2-acylaminothiazole derivative or salt thereof

Abstract

[Problem]To provide a compound which is useful as an active ingredient for a pharmaceutical composition for preventing or treating urine storage dysfunction, voiding dysfunction, lower urinary tract dysfunction, and the like.[Means for Solution]The present inventors have found that a thiazole derivative substituted with pyrazinylcarbonylamino at the 2-position is an excellent muscarinic M3 receptor-positive allosteric modulator and is expected as an agent for preventing or treating bladder/urinary tract diseases associated with bladder contractions via a muscarinic M3 receptor, thereby completing the present invention. 2-Acylaminothiazole derivative or a salt thereof of the present invention is expected as an agent for preventing or treating bladder/urinary tract diseases associated with bladder contractions via a muscarinic M3 receptor, for example voiding dysfunction such as underactive bladder.

The invention claimed is: 
     
       1. A compound of formula (I) or a salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is —N(—R 12 )(—R 12 ) —N(—R 11 )(—R 12 ), or optionally-substituted cyclic amino, 
         R 11  is C 1-6  alkyl, 
         R 12  is optionally-substituted C 1-6  alkyl, or optionally-substituted C 3-8  cycloalkyl, 
         R 2  is optionally-substituted aryl, optionally-substituted monocyclic aromatic hetero ring, or optionally-substituted bicyclic aromatic hetero ring, 
         each R 3  if present is, independently, C 1-6  alkyl, 
         W is C 1-6  alkylene, and 
         n is an integer of 0 to 4. 
       
     
     
       2. The compound or salt thereof according to  claim 1 , wherein
 R 1  is cyclic amino optionally substituted with 1 to 5 of a substituent G and/or an oxo substituent, or R 3  is —N(—R 11 )(—R 12 ), 
 R 11  is C 1-6  alkyl 
 R 12  is C 1-6  alkyl optionally substituted with 1 to 3 substituents selected from the group consisting of
 —OH, 
  O—C 1-6  alkyl optionally substituted with at least one group selected from the group consisting of —OH, —O—(C 1-6  alky), —CN, —SO 2 —(C 1-6  alkyl), and halogen, 
 C 3-8  cycloalkyl,
 O—(C 3-8  cycloalkyl), 
 
 halogen, 
 —CN, and 
 a saturated hetero ring, 
 
 R 2  is phenyl optionally substituted with 1 to 5 substituents G, thienyl optionally substituted with 1 to 3 substituents G, pyridyl optionally substituted with 1 to 3 substituents G, or benzothienyl optionally substituted with 1 to 5 substituents G, and 
 each substituent G is a sustituent selected from the group consisting of: 
 C 1-6  alkyl optionally substituted with at least one group selected from the group consisting of —OH, —O—(C 1-6  alkyl), —CN, —SO 2 —(C 1-6  alkyl), and halogen, 
 —OH, 
 —O—C 1-6  alkyl optionally substituted with at least one group selected from the group consisting of —OH, —O—(C 1-6  alkyl), —CN, —SO 2 —(C 1-6  alkyl), and halogen, 
 C 3-8  cycloalkyl, 
 —O—(C 3-8  cycloalkyl), 
 halogen, 
 —CN, 
 —SO 2 —(C 1-6  alkyl), 
 —CO 2 —(C 1-6  alkyl), 
 —COOH, 
 —CO—N(C 1-6  alkyl) 2 , 
 —CO—NH(C 1-6  alkyl), 
 —CONH 2 , 
 —CO—(C 1-6  alkyl), 
 —SO 2 —N(C 1-6  alkyl) 2 , 
 —SO 2 —NH(C 1-6  alkyl), 
 —SO 2 NH 2 , 
 —N(C 1-6  alkyl) 2 , 
 —NH(C 1-6  alkykl), 
 —NH 2 , 
 a saturated hetero ring, and 
 —O-saturated hetero ring. 
 
     
     
       3. The compound or a salt thereof according to  claim 2 , wherein
 R 1  is pyrrolidin-1-yl or piperidin-1-yl, each substituted with 1 to 2 substituents selected from the group consisting of C 1-6  alkyl and haogeno-C 1-6  alkyl, or wherein R 1  is —N(—R 11 )(—R 12 ), 
 R 11  is C 1-6  alkyl, and 
 R 12  is C 1-6  alkyl optionally substituted with one group selected from the group consisting of C 3-8  cycloalkyl and —O—(C 1-6  alkyl), 
 R 2  
 phenyl optionally substituted with 1 to 3 groups selected from the group consisting of C 1-6  alkyl, halogeno-C 1-6  alkyl, —O—(C 1-6  alkyl), —O-(halogeno-C 1-6  alkyl), halogen, C 3-8  cycloalkyl, and —CN; 
 thienyl optionally substituted with 1 to 3 groups selected from the group consisting of C 1-6  alkyl, halogeno-C 1-6  alkyl, —O—(C 1-6  alkyl), C 3-8  cycloalkyl, and halogen; 
 pyridyl optionally substituted with 1 to 3 groups selected from the group consisting of C 1-6  alkyl, halogeno-C 1-6  alkyl, —O—(C 3-8  alkyl), C 3-8  cycloalkyl, and halogen; or 
 benzothienyl, 
 
 W is C 1-6  alkylene, and 
 n is 0 or 1. 
 
     
     
       4. The compound or a salt thereof according to  claim 3 , wherein
 R 2  is phenyl di-substituted with trifluoromethyl and fluoro, thienyl mono-substituted with trifluoromethyl or chloro, or pyridyl di-substituted with trifluoromethyl and methoxy, and 
 W is methylene or ethylene. 
 
     
     
       5. The compound or a salt thereof according to  claim 3 , wherein
 R 1  is pyrrolidin-1-yl or piperidin-1-yl, each substituted with 1 to 2 substituents selected from the group consisting of C 1-6  alkyl and halogeno-C 1-6  alkyl, 
 R 2  is thienyl optionally substituted with 1 or 2 substituents selected from the group consisting of halogeno-C 1-6  alkyl and halogen, or wherein R 2  is phenyl optionally substituted with 1 or 2 substituents selected from the group consisting of halogeno-C 1-6  alkyl and halogen, and 
 W is methylene or ethylene. 
 
     
     
       6. The compound or a salt thereof according to  claim 1 , wherein the compound is a compound selected from the group consisting of:
 3-[(2S)-4-(5-{[4-(4-chlorothiophen-2-yl)-5-{[(2R)-2-methylpyrrolidin-1-yl]methyl}-1,3-thiazol-2-yl]carbamoyl}pyrazin-2-yl)-2-methylpiperazin-1-yl]propanoic acid, 
 3-[(3R)-4-{5-[(4-[3-fluoro-5-(trifluoromethyl)phenyl]-5-{[(2R)-2-methylpyrrolidin-1-yl]methyl}-1,3-thiazol-2-yl)carbamoyl]pyrazin-2-yl}-3-methylpiperazin-1-yl]propanoic acid, 
 [(3R)-4-{5-[(4-[3-fluoro-5-(trifluoromethyl)phenyl]-5-{[(2R)-2-methylpyrrolidin-1-yl]methyl}-1,3-thiazol-2-yl)carbamoyl]pyrazin-2-yl}-3-methylpiperazin-1-yl]acetic acid, 
 3-(4-{5-[(4-[3-fluoro-5-(trifluoromethyl)phenyl]-5-{[(2R)-2-methylpyrrolidin-1-yl]methyl}-1,3-thiazol-2-yl)carbamoyl]pyrazin-2-yl}piperazin-1-yl)propanoic acid, 
 3-[(2R)-4-(5-{[4-(4-chlorothiophen-2-yl)-5-{[(2R)-2-ethylpyrrolidin-1-yl]methyl}-1,3-thiazol-2-yl]carbamoyl}pyrazin-2-yl)-2-methylpiperazin-1-yl]propanoic acid, 
 3-[(3R)-3-methyl-4-{5-[(5-{[(2R)-2-methylpyrrolidin-1-yl]methyl)}-4-[4-(trifluoromethyl)thiophen-2-yl]-1,3-thiazol-2-yl)carbamoyl]pyrazin-2-yl}piperazin-1-yl]propanoic acid, 
 3-(4-{5-[(5-{[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]methyl}-4-[3-fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl)carbamoyl]pyrazin-2-yl}piperazin-1-yl)propanoic acid, and 
 3-{(2R)-4-[5-({5-[(diethylamino)methyl]-4-[3-fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}carbamoyl)pyrazin-2-yl]-2-methylpiperazin-1-yl}propanoic acid. 
 
     
     
       7. A pharmaceutical composition, comprising:
 the compound or a salt thereof according to  claim 1 ; and 
 a pharmaceutically acceptable excipient. 
 
     
     
       8. A method for treating a bladder/urinary tract disease associated with bladder contractions via a muscarinic M 3  receptor, the method comprising:
 administering, to a subject in need thereof, an effective amount of the compound or a salt thereof according to  claim 1 . 
 
     
     
       9. The method according to  claim 8 , wherein the bladder/urinary tract disease associated with bladder contractions via a muscarinic M 3  receptor is voiding dysfunction or urine storage dysfunction in underactive bladder, hypotonic bladder, acontractile bladder, detrusor underactivity, or neurogenic bladder. 
     
     
       10. The compound or a salt thereof according to  claim 6 , wherein the compound is 3-[(2S)-4-(5-{[4-(4-chlorothiophen-2-yl)-5-{[(2R)-2-methylpyrrolidin-1-yl]methyl}-1,3-thiazol-2-yl]carbamoyl}pyrazin-2-yl)-2-methylpiperazin-1-yl]propanoic acid. 
     
     
       11. The compound or a salt thereof according to  claim 6 , wherein the compound is 3-[(3R)-4-{5-[(4-[3-fluoro-5-(trifluoromethyl)phenyl]-5-{[(2R)-2-methylpyrrolidin-1-yl]methyl}-1,3-thiazol-2-yl)carbamoyl]pyrazin-2-yl}-3-methylpiperazin-1-yl]propanoic acid. 
     
     
       12. The compound or a salt thereof according to  claim 6 , wherein the compound is [(3R)-4-{5-[(4-[3-fluoro-5-(trifluoromethyl)phenyl]-5-{[(2R)-2-methylpyrrolidin-1-yl]methyl}-1,3-thiazol-2-yl)carbamoyl]pyrazin-2-yl}-3-methylpiperazin-1-yl]acetic acid. 
     
     
       13. The compound or a salt thereof according to  claim 6 , wherein the compound is 3-(4-{5-[(4-[3-fluoro-5-(trifluoromethyl)phenyl]-5-{[(2R)-2-methylpyrrolidin-1-yl]methyl}-1,3-thiazol-2-yl)carbamoyl]pyrazin-2-yl}piperazin-1-yl)propanoic acid. 
     
     
       14. The compound or a salt thereof according to  claim 6 , wherein the compound is 3-[(2R)-4-(5-{[4-(4-chlorothiophen-2-yl)-5-{[(2R)-2-ethylpyrrolidin-1-yl]methyl}-1,3-thiazol-2-yl]carbamoyl}pyrazin-2-yl)-2-methylpiperazin-1-yl]propanoic acid. 
     
     
       15. The compound or a salt thereof according to  claim 6 , wherein the compound is 3-[(3R)-3-methyl-4-{5-[(5-{[(2R)-2-methylpyrrolidin-1-yl]methyl]-4-[4-(trifluoromethyl)thiophen-2-yl]-1,3-thiazol-2-yl)carbamoyl]pyrazin-2-yl}piperazin-1-yl]propanoic acid. 
     
     
       16. The compound or a salt thereof according to  claim 6 , wherein the compound is 3-(4-{5-[(5-([(2R,5R)-2,5-dimethylpyrrolidin-1-yl]methyl}-4-[3-fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl)carbamoyl]pyrazin-2-yl}piperazin-1-yl)propanoic acid. 
     
     
       17. The compound or a salt thereof according to  claim 6 , wherein the compound is 3-{(2R)-4-[5-([5-[(diethylamino)methyl]-4-[3-fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}carbamoyl)pyrazin-2-yl]-2-methylpiperazin-1-yl}propanoic acid. 
     
     
       18. The compound of claim 1 which is 3-[(2S)-4-(5-{[4-(4-chlorothiophen-2-yl)-5-{[(2R)-2-methylpyrrolidin-1-yl]methyl}-1,3-thiazol-2-yl]carbamoyl}pyrazin-2-yl)-2-methylpiperazin-1-yl]propanoic acid dimaleate.  
     
     
       19. A crystal polymorph of the compound of claim 18.   
     
     
       20. The crystal polymorph of claim 19 having peaks at 2θ (°) of 5.7, 6.6, 10.5, 12.0, 13.3, 15.8, 16.6, 17.3, 19.0, and 26.2 when measured by powder X-ray diffraction.  
     
     
       21. A pharmaceutical composition comprising the crystal polymorph of claim 20.   
     
     
       22. A method for treating bladder/urinary tract diseases associated with bladder contractions via a muscarinic M 3  receptor, comprising administering the composition of claim 21.   
     
     
       23. A method for treating bladder/urinary tract diseases associated with bladder contractions via a muscarinic M3 receptor voiding dysfunction or urine storage
 dysfunction in underactive bladder, hypotonic bladder, acontractile bladder, detrusor underactivity, or neurogenic bladder comprising administering the composition of claim 21.