Synthetic process and novel intermediates

Abstract

The present disclosure describes a synthetic process and novel intermediates related to spirocyclic azetidenyl-isobenzofuran derivatives having an isothiazoline moiety, which are useful as antiparasitics.

We claim: 
     
         1 . A compound selected from:
 4-methyl-N-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)carbamoyl) benzenesulfonamide;   2-ethyl-6,8-dimethylimidazo[1,2-a]pyrazine; and   3-bromo-2-ethyl-6,8-dimethylimidazo[1,2-a]pyrazine,   or a veterinary or pharmaceutically acceptable salt thereof.   
     
     
         2 . A method of treating pain, the method comprising the step of:
 administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula (II) or veterinary or pharmaceutically acceptable salt thereof:   
       
         
           
           
               
               
           
         
         wherein: 
         X is N or CR 1 , where R 1  is hydrogen, halogen, CN, C 1-3  alkyl, or C 1-3  haloalkyl; 
         R 2  is hydrogen, halogen, C 1-3  alkyl, C 1-3  haloalkyl, CN, aryl, or heteroaryl; 
         R 3  is hydrogen, halogen, C 1-3  alkyl, C 1-3  haloalkyl, or CN; 
         R 4  is hydrogen, C 1-3  alkyl, C 1-3  haloalkyl, C 3-6  cycloalkyl, heterocyclyl, heteroaryl, or aryl; 
         Z is phenyl substituted with R 5 , where R 5  is hydrogen, halogen, CN, C 1-3  alkyl, C 1-3  haloalkyl, C 1-3  haloalkoxy, or C 1-3  alkoxy; 
         Ar is phenyl, pyridyl, or thiophenyl, each optionally substituted with one or more halogen, CN, NO 2 , NH 2 , N(C 1-3  alkyl) 2 , OH, C 1-3  alkoxy, C 1-3  alkyl, or C 1-3  haloalkyl; and 
         L is CH 2 CH 2 , CH 2 CH 2 CH 2 , or OCH 2 CH 2 . 
       
     
     
         3 . The method of  claim 2 , wherein the mammal is a companion animal. 
     
     
         4 . The method of  claim 2 , wherein the pain is selected from the group consisting of joint pain, musculoskeletal pain, lower back pain, neck pain, skeletal pain, sprain, strain, myositis, neuralgia, fibromyalgia, synovitis, arthritis, rheumatoid arthritis, degenerative joint disease, osteoarthritis, gout, ankylosing spondylitis, and bursitis. 
     
     
         5 . The method of  claim 2 , wherein
 X is N,   R 2  is C 1-3  alkyl,   R 3  is C 1-3  alkyl,   R 4  is C 1-3  alkyl,   Ar is phenyl,   L is CH 2 CH 2 , and   Z is phenyl substituted with one R 5 .   
     
     
         6 . The method of  claim 5 , wherein R 2  is methyl, R 3  is methyl, R 4  is ethyl, Ar is unsubstituted phenyl, and R 5  is C 1-3  alkyl. 
     
     
         7 . The method of  claim 6 , wherein R 5  is methyl. 
     
     
         8 . The method of  claim 7 , wherein the compound of Formula (II) is 1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea. 
     
     
         9 . The method of  claim 2 , wherein the therapeutically effective amount of a compound of Formula (II) or veterinary or pharmaceutically acceptable salt thereof is combined with a veterinary or pharmaceutically acceptable excipient, diluent, or carrier. 
     
     
         10 . The method of  claim 2 , wherein the therapeutically effective amount of a compound of Formula (II) or veterinary or pharmaceutically acceptable salt thereof is formulated as an oral formulation, injectable formulation, topical formulation, dermal formulation, or subdermal formulation. 
     
     
         11 . The method of  claim 10 , wherein the oral formulation is a dietary supplement, troche, lozenge, chewable, tablet, hard or soft capsule, emulsion, aqueous or oily suspension, aqueous or oily solution, dispersible powder, dispersible granule, syrup, or elixir. 
     
     
         12 . The method of  claim 2 , wherein the step of administering to a mammal in need thereof includes directly introducing the therapeutically effective amount of a compound of Formula (II) or veterinary or pharmaceutically acceptable salt thereof to the mammal via contact with skin, fur, or feathers. 
     
     
         13 . The method of  claim 12 , wherein directly introducing the therapeutically effective amount of a compound of Formula (II) or veterinary or pharmaceutically acceptable salt thereof includes feeding or injecting the mammal. 
     
     
         14 . The method of  claim 2 , wherein the step of administering to a mammal in need thereof includes indirectly introducing the therapeutically effective amount of a compound of Formula (II) or veterinary or pharmaceutically acceptable salt thereof to the mammal via contact with a local environment in which the mammal dwells. 
     
     
         15 . The method of  claim 2 , wherein the therapeutically effective amount of a compound of Formula (II) or veterinary or pharmaceutically acceptable salt thereof is present in a formulation at a concentration of about 0.05 to 10% weight/volume. 
     
     
         16 . The method of  claim 2 , wherein the therapeutically effective amount of a compound of Formula (II) or veterinary or pharmaceutically acceptable salt thereof is administered daily, weekly, semi-monthly, monthly, bi-monthly, quarterly, tri-annually, semi-annually, or annually.