to the control.

[ organ bath experiment for measuring capsaicin-induced bladder contraction ] (experiment 3)

Male Wistar rats (10 weeks) were anesthetized with ether and sacrificed by head and neck translocation. The whole bladder was excised and placed in an oxygenated modified Krebs-Henseleit solution (pH7.4) consisting of: 112mM NaCl, 5.9mM KCl, 1.2mM MgCl₂、1.2mM NaH₂PO₄、2mM CaCl₂、2.5mM NaHCO₃12mM glucose. Following the previously described method [ MaggiCA et al: br.j. pharmacol.108: 801-805, 1993]The contractile response of the bladder was studied. Isometric tension (Isometric tension) of rat detrusor longitudinal bars under a load of 1g was recorded. The bladder strips were allowed to equilibrate for 60 minutes prior to each stimulation. The time interval between the re-observation of the contraction reaction was 15 minutes at 80mM KCl. Responses to KCl were used as a separation criterion to evaluate maximal responses to capsaicin. The effect of the compound was studied by incubating the strips with the compound for 30 min before stimulation with 1 μ M capsaicin (medium: 80% saline, 10% EtOH and 10% tween 80). Prepared from the same animalOne of these preparations served as a control, while the other was used to evaluate the compound. The effect of the test compound on capsaicin-induced contraction was evaluated by calculating the ratio of each capsaicin-induced contraction to the internal standard (i.e., KCl-induced contraction).

[ determination of Ca in human P2X 1-transfected CHO cell line²⁺Inflow rate of fluid]

(1) Preparation of human P2X 1-transfected CHOluc9aeq cell line

The human P2X 1-transfected CHOluc9aeq cell line was established and maintained in Dulbecco's modified Eagle's medium (DMEM/F12) supplemented with 7.5% FCS, 20mM HEPES-KOH (pH7.4), 1.4mM sodium pyruvate, 100U/ml penicillin, 100. mu.g/ml streptomycin, 2mM glutamine (Gibco BRL) and 0.5 units/ml apyrase (grade I, Sigma). At 3X 10³Mu.l wells, and the suspended cells were plated in each well of 384-well optical bottom black plates (Nalge Nunc International). The cells were then cultured for 48 hours to adhere to the plate.

(2) Intracellular Ca²⁺Determination of the level

Using fluorescent Ca²⁺Determination of P2X1 receptor agonist-mediated intracytoplasmic Ca by chelate dye, Fluo-3AM (molecular Probe)²⁺The level is increased. The cells adhered to the plate were washed twice with washing buffer (HBSS, 17mM HEPES-KOH (pH7.4), 0.1% BSA and 0.5 units/ml apyrase) and incubated for 1 hour in 40. mu.l of loading buffer (1. mu.M Fluo-3AM, 1mM probenecid, 1. mu.M cyclosporin A, 0.01% pluronic (molecular probe) in washing buffer) in the dark. The plate was washed twice with 40 μ l wash buffer and 35 μ l wash buffer was added to each well together with 5 μ l test compound or 2 ', 3 ' -o- (2, 4, 6-trinitrophenyl) adenosine 5 ' -triphosphate (triphpphyte) (molecular probe) as a control. After another 10 min incubation in the dark, Ca was triggered by the addition of 200nM alpha, beta-methylene ATP agonist²⁺And (4) moving. At 250 millisecond intervals, through FDSS-6000 (lambda)_ex＝410nm，λ_em＝510nm/Hamamatsu Photonics) to determine the fluorescence intensity. From this value, an integral ratio is calculated and compared with that of the control.

[ measurement of capsaicin-induced bladder contraction in anesthetized rats ] (experiment 4)

(1) Animal(s) production

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

(2) Catheter insertion

Rats were anesthetized by intraperitoneal administration of 1.2g/kg urethane (Sigma). The abdominal cavity was opened via a medial incision and a polyethylene catheter (BECTON DICKINSON, PE50) was inserted into the bladder via the fornix. Meanwhile, the inguinal site was incised, and a polyethylene catheter (Hibiki, size 5) containing a 2IU/ml solution of Heparin (Novo Heparin, Aventis Pharma) in saline (Otsuka) was inserted into the common iliac artery.

(3) Cystometrography

The bladder catheter was connected via T-tubing to a pressure transducer (Viggo-spectral PteLtd, DT-XXAD) and a micro-syringe pump (TERUMO). Saline was delivered into the bladder at room temperature at a rate of 2.4 ml/h. Intravesical pressure was continuously recorded on an image plotter (Yokogawa). At least 3 repeated micturition cycles were recorded over a 20 minute period prior to administration of the test compound and served as a baseline.

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

Saline infusion was stopped prior to compound administration. Test compounds were dissolved in a mixture of ethanol, tween 80(ICN Biomedicals Inc.) and saline (1: 8 by volume) and then administered intra-arterially at 10 mg/kg. 2 minutes after administration of the compound, 10. mu.g of capsaicin (Nacalai Tesque) in ethanol was administered intra-arterially.

(5) Analysis of cystometrics parameters

Capsaicin-induced relative increases in intravesical pressure can be analyzed from cystometrography data. Capsaicin-induced bladder pressure is compared to the maximum bladder pressure during urination without capsaicin challenge. Student's t-test was used to evaluate test compound-mediated inhibition of elevated bladder pressure. A probability level of less than 5% is a significant difference.

[ measurement of overactive bladder in anesthetized cystitis rats ] (experiment 5)

(1) Animal(s) production

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

(2) Catheter insertion

Rats were anesthetized by intraperitoneal administration of 1.25g/kg urethane (Sigma). The abdominal cavity was opened via a medial incision and a polyethylene catheter (BECTON DICKINSON, PE50) was inserted into the bladder via the fornix. Simultaneously, the inguinal site was incised and a polyethylene catheter (BECTONDICKINSON, PE50) containing saline (Otsuka) was inserted into the femoral vein. After the bladder was emptied, the rats were left for 1 hour to recover from surgery.

(3) Cystometrography

The bladder catheter was connected via T-tubing to a pressure transducer (Viggo-spectral PteLtd, DT-XXAD) and a micro-syringe pump (TERUMO). Saline was infused into the bladder at a rate of 3.6ml/hr for 20 minutes at room temperature. Intravesical pressure was continuously recorded on an image plotter (Yokogawa). At least 3 repeated micturition cycles were recorded over a 20 minute period prior to administration of the test compound.

(4) Administration of test Compounds

Test compounds were dissolved in a mixture of ethanol, Tween 80(ICN Biomedicals Inc.) and saline (1: 8, V/V/V) and then administered intravenously at 0.05mg/kg, 0.5mg/kg or 5 mg/kg. After 3 minutes of administration of the compound, saline (Nacalai Tesque) was infused into the bladder at a rate of 3.6ml/hr at room temperature.

(5) Analysis of cystometrics parameters

Cystometrography parameters were analyzed as previously described [ Lecci a et al: eur.j.pharmacol.259: 129-135, 1994]. The frequency of urination, calculated from the urination interval, and the bladder capacity, calculated from the volume of saline input prior to the first urination, were analyzed from cystometrogram data. Unpaired Student's t-test was used to evaluate test compound-mediated inhibition of frequency of urination and test compound-mediated increase in bladder capacity. A probability level of less than 5% is a significant difference. Data from 4-7 rats were analyzed as mean ± SEM.

[ measurement of severe pain ]

Severe pain in rats is mainly measured on a hot plate. Two hot plate experimental methods were used: in the classical method, the animal is placed on a hot surface (52 ℃ -56 ℃) and the latency time is measured until the animal shows an impaired behaviour (e.g. stepping or licking); the other method is a gradually-heating hot plate method, wherein the experimental animal is placed on the surface of a hot plate at a natural temperature; the surface is then slowly but continuously heated until the animal begins to lick the hindpaw; the temperature reached when the hindpaw was started to lick was the pain threshold.

Control group treated with vehicle was used as control test compound. Prior to the pain test, the substance administration was carried out at different time points via different routes of administration (i.v., i.p., p.o., i.t., i.c.v., s.c., intradermal, transdermal).

[ measurement of persistent pain ]

Persistent pain was measured using formalin or capsaicin assay, mainly in rats. A1% -5% formalin solution or 10-100 μ g capsaicin was injected into one hind paw of the experimental animal. After formalin or capsaicin administration, the animals show nociceptive responses such as flinching, licking or biting of the infected paw. The number of nociceptive reactions within 90 minutes is a measure of the intensity of pain.

Control group treated with vehicle was used as control test compound. Prior to formalin or capsaicin administration, the substances are administered via different routes of administration (i.v., i.p., p.o., i.t., i.c.v., s.c., intradermal, transdermal) at different time points.

[ measurement of neuropathic pain ]

Neuropathic pain in rats is mainly induced by different unilateral sciatic nerve injuries. The procedure was performed under anesthesia. The first sciatic nerve injury was created by loose ligation around the sciatic nerve (Bennett and Xie, Pain 33 (1988): 87-107). The second is to tightly ligate the sciatic nerve to about half its diameter (Seltzer et al, Pain 43 (1990): 205-218). In the next method, a set of models in which the L5 and L6 spinal nerves or only the L5 spinal nerves were tightly ligated or severed (KIM SH; CHUNG JM, an experimental model of peripheral neuropathy prepared by ligating part of the spinal nerves of rats, PAIN 50(3) (1992) 355-. The fourth method involves axonotomy of two of the terminal branches of the three sciatic nerves (tibial and common peroneal nerves) leaving only the sural nerve intact. While the last involved axonotomy of only the tibial branch, neither the sural nerve nor the total nerve was damaged. Control animals were sham operated.

These nerve-injured animals develop chronic mechanical allodynia (mechanical allodynia), cold allodynia (cold allodynia), and thermal hyperalgesia post-operatively. Mechanical allodynia was measured by pressure sensors (Electronic von free Anesthesiometer, IITC Inc. -Life Science Instruments, Woodland Hills, SA, USA; Electronic von Frey System, Somedia Sales AB, H-rby, Sweden). Thermal hyperalgesia was measured by a radioactive heat source (Plantar Test, Ugo Basile, comeio, Italy) or by a cold plate at 5-10 ℃, and the number of nociceptive reactions in the affected paw was recorded as a measure of pain intensity. Further experiments for cold induced pain were to record the number of nociceptive responses, or to record the duration of nociceptive responses following acetone administration to the soles of infected hind limbs. Chronic pain is generally assessed by recording the approximate circadian rhythm of activity (circadanian rhytms) (Surjo and Amdt, Universal _ t zu K _ ln, Cologne, Germany) and the score for dyssynchrony (foot print patterns; FOOTPRINT program, Klapdor et al, 1997, a low cost method of analyzing foot print patterns, J.Neurosci.methods 75, 49-54).

Control groups treated with sham surgery and vehicle were used as controls for test compounds. Before the pain test, the substances were administered via different routes of administration (i.v., i.p., p.o., i.t., i.c.v., s.c., intradermal, transdermal) at different time points.

[ measurement of inflammatory pain ]

Inflammatory pain in rats was mainly induced by injection of 0.75mg of carrageenan or Freund's complete adjuvant into one hind paw. These animals develop edema that is associated with both mechanical allodynia and thermal hyperalgesia. Mechanical allodynia was measured by a pressure transducer (electronic von FreyAnestheometer, IITC Inc. -Life Science Instruments, Woodland Hills, SA, USA). Thermal hyperalgesia was determined by radioactive heat sources (Plantar Test, Ugo Basile, Comerio, Italy, Paw thermal stimulator, g. For edema, two methods can be used to determine. In the first method, animals are sacrificed and the infected hind paws are sectioned and weighed. The second method involves paw volume differentiation, determined by measuring the volume of the water penetration using an organ fullness tester (Ugo Basile, comeio, Italy).

Control groups, which were not inflamed and treated with vehicle, were used as control test compounds. Before the pain test, the substances were administered via different routes of administration (i.v., i.p., p.o., i.t., i.c.v., s.c., intradermal, transdermal) at different time points.

[ measurement of diabetic neuropathic pain ]

Rats treated with a single dose of 50-80mg/kg streptozotocin by intraperitoneal injection developed profound hyperglycemia and mechanical allodynia within 1-3 weeks. Mechanical allodynia was measured by a pressure transducer (electronic von Frey Anesthesiometer, IITC inc. -Life sciences instruments, Woodland Hills, SA, USA).

Control animals treated with both diabetic and non-diabetic vehicle were used as control test compounds. Before the pain test, the substances were administered via different routes of administration (i.v., i.p., p.o., i.t., i.c.v., s.c., intradermal, transdermal) at different time points.

Capsaicin-induced Ca in human VR 1-transfected CHO cell lines²⁺IC of inflow₅₀The results are shown in the examples and are tabulated in the examples below. These data are consistent with the compounds obtained by solid phase synthesis and therefore are at a level of purity of about 40% to 90%. For practical reasons, the activity of the compounds is classified into the following four classes:

IC₅₀a (< or ═ 0.1 μ M < B (< or ═)0.5 μ M < C (< or ═)1 μ M < D

In the other experiments (2) to (5) above, the compounds of the present invention also showed excellent selectivity and strong activity.

Process for producing starting compound

[ starting Compound A ]

To a stirred solution of 8-amino-2-naphthol (50.0g, 314mmol) in tetrahydrofuran (1000mL) was added di-tert-butyl dicarbonate (68.6g, 314 mmol). The mixture was stirred at 70 ℃ for 18 hours. After the mixture was cooled to room temperature, the solvent was removed under reduced pressure. Ethyl acetate was added to the residue and washed with saturated aqueous sodium carbonate solution and then with water. Extracting the organic layer with Na₂SO₄Drying, filtering and concentrating under reduced pressureAnd (4) shrinking. To the resulting residue was added isopropyl ether, and then the precipitate was filtered and dried to give N-tert-butoxycarbonyl-8-amino-2-naphthol (64.2g, 79% yield).

MS(ESI)m/z 259[M]⁺

¹H NMR(DMSO-d6)δ1.48(s，9H)，7.07(dd，J＝2.2Hz and 8.85Hz，1H)，7.20(t，J＝7.9Hz，1H)，7.24(d，J＝2.2Hz，1H)，7.36(d，J＝7.25Hz，1H)，7.60(d，J＝8.2Hz，1H)，7.75(d，J＝8.8Hz，1H)，8.92(s，1H).

Iodothane (42.3g, 272mmol) was then added to a mixture of N-tert-butoxycarbonyl-8-amino-2-naphthol (64.0g, 247mmol) and cesium carbonate (161g, 493mmol) in 300mL anhydrous DMF at room temperature. The mixture was stirred at 60 ℃ 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, Na₂SO₄Dried, filtered and concentrated under reduced pressure. To the resulting residue was added isopropyl ether, and then the precipitate was collected and dried to give (7-ethoxy-naphthalen-1-yl) -carbamic acid-tert-butyl ester (47.9g, 67.5% yield).

MS(ESI)m/z 287[M]⁺

¹H NMR(DMSO-d6)δ1.41(t，J＝6.95Hz，3H)，1.50(s，9H)，4.16(q，J＝6.95Hz，2H)，7.15(dd，J＝2.55 and 8.8 Hz，1H)，7.28(t，J＝8.8 Hz，1H)，7.36(d，J＝2.2Hz，1H)，7.54(d，J＝7.25Hz，1H)，7.61(d，J＝8.2Hz，1H)，7.80(d，J＝8.85Hz，1H)，9.12(s，1H)。

Next, to a solution of (7-ethoxy-naphthalen-1-yl) -carbamic acid-tert-butyl ester (47.9g, 167mmol) in 100mL of anhydrous 1, 4-dioxane was added a 4N solution of HCl in 1, 4-dioxane (100 mL). The mixture was stirred at room temperature for 2 hours. Isopropyl ether was added to the reaction mixture, and then the precipitate was filtered. To the resulting solid was added a saturated sodium bicarbonate solution, and the product was extracted with ethyl acetate. The organic layer was washed with Na₂SO₄Drying, filtering and concentrating under reduced pressureCondensation gave 7-ethoxy-naphthalen-1-yl-amine (27.0g, 86.3% yield).

MS(ESI)m/z 187[M]⁺

¹H NMR(DMSO-d6)δ1.39(t，J＝11.3Hz，3H)，4.15(q，J＝11.3Hz，2H)，5.52(s(br)，2H)，6.64(dd，J＝3.75 and 10.05Hz，1H)，7.01-7.07(m，3H)，7.39(d，J＝3.8Hz，1H)，7.63(d，J＝14.45Hz，1H).

Next, to a flask containing a mixture of 7-ethoxy-naphthalen-1-yl-amine (1.80g, 9.61mmol) and tert-butanol (2.13g, 28.8mmol) in tetrahydrofuran (20mL) was added liquid ammonia (300mL) at-78 ℃. Lithium (0.200g, 28.8mmol) was added to the mixture over 30 min and stirred at-78 ℃ for 1 h. Methanol and water were added and the mixture was stirred at room temperature for 16 hours to evaporate the ammonia. To the resulting residue was added ethyl acetate. The organic layer was washed with water, Na₂SO₄Drying, filtration and concentration under reduced pressure gave 7-ethoxy-5, 8-dihydronaphthalen-1-yl-amine (1.37g, 76% yield).

[ starting Compound B ]

To a stirred solution of 7-ethoxy-5, 8-dihydronaphthalen-1-yl-amine (1.07g, 5.65mmol) in tetrahydrofuran (30mL) was added 2N HCl (10mL) in water and stirred at 40 ℃ for 1 hour. Sodium bicarbonate was added to neutralize the mixture and the product was extracted with ethyl acetate. The organic layer was washed with water, Na₂SO₄Drying, filtration and concentration under reduced pressure gave 8-amino-3, 4-dihydro-1H-naphthalen-2-one (0.71g, 78% yield).

MS(ESI)m/z 162[M+H]⁺

¹H NMR(CDC13)δ2.62-2.65(m，2H)，3.07(t，J＝7.25Hz，2H)，3.34(s，2H)，6.65(d，J＝7.85，-1H)，6.70(d，J＝7.25Hz，1H)，7.07(t，J＝7.55Hz，1H).

Next, sodium borohydride (0.030g, 0.175mmol) was added to 8-amino-3, 4-dihydro-1H-naphthalen-2-one (0.050g, 0.318mmol) in methanol (10mL) at 0 deg.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 washed with Na₂SO₄Drying, filtration and concentration under reduced pressure gave 8-amino-1, 2, 3, 4-tetrahydro-naphthalen-2-ol (0.037g, 71% yield).

MS(ESI)m/z 163[M]⁺

¹H NMR(DMSO-d6)δ1.53-1.57(m，1H)，1.81-1.85(m，1H)，2.16(dd，J＝7.7 and16.4Hz，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＝7.7Hz，1H)，6.76(t，J＝7.55Hz，1H).

[ starting Compound C ]

A stirred solution of phenylruthenium (II) chloride (benzanethenium (II) chloride) dimer (3.10mg, 0.006mmol) and (1S, 2R) - (-) -cis-1-amino-2-indanol (3.7mg, 0.025mmol) in degassed isopropanol was heated at 80 deg.C for 20 minutes under argon protection. The mixture was added to a solution of 8-amino-3, 4-dihydro-1H-naphthalen-2-one (50mg, 0.310mmol) in isopropanol (3mL) at room temperature. A solution of potassium hydroxide (3.48mg, 0.062mmol) in isopropanol (1mL) was added and the mixture was stirred at 45 ℃ 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 8-amino-1, 2, 3, 4-tetrahydro-naphthalen-2-ol enantiomer (33.0mg, 65% yield).

MS(ESI)m/z 163[M]⁺

¹H NMR(DMSO-d6)δ1.53-1.57(m，1H），1.81-1.85(m，1H)，2.16(dd，J＝7.7 and16.4Hz，-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＝7.7Hz，1H)，6.76(t，J＝7.55Hz，1H).

[ starting Compound D ]

A stirred solution of phenylruthenium (II) chloride (benzanethenium (II) chloride) dimer (1.55g) and (1S, 2R) - (-) -cis-1-amino-2-indanol (1.85g) in degassed isopropanol (500ml) was heated at 80 ℃ for 20 minutes under argon protection and then cooled to room temperature. This mixture was added to a solution of 8-amino-3, 4-dihydro-1H-naphthalen-2-one (25.0g) in isopropanol (700mL) at room temperature, followed by addition of a solution of the prepared potassium hydroxide (1.74g) in isopropanol (300mL) (prepared beforehand, dissolved at 45 ℃ C. and then cooled to room temperature). After stirring for 30 minutes at 45 ℃, the mixture was cooled to room temperature, passed through a pad of silica gel and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting solid was dissolved in dichloromethane and then treated with activated carbon for 10 minutes. After filtration through a pad of silica gel, the mixture was concentrated under reduced pressure. The resulting product was recrystallized from dichloromethane to give (R) -8-amino-1, 2, 3, 4-tetrahydro-naphthalen-2-ol (14g, 56% yield) as red crystals.

MS(ESI)m/z 163[M]⁺

¹H NMR(DMSO-d6)δ1.53-1.57(m，1H)，1.81-1.85(m，1H)，2.16(dd，J＝7.7 and16.4Hz，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＝7.7Hz，1H)，6.76(t，J＝7.55Hz，1H).

(S) -8-amino-1, 2, 3, 4-tetrahydro-naphthalen-2-ol is generated using (1R, 2S) - (+) -cis-1-amino-2-indanol.

Phenyl chloroformate (28.8mL) was then added to a solution of (R) -8-amino-1, 2, 3, 4-tetrahydro-naphthalen-2-ol (36.2g) and pyridine (18.8mL) in THF (850mL) at 0 ℃ under cooling. The mixture was stirred at room temperature for 3 hours and then poured into ethyl acetate. By NH₄The mixture was washed with aqueous Cl solution, then with water, and the organic layer was washed with Na₂SO₄Dried, filtered and concentrated under reduced pressure. Ethylonitrile was added to the obtained residue, and the precipitate was collected and washed with a mixed solvent of acetonitrile and isopropyl ether (2: 3) to give { (R) -7-hydroxy-5, 6, 7, 8-tetrahydro-naphthalen-1-yl } -carbamic acid phenyl ester (33.0 g).

MS(ESI)m/z 284[M+H]⁺

¹H NMR(DMSO-d6)δ1.59-1.64(m，1H)，1.83-1.89(m，1H)，2.68-2.99(m，4H)，3.90-3.92(m，1H)，4.84(dd，J＝3.8Hz and 29.9Hz，1H)，6.75(d，J＝7.9Hz，1H)，7.07-7.25(m，6H)，7.42(t，J＝7.85Hz，1H)，9.29(s，1H).

Examples 1 to 1

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

This example was carried out according to general procedure F.

To a stirred solution of 7-ethoxy-5, 8-dihydronaphthalen-1-ylamine (0.16g, 0.84mmol) in tetrahydrofuran (15mL) was added 4-chloro-3-trifluoromethyl-phenyl isocyanate (0.22g, 1.0 mmol). The mixture was stirred at room temperature for 1.5 hours, and then poured into water. The product was extracted with ethyl acetate and the organic layer was washed with Na₂SO₄Drying, filtration and concentration under reduced pressure gave N- (4-chloro-3-trifluoromethyl-phenyl) -N' - (7-ethoxy-5, 8-dihydro-naphthalen-1-yl) urea (0.31g, 89% yield). Then, to N- (4-chloro-3-)To a solution of trifluoromethyl-phenyl) -N' - (7-ethoxy-5, 8-dihydro-naphthalen-1-yl) urea (0.21g, 0.51mmol) in tetrahydrofuran (20mL) was added 1N aqueous hydrochloric acid (5mL) and the mixture was stirred at 40 ℃ for 45 minutes. The mixture was neutralized by adding 10% aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with Na₂SO₄Drying, filtration and concentration under reduced pressure gave N- (4-chloro-3-trifluoromethyl-phenyl) -N' - (7-oxo-5, 6, 7, 8-tetrahydro-naphthalen-1-yl) urea (0.16g, 85% yield). Next, to N- (4-chloro-3-trifluoromethyl-phenyl) -N' - (7-oxo-5, 6, 7, 8-tetrahydro-naphthalen-1-yl) urea (0.07g, 0.18mmol) in methanol (10mL) was added sodium borohydride (0.04g, 0.09mmol) at 0 deg.C and the mixture was stirred for 30 minutes. The mixture was then poured into water and the product was extracted with ethyl acetate. The organic layer was washed with Na₂SO₄Drying, filtering and concentrating under reduced pressure, then recrystallizing the obtained product from ethyl acetate/hexane (1/2) solution to obtain N- [ 4-chloro-3- (trifluoromethyl) phenyl]-N' - (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) urea (41mg, 59% yield).

¹H NMR(DMSO-d6)δ1.57-1.58(m，1H)，1.87-1.90(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＝7.6Hz，1H)，7.06(t，J＝7.6Hz，1H)，7.58(d，J＝7.6Hz，1H)，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℃

Classification of in vitro activity: a. the

Examples 1 to 2

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

The corresponding R-isomer (8.3mg) was isolated from a racemic mixture of N- [ 4-chloro-3- (trifluoromethyl) phenyl ] -N' - (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) urea (30.0mg) using chiral HPLC (Daicel OD column, N-hexane: 2-propanol ═ 98: 2). Chiral HPLC (Chiral Cel od0.49cm × 25cm column, n-hexane/ethanol 97/3, flow rate 1.5mL/min), and R-isomer was detected at 20.1 min.

Molecular weight: 384.8

MS(M+H)：384

Examples 1 to 3

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

The corresponding S-isomer (2.2mg) was isolated from a racemic mixture of N- [ 4-chloro-3- (trifluoromethyl) phenyl ] -N' - (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) urea (30.0mg) using chiral HPLC (Daicel OD column, N-hexane: 2-propanol ═ 98: 2). Chiral HPLC (Chiral CelOD 0.49cm × 25cm column, n-hexane/ethanol 97/3, flow rate 1.5mL/min), and S-isomer was detected at 17.6 min.

Molecular weight: 384.8

MS(M+H)：384

Example 2-1

N-phenyl-N' - (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) urea

This example was carried out according to general procedure a.

Phenyl isocyanate (14.6mg, 0.123mmol) was added to a solution of 8-amino-1, 2, 3, 4-tetrahydro-naphthalen-2-ol (20.0mg, 0.123mmol) in 1, 4-dioxane (1.0mL) at room temperature. The mixture was stirred for 16 hours, then isopropyl ether and hexane were added. The precipitate was filtered and dried to give N-phenyl-N' - (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) urea (17.8mg, 51% yield).

Molecular weight: 282.3

MS(M+H)：283

mp：198-199℃

And (3) activity classification: c

The compounds of examples 2-2 to 2-41 were synthesized and tested using starting material B and following a procedure analogous to example 2-1 above.

TABLE 1

Example 3-1

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

This example was carried out according to general procedure G.

To a solution of 8-amino-1, 2, 3, 4-tetrahydro-naphthalen-2-ol enantiomer (33.0mg, 0.202mmol) in 1, 4-dioxane (3.0mL) was added (4-chloro-3-trifluoromethyl-phenyl) isocyanate (44.8mg, 0.202mmol) at room temperature. The mixture was stirred for 16 hours, then isopropyl ether and hexane were added. The precipitate was filtered and dried to give chiral N- (4-chloro-3- (trifluoromethyl) phenyl) -N' - (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) urea (54.0mg, 69% yield). Enantiomeric excess (% ee) was determined using a Chiral Cel OD column (15% isopropanol/hexane as eluent, flow rate 1 ml/min).

Molecular weight: 384.8

MS(M+H)：384

mp：227-228℃

Classification of in vitro activity: a. the

Example 4-1

N- (7-hydroxy-5, 6, 7, 8-tetrahydro-naphthalen-1-yl) -N' - (4-trifluoromethoxy-benzyl) -urea

This example was carried out according to general procedure C.

A mixture of 7-hydroxy-5, 6, 7, 8-tetrahydro-naphthalen-1-yl) -carbamic acid phenyl ester (30.0mg, 0.11mmol) and 4-trifluoromethoxy-benzylamine (21.3mg, 0.11mmol) in DMSO (1.0ml) was stirred at 100 ℃ for 17 h. The reaction mixture was cooled to room temperature and water was added. The precipitate was filtered, washed with water and then acetonitrile to give N- (7-hydroxy-5, 6, 7, 8-tetrahydro-naphthalen-1-yl) -N' - (4-trifluoromethoxy-benzyl) -urea (6.70mg, 17% yield).

¹H NMR(DMSO-d6)δ1.54-1.65(m，1H)，1.81-1.92(m，1H)，2.25-2.38(m，1H)，2.68-2.88(m，3H)，3.86-3.98(m，1H)，4.32(d，J＝6.0Hz，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，1H)，7.34(d，J＝8.3Hz，2H)，7.43(d，J＝8.3Hz，2H)，7.63(d，J＝7.5Hz，1H)，7.5(s，1H).

Molecular weight: 380.36

MS(M+H)：381

mp：213℃

Classification of in vitro activity: a. the

Example 4 to 2

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

This example was carried out according to general procedure C.

A mixture of (R) - (7-hydroxy-5, 6, 7, 8-tetrahydro-naphthalen-1-yl) -phenyl carbamate (147.3mg, 0.52mmol) and 4-trifluoromethoxy-benzylamine (99.4mg, 0.52mmol) in DMSO (1.5ml) was stirred at 150 ℃ for 1.5 h. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added. The extracted organic layer was washed with water, then brine, and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The resulting residue was triturated with dichloromethane and hexanes to give N- { (R) -7-hydroxy-5, 6, 7, 8-tetrahydro-naphthalen-1-yl } -N' - (4-trifluoromethoxy-benzyl) -urea (168.0mg, 85% yield).

¹H NMR(DMSO-d₆)δ1.54-1.65(m，1H)，1.81-1.92(m，1H)，2.25-2.38(m，1H)，2.68-2.88(m，3H)，3.86-3.98(m，1H)，4.32(d，J＝6.0Hz，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，1H)，7.34(d，J＝8.3Hz，2H)，7.43(d，J＝8.3Hz，2H)，7.63(d，J＝7.5Hz，1H)，7.5(s，1H).

Molecular weight: 380.36

MS(M+H)：381

Classification of in vitro activity: a. the

Chiral HPLC (ChiralCel AD 0.49cm × 25cm column, n-hexane/ethanol 90/10, flow rate 15mL/min), detected the R-isomer at 17.7 min.

Examples 4 to 3

N- { (S) -7-hydroxy-5, 6, 7, 8-tetrahydro-naphthalen-1-yl } -N' - (4-trifluoromethoxy-benzyl) -urea

This example was carried out according to general procedure C.

A mixture of (S) - (7-hydroxy-5, 6, 7, 8-tetrahydro-naphthalen-1-yl) -carbamic acid phenyl ester (85.0mg, 0.30mmol) and 4-trifluoromethoxy-benzylamine (57.4mg, 0.30mmol) in DMSO (1.0ml) was stirred at 150 ℃ for 1.5 h. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added. The extracted organic layer was washed with water, then brine, and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The resulting residue was triturated in dichloromethane and hexanes to give N- { (S) -7-hydroxy-5, 6, 7, 8-tetrahydro-naphthalen-1-yl } -N' - (4-trifluoromethoxy-benzyl) -urea (95.0mg, 83% yield).

¹H NMR(DMSO-d₆)δ1.54-1.65(m，1H)，1.81-1.92(m，1H)，2.25-2.38(m，iH)，2.68-2.88(m，3H)，3.86-3.98(m，1H)，4.32(d，J＝6.0Hz，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，1H)，7.34(d，J＝8.3Hz，2H)，7.43(d，J＝8.3Hz，2H)，7.63(d，J＝7.5Hz，1H)，7.5(s，1H).

Molecular weight: 380.36

MS(M+H)：381

Classification of in vitro activity: a. the

Chiral HPLC (ChiralCel AD 0.49cm × 25cm column, n-hexane/ethanol 90/10, flow rate 1.5mL/min), S-isomer was detected at 13.2 min.

Examples 4 to 4

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

This example was carried out according to general procedure C.

A mixture of (R) - (7-hydroxy-5, 6, 7, 8-tetrahydro-naphthalen-1-yl) -phenyl carbamate (150.0mg, 0.53mmol) and 4-trifluoromethyl-benzylamine (92.7mg, 0.53mmol) in DMSO (2.0ml) was stirred at 100 ℃ for 1.5 h. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added. The extracted organic layer was washed with water, then brine, and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The resulting residue was triturated in dichloromethane and hexanes to give N- { (R) -7-hydroxy-5, 6, 7, 8-tetrahydro-naphthalen-1-yl } -N' - (4-trifluoromethyl-benzyl) -urea (156mg, 81% yield).

¹H NMR(DMSO-d6)δ1.58-1.59(m，1H)，1.85-1.86(m，1H)，2.33-2.85(m，4H)，3.91-3.92(m，1H)，4.39(d，J＝5.7Hz，2H)，4.84(d，J＝4.1Hz，1H)，6.72(d，J＝7.25Hz，1H)，6.98(t，J＝7.9Hz，1H)，7.12(t，J＝6.0Hz，1H)，7.51-7.71(m，6H).

Molecular weight: 364.37

MS(M+H)：366

mp：204.3℃

Classification of in vitro activity: a. the

Chiral HPLC (ChiralCel AD 0.49cm × 25cm column, n-hexane/ethanol 90/10, flow rate 1.5mL/min), R-isomer was detected at 16.2 min.

Examples 4 to 5

N- { (S) -7-hydroxy-5, 6, 7, 8-tetrahydro-naphthalen-1-yl } -N' - (4-trifluoromethyl-benzyl) -urea

This example was carried out according to general procedure C.

A mixture of (S) - (7-hydroxy-5, 6, 7, 8-tetrahydro-naphthalen-1-yl) -carbamic acid phenyl ester (100.0mg, 0.35mmol) and 4-trifluoromethyl-benzylamine (61.8mg, 0.35mmol) in DMSO (1.5ml) was stirred at 100 ℃ for 1.5 h. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added. The extracted organic layer was washed with water, then brine, and Na₂SO₄Dried, filtered and concentrated under reduced pressure. The resulting residue was triturated in dichloromethane and isopropyl ether to give N- { (S) -7-hydroxy-5, 6, 7, 8-tetrahydro-naphthalen-1-yl } -N' - (4-trifluoromethyl-benzyl) -urea (109mg, 85% yield).

¹H NMR(DMSO-d6)δ1.58-1.59(m，1H)，1.85-1.86(m，1H)，2.33-2.85(m，4H)，3.91-3.92(m，1H)，4.39(d，J＝5.7Hz，2H)，4.84(d，J＝4.1Hz，1H)，6.72(d，J＝7.25Hz，1H)，6.98(t，J＝7.9Hz，1H)，7.12(t，J＝6.0Hz，1H)，7.51-7.7i(m，6H).

Molecular weight: 364.37

MS(M+H)：366

Classification of in vitro activity: a. the

Chiral HPLC (ChiralCel AD 0.49cm × 25cm column, n-hexane/ethanol 90/10, flow rate 1.5mL/min), R-isomer was detected at 11.7 min.

The compounds of examples 4-6 to 4-54 were synthesized in analogy to the methods of examples 4-1, 4-2, 4-3, 4-4 and 4-5 above.

TABLE 2

Examples 4 to 48

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

This example was carried out according to general procedure C.

A mixture of (7-hydroxy-5, 6, 7, 8-tetrahydro-naphthalen-1-yl) -carbamic acid phenyl ester (100.0mg, 0.35mmol) and 2- (4-trifluoromethyl-phenyl) ethylamine (66.7mg, 0.35mmol) in DMSO (1.0ml) was stirred at 60 ℃ for 3 hours. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was washed with Na₂SO₄Dried and evaporated to dryness. The crude product was stirred with diethyl ether, the precipitate was filtered and dried in vacuo to give N- [ (7R) -7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl]-N' - {2- [4- (trifluoromethyl) phenyl]Ethyl } urea (125mg, 94% yield).

¹H NMR(DMSO-d₆)δ1.45-1.68(m，1H)，1.78-1.93(m，1H)，2.29(dd，1H)，2.65-2.93(m，5H)，3.39(dt，2H)，3.80-4.00(m，1H)，4.88(d，1H)，6.57(t，1H)，6.70(d，1H)，6.98(t，1H)，7.42-7.75(m，6H）.

Molecular weight: 378.39

MS(M+H)：379

Examples 4 to 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 procedure C.

A mixture of phenyl (7-hydroxy-5, 6, 7, 8-tetrahydro-naphthalen-1-yl) -carbamate (100mg, 0.35mmol) and 2- (4-trifluoromethoxy-phenyl) ethylamine (72.4mg, 0.35mmol) in DMSO (1.0ml) was stirred at 60 ℃ for 2.5 h. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was washed with Na₂SO₄Dried and evaporated to dryness. The crude product is stirred with diethyl ether, the precipitate is filtered and dried in vacuo to give N- [ (7R) -7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl]-N' - {2- [4- (trifluoromethoxy) phenyl ]]Ethyl } urea (109mg, 94% yield).

¹H NMR(DMSO-d₆)δ1.50-1.65(m，1H)，1.80-1.91(m，1H)，2.30(dd，1H)，2.60-2.88(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)，7.59(d，1H).

Molecular weight: 394.39

MS(M+H)：395

TABLE 3

Example 5-1

N- (7-hydroxy-5, 6, 7, 8-tetrahydro-naphthalen-1-yl) -N' - (4-trifluoromethoxy-phenyl) -urea

This example was carried out according to general procedure E.

A mixture of 8-amino-1, 2, 3, 4-tetrahydro-naphthalen-2-ol (32.6mg, 0.20mmol) and (4-trifluoromethoxy-phenyl) -carbamic acid phenyl ester (59.5mg, 0.20mmol) in DMSO (1.0ml) was stirred at 100 ℃ for 1.5 h. The mixture was concentrated under reduced pressure and then purified by preparative HPLC to give N- (7-hydroxy-5, 6, 7, 8-tetrahydro-naphthalen-1-yl) -N' - (4-trifluoromethoxy-phenyl) -urea (15.5mg, 21% yield).

¹H NMR(DMSO-d6)δ1.61(m，1H)，1.87(m，1H)，2.40(m，1H)，2.85(m，2H)，3.96(m，1H)，4.88(d，J＝4.2Hz，1H)，6.80(d，J＝7.2Hz，1H)，7.05(t，J＝7.2Hz，1H)，7.28(d，J＝8.7Hz，2H)，7.55(d，J＝9.3Hz，2H)，7.63(d，J＝7.2Hz，1H)，7.85(s，1H)，9.24.(s，1H).

Molecular weight: 366.34

MS(M+H)：367

mp：198-200℃

Classification of in vitro activity: a. the

The compounds of examples 5-2 to 5-24 were synthesized in analogy to the procedure of example 5-1 above.

Claims (21)

1. A hydroxy-tetrahydro-naphthalenylurea derivative of formula (I), a tautomer or stereoisomer thereof, or a salt thereof:

wherein

X represents C_1-6Alkyl, aryl, heteroaryl, and heteroaryl,

Or

Wherein

Y represents a chemical bond,

Or

R¹、R²And R³Independently represent: hydrogen, halogen, hydroxy, nitro, carboxy, amino, C_1-6Alkylamino, di (C)_1-6Alkyl) amino, C_3-8Cycloalkylamino, C_1-6Alkoxycarbonyl, phenyl, benzyl, sulfamoyl, C_1-6Alkanoyl radical, C_1-6Alkanoylamino, carbamoyl, C_1-6Alkylcarbamoyl, cyano, C optionally substituted by cyano_1-6Alkyl radical, C_1-6Alkoxycarbonyl or mono-, di-or tri-halogen, C optionally substituted by mono-, di-or tri-halogen_1-6Alkoxy, optionally substituted by halogen or C_1-6Alkyl-substituted phenoxy or C optionally substituted by mono-, di-or tri-halogen_1-6An alkylthio group;

R⁴、R⁵、R⁶and R⁷Independently represent: hydrogen, C_1-6Alkyl or phenyl;

Z¹represents hydrogen or C_1-6An alkyl group; and is

Z²Represents hydrogen, halogen or C_1-6An alkyl group.

2. A hydroxy-tetrahydro-naphthalenylurea derivative of formula (I), a tautomer or stereoisomer thereof, or a salt thereof according to claim 1,

wherein

X represents

Or

Wherein

Y represents a bond, or

R¹、R²And R³Independently represent: hydrogen, halogen, hydroxy, nitro, carboxy, amino, C_1-6Alkylamino, di (C)_1-6Alkyl) amino, C_3-8Cycloalkylamino, C_1-6Alkoxycarbonyl, phenyl, benzyl, sulfamoyl, C_1-6Alkanoyl radical, C_1-6Alkanoylamino, carbamoyl, C_1-6Alkylcarbamoyl, cyano, C optionally substituted by cyano_1-6Alkyl radical, C_1-6Alkoxycarbonyl or mono-, di-or tri-halogen, C optionally substituted by mono-, di-or tri-halogen_1-6Alkoxy, optionally substituted by halogen or C_1-6Alkyl-substituted phenoxy or C optionally substituted by mono-, di-or tri-halogen_1-6An alkylthio group;

R⁴and R⁵Independently represent hydrogen or C_1-6An alkyl group; and

Z¹and Z²Each represents hydrogen.

3. A hydroxy-tetrahydro-naphthalenylurea derivative of formula (I), a tautomer or stereoisomer thereof, or a salt thereof according to claim 1,

wherein

X represents

Or

Wherein

Y represents a bond, or

R¹、R²And R³Independently represent: hydrogen, halogen, di (C)_1-6Alkyl) amino, C_3-8Cycloalkylamino, C_1-6Alkoxycarbonyl, optionally cyano-substituted C_1-6Alkyl radical, C_1-6Alkoxycarbonyl or mono-, di-or tri-halogen, C optionally substituted by mono-, di-or tri-halogen_1-6Alkoxy, optionally substituted by halogen or C_1-6Alkyl-substituted phenoxy or C optionally substituted by mono-, di-or tri-halogen_1-6An alkylthio group;

R⁴and R⁵Each represents hydrogen; and

Z¹and Z²Each represents hydrogen.

4. Hydroxy-tetrahydro-naphthalenylurea derivatives of formula (I), tautomers or stereoisomers thereof or salts thereof according to claim 1,

wherein

X represents

Wherein

Y represents a bond or

Wherein

R¹And R²Independently represent: hydrogen, chloro, bromo, fluoro, cyclopentylamino, trifluoromethyl or trifluoromethoxy;

R³、R⁴and R⁵Each represents hydrogen; and

Z¹and Z²Each represents hydrogen.

5. A hydroxy-tetrahydro-naphthalenylurea derivative of formula (I), a tautomer or stereoisomer thereof, or a salt thereof according to claim 1,

wherein

X represents

Wherein

Y represents a bond, or

Wherein

R¹And R²Independently represent: hydrogen, chloro, bromo, fluoro, cyclopentylamino, trifluoromethyl or trifluoromethoxy;

R³、R⁴and R⁵Each represents hydrogen; and

Z¹and Z²Each represents hydrogen.

6. The hydroxy-tetrahydro-naphthalenylurea derivative of formula (I), a tautomer or stereoisomer thereof, or a salt thereof according to claim 1, wherein said hydroxy-tetrahydro-naphthalenylurea derivative of formula (I) is selected from the following compounds:

1) n- [ 4-chloro-3- (trifluoromethyl) phenyl ] -N' - (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) urea;

2) n- (3-chlorophenyl) -N' - (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) urea;

3) n- (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) -N' - [3- (trifluoromethyl) phenyl ] urea;

4) n- (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) -N' - [4- (trifluoromethyl) phenyl ] urea;

5) ethyl 3- ({ [ (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthalenyl) amino ] carbonyl } amino) benzoate;

6) n- (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) -N' - (1-naphthyl) urea;

7) n- (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) -N' - (2-naphthyl) urea;

8) n- (3, 4-dichlorophenyl) -N' - (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) urea;

9) n- (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) -N' - (4-isopropylphenyl) urea;

10) n- (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) -N' - (4-phenoxyphenyl) urea;

11) n- [ 4-chloro-3- (trifluoromethyl) phenyl ] -N' - (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) urea;

12) n- (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) N' -phenylurea;

13) n- (4-chlorophenyl) -N' - (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) urea;

14) n- (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) -N' - [2- (trifluoromethyl) phenyl ] urea;

15) n- (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) -N' - [4- (trifluoromethyl) phenyl ] urea;

16) n- (3, 4-dichlorophenyl) -N' - (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) urea;

17) n- (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) -N' - [4- (trifluoromethoxy) phenyl ] urea;

18) n- (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) -N' - [4- (trifluoromethoxy) benzyl ] urea;

19) n- (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) -N' - (2, 4, 6-trimethoxybenzyl) urea;

20) n- (2, 6-difluorobenzyl) -N' - (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) urea;

21) n- (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) -N' - [4- (trifluoromethyl) benzyl ] urea;

22) n- (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) -N' - [4- (trifluoromethoxy) benzyl ] urea;

23) n- [2- (4-chlorophenyl) ethyl ] -N' - (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) urea; and

24) n- [ 3-fluoro-4- (trifluoromethyl) benzyl ] -N' - (7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl) urea.

7. The hydroxy-tetrahydro-naphthalenylurea derivative of formula (I), a tautomer or stereoisomer thereof, or a salt thereof according to claim 1, wherein said hydroxy-tetrahydro-naphthalenylurea derivative of formula (I) is selected from the following compounds:

1) n- [ 4-chloro-3- (trifluoromethyl) phenyl ] -N' - [ (7S) -7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl ] urea;

2) n- [ 4-chloro-3- (trifluoromethyl) phenyl ] -N' - [ (7R) -7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl ] urea;

3) n- [ (7R) -7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl ] -N' - [4- (trifluoromethyl) benzyl ] urea;

4) n- [ (7S) -7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl ] -N' - [4- (trifluoromethyl) benzyl ] urea;

5) n- [ (7R) -7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl ] -N' - [4- (trifluoromethoxy) benzyl ] urea; and

6) n- [ (7S) -7-hydroxy-5, 6, 7, 8-tetrahydro-1-naphthyl ] -N' - [4- (trifluoromethoxy) benzyl ] urea.

8. A medicament comprising a hydroxy-tetrahydro-naphthalenylurea derivative of formula (I), a tautomer or stereoisomer thereof, or a physiologically acceptable salt thereof, according to claim 1, as an active ingredient.

9. The medicament of claim 8, further comprising one or more pharmaceutically acceptable excipients.

10. The medicament of claim 8, wherein the hydroxy-tetrahydro-naphthalenylurea derivative of formula (I), a tautomer or stereoisomer thereof, or a physiologically acceptable salt thereof is a VR1 antagonist.

11. A medicament according to claim 8 for the treatment and/or prevention of a disorder or disease of the urinary system.

12. The medicament according to claim 11, wherein the urinary system disorder or disease is acute urinary incontinence or overactive bladder.

13. The medicament of claim 8 for the treatment and/or prevention of pain.

14. The medicament of claim 13, wherein the pain is chronic pain, neuropathic pain, post-operative pain, or rheumatoid arthritic pain.

15. A medicament according to claim 8 for the treatment and/or prevention of disorders or diseases involving pain.

16. The medicament of claim 15, wherein the disorder or disease involving pain is neuropathic pain, neuropathy, hyperesthesia, nerve injury, ischemia, neurodegeneration, or stroke.

17. The medicament of claim 8 for the treatment and/or prevention of an inflammatory disorder or disease.

18. The medicament of claim 17, wherein the inflammatory disorder or disease is asthma or COPD.

19. Use of a compound according to claim 1 for the preparation of a medicament for the treatment and/or prevention of a disorder or disease of the urinary system.

20. Use of a compound according to claim 1 for the preparation of a medicament for the treatment and/or prevention of pain.

21. Use of a compound according to claim 1 for the preparation of a medicament for the treatment and/or prevention of an inflammatory disorder or disease.