Hydroxy-tetrahydro-naphthalenylurea derivatives

1. A hydroxy-tetrahydro-naphthalenylurea derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof:

wherein

n represents an integer of 1 to 6;

R 1 represents hydrogen or C 1-6 alkyl;

R 2 , R 3 and R 4 independently represents hydrogen, halogen, hydroxy, 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 alkylcarbamoyl, cyano, C 1-6 alkyl optionally substituted by cyano, C 1-6 alkoxycarbonyl or mono-, di-, or tri-halogen, C 1-6 alkoxy optionally substituted by mono-, di-, or tri-halogen, phenoxy optionally substituted by halogen or C 1-6 alkyl, or C 1-6 alkylthio optionally substituted by mono-, di-, or tri-halogen;

X represents O, S or N—R 5 ; and

R 5 represents hydrogen, benzyl or C 1-6 alkyl.

2. The hydroxy-tetrahydro-naphthalenylurea derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1 ,

wherein

n represents an integer of 1 to 4;

R 1 represents hydrogen;

R 2 and R 3 independently represents hydrogen, halogen, hydroxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 3-8 cycloalkylamino, C 1-6 alkoxycarbonyl, phenyl, benzyl, C 1-6 alkanoyl, C 1-6 alkanoylamino, carbamoyl, C 1-6 alkylcarbamoyl, C 1-6 alkyl optionally substituted by C 1-6 alkoxycarbonyl or mono-, di-, or tri-halogen, C 1-6 alkoxy optionally substituted by mono-, di-, or tri-halogen, phenoxy optionally substituted by halogen or C 1-6 alkyl, or C 1-6 alkylthio optionally substituted by mono-, di-, or tri-halogen;

R 4 represents hydrogen;

X represents O or N—R 5 ; and

R 5 represents C 1-6 alkyl.

3. The 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-naphthalenylurea derivative of the formula (I) is selected from the group consisting of:

N-[2-(2-Fluorophenoxy)ethyl]-N′-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-urea;

Ethyl 2-Fluoro-6-{2-[3-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-ureido]-ethoxy}benzoate;

N-[2-(4-Fluorophenoxy)ethyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;

N-{2-[3,5-Bis(trifluoromethyl)phenoxy]ethyl}-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;

N-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[2-(2-piperidin-1-yl-phenoxy)ethyl]urea;

N-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[2-(2-methoxyphenoxy)ethyl]urea;

N-[2-(4-Fluorophenoxy)ethyl]-N′-[(7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]urea;

N-[2-(4-Fluorophenoxy)ethyl]-N′-[(7S)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]urea;

N-{2-[Ethyl(m-tolyl)amino]ethyl]-N′-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)urea;

N-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-{2-[methyl(m-tolyl)amino]-ethyl}urea;

N-{2-[Ethyl(m-tolyl)amino]ethyl}-N′-[(7R)-7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl]urea;

N-{2-[Ethyl(m-tolyl)amino]ethyl}-N′-[(7S)-7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl]urea; and

N-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[3-(methyl-phenyl-amino)propyl]urea.

4. A pharmaceutical composition comprising a hydroxy-tetrahydro-naphthalenylurea derivative of the formula (I) its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof, as claimed in claim 1 , as an active ingredient plus a pharmaceutically acceptable carrier.

5. The pharmaceutical composition as claimed in claim 4 , further comprising one or more additional pharmaceutically acceptable excipients.

6. The pharmaceutical composition as claimed in claim 4 , wherein said hydroxy-tetrahydro-naphthalenylurea derivative of the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof is a VR1 antagonist.

7. A method for the treatment of an urological disorder or disease comprising administering to a human or animal a pharmaceutically effective amount of a compound of claim 1 .

8. The method as claimed in claim 7 , wherein said urological disorder or disease is urge urinary incontinence or overactive bladder.

9. A method for the treatment of pain comprising administering to a human or animal a pharmaceutically effective amount of a compound of claim 1 .

10. The method as claimed in claim 9 , wherein said pain is chronic pain, neuropathic pain, postoperative pain, or rheumatoid arthritic pain.

11. A method for the treatment of a disorder or disease that causes pain comprising administering to a human or animal a pharmaceutically effective amount of a compound according to claim 1 .

12. The method as claimed in claim 11 , wherein said disorder or disease that causes pain is neuralgia, neuropathies, algesia, nerve injury, ischaemia, neurodegeneration, or stroke.

13. A method for the treatment of an inflammatory disorder or disease comprising administering to a human or animal a pharmaceutically effective amount of a compound according to claim 1 .

14. The method as claimed in claim 13 , wherein said inflammatory disorder or disease is asthma or COPD.

15. A process for treating a urological disorder or disease in a human or animal, comprising administering a VR1-antagonistically effective amount of at least one compound according to claim 1 .

16. A process for treating pain in a human or animal comprising administering a VR1-antagonistically effective amount of at least one compound according to claim 1 .

17. A process for treating an inflammatory disorder or disease in a human or animal comprising administering a VR1-antagonistically effective amount of at least one compound according to claim 1 .