3,4-dihydrobenzoxazine compounds and inhibitors of vanilloid receptor subtype 1 (vri) activity

Abstract

A 3,4-dihydrobenzoxazine compound of the present invention is represented by the following formula [1] (wherein X is a nitrogen atom or CR 3 ; R 1 is a hydrogen atom or a halogen atom; R 2 is a C1-6 alkoxy group which may be substituted with the same or different 1 to 5 substituents selected from a halogen atom and a hydroxyl group; and R 3 is a halogen atom. However, R 1 is a halogen atom when X is CR 3 ). This compound is effective in treating diseases to which the vanilloid receptor subtype 1 (VR1) activity is involved, such as pain, etc.

1 . A 3,4-dihydrobenzoxazine compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein X is 
         (1) a nitrogen atom or 
         (2) CR 3 ; 
         R 1  is 
         (1) a hydrogen atom or 
         (2) a halogen atom; 
         R 2  is a C1-6 alkoxy group which may be substituted with the same or different 1 to 5 substituents selected from the following group: 
         (1) a halogen atom and 
         (2) a hydroxyl group; and 
         R 3  is a halogen atom, 
         with the proviso that R 1  is a halogen atom when X is CR 3 . 
       
     
     
         2 . The 3,4-dihydrobenzoxazine compound according to  claim 1  selected from the following group or a pharmaceutically acceptable salt thereof:
 1) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(4-tert-butoxy-3,5-difluorophenyl)-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide, 
 2) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(3,5-difluoro-4-isopropoxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide, 
 3) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(3,5-difluoro-4-ethoxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide, 
 4) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[2-(2,2-dimethylpropyloxy)pyridin-5-yl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide, 
 5) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(2-tert-butoxypyridin-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide, 
 6) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[2-(2,2,2-trifluoroethyloxy)pyridin-5-yl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide, 
 7) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(2-isobutoxypyridin-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide, 
 8) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide, 
 9) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(2-hydroxy-2-methylpropyloxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide, and 
 10) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(1,1-dimethyl-2-hydroxyethyloxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide. 
 
     
     
         3 . A pharmaceutical composition comprising (a) a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof according to  claim 1  and (b) a pharmaceutically acceptable carrier. 
     
     
         4 . (canceled) 
     
     
         5 . A pharmaceutical composition comprising (a) a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof according to  claim 1  and (b) a pharmaceutically acceptable carrier. 
     
     
         6 .- 10 . (canceled) 
     
     
         11 . A commercial package comprising a pharmaceutical composition of  claim 3  and written instructions concerning said pharmaceutical composition stating that said composition can be used or should be used for treating and/or preventing a disease selected from the group consisting of pain, acute pain, chronic pain, neuropathic pain, rheumatoid arthritis pain, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute post herpetic neuralgia, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative pain, cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegenerative disease, cerebral apoplexy, ischemic symptom, nerve injury, neurogenic skin disorder, inflammatory disease, pruritus, allergic rhinitis, apoplexy, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, stomach and duodenal ulcer, inflammatory bowel disease, bladder hypersensitivity, frequent urination, and urinary incontinence. 
     
     
         12 . A commercial package comprising a pharmaceutical composition of  claim 5  and written instructions concerning said pharmaceutical composition stating that said composition can be used or should be used for treating and/or preventing a disease selected from the group consisting of pain, acute pain, chronic pain, neuropathic pain, rheumatoid arthritis pain, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute post herpetic neuralgia, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative pain, cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegenerative disease, cerebral apoplexy, ischemic symptom, nerve injury, neurogenic skin disorder, inflammatory disease, pruritus, allergic rhinitis, apoplexy, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, stomach and duodenal ulcer, inflammatory bowel disease, bladder hypersensitivity, frequent urination, and urinary incontinence. 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . A pharmaceutical composition comprising (a) a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof according to  claim 1 , (b) a pharmaceutically acceptable carrier, and (c) one or more agents selected from the group consisting of an anti-virus agent, an antidepressant, an anticonvulsant, an antiarrhythmic, a local anesthetic, an anesthetic, an N-methyl-D-aspartate receptor antagonist, an adrenal cortical steroid, a nerve block, a nonsteroidal antiinflammatory analgesic, a narcotic, an antagonist analgesic, an α 2 -adrenaline receptor agonist, a medicine for external application, a calcium channel antagonist, a potassium channel opener, and an antipyretic agent. 
     
     
         16 .- 19 . (canceled) 
     
     
         20 . The pharmaceutical composition of  claim 15 , wherein the 3,4-dihydrobenzoxazine compound is selected from the following group or a pharmaceutically acceptable salt thereof:
 1) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(4-tert-butoxy-3,5-difluorophenyl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   2) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(3,5-difluoro-4-isopropoxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   3) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(3,5-difluoro-4-ethoxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   4) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[2-(2,2-dimethylpropyloxy)pyridin-5-yl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   5) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(2-tert-butoxypyridin-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   6) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[2-(2,2,2-trifluoroethyloxy)pyridin-5-yl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   7) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(2-isobutoxypyridin-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   8) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   9) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(2-hydroxy-2-methylpropyloxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide, and   10) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(1,1-dimethyl-2-hydroxyethyloxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide.   
     
     
         21 . A method for treating and/or preventing a disease of an animal, wherein the method comprises administering a pharmacologically effective amount of a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof according to  claim 1  to an animal with or at risk of a disease selected from the group consisting of pain, acute pain, chronic pain, neuropathic pain, rheumatoid arthritis pain, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative pain, cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegenerative disease, cerebral apoplexy, ischemic symptom, nerve injury, neurogenic skin disorder, inflammatory disease, pruritus, allergic rhinitis, apoplexy, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, stomach and duodenal ulcer, inflammatory bowel disease, bladder hypersensitivity, frequent urination, and urinary incontinence, whereby the disease of the animal is treated and/or prevented. 
     
     
         22 . The method of  claim 21 , wherein the 3,4-dihydrobenzoxazine compound is selected from the following group or a pharmaceutically acceptable salt thereof:
 1) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(4-tert-butoxy-3,5-difluorophenyl)-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide,   2) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(3,5-difluoro-4-isopropoxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   3) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(3,5-difluoro-4-ethoxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide,   4) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[2-(2,2-dimethylpropyloxy)pyridin-5-yl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   5) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(2-tert-butoxypyridin-5-yl)-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide,   6) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[2-(2,2,2-trifluoroethyloxy)pyridin-5-yl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   7) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(2-isobutoxypyridin-5-yl)-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide,   8) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide,   9) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(2-hydroxy-2-methylpropyloxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide, and   10) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(1,1-dimethyl-2-hydroxyethyloxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide.   
     
     
         23 . A method for treating and/or preventing pain of an animal, wherein the method comprises administering a pharmacologically effective amount of a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof according to  claim 1  to an animal with or at risk of pain, whereby the pain of the animal is treated and/or prevented. 
     
     
         24 . The method of  claim 23 , wherein the 3,4-dihydrobenzoxazine compound is selected from the following group or a pharmaceutically acceptable salt thereof:
 1) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(4-tert-butoxy-3,5-difluorophenyl)-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide,   2) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(3,5-difluoro-4-isopropoxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide,   3) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(3,5-difluoro-4-ethoxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide,   4) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[2-(2,2-dimethylpropyloxy)pyridin-5-yl]-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide,   5) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(2-tert-butoxypyridin-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   6) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[2-(2,2,2-trifluoroethyloxy)pyridin-5-yl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   7) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(2-isobutoxypyridin-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   8) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   9) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(2-hydroxy-2-methylpropyloxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide, and   10) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(1,1-dimethyl-2-hydroxyethyloxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide.   
     
     
         25 . The method of  claim 23 , wherein the pain is selected from the group consisting of acute pain, chronic pain, neuropathic pain, rheumatoid arthritis pain, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative pain, cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, and neurodegenerative disease. 
     
     
         26 . The method of  claim 25 , wherein the 3,4-dihydrobenzoxazine compound is selected from the following group or a pharmaceutically acceptable salt thereof:
 1) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(4-tert-butoxy-3,5-difluorophenyl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   2) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(3,5-difluoro-4-isopropoxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   3) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(3,5-difluoro-4-ethoxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   4) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[2-(2,2-dimethylpropyloxy)pyridin-5-yl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   5) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(2-tert-butoxypyridin-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   6) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[2-(2,2,2-trifluoroethyloxy)pyridin-5-yl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   7) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(2-isobutoxypyridin-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   8) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   9) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(2-hydroxy-2-methylpropyloxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide, and   10) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(1,1-dimethyl-2-hydroxyethyloxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide.   
     
     
         27 . A method for treating and/or preventing a disease of an animal, wherein the method comprises (a) administering one or more agents selected from the group consisting of an anti-virus agent, an antidepressant, an anticonvulsant, an antiarrhythmic drug, a local anesthetic, an anesthetic drug, an N-methyl-D-aspartate receptor antagonist, adrenal cortical steroid, a nerve block, a nonsteroidal antiinflammatory analgesic, narcotics, an antagonist analgesic, α 2 -adrenaline receptor agonist, a medicine for external application, a calcium channel antagonist, a potassium channel opener, and an antipyretic agent to an animal in combination with (b) administering a pharmacologically effective amount of a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof according to  claim 1  to the animal with or at risk of a disease selected from the group consisting of pain, acute pain, chronic pain, neuropathic pain, rheumatoid arthritis pain, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute post herpetic neuralgia, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative pain, cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegenerative disease, cerebral apoplexy, ischemic symptom, nerve injury, neurogenic skin disorder, inflammatory disease, pruritus, allergic rhinitis, apoplexy, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, stomach and duodenal ulcer, inflammatory bowel disease, bladder hypersensitivity, frequent urination, and urinary incontinence, whereby the disease of the animal is treated and/or prevented. 
     
     
         28 . The method of  claim 27 , wherein the 3,4-dihydrobenzoxazine compound is selected from the following group or a pharmaceutically acceptable salt thereof:
 1) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(4-tert-butoxy-3,5-difluorophenyl)-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide,   2) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(3,5-difluoro-4-isopropoxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide,   3) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(3,5-difluoro-4-ethoxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   4) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[2-(2,2-dimethylpropyloxy)pyridin-5-yl]-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide,   5) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(2-tert-butoxypyridin-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   6) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[2-(2,2,2-trifluoroethyloxy)pyridin-5-yl]-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide,   7) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(2-isobutoxypyridin-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   8) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide,   9) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(2-hydroxy-2-methylpropyloxy)phenyl]-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide, and   10) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(1,1-dimethyl-2-hydroxyethyloxy)phenyl]-3,4-dihydro-2H-benzo[1,4]ox-8-carboxamide.   
     
     
         29 . A method for treating and/or preventing pain of an animal, wherein the method comprises administration of a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof according to  claim 1  to an animal with or at risk of pain in combination with effecting stimulation-produced analgesia by subjecting the animal to one or more of the therapies selected from the group consisting of acupuncture, transcutaneous electroacupuncture stimulation therapy, transcutaneous electrical nerve stimulation therapy, silver spike point (SSP) therapy, peripheral nerve stimulation therapy, spinal cord electrical stimulation therapy, electroconvulsive therapy, laser therapy and low-frequency therapy, whereby the pain of the animal is treated and/or prevented. 
     
     
         30 . The method of  claim 29 , wherein the 3,4-dihydrobenzoxazine compound is selected from the following group or a pharmaceutically acceptable salt thereof:
 1) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(4-tert-butoxy-3,5-difluorophenyl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   2) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(3,5-difluoro-4-isopropoxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide,   3) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(3,5-difluoro-4-ethoxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide,   4) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[2-(2,2-dimethylpropyloxy)pyridin-5-yl]-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide,   5) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(2-tert-butoxypyridin-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   6) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[2-(2,2,2-trifluoroethyloxy)pyridin-5-yl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   7) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(2-isobutoxypyridin-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   8) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   9) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(2-hydroxy-2-methylpropyloxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide, and   10) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(1,1-dimethyl-2-hydroxyethyloxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide.   
     
     
         31 . A method for treating and/or preventing postoperative neuralgia in an animal, wherein the method comprises administrating a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof according to  claim 1  to an animal after performing a surgical operation selected from the group consisting of cicatrectomy, nerve freezing solidification, peripheral nerve excision, spinal cord dorsal root excision, sympathectomy, spinal cord dorsal root entry zone destruction, cordotomy, and frontal lobe excision on the animal, whereby postoperative neuralgia in the animal is treated and/or prevented. 
     
     
         32 . The method of  claim 31 , wherein the 3,4-dihydrobenzoxazine compound is selected from the following group or a pharmaceutically acceptable salt thereof:
 1) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(4-tert-butoxy-3,5-difluorophenyl)-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide,   2) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(3,5-difluoro-4-isopropoxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide,   3) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(3,5-difluoro-4-ethoxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide,   4) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[2-(2,2-dimethylpropyloxy)pyridin-5-yl]-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide,   5) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(2-tert-butoxypyridin-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   6) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[2-(2,2,2-trifluoroethyloxy)pyridin-5-yl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   7) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(2-isobutoxypyridin-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   8) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   9) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(2-hydroxy-2-methylpropyloxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide, and   10) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(1,1-dimethyl-2-hydroxyethyloxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide.   
     
     
         33 . A method of inhibiting vanilloid receptor subtype 1 (VR1) activity in an animal comprising administering an effective amount of a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof according to  claim 1  to an animal in need thereof so as to inhibit VR1 activity. 
     
     
         34 . The method of  claim 33 , wherein the 3,4-dihydrobenzoxazine compound is selected from the following group or a pharmaceutically acceptable salt thereof:
 1) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(4-tert-butoxy-3,5-difluorophenyl)-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide,   2) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(3,5-difluoro-4-isopropoxyphenyl)-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide,   3) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(3,5-difluoro-4-ethoxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   4) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[2-(2,2-dimethylpropyloxy)pyridin-5-yl]-3,4-dihydro-2H-benzo[1,4] oxazine-8-carboxamide,   5) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(2-tert-butoxypyridin-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   6) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[2-(2,2,2-trifluoroethyloxy)pyridin-5-yl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   7) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-(2-isobutoxypyridin-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   8) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide,   9) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(2-hydroxy-2-methylpropyloxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide, and   10) (S)-4-(5-picolin-2-yl)-3-hydroxymethyl-N-[3,5-difluoro-4-(1,1-dimethyl-2-hydroxyethyloxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide.