CN101351462A - 3,4-dihydrobenzoxazine compound and inhibitor of vanilloid receptor type 1(VR1) activity - Google Patents

Abstract

Disclosed is a 3,4-dihydrobenzoxazine compound represented by the formula [1] below, which is useful for the treatment of a disease associated with the activity of a vanilloid receptor type 1 (VR1) such as pain, wherein X represents a nitrogen atom or CR<3>; R<1> represents a hydrogen or halogen atom; R<2> represents a C1-6 alkoxy group which may be substituted by 1 to 5 substituents independently selected from a halogen atom and a hydroxyl group; and R<3> represents a halogen atom, provided that R<1> is a halogen atom when X is CR<3>.

Description

3,4-dihydrobenzo piperazine compound and vanilloid receptor 1 type (VR1) activity inhibitor

Technical field

The present invention relates to have novel 3 of vanilloid receptor 1 type (VR1) activity inhibition, 4-Er hydrogen benzoxazine compound and at the salt that pharmaceutically allows, with these compounds or its at the medical composition of the salt that pharmaceutically allows, and for pain, acute pain, chronic pain, neurological disorder pain, chronic joint rheumatalgia, neurodynia etc. and vanilloid receptor 1 type (VR1) active relevant disease, particularly treatment of pain method and/or prevention method as effective constituent.

Background technology

Capsaicine (Capsaicin) as the main component of capsicum is pungent composition, also is the material that causes pain simultaneously.Report has many injury sensory nerves, does not particularly have myelin C fiber and have capsaicin-sensitive, and known rodent to juvenile stage gives capsaicine, and then the C fiber optionally comes off.Also report has: the site of action of capsaicine is distributed in skin or cornea, oral mucosa more, also confirmed the distribution in muscle, internal organ, particularly cardiovascular systems, respiratory organs system, bladder urethra system in addition, it is very important for sensorineural activity.In addition, in the nerve of looking the proparea of thalamus, also observe capsaicin-sensitive, infer relevant with thermoregulation.In the injury sensory nerve, observe because Na by the capsaicine administration ⁺, Ca ²⁺The depolarize that flows into and cause causes from the maincenter side L-glutamic acid of the primary afferent fiber of cornu dorsale medullae spinalis and the release of neuropeptide (mainly being p material and calcitonin-gene-related peptide).By the specific binding activity of affirmation generation with the resiniferatoxin (RTX) of capsaicine same purpose, and clear and definite capsaicine (capsazepine) is as competitive inhibitor, think that thus fat-soluble capsaicine is applied in receptor protein (Szallasi A, BlumbergPM. (1999) Pharmacol.Rev.51,159-212 (non-patent literature 1)).

Cloned capsaicin receptor gene (for example, with reference to Caterina MJ, SchumacherMA Tominaga M, Posen TA, Levine JD, Julius D. (1997) Nature 389,816-824 (non-patent literature 2)) in 1997.Infer that from its aminoacid sequence it is to have the ionic channel of striding the film district for 6 times.Because capsaicine has vanilla (vanillyl) base on its structure, therefore be generically and collectively referred to as vanillic acid (vanilloid) with similar substances such as RTX, acceptor called after vanilloid receptor 1 type (vanilloid receptor subtype 1 (following is VR1)) (in addition, this VR1 is also referred to as TRPV1 (transient receptor potential vanilloid 1)) with the clone.Thereafter, express VR1 in xenopus leavis oocytes and the culturing cell from the people, used the electrophysiological biological function explore of patch clamp method, clear and definite VR1 by second messenger in the cell but directly by the capsaicine activation (for example, with reference to Caterina MJ, Schumacher MA Tominaga M, Posen TA, Levine JD, Julius D. (1997) Nature 389,816-824 (non-patent literature 2)), in addition, VR1 is the Ca with outward rectification ²⁺The non-selective cationic ion passage that perviousness is high (for example, with reference to Premkumar LS, Agarwal S, Steffen D. (2002) J.Physiol.545,107-117 (non-patent literature 3)).

Capsaicine is the material that causes pain, but, can be used as anodyne and use (for example, with reference to Szallasi A in order to alleviate the neurosal pain of diabetic neuropathy or rheumatic, Blumberg PM. (1999) Pharmacol.Rev.51,159-212 (non-patent literature 1)).This can be understood as is that the sensory nerve end that is exposed in the capsaicine is not replied, is that desensitization causes for pain stimulation.Can think VR1 desensitization mechanism with pass through Ca ²⁺Adjusting, depend on the adjusting of current potential or the VR1 by phosphorylation/dephosphorylation activity control etc. relevant, but a lot of not clear parts are arranged still.

Same with capsaicine, heat and acid also cause pain, and the injury sensory nerve of known capsaicine susceptibility is replied repeatedly stimulating to produce.Clear and definite: VR1 is not only by capsaicine, and also directly activates (for example, with reference to Yang D, Gereau RW 4th. (2002) J.Neurosci.22,6388-6393 (non-patent literature 4)) by the thermal stimulus more than 43 ℃.43 ℃ of temperature cause that with humans and animals the temperature threshold of pain is almost consistent, and prompting VR1 participates in nocuity thermal stimulus induction.

What produce when known inflammation or ischemic organizes acidifying to cause or strengthens pain (for example, with reference to BevanS, Geppetti P. (1994) Trends Neurosci.17,509-512 (non-patent literature 5)).It is known when external pH is reduced, separately can be by acidifying (proton) with the VR1 direct activation, the molecule virtual condition of organizing the caused boost inductor of acidifying that supposition VR1 produces when being inflammation or ischemic (for example, with reference to Yang D, Gereau RW 4th. (2002) J.Neurosci.22,6388-6393 (non-patent literature 4)).

Resolve affirmation by the immunohistology of having used specific antibody: the number of comparing the no myelin C fiber of expressing VR1 at inflammation part with normal position (for example increases, with reference to Carlton SM, Coggeshall RE. (2001) Neurosci.Lett.310,53-56 (non-patent literature 6)).In fact, confirmed that increase that in the inflammatory bowel of the human body VR1 in the meissnar's plexus expresses (for example, with reference to Yiangou Y, Facer P, Dyer NH, Chan CL, Knowles C, Williams NS, AnandP. (2001) Lancet 357,1338-1339 (non-patent literature 7)).Think that the increase of expression amount of such VR1 causes the periphery sensitization in the inflammation tissue, helps struvite hyperalgesic continuing.

Reported that also effect of extracellular ATP, bradykinin, nerve growth factor as the inflammation related substances (for example make the active increase of VR1, with reference to Tominaga M, Wada M, Masu M. (2001) Proc.Natl.Acad.Sci.USA 98,6951-6956 (non-patent literature 8); Shu X, Mendell LM. (1999) Neurosci.Lett.274,159-162 (non-patent literature 9); Chuang HH, Prescott ED, KongH, Shields S, Jordt SE, Basbaum AI, Chao, MV, Julius D. (2001) Nature 411,957-962 (non-patent literature 10); And Sugiura T, Tominaga M, Katsuya H, Mizumura K. (2002) J.Neurophysiol.88,544-548 (non-patent literature 11)), it is said participate in the pain that causes by inflammation or hyperpathia by VR1 there is no question about true (for example, with reference to Numazaki M, Tominaga M (2003) is biochemical 75,359-371 (non-patent literature 12)).

The sensory neurone of VR1 deficient mice for capsaicine, proton and pine for any stimulate all and do not react.Also report has: in behavior is resolved, the VR1 deficient mice does not have to show the pain reaction that produces owing to the capsaicine administration, the thermal stimulus irritability reduces, (for example do not observe struvite hyperpathia in addition yet, with reference to Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Peterson-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D. (2000) Science 288,306-313 (non-patent literature 13) and Davis LB, Gray J, (2000) Nature 405 such as Gunthorpe MJ, 183-187 (non-patent literature 14)).Thus, by the parsing of VR1 deficient mice, confirmed that VR1 also plays a role as the pain stimulation acceptor of wide region in individual level.

In addition, about the relation of vanilloid receptor 1 type (VR1) and disease, mostly reported that suppressing the active material of VR1 is useful as the therapeutical agent of various diseases.

Particularly about the pain therapy medicine, reported as the known capsaicine of VR1 antagonist and (for example in animal model, shown significant analgesic effect, with reference to Ikeda Y, Ueno A, Naraba H, Oh-ishi S, (2001) Life Science 69,2911-2919 (non-patent literature 15)), can expect to use as novel pain therapy medicine with VR1 activity inhibition.

Cross catatonic type frequent micturition/urinary incontinence about bladder, confirmed the bladder contracts function reduction of VR1 deficient mice, report has: have the capsaicine sample pharmacological mechanism compound or show inhibiting compound, promptly suppress the active material of vanilloid receptor 1 type (VR1) to be useful for VR1 for the improvement of bladder function, for example, as frequent micturition, the urinary incontinence etc. effectively curative also be useful (for example, with reference to (2002) Nat.Neurosci.5,856-860 (non-patent literature 16)).

In addition, according to other document, also reported: material with vanilloid receptor 1 type (VR1) antagonistic activity, the antagonist of VR1 acceptor particularly, the prevention and treatment of diseases that relates to for the VR1 activity is useful, particularly for urge incontinence, overactive bladder, chronic pain, neurological disorder pain, post-operative pain, chronic joint rheumatalgia, neurodynia, DPN, hyperpathia, nerve injury, ischemia, neurodegeneration, cerebral apoplexy, the urinary incontinence, and the prevention of diseases associated with inflammation and treatment are useful (for example, with reference to TOHKEMY 2003-192673 (patent documentations 1)).

In addition, can comprise pain in the relevant disease of activity known and vanilloid receptor, acute pain, chronic pain, neurological disorder pain, postoperative pain, migraine, arthrodynia, neurological disorder, nerve injury, diabetic neuropathy, neurodegenerative disease, the nervosa dermatosis, cerebral apoplexy, irritable bladder disease, irritable bowel syndrome, respiratory organs such as asthma and chronic obstructive pulmonary disease is unusual, skin, the stimulation of eye or mucous membrane, heating, gastroduodenal ulcer, inflammatory bowel, and diseases associated with inflammation etc. (for example, with reference to Japanese Unexamined Patent Application Publication 2004-506714 communique (patent documentation 2)).

Like this, it is said: material with vanilloid receptor 1 type (VR1) antagonistic activity, the morbid state that relates to for the C fiber, for example, pruritus, supersensitivity and allergic rhinitis, bladder excessive activities type frequent micturition/urinary incontinence, apoplexy, irritable bowel syndrome, respiratory illnesses such as asthma/chronic obstructive pulmonary disease, dermatitis, mucositis, gastro-duodenal ulcer, inflammatory bowel syndrome etc. naturally needless to say, as pain, acute pain, chronic pain, neurological disorder pain, postoperative pain, migraine, arthrodynia, neurological disorder, nerve injury, diabetic neuropathy, neurodegenerative disease, chronic joint rheumatalgia, neurodynia, DPN, hyperpathia, the nervosa dermatosis, cerebral apoplexy, fat, urge incontinence, ischemia, the curative of diseases associated with inflammation etc. also is useful.

Below, for be considered to known vanilloid receptor 1 type (VR1) antagonist and The compounds of this invention closer like compound describe.

Among the WO03/068749,, put down in writing amides (with reference to patent documentation 3) by following general formula [A], [B], [C] expression as the compound that shows antagonistic action for VR1.

Among the WO03/080578,, put down in writing urea compound (with reference to patent documentation 4) by following general formula [D] expression as the compound that shows antagonistic action for VR1.

Among the WO03/006019, show inhibiting compound as bringing out the plasma proteins vascular exosmosis for capsaicine in bladder, put down in writing rubane-3 '-Ji 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylicesters (with reference to patent documentation 5).Among the WO03/053945,, put down in writing urea compound (with reference to patent documentation 6) by following general formula [E] expression as the compound that shows antagonistic action for VR1.

Among the WO03/099284,, put down in writing compound (with reference to patent documentation 7) by following general formula [F] expression as showing in conjunction with active compound for VR1.

But these compounds are structurally different with compound of the present invention, in addition, also do not find the record of enlightenment The compounds of this invention.

In addition, described in reference, also carried out applying for (PCT/JP2005/013446 (patent documentation 8)) for the VR1 inhibitor of representing by following formula before the inventor.

Non-patent literature 1:Szallasi A, Blumberg PM. (1999) Pharmacol.Rev.51,159-212

Non-patent literature 2:Caterina MJ, Schumacher MA Tominaga M, Posen TA, Levine JD, Julius D. (1997) Nature 389,816-824

Non-patent literature 3:Premkumar LS, Agarwal S, Steffen D. (2002) J.Physiol.545,107-117

Non-patent literature 4:Yang D, Gereau RW 4th. (2002) J.Neurosci.22,6388-6393

Non-patent literature 5:Bevan S, Geppetti P. (1994) Trends Neurosci.17,509-512

Non-patent literature 6:Carlton SM, Coggeshall RE. (2001) Neurosci.Lett.310,53-56

Non-patent literature 7:Yiangou Y, Facer P, Dyer NH, Chan CL, Knowles C, Williams NS, Anand P. (2001) Lancet 357,1338-1339

Non-patent literature 8:Tominaga M, Wada M, Masu M. (2001) Proc.Natl.Acad.Sci.USA 98,6951-6956

Non-patent literature 9:Shu X, Mendell LM. (1999) Neurosci.Lett.274,159-162

Non-patent literature 10:Chuang HH, Prescott ED, Kong H, Shields S, Jordt SE, Basbaum AI, Chao, MV, Julius D. (2001) Nature 411,957-962

Non-patent literature 11:Sugiura T, Tominaga M, Katsuya H, Mizumura K. (2002) J.Neurophysiol.88,544-548

Non-patent literature 12:Numazaki M, Tominaga M (2003) Biochemistry 75,359-371

Non-patent literature 13:Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Peterson-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D. (2000) Science 288,306-313

Non-patent literature 14:Davis LB, Gray J, (2000) Nature 405 such as Gunthorpe MJ, 183-187

Non-patent literature 15:Ikeda Y, Ueno A, Naraba H, Oh-ishi S, (2001) LifeScience 69,2911-2919

Non-patent literature 16:(2002) Nat.Neurosci.5,856-860

Patent documentation 1: TOHKEMY 2003-192673 communique

Patent documentation 2: Japanese Unexamined Patent Application Publication 2004-506714 communique

Patent documentation 3:WO03/068749 communique

Patent documentation 4:WO03/080578 communique

Patent documentation 5:WO03/006019 communique

Patent documentation 6:WO03/053945 communique

Patent documentation 7:WO03/099284 communique

Patent documentation 8:PCT/JP2005/013446

Summary of the invention

At present, mainly use narcotic analgesic (morphine etc.), non-narcotic analgesics (NSAID (NSAID (non-steroidal anti-inflammatory drug))) etc. as anodyne.But narcotic analgesic is owing to generation resistance/dependency or other serious side effects, thereby its use is subjected to strict restriction.Upper digestive tract obstacle and hepatopathy take place in also known non-narcotic analgesics high frequency ground under long term administration, urgently expect the anodyne that analgesic effect is higher and side effect is little.In addition, also do not find effective anodyne, expect exploitation yet for their effective anodynes for diabetic neuropathy pain, postherpetic neuralgia, the such neuropathic pain of trigeminal neuralgia.

Can think: the compound that acts on the capsaicine sample of VR1, based on the diverse pharmacological mechanism of anodyne in the past (the sensorineural retardance of capsaicine), shown analgesic effect, as for the inoperative neuropathic pain of anodyne in the past be main, by the treatment of pain medicine that various morbid state such as rheumatic arthritis cause, can expect its validity.

The final target of various inflammation related substanceses is the fact of VR1, and the medicament that demonstrates effect and VR1 is for various inflammatory pains or the effective possibility of interstitial cystitis, and instead the anodyne of these medicaments in the past can be expected its validity.

Therefore, the objective of the invention is to, provide based on the novel anodyne of the diverse pharmacological mechanism of anodyne in the past (the sensorineural retardance of capsaicine), be the VR1 activity inhibitor, and the novel cpd that is provided for it.

More specifically, the object of the present invention is to provide a kind of VR1 activity inhibitor, it not only has VR1 and suppresses active, and absorptivity, persistence excellence, further the possibility height of practicability.

In addition, other purpose is to provide pain, acute pain, chronic pain, neurological disorder pain, chronic joint rheumatalgia, neurodynia etc. and vanilloid receptor 1 type (VR1) active relevant disease, particularly treatment of pain method and/or prevention method.

The inventor is in order to develop anodynes in the past such as replacing non-narcotic analgesics, pyrazoline ketone anodyne, non-pyrazoline ketone anodyne, NSAIDs, anodyne based on new mechanism of action, carried out deep research, found that having excellent VR1 effect suppresses active and have excellent more absorptivity, the condensation benzo amides of the persistence of excellence more, thereby finished the present invention.The present invention is more detailed be described as follows described.

1. by 3 of following general formula [1] expression, 4-Er hydrogen benzoxazine compound or its be at the salt that pharmaceutically allows,

[in the formula, X is:

(1) nitrogen-atoms or

(2)CR ³；

R ¹For:

(1) hydrogen atom or

(2) halogen atom;

R ²Be the C1-6 alkoxyl group that 1～5 identical or different substituting group that can be selected from following group replaces, described group is:

(1) halogen atom or

(2) hydroxyl;

R ³(but work as X is CR for halogen atom ³The time, R ¹Be halogen atom)].

2. as above-mentioned 1 described 3,4-two hydrogen benzoxazine compounds or its are at the salt that pharmaceutically allows, and it is selected from:

1) (S)-4-(5-picoline-2-yl)-3-methylol-N-(4-tert.-butoxy-3,5-difluorophenyl)-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide,

2) (S)-4-(5-picoline-2-yl)-3-methylol-N-(3,5-two fluoro-4-isopropyl phenyls)-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide,

3) (S)-4-(5-picoline-2-yl)-3-methylol-N-(3,5-two fluoro-4-phenelyls)-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide,

4) (S)-and 4-(5-picoline-2-yl)-3-methylol-N-[2-(2,2-dimethyl propoxy-) pyridine-5-yl]-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide,

5) (S)-4-(5-picoline-2-yl)-3-methylol-N-(2-tert.-butoxy pyridine-5-yl)-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide,

6) (S)-and 4-(5-picoline-2-yl)-3-methylol-N-[2-(2,2, the 2-trifluoro ethoxy) pyridine-5-yl]-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide,

7) (S)-4-(5-picoline-2-yl)-3-methylol-N-(2-isobutoxy pyridine-5-yl)-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide,

8) (S)-and 4-(5-picoline-2-yl)-3-methylol-N-[3,5-two fluoro-4-(2,2, the 2-trifluoro ethoxy) phenyl]-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide,

9) (S)-4-(5-picoline-2-yl)-3-methylol-N-[3,5-two fluoro-4-(2-hydroxy-2-methyl propoxy-) phenyl]-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide and

10) (S)-and 4-(5-picoline-2-yl)-3-methylol-N-[3,5-two fluoro-4-(1,1-dimethyl-2-hydroxyl-oxethyl) phenyl]-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide.

3. medical composition wherein, contains claim 1 or 2 described 3, and 4-Er hydrogen benzoxazine compound or its be at the salt that pharmaceutically allows, and at the carrier that pharmaceutically allows.

4. medical composition, wherein, contain claim 1 or 2 described 3,4-Er hydrogen benzoxazine compound or its are at the salt that pharmaceutically allows, and, be used for the treatment of and/or prevent to be selected from pain at the carrier that pharmaceutically allows, acute pain, chronic pain, neurological disorder pain, chronic joint rheumatalgia, neurodynia, DPN, hyperpathia disease, migraine, arthrodynia, neurodynia behind the acute herpes zoster, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neurodynia, cancer pain, inflammatory pain, interstitial cystitis, neurodynia after the wound, diabetic neuropathy, neurodegenerative disease, cerebral apoplexy, ischemia, nerve injury disease, the nervosa dermatosis, diseases associated with inflammation, pruritus, allergic rhinitis, apoplexy, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, gastro-duodenal ulcer, inflammatory bowel syndrome, irritable bladder disease, disease in the frequent micturition and the urinary incontinence.

5. medical composition wherein, contains above-mentioned 1 or 2 describedly 3, and 4-Er hydrogen benzoxazine compound or its are used for the treatment of and/or prevent irritation at the salt that pharmaceutically allows and at the carrier that pharmaceutically allows.

6. as above-mentioned 5 described medical compositions, wherein, pain is neurodynia after neurodynia behind acute pain, chronic pain, neurological disorder pain, chronic joint rheumatalgia, neurodynia, DPN, hyperpathia disease, migraine, arthrodynia, the acute herpes zoster, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neurodynia, cancer pain, inflammatory pain, interstitial cystitis, the wound, diabetic neuropathy or neurodegenerative disease.

7. capsaicin receptor 1 type (VR1) activity inhibitor wherein, contains above-mentioned 1 or 2 describedly 3, and 4-Er hydrogen benzoxazine compound or its be at the salt that pharmaceutically allows, and at the carrier that pharmaceutically allows.

8. one kind is selected from pain, acute pain, chronic pain, neurological disorder pain, chronic joint rheumatalgia, neurodynia, DPN, hyperpathia disease, migraine, arthrodynia, neurodynia behind the acute herpes zoster, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neurodynia, cancer pain, inflammatory pain, interstitial cystitis, neurodynia after the wound, diabetic neuropathy, neurodegenerative disease, cerebral apoplexy, ischemia, nerve injury disease, the nervosa dermatosis, diseases associated with inflammation, pruritus, allergic rhinitis, apoplexy, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, gastro-duodenal ulcer, inflammatory bowel syndrome, irritable bladder disease, treatment of diseases method and/or prevention method in the frequent micturition and the urinary incontinence, wherein, give the above-mentioned 1 or 2 described 3 of significant quantity pharmaceutically, 4-Er hydrogen benzoxazine compound or its are at the salt that pharmaceutically allows.

9. treatment of pain method and/or prevention method wherein, give the above-mentioned 1 or 2 described 3 of significant quantity pharmaceutically, and 4-two hydrogen benzoxazine compounds or its are at the salt that pharmaceutically allows.

10. as above-mentioned 9 described methods of treatment and/or prevention methods, wherein, pain is neurodynia after neurodynia behind acute pain, chronic pain, neurological disorder pain, chronic joint rheumatalgia, neurodynia, DPN, hyperpathia disease, migraine, arthrodynia, the acute herpes zoster, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neurodynia, cancer pain, inflammatory pain, interstitial cystitis, the wound, diabetic neuropathy or neurodegenerative disease.

11. commodity cover bag, wherein, comprise each described medical composition in above-mentioned 3～6, and about the specification sheets of this medical composition, described specification sheets has been put down in writing and has been selected from pain, acute pain, chronic pain, neurological disorder pain, chronic joint rheumatalgia, neurodynia, DPN, hyperpathia disease, migraine, arthrodynia, neurodynia behind the acute herpes zoster, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neurodynia, cancer pain, inflammatory pain, interstitial cystitis, neurodynia after the wound, diabetic neuropathy, neurodegenerative disease, cerebral apoplexy, ischemia, nerve injury disease, the nervosa dermatosis, diseases associated with inflammation, pruritus, allergic rhinitis, apoplexy, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, gastro-duodenal ulcer, inflammatory bowel syndrome, irritable bladder disease, can use in the treatment of diseases in the frequent micturition and the urinary incontinence and/or the purposes of prevention, maybe should use this medical composition.

12. above-mentioned 1 or 2 is described 3,4-Er hydrogen benzoxazine compound or its are used to be selected from the pain described in above-mentioned 4 at the salt that pharmaceutically allows in manufacturing, acute pain, chronic pain, neurological disorder pain, chronic joint rheumatalgia, neurodynia, DPN, hyperpathia disease, migraine, arthrodynia, neurodynia behind the acute herpes zoster, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neurodynia, cancer pain, inflammatory pain, interstitial cystitis, neurodynia after the wound, diabetic neuropathy, neurodegenerative disease, cerebral apoplexy, ischemia, nerve injury disease, the nervosa dermatosis, diseases associated with inflammation, pruritus, allergic rhinitis, apoplexy, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, gastro-duodenal ulcer, inflammatory bowel syndrome, irritable bladder disease, application in the treatment of diseases in the frequent micturition and the urinary incontinence and/or the medical composition of prevention.

13. above-mentioned 1 or 2 is described 3,4-Er hydrogen benzoxazine compound or its are used for the application of the medical composition of above-mentioned 5 or 6 described treatment of pain and/or prevention in manufacturing at the salt that pharmaceutically allows.

14. as above-mentioned 13 described 3,4-Er hydrogen benzoxazine compound or its application at the salt that pharmaceutically allows, wherein, pain is neurodynia after neurodynia behind acute pain, chronic pain, neurological disorder pain, chronic joint rheumatalgia, neurodynia, DPN, hyperpathia disease, migraine, arthrodynia, the acute herpes zoster, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neurodynia, cancer pain, inflammatory pain, interstitial cystitis, the wound, diabetic neuropathy or neurodegenerative disease.

15. a medicine, by following both constitute, described both are:

Contain above-mentioned 1 or 2 describedly 3,4-Er hydrogen benzoxazine compound or its are at salt that pharmaceutically allows and the medical composition that constitutes at the carrier that pharmaceutically allows;

Be selected from antiviral agent, thymoleptic, spasmolytic, antiarrhythmics, local anesthetic, narcotic, N-methyl-D-aspartate receptor antagonist, adrenocortical steroid, nerve block agent, non-steroidal anti-inflammatory analgesics, narcotics, antagonism anodyne, α ₂The medicament more than a kind in adrenoceptor agonists, externally applied agent, calcium-channel antagonists, potassium channel openers and the antipyretic.

16. above-mentioned 1 or 2 is described 3,4-Er hydrogen benzoxazine compound or its are being made application in the above-mentioned 15 described medicines at the salt that pharmaceutically allows.

17. be selected from pain, acute pain, chronic pain, neurological disorder pain, chronic joint rheumatalgia, neurodynia, DPN, hyperpathia disease, migraine, arthrodynia, neurodynia behind the acute herpes zoster, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neurodynia, cancer pain, inflammatory pain, interstitial cystitis, neurodynia after the wound, diabetic neuropathy, neurodegenerative disease, cerebral apoplexy, ischemia, nerve injury disease, the nervosa dermatosis, diseases associated with inflammation, pruritus, allergic rhinitis, apoplexy, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, gastro-duodenal ulcer, inflammatory bowel syndrome, irritable bladder disease, treatment of diseases method and/or prevention method in the frequent micturition and the urinary incontinence, it is characterized in that, will be selected from antiviral agent, thymoleptic, spasmolytic, antiarrhythmics, local anesthetic, narcotic, the N-methyl-D-aspartate receptor antagonist, adrenocortical steroid, the nerve block agent, the non-steroidal anti-inflammatory analgesics, narcotics, the antagonism anodyne, α ₂The medicament more than a kind in adrenoceptor agonists, externally applied agent, calcium-channel antagonists, potassium channel openers and the antipyretic, above-mentioned 1 or 2 described 3 with in significant quantity pharmaceutically, 4-Er hydrogen benzoxazine compound or its carry out and use at the salt that pharmaceutically allows.

18. treatment of pain method and/or prevention method, wherein, with above-mentioned 1 or 2 described 3,4-two hydrogen benzoxazine compounds or its give the salt that pharmaceutically allows, and are selected from acupuncture, stimulate stimulation produced analgesia therapy in analgesic therapy (SSP), peripheral nerve stimulation therapy, backbone electricity irritation, Electroconvulsive Therapy, laser therapy and the low frequency therapy to carry out and use through skin electroacupuncture stimulation therapy, transcutaneous electrical nerve stimulation therapy, point.

19. the methods of treatment of a post-operative pain and/or prevention method, wherein, after root goes into to distinguish surgical operation in Destruction, cordotomy and the frontal lobectomy behind radectomy, sympathectomy, the spinal cord after being selected from cicatrectomy, neural cryocoagulation art, peripheral nerve surgical blanking, spinal cord, give above-mentioned 1 or 2 describedly 3,4-Er hydrogen benzoxazine compound or its are at the salt that pharmaceutically allows.

Of the present invention 3,4-Er hydrogen benzoxazine compound is owing to effectively suppress the activity of vanilloid receptor 1 type (VR1), therefore, for pain, acute pain, chronic pain, neurological disorder pain, chronic joint rheumatalgia, neurodynia, DPN, hyperpathia disease, migraine, arthrodynia, neurodynia behind the acute herpes zoster, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neurodynia, cancer pain, inflammatory pain, interstitial cystitis, neurodynia after the wound, diabetic neuropathy, neurodegenerative disease, cerebral apoplexy, ischemia, nerve injury disease, the nervosa dermatosis, diseases associated with inflammation, pruritus, allergic rhinitis, apoplexy, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, gastro-duodenal ulcer, inflammatory bowel syndrome, irritable bladder disease, bladder excessive activities type frequent micturition, and treatment of diseases such as the bladder excessive activities type urinary incontinence and/or prevention are effective.

Particularly, effective as neurodynia, diabetic neuropathy, neurodegenerative disease etc. after neurodynia, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neurodynia, cancer pain, inflammatory pain, interstitial cystitis, the wound behind pain, acute pain, chronic pain, neurological disorder pain, chronic joint rheumatalgia, neurodynia, DPN, hyperpathia disease, migraine, arthrodynia, the acute herpes zoster with treatment of diseases medicine, the prophylactic agent of pain symptom.In addition, the also effect that produces owing to the mechanism different of expectation with anodyne in the past.

In addition, by of the present invention 3 of above-mentioned general formula [1] expression, 4-Er hydrogen benzoxazine compound, not only has remarkable VR1 activity inhibition, and be difficult to oxidized metabolism, also having remarkable effect aspect this inhibiting persistence, has the high and/or stable high characteristic in gastric juice of absorptivity.Even such effect also is unforeseeable for those skilled in the art.

Therefore, higher as the medicine operational feasibility, the excellent compound of novel cpd of the present invention.

Embodiment

The various terms that use in this specification sheets are defined as follows.

" C1-6 alkyl " is meant that carbonatoms is 1～6 straight or branched alkyl, is preferably " C1-4 alkyl ".As " C1-6 alkyl ", specifically can enumerate: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, tert-pentyl, hexyl etc.In addition, " C1-4 alkyl " is meant that carbonatoms is 1～4 straight or branched alkyl, specifically can enumerate: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl etc.

" halogen atom " is fluorine atom, chlorine atom, bromine atoms or iodine atom, is preferably fluorine atom, chlorine atom, is preferably fluorine atom especially.

" C1-6 alkoxyl group " is that its alkyl position is the alkoxyl group of " the C1-6 alkyl " of above-mentioned definition, specifically can enumerate: methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy, isopentyloxy, 2-methyl butoxy, neopentyl oxygen, 1-ethyl propoxy-, hexyloxy, 4-methyl pentyloxy, 3-methyl pentyloxy, 2-methyl pentyloxy, 1-methyl pentyloxy, 3,3-dimethyl butoxy, 2,2-dimethyl butoxy, 1,1-dimethyl butoxy, 1,2-dimethyl butoxy, 1,3-dimethyl butoxy, 2,3-dimethyl butoxy, 2-ethyl butoxy etc.

In addition, " the C1-6 alkoxyl group that can be replaced by 1～5 halogen atom " is meant above-mentioned " C1-6 alkoxyl group " in addition, " the C1-6 alkyl " that constitutes its C1-6 alkoxyl group part by 1～5, preferably by 1～3, more preferably by 3 identical or different halogen atoms, the halogenated alkoxy that preferably replaced by 3 identical halogen atoms.Such halogenated alkoxy, specifically can enumerate: fluoro methoxyl group, difluoro-methoxy, trifluoromethoxy, bromo methoxyl group, chloro methoxyl group, dichloro methoxyl group, 2-chloroethoxy, 1,2-two chloroethoxies, 2,2-two chloroethoxies, trichlorine methoxyl group, 2-fluorine oxyethyl group, 2,2,2-trifluoro ethoxy, 2,2,2-three chloroethoxies, 4-fluorine butoxy etc.

In addition, " the C1-6 alkoxyl group that can be replaced by 1～5 hydroxyl " is meant above-mentioned " C1-6 alkoxyl group " in addition, " the C1-6 alkyl " that constitutes its C1-6 alkoxyl group part by 1～5, preferably by 1～2, the alkoxyl group that further preferably replaced by 1 hydroxyl.The alkoxyl group that is replaced by hydroxyl so specifically can be enumerated: hydroxyl methoxyl group, 2-hydroxyl-oxethyl, 1-hydroxyl-oxethyl, 3-hydroxyl propoxy-, 4-hydroxyl butoxy, 5-hydroxyl pentyloxy, 6-hydroxyl hexyloxy, 2-hydroxy-2-methyl propoxy-, 1,1-dimethyl-2-hydroxyl-oxethyl etc.

In general formula [1], the preferred example and the more preferred example of each symbol are as follows.But the present invention is not limited to this.

[preferred R ¹]

R ¹Be hydrogen atom or halogen atom.At this, as halogen atom, be preferably fluorine atom or chlorine atom, be preferably fluorine atom especially.

But, when X is nitrogen-atoms, R ¹Be preferably hydrogen atom, when X is CR ³The time, R ¹Be preferably halogen atom, be preferably fluorine atom especially.

R more preferably ³And R ¹Be the situation of fluorine atom simultaneously.More specifically, as follows.

R ₁For:

(1) hydrogen atom or

(2) halogen atom,

Be preferably:

(1) hydrogen atom or

(2) fluorine atom.

(still, when X be CR ³The time, R ¹Preferred fluorine atom).

[preferred R ²]

R ²Can be selected from the C1-6 alkoxyl group that 1～5 the identical or different substituting group in halogen atom and the hydroxyl replaces, being preferably can be by 1～3 halogen atom or 1～3 C1-6 alkoxyl group that hydroxyl replaces.

At this, should " C1-6 alkoxyl group " can be that the alkyl position is the alkoxyl group of straight chain, also can be the alkoxyl group of side chain.

Preferably " C1-6 alkoxyl group " is can ramose C2-5 alkoxyl group, specifically can enumerate: isopropoxy, isobutoxy, tert.-butoxy, 2,2-dimethyl-propoxy-etc.

" the C1-6 alkoxyl group that can be replaced by 1～3 halogen atom " is meant above-mentioned " C1-6 alkoxyl group " in addition, the C1-6 alkoxyl group that is replaced by 1～3 halogen atom.In addition, by the C1-6 alkoxyl group that 1～3 halogen atom replaces, be meant by 1～3 identical or different halogen atom, preferably by 1～3 identical halogen atom, the C1-6 alkoxyl group that especially preferably replaced by 1～3 fluorine atom, specifically can enumerate: 2,2,2-three fluoro-oxyethyl groups, 2,2,2-three chloro-oxyethyl groups, 2,2,2-three bromo-oxyethyl groups, 2,2,2-three iodo-oxyethyl groups etc.Particularly preferred " by the C1-6 alkoxyl group of 1～3 fluorine atom replacement " is by the C2-5 alkoxyl group of 1～3 fluorine atom replacement, specifically can enumerate 2,2,2-three fluoro-oxyethyl groups etc.

" the C1-6 alkoxyl group that can be replaced by 1～3 hydroxyl " be meant beyond the above-mentioned C1-6 alkoxyl group, by 1～3 hydroxyl, the C1-6 alkoxyl group that preferably replaced by 1 hydroxyl.In addition,, be preferably the C2-5 alkoxyl group that is replaced by 1 hydroxyl, specifically can enumerate: 2-hydroxy-2-methyl-propoxy-, 2-hydroxyl-1,1-dimethyl-oxyethyl group etc. as the C1-6 alkoxyl group that is replaced by 1～3 hydroxyl.

[preferred R ³]

R ³Be halogen atom, at this, halogen atom is preferably fluorine atom or chlorine atom, is preferably fluorine atom especially.Be more preferably R ³And R ¹Be fluorine atom simultaneously.

[preferred R when X is nitrogen-atoms ¹And R ²]

When X is nitrogen-atoms, preferred R ¹Be hydrogen atom, R ²It is the C1-6 alkoxyl group that can be replaced by 1～3 identical or different halogen atom.

Preferred especially R ¹Be hydrogen atom, R ²Be C1-6 alkoxyl group that can be replaced or the C1-6 alkoxyl group that is replaced by 1 hydroxyl by 3 identical halogen atoms, further preferred R ¹Be hydrogen atom, R ²Be tert.-butoxy, isobutoxy, 2,2,2-three fluoro-oxyethyl groups or 2,2-dimethyl-propoxy-.

[when X is CR ³The time preferred R ¹, R ²And R ³]

When X is CR ³The time preferred R ¹And R ³Be: R ¹And R ³Be identical or different halogen atom, be preferably identical halogen atom especially.

Further preferred R ³And R ¹Be the situation of fluorine atom simultaneously.

When X is CR ³The time preferred R ², be oxyethyl group, isopropoxy, isobutoxy, tert.-butoxy, 2, C2-5 alkoxyl groups such as 2-dimethyl-propoxy-; 2,2,2-three fluoro-oxyethyl groups, 2,2,2-three chloro-oxyethyl groups, 2,2,2-three bromo-oxyethyl groups, 2,2,2-three iodo-oxyethyl groups etc. are by 1～3 halogen atom, the C1-6 alkoxyl group that preferably replaced by fluorine atom; Perhaps 2-hydroxy-2-methyl-propoxy-, 2-hydroxyl-1,1-dimethyl-oxyethyl group etc. are by 1 or 2 C1-6 alkoxyl groups that hydroxyl replaces.

More specifically, when X be CR ³The time, R ¹And R ³Be preferably identical or different halogen atom, be preferably fluorine atom especially.R ²Preferably be selected from the C1-6 alkoxyl group that 1～3 the identical or different substituting group in fluorine atom and the hydroxyl replaces, more specifically be oxyethyl group, tert.-butoxy, isopropoxy, 2,2,2-three fluoro-oxyethyl groups, 2-hydroxy-2-methyl-propoxy-or 2-hydroxyl-1,1-dimethyl-oxyethyl group.

" the pharmaceutically salt of Yun Xuing " among the present invention is as long as can form compound and the salt of being represented by above-mentioned general formula [1], then can be any salt, for example, can be by obtaining with following acid-respons, described acid is: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide; Or organic acid such as oxalic acid, propanedioic acid, citric acid, fumaric acid, lactic acid, oxysuccinic acid, succsinic acid, tartrate, acetic acid, trifluoracetic acid, gluconic acid, xitix, methylsulfonic acid, tosic acid, Phenylsulfonic acid, benzyl sulfonic acid; Or amino acid such as Methionin, arginine, L-Ala.In addition, among the present invention, also comprise hydrate or the hydrate and the solvate of each compound.

In addition, in the compound by above-mentioned general formula [1] expression, there are various isomer.For example, there are E body and Z body, in addition, exist under the situation of unsymmetrical carbon, have enantiomorph and diastereomer, can have tautomer as steric isomer based on them as geometrical isomer.Therefore, comprise these all isomer and their mixture in the scope of the present invention.In addition, the present invention also comprises the preceding drug compound and the metabolic compounds of these compounds as isovalent compounds except the compound by above-mentioned general formula [1] expression.

" prodrug " is the derivative of The compounds of this invention, it has chemically or the group that can decompose in the metabolism, in chemical transformation after the organism administration is the active compound that has as medicine, and shows original drug effect, comprises the mixture and the salt that are not by covalent linkage formation.

Prodrug is used in absorption that for example improves in oral administration or the target that arrives target site.As the modification position that is used for prodrugization, can enumerate: the hydroxyl in the The compounds of this invention, the functional group that amino isoreactivity is high.As the modification group of hydroxyl, specifically can enumerate: ethanoyl, propionyl, isobutyryl, pivaloyl group, benzoyl, 4-methyl benzoyl, formyl-dimethylamino, sulfo group etc.Modification group as amino; specifically can enumerate: hexyl formamyl, 3-methylthio group-1-(kharophen) propyl group formamyl, 1-sulfo group-1-(3-oxyethyl group-4-hydroxy phenyl) methyl, (5-methyl-2-oxygen-1,3-two oxa-s-4-yl) methyl etc.

" medical composition " contains mixture with other medicaments etc. except by the what is called " composition " that constitutes as the effective constituent of medicine and Synergist S-421 95 etc.This composite medicine in the on-the-spot scope that allows of medical treatment can with other medicament and usefulness arbitrarily, this is certain.Therefore, this medical composition also can be described as and is used for and other the medicament and the medical composition of usefulness.

" pain " though its symptom how (for example, no matter be dull pain or sharp pain, chronic or acute etc.), in addition, no matter how (for example as the kind of the disease of this pain cause, no matter be pain of causing of the pain that causes of rheumatism or cancer etc.), be meant the symptom of all pain.Therefore, " pain " also comprises the pain of neurodynia after neurodynia behind acute pain, chronic pain, neurological disorder pain, chronic joint rheumatalgia, neurodynia, DPN, hyperpathia disease, migraine, arthrodynia, the acute herpes zoster, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neurodynia, cancer pain, inflammatory pain, interstitial cystitis, the wound, diabetic neuropathy and neurodegenerative disease except the pain that is called as " pain ".

" vanilloid receptor 1 type (VR1) activity inhibitor " is meant the function as ionic channel that suppresses vanilloid receptor 1 type, eliminates or weakens its active material.Specifically can enumerate vanilloid receptor 1 type antagonist etc.Vanilloid receptor 1 type antagonist be meant restraining effect in the effect of the agonist of vanilloid receptor 1 type, suppress the material of vanilloid receptor 1 type as the function of ionic channel.In addition, this inhibitor can be not with agonist competition but also suppress material as the function of VR1 ionic channel.As the agonist that acts on vanilloid receptor 1 type, specifically can enumerate: capsaicine, capsaicin derivates, acid stimulate (proton), thermal stimulus etc., but vanilloid receptor 1 type (VR1) activity inhibitor can be to stimulating the agonist of (proton) or thermal stimulus to stimulate Ca in the cell that causes by such capsaicine, acid ²⁺The material that inflow suppresses.

In addition, medical composition of the present invention is not limited to the people, can be to other Mammalss (mouse, rat, hamster, rabbit, cat, dog, ox, horse, sheep, monkey etc.) administration.Therefore, medical composition of the present invention from needless to say, also is useful as the animal-use drug product for the people.

When using The compounds of this invention as pharmaceutical preparation, with the carrier that allows in the usually known pharmacy own, vehicle, thinner, swelling agent, disintegrating agent, stablizer, preservatives, buffer reagent, emulsifying agent, perfume compound, tinting material, sweeting agent, thickening material, correctives, solubility promoter, and other additives, be specially water, vegetables oil, alcohol such as ethanol or phenylcarbinol, polyoxyethylene glycol, Vanay, gelatin, lactose, carbohydrate such as starch, Magnesium Stearate, talcum, lanolin, Vaseline etc. mix, make tablet according to well-established law, pill, powder, particle, suppository, injection, eye drops, liquid preparation, capsule, coated tablet, aerosol, elixir, suspensoid, emulsion, forms such as syrup thus can be at whole body or local by the oral or non-oral administration of carrying out.

Dosage is according to age, body weight, symptom, result of treatment, medication etc. and different, usually, is grown up everyone at every turn in the scope of 0.01mg～1g, 1 time on the 1st～for several times, can the through port formulation or the form of injection such as intravenous injection etc. carry out administration.

" prevention " is so-called prevention, for example, is meant and prophylactically suppresses neuralgic disease or neuralgic chronicity.About pain, specifically can enumerate prophylactically suppress behind the acute herpes zoster neuralgic disease, postherpetic neuralgia send out disease, from acute herpes zoster pain neuralgic chronicity etc. after neuralgic disease after the chronicity of sending out disease, inflammatory pain of sending out disease, interstitial cystitis of the chronicity of sending out disease, cancer pain of neuralgic disease of transformation, the chronicity of postherpetic neuralgia, postoperative of postherpetic neuralgia, the neuralgic chronicity of postoperative, cancer pain, inflammatory pain, the wound or wound.

" medicine that is made of mixture " is meant: a kind of medicine, it is characterized in that it is to contain medical composition that is made of at the salt that pharmaceutically allows The compounds of this invention [1] or its and the Synergist S-421 95 that can form with the medical composition or the medicament of these combination of compositions; A kind of medicine is characterized in that, it is to contain the medicine box that the medical composition that is made of at the salt that pharmaceutically allows The compounds of this invention [1] or its and the medical composition that can make up with these compositions or medicament form; A kind of medicine is characterized in that, by identical or different route of administration, contain the medical composition that constitutes at the salt that pharmaceutically allows by The compounds of this invention [1] or its and can with the medical composition or the medicament of these combination of compositions.

Compound of the present invention or medical composition can be by the general methods that carries out at common medical scene, carry out with a kind or multiple other medicament and use.Carrying out and the time spent, should carry out and the medicament administration simultaneously of usefulness, the time difference perhaps is set carries out administration respectively.With compound of the present invention can and the medicament of usefulness have multiplely, but be preferably antiviral agent, thymoleptic, Anticonvulsants, antiarrhythmics, local anesthetic, narcotic, N-methyl-D-aspartate receptor antagonist, adrenocortical steroid, nerve block agent, non-steroidal anti-inflammatory analgesics, narcotics, antagonism anodyne, α especially ₂Adrenoceptor agonists, stimulation produced analgesia method, externally applied agent, calcium-channel antagonists, potassium channel openers, antipyretic.

As antiviral agent, specifically can enumerate: vidarabine, aciclovir, ganciclovir, zidovudine, Didanosine, amantadine, iodoxuridine, Interferon, rabbit etc.

As thymoleptic, specifically can enumerate: amitriptyline, Mi Paming, clomipramine, Trimipramine, Tymelvt, dothiepin, Desipramine, amoxapine, nortriptyline, fluoxetine, Fluvoxamine, maprotiline, mianserin, setiptilinie, trazodone etc.

As Anticonvulsants, specifically can enumerate: gabapentin, Pregabalin, phenylethyl barbituric acid, Primidone, Phenytoin Sodium Salt, mephenytoin, nirvanol, ethotoin, Trimethadione, ethosuximide, acetylpheneturide, Carbamzepine, zonisamide, acetazolamide, diazepam, clonazepam, nitrazepam, diphenyl hydantoin, valproic acid, baclofen etc.

As antiarrhythmics, specifically can enumerate: Quinidine, norpace (disopyramide), procainamide, Ajmaline, neo-gilurytmal, cibenzoline, lignocaine, mexiletine, Lilly 99170, throwing Ni Kade (tonicaid), Phenytoin Sodium Salt, Tamboar, pilsicainide, Propafenone, Proprasylyte, amiodarone, verapamil, Bepridil etc.

As local anesthetic, specifically can enumerate: lignocaine, mexiletine, Cocaine, PROCAINE HCL, PHARMA GRADE, bupivacaine, mepivacaine, prilocaine, tetracaine, Percamine, Benzocaine etc.

As narcotic, specifically can enumerate: benzodiazepines, diazepam, midazolam, Thiopental Sodium, thiosezonal, Rapinovet, baclofen, Droperidol, sufentanil etc.As the N-methyl-D-aspartate receptor antagonist, specifically can enumerate: ketamine, Dextromethorphane Hbr, memantine, amantadine etc.

As adrenocortical steroid, specifically can enumerate: hydrocortisone, cortisone, dehydrohydro-cortisone, triamcinolone, dexamethasone, Betamethasone Valerate, dillar, Metosyn, fluocinolone acetonide, beclometasone, fluohydrocortisone etc.

As nerve block, specifically can enumerate: stellate ganglion block, epidural block, brachial plexus block, nerve root retardance, chest/waist sympathetic block, Trigger point block, the retardance of arachnoid membrane inferior ganglion, trigeminal nerve block, sympatholytic, local infiltration retardance, peripheral nerve block etc.

As the non-steroidal anti-inflammatory analgesics, specifically can enumerate: celecoxib, rofecoxib, R-ETODOLAC, meloxicam, nimesulide, diclofenac sodium, mefenamic acid, zaltoprofen, loxoprofen sodium, sulindac, Maxicom, Diflonid, piroxicam, Ibuprofen BP/EP, naprosine, fenoprofen, acetylsalicylic acid, Tolmetin, indomethacin, U-27182 Evil promazine, Ketoprofen BP 93, N-22, paracetamol, ketorolac, Zomepirac sodium salt, the nitro acetylsalicylic acid, thiophene Lip river sweet smell, Ampiroxicam, FK-1160, epirizole etc.

As narcotics, specifically can enumerate: morphine, fentanyl, oxycodone, methadone, morphine monomethyl ether, Cocaine, pethidine, opium, ipecac etc.

As the antagonism anodyne, specifically can enumerate: Pan Dakang, buprenorphine, nalorphine, Cyc, butorphanol etc.

As α ₂Adrenoceptor agonists specifically can be enumerated: clonidine, dexmedetomidine, tizanidine, guanfacine, guanabenz etc.

As externally applied agent, specifically can enumerate: capsaicine cream etc.

As antipyretic, specifically can enumerate: diclofenac sodium, mefenamic acid, loxoprofen sodium, Ibuprofen BP/EP, acetylsalicylic acid, indomethacin, paracetamol etc.

As the stimulation produced analgesia method, specifically can enumerate: acupuncture, stimulate analgesic therapy (silver spike point (SSP)), peripheral nerve stimulation therapy, backbone electricity irritation, Electroconvulsive Therapy, laser therapy, low frequency therapy etc. through skin electroacupuncture stimulation therapy, transcutaneous electrical nerve stimulation therapy, point.

In addition, compound of the present invention according to the method for carrying out, by administration after carrying out surgical operation, can be used for prevention or treatment pain in general medicine.Can have multiplely with the surgical operation of compound of the present invention and usefulness, but root goes into to distinguish Destruction, cordotomy, frontal lobectomy after being preferably radectomy behind cicatrectomy, neural cryocoagulation art, peripheral nerve surgical blanking, the spinal cord, sympathectomy, spinal cord especially.

Above explanation, mainly be that purposes as pain and prevention or treatment describes application of compound of the present invention, but, even the prevention or the treatment of the respiratory illness of the morbid state, for example pruritus, supersensitivity and the allergic rhinitis that relate to for the C fiber, bladder excessive activities type frequent micturition/urinary incontinence, apoplexy, irritable bowel syndrome, asthma/chronic obstructive pulmonary disease and so on, dermatitis, mucositis, gastro-duodenal ulcer, inflammatory bowel syndrome etc. also can be used compound of the present invention.

Below, specifically describe for manufacture method, but the present invention is not limited to these manufacture method certainly by the The compounds of this invention of general formula [1] expression.

Therefore, The compounds of this invention can synthesize by following manufacture method A or B, also can perhaps make with reference to these method for makings according to embodiment described later.When making The compounds of this invention, reaction sequence can suit to change.Can be from thinking rational operation or replace the position and react.For example, can introduce compound (X) before at introducing compound (II), also can be opposite.In addition, for 3, the formation of 4-Er hydrogen benzoxazine ring, introducing compound (II) and/or compound (X) before, can carry out in order to form this heterocyclic ring-closure reaction, perhaps, introducing compound (II) and/or compound (X) afterwards, can carry out in order to form this heterocyclic ring-closure reaction.Have under the situation of reactive functional groups, protection, deprotection can suit.For the carrying out that promotes to react, can suit to use the reagent in addition of the reagent shown in the example.

Following manufacturing process process is an example of the manufacture method of representative, but the manufacturing of The compounds of this invention is not particularly limited in following method.The compound that obtains in each operation can all separate and purifying according to ordinary method, according to circumstances, does not carry out separation and purification and also can carry out following operation.

1. manufacture method A

(in the formula; R represents that carboxyl-protecting group is (at this; carboxyl-protecting group is meant normally used carboxyl-protecting group in the Synthetic Organic Chemistry field; for example; can enumerate: methyl, ethyl, propyl group, the tertiary butyl, benzyl, to methoxy-benzyl etc.); by hydrolysis or catalytic hydrogenation etc., form the ester that is incorporated in the carboxylic acid easily.X ' and X " can be identical or different respectively, halogen atom or sulfonyloxies such as 3-oil of mirbane sulfonyloxy, tolysulfonyl oxygen base, phenylsulfonyloxy, brosyl oxygen base, methanesulfonyloxy group or trifluoromethane sulfonyloxy such as expression chlorine, bromine.The protecting group of the phenol hydroxyl that R ' expression can easily be removed by hydrolysis or catalytic hydrogenation etc. is (at this; the protecting group of phenol hydroxyl is meant normally used phenol hydroxyl protecting group in the Synthetic Organic Chemistry field; for example, can enumerate: methoxymethyl, methoxy ethoxy methyl, benzyl, the tertiary butyl, THP trtrahydropyranyl, ethanoyl etc.).R " the protecting group (at this; protecting group of hydroxyl is meant normally used hydroxyl protecting group in the Synthetic Organic Chemistry field; for example, can enumerate: methoxymethyl, methoxy ethoxy methyl, benzyl, THP trtrahydropyranyl, ethanoyl etc.) of the hydroxyl that expression can easily be removed by hydrolysis or catalytic hydrogenation etc.Other each symbols are implication same as described above respectively.)

The 1st operation

This is the operation that is obtained compound (III) by compound (I) and compound (II) by palladium catalyst Buchwald/Hartwig type ammoxidation.

At toluene, 1, in 4-diox, tetrahydrofuran (THF) etc. or their mixed solvent, use palladium and 2,2 '-two (diphenylphosphino)-1,1 '-palladium catalyst such as the mixture of dinaphthyl or two (diphenylphosphino) ferrocene Palladous chloride (II), three (dibenzalacetones), two palladiums and yellow soda ash, Tripotassium phosphate (K ₃PO ₄), alkali such as salt of wormwood, cesium carbonate, sodium bicarbonate, saleratus, potassium tert.-butoxide, 20 ℃ to reflux temperature, preferred 60 ℃ to reflux temperature, make compound (I) and compound (II) reaction 5 hours to 96 hours, preferred 8 hours to 48 hours, can obtain compound (III) thus.

The 2nd operation

This is the operation that the R ' that removes compound (III) obtains compound (IV).

For example; when R ' is methoxymethyl, benzyloxymethyl, methoxy ethoxy methyl, the tertiary butyl, THP trtrahydropyranyl, ethanoyl; in solvent-free or water, methyl alcohol, ethanol, propyl alcohol, tetrahydrofuran (THF) etc. or their admixture solvent; use acid such as hydrochloric acid, trifluoracetic acid; at 0 ℃ to reflux temperature, preferred 0 ℃ to 50 ℃; make compound (III) reaction 0.5 hour to 24 hours, preferred 0.5 hour to 8 hours, can obtain compound (IV) thus.

In addition, when R ' is benzyl etc., in methyl alcohol, ethanol, propyl alcohol, tetrahydrofuran (THF) etc. or their mixture solution, in the presence of palladium-carbon catalyst etc., use hydrogen or ammonium formiate etc., about 0 ℃ to reflux temperature, preferred about 20 ℃ to 50 ℃, make its reaction 0.5 hour to 96 hours, preferred 1 hour to 48 hours, can obtain compound (IV) thus.

The 3rd operation

This is to make compound (IV) and compound (V) reaction obtain the operation of compound (VI) under alkaline condition.

At chloroform, tetrahydrofuran (THF), N, dinethylformamide, dimethyl sulfoxide (DMSO), N, the N-N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO), vinyl acetic monomer, methyl alcohol, in water or their mixed solvent, at yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide, alkali such as triethylamine exist down, at 0 ℃ to reflux temperature, under preferred 0 ℃ to 60 ℃, making compound (IV) and compound (V) is the Racemic glycidol muriate, the Racemic glycidol tosylate, reaction such as Racemic glycidol nitrobenzene-sulfonic acid ester (glycidyl nosylate) 0.5 hour to 24 hours obtains compound (VI) thus.

The 4th operation

This is under alkaline condition, compound (VI) is incorporated into the operation of compound (VII).

At chloroform, tetrahydrofuran (THF), N, dinethylformamide, N, in N-N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO), vinyl acetic monomer or their mixed solvent, in the presence of alkali such as yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide, triethylamine, at 0 ℃ to reflux temperature, preferred 0 ℃ to 60 ℃, make compound (VI) reaction 0.5 hour to 24 hours, obtain compound (VII) thus.

The 5th operation

This is the operation that the R that removes compound (VII) obtains compound (VIII).

For example, when R is methyl, ethyl, propyl group etc., in water, methyl alcohol, ethanol, propyl alcohol, tetrahydrofuran (THF) etc. or their admixture solvent, use alkali such as sodium hydroxide, potassium hydroxide, lithium hydroxide, salt of wormwood, yellow soda ash,-20 ℃ to reflux temperature, preferred 20 ℃ to reflux temperature, compound (VII) was hydrolyzed 0.5 hour to 24 hours, preferred 0.5 hour to 8 hours, can obtains compound (VIII) thus.

For example, when R is the tertiary butyl, in solvent-free or water, methyl alcohol, ethanol, propyl alcohol, tetrahydrofuran (THF) etc. or their mixed solvent, use acid such as hydrochloric acid, trifluoracetic acid, at 0 ℃ to reflux temperature, preferred 0 ℃ to 50 ℃, make compound (VII) reaction 0.5 hour to 24 hours, preferred 0.5 hour to 8 hours, can obtain compound (VIII) thus.

When R be benzyl, during to methoxy-benzyl etc., in methyl alcohol, ethanol, propyl alcohol, tetrahydrofuran (THF) etc. or their mixed solvent, in the presence of palladium-carbon catalyst etc., use hydrogen or ammonium formiate etc., about 0 ℃ to reflux temperature, preferred about 20 ℃ to 50 ℃, make compound (VII) reaction 0.5 hour to 96 hours, preferred 1 hour to 48 hours, can obtain compound (VIII) thus.

The 6th operation

This is the operation that the hydroxyl protection of compound (VIII) is obtained compound (IX).

For example; as R " when being ethanoyl; chloroform, tetrahydrofuran (THF), toluene, vinyl acetic monomer, pyridine or solvent-free down; use Acetyl Chloride 98Min. or acetic anhydride; in the existence of alkali such as pyridine, triethylamine or not; 0 ℃ to reflux temperature, preferred 0 ℃ to 50 ℃, make compound (VIII) reaction 0.5 hour to 24 hours, preferred 0.5 hour to 8 hours, can obtain compound (IX) thus.

As R " when being THP trtrahydropyranyl; chloroform, tetrahydrofuran (THF), toluene, vinyl acetic monomer or solvent-free down; use 2; 3-dihydropyrane; in the presence of acid catalysts such as tosic acid, hydrogenchloride; 0 ℃ to reflux temperature, preferred 0 ℃ to 50 ℃, compound (VIII) was reacted 0.5 hour to 24 hours, preferred 0.5 hour to 8 hours, can obtain compound (IX) thus.

As R " when being methoxymethyl, methoxy ethoxy methyl, benzyl; at tetrahydrofuran (THF), N; in the dinethylformamide equal solvent; in the presence of alkali such as sodium hydroxide, dipropyl acidamide lithium; use methoxymethyl chlorine, methoxy ethoxy methyl chloride, benzyl chloride or bromotoluene; 0 ℃ to reflux temperature, preferred 0 ℃ to 50 ℃, make compound (VIII) reaction 0.5 hour to 24 hours, preferred 0.5 hour to 8 hours, can obtain compound (IX) thus.

The 7th operation

This is the operation that obtains compound (XI) by the compound (IX) and the condensation reaction of compound (X).

For example, when using condensing agent to carry out condensation reaction, at N, in dinethylformamide, methylene dichloride, chloroform etc. or their mixed solvent, use dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylamino-propyl)-condensing agents such as carbodiimide,-20 ℃ to reflux temperature, preferred 0 ℃ to 50 ℃, make compound (IX) and compound (X) reaction about 1 hour to 48 hours, preferred 1 hour to 24 hours, can obtain compound (XI) thus.At this moment, also can add additives such as hydroxybenzotriazole, N-hydroxy succinic acid imines.

When carrying out condensation reaction by chloride of acid; in chloroform, methylene dichloride, tetrahydrofuran (THF) etc. or their mixed solvent; make compound (IX) and reactions such as thionyl chloride, oxalyl chloride; obtain the chloride of acid of (IX); make itself and compound (X) in toluene, chloroform, tetrahydrofuran (THF) etc. or their mixed solvent; in the presence of alkali such as triethylamine, pyridine; reacted about 0.5 hour to 24 hours, preferred 0.5 hour to 12 hours to reflux temperature, preferred 0 ℃ to 40 ℃ at-20 ℃, can obtain compound (XI) thus.

The 8th operation

This is that hydroxyl protecting group with compound (XI) carries out deprotection and obtains operation by the compound of general formula [1] expression.

For example; as R " when being ethanoyl; in tetrahydrofuran (THF), ethanol, methyl alcohol, Virahol, water or their mixed solvent; in the presence of alkali such as lithium hydroxide, sodium hydroxide, potassium hydroxide, salt of wormwood; at-20 ℃ to reflux temperature, preferred about 0 ℃ to 40 ℃; make compound (XI) reaction 0.5 hour to 24 hours, preferred 0.5 hour to 12 hours, can obtain compound thus by general formula [1] expression.

As R " when being methoxymethyl, methoxy ethoxy methyl, THP trtrahydropyranyl, ethanoyl; in solvent-free or water, methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF) etc. or their mixed solvent; use acid such as hydrochloric acid, trifluoracetic acid; at 0 ℃ to reflux temperature, preferred 0 ℃ to 50 ℃; make compound (XI) reaction 0.5 hour to 24 hours, preferred 0.5 hour to 8 hours, can obtain compound thus by general formula [1] expression.

As R " when being benzyl etc.; in methyl alcohol, ethanol, propyl alcohol, tetrahydrofuran (THF) etc. or their mixed solvent; in the presence of palladium-carbon catalyst etc.; use hydrogen or ammonium formiate etc.; about 0 ℃ to reflux temperature, preferred about 20 ℃ to 50 ℃; make compound (XI) reaction 0.5 hour to 96 hours, preferred 1 hour to 48 hours, can obtain compound thus by general formula [1] expression.

Therefore, above-mentioned compound by general formula (I) to (XI) expression is useful as the intermediate that is used for making by the The compounds of this invention of general formula [1] expression.

2. manufacture method B

This is not carry out the protection of hydroxyl and directly introduce manufacture method by the The compounds of this invention of general formula [1] expression from compound (VIII).

(each symbol difference in the formula is implication as hereinbefore).

At N, in dinethylformamide, methylene dichloride, chloroform etc. or their mixed solvent, use dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylamino-propyl)-condensing agents such as carbodiimide, at-20 ℃ to reflux temperature, preferred about 0 ℃ to 50 ℃, compound (VIII) and compound (X) were reacted about 1 hour to 48 hours, preferred about 1 hour to 24 hours, can obtain The compounds of this invention thus by general formula [1] expression.At this moment, also can add additives such as hydroxybenzotriazole, N-hydroxy succinic acid imines.

3. manufacture method C

By the salt of the The compounds of this invention of general formula [1] expression, can be according to conventional methods, for example as following the manufacturing.

Will be at solvent (for example by the The compounds of this invention of general formula [1] expression, water, methyl alcohol, ethanol, Virahol, acetone, 2-butanone, tetrahydrofuran (THF), vinyl acetic monomer, isobutyl acetate, diethyl ether, Di Iso Propyl Ether, toluene, normal hexane, normal heptane, or their mixed solvent) dissolving or suspendible in, (for example add oxygen-free acid (hydroacid), hydrochloric acid, Hydrogen bromide, sulfuric acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, Phenylsulfonic acid, naphthalene-1, the 5-disulfonic acid, naphthalene-2-sulfonic acid, fumaric acid or toxilic acid etc.) as solid, stoste or diluent are (as diluting solvent, for example, water, methyl alcohol, ethanol, Virahol, acetone, 2-butanone, tetrahydrofuran (THF), vinyl acetic monomer, isobutyl acetate, diethyl ether, Di Iso Propyl Ether, toluene, normal hexane, normal heptane, or their mixed solvent), at-20 ℃ to reflux temperature, under preferred about 0 ℃ to 50 ℃, stirred or leave standstill 1 hour to 48 hours, preferred about 1 hour to 24 hours, can obtain salt thus by the The compounds of this invention of general formula [1] expression.

[embodiment]

Manufacturing to The compounds of this invention specifically describes by the following examples.But the present invention is not limited by these embodiment.In addition, the NMR data of each compound of making have also been write down simultaneously.

[embodiment 1-1]

(S)-and 4-(5-picoline-2-yl)-3-methylol-N-(4-tert.-butoxy-3,5-difluorophenyl)-3,4- Dihydro-2H-benzo [1,4] oxazine-8-carboxamide

Operation 1

The manufacturing of 3-Nitrosalicylic Acid methyl esters

3-Nitrosalicylic Acid (500g) is dissolved in the methyl alcohol (2.25L), adds the vitriol oil (0.25L), refluxed 22 hours.Reaction solution is carried out the ice bath cooling, filter the solid of being separated out, carry out drying, obtain title compound (517.3g).

(400MHz，DMSO-d6)：3.95(s，3H)，7.16(t，J＝8.1Hz，1H)，8.11(dd，J＝7.9，1.9Hz，1H)，8.21(dd，J＝8.3，1.9Hz，1H)，11.49(s，1H).

Operation 2

The manufacturing of 2-(2-methoxy ethoxy) methyl oxygen base-3-nitrobenzoic acid methyl esters

To be dissolved in N by the 3-Nitrosalicylic Acid methyl esters (516.3g) that last operation obtains, in the dinethylformamide (2.0L), add salt of wormwood (362g), under the ice bath cooling and stirring, add 1-chlorine methoxyl group-2-methyl ethyl ether (0.329L), at room temperature stirred 1 hour.Between water-vinyl acetic monomer, reaction solution is carried out layering, wash the vinyl acetic monomer layer with water, concentrate, obtain title compound (706.9g).

(400MHz，DMSO-d6)：3.22(s，3H)，3.41-3.43(m，2H)，3.65-3.68(m，2H)，3.87(s，3H)，5.16(s，2H)，7.47(t，J＝7.9Hz，1H)，8.06(dd，J＝7.9，1.8Hz，1H)，8.11(dd，J＝7.9，1.8Hz，1H).

Operation 3

The manufacturing of 3-amino-2-(2-methoxy ethoxy) methyl aminobenzoic acid methyl esters

To be dissolved in vinyl acetic monomer (1L), the tetrahydrofuran (THF) (1L) by 2-(2-methoxy ethoxy) methoxyl group-3-nitrobenzoic acid methyl esters (704.5g) that last operation obtains, add 5% palladium carbon (moisture 50%) (35g), under atmosphere of hydrogen, stirred 4 hours.With resulting reacting liquid filtering, concentrated filtrate obtains title compound (617.7g).

(400MHz，DMSO-d6)：3.24(s，3H)，3.46-3.48(m，2H)，3.78-3.79(m，5H)，4.98(s，2H)，5.16(s，2H)，6.84-6.84(m，1H)，6.88-6.91(m，2H).

Operation 4

The manufacturing of 3-(5-picoline-2-yl) aminosallcylic acid methyl esters

In toluene (1L), add cesium carbonate (415g), palladium (8.8g), 2 successively, 2 '-two (diphenylphosphino)-1,1 '-dinaphthyl (25g), 3-amino-2-(2-methoxy ethoxy) methoxyl methyl benzoate (200g), the 2-chloro-5-picoline (103g) that obtain by last operation, stirred 2 days down at 100 ℃.Reaction solution is filtered concentration of reaction solution.In residue, add methyl alcohol (500mL), 6N hydrochloric acid (200mL), reflux and stirred 0.5 hour.In reaction solution, add gac (25g), stir and filter after 1 hour, in filtrate, add Tripotassium Citrate (2L), (218g) filtered and collect in the crystallization of separating out.Be dissolved in the vinyl acetic monomer (1L) filtering the crystallization of collecting, add silica gel (100g), after at room temperature stirring, filter concentrated filtrate.Residue (2L) is carried out recrystallization with acetone-water (2: 1), and filtering for crystallizing is carried out drying, obtains title compound (128g).

(400MHz，DMSO-d6)：2.18(s，3H)，3.92(s，3H)，6.89(t，J＝8.0Hz，1H)，7.04(d，J＝8.6Hz，1H)，7.35(dd，J＝7.9，1.5Hz，1H)，7.42(dd，J＝8.4，2.4Hz，1H)，7.98(s，1H)，8.19(s，1H)，8.48(dd，J＝8.2，1.5Hz，1H)，11.30(s，1H).

Operation 5

(R)-system of 2-(oxyethane-2-yl) methyl oxygen base-3-(5-picoline-2-yl) Methyl anthranilate Make

3-(5-picoline-2-yl) the aminosallcylic acid methyl esters (139.5g), (the R)-glycidyl nitrobenzene-sulfonic acid ester (139.7g) that obtain in the last operation are dissolved in the dimethyl sulfoxide (DMSO) (700mL), add salt of wormwood (74.6g), at room temperature stirred 1 hour.In reaction solution, add vinyl acetic monomer (1L), filter.After filtrate washed, behind anhydrous sodium sulfate drying, concentrate.Residue is suspended in the 2-propyl alcohol (400mL), stirs under the room temperature and separate out crystallization.Crystallization is filtered, carry out drying, obtain title compound (124g).

(400MHz，DMSO-d6)：2.19(s，3H)，2.76(q，J＝2.6Hz，1H)，2.86(dd，J＝5.0，4.3Hz，1H)，3.40-3.41(m，1H)，3.86(s，3H)，3.93(q，J＝5.7Hz，1H)，4.16(dd，J＝11.2，2.6Hz，1H)，6.94(d，J＝8.4Hz，1H)，7.16(t，J＝7.9Hz，1H)，7.24(dd，J＝7.7，1.8Hz，1H)，7.46(dd，J＝8.5，2.3Hz，1H)，8.01(d，J＝2.2Hz，1H)，8.19(s，1H)，8.53(dd，J＝8.2，1.8Hz，1H).

Operation 6

(S)-and methyl 4-(5-picoline-2-yl)-3-methylol-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic The manufacturing of acid esters

(R)-2-(oxyethane-2-yl) methyl oxygen base-3-(5-picoline-2-yl) Methyl anthranilate (124g) that obtains in the last operation is dissolved in N, in the dinethylformamide (1.24L), add salt of wormwood (81.8g), stirred 2 hours down at 100 ℃.Between water-vinyl acetic monomer, reaction solution is carried out layering, after the vinyl acetic monomer layer is washed, use anhydrous magnesium sulfate drying, concentrate, obtain title compound (142.1g).

(400MHz，DMSO-d6)：2.23(s，3H)，3.57-3.62(m，1H)，3.80(s，3H)，3.98-4.00(m，1H)，4.06-4.11(m，1H)，4.36-4.38(m，1H)，4.55(d，J＝10.8Hz，1H)，5.15(t，J＝5.4Hz，1H)，6.84(t，J＝7.9Hz，1H)，7.17-7.18(m，2H)，7.35(d，J＝8.2Hz，1H)，7.53(d，J＝8.4Hz，1H)，8.15(s，1H).

Operation 7

(S)-and 4-(5-picoline-2-yl)-3-methylol-3, the 4-dihydro-2H-benzo [system of 1,4] oxazine-8-carboxylic acid Be equipped with

With (S)-methyl 4-(5-picoline-2-the yl)-3-methylol-3 that obtains in the last operation, 4-dihydro-2H-benzo [in the methyl alcohol (700mL), adds 4N sodium hydroxide (150mL) in 1,4] oxazine-8-carboxylicesters (142g) dissolving, refluxes and stirred 2 hours.Concentration of reaction solution after neutralizing with 6N hydrochloric acid, extracts with vinyl acetic monomer.Washing vinyl acetic monomer layer is with concentrating behind the anhydrous magnesium sulfate drying.Add vinyl acetic monomer (50mL), diisopropyl ether (400mL) in residue, the solid of separating out is filtered, drying obtains title compound (101.6g).

(400MHz，DMSO-d6)：2.23(s，3H)，3.38(t，J＝9.9Hz，1H)，3.59(dd，J＝10.6，5.7Hz，1H)，3.98(dd，J＝10.8，2.6Hz，1H)，4.37-4.39(m，1H)，4.55(dd，J＝10.9，1.2Hz，1H)，5.14(br?s，1H)，6.82(t，J＝7.9Hz，1H)，7.16-7.18(m，2H)，7.32(dd，J＝8.2，1.5Hz，1H)，7.53(dd，J＝8.4，2.4Hz，1H)，8.14-8.14(m，1H)，12.66(br?s，1H).

Operation 8

(S)-and 4-(5-picoline-2-yl)-3-methylol-N-(4-tert.-butoxy-3,5-difluorophenyl)-3, the 4-dihydro [the manufacturing of 1,4] oxazine-8-carboxamide of-2H-benzo

With (S)-4-(5-picoline-2-the yl)-3-methylol-3 that obtains in the last operation, 4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid (400mg) is dissolved in N, in the dinethylformamide (2mL), add 4-tert.-butoxy-3 successively, 5-difluoroaniline (268mg), I-hydroxybenzotriazole (204mg), 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (281mg) at room temperature stir a whole night.After in reaction solution, adding entry, saturated sodium bicarbonate water, extract with vinyl acetic monomer.The vinyl acetic monomer layer is washed with saturated aqueous common salt, with concentrating behind the anhydrous magnesium sulfate drying.With residue with silica gel column chromatography (hexane: vinyl acetic monomer=4: 3) carry out purifying, obtain title compound (364mg).

[embodiment 1-2]

(S)-and 4-(5-picoline-2-yl)-3-methylol-N-(3,5-two fluoro-4-isopropyl phenyls)-3, the 4-dihydro [the manufacturing of 1,4] oxazine-8-carboxamide of-2H-benzo

(the S)-4-that obtains in the operation 7 with embodiment 1-1 (5-picoline-2-yl)-3-methylol-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid (400mg) is dissolved in N, in the dinethylformamide (2mL), add 3 successively, 5-two fluoro-4-isopropoxy anilines (249mg), I-hydroxybenzotriazole (204mg), 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (281mg) at room temperature stir a whole night.After in reaction solution, adding entry, saturated sodium bicarbonate water, extract with vinyl acetic monomer.The vinyl acetic monomer layer is washed with saturated aqueous common salt, with concentrating behind the anhydrous magnesium sulfate drying.With residue with silica gel column chromatography (hexane: vinyl acetic monomer=4: 3) carry out purifying, obtain title compound (332mg).

[embodiment 1-3]

(S)-and 4-(5-picoline-2-yl)-3-methylol-N-(3,5-two fluoro-4-phenelyls)-3,4-dihydro-2H-benzene And [the manufacturing of 1,4] oxazine-8-carboxamide

(the S)-4-that obtains in the operation 7 with embodiment 1-1 (5-picoline-2-yl)-3-methylol-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid (400mg) is dissolved in N, in the dinethylformamide (2mL), add 3 successively, 5-two fluoro-4-phenetidines (230mg), I-hydroxybenzotriazole (204mg), 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (281mg) at room temperature stir a whole night.After in reaction solution, adding entry, saturated sodium bicarbonate water, extract with vinyl acetic monomer.The vinyl acetic monomer layer is washed with saturated aqueous common salt, with concentrating behind the anhydrous magnesium sulfate drying.With residue with silica gel column chromatography (hexane: vinyl acetic monomer=5: 4) carry out purifying, obtain title compound (358mg).

[embodiment 1-4]

(S)-and 4-(5-picoline-2-yl)-3-methylol-N-[2-(2,2-dimethyl propoxy-) pyridine-5-yl]-3,4- [the manufacturing of 1,4] oxazine-8-carboxamide of dihydro-2H-benzo

(the S)-4-that obtains in the operation 7 with embodiment 1-1 (5-picoline-2-yl)-3-methylol-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid (300mg) is dissolved in N, in the dinethylformamide (3mL), add 5-amino-2-(2 successively, 2-dimethyl propoxy-) pyridinium salt acid solution (253mg), triethylamine (0.14mL), 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (211mg) at room temperature stir a whole night.After in reaction solution, adding entry, saturated sodium bicarbonate water, extract with vinyl acetic monomer.The vinyl acetic monomer layer is washed with saturated aqueous common salt, with concentrating behind the anhydrous magnesium sulfate drying.Residue is carried out purifying with silica gel column chromatography, obtain title compound (340mg).

[embodiment 1-5]

(S)-and 4-(5-picoline-2-yl)-3-methylol-N-(2-tert.-butoxy pyridine-5-yl)-3,4-dihydro-2H- Benzo [the manufacturing of 1,4] oxazine-8-carboxamide

(the S)-4-that obtains in the operation 7 with embodiment 1-1 (5-picoline-2-yl)-3-methylol-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid (148mg) is dissolved in N, in the dinethylformamide (5mL), add 5-amino-2-tert.-butoxy pyridine (82mg), 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (103mg) successively, at room temperature stir a whole night.After in reaction solution, adding entry, saturated sodium bicarbonate water, extract with vinyl acetic monomer.The vinyl acetic monomer layer is washed with saturated aqueous common salt, with concentrating behind the anhydrous magnesium sulfate drying.With resulting residue with silica gel column chromatography (hexane: vinyl acetic monomer=1: 1) carry out purifying, obtain title compound (94mg).

[embodiment 1-6]

(S)-and 4-(5-picoline-2-yl)-3-methylol-N-[2-(2,2, the 2-trifluoro ethoxy) pyridine-5-yl]-3,4- [the manufacturing of 1,4] oxazine-8-carboxamide of dihydro-2H-benzo

(the S)-4-that obtains in the operation 7 with embodiment 1-1 (5-picoline-2-yl)-3-methylol-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid (150mg) is dissolved in N, in the dinethylformamide (1.5mL), add 5-amino-2-(2 successively, 2,2-trifluoro ethoxy) pyridine hydrochloride (114mg), triethylamine (0.07mL), 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (105mg) at room temperature stir a whole night.After in reaction solution, adding entry, saturated sodium bicarbonate water, extract with vinyl acetic monomer.The vinyl acetic monomer layer is washed with saturated aqueous common salt, with concentrating behind the anhydrous magnesium sulfate drying.With resulting residue with silica gel column chromatography (hexane: vinyl acetic monomer=1: 1) carry out purifying, obtain title compound (154mg).

[embodiment 1-7]

(S)-and 4-(5-picoline-2-yl)-3-methylol-N-(2-isobutoxy pyridine-5-yl)-3,4-dihydro-2H- Benzo [the manufacturing of 1,4] oxazine-8-carboxamide

(the S)-4-that obtains in the operation 7 with embodiment 1-1 (5-picoline-2-yl)-3-methylol-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid (388mg) is dissolved in N, in the dinethylformamide (4mL), add 5-amino-2-isobutoxy pyridine hydrochloride (262mg), triethylamine (0.18mL), 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (272mg) successively, at room temperature stir a whole night.After in reaction solution, adding entry, saturated sodium bicarbonate water, extract with vinyl acetic monomer.The vinyl acetic monomer layer is washed with saturated aqueous common salt, with concentrating behind the anhydrous magnesium sulfate drying.With residue with silica gel column chromatography (hexane: vinyl acetic monomer=1: 1) carry out purifying, obtain title compound (402mg).

[embodiment 1-8]

(S)-and 4-(5-picoline-2-yl)-3-methylol-N-[3,5-two fluoro-4-(2,2, the 2-trifluoro ethoxy) benzene Base]-3, [the manufacturing of 1,4] oxazine-8-carboxamide of 4-dihydro-2H-benzo

Operation 1

(S)-and 3-acetyl-o-methyl-4-(5-picoline-2-yl)-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid Manufacturing

(the S)-4-that obtains in the operation 7 with embodiment 1-1 (5-picoline-2-yl)-3-methylol-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid (24.1mg) is dissolved in the tetrahydrofuran (THF) (240mL), add 4-(dimethylamino) pyridine (9.8mg), acetic anhydride (7.6mL), at room temperature stirred 0.5 hour.Between vinyl acetic monomer-rare citric acid, reaction solution is carried out layering, behind the washing vinyl acetic monomer layer, carry out drying, concentrate with anhydrous magnesium sulfate.In concentrated residue, add Di Iso Propyl Ether, filter the crystallization of being separated out, carry out drying, obtain title compound (23.33g).

(400MHz，DMSO-d6)1.99(s，3H)，2.23(s，3H)，4.03-4.11(m，2H)，4.18-4.21(m，1H)，4.48(d，J＝11.25Hz，1H)，4.72-4.74(m，1H)，6.86(dd，J＝7.61，7.61Hz，1H)，7.17-7.20(m，2H)，7.33(dd，J＝8.16，0.88Hz，1H)，7.54(dd，J＝8.49，2.32Hz，1H)，8.15(d，J＝1.54Hz，1H)，12.64(br?s，1H).

Operation 2

(S)-and 3-acetyl-o-methyl-4-(5-picoline-2-yl)-N-[3,5-two fluoro-4-(2,2, the 2-trifluoro ethoxy) benzene Base]-3, [the manufacturing of 1,4] oxazine-8-carboxamide of 4-dihydro-2H-benzo

With (the S)-3-acetyl-o-methyl-4-(5-picoline-2-yl)-3 that obtains in the last operation, [1,4] oxazine-8-carboxylic acid (400mg) is dissolved in the tetrahydrofuran (THF) (4mL) 4-dihydro-2H-benzo, under ice bath stirs, add thionyl chloride (0.102mL), stirred 1.5 hours.Concentration of reaction solution dilutes residue in tetrahydrofuran (THF) (4mL), add triethylamine (0.245mL), 3 under the stirring at room, and 5-two fluoro-4-(2,2, the 2-trifluoro ethoxy) aniline (267mg) stirred 0.5 hour.Between water-vinyl acetic monomer, reaction solution is carried out layering, behind saturated common salt water washing vinyl acetic monomer layer, carry out drying, concentrate with anhydrous magnesium sulfate.Obtain title compound (749mg).

(400MHz，DMSO-d6)1.99(s，3H)，2.25(s，3H)，4.12-4.16(m，2H)，4.22-4.25(m，1H)，4.52(d，J＝11.25Hz，1H)，4.75-4.77(m，3H)，6.93(dd，J＝7.94，7.94Hz，1H)，7.12(d，J＝7.72Hz，1H)，7.19(d，J＝8.60Hz，1H)，7.36(d，J＝8.16Hz，1H)，7.56-7.58(m，3H)，8.17(d，J＝1.54Hz，1H)，10.47(s，1H).

Operation 3

(S)-and 4-(5-picoline-2-yl)-3-methylol-N-[3,5-two fluoro-4-(2,2, the 2-trifluoro ethoxy) benzene Base]-3, [the manufacturing of 1,4] oxazine-8-carboxamide of 4-dihydro-2H-benzo

With (S)-3-acetyl-o-methyl-4-(5-picoline-2-the yl)-N-[3 that obtains in the last operation, 5-two fluoro-4-(2,2, the 2-trifluoro ethoxy) phenyl]-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide (749mg) is dissolved in the methyl alcohol (4mL), adds 4N sodium hydroxide (0.35mL), at room temperature stirs 5 hours.After reaction solution concentrated, between water-vinyl acetic monomer, carry out layering, behind the resulting vinyl acetic monomer layer of saturated common salt water washing, carry out drying, concentrate with anhydrous magnesium sulfate.Residue is carried out purifying with silica gel column chromatography, obtain title compound (340mg).

[embodiment 1-9]

(S)-and 4-(5-picoline-2-yl)-3-methylol-N-[3,5-two fluoro-4-(2-hydroxy-2-methyl propoxy-) benzene Base]-3, [the manufacturing of 1,4] oxazine-8-carboxamide of 4-dihydro-2H-benzo

Operation 1

(S)-and 4-(5-picoline-2-yl)-3-methylol-N-(3,5-two fluoro-4-hydroxyphenyl)-3,4-dihydro-2H-benzo [the manufacturing of 1,4] oxazine-8-carboxamide

(the S)-4-that obtains in the operation 7 with embodiment 1-1 (5-picoline-2-yl)-3-methylol-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid (900mg) is dissolved in N, in the dinethylformamide (4.5mL), add 3 successively, 5-two fluoro-4-hydroxyanilines (330mg), 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride (630mg) at room temperature stir a whole night.After in reaction solution, adding entry, saturated sodium bicarbonate water, extract with vinyl acetic monomer.The vinyl acetic monomer layer is washed with saturated aqueous common salt, with concentrating behind the anhydrous magnesium sulfate drying.With residue with silica gel column chromatography (hexane: vinyl acetic monomer=1: 1) carry out purifying, obtain title compound (550mg).

(400MHz，DMSO-d6)2.25(s，3H)，3.44-3.46(m，1H)，3.63-3.65(m，1H)，4.05-4.08(m，1H)，4.39-4.41(m，1H)，4.60(d，J＝9.74Hz，1H)，5.15(br?s，1H)，6.89(dd，J＝7.88，7.88Hz，1H)，7.10(dd，J＝7.65，1.62Hz，1H)，7.21(d，J＝8.35Hz，1H)，7.34(dd，J＝8.12，1.62Hz，1H)，7.46-7.49(m，2H)，7.56(dd，J＝8.35，1.86Hz，1H)，8.17(dd，J＝1.16，1.16Hz，1H)，9.91(br?s，1H)，10.23(s，1H).

Operation 2

(S)-and 4-(5-picoline-2-yl)-3-methylol-N-[3,5-two fluoro-4-(ethoxycarbonyl methoxyl group) benzene Base]-3, [the manufacturing of 1,4] oxazine-8-carboxamide of 4-dihydro-2H-benzo

With (S)-4-(5-picoline-2-the yl)-3-methylol-N-(3 that obtains in the last operation, 5-two fluoro-4-hydroxyphenyl)-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide (459mg) is dissolved in N, in the dinethylformamide (4.5mL), add salt of wormwood (150mg), ethyl bromoacetate (180mg), stirred 3 hours down at 60 ℃.Between water-vinyl acetic monomer, reaction solution is carried out layering, behind saturated common salt water washing vinyl acetic monomer layer, carry out the drying back with anhydrous magnesium sulfate and concentrate.With residue with silica gel column chromatography (hexane: vinyl acetic monomer=2: 3) carry out purifying, obtain title compound (310mg).

(400MHz，DMSO-d6)1.21(t，J＝7.06Hz，3H)，2.24(s，3H)，3.43-3.45(m，1H)，3.60-3.65(m，1H)，4.04-4.08(m，1H)，4.16(q，J＝7.06Hz，2H)，4.38-4.39(m，1H)，4.59(d，J＝10.81Hz，1H)，4.79(s，2H)，5.12(t，J＝5.51Hz，1H)，6.89(dd，J＝7.83，7.83Hz，1H)，7.08(dd，J＝7.50，1.32Hz，1H)，7.20(d，J＝8.60Hz，1H)，7.33(dd，J＝8.16，1.32Hz，1H)，7.52-7.56(m，3H)，8.16(d，J＝2.43Hz，1H)，10.39(s，1H).

Operation 3

(S)-and 4-(5-picoline-2-yl)-3-methylol-N-[3,5-two fluoro-4-(2-hydroxy-2-methyl propoxy-) benzene Base]-3, [the manufacturing of 1,4] oxazine-8-carboxamide of 4-dihydro-2H-benzo

With (S)-4-(5-picoline-2-the yl)-3-methylol-N-[3 that obtains in the last operation, 5-two fluoro-4-(ethoxycarbonyl methoxyl group) phenyl]-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide (310mg) is dissolved in the tetrahydrofuran (THF) (3.1mL), under ice bath stirs, drip lithium methide (0.98M tetrahydrofuran solution) (3.7mL), stirred afterwards 1.5 hours.Reaction solution is injected in 5% citric acid water, extracts with vinyl acetic monomer.With saturated common salt water washing vinyl acetic monomer layer, carry out the drying back with anhydrous magnesium sulfate and concentrate.With residue with silica gel column chromatography (hexane: vinyl acetic monomer=1: 3) carry out purifying, obtain title compound (72mg).

[embodiment 1-10]

(S)-and 4-(5-picoline-2-yl)-3-methylol-N-[3,5-two fluoro-4-(1,1-dimethyl-2-hydroxyl-oxethyl) Phenyl]-3, [the manufacturing of 1,4] oxazine-8-carboxamide of 4-dihydro-2H-benzo

Operation 1

(S)-and 4-(5-picoline-2-yl)-3-methylol-N-[3,5-two fluoro-4-(1-ethoxycarbonyl-1-methyl) ethoxy The base phenyl]-3, [the manufacturing of 1,4] oxazine-8-carboxamide of 4-dihydro-2H-benzo

(the S)-4-that obtains in the operation 1 with embodiment 1-9 (5-picoline-2-yl)-3-methylol-N-(3,5-two fluoro-4-hydroxyphenyl)-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide (780mg) is dissolved in the dimethyl sulfoxide (DMSO) (7.8mL), add salt of wormwood (240mg), 2 bromo 2 methyl propionic acid ethyl ester (0.279mL), stirred 1 hour down at 80 ℃.Between water-vinyl acetic monomer, reaction solution is carried out layering, behind saturated common salt water washing vinyl acetic monomer layer, carry out the drying back with anhydrous magnesium sulfate and concentrate.With residue with silica gel column chromatography (hexane: vinyl acetic monomer=1: 1) carry out purifying, obtain title compound (740mg).

(400MHz，DMSO-d6)1.24(t，J＝7.19Hz，4H)，1.49(s，6H)，2.25(s，3H)，3.44-3.46(m，1H)，3.63-3.66(m，1H)，4.06-4.09(m，1H)，4.17(q，J＝7.11Hz，2H)，4.39-4.41(m，1H)，4.60(d，J＝10.20Hz，1H)，5.15(t，J＝5.57Hz，1H)，6.90(dd，J＝7.88，7.88Hz，1H)，7.09(dd，J＝7.42，1.39Hz，1H)，7.22(d，J＝8.81Hz，1H)，7.35(dd，J＝8.12，1.62Hz，1H)，7.53-7.57(m，3H)，8.17-8.17(m，1H)，10.47(s，1H).

Operation 2

(S)-and 4-(5-picoline-2-yl)-3-methylol-N-[3,5-two fluoro-4-(1-carboxyl-1-methyl) phenetole Base]-3, [the manufacturing of 1,4] oxazine-8-carboxamide of 4-dihydro-2H-benzo

With (S)-4-(5-picoline-2-the yl)-3-methylol-N-[3 that obtains in the last operation, 5-two fluoro-4-(1-ethoxycarbonyl-1-methyl) ethoxyl phenenyl]-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide (740mg) is dissolved in the ethanol (7.4mL), add the aqueous sodium hydroxide solution (0.38mL) of 4N, at room temperature stir a night.Reaction solution is injected in 5% citric acid water, extracts with tetrahydrofuran (THF).With saturated common salt water washing tetrahydrofuran (THF) layer, carry out the drying back with anhydrous magnesium sulfate and concentrate.Obtain title compound (586mg).

(400MHz，DMSO-d6)1.45(s，6H)，2.25(s，3H)，3.45(dd，J＝9.97，9.97Hz，1H)，3.63-3.64(m，1H)，4.06-4.08(m，2H)，4.38-4.41(m，1H)，4.59(d，J＝10.20Hz，1H)，6.90(dd，J＝7.88，7.88Hz，1H)，7.09(dd，J＝7.65，1.62Hz，1H)，7.21(d，J＝8.81Hz，1H)，7.35(dd，J＝8.12，1.62Hz，1H)，7.53-7.56(m，3H)，8.17(dd，J＝1.16，0.58Hz，1H)，10.45(s，1H)，12.94(br?s，1H).

Operation 3

(S)-and 4-(5-picoline-2-yl)-3-methylol-N-[3,5-two fluoro-4-(1,1-dimethyl-2-hydroxyl-oxethyl) Phenyl]-3, [the manufacturing of 1,4] oxazine-8-carboxamide of 4-dihydro-2H-benzo

In tetrahydrofuran (THF) (3mL), ice bath stirs down, add triethylamine (0.191mL), chlorine ethyl-carbonate (0.131mL), then will go up (S)-4-(5-picoline-2-the yl)-3-methylol-N-[3 that obtains in the operation, 5-two fluoro-4-(1-carboxyl-1-methyl) ethoxyl phenenyl]-3,4-dihydro-2H-benzo [1, the tetrahydrofuran (THF) suspension (5.9mL) of 4] oxazine-8-carboxamide (586mg) at room temperature stirred 1 hour.Reaction solution is cooled off under ice bath, add sodium boorohyride (43mg), methyl alcohol (5.9mL).Reaction solution is injected in 10% aqueous ammonium chloride solution, extracts with vinyl acetic monomer.With saturated common salt water washing vinyl acetic monomer layer, carry out the drying back with anhydrous magnesium sulfate and concentrate.With residue with silica gel column chromatography (hexane: vinyl acetic monomer=2: 1) carry out purifying, obtain title compound (136mg).

The chemical structural formula and the NMR data of the compound that will obtain by the foregoing description 1-1 to 1-10 are shown in table 1, the table 2.

Table 1

Table 2

The test example

Below, describe for the inhibiting evaluation method of the VR1 of The compounds of this invention.

Use the comparative example compound shown in The compounds of this invention and the following table 3, as external evaluation, study for following test, described test is: for the Ca in cell that produces by the proton as the VR1 agonist ²⁺Metabolic stability test (test example [2]) among the restraining effect of inflow effect (test example [1]), the liver S9, external film perviousness test (test example [3]) and the stability test in Japanese Pharmacopoeia 1 solution (embodiment [4]).The comparative example compound obtains according to the manufacture method of putting down in writing among the PCT/JP2005/013446.

Table 3

Test example [1]: Ca in the cell ²⁺ Flow into inhibiting research

By measuring to intracellular Ca ²⁺Picked-up is estimated the active restraining effect of VR1.

With rat neurospongioma (C6BU1) cell of stably express people VR1 at 20mM MES damping fluid (pH 6.8/20mM 2-morpholinyl esilate (following is MES), 115mM NaCl, 5mMKCl, 1mM MgCl ₂, 14mM D-glucose) in carry out suspendible, making becomes 1 * 10 ⁶Cell/mL.In this cell suspension, add Fura 2-AM solution (colleague's chemistry institute Co., Ltd. as fluorochrome, Cat.No.343-05401), making concentration is 5 μ M, add Pluronic F-127 again (with the pure medicine of light Co., Ltd., Cat.No.P6866), making concentration is 0.01%, cultivates under 37 ℃ 30 minutes afterwards.After 20mM MES damping fluid washing 2 times, carry out suspendible again, making cell count is 5 * 10 ⁵Cell/mL.(this cell suspension 500 μ L are measured in Cat.No.SSR3121) in MC MEDICAL Co., Ltd., add therein and contain 250mM CaCl at test tube ₂20mM MES damping fluid 10 μ L, thereby in cell, sneak into Ca ²⁺Meanwhile, add test substance and (be diluted to the 5 μ L (ultimate density is 1 μ M to 0.01nM) of 100 μ M～10nM) with DMSO, perhaps only add DMSO 5 μ L (ultimate density 1%DMSO) in contrast, after adding 10 minutes, be encased in ion measurement device (CAF-110 in the cell; Japan beam split Co., Ltd.) in.As agonist, making the pH of cell suspension by the 20mM MES damping fluid 50 μ L that add pH 1.1 is 5.7, and applying proton stimulates.Measure the activity of test substance by the minimum value of the fluorescence intensity before the stimulation of agonist and the difference of the maximum value of post-stimulatory fluorescence intensity, by calculating IC with respect to the inhibiting rate that contrasts ₅₀Value.

The research of the metabolic stability test among test example [2] liver S9

(ultimate density: 2mg protein/mL) is suspended in the 100mM potassium phosphate buffer and (pH 7.4, comprises β-Triphosphopyridine nucleotide, reduced: 1.3mM with people's liver S9, D-G-6-P ester: 3.3mM, magnesium chloride: 3.3mM, glucose-6-phosphate dehydrogenase: 0.45U/mL), further mix with dissolved test substance in DMSO.Cultivation is after 0 and 60 minute down at 37 ℃, and adding contains the acetonitrile of formic acid (ultimate density 0.1%), uses high performance liquid chromatography/mass spectroscopy (LC/MS) that the test substance in the supernatant liquor after the centrifugation (not changing body) is measured.Calculate survival rate (%) according to resulting measured value in order to following formula.

Survival rate (%)=(cultivating the determinand quality of determinand quality/cultivation in the time of 0 minute after 60 minutes) * 100

The research of the external film perviousness test of test [3]

The 10mM DMSO solution of test substance is diluted to the concentration of 25 μ M with Hanks damping fluid (pH 6.5), makes test substance solution.Seeing through test upward Apical side (mucous membrane side) interpolation Apical damping fluid (Hanks damping fluid (pH 6.5)) the 300 μ L of the Caco2 cell of inoculation (6 days cell of inoculation back cultivation) of plate (BIOCOAT HTS Caco2 Assaysystem:BD Biosciences), add Basolateral damping fluid (4.5% contains the Hanks damping fluid (pH 7.4) of BSA) 1mL in Basolateral side (serosa side), cultivation is after 20 minutes down at 37 ℃, and mensuration is through the epithelium resistance value.After Apical side and Basolateral side damping fluid are separately removed in suction, the Basolateral damping fluid that adds 1mL at Apical side adding test substance solution 300 μ L, in the Basolateral side, under 600rpm, stir, cultivated 2 hours down at 37 ℃ simultaneously.Afterwards,, add acetonitrile, carry out centrifugation, use high performance liquid phase/tandem mass spectrometry (LC/MS/MS:Quantum, Thermo Quest), the test substance in the supernatant liquor (not changing body) is measured respectively by Apical side and Basolateral side-draw sample.

Calculate film transmission coefficient (Papp) by following formula.

Papp (cm/ second)=(dx/dt)/(A * C ₀)

(at this, dx is test substance (the not changing body) amount of the Basolateral side after cultivating, and dt is an incubation time, and A is the surface-area of cytolemma, C ₀Test substance starting point concentration for the Apical side).

The research of test example [4] stability test in Japanese Pharmacopoeia 1 liquid

Test substance is dissolved in CH ₃In the mixed solution of CN and Japanese Pharmacopoeia 1 liquid (volume ratio 3: 7), be adjusted to 0.05mM in vial at HPLC.Test substance is being measured after 0 and 8 hour by HPLC under 40 ℃.0 hour measured value is made as 100%, tries to achieve the survival rate of the test substance after 8 hours.

At this, " Japanese Pharmacopoeia 1 liquid " is meant and adds concentrated hydrochloric acid 21ml is adjusted to 3L again with distilled water solution in sodium-chlor 6g.

With above-mentioned for Ca in cell ²⁺Metabolic stability test (test example [2]) and the test of external film perviousness (test example [3]) the results are shown in following table 4～6 among the restraining effect of inflow effect (test example [1]), the liver S9.

Table 4

Table 5

Table 6

[1] About Ca in the cell ²⁺ Flow into the investigation (test example [1]) of inhibiting test-results;

The IC of the compound of the embodiment 1-1 to 1-10 that in The compounds of this invention, comprises by general formula [1] expression ₅₀Value shown in table 4～6, is respectively 0.024nM, 0.038nM, 0.24nM, 0.019nM, 0.66nM, 0.15nM, 0.14nM, 0.038nM, 0.54nM, 0.69nM, the average IC of these 10 compounds ₅₀Value is 0.25nM.

The IC of the compound of embodiment 1-1,1-2,1-4 and 1-8 particularly ₅₀Value is respectively 0.024,0.038,0.019,0.038, has the remarkable active restraining effect of VR1.

On the other hand, the IC of the compound of comparative example 1 to 13 ₅₀Value is respectively 3nM, 1.3nM, 18nM, 5.2nM, 42.0nM, 0.3nM, 0.4nM, 7nM, 0.12nM, 0.04nM, 0.36nM, 0.03nM, 0.12nM shown in table 4～6, the average IC of these 13 comparative example compounds ₅₀Value is 5.99nM.

Like this, The compounds of this invention compares with the comparative example compound, at average IC ₅₀Has about 24 times inhibition activity on the value.

[2] about the investigation of the metabolic stability test-results among the people liver S9 (test example [2]);

The people liver S9 survival rate of the compound of the embodiment 1-1 to 1-10 that in The compounds of this invention, comprises by general formula [1] expression, shown in table 4～6, be respectively 90.8%, 65.3%, 59.6%, 39.7%, 82.2%, 91.8%, 50.4%, 91.5%, 77.3%, 92.2%, the average man liver S9 survival rate of these 10 compounds is 74%.

Particularly the survival rate of the compound of embodiment 1-1,1-6,1-8 and 1-10 is more than 90%, shows significantly high survival rate,, shows the metabolic stability among the significantly high liver S9 that is.Therefore, these compounds are difficult to be subjected to oxidative metabolism, have the persistence of effect, in these areas, are useful as the medicine of remarkable excellence.

On the other hand, the people liver S9 survival rate of the compound of comparative example 1 to 13, shown in table 4～6, be respectively 86.3%, 90.1%, 89.4%, 92.5%, 64.9%, 77.3%, 55.1%, 62.9%, 65.9%, 82.3%, 66.7%, 54.5%, 91.3%, the average survival rate of these 13 comparative example compounds is 75%.

[3] about the investigation of external film perviousness test-results (test example [3]);

The external film perviousness of the compound of the embodiment 1-1 to 1-10 that comprises in the The compounds of this invention by general formula [1] expression, shown in table 4～6, the Papp value is respectively 8.59 * 10 in (cm/ second) ^-6, 20.96 * 10 ^-6, 26.93 * 10 ^-6, 30.25 * 10 ^-6, 38.07 * 10 ^-6, 37.53 * 10 ^-6, 37.94 * 10 ^-6, 13.61 * 10 ^-6, 50.36 * 10 ^-6, 39.22 * 10 ^-6, the mean P app value of these 10 compounds (cm/ second) is 30.35 * 10 ^-6

Particularly the film perviousness of the compound of embodiment 1-2 to 1-10 is 10 * 10 ^-6More than (cm/ second), show significantly high film perviousness.Therefore, these compounds not only have remarkable IC ₅₀Value, and have integral high-absorbable during as medicine practicability, therefore, have extremely excellent characteristic as medicine.

On the other hand, the Papp value of the compound of comparative example 1 to 13 (cm/ second) shown in table 4～6, is respectively 27.1 * 10 ^-6, 24.2 * 10 ^-6, 25.6 * 10 ^-6, 5.3 * 10 ^-6, 7.9 * 10 ^-6, 21.1 * 10 ^-6, 18.2 * 10 ^-6, 43.1 * 10 ^-6, 19.4 * 10 ^-6, 6.7 * 10 ^-6, 40.3 * 10 ^-6, 10.4 * 10 ^-6, 28.6 * 10 ^-6, the mean P app value of these 13 comparative example compounds (cm/ second) is 21.38 * 10 ^-6

Like this, The compounds of this invention is compared with the comparative example compound, has about 1.4 times film perviousness on average Papp value.

[4] about the investigation of stability test result in Japanese Pharmacopoeia 1 liquid (test example [4]);

Compound survival rate in the stability test in Japanese Pharmacopoeia 1 liquid of the embodiment 1-6 to 1-8 that comprises in the The compounds of this invention by general formula [1] expression is respectively 100 and 101%.On the other hand, the survival rate of comparative example compound 13 is 62.1%.

Suppose that Japanese Pharmacopoeia 1 liquid and hydrochloric acid in gastric juice have equal pH, therefore, known stability therein is the stability of prompting in gastric juice usually.

Therefore, these compounds are compared with comparative example compound 13, are useful as excellent medicine stable in gastric juice.

[5] sum up;

(1) About IC ₅₀ Value;

As suppressing the known BCTC of the active material of VR1, according to document (J Pharmacol ExpTher.2003 Jul; 306 (1): 377-86), known its suppresses active (IC ₅₀Value) is number nM.In addition, in the test that we carry out, confirmed the IC of BCTC ₅₀Value is number nM.

The compounds of this invention, particularly, the IC of the compound of embodiment 1-1 to 1-10 ₅₀Value all is lower than 1nM.

On the other hand, in the comparative example compound, IC ₅₀The compound that value is lower than 1nM is 7 compounds of comparative example 6,7,9,10,11,12,13.But, these 7 comparative example compounds, perhaps the survival rate in the test of the metabolic stability in liver S9 is lower than 80%, and/or the Papp value of film perviousness is lower than 10 * 10 ^-6, perhaps poor stability in gastric juice etc. when comprehensively judging, not necessarily can all satisfy.

(2) About the metabolic stability in people liver S9;

Metabolic stability is as one of important key element of medicine, preferably has the metabolic stability more than 80%.The survival rate of the compound of embodiment 1-1,1-6,1-8 and 1-10 is more than 90%, shows significantly high survival rate,, shows the metabolic stability among the significantly high liver S9 that is.

On the other hand, comparative example compound 1,2,3,4,10,13 etc. also show excellent metabolic stability, but the IC of comparative example compound 1,2,3 and 4 ₅₀More than 1nM, can not satisfy aspect active suppressing.In addition, the Papp value of comparative example compound 10 is 6.7 * 10 ^-6, can not satisfy aspect the film perviousness.In addition, the poor stability of comparative example compound 13 in gastric juice differs and satisfies surely.

(3) About film perviousness test-results;

About the film perviousness, as mentioned above, The compounds of this invention is compared with the comparative example compound, has about 1.4 times film perviousness on average Papp value.Particularly to have on the Papp value be 30 * 10 for embodiment 1-4,1-5,1-6,1-7,1-9,1-10 ^-6Above high film perviousness.

On the other hand, in the comparative example compound, comparative example 8 and 11 compound have high film perviousness, but the active IC of inhibition of comparative example 8 compounds ₅₀Value is for 7nM, can not satisfy aspect active suppressing, and in addition, comparative example 11 compounds are 66.7% as the people liver S9 survival rate of the index of metabolic stability, also may not satisfy as medicine.

(4) Feature from the observed The compounds of this invention of chemical structure;

If the compound of the compound of comparative example 11 and embodiment 1-2 compares, then the former only has 1 fluorine atom on phenyl, and relative therewith, the latter has 2 fluorine atoms, and both are different in this.The latter's IC ₅₀Value is compared with the former, rises 10 times approximately.

If the compound of the compound of comparative example 8 and embodiment 1-6 compares, then the former substituting group on pyridine is a trifluoromethyl, and relative therewith, the latter is 2,2, the 2-trifluoro ethoxy, and both are only different in this.The latter compares with the former, and liver S9 survival rate is improved as about 1.5 times, in addition IC ₅₀Value also is improved as about 50 times.

If the compound of the compound of comparative example 7 and comparative example 9 and embodiment 1-8 compares, then the compound of embodiment 1-8 has 2 fluorine atoms and 12 as the substituting group on the phenyl, 2, the 2-trifluoro ethoxy, and relative therewith, the compound of comparative example 7 only has 1 trifluoromethyl, different in this, in addition, the compound of comparative example 9 only has 1 fluorine atom and 1 trifluoromethyl, and is different in this.But the compound of embodiment 1-8 is compared with the compound of comparative example 9 with comparative example 7, and liver S9 survival rate is improved as about 1.4 times to 1.7 times, in addition IC ₅₀Value also is improved as about 3 times to 11 times.

If the compound of the compound of comparative example 13 and embodiment 1-1 compares, then the former only has 1 fluorine atom on phenyl, and relative therewith, the latter has 2 fluorine atoms, and is different in this.The latter compares with the former, IC ₅₀Value rises to about 5 times, is the surprising result that those skilled in the art can not envision.

At compound, the particularly compound of embodiment 1-1 to 1-10, be to have remarkable VR1 to suppress active and have metabolic stability among the excellent liver S9 concurrently and/or the compound of high film perviousness by general formula [1] expression.

Therefore, the compound of the embodiment 1-1 to 1-10 that in The compounds of this invention, comprises by general formula [1] expression, be useful on as the validity of VR1 activity inhibitor not only as significantly excellent medicine, and as aspect the persistence that is difficult to be subjected to oxidative metabolism, have effect, have high-absorbable aspect also significantly excellent medicine also be useful.

Therefore, these compounds are useful as significantly excellent medicine on as the validity of VR1 activity inhibitor not only, and can expect as aspect the persistence that is difficult to be subjected to oxidative metabolism, have effect and have high-absorbable aspect the also remarkable practicability of excellent medicine.

The possibility of utilizing on the industry

Of the present invention 3,4-Er hydrogen benzoxazine compound is because establishment vanilloid receptor1 type (VR1) therefore activity, aches as pain, Acute Pain, chronic ache, neurological disorder Bitterly, chronic joint rheumatalgia, neuralgia, DPN, hyperalgia disease, antimigraine, arthralgia, Neuralgia, PHN, chronic PHN, art behind the acute herpes zoster Neuralgia, glycosuria after rear neuralgia, cancer pain, inflammatory pain, interstitial cystitis, the wound Characteristic of disease DPN, neurodegenerative disease, headstroke, ischemic disease, neurotrosis disease, nerve skin Skin disease, diseases associated with inflammation, pruritus, allergic rhinitis, apoplexy, irritable bowel syndrome, heavy breathing Breathe heavily, chronic obstructive pulmonary disease, dermatitis, catarrh, gastroduodenal ulcer, inflammatory bowel combine Simulator sickness, cysterethism disease, bladder excessive activities type frequent micturition and the bladder excessive activities type urinary incontinence etc. The curative of disease and/or preventive medicine are effective.

Claims (19)

1. by 3 of following general formula [1] expression, 4-Er hydrogen benzoxazine compound or its be at the salt that pharmaceutically allows,

In the formula, X is:

(1) nitrogen-atoms or

(2)CR ³；

R ¹For:

(1) hydrogen atom or

(2) halogen atom,

When X is CR ³The time, R ¹Be halogen atom;

R ²Be the C1-6 alkoxyl group that 1～5 identical or different substituting group that can be selected from following group replaces, described group is:

(1) halogen atom or

(2) hydroxyl;

R ³Be halogen atom.

2. as claimed in claim 13,4-Er hydrogen benzoxazine compound or its is characterized in that at the salt that pharmaceutically allows, are selected from:

1) (S)-4-(5-picoline-2-yl)-3-methylol-N-(4-tert.-butoxy-3,5-difluorophenyl)-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide,

2) (S)-4-(5-picoline-2-yl)-3-methylol-N-(3,5-two fluoro-4-isopropyl phenyls)-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide,

3) (S)-4-(5-picoline-2-yl)-3-methylol-N-(3,5-two fluoro-4-phenelyls)-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide,

4) (S)-and 4-(5-picoline-2-yl)-3-methylol-N-[2-(2,2-dimethyl propoxy-) pyridine-5-yl]-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide,

5) (S)-4-(5-picoline-2-yl)-3-methylol-N-(2-tert.-butoxy pyridine-5-yl)-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide,

6) (S)-and 4-(5-picoline-2-yl)-3-methylol-N-[2-(2,2, the 2-trifluoro ethoxy) pyridine-5-yl]-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide,

7) (S)-4-(5-picoline-2-yl)-3-methylol-N-(2-isobutoxy pyridine-5-yl)-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide,

8) (S)-and 4-(5-picoline-2-yl)-3-methylol-N-[3,5-two fluoro-4-(2,2, the 2-trifluoro ethoxy) phenyl]-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide,

9) (S)-4-(5-picoline-2-yl)-3-methylol-N-[3,5-two fluoro-4-(2-hydroxy-2-methyl propoxy-) phenyl]-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide and

10) (S)-and 4-(5-picoline-2-yl)-3-methylol-N-[3,5-two fluoro-4-(1,1-dimethyl-2-hydroxyl-oxethyl) phenyl]-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide.

3. medical composition is characterized in that, contains claim 1 or 2 described 3, and 4-Er hydrogen benzoxazine compound or its be at the salt that pharmaceutically allows, and at the carrier that pharmaceutically allows.

4. medical composition, it is characterized in that, contain claim 1 or 2 described 3,4-Er hydrogen benzoxazine compound or its are at the salt that pharmaceutically allows, and, be used for the treatment of and/or prevent to be selected from pain at the carrier that pharmaceutically allows, acute pain, chronic pain, neurological disorder pain, chronic joint rheumatalgia, neurodynia, DPN, hyperpathia disease, migraine, arthrodynia, neurodynia behind the acute herpes zoster, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neurodynia, cancer pain, inflammatory pain, interstitial cystitis, neurodynia after the wound, diabetic neuropathy, neurodegenerative disease, cerebral apoplexy, ischemia, nerve injury disease, the nervosa dermatosis, diseases associated with inflammation, pruritus, allergic rhinitis, apoplexy, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, gastro-duodenal ulcer, inflammatory bowel syndrome, irritable bladder disease, disease in the frequent micturition and the urinary incontinence.

5. medical composition is characterized in that, contains claim 1 or 2 described 3, and 4-Er hydrogen benzoxazine compound or its are used for the treatment of and/or prevent irritation at the salt that pharmaceutically allows and at the carrier that pharmaceutically allows.

6. medical composition as claimed in claim 5, it is characterized in that pain is neurodynia after neurodynia behind acute pain, chronic pain, neurological disorder pain, chronic joint rheumatalgia, neurodynia, DPN, hyperpathia disease, migraine, arthrodynia, the acute herpes zoster, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neurodynia, cancer pain, inflammatory pain, interstitial cystitis, the wound, diabetic neuropathy or neurodegenerative disease.

7. capsaicin receptor 1 type (VR1) activity inhibitor is characterized in that, contains claim 1 or 2 described 3, and 4-Er hydrogen benzoxazine compound or its be at the salt that pharmaceutically allows, and at the carrier that pharmaceutically allows.

8. one kind is selected from pain, acute pain, chronic pain, neurological disorder pain, chronic joint rheumatalgia, neurodynia, DPN, hyperpathia disease, migraine, arthrodynia, neurodynia behind the acute herpes zoster, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neurodynia, cancer pain, inflammatory pain, interstitial cystitis, neurodynia after the wound, diabetic neuropathy, neurodegenerative disease, cerebral apoplexy, ischemia, nerve injury disease, the nervosa dermatosis, diseases associated with inflammation, pruritus, allergic rhinitis, apoplexy, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, gastro-duodenal ulcer, inflammatory bowel syndrome, irritable bladder disease, treatment of diseases method and/or prevention method in the frequent micturition and the urinary incontinence, it is characterized in that, give the claim 1 of significant quantity pharmaceutically or 2 described 3,4-Er hydrogen benzoxazine compound or its are at the salt that pharmaceutically allows.

9. treatment of pain method and/or prevention method is characterized in that, give the claim 1 of significant quantity pharmaceutically or 2 described 3, and 4-two hydrogen benzoxazine compounds or its are at the salt that pharmaceutically allows.

10. methods of treatment as claimed in claim 9 and/or prevention method, it is characterized in that pain is neurodynia after neurodynia behind acute pain, chronic pain, neurological disorder pain, chronic joint rheumatalgia, neurodynia, DPN, hyperpathia disease, migraine, arthrodynia, the acute herpes zoster, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neurodynia, cancer pain, inflammatory pain, interstitial cystitis, the wound, diabetic neuropathy or neurodegenerative disease.

11. commodity cover bag, it is characterized in that, comprise each described medical composition in the claim 3～6, and about the specification sheets of this medical composition, described specification sheets has been put down in writing and has been selected from pain, acute pain, chronic pain, neurological disorder pain, chronic joint rheumatalgia, neurodynia, DPN, hyperpathia disease, migraine, arthrodynia, neurodynia behind the acute herpes zoster, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neurodynia, cancer pain, inflammatory pain, interstitial cystitis, neurodynia after the wound, diabetic neuropathy, neurodegenerative disease, cerebral apoplexy, ischemia, nerve injury disease, the nervosa dermatosis, diseases associated with inflammation, pruritus, allergic rhinitis, apoplexy, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, gastro-duodenal ulcer, inflammatory bowel syndrome, irritable bladder disease, can use in the treatment of diseases in the frequent micturition and the urinary incontinence and/or the purposes of prevention, maybe should use this medical composition.

12. claim 1 or 2 described 3,4-Er hydrogen benzoxazine compound or its are used to be selected from the pain described in the claim 4 at the salt that pharmaceutically allows in manufacturing, acute pain, chronic pain, neurological disorder pain, chronic joint rheumatalgia, neurodynia, DPN, hyperpathia disease, migraine, arthrodynia, neurodynia behind the acute herpes zoster, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neurodynia, cancer pain, inflammatory pain, interstitial cystitis, neurodynia after the wound, diabetic neuropathy, neurodegenerative disease, cerebral apoplexy, ischemia, nerve injury disease, the nervosa dermatosis, diseases associated with inflammation, pruritus, allergic rhinitis, apoplexy, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, gastro-duodenal ulcer, inflammatory bowel syndrome, irritable bladder disease, application in the treatment of diseases in the frequent micturition and the urinary incontinence and/or the medical composition of prevention.

13. claim 1 or 2 described 3,4-Er hydrogen benzoxazine compound or its are used for the application of the medical composition of claim 5 or 6 described treatment of pain and/or prevention in manufacturing at the salt that pharmaceutically allows.

14. as claimed in claim 13 3,4-Er hydrogen benzoxazine compound or its application at the salt that pharmaceutically allows, it is characterized in that pain is neurodynia after neurodynia behind acute pain, chronic pain, neurological disorder pain, chronic joint rheumatalgia, neurodynia, DPN, hyperpathia disease, migraine, arthrodynia, the acute herpes zoster, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neurodynia, cancer pain, inflammatory pain, interstitial cystitis, the wound, diabetic neuropathy or neurodegenerative disease.

15. a medicine, by following both constitute, described both are:

Contain claim 1 or 2 described 3,4-Er hydrogen benzoxazine compound or its are at salt that pharmaceutically allows and the medical composition that constitutes at the carrier that pharmaceutically allows;

Be selected from antiviral agent, thymoleptic, spasmolytic, antiarrhythmics, local anesthetic, narcotic, N-methyl-D-aspartate receptor antagonist, adrenocortical steroid, nerve block agent, non-steroidal anti-inflammatory analgesics, narcotics, antagonism anodyne, α ₂The medicament more than a kind in adrenoceptor agonists, externally applied agent, calcium-channel antagonists, potassium channel openers and the antipyretic.

16. claim 1 or 2 described 3,4-two hydrogen benzoxazine compounds or its are being made application in the described medicine of claim 15 at the salt that pharmaceutically allows.

17. be selected from pain, acute pain, chronic pain, neurological disorder pain, chronic joint rheumatalgia, neurodynia, DPN, hyperpathia disease, migraine, arthrodynia, neurodynia behind the acute herpes zoster, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative neurodynia, cancer pain, inflammatory pain, interstitial cystitis, neurodynia after the wound, diabetic neuropathy, neurodegenerative disease, cerebral apoplexy, ischemia, nerve injury disease, the nervosa dermatosis, diseases associated with inflammation, pruritus, allergic rhinitis, apoplexy, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, gastro-duodenal ulcer, inflammatory bowel syndrome, irritable bladder disease, treatment of diseases method and/or prevention method in the frequent micturition and the urinary incontinence, it is characterized in that, will be selected from antiviral agent, thymoleptic, spasmolytic, antiarrhythmics, local anesthetic, narcotic, the N-methyl-D-aspartate receptor antagonist, adrenocortical steroid, the nerve block agent, the non-steroidal anti-inflammatory analgesics, narcotics, the antagonism anodyne, α ₂The medicament more than a kind in adrenoceptor agonists, externally applied agent, calcium-channel antagonists, potassium channel openers and the antipyretic, with in the claim 1 of significant quantity pharmaceutically or 2 described 3,4-Er hydrogen benzoxazine compound or its carry out and use at the salt that pharmaceutically allows.

18. treatment of pain method and/or prevention method, it is characterized in that, with claim 1 or 2 described 3,4-two hydrogen benzoxazine compounds or its give the salt that pharmaceutically allows, and are selected from acupuncture, stimulate stimulation produced analgesia therapy in analgesic therapy, peripheral nerve stimulation therapy, backbone electricity irritation, Electroconvulsive Therapy, laser therapy and the low frequency therapy to carry out and use through skin electroacupuncture stimulation therapy, transcutaneous electrical nerve stimulation therapy, point.

19. the methods of treatment of a post-operative pain and/or prevention method, it is characterized in that, after root goes into to distinguish surgical operation in Destruction, cordotomy and the frontal lobectomy behind radectomy, sympathectomy, the spinal cord after being selected from cicatrectomy, neural cryocoagulation art, peripheral nerve surgical blanking, spinal cord, give claim 1 or 2 described 3,4-Er hydrogen benzoxazine compound or its are at the salt that pharmaceutically allows.