BRPI0620757A2 - 3,4-dihydrobenzoxazine compounds, pharmaceutical compositions, subtype 1 (vr1) vanilloid receptor activity inhibitors, commercial package, and uses of said compounds - Google Patents

Abstract

3,4-DIHYDROBENZOXAZINE COMPOUNDS, PHARMACEUTICAL COMPOSITIONS, VANILOID RECEPTOR SUBTIPLE 1 (VRI) ACTIVITY INHIBITORS, COMMERCIAL PACKAGE, AND USES OF THE COMPOUND REFERENCES. The present invention relates to a 3,4-dihydrobenzoxazine compound which is represented by the following formula L [1] where x is a nitrogen atom or CR ^ 3 ^; R ^ 1 ^ is a hydrogen atom or a halogen atom; R ^ 2 ^ is a C1-6 alkoxy group that can be substituted with 1 to 5 identical or different substituents selected from a halogen atom and a hydroxyl group; and R ^ 3 ^ is a halogen atom. However, R ^ 1 ^ is a halogen atom when X is CR ^ 3 ^). This compound is effective in the treatment of diseases in which subtype 1 vanilloid receptor (VRI) activity is involved, such as pain etc.

Description

Patent Descriptive Report for "3,4-DIHYDROBENZOXAZINE COMPOUNDS, PHARMACEUTICAL COMPOSITIONS, SUBTITLE 1 (VR1) RECEIVER ACTIVITY INHIBITORS, COMMERCIAL PACKAGE, AND USES OF SUCH COMPOUNDS".

Field of the Invention

The present invention relates to a novel 3,4-dihydrobenzoxazine compound having an inhibitory effect on subtype 1 vanilloid receptor (VR1) activity and a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the compound or pharmaceutically salt thereof. acceptable as an active ingredient, and a method for treating and / or preventing diseases in which subtype 1 vanilloid receptor (VR1) activity is involved, such as pain, acute pain, chronic pain, neuropathic pain , pain associated with rheumatoid arthritis, neuralgia etc., particularly pain.

Background Art

Capsaicin, which is the main ingredient in red pepper, is an acid-causing ingredient as well as a pain-producing substance. Many nociceptive nerves, particularly unmyelinated C fibers, have been reported to have capsaicin sensitivity, and C fibers are known to disappear when capsaicin is administered to a rodent pup. It has also been reported that there are many action points for capsaicin distributed on the skin, cornea, and oral mucosa, and capsaicin distribution is also observed in muscles, joints, internal organs, particularly in the cardiovascular system, respiratory system, and sis. - theme of urinary tract, and it is important for sensory nerve activation. In addition, capsaicin sensitivity is also observed in the nerves of the thalamus preoptic area, and its involvement in regulating body temperature is presumed. Depolarization of Na + and Ca2 + influx by capsaicin administration is observed in the nociceptive nerves and results in the discharge of glutamic acid and neuropeptides (primarily peptide associated with the substance P and calcitonin gene) from the central lateral end of the primary afferent fiber. of the spinal dorsal horn. Now that the specific binding activity of resiniferatoxin (RTX) that produces effects similar to that of capsaicin, which has been revealed as capsazepine as a competitive inhibitor, has been found, it is considered that liposoluble capsaicin acts on the receptor protein (see Szallasi A, Blumberg PM (1999) Pharmacol. Rev. 51, 159-212 (Non-Patent Document 1)).

The capsaicin receptor gene was cloned in 1997 (see, for example, Caterina MJ1 Schumacher MA Tominaga M, Posen TA, Levine JD, Julius D. (1997) Nature 389, 816-824 (Non-Patent Document 2)). It was assumed from its amino acid sequence that it was a tonic channel with a hexatransmembrane domain. Because capsaicin has a vanillyl group in its structure, it is generically called vanilloys together with its analogues such as RTX, and the cloned receptor was called a subtype 1 vanilloid receptor (hereinafter referred to as VR 1; this VR1 can also be called TRPV1 (vanilloid). transient receptor potential 1)). Then, an electrophysiological functional analysis using the plate clamping method was performed by causing Xenopus Iaevis oocytes and cultured cells derived from man to express VR1, and it was shown that VR1 is directly activated by capsaicin. , without mediation of a second intracellular messenger (see, for example, Caterina MJ, Schumacher MA Tominaga M, Posen TA, Levine JD, Julius D. (1997) Nature 389, 816-824 (Non-Patent Document 2)), and that VR1 is a non-selective cationic tonic channel having high Ca2 + permeability with an external rectification property (see, for example, Premkumar LS, Agarwal S, Steffen D. (2002) J, Physiol. 545,107- 117 (Non-patent document 3)).

Although capsaicin is a pain-causing substance, it is used as an analgesic agent to mitigate pain in diabetic neuropathy or rheumatic neurosis (see, for example, Szallasi A, Blumberg PM. (1999) Pharmacol. Rev. 51, 159-212 (Non-patent document 1)). This mitigation is known to result from a phenomenon that the end of the sensory nerve exposed to capsaicin no longer responds to the pain stimulus, ie, desensitization. Although it is considered that the VR1 desensitization mechanism involves Ca2 + mediated regulation, potential dependent regulation, control of VR1 activity by phosphorylation and dephosphorylation, etc., many points remain unexplained.

Like capsaicin, heat and acid also cause pain, and capsaicin-sensitive nociceptive nerves are known to respond to two or more types of stimulation. VR1 has been found to be directly activated not only by capsaicin but by heat stimulation of 43 ° C or more (see, for example, Yang D, Gereau RW 4th. (2002) J. Neurosci. 22, 6388 -6393 (Non-Patent Document 4)). The temperature of 43 ° C is very consistent with the temperature threshold that causes pain in humans and animals, suggesting that VR1 participates in the reception of nociceptive thermal stimulation.

Acidification occurs in an organ in case of inflammation or ischemia and is known to cause or increase pain (see, for example, Bevan S, Geppetti P. (1994) Trends Neurosci. 17, 509-512 ( Non-patent document 5)). It turns out that when the pH outside the cells is reduced within the limits where acidification occurs in the case of an organ injury, VR1 can be directly active only by acidification (proton), and a - it is believed that VR1 be the true molecule that receives acidification stimulation in an organ that occurs in the event of inflammation or ischemia (see, for example, Yang D, Gereau RW 4th. (2002) J. Neurosci. 22, 6388-6393 (Document non-patenting 4)).

Immunohistological analysis using a specific antibody confirmed that the number of unmyelinated C-fiber fibers expressing VR1 increases in an inflamed region compared to a normal region (see, for example, Carlton SM, Coggeshall RE. (2001) Neurosci. Lett 310, 53-56 (Non-Patent Document 6)). Increased expression of VR1 in the submucosal plexus was indeed observed in inflamed bowel disease in man (see, for example, Yiangou Y, Facer P, Dyer NH1 Chan CL, Knows C, Williams NS, Anand P. (2001 ) Lancet 357, 1338-1339 (Non-Patent Document 7)). Such increase in the amount of VR1 expression causes peripheral sensitization in an inflamed organ and supposedly contributes to the duration of inflammatory hyperalgesia.

Extracellular ATP, bradykinin and a neural growth factor that are substances associated with inflammation have also been reported to increase VR1 activity (see, for example, Tominaga M, Wada M, Masu M. (2001) Proc. Natl. Acad. Sci USA 98, 6951-6956 (Non-Patent Document 8); Shu X, Mendell L. (1999) Neurosci Lett. 274, 159-162 (Non-Patent Document 9); Chuang HH, Prescott ED, Kong H, Shields S, Jordt SE, Basbaum Al, Ground MV, Julius D. (2001) Nature 411, 957-962 (Non-Patent Document 10), and Sugiura T, Tominaga M, Katsuya H, Mini- zumura K. (2002) J. Neurophysiol. 88, 544-548 (Non-patent document 11)) and it is arguably a fact that VR1 is involved in pain and pain hypersensitivity including those caused by inflammation (see, for example, Numazaki M , Tominaga M (2003) Biochemistry 75, 359-371 (Non-Patent Document 12)).

Sensory nerve cells in VR1-deficient mice did not respond to stimulation with capsaicin, proton and heat. It has also been reported that in action analysis, the VR1-deficient mouse shows no reaction to pain following administration of capsaicin, and sensitivity to heat stimulation decreases and no inflammatory hyperalgesia is observed (see, for example, Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Peterson-Zeitz KR, Koltzenburg M, Basbaum Al, Julius D. (2000) Science 288, 306-313 (Non-Patent Document 13) and Davis LB, Gray J , Gunthorpe MJ et al. (2000) Nature 405, 183-187 (Non-Patent Document 14)). Therefore, it was also confirmed at the individual level from the analysis of the VR1 deficient mouse that VR1 functions as a receptor for broad spectrum pain stimulation.

In addition, regarding the relationship between subtype 1 vanilloid receptor (VR1) and a disease, it has been reported that a substance that inhibits VR1 activity is useful as a therapeutic agent for various diseases.

Particularly with respect to a pain therapeutic agent, there is a document describing that capsazepine which is known as a VR1 antagonist had a significant analgesic effect in an animal model (see, for example, Ikeda Y, Ueno A , Naraba H, Oh-ishi S, (2001) Life Science 69, 2911-2919 (Non-Patent Document 15)), and its use is experienced as a new pain therapeutic agent having an inhibitory effect on VR1 activity.

It has been confirmed with regard to frequent urination bladder overexertion and urinary incontinence that the VR1-deficient mouse bladder contraction function decreases that there is a document describing that a compound having a pharmacological mechanism similar to capsaicin or a compound having a inhibitory action on VR1, that is, a compound inhibiting subtype 1 vanilloid receptor (VR1) activity is useful for improving bladder function, for example as a therapeutic agent for frequent urination, urinary incontinence, etc. (see, for example, (2002) Nat. Neurosci. 5, 856-860 (Non-Patent Document 16)).

In addition, another reference describes that a substance having a subtype 1 vanilloid receptor (VR1) inhibitory effect, particularly VR1 receptor antagonist, is useful for preventing and treating diseases associated with VR1 activity, particularly urinary urinary incontinence. , overactive bladder, chronic pain, neuropathic pain, postoperative pain, pain associated with rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, nerve injury, ischemic symptom, neurodegenerative disease, cerebral stroke, incontinence, and inflammatory disease (see, for example, JP 2003-192673

(Patent Document 1)).

In addition, it is known that diseases relevant to vanilloid receptor activity may include pain, acute pain, chronic pain, neuropathic pain, postoperative pain, migraine, joint pain, neuropathy, nerve injury, diabetic nerve disease, neurodegenerative disease, neurogenic skin disorder, cerebral stroke, bladder hypersensitivity, irritable bowel syndrome, respiratory organ abnormalities such as asthma and chronic obstructive pulmonary disease, stimulation of the skin, eye or mucosa, fever, stomach or duodenal ulcer, inflamed bowel disease, inflammatory disease, etc. (see, for example, JP 2004-506714 T2 (Patent Document 2)).

It can therefore be said that substances having subtype 1 vanilloid receptor (VR1) antagonistic activity are useful as a therapeutic agent for conditions in which C fibers take part, for example not to mention pruritus, allergy and allergic rhinitis, frequent urinary bladder and urinary incontinence, stroke, irritable bowel syndrome, respiratory diseases such as asthma and chronic obstructive pulmonary disease, dermatitis, mucositis, stomach and duodenal ulcer, inflamed bowel disease, etc. but also pain, acute pain, chronic pain, neuropathic pain, postoperative pain, migraine, joint pain, neuropathy, nerve injury, diabetic nerve disease, neurodegenerative disease, pain associated with rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, neurogenic disorder rash, stroke, overweight, urgent urinary incontinence, ischemic symptom and an inflammatory disease, etc.

Listed below are compounds considered to be relatively similar to the known subtype 1 vanilloid receptor antagonist (VR1) and the compound of the present invention.

Amide-type compounds represented by the following general formula [A], [B] and [C] are described in W003 / 068749 as compounds exhibiting antagonism to VR1 (Patent Document

<formula> formula see original document page 7 </formula> The urea-type compound represented by the following general formula [D] is described in WO03 / 080578 as a VR1 antagonist compound (Patent Document 4).

<formula> formula see original document page 8 </formula>

Quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate is described as a compound that has an inhibitory effect against capsaicin-induced extravasation of a plasma protein in the bladder and is described. in WO03 / 006019 (Patent Document 5).

The urea-type compound represented by the following general formula [E] is described in WO03 / 053945 as a VR1 antagonist compound (Patent Document 6).

<formula> formula see original document page 8 </formula>

The compound represented by the following general formula [F] is described in WO03 / 099284 as a compound which exhibits binding activity for VR1 (Patent Document 7). However, these compounds are different from the compound of the present invention in structure, and there are no descriptions that suggested the compound of the present invention.

By way of reference, the present inventors have already filed a patent application for a VR1 inhibitor represented by the following formula (PCT / JP2005 / 013446 (Patent Document 8)):

<formula> formula see original document page 9 </formula>

[Non-patent document 1] Szallasi A, Blumberg PM. (1999) Pharmacol. Rev. 51, 159-212

[Non-patent document 2] Caterina MJ1 Schumacher MA Tominaga M, Posen TA, Levine JD, Julius D. (1997) Nature 389, 816-824

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

[Non-patent document 4] Yang D, Gereau RW 4th. (2002) J. Neurosci. 22, 6388-6393

[Non-patent document 5] Bevan S, Geppetti P. (1994) Trends Neurosci. 17,509-512

[Non-patent document 6] Carlton SM, Coggeshall RE. (2001) Neurosci. Lett. 310, 53-56

[Non-patent document 7] Yiangou Y, Facer P, NH Dyer, Chan CL, Knows C, Williams NS, Anand P. (2001) Lancet 357, 1338-1339

[Non-patent document 8] Tominaga M, Wada M, Masu M. (2001) Proc. Natl. Acad. Know. USA 98, 6951 -6956

[Non-patent document 9] Shu X, Mendell LM. (1999) Neurosci. Lett. 274, 159-162

[Non-patent document 10] Chuang HH, Prescott ED, Kong H1 Shields S, Jordt SE, Basbaum Al, Ground, MV, Julius D. (2001) Nature 411, 957-962 [Non-patent document 11] Sugiura T, Tominaga M , Katsuya H, Mizumura K. (2002) J. Neurophysiol. 88, 544-548

[Non-patent document 12] Numazaki M, Tominaga M (2003) Biochemistry try 75, 359-371

[Non-patent document 13] Caterina MJ, Leffler A, Malmberg AB, Martin WJ1 Trafton J, Peterson-Zeitz KR, Koitzenburg M, Basbaum Al, Julius D. (2000) Science 288, 306-313

[Non-patent document 14] Davis LB1 Gray J, Gunthorpe MJ et al. (2000) Nature 405, 183-187

[Non-patent document 15] Ikeda Y, Ueno A, Naraba H, Oh-ishi S, (2001) Life Science 69, 2911-2919

[Non-patent document 16] (2002) Nat. Neurosci. 5, 856-860

[Patent Document 1] JP 2003-192673 A2

[Patent Document 2] JP 2004-506714 T2

[Patent Document 3] W003 / 068749

[Patent Document 4] W003 / 080578

[Patent Document 5] W003 / 006019

[Patent Document 6] W003 / 053945

[Patent Document 7] W003 / 099284

[Patent Document 8] PCT / JP2005 / 013446 Description of the Invention

Problems to be solved by the invention Narcotic analgesics (morphine etc.), non-narcotic analgesics (NSAID (non-steroidal anti-inflammatory drug)) etc. They are today mainly used as analgesic agents. However, the use of narcotic analgesics is strictly limited due to the development of resistance / dependence and other serious side effects. It is well known that an upper gastrointestinal tract disorder and a hepatic disorder often occur during prolonged administration of non-narcotic analgesics, and an analgesic agent with few side effects and more analgesic effect is extremely desired. In addition, for diabetes-induced neuropathic pain, postherpetic neuralgia, and neuropathic pain such as trigeminal neuralgia, an effective analgesic agent has not yet been found and the development of an effective analgesic agent is also expected.

Capsaicin-like compounds acting on VR1 are considered to develop the analgesic effect based on a pharmacological mechanism completely different from those of existing analgesic agents (capsaicin-sensitive nerve block), and their efficacy is quite as expected. a therapeutic agent for neuropathic pain and pain that originates in various conditions such as rheumatic arthritis for which existing analgesic agents are not effective.

The fact that the ultimate target of various inflammation-associated substances is VR1 suggests the possibility that a VR1-acting agent may be effective for various types of pain associated with inflammation and interstitial cystitis, and its efficacy is highly anticipated as an analgesic agent. replace existing analgesic agents.

Accordingly, the aim of the present invention is to provide a new analgesic agent based on the pharmacological mechanism completely different from those of existing analgesic agents (capsaicin-sensitive nerve block), ie inhibitors of VR1 activity and to provide a new one. compound for the same.

More specifically, the aim of the present invention is to provide an excellent inhibitor of VR1 activity not only in VR1 inhibitory activity but also in the absorbability and sustainability with which it is likely to be used in practice.

Another object of the present invention is to provide a method for the treatment and / or prevention of diseases in which subtype 1 vanilloid receptor (VR1) activity is involved, such as pain, acute pain, chronic pain, neuropathic pain, pain. associated with rheumatoid arthritis, neuralgia, etc., particularly pain.

Means to solve problems

As a result of a long study to develop an analgesic agent based on a novel mechanism of action that will replace conventional analgesic agents such as non-narcotic analgesics, pyrazolone analgesics, non-pyrazole analgesics and NSAIDs1 present The inventors have found a 3,4-dihydrobenzoxazine compound that has excellent inhibitory activity on VR1 action and has better absorption capacity and better sustainability, and have completed the present invention. The present invention is described below in more detail.

1. A 3,4-dihydrobenzoxazine compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof:

<formula> formula see original document page 12 </formula>

where X is

(1) a nitrogen atom or

(2) CR3;

R1 is

(1) a hydrogen atom or

(2) a halogen atom;

R2 is a C1-6 alkoxy group which may be substituted with 1 to 5 same or different substituents selected from the following group:

(1) a halogen atom and

(2) a hydroxyl group; and

R3 is a halogen atom (however, R1 is a halogen atom when X is CR3)].

2. The 3,4-dihydrobenzoxazine compound according to item 1 above selected from the following group or a pharmaceutically acceptable salt thereof:

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

2) (S) -4- (5-picolin-2-yl) -3-hydroxymethyl-N- (3,5-difluoro-4-isopropoxyphenyl) -3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide,

3) (S) -4- (5-picolin-2-yl) -3-hydroxymethyl-N- (3,5-difluoro-4-ethoxyphenyl) -3,4-di 2H-benzo [1,4] oxazine -8-carboxamide,

4) (S) -4- (5-picolin-2-yl) -3-hydroxymethyl-N- [2- (2,2-dimethylpropyloxy) pyridin-5-yl] 3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide,

5) (S) -4- (5-picolin-2H-yl) -3-hydroxymethyl-N- (2-tert-butoxypyridin-5-yl) -3,4-dih 2H-benzo [1,4] oxazine -8-carboxamide,

6) (S) -4- (5-picolin-2-yl) -3-hydroxymethyl-N- [2- (2,2,2-trifluoroethyloxy) pyridin-5 3,4-dihydro-2H-benzo [1 , 4] oxazine-8-carboxamide,

7) (S) -4- (5-picolin-2-yl) -3-hydroxymethyl-N- (2-isobutoxypyridin-5-yl) -3,4-dihydro-2H-benzo [1,4] oxazine- 8-carboxamide,

8) (S) -4- (5-picolin-2-yl) -3-hydroxymethyl-N- [3,5-difluoro-4- (2,2,2-triflouroethoxy) phenyl] -3,4 -dihydro-2H-benzo [1,4] oxazine-8-carboxamide,

9) (S) -4- (5-picolin-2-yl) -3-hydroxymethyl-N- [3,5-difluoro-4- (2-hydroxy-2-methylpropyloxy) phenyl] -3,4- dihydro-2H-benzo [1,4] oxazine-8-carboxamide, and

10) (S) -4- (5-picolin-2-yl) -3-hydroxymethyl-N- [3,5-difluoro-4- (1,1-dimethyl-2-hydroxyethyloxy) phenyl] -3 4,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide.

3. A pharmaceutical composition comprising a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof according to item 1 or 2 above and a pharmaceutically acceptable carrier.

4. A pharmaceutical composition comprising a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof according to item 1 or 2 above and a pharmaceutically acceptable carrier for the treatment and / or prevention of a disease. pain, acute pain, chronic pain, neuropathic pain, pain associated with rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postherpetic neuralgia, chronic postherpetic neuralgia , postoperative pain, cancer-associated pain, inflammation-associated pain, interstitial cystitis, post-traumatic neuralgia, diabetic neuropathy, neurodegenerative disease, cerebral stroke, ischemic symptom, nerve injury, neurogenic skin disorder, inflammatory disease, pruritus, rhinitis allergic disease, stroke, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, stomach and duodenal ulcer, disease inflamed intestine, bladder hypersensitivity, frequent urination, and urinary incontinence.

A pharmaceutical composition for the treatment and / or prevention of pain comprising a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof according to item 1 or 2 above and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition according to item 5 above where the pain is acute pain, chronic pain, neuropathic pain, pain associated with rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postural neuralgia. -herpetic, chronic postherpetic neuralgia, postoperative pain, cancer-associated pain, inflammation-associated pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, or neurodegenerative disease.

7. A subtype 1 vanilloid receptor (VR1) activity inhibitor comprising a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof according to item 1 or 2 above and a pharmaceutically acceptable carrier.

8. A method for treating and / or preventing a selected disease of pain, acute pain, chronic pain, neuropathic pain, pain associated with rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, neuralgia. acute postherpetic neuropathy, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative pain, cancer-associated pain, pain associated with inflammation, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegenerative disease, apoplexy stroke, ischemic symptom, nerve injury, neurogenic skin disorder, inflammatory disease, pruritus, allergic rhinitis, stroke, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, stomach and duodenal ulcer, inflamed bowel, bladder hypersensitivity, frequent urination, and urinary incontinence characterized by the method comprising administering a pharmacologically of a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof according to item 1 or 2 above.

9. A method for the treatment and / or prevention of pain, wherein the method comprises administering a pharmacologically effective amount of a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof according to item 1. or 2 above.

10. The method of treatment and / or prevention according to item 9 above where the pain is acute pain, chronic pain, neuropathic pain, pain associated with rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, neuralgia. acute postherpetic neuropathy, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative pain, cancer-associated pain, pain associated with inflammation, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, or neurodegenerative disease.

11. A commercial package comprising a pharmaceutical composition according to any of items 3 to 6 above and written instructions concerning said pharmaceutical composition stating that said composition may be used or should be used for treatment and / or prevention. of a selected disease of pain, acute pain, chronic pain, neuropathic pain, pain associated with rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postherpetic neuralgia, postural neuralgia -herpetic pain, postoperative pain, cancer-associated pain, inflammation-associated pain, interstitial cystitis, posttraumatic neuropathy, diabetic neuropathy, neurodegenerative disease, cerebral stroke, ischemic symptom, nerve injury, neurogenic skin disorder , inflammatory disease, pruritus, allergic rhinitis, stroke, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, stomach and duodenal ulcer, inflamed bowel disease, bladder hypersensitivity, frequent urination, and urinary incontinence.

Use of a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof according to item 1 or 2 above for the preparation of a pharmaceutical composition according to item -4 above for treatment and / or prevention of a selected disease of pain, acute pain, chronic pain, neuropathic pain, pain associated with rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postherpetic neuralgia, postural chronic herpetic, postoperative pain, cancer-associated pain, inflammation-associated pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegenerative disease, cerebral stroke, ischemic symptom, nerve injury, neurogenic skin disorder, inflammatory disease , pruritus, allergic rhinitis, stroke, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, stomach and duodenal ulcer, disease inflamed intestine, bladder hypersensitivity, frequent urination, and urinary incontinence.

Use of a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof according to item 1 or 2 above for the preparation of a pharmaceutical composition for the treatment and / or prevention of pain according to item 5 or 6 above.

14. The use of a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof according to item 13 above where the pain is acute pain, chronic pain, neuropathic pain, rheumatoid arthritis-associated pain, neuralgia, , neuropathy, hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative pain, cancer-associated pain, inflammation-associated pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy or neurodegenerative disease.

A drug comprising a combination of a pharmaceutical composition comprising a compound of 3,4-dihydrobenzoxazine or a pharmaceutically acceptable salt thereof according to item 1 or 2 above and a pharmaceutically acceptable carrier with one or more agents selected from the group comprising: It consists of an antiviral agent, an antidepressant, an anticonvulsant, an antiarrhythmic, a local anesthetic, an anesthetic, an N-methyl-D-aspartate receptor antagonist, an adrenal cortical steroid, a nerve blocker, an analgesic. nonsteroidal antiinflammatory drug, a narcotic, an antagonist analgesic, an α2-adrenaline receptor agonist, a drug for external use, a calcium channel antagonist, a potassium channel blocker, and an antipyretic agent.

Use of a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof according to item 1 or 2 above for the preparation of a drug according to item 15 above.

17. A method for treating and / or preventing a selected disease of pain, acute pain, chronic pain, neuropathic pain, pain associated with rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, neuralgia. acute postherpetic neuropathy, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative pain, cancer-associated pain, pain associated with inflammation, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegenerative disease, apoplexy stroke, ischemic symptom, nerve injury, neurogenic skin disorder, inflammatory disease, pruritus, allergic rhinitis, stroke, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, stomach and duodenal ulcer, inflamed bowel, bladder hypersensitivity, frequent urination, and urinary incontinence characterized by the fact that one or more agents selected from the group consisting of one agent antiviral, an antidepressant, an anticonvulsant, an antiarrhythmic drug, a local anesthetic, an anesthetic drug, an N-methyl-D-aspartate receptor antagonist, an adrenal cortical steroid, a nerve blocker, a non-steroidal anti-inflammatory analgesic , a narcotic, an antagonist analgesic, an α2-adrenaline receptor agonist, an external medicine, a calcium channel antagonist, a potassium channel blocker, and an antipyretic agent are used in combination with a pharmacologically effective amount of a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof according to item 1 or 2 above.

18. A method for the treatment and / or prevention of pain characterized in that the method uses the administration of a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof according to item 1 or 2 above. in combination with analgesia produced by selected acupuncture stimulation, transcutaneous electroacupuncture stimulation therapy, transcutaneous electrical nerve stimulation therapy, silver-tip therapy (SSP), peripheral nerve stimulation therapy, electrical cord stimulation therapy spinal cord, electroconvulsive therapy, laser therapy and low frequency therapy.

19. A method for the treatment and / or prevention of postoperative neuralgia characterized in that a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof according to item 1 or 2 above is administered after administration. a selected surgical procedure for scarectomy, nerve freezing, peripheral nerve excision, spinal cord dorsal root excision, sympathectomy, destruction of the spinal cord dorsal root entry zone, cordotomy, and frontal lobe excision.

Advantages of the Invention

The 3,4-dihydrobenzoxazine compound of the present invention effectively inhibits subtype 1 vanilloid receptor (VR1) activity, and is therefore effective in the medical treatment and / or prevention of diseases such as pain, acute pain. , chronic pain, neuropathic pain, pain associated with rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative pain, associated pain cancer, pain associated with inflammation, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegenerative disease, stroke, ischemic symptom, nerve damage, neurogenic skin disorder, inflammatory disease, pruritus, allergic rhinitis, stroke, irritable bowel, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, stomach and duodenal ulcer, inflamed bowel disease, bladder hypersensitivity, frequent urinary bladder overactive bladder, and urinary incontinence bladder overactive bladder.

Particularly, it is effective as a therapeutic agent and a preventive agent for diseases accompanied by painful conditions such as pain, acute pain, chronic pain, neuropathic pain, rheumatoid arthritis associated pain, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, neuralgia. acute postherpetic neuropathy, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative pain, cancer-associated pain, pain associated with inflammation, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, and neurodegenerative disease. In addition, effects are also expected by a mechanism other than conventional analgesics.

The 3,4-dihydrobenzoxazine compound of the present invention represented by the above-mentioned general formula (1) not only has excellent inhibitory effect on VR1 activity but also resists oxidative metabolism and has excellent effects with respect to sustainability. of the inhibitory effect. The compound of the present invention further has properties such as an extraordinarily high absorption capacity, and / or extraordinarily stability in the gastric juice. Such effects were not foreseen even by those skilled in the art.

Therefore, the novel compound of the present invention is an excellent compound which in practice will possibly be used as a drug. Best Mode for Carrying Out the Invention

The definition of each term used in this report is given below.

A "C1-6 alkyl group" represents a straight or branched alkyl group having 1 to 6 carbon atoms, preferably "a C-14 alkyl group". A "C1-6 alkyl group" specifically includes a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl, an isopentyl group, a ter-pentyl group, a hexyl group etc. A "C1-4 alkyl group" represents a straight or branched alkyl group having 1 to 4 carbon atoms, and specifically includes a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group etc.

A "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and a fluorine atom and a chlorine atom are preferred, and a fluorine atom is particularly preferred. .

A "C1-6 alkoxy group" is an alkoxy group in which its alkyl moiety is a "C1-6 alkyl group" of the above definition. Specifically, it includes a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butyloxy group, a pentyloxy group, an isopentyloxy group, 2-methylbutoxy group, neopentyloxy group, 1-ethylpropoxy group, hexyloxy group, 4-methylpentyloxy group, 3-methylpentyloxy group, 2-methylpentyloxy group, 1-methylpentyloxy group, 3 group, 3-dimethylbutoxy, a 2,2-dimethylbutoxy group, a 1,1-dimethylbutoxy group, a 1,2-dimethylbutoxy group, a 1,3-dimethylbutoxy group, a 2,3-dimethylbutoxy group, a 2-group ethylbutoxy etc.

A "C1-6 alkoxy group which may be substituted with 1 to 5 halogen atoms" represents in addition to the "C1-6 alkoxy group" mentioned above, a haloalkoxy group in which the "C1-6 alkyl group" which The part of the C1-6 alkoxy group is substituted with 1 to 5, preferably 1 to 3, more preferably 3 same or different halogen atoms, preferably 3 equal halogen atoms. Specifically, such as haloalkoxy group includes a fluoromethoxy group, one. difluoromethoxy group, trifluoromethoxy group, bromomethoxy group, chloromethoxy group, dichloromethoxy group, 2-chloroethoxy group, 1,2-dichloroethoxy group, 2,2-dichloroethoxy group, trichloromethoxy group, 2 -fluoroethoxy, a 2,2,2-trifluoroethoxy group, a 2,2,2-trichloroethoxy group, a 4-fluorobutoxy group, etc.

A "C1-6 alkoxy group which may be substituted with 1 to 5 hydroxyl atoms" represents in addition to the "C1-6 alkoxy group" mentioned above, an alkoxy group in which the "C1-6 alkyl group" which The part of the C1-6 alkoxy group is substituted with 1 to 5, preferably 1 to 2, more preferably 1 hydroxyl group. Specifically, such alkoxy group substituted with a hydroxyl group includes a hydroxymethoxy group, a 2-hydroxyethoxy group, a 1-hydroxypropoxy group, a 3-hydroxypropoxy group, a 4-hydroxybutoxy group, a 5-hydroxypentyloxy group, a group 6 -hydroxyhexyloxy, a 2-hydroxy-2-methylpropyloxy group, a 1,1-dimethyl-2-hydroxyethyloxy group, etc.

In the general formula [1], preferred examples and particularly preferred examples of each symbol are as follows. However, the present invention is not limited thereto. (R1 preferable)

R1 is a hydrogen atom or a halogen atom. The halogen atom is preferably a fluorine atom or a chlorine atom, particularly preferably a fluorine atom.

However, R1 is preferably a hydrogen atom when X is a nitrogen atom, and R1 is a halogen atom, particularly preferably a fluorine atom when X is CR3.

More preferably, R3 and R1 are both fluorine atoms. More especially, R1 is as follows:

Ri is

(1) a hydrogen atom or

(2) a halogen atom, preferably

(1) a hydrogen atom or

(2) a fluorine atom

(however, R1 is preferably

a fluorine atom

when X is CR3).

(R2 preferable)

R2 is a C1-6 alkoxy group which may be substituted with 1 to 5 same or different substituents selected from a halogen atom and a hydroxyl group, preferably a C1-6 alkoxy group which may be substituted with 1 to 3 atoms halogen or 1 to 3 hydroxyl groups.

The "C1-6 alkoxy group" may be an alkoxy group in which the alkyl group part is straight or an alkoxy group in which the alkyl group part is branched.

A preferred "C1-6 alkoxy group" is a branched C2-5 alkoxy group. Specifically, it includes an ethoxy group, isopropoxy group, isobutoxy group, tert-butoxy group, 2,2-dimethyl propoxy group, etc.

A "C1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms" represents in addition to the C1-6 alkoxy group mentioned above, the C1-6 alkoxy group substituted with 1 to 3 halogen atoms. The C1-6 alkoxy group substituted with 1 to 3 halogen atoms represents a C1-6 alkoxy group substituted with 1 to 3 equal or different halogen atoms, preferably 1 to 3 equal halogen atoms, particularly preferably 1 to 3 fluorine atoms. Specifically, it includes a 2,2,2-trifluoroethoxy group, a 2,2,2-trichloroethoxy group, a 2,2,2-tribromoethoxy group, a 2,2,2-triiodo-ethoxy group. ethoxy, etc. A particularly preferred "C1-6 alkoxy substituted group of 1 to 3 fluorine atoms" is a C2-5 alkoxy group substituted with 1 to 3 fluorine atoms. Specifically, it includes a 2,2,2-trifluoroethoxy group, etc.

A "C1-6 alkoxy group which may be substituted with 1 to 3 hydroxyl groups" represents in addition to the above-mentioned G1-6 alkoxy group, a C1-6 alkoxy group substituted with 1 to 3 hydroxyl groups, preferably 1 hydroxyl group . The C1-6 alkoxy group substituted with 1 to 3 hydroxyl groups is preferably a C2-5 alkoxy group substituted with 1 hydroxyl group. Specifically, it includes a 2-hydroxy-2-methylpropoxy group, a 2-hydroxy-1,1-dimethyl ethoxy group, etc. (R3 preferable)

R3 is a halogen atom. The halogen atom is preferably a fluorine atom or a chlorine atom, particularly preferably a fluorine atom. Particularly preferably R3 and R1 are both fluorine atoms.

(R1 and R2 preferred when X is a nitrogen atom)

When X is a nitrogen atom, preferably R1 is a hydrogen atom and R2 is a C1-6 alkoxy group which may be substituted with 1 to 3 same or different halogen atoms.

Particularly preferably R1 is a hydrogen atom and R2 is a C1-6 alkoxy group which may be substituted with 3 equal halogen atoms. More preferably R 1 is a hydrogen atom and R 2 is a tert-butoxy group, isobutoxy group, 2,2,2-trifluoroethoxy group or 2,2-dimethyl propoxy group. (R1, R2 and R3 preferable when X is CR3)

When X is CR31 R1 and R3 are preferably R1 and R3 which are the same or different halogen atoms, particularly preferably equal halogen atoms.

More preferably, R3 and R1 are both fluorine atoms.

When X is CR 3, R 2 is preferably a C 2-5 alkoxy group such as an ethoxy group, an isopropoxy group, an isobutoxy group, a tert-butoxy group, a 2,2-dimethyl propoxy group, etc .; a C1-6 alkoxy group substituted with 1 to 3 halogen atoms, preferably fluorine atoms, such as a 2,2,2-trifluoroethoxy group, a 2,2,2-trichloroethoxy group, a group 2 2,2-tribromo-ethoxy, a 2,2,2-triiodo-ethoxy group, etc .; or a C1-6 alkoxy group substituted with 1 or 2 hydroxyl groups, such as a 2-hydroxy-2-methylpropoxy group, a 2-hydroxy-1,1-dimethyl ethoxy group, etc.

More specifically, when X is CR3, R1 and R3 are preferably the same or different halogen atoms, particularly preferably a fluorine atom and R2 preferably a C1-6 alkoxy group which may be substituted with 1 to 3 same or different substituents selected from a fluorine atom and a hydroxyl group, more specifically an ethoxy group, a tert-butoxy group, an isopropoxy group, a 2,2,2-trifluoroethoxy group, a 2-hydroxy group -2-methylpropoxy or a 2-hydroxy-1,1-dimethylethoxy group.

A "pharmaceutically acceptable salt" in the present invention may be any type of salt as long as it forms a salt with a compound represented by the above-mentioned general formula [1], and may be obtained by reaction thereof with, for example, an acid. inorganic such as hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid; an organic acid such as oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, glyconic acid, ascorbic acid, methylsulfonic acid, p-toluenesulfonic acid benzenesulfonic acid or benzyl sulfonic acid; or an amino acid such as lysine, arginine or alanine. A hydrated compound, hydrate and solvate of each compound are also included in the present invention.

In addition, there are various isomeric forms for the compound represented by the above mentioned general formula (1). For example, the E and Z isomer exist as geometric isomers, and when there is an asymmetric carbon atom, there are enantiomers and diastereomers as stereoisomers based on them, and there may be tautomers. Accordingly, all such isomers and mixtures thereof are included within the scope of the present invention. Furthermore, the present invention also encompasses prodrug compounds of these compounds and metabolite compounds as equivalent compounds in addition to the compound represented by the above mentioned general formula (1).

A "prodrug" is a derivative of the compound of the present invention with a group that can be chemically or metabolically decomposed and once administered to a living body it undergoes a chemical change resulting in a compound having an activity as a drug and has its original pharmacological effect, and complexes and salts not by covalent bonding are included.

A prodrug is used to improve oral absorption after oral administration or vectorization to a target site. Portions to be shaped to form a prodrug include reactive functional groups such as a hydroxyl group and an amino group in the compound of the present invention. Specific examples of the modifying group for a hydroxyl group include an acetyl group, a propionyl group, an isobutyryl group, a pivaloyl group, a benzoyl group, a 4-methylbenzoyl group, a dimethylcarbamoyl group, a sulfo group, etc. Specific examples of the modifying group for an amino group include a hexylcarbamoyl group, a 3-methylthio-1- (acetylamino) propylcarbonyl group, a 1-sulfo-1- (3-ethoxy-4-hydroxyphenyl) methyl group, a methyl (5-methyl-2-oxo-1,3-dioxol-4-yl), etc.

A "pharmaceutical composition" encompasses a drug combined with other drugs etc., in addition to the so-called "composition" which comprises a drug active ingredient and a combining agent etc. Needless to say, the pharmaceutical composition of the present invention may be used in combination with any type of other drugs as long as it is permitted in the medical field. Accordingly, it can also be stated that this pharmaceutical composition is a pharmaceutical composition for use in combination with other drugs.

"Pain" means any kind of painful condition regardless of the condition (for example, whether it is vague pain or severe, chronic or acute pain, etc.), regardless of which disease causes the pain (for example, regardless of whether pain is a result of rheumatism, or pain is a result of cancer, etc.). Accordingly, "pain" as used in this report covers, in addition to so-called "pain", acute pain, chronic pain, neuropathic pain, pain associated with rheumatoid arthritis, neuralgia, neuropathla, hyperalgesia, migraine, joint pain, postural neuralgia. acute herpetic, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative pain, cancer-associated pain, pain associated with inflammation, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, and neurodegenerative disease.

A "subtype 1 vanilloid receptor (VR1) activity inhibitor" means a substance that inhibits the function of the vanilloid subtype 1 receptor as an ion channel, and eliminates or attenuates activity. Specifically, it includes subtype 1 vanilloid receptor antagonist, etc. The subtype 1 vanilloid receptor antagonist means a substance that inhibits the effect of the subtype 1 vanilloid receptor agonist, thereby inhibiting the function of the subtype 1 vanilloid receptor as an ion channel. The inhibitor of the present invention does not have to compete with the agonist but can also inhibit function as a VR1 ion channel. Specifically, subtype 1 vanilloid receptor agonists include capsaicin, capsaicin derivatives, acid stimulation (proton), heat stimulation etc., the subtype 1 vanilloid receptor (VR1) activity inhibitor may be a substance that inhibits the influx of Ca2 + into the cell caused by capsaicin agonist stimulation, acid (proton) stimulation or heat stimulation.

The pharmaceutical composition of the present invention may be administered to a human as well as other animals (mouse, rat, hamster, rabbit, cat, dog, cow, horse, ram, monkey etc.).

Therefore, the pharmaceutical composition of the present invention is also useful as a drug for animals not to mention humans.

When the compound of the present invention is used as a pharmaceutical preparation, it may be mixed with a commonly known pharmaceutically acceptable carrier, excipient, diluent, extender, disintegrating agent, stabilizer, preservative, buffer, emulsifier, flavoring, coloring agent, sweetener, thickener, correction agent, dissolving aid, and other additives, specifically water, vegetable oil, alcohol such as ethanol or benzyl alcohol, carbohydrates such as polyethylene glycol, glycerol triacetate, gelatin, lactose and starch, magnesium stearate, talc, lanolin, petroleum jelly etc. to prepare a drug in the form such as a tablet, pill, powder, granule, suppository, injectable agent, eye drops, liquid medicine, capsule, troches, aerosol, elixir, suspension, emulsion and syrup for local or systemic administration. orally or parenterally.

Although the dosage varies depending on age, weight, condition, therapeutic effect, methods of administration etc., it is generally administered at a dose in the range 0.01 mg to 1 g per dose once several times a day to adults in the form of an oral preparation or an injectable preparation such as an intravenous injection etc.

"Preventing" is called prevention, and means, for example, suppressing the onset of neuralgia or chronicity of prophylactically neuralgia. With regard to pain, it is specifically included to profoundly suppress the onset of acute postherpetic neuralgia, onset of postherpetic neuralgia, transition to postherpetic neuralgia of acute herpetic pain, chronicity of postherpetic neuralgia, onset of postoperative pain, postoperative pain chronicity, onset of cancer-associated pain symptoms, cancer-associated pain chronicity, onset of inflammation-associated pain symptoms, onset of interstitial cystitis, inflammation-associated pain chronicity , appearance of posttraumatic neuralgia or chronicity of posttraumatic neuralgia.

A "drug comprising a combination" means a drug characterized in that it is a formulation containing a pharmaceutical composition comprising compound (1) or a pharmaceutically acceptable salt thereof of the present invention and a pharmaceutical composition or agent for combining with the composition of the present invention, a drug comprising a kit comprising a pharmaceutical composition comprising compound (1) or a pharmaceutically acceptable salt thereof of the present invention and a pharmaceutical composition or agent for combining composition of the present invention, a drug characterized in that a pharmaceutical composition comprising the compound (1) or a pharmaceutically acceptable salt thereof of the present invention and a pharmaceutical composition or an agent to be combined with the composition of the present invention. present invention are administered by the same route of administration. administration or by different routes of administration, respectively, etc.

The compound and pharmaceutical composition of the present invention may be used in combination with one or more other agents by following a general method currently performed at the usual average site. When used in combination, the drug to be used with it may be administered simultaneously or separately over a period of time. While there are various compounds which may be used in combination with the compound of the present invention, particularly preferred are an antiviral agent, an antidepressant, an anticonvulsant, an antiarrhythmic drug, a local anesthetic, an anesthetic drug, an N receptor antagonist. -methyl-D-aspartate, an adrenal cortical steroid, a nervous blocker, a non-steroidal antiinflammatory analgesic, a narcotic, an antagonist analgesic, an ofc -adrenaline receptor agonist. a stimulating analgesic method, drugs for external application, a calcium channel antagonist, a potassium channel blocker, and an antipyretic agent.

The antiviral agent specifically includes vidarabine, acyclovir, ganciclovir, zidovudine, didanosine, amantadine, and oxidouridine, interferon, etc.

The antidepressant specifically includes amitriptyline, imipramine, clomipramine, trimipramine, lofepramine, dosulepine, desipramine, amoxapine, nortriptyline, fluoxetine, fluvoxamine, maprotiline, mianserine, setiptyline, trazodone, etc.

Anticonvulsant specifically includes gabapentin, pregabalin, phenobarbital, primidone, phenytoin, mefenitoin, nirvanol, ettoin, trimethadione, ethosuximide, acetylpheneturide, carbamazepine, zonisamide, acetalamide, diazepam, clonazenam, valrazenamide, nitrazepam, valazenamide etc.

The antiarrhythmic drug specifically includes quinidine, disopyramide, procainamide, ajmaline, prajmium, cybenzoline, lidocaine, mexiletine, aprindine, tonicaide, phenytoin, flecainide, propafenone, propanolol, amiodarone, verapamil, beapidil, beapidil, beeparil, etc.

Local anesthetics specifically include lidocaine, mexiletine, cocaine, procaine, bupivacaine, mepivacaine, prilocaine, tetracaine, dibucaine, ethyl aminobenzoate, etc.

The anesthetic drug specifically includes benzodiazepine, diazepam, midazolam, thiopental, thiamylal, propofol, baclofen, droperidol, sufentanil, etc. are mentioned. The N-methyl-D-aspartate receptor antagonist specifically includes ketamine, dextromethorphan, memantine, amantadine, etc. Are included.

The cortical adrenal steroid specifically includes cortisol, cortisone, prednisolone, triamcinolone, dexamethasone, betamethasone, paramethasone, fluocinolone acetonide, fluocinonide, beclomethasone, fludrocortisone, etc.

Nerve blocker specifically includes stellate ganglion blocker, epidural ganglion blocker, brachial plexus ganglion blocker, nerve root blocker, thoracic / lumbar sympathetic ganglion, trigger point blocker, subarachnoid ganglion blocker, sympathetic nerve blocker, local infiltration blocker, peripheral nerve blocker, etc.

Nonsteroidal antiinflammatory analgesic specifically includes celecoxib, rofecoxib, etodolac, meloxicam, nimesulide, diclofenac sodium, mefenamic acid, zaltoprofen, loxoprofen sodium, sulindac, na- bumetone, diflunisal, piroxenic acid, piroxenic acid, piroxenic acid tolmetin, indomethacin, flurbiprofen, oxaprozin, ketoprofen, mofezolac, acetaminophen, ketorolac, zomepirac, nitroaspirin, thiaprofen, ampiroxicam, thiaramide, epirizol, etc.

Narcotics specifically include morphine, fentanyl, oxycodone, methadone, codeine, cocaine, pethidine, opium, ipecac, etc.

antagonist analgesic specifically includes pentagin, buprenorphine, nalorphine, cyclazocine, butorphanol, etc.

Receptor agonist α2-adrenaline specifically includes clonidine, dexmedetomidine, tizanidine, guanfacine, guanabenz, etc.

The medicine for external application specifically includes capsaicin cream etc.

The antipyretic agent specifically includes diclofenac sodium, mefenamic acid, ioxoprofen, sodium, ibuprofen, acetylsalicylic acid, dometacin, acetaminophen, and the like.

The stimulation analgesic method specifically includes acupuncture, percutaneous electroacupuncture stimulation therapy, percutaneous nerve electrical stimulation therapy, silver-tipped therapy (SSP), peripheral nerve stimulation therapy, spinal electrical stimulation therapy , electrical spasm therapy, laser therapy, low frequency therapy, etc.

In addition, the compound of the present invention may be used after the general method usually performed in the art by administration after performing a surgical procedure to prevent or treat pain. Although various surgical procedures may be performed in combination with the compound of the present invention, cicatrectomy, nerve freezing, peripheral nerve excision, backbone root excision, sympathectomy, destruction of the dorsal root entry zone of the spinal cord. , cordotomy, and frontal lobe excision are particularly preferable.

Although application of the compound of the present invention has been described primarily as a use to prevent or treat pain, the compound of the present invention may be applied to conditions in which C fibers participate, for example, pruritus, allergic and allergic rhinitis, overactive bladder. frequent urination and urinary incontinence, stroke, irritable bowel syndrome, respiratory diseases such as asthma and chronic obstructive pulmonary disease, dermatitis, mucositis, stomach and duodenal ulcer, inflamed bowel disease, etc.

In the following, we specifically describe a method of preparing the compound of the present invention represented by the general formula (1) but, needless to say, the present invention is not limited to these methods of preparation.

Therefore, the compound of the present invention may be synthesized according to the following preparation methods A or B, but it may be prepared according to the examples mentioned below, or referring to these processes. In preparing the compound of the present invention, the order of the reaction operation may be changed accordingly. It can be done from the reaction step or from the substitution part considered rational. For example, compound (X) may be introduced before compound (II) is introduced, and this order may be reversed. For the formation of 3,4-dihydrooxoxazine, a closed ring reaction may be performed to form this hetero ring prior to the introduction of compound (II) and / or compound (X) or alternatively a closed ring reaction. may be made to form this hetero ring upon introduction of compound (II) and / or compound (X). Protection and deprotection can be properly conducted when there is a reactive functional group. To improve reaction development, reagents other than those illustrated may be used appropriately. The following production process diagram is an example of the typical preparation method, but the preparation of the compound of the present invention is not particularly limited to the following method. Each compound obtained in each step can be isolated and purified by a usual method, but depending on the case the compound can be used in the next step without being isolated and purified. 1. Method of preparation A; <formula> formula see original document page 31 </formula> (where R represents a carboxyl protecting group (the carboxyl protecting group represents a carboxyl protecting group commonly used in the technique of synthetic organic chemistry and includes, a methyl group, an ethyl group, a propyl group, a tert-butyl group, a benzyl group, a paramethoxy benzyl group, etc.), and form an ester which is easily transformed into a carboxylic acid by a hydrolysis or catalytic hydrogenation reaction. X 'and X "are the same or different and each represents a halogen atom such as chlorine and bromine or a sulfonyloxy group such as a 3-nitrobenzene sulfonyloxy group, a p-toluenesulfonyloxy group, a group benzene sulfonyloxy, a p-bromobenzenesulfonyloxy group, a methanesulfonyloxy group or a trifluoromethanesulfonyloxy group R1 represents a protecting group from a phenolic hydroxyl group which can be easily removed by a hydrolysis or catalytic hydrogenation action (the protecting group of a phenolic hydroxyl group represents a protecting group of a phenolic hydroxyl group generally used in the synthetic organic chemistry technique and includes, for example, a methoxymethyl group, a methoxyethoxymethyl group, a benzyl, a tert-butyl group, a tetrahydropyranyl group, an acetyl group, etc.). R 'represents a protecting group of a hydroxyl group which can be easily removed by a hydrolysis or catalytic hydrogenation reaction (the protecting group of a hydroxyl group represents a protecting group of a hydroxyl group commonly used in the synthetic organic chemistry technique and includes, for example, a methoxymethyl group, a methoxyethoxymethyl group, a benzyl group, a tetrahydropyranyl group, an acetyl group, etc.). Each symbol is the same as above.) First step

This is the step to obtain a compound (III) by the palladium catalyzed Buchwald / Hartwig amination amination reaction from a compound (I) and a compound (II).

Compound (III) may be obtained by reacting (I) with compound (II) in toluene, 1,4-dioxane, tetrahydrofuran or the like or a mixed solvent thereof using a palladium-based catalyst such as as a mixture of palladium acetate and 2,2'-bis (diphenylphosphino) -1,1'-binafil, bis (diphenylphosphino) ferrocene palladium (II) chloride or tris (dibenzylideneacetone) dipaladium together with a base such as sodium carbonate, tripotassium phosphate (Κ3ΡΟ4), potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate or potassium tert-butoxide at a temperature between 20 ° C and the reflux temperature, preferably 60 ° C and at reflux temperature for 5 hours to 96 hours, preferably for 8 hours to 48 hours.

Second stage

This is the step for removing R 'from compound (III) and obtaining compound (IV).

For example, when R1 is a methoxymethyl group, a benzyloxymethyl group, a methoxyethoxymethyl group, a tert-butyl group, a tetrahydropyranyl group or an acetyl group, compound (IV) may be obtained by reaction of compound (III) without solvent or in water, methanol, ethanol, propanol, tetrahydrofuran etc. or a mixed solvent thereof using an acid such as hydrochloric acid or trifluoroacetic acid at a temperature between 0 ° C and reflux temperature, preferably between 0 ° C and 50 ° C for 0.5 hour to 24 hours, preferably by 0.5 hour to 8 hours.

When R1 is a benzyl group etc., compound (IV) may be obtained by reaction in methanol, ethanol, propanol, tetrahydrofuran or a mixed solvent thereof in the presence of a palladium-carbon catalyst, etc. using hydrogen or ammonium formate at a temperature of about 0 ° C at reflux temperature, preferably about 20 ° C at reflux temperature for 0.5 hour to 96 hours, preferably 1 hour at 48 hours. ras.

Third stage

This is a step to obtain a compound (VI) by reacting compound (IV) and a compound (V) under basic conditions.

Compound (VI) can be obtained by reacting compound (IV) and compound (V), ie glycidyl chloride, glycidyl tosylate, glycylcyl nosylate etc. in chloroform, tetrahydrofuran, Ν, Ν-dimethylformamide, dimethyl sulfoxide, Ν, Ν-dimethylacetamide, ethyl acetate, methanol, water or a mixed solvent thereof in the presence of a base such as sodium carbonate, potassium carbonate, hydroxide of sodium, potassium hydroxide or triethylamine at a temperature between 0 ° C and reflux temperature, preferably between 0 ° C and 60 ° C for 0.5 hour to 24 hours. Fourth Stage

This is a step to transform compound (VI) into compound (VII) under basic conditions.

Compound (VII) can be obtained by reacting compound (VI) in chloroform, tetrahydrofuran, Δ, dim-dimethylformamide, NN-dimethylacetamide, dimethyl sulfoxide, ethyl acetate or a mixed solvent thereof in the presence of a base such as carbonate. sodium, potassium carbonate, sodium hydroxide, potassium hydroxide or triethylamine at a temperature between 0 ° C and reflux temperature, preferably between 0 ° C and 60 ° C for 0.5 hour to 24 hours.

Fifth step

This is a step for removing R from compound (VII) and obtaining a compound (VIII).

For example, when R is a methyl group, an ethyl group, a propyl group, etc., compound (VIII) may be obtained by hydrolysis of compound (VII) in water, methanol, ethanol, propanol, tetrahydrofuran, etc. . or a mixed solvent thereof using a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate or sodium carbonate at a temperature between -20 ° C and reflux temperature, preferably between 20 ° C and reflux temperature for 0.5 hour to 24 hours, preferably 0.5 hour to 8 hours.

For example, when R is a tert-butyl group, compound (VIII) may be obtained by reaction of compound (VII) without solvent or in water, methanol, ethanol, propanol, tetrahydrofuran, etc. or a mixed solvent thereof using an acid such as hydrochloric acid or trifluoroacetic acid at a temperature between 0 ° C and reflux temperature, preferably between 0 ° C and 50 ° C for 0.5 hour to 24 hours, preferably by 0.5 hour to 8 hours.

When R is a benzyl group, a paramethoxybenzyl group, etc., compound (VIII) may be obtained by reaction of compound (VII) in methanol, ethanol, propanol, tetrahydrofuran, etc. or a mixed solvent thereof using hydrogen or ammonium formate in the presence of a palladium and carbon based catalyst, etc. at a temperature between about 0 ° C and reflux temperature, preferably between about 20 ° C and 50 ° C for 0.5 hour to 96 hours, preferably 1 hour to 48 hours.

Sixth step

This is a step for protecting the hydroxyl group of compound (VIII) and obtaining a compound (IX).

For example, when R 'is an acetyl group, compound (IX) may be obtained by reacting compound (VIII) in chloroform, tetrahydrofuran, toluene, ethyl acetate, pyridine or without solvent using acetyl chloride or acetic anhydride. in the presence or absence of a base such as pyridine or triethylamine at a temperature between 0 ° C and the reflux temperature, preferably between 0 ° C and 50 ° C for 0.5 hour to 24 hours, preferably for 0.5 hour to 8 hours.

When R 'is a tetrahydropyranyl group, compound (IX) may be obtained by reacting compound (VIII) in chloroform, tetrahydrofuran, toluene, ethyl acetate or without solvent using 2,3-dihydropyran in the presence of an acid catalyst. such as p-toluenesulfonic acid or hydrogen chloride at a temperature between 0 ° C and reflux temperature, preferably between 0 ° C and 50 ° C for 0.5 hour to 24 hours, preferably for 0.5 hour. at 8 o'clock.

When R 'is a methoxymethyl group, a methoxyethoxymethyl group or a benzyl group, compound (IX) may be obtained by reaction of compound (VIII) in a solvent such as tetrahydrofuran or N1N-dimethylformamide using methoxymethyl chloride, methoxyethoxymethyl, benzyl chloride or benzyl bromide in the presence of a base such as sodium hydride or lithium diisopropylamide at a temperature between 0 ° C and reflux temperature, preferably between 0 ° C and 50 ° C for 0 ° C. 1.5 hours to 24 hours, preferably 0.5 hours to 8 hours.

Seventh step

This is a step to obtain a compound (XI) by a condensation reaction of a compound (IX) and a compound (X).

For example, when the condensation reaction is carried out using a condensing agent, a compound (IX) is reacted with a compound (X) in Ν, Ν-dimethylformamide, methylene chloride, chloroform etc. or a mixed solvent thereof using a condensing agent such as dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide at a temperature between -20 ° C and reflux temperature, preferably between about 0 ° C. C and 50 ° C for 1 hour to 48 hours, preferably for about 1 hour to 24 hours to obtain compound (XI). In this case, additives such as hydroxybenzotriazole or N-hydroxysuccinic acid imide may be added.

When the condensation reaction occurs via an acid chloride, compound (IX) is reacted with thionyl chloride, oxalyl chloride etc. in chloroform, methylene chloride, tetrahydrofuran, etc. or a mixed solvent thereof to obtain an acid chloride of (IX) and it is reacted with a compound (X) in toluene, chloroform, tetrahydrofuran or a mixed solvent thereof in the presence of a base such as triethylamine or pyridine at a temperature between -20 ° C and the reflux temperature, preferably from about 0 ° C to 40 ° C for 0.5 hour to 24 hours, preferably for about 0.5 hour to 12 hours to obtain compound (XI). Eighth stage

This is a step for deprotecting the hydroxyl protecting group of compound (XI) and obtaining a compound represented by the general formula (1).

For example, when R 'is an acetyl group, the compound represented by the general formula (1) may be obtained by reacting compound (XI) in tetrahydrofuran, ethanol, methanol, isopropanol, water or a mixed solvent thereof. presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide or potassium carbonate at a temperature between -20 ° C and reflux temperature, preferably between about 0 ° C and 40 ° C by 0 ° C, 5 hour to 24 hours, preferably 0.5 hour to 12 hours.

When R 'is a methoxymethyl group, a methoxyethoxymethyl group, a tetrahydropyranyl group or an acetyl group, the compound represented by the general formula (1) may be obtained by reaction of compound (XI) without solvent or in methanol water, ethanol, propanol, tetrahydrofuran, etc. or a mixed solvent thereof using an acid such as hydrochloric acid or trifluoroacetic acid at a temperature between 0 ° C and reflux temperature, preferably between 0 ° C and 50 ° C by 0.5 hour to 24 hours, preferably 0.5 hour to 8 hours.

When R 'is a benzyl group, the compound represented by the general formula (1) may be obtained by reacting compound (XI) in methanol, ethanol, propanol, tetrahydrofuran, etc. or a mixed solvent thereof using hydrogen or ammonium formate in presence of a palladium and carbon based catalyst, etc. at a temperature between about 0 ° C and the reflux temperature, preferably between about 20 ° C and 50 ° C for 0.5 hour to 96 hours preferably 1 hour to 48 hours.

Therefore, the compounds represented by the general formulas (I) to (XI) mentioned above are useful as intermediates for producing the compound of the present invention represented by the general formula (1).

2. Preparation Method B:

This is a method for preparing the compound of the present invention represented by the general formula [1] which is conducted directly from compound (VIII) without protecting the hydroxyl group.

(where each symbol is the same as above.)

The compound of the present invention represented by the general formula [1] can be obtained by reacting compound (VIII) with a compound (X) in Ν, Ν-dimethylformamide, methylene chloride, chloroform, etc. or a mixed solvent thereof using a condensing agent such as dicyclohexyl carbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide at a temperature between -20 ° C and reflux temperature, preferably between about 0 ° C. ° C and 50 ° C for 1 hour to 48 hours, preferably for about 1 hour to 24 hours. In this case, an additive such as hydroxybenzotriazole or N-hydroxysuccinic acid may be added.

3. Method of Preparation C

The salt of the compound of the present invention represented by the general formula [1] may be prepared according to a usual method, for example as follows:

The compound of the present invention represented by the general formula [1] is dissolved or suspended in a solvent (e.g. water, methanol, ethanol, isopropyl alcohol, acetone, 2-butanone, tetrahydrofuran, ethyl acetate, isobutyl acetate, diethyl ether, diisopropyl ether, tolene, n-hexane, n-heptane or a mixed solvent thereof) and supplemented with a solid, undiluted or diluted solution form (such as a dilution solvent, for example water, methanol, ethanol, isopropyl alcohol, acetone , 2-butanone, tetrahydrofuran, ethyl acetate, isobutyl acetate, diethyl ether, diisopropyl ether, tolene, n-hexane, n-heptane or a mixed solvent thereof) (for example hydrochloric acid, hydrobromic acid, acid sulfuric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, fumaric acid or maleic acid, etc.), and the mixture may be stirred or allowed to stand at a temperature of from -20 ° C to reflux temperature, preferably from about 0 ° C to 50 ° C for 1 hour to 48 hours. preferably for about 1 hour to 24 hours to obtain the salt of the compound of the present invention represented by the general formula [1].

[Examples]

In the following, the production of a compound of the present invention will be specifically described with reference to the examples. However, the present invention is not intended to be limited to these examples. NMR data for each compound produced are described together with them. [Example 1-1]

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-N- (4-tert-butoxy-3,5-difluorphenyl) -3,4-dihydro-2H-benzof1.41oxazine-production 8-carboxamide:

First step

Methyl 3-nitrosalicylate production;

3-Nitrosalicylic acid (500 g) was dissolved in methanol (2.25 l), concentrated sulfuric acid (0.25 l) was added, and the mixture was refluxed for 22 hours. The reaction solution was cooled on ice, and the precipitated solid was collected by filtration and dried to obtain the title compound (517.3 g). (400 MHz1 DMSO-d6): 3.95 (s, 3H), 7.16 (t, J = 8.1 Hz, 1H), 8.11 (dd, J = 7.9, 1.9 Hz, 1H), 8.21 (dd, J = 8.3, 1.9 Hz, 1H), 11.49 (s, 1H).

Second stage

Production of methyl 2- (2-methoxyethoxy) methyloxy-3-nitrobenzoate;

Methyl 3-nitrosalicylate (516.3 g) obtained in the previous step was dissolved in N, N-dimethylformamide (2.0 I), potassium carbonate (362 g) was added, 1-chloromethoxy-2-methoxyethane (0.329 I) was further added with ice-cooling stirring, and the mixture was stirred at room temperature for 1 hour. The reaction solution was partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with water and then concentrated to obtain the title compound (706.9 g).

(400 MHz, DMSO-d 6): 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 = 7.9 Hz, 1H), 8.06 (dd, J = 7.9, 1.8 Hz, 1H), 8, 11 (dd, J = 7.9, 1.8 Hz, 1H).

Third stage

Production of methyl 3-amino-2- (2-methoxyethoxy) methyloxybenzoate;

Methyl 2- (2-methoxyethoxy) methyloxy-3-nitrobenzoate (704.5 g) obtained in the previous step was dissolved in ethyl acetate (1 I) and tetrahydrofuran (1 I), 5% palladium on carbon (water content 50 %) (35 g) was added, and the mixture was stirred for 4 hours in a hydrogen atmosphere. The obtained reaction solution was filtered, and the filtrate was concentrated to obtain the title compound (617.7 g).

(400 MHz, DMSO-d 6): 3.24 (s, 3H), 3.46-3.48 (m, 2H), 3.78-3.79 (m, 5H), 4.98 (s, 2Η), 5.16 (s, 2Η), 6.84-6.84 (m, 1Η), 6.88-6.91 (m, 2Η).

Fourth Stage

Production of methyl 3- (5-picoline-2-yl) aminosalicylate;

Cesium Carbonate (415 g), Palladium Acetate (8.8 g), 2,2'-Bis (diphenylphosphino) -1,1'-Binaftyl (25 g), Methyl 3-amino-2- (2-methoxyethoxy) ) methyloxybenzoate (200 g) obtained in the previous step, and 2-chloro-5-picoline (103 g) were added to toluene (1 I) in that order and the mixture was stirred at 100 ° C for 2 days. The reaction solution was filtered, and the filtrate was concentrated. Methanol (500 mL) and 6 N hydrochloric acid (200 mL) were added to the residue, and the mixture was refluxed and stirred for 0.5 hour. Active charcoal (25 g) was added to the reaction solution, and the mixture was stirred for 1 hour and then filtered. 1 N potassium citrate (2 L) was added to the filtrate, and the precipitated crystal was collected by filtration (218 g). The crystal collected by filtration was dissolved in ethyl acetate (1 L) and supplemented with silica gel (100 g), and the mixture was stirred at room temperature and then filtered. The filtrate was concentrated. The residue was recrystallized from acetone: water (2: 1) (2 l), and the crystal was filtered and dried to obtain the title compound (128 g).

(400 MHz, DMSO-d 6): 2.18 (s, 3H), 3.92 (s, 3H), 6.89 (t, J = 8.0 Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 7.35 (dd, J = 7.9, 1.5 Hz, 1H), 7.42 (dd, J = 8.4, 2.4 Hz, 1H), 7 , 98 (s, 1H), 8.19 (s, 1H), 8.48 (dd, J = 8.2, 1.5 Hz, 1H), 11.30 (s, 1H).

Fifth step

Production of methyl (R) -2- (oxirane-2-ymethyloxy-3- (5-picoline-2-yaminobenzoate);

Methyl 3- (5-picolin-2-yl) aminosalicylate (139.5 g) obtained in the previous step and glycidyl (R) -nosylate (139.7 g) were dissolved in dimethyl sulfoxide (700 ml), carbonate Potassium salt (74.6 g) was added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (1l) was added to the reaction solution, and the mixture was filtered. The filtrate was washed with water, and then dried over anhydrous sodium sulfate and then concentrated. The residue was suspended in 2-propanol (400 mL), and the suspension was stirred at room temperature and crystallized. The crystal was collected by filtration and dried to obtain the title compound (124 g). (400 MHz, DMSO-d 6): 2.19 (s, 3H), 2.76 (q, J = 2.6 Hz, 1H), 2.86 (dd, J = 5.0, 4.3 Hz 1H), 3.40-3.41 (m, 1H), 3.86 (s, 3H), 3.93 (q, J = 5.7 Hz, 1H), 4.16 (dd, J = 11.2, 2.6 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H), 7.24 (dd, J = 7.7, 1.8 Hz, 1H), 7.46 (dd, J = 8.5, 2.3 Hz, 1H), 8.01 (d, J = 2.2 Hz1 1H), 8.19 (s, 1H), 8.53 (dd, J = 8.2, 1.8 Hz, 1H). Sixth step

Production of (S) -methyl 4- (5-picoline-2-yl) -3-hydroxymethyl-3,4-dihydro-2H-benzoM.41oxazine-8-carboxylate;

Methyl (R) -2- (oxiran-2-yl) methyloxy-3- (5-picoline-2-yl) aminobenzoate (124 g) obtained in the previous step was dissolved in N, N-dimethylacetamide (1.24 I) Potassium carbonate (81.8 g) was added, and the mixture was stirred at 100 ° C for 2 hours. The reaction solution was partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with water, and then dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (142.1 g).

(400 MHz, DMSO-d 6): 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 = 10.8 Hz, 1H), 5.15 (t , J = 5.4 Hz, 1H), 6.84 (t, J = 7.9 Hz, 1H), 7.17-7.18 (m, 2H), 7.35 (d, J = 8, 2 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 8.15 (s, 1H). Seventh step

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-3,4-dihydro-2H-benzoyl 1,441oxazine-8-carboxylic acid production: (S) -methyl 4- (5-picoline-2 -yl) -3-hydroxymethyl-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylate (142 g) obtained in the previous step was dissolved in methanol (700 ml), sodium hydroxide a 4 N (150 mL) was added, and the mixture was refluxed and stirred for 2 hours. The reaction solution was concentrated, neutralized with 6 N hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and then concentrated. Ethyl acetate (50 mL) and diisopropyl ether (400 mL) were added to the residue, and the precipitated solid was filtered and dried to obtain the title compound (101.6 g). (400 MHz1 DMSO-d6): 2.23 (s, 3H), 3.38 (t, J = 9.9 Hz 1H), 3.59 (dd, J = 10.6, 5.7 Hz, 1H ), 3.98 (dd, J = 10.8, 2.6 Hz, 1H), 4.37-4.39 (m, 1H), 4.55 (dd, J = 10.9, 1.2 Hz, 1H), 5.14 (br s, 1H), 6.82 (t, J = 7.9 Hz, 1H), 7.16-7.18 (m, 2H), 7.32 (dd, J = 8.2, 1.5 Hz, 1H), 7.53 (dd, J = 8.4, 2.4 Hz, 1H), 8.14-8.14 (m, 1H), 12.66 (br s, 1H).

Eighth stage

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-N- (4-tert-butoxy-3,5-difluorphenyl) -3,4-dihydro-2H-benzo [1, 4] oxazine-8-carboxamide:

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid (400 mg) obtained in the previous step was dissolved in N, N-dimethylformamide (2 ml). 4-tert-Butoxy-3,5-difluoraniline (268 mg), 1-hydroxybenzotriazole (204 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (281 mg) were added in this order and the mixture it was stirred for one night at room temperature. Water and a saturated sodium bicarbonate solution were added to the reaction solution and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 4: 3) to obtain the title compound (364 mg).

[Example 1 -2]

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-N- (3,5-difluoro-4-isopropoxyphenyl) -3,4-dihydro-2H-benzo [1, 4] oxazine-8-carboxamide;

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid (400 mg) obtained in the seventh step of Example ple 1-1 was dissolved in α-β-dimethylformamide (2 ml). 3,5-Difluoro-4-isopropoxyaniline (249 mg), 1-hydroxybenzotriazole (204 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (281 mg) were added in this order and the mixture was stirred for one night at room temperature. Water and a saturated sodium bicarbonate solution were added to the reaction solution and then extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel chromatography (hexane.ethyl acetate = 4: 3) to obtain the title compound (332 mg).

[Example 1-3]

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-N- (3,5-difluoro-4-ethoxyphenyl) -3,4-dihydro-2H-benzo [1,4] production oxazine-8-carboxamide;

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid (400 mg) obtained in the seventh step of the Example 1-1 was dissolved in N, N-dimethylformamide (2 mL). 3,5-Difluoro-4-ethoxyaniline (230 mg), 1-hydroxybenzotriazole (204 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (281 mg) were added in this order and the mixture was stirred for one night at room temperature. Water and a saturated sodium bicarbonate solution were added to the reaction solution and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 5: 4) to obtain the title compound (358 mg).

[Example 1 -4]

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-N- [2- (2,2-dimethylproDyloxy) pyridin-5-yl1,4,4-dihydro-2H-benzo [ 1,4] oxazine-8-carboxamide;

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid (300 mg) obtained in the seventh step of Example Pio 1-1 was dissolved in N, N-dimethylformamide (3 ml). 5-Amino-2- (2,2-dimethylpropyloxy) pyridine hydrochloride (253 mg), triethylamine (0.14 ml) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (211 mg) were added in this order and the mixture was stirred overnight at room temperature. Water and a saturated sodium bicarbonate solution were added to the reaction solution and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel chromatography to obtain the title compound (340 mg).

[Example 1 -5]

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-N- (2-tert-butoxypyridin-5-yl) -3,4-dihydro-2H-benzo [4,1] production oxazine-8-carboxamide:

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid (148 mg) obtained in the seventh step of Example ple 1-1 was dissolved in α-β-dimethylformamide (5 ml). 5-Amino-2-tert-butoxypyridine (82 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (103 mg) were added in this order and the mixture was stirred overnight at room temperature. . Water and a saturated sodium bicarbonate solution were added to the reaction solution and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated. The obtained residue was purified by silica gel chromatography (ethyl hexanoracetate = 1: 1) to obtain the title compound (94 mg).

[Example 1-6]

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-N- [2- (2,2,2-trifluoroethyl) pyridin-5-yl] -3,4-dihydro-2H production benzo [1,4] oxazine-8-carboxamide;

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid (150 mg) obtained in the seventh step of Example ple 1-1 was dissolved in α-β-dimethylformamide (1.5 ml). 5-Amino-2- (2,2,2-trifluoroethyl) pyridine hydrochloride (114 mg), triethylamine (0.07 ml) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (105 mg) were added in this order and the mixture was stirred overnight at room temperature. Water and a saturated sodium bicarbonate solution were added to the reaction solution and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated. The obtained residue was purified by silica gel chromatography (ethyl hexane noracetate = 1: 1) to obtain the title compound (154 mg). [Example 1-7]

Production of (S) -4- (5-picoline-2H0-3-hydroxymethyl-N- (2-isobuttoxypyridin-5-yl) -3,4-dihydro-2H-benzof 1,41oxazine-8-carboxamide;

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid (388 mg) obtained in the seventh step of the Example 1-1 was dissolved in N, N-dimethylformamide (4 mL). 5-Amino-2-isobutoxypyridine hydrochloride (262 mg), triethylamine (0.18 ml) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (272 mg) were added in this order and the mixture was stirred for one night at room temperature. Water and a saturated sodium bicarbonate solution were added to the reaction solution and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain the title compound (402 mg).

[Example 1-8]

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-N- [3,5-difluoro-4- (2.2.2-trifluorooxy) phenyl1-3.4-dihydro-2H-benzo [Production of] 1,41oxazine-8-carboxamide;

First step

(S) -3-Acetoxymethyl-4- (5-picoline-2-yn-3,4-dihydro-2H-benzoyl41.oxoxin-8-carboxylic acid production).

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid (24.1 g) obtained in the seventh step of Example 1-1 was dissolved in tetrahydrofuran (240 ml). 4- (Dimethylamino) pyridine (9.8 g) and acetic anhydride (7.6 ml) were added and the mixture was stirred at room temperature for 0.5 hour. The reaction solution was partitioned between ethyl acetate and a dilute citric acid solution, and the ethyl acetate layer was washed with water, and then dried over anhydrous magnesium sulfate and concentrated. Diisopropyl ether was added to the concentrated residue, and the precipitated crystal was collected by filtration and dried to obtain the title compound (23.33 g). (400 MHz, DMSO-d 6) 1.99 (s, 3H), 2.23 (s, 3H), 4.03-4.11 (m, 2H), 4.18-4.21 (m, 1 Δ), 4.48 (d, J = 11.25 Hz, 1Η), 4.72-4.74 (m, 1H), 6.86 (dd, J = 7.61, 7.61 Hz, 1H ), 7.17-7.20 (m, 2H), 7.33 (dd, J = 8.16, 0.88 Hz, 1H), 7.54 (dd, J = 8.49, 2.32 Hz, 1H), 8.15 (d, J = 1.54 Hz, 1H), 12.64 (br s, 1H).

Second stage

(S) -3-Acetoxymethyl-4- (5-picoline-2-yn-N- [3,5-difluoro-4- (2,2,2-trifluorooxy) phenyl] 3,4-dihydro-2H production -benzoi [1,4] oxazine-8-carboxamide:

(S) -3-Acetoxymethyl-4- (5-picoline-2-yl) -3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid (400 mg) obtained in the previous step was dissolved In tetrahydrofuran (4 mL), thionyl chloride (0.102 mL) was added with stirring with ice cooling, and the mixture was stirred for 1.5 hours. The reaction solution was concentrated, and the residue was diluted with tetrahydrofuran (4 mL). Triethylamine (0.245 mL) and 3,5-difluoro-4- (2,2,2-trifluorooxy) aniline (267 mg) were added with stirring at room temperature and the mixture was stirred for 0.5 hour. The reaction solution was partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (749 mg). . (400 MHz, DMSO-d 6) 1.99 (s, 3H), 2.25 (s, 3H), 4.12-4.16 (m, 2H), 4.22-4.25 (m, 1H ), 4.52 (d, J = 11.25 Hz, 1H), 4.75-4.77 (m, 3H), 6.93 (dd, J = 7.94, 7.94 Hz, 1H) , 7.12 (d, J = 7.72 Hz, 1H), 7.19 (d, J = .8.60 Hz, 1H), 7.36 (d, J = 8.16 Hz, 1H), 7.56-7.58 (m, 3H), 8.17 (d, J = 1.54 Hz, 1H), 10.47 (s, 1H).

Third stage

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-N-η 3 -5-difluoro-4- (2.2.2-trifluorooxy) phenin-3,4-dihydro-2H-benzon.41oxazine production -8-carboxamide:

(S) -3-Acetoxymethyl-4- (5-picoline-2-yl) -N- [3,5-difluoro-4- (2,2,2-trifluorooxy) phenyl] -3,4-dihydro-2H -benzo [1,4] oxazine-8-carboxamide (749 mg) obtained in the previous step was dissolved in methanol (4 ml), 4 N sodium hydroxide (0.35 ml) was added, and the mixture was stirred at room temperature. room temperature for 0.5 hour. The reaction solution was concentrated and then partitioned between water and ethyl acetate, and the obtained ethyl acetate layer was washed with saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate and concentrated. . The residue was purified by silica gel chromatography to obtain the title compound (340 mg).

[Example 1 -9]

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-N- [3,5-difluoro-4- (2-hydroxy-2-methylpropyloxy) phenyl) -3,4-dihydro production -2H-benzo [1,4] oxazine-8-carboxamide;

First step

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-N- (3,5-difluoro-4-hydroxyphenyl) -3,4-dihydro-2H-benzon production [1,4] oxazine-8-carboxamide;

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid (900 mg) obtained in the seventh step of Example ple 1-1 was dissolved in α-β-dimethylformamide (4.5 ml). 3,5-Difluoro-4-hydroxyaniline (330 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (630 mg) were added in this order and the mixture was stirred overnight at room temperature. . Water and a saturated sodium bicarbonate solution were added to the reaction solution and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel chromatography (hexane.ethyl acetate = 1: 1) to obtain the title compound (550 mg).

(400 MHz, DMSO-d 6) 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 = 9.74 Hz, 1H), 5.15 (br s, 1H), 6.89 (dd , J = 7.88, 7.88 Hz, 1H), 7.10 (dd, J = 7.65, 1.62 Hz, 1H), 7.21 (d, J = 8.35 Hz, 1H) 7.34 (dd, J = 8.12, 1.62 Hz, 1H), 7.46-7.49 (m, 2H), 7.56 (dd, J = 8.35, 1.86 Hz , 1H), 8.17 (dd, J = 1.16, 1.16 Hz, 1H), 9.91 (br s, 1H), 10.23 (SiH).

Second stage

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-N- [3,5-difluoro-4- (ethoxycarbonylmethyloxy) phenyl] -3,4-dihydro-2H-benzol production [1,4] oxazine-8-carboxamide:

(S) -4- (5-picoline-2-yl) -3-hydroxymethyl-N- (3,5-difluoro-4-hydroxyphenyl) 3,4-dihydro-2H-benzo [1,4] oxazine 8-Carboxamide (459 mg) obtained in the previous step was dissolved in α, β-dimethylformamide (4.5 ml). Potassium carbonate (150 mg) and ethyl bromoacetate (180 mg) were added and the mixture was stirred at 60 ° C for 3 hours. The reaction solution was partitioned between water and ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 3) to obtain the title compound (310 mg).

(400 MHz, DMSO-d 6) 1.21 (t, J = 7.06 Hz1 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 = 7.06 Hz, 2H), 4.38-4.39 (m, 1H), 4.59 (d, J = 10.81 Hz, 1H), 4.79 (s, 2H), 5.12 (t, J = 5.51 Hz, 1H), 6.89 (dd, J = 7 , 83, 7.83 Hz, 1H), 7.08 (dd, J = 7.50, 1.32 Hz, 1H), 7.20 (d, J = 8.60 Hz, 1H), 7.33 (dd, J = 8.16, 1.32 Hz, 1H), 7.52-7.56 (m, 3H), 8.16 (d, J = 2.43 Hz, 1H), 10.39 ( s, 1H). Third stage

Production of (S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-N-η 3 -5-difluoro-4- (2-hydroxy-2-methylpropyloxy) phenin-3,4-dihydro-2H-benzon Oxoxazine-8-carboxamide;

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-N- [3,5-difluoro-4- (ethoxycarbonylmethyloxy) phenyl] -3,4-dihydro-2H-benzo [1,4 ] oxazine-8-carboxamide (310 mg) obtained in the previous step was dissolved in tetrahydrofuran (3.1 ml), and methyl lithium (0.98 M solution of tetrahydrofuran) (3.7 ml) was added dropwise with stirring. with ice cooling and then and the mixture was stirred for 1.5 hours. The reaction solution was poured into a 5% citric acid solution and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 3) to obtain the title compound (72 mg). [Example 1-10]

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-N- [3,5-difluoro-4- (1,1-dimethyl-2-hydroxyethyloxy) phenyl1-3,4-dihydro-2H-production benzon.41oxazine-8-carboxamide; First step

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-N- [3,5-difluoro-4- (1-ethoxycarbonyl-1-methyl) ethyloxyphenyl-3- dihydro-2H-benzo [1.41oxazine-8-carboxamide; (S) -4- (5-picoline-2-yl) -3-hydroxymethyl-N- (3,5-difluoro-4-hydroxyphenyl) 3,4-dihydro-2H-benzo [1,4] oxazine 8-Carboxamide (780 mg) obtained in the first step of Example 1-9 was dissolved in dimethyl sulfoxide (7.8 ml). Potassium carbonate (240 mg) and ethyl 2-bromo-2-methylpropionate (0.279 ml) were added and the mixture was stirred at 80 ° C for 1 hour. The reaction solution was partitioned between water and ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain the title compound (740 mg).

(400 MHz, DMSO-d 6) 1.24 (t, J = 7.19 Hz, 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 = 7.11 Hz, 2H), 4.39 -4.41 (m, 1H), 4.60 (d, J = 10.20 Hz, 1H), 5.15 (t, J = 5.57 Hz, 1H), 6.90 (dd, J = 7.88, 7.88 Hz, 1H), 7.09 (dd, J = 7.42, 1.39 Hz, 1H), 7.22 (d, J = 8.81 Hz, 1H), 7, 35 (dd, J = 8.12, 1.62 Hz, 1H), 7.53-7.57 (m, 3H), 8.17-8.17 (m, 1H), 10.47 (s, 1H).

Second stage

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-N- [3,5-difluoro-4- (1-carboxy-1-methyl) ethyloxyphenyl] -3,4-dihydro production -2H-benzo [1,4] oxazine-8-carboxamide:

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-N- [3,5-difluoro-4- (1-ethoxycarbonyl-1-methyl) ethyloxyphenyl] -3,4-dihydro -2H-benzo [1,4] oxazine-8-carboxamide (740 mg) obtained in the previous step was dissolved in ethanol (7.4 ml), a 4 N solution of sodium hydroxide (0.38 ml). was added, and the mixture was stirred overnight at room temperature. The reaction solution was poured into a 5% citric acid solution and extracted with tetrahydrofuran. The tetrahydrofuran layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated to obtain the title compound (586 mg).

(400 MHz, DMSO-d 6) 1.45 (s, 6H), 2.25 (s, 3H), 3.45 (dd, J = 9.97, 9.97 Hz, 1H), 3.63- 3.64 (m, 1H), 4.06-4.08 (m, 2H), 4.38-4.41 (m, 1H), 4.59 (d, J = 10.20 Hz, 1H) 6.90 (dd, J = 7.88, 7.88 Hz, 1H), 7.09 (dd, J = 7.65, 1.62 Hz, 1H), 7.21 (d, J = 8 , 81 Hz, 1H), 7.35 (dd, J = 8.12, 1.62 Hz, 1H), 7.53-7.56 (m, 3Η), 8.17 (dd, J = 1, 16, 0.58 Hz, 1Η), 10.45 (s, 1Η), 12.94 (brs, 1Η). Third stage

(S) -4- (5-Picoline-2-yl) -3-hydroxymethyl-N-f3,5-difluoro-4- (1,1-dimethyl-2-hydroxyethyloxy) phenin-3,4-dihydro-2H-benzon production .41oxazine-8-carboxamide: Triethylamine (0.191 mL), ethyl chlorocarbonate (0.131 mL) and then a suspension of (S) -4- (5-picoline-2-yl) -3-hydroxymethyl-N- [ 3,5-difluoro-4- (1-carboxy-1-methyl) ethyloxyphenyl] -3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide (586 mg) obtained in the previous step in tetrahydrofuran ( 5.9 ml) was added to tetrahydrofuran (3 ml) with ice-cooling stirring and the mixture was stirred at room temperature for 1 hour. The reaction solution was cooled on ice and sodium borohydride (43 mg) and methanol (5.9 ml) were added. The reaction solution was poured into a 10% ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1) to obtain the title compound (136 mg).

The chemical structures and NMR data of the compounds obtained in Examples 1-1 to 1-10 are shown in Table 1 and Table 2.

[Table 1]

<table> table see original document page 50 </column> </row> <table> <table> table see original document page 51 </column> </row> <table> <table> table see original document page 52 < / column> </row> <table>

[Table]

<table> table see original document page 52 </column> </row> <table> <table> table see original document page 53 </column> </row> <table>

Test Example

The assay for evaluating VR1 inhibition by the compounds of the present invention will be described below.

The assay was intended to evaluate in vitro an inhibitory effect on proton-induced Ca2 + cell entry, an effect of VR1 agonists (test example [1]), a hepatic S9 metabolic stability test (test example). [2]), an in vitro membrane permeability test (Test Example [3]) and a Japanese Pharmacopoeia Solution Stability Test 1 (Test Example [4]) using the compound of the present invention and the compounds comparative examples shown in Table 3 below. The compounds of the comparative examples were obtained according to the preparation method described in PCT / JP2005 / 013446. [Table 3]

<table> table see original document page 54 </column> </row> <table>

Test example [1]: inhibition of Ca2 + entry into cells.

An inhibitory effect on VR1 activity was assessed by measuring Ca2 + uptake in cells.

Rat glioma (C6BU1) cells stably expressing human VR1 were suspended in 20 mM MES buffer (at pH 6.8 containing 20 mM 2-morpholinoethanesulfonate (hereinafter referred to as MES), 115 mM NaCl, 5 mM KCl, MgCl2 1). mM and 14 mM D-glucose) to result in a cell density of 1x10 6 cells / ml. A fluorescent dye, Fura 2-AM solution (Dojindo Corporate, Cat. No. 343-05401) was added to the suspension to give a concentration of 5 μΜ. In addition, Pluronic F-127 (Wako Pure Chemical Industries, Ltd., Cat. No. P6866) was added to give a 0.1% content thereof. Then the suspension was incubated at 37 ° C for 30 minutes. Cells were harvested and washed twice with 20 mM MES buffer. The cells were resuspended to yield a cell density of 5x10 5 cells / ml. A 500 μl portion of the suspension was removed with a cuvette (MC MEDICAL, INC., Cat. No. SSR3121), to which 10 μl of the 20 mM MES buffer containing 250 mM CaCl2 was added to incorporate Ca2 + into the cells. At the same time, 5 μl of a test compound solution (in the range of 100 μΜ to 10 nM in DMSO) were also added to a final concentration of the same in the range of 1 μΜ to 0.1 nM. Alternatively, 5 μl DMSO was added as a control to give a final concentration of 1% DMSO. The suspension was placed on an intracellular ionometer (CAF-110; JASCO) for 10 minutes after these additions. Cells were stimulated with protons by adding 40 µl of 20 mM MES buffer at pH 1.1 to the suspension to adjust its pH to 5.7. Test compound activity was determined as the difference between the minimum fluorescence intensity before agonist stimulation and the maximum after stimulation. The IC 50 value was derived from the percent inhibition by the test compound compared to the control.

Test Example [21: Liver S9 metabolic stability test.

Human liver S9 (final concentration: 2 mg protein / ml) was suspended in 100 mM potassium phosphate buffer (at pH 7.4 which contained β-nicotinamide adenine dinucleotide phosphate: 1.3 mM, D-glucose- 6-phosphate: 3.3 mM, magnesium chloride: 3.3 mM and glucose-6-phosphate dehydrogenase: 0.45 U / ml) and was further mixed with the test compound dissolved in DMSO. The mixture was incubated at 37 ° C for 0 and 60 minutes and then supplemented with acetonitrile containing formic acid (0.1% final concentration). Test compound (uncharged) in a supernatant after centrifugation was measured using high performance liquid chromatography / mass spectrometry (LC / MS). A remaining ratio (%) was calculated from the measurement value obtained according to the following equation:

Remaining ratio (%) = (amount of test compound after 60 minutes incubation / amount of test compound in 0 minute incubation) x100

Test Example [31: In vitro membrane permeability test.

The test compound solution in 10 mM DMSO was diluted with Hanks buffer (pH 6.5) to 25 μΜ to make a test compound solution. 300 μΙ Apical buffer (Hanks buffer (pH 6.5)) and 1 ml Basolateral buffer (Hanks buffer containing 4.5% BSA (pH 7.4)) were added to the apical side (mucosal side) and basolateral (serous side), respectively, of Caco2 cells (cells cultured for 6 days after sowing) sown in a permeability plate (BIOCOAT HTS Caco2 Assay system: BD Biosciences) and preincubated at 37 ° C ° C for 20 minutes, followed by measurement of a transepithelial electrical resistance value. Each plug on the apical and basal side was removed by aspiration. Then 300 μΙ of the test compound solution and 1 ml of the Basolateral Buffer were added to the apical and basolateral sides, respectively, and incubated at 37 ° C for 2 hours with shaking at 60 rpm. Then, a sample was collected from the apical and basolateral sides, and the sample was supplemented with acetonitrile and centrifuged. Test compound (uncharged) in the supernatant was measured using high performance liquid chromatography / tandem mass spectrometry (LC / MS / MS: Quantum, Thermo Quest).

A membrane permeability coefficient (Papp) was calculated according to the following equation:

Papp (cm / sec) = (dx / dt) / (AxC0) (where dx is the amount of test compound (uncharged) on the basolateral side after incubation, dt is the incubation time, A is the super area - Cell membrane membrane, and C0 is the initial concentration of the test compound on the apical side.)

Test Example [41: Japanese Pharmacopoeia Solution Stability Test 1.

The test compound was dissolved in a mixed solution of CH3CN and Japanese Pharmacopoeia 1 solution (3: 7 volume ratio) and adjusted in an HPLC flask to a concentration of 0.05 mM. The test compound was measured by HPLC at 40 ° C after 0 and 8 hours. The 0 hour measurement value was set to 100% to determine the remaining proportion of the test compound after 8 hours.

The "Japanese Pharmacopoeia Solution 1" represents a solution of 21 ml of concentrated hydrochloric acid added to 6 g of sodium chloride and further adjusted to 3 l with distilled water.

The results of the inhibitory effect on Ca2 + entry into cells (Test Example [1]), Liver S9 Metabolic Stability Test (Test Example [2]) and Membrane Permeability Test (In vitro Example [3]) are shown in Tables 4 to 6 below.

[Table 4]

<table> table see original document page 57 </column> </row> <table> <table> table see original document page 58 </column> </row> <table>

[Table 5]

<table> table see original document page 58 </column> </row> <table> <table> table see original document page 59 </column> </row> <table>

[Table 6] <table> table see original document page 59 </column> </row> <table> <table> table see original document page 60 </column> </row> <table>

[1] Discussion of test result of inhibitory effect on Ca2 + entry into cells (Test Example [1]).

IC50 values of the compounds of examples 1-1 to 1-10 included in the compound of the present invention represented by the general formula [1] were, as shown in Tables 4 to 6, 0.024 nM, 0.038 nM, 0.24 nM 0.019 nM, 0.66 nM, 0.15 nM, 0.14 nM, 0.038 nM, 0.54 nM and 0.69 nM, respectively, and the mean IC50 value of these ten compounds was 0.25. No.

Particularly the compounds of examples 1-1, 1-2, 1-4 and 1-8 had IC50 values of 0.024, 0.038, 0.019 and 0.038, respectively, and had an excellent inhibitory effect on VR1 activity.

On the other hand, IC50 values of the compounds of comparative examples 1 to 13 were, as shown in Tables 4 to 6, 3 nM, 1.3 nM, 18 nM, 5.2 nM, 42.0 nM, 0.3 nM, 0.4 nM, 7 nM, 0.12 nM, 0.04 nM, 0.36 nM, 0.03 nM and 0.12 nM, respectively ^ and the mean IC50 value of these thirteen compounds from the comparative examples was of 5.99 nM.

As described above, the compound of the present invention had inhibitory activity about 24 times greater than that of the comparative examples in terms of the average IC 50 values.

[2] Discussion of the outcome of the human liver S9 metabolic stability test (Test example [2]).

The remaining ratios of human liver S9 of the compounds of examples 1-1 to 1-10 included in the compound of the present invention represented by the general formula [1] were, as shown in Tables 4 to 6, 90.8%. 65.3%, 59.6%, 39.7%, 82.2%, 91.8%, 50.4%, 91.5%, 77.3% and 92.2%, respectively, and the The average remaining proportion of human liver S9 of these ten compounds was 74%. Particularly the compounds of examples 1-1, 1-6, 1-8 and 1-10 had remnant ratios of 90% or more and had remarkably high remnant proportions, i.e., remarkably high metabolic stability in liver S9. . Therefore, such compounds will be useful as remarkably excellent drugs in that they can resist oxidative metabolism and have the sustainability of effect.

On the other hand, the remaining proportion of human liver S9 of the compounds of comparative examples 1 to 13 were, as shown in Tables 4 to 6, 86.3%, 90.1%, 89.4%, 92 , 5%, 64.9%, 77.3%, 55.1%, 62.9%, 65.9%, 82.3%, 66.7%, 54.5% and 91.3%, respectively , and the average remaining proportion of these thirteen compounds from the comparative examples was 75%.

[3] Discussion of the result of the in vitro membrane permeability test (Test example [3]).

The in vitro membrane permeability of the compounds of examples 1-1 to 1-10 included in the compound of the present invention represented by the general formula [1] was, as shown in Tables 4 to 6, 8.59x10-6, 20.96x10-6, 26.93x10-6, 30.25x10-6, 38.07x10-6, 37.53x10-6, 37.94x10-6, 13.61x10-6, 50.36x10-6 and 39, 22x10-6, respectively, in terms of Papp values (cm / sec), and the mean Papp value (cm / sec) of these ten compounds was 30.35x10-6.

Particularly the compounds of examples 1-2 to 1-10 had a membrane permeability of 10x10-6 (cm / sec) or more and showed remarkably high membrane permeability. Therefore, these compounds have extraordinarily excellent properties as drugs because they have not only excellent IC 50 values but also high absorbability which is imperative to be used as a drug in practice.

On the other hand, the Papp values (cm / sec) of the compounds of comparative examples 1 to 13 were, as shown in Tables 4 to 6, 27.1x10-6, 24.2x10-6, 25.6x10-6, 5 , 3x10-6, 7.9x10-6, 21.1x10-6 18.2x10-6, 43.1x10 "6, 19.4x10'6, 6.7x10" 6, 40.3x10 "6, 10.4x10 6 and 28.6x10-6, respectively, and the mean Papp value (cm / sec) of these thirteen compounds from the comparative examples was 21.38x10-6.

As described above, the compound of the present invention had membrane permeability about 1.4 times greater than those of the compounds of the comparative examples in terms of average Papp values.

[4] Discussion of the stability test result in the Japanese Pharmacopoeia solution 1 (Test Example f41);

In the stability test in the Japanese Pharmacopoeia 1 solution, the remaining proportions of the compounds of examples 1-6 and 1-8 included in the compound of the present invention represented by the general formula [1] were 100 and 101%, respectively. On the other hand, the remaining proportion of the compound of Comparative Example 13 was 62.1%.

As the Japanese Pharmacopoeia 1 solution is assumed to have a pH equal to that of gastric acid, it is generally known that stability in this solution suggests stability in the gastric juice.

Therefore, such compounds, compared to the compound of Comparative Example 13, will be useful as excellent drugs in that they can be stable in the gastric juice.

[5] Summary.

(1) About the value of ICsn;

According to the document (J Pharmacol Exp Ther. 2003 Jul; 306 (1): 377-86), it is known that BCTC, which is known as a substance that inhibits VR1 activity, has its inhibitory activity (IC50 value). of several nM. In addition, we have also confirmed in our tests that the BCTC IC50 value is several nM.

All IC50 values of the compound of the present invention, specifically the compounds of the present examples 1-1 to 1-10 are less than 1 nM.

On the other hand, of the compounds of the comparative examples, seven compounds of the comparative examples 6, 7, 9, 10, 11, 12 and 13 had IC 50 values of less than 1 nM. However, these seven compounds from the comparative examples were not necessarily satisfactory in all things considered, for reasons such as the fact that they have remnant ratios of less than 80% in the liver S9 metabolic stability test and / or of Papp less than 10x10-6 corresponding to membrane permeability or having less stability in the gastric juice.

(2) About metabolic stability in S9 of human liver.

Metabolic stability is one of the important requirements for a drug, and those with 80% or more metabolic stability are preferred. The compounds of examples 1-1, 1-6, 1-8 and 1-10 had remnant ratios of 90% or more and had remarkably high remnant ratios, that is, remarkably high metabolic stability in liver S9.

On the other hand, the compounds of comparative examples 1, 2, 3, 4, 10, 13, etc. also showed excellent metabolic stability. Therefore, the compounds of comparative examples 1, 2, 3 and 4 had IC 50 values of 1 nM or more and were unsatisfactory in terms of inhibitory activity. The compound of comparative example 10 had a Papp value of 6.7x10-6 and was not satisfactory in terms of membrane permeability. In addition, the compound of comparative example 13 had lower gastric juice stability and was not necessarily satisfactory.

(3) About the result of the membrane permeability test.

With respect to membrane permeability, the compound of the present invention had membrane permeability about 1.4 times greater than those of the compounds of the comparative examples in terms of average Papp values, as described above. Particularly the compounds of examples 1-4, 1-5, 1-6, 1-7, 1-9 and 1-10 had membrane permeability of 30x10-6 or more in terms of Papp values.

On the other hand, of the comparative examples compounds, the comparative examples 8 and 11 compounds had high membrane permeability. However, the compound of Comparative Example 8 had an IC 50 value of 7 nM corresponding to inhibitory activity and was unsatisfactory in terms of inhibitory activity. In addition, the compound of comparative example 11 had a remaining proportion of human liver S9 of 66.7% serving as an index of metabolic stability and was not necessarily satisfactory as a drug.

(4) Characteristics of the compound of the present invention from a chemical structure standpoint.

When the compound of comparative example 11 and the compound of example 1-2 are compared, they are different in that the former has only one fluorine atom in the phenyl group whereas the latter has two fluorine atoms. The second has an IC50 value about 10 times higher than the first.

When the compound of comparative example 8 and the compound of example 1-6 are compared, they are different only in that the former has a trifluoromethyl group as a substituent for pyridine whereas the latter has a 2,2,2-trifluorooxy group. . The second is enhanced in terms of its remaining proportion of liver S9 which is about 1.5 times higher than the former and in terms of its IC50 value which is about 50 times higher than the former.

When the compounds of comparative examples 7 and 9 and the compound of Example 1-8 are compared, the compound of Example 1-8 which has two fluorine atoms and one 2,2,2-trifluorooxy group as substituents for one group. Phenyl is different from others in that Comparative Example 7 has only one trifluoromethyl group and Comparative Example 9 simply has a fluorine atom and a trifluoromethyl group. However, the compound of Example 1-8 is enhanced in terms of its remaining proportion of liver S9 which is about 1.4 to 1.7 times greater than that of the compounds of comparative examples 7 and 9 and in terms of its IC50 value which is about 3 to 11 times greater than that of the compounds of comparative examples 7 and 9.

When the compound of comparative example 13 and the compound of example 1-1 are compared, they are different in that the former has only one fluorine atom in the phenyl group whereas the latter has two fluorine atoms. The second has an IC50 value about 5 times that of the first. This was a result that was not expected even by those skilled in the art.

The compound represented by the general formula [1], particularly the compounds of examples 1-1 to 1-10 are compounds with excellent inhibitory activity on VR1 as well as excellent liver S9 metabolic stability and / or high permeability in membrane.

Therefore, the compounds of examples 1-1 to 1-10 included in the compound represented by the general formula [1] are not only useful as remarkably excellent drugs as inhibitors of VR1 activity but also useful as remarkably excellent drugs. in the sense that they can resist oxidative metabolism and have the sustainability of the effect as well as may have high absorbability.

As a result, these compounds are not only useful as drugs of remarkably excellent efficacy as inhibitors of VR1 activity but are also expected to be used in practice as remarkably excellent drugs in that they can resist oxidative metabolism and have the sustainability of the drug. effect as well as may have high absorbability.

Industrial Applicability

The 3,4-dihydrobenzoxazine compound of the present invention effectively inhibits subtype 1 vanilloid receptor (VR1) activity, and is therefore effective in the medical treatment and / or prevention of diseases such as pain, acute pain, chronic pain. , neuropathic pain, rheumatoid arthritis-associated pain, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute herpetic pain, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative pain, cancer-associated pain, associated pain inflammation, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegenerative disease, stroke, ischemic symptom, nerve damage, neurogenic skin disorder, inflammatory disease, pruritus, allergic rhinitis, stroke, irritable bowel syndrome, asthma, lung disease chronic obstructive disease, dermatitis, mucositis, stomach and duodenal ulcer, inflamed bowel disease, bladder hypersensitivity, overactive bladder frequent urination, and overactive bladder urinary incontinence.

Claims (24)

3,4-Dihydrobenzoxazine compound, characterized in that it is represented by the following general formula [1]: <formula> formula or original pharmaceutically acceptable salt thereof wherein X is ( i) a nitrogen atom or (ii) CR3; R1 is (i) a hydrogen atom or (ii) a halogen atom; R2 is a C1-6 alkoxy group which may be substituted with 1 to 5 same or different substituents selected from the following group: (i) a halogen atom and (ii) a hydroxyl group; and R3 is a halogen atom (however, R1 is a halogen atom when X is CR3). 3,4-Dihydrobenzoxazine compound according to Claim 1, characterized in that it is selected from the following group: (a) (S) -4- (5-picolin-2-yl) -3-hydroxymethyl -N- (4-tert-butoxy-3,5-difluorphenyl) -3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide, b) (S) -4- (5-picolin-2-one) 2-yl) -3-hydroxymethyl-N- (3,5-difluoro-4-isopropoxyphenyl) -3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide, c) (S) -4 - (5-picolin-2-yl) -3-hydroxymethyl-N- (3,5-difluoro-4-ethoxyphenyl) -3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide, d ) (S) -4- (5-picolin-2-yl) -3-hydroxymethyl-N- [2- (2,2-dimethylpropyloxy) pyridin-5-yl] -3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide, e) (S) -4- (5-picolin-2-yl) -3-hydroxymethyl-N- (2-tert-butoxypyridin-5-yl) -3,4 - dihydro-2H-benzo [1,4] oxazine-8-carboxamide, f) (S) -4- (5-picolin-2-yl) -3-hydroxymethyl-N- [2- (2,2,2 -trifluoroethyloxy) pyridin-5-yl] -3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide, g) (S) -4- (5-picolin-2-yl) -3 -hydroxymethyl-N- (2-isobutoxypyridin-5-yl) -3,4-dihydro-2H-benzo [1 , 4] oxazine-8-carboxamide, h) (S) -4- (5-picolin-2-yl) -3-hydroxymethyl-N- [3,5-difluoro-4- (2,2,2-trifluorooxy ) phenyl] -3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide, i) (S) -4- (5-picolin-2-yl) -3-hydroxymethyl-N- [3] , 5-Difluoro-4- (2-hydroxy-2-methylpropyloxy) phenyl] -3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide, ej) (S) -4- (5- picolin-2-yl) -3-hydroxymethyl-N- [3,5-difluoro-4- (1,1-dimethyl-2-hydroxyethyloxy) phenyl] -3,4-dihydro-2H-benzo [1,4] oxazine-8-carboxamide, or a pharmaceutically acceptable salt thereof. 3,4-Dihydrobenzoxazine compound according to Claim 1, characterized in that it is represented by the following formula: <formula> formula see original document page 68 </formula> or a pharmaceutically acceptable salt thereof. same. 3,4-Dihydrobenzoxazine compound according to Claim 1, characterized in that it is represented by the following formula: or a pharmaceutically acceptable salt thereof. 3,4-Dihydrobenzoxazine compound according to Claim 1, characterized in that it is represented by the following formula: <formula> formula see original document page 69 </formula> or a pharmaceutically acceptable salt thereof. same. 3,4-Dihydrobenzoxazine compound according to Claim 1, characterized in that it is represented by the following formula: <formula> formula see original document page 69 </formula> or a pharmaceutically acceptable salt thereof. same. A 3,4-dihydrobenzoxazine compound according to claim 1, characterized in that it is represented by the following formula: <formula> formula see original document page 69 </formula> or a pharmaceutically acceptable salt thereof. same. Pharmaceutical composition, characterized in that it comprises a 3,4-dihydrobenzoxazine compound, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 7, and a pharmaceutically acceptable carrier. Pharmaceutical composition, characterized in that it comprises a compound of 3,4-dihydrobenzoxazine, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 7, and a pharmaceutically acceptable carrier for the treatment and / or prevention of a selected disease of pain, acute pain, chronic pain, neuropathic pain, pain associated with rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative pain, cancer-associated pain, inflammation-associated pain, interstitial cystitis, posttraumatic neuropathy, diabetic neuropathy, neurodegenerative disease, cerebral apex, ischemic symptom, nerve injury, neurogenic skin disorder, inflammatory disease, pruritus, allergic rhinitis, stroke, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, derma titis, mucositis, stomach and duodenal ulcer, inflamed bowel disease, bladder hyper-sensitivity, frequent urination, and urinary incontinence. Pharmaceutical composition, characterized in that it is for the treatment and / or prevention of pain, comprising a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 7. and a pharmaceutically acceptable carrier. Pharmaceutical composition according to claim 10, characterized in that the pain is acute pain, chronic pain, neuropathic pain, pain associated with rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, postural neuralgia. acute herpetic, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative pain, cancer-associated pain, pain associated with inflammation, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy or neurodegenerative disease. Subtype 1 vanilloid receptor (VR1) activity inhibitor, characterized in that it comprises a compound of 3,4-dihydrobenzoxazine, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 7, and a pharmaceutically acceptable vehicle. 13. Method for treating and / or preventing a selected disease of pain, acute pain, chronic pain, neuropathic pain, rheumatoid arthritis-associated pain, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, postherpetic neuralgia acute, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative pain, cancer-associated pain, pain associated with inflammation, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegenerative disease, cerebral apoplexy, ischemic symptom, nerve injury, neurogenic skin disorder, inflammatory disease, pruritus, allergic rhinitis, stroke, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, stomach and duodenal ulcer, inflamed bowel disease, bladder hypersensitivity, frequent urination and urinary incontinence, characterized by the fact that it comprises administering a pharmacologically effective a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 7. A method for treating and / or preventing pain, comprising administering a pharmacologically effective amount of a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 7. Method of treatment and / or prevention according to claim 14, characterized in that the pain is acute pain, chronic pain, neuropathic pain, pain associated with rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, pain. joint, acute postherpetic neuralgia, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative pain, cancer-associated pain, inflammation-associated pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, or neurodegenerative disease . Commercial package, characterized in that it comprises a pharmaceutical composition as defined in any one of claims 8 to 11 and written instructions concerning said pharmaceutical composition stating that said composition may be used or must be used for treatment and / or prevention of a selected disease of pain, acute pain, chronic pain, neuropathic pain, rheumatoid arthritis-associated pain, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, neuralgia postherpetic, chronic postherpetic neuralgia, postoperative pain, cancer-associated pain, inflammation-associated pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegenerative disease, cerebral apoplexy, ischemic symptom, nerve injury, neurogenic skin disorder, inflammatory disease, pruritus, allergic rhinitis, stroke, irritable bowel syndrome, asthma, p chronic obstructive ulmonary disease, dermatitis, mucositis, stomach and duodenal ulcer, inflamed bowel disease, bladder hypersensitivity, frequent urination, and urinary incontinence. Use of a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 7, characterized in that it is for the preparation of a pharmaceutical composition as defined in claim 9 for treatment and / or prevention of a selected disease of pain, acute pain, chronic pain, neuropathic pain, pain associated with rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postural neuralgia. herpetic, chronic postherpetic neuralgia, postoperative pain, cancer-associated pain, inflammation-associated pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegenerative disease, cerebral apoplexy, ischemic symptom, nerve injury, neurogenic skin disorder, inflammatory disease, pruritus, allergic rhinitis, stroke, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease , dermatitis, mucositis, stomach and duodenal ulcer, inflamed bowel disease, bladder hypersensitivity, frequent urination, and urinary incontinence. Use of a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 7, characterized in that it is for the preparation of a pharmaceutical composition for the treatment and / or pain prevention as defined in claim 10 or 11. Use of a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof according to claim 18, characterized in that the pain is acute pain, chronic pain, neuropathic pain, pain associated with rheumatoid arthritis. , neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute postherpetic neuralgia, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative pain, cancer-associated pain, inflammation-associated pain, interstitial cystitis, postoperative neuralgia. traumatic disease, diabetic neuropathy or neurodegenerative disease. A drug comprising a combination of a pharmaceutical composition comprising a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 7, and a carrier. pharmaceutically acceptable, with one or more agents selected from the group consisting of an antiviral agent, an antidepressant, an anticonvulsant, an antiarrhythmic agent, a local anesthetic, an anesthetic, an N-methyl-D-aspartate receptor antagonist , an adrenal cortical steroid, a nervous blocker, a non-steroidal antiinflammatory analgesic, a narcotic, an antagonist analgesic, a 0C2-adrenaline receptor agonist, a medicine for external use, a calcium channel antagonist, a channel blocker potassium, and an antipyretic agent. Use of a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 7, characterized in that it is for the preparation of a drug as defined in claim 20. 22. Method for treating and / or preventing a selected disease of pain, acute pain, chronic pain, neuropathic pain, rheumatoid arthritis-associated pain, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, postherpetic neuralgia acute, postherpetic neuralgia, chronic postherpetic neuralgia, postoperative pain, cancer-associated pain, pain associated with inflammation, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegenerative disease, cerebral apoplexy, ischemic symptom, nerve injury, neurogenic skin disorder, inflammatory disease, pruritus, allergic rhinitis, stroke, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, stomach and duodenal ulcer, inflamed bowel disease, bladder hypersensitivity, frequent urination, and urinary incontinence, characterized in that one or more agents selected from the group consisting of an agent an antidepressant, an anticonvulsant, an antiarrhythmic drug, a local anesthetic, an anesthetic drug, an N-methyl-D-aspartate receptor antagonist, an adrenal cortical steroid, a nervous blocker, a noninflammatory analgesic steroid, a narcotic, an antagonist analgesic, a ct2-adrenaline receptor agonist, an external medicinal product, a calcium channel antagonist, a potassium channel blocker, and an antipyretic agent are used in combination with a pharmacologically effective amount of a 3,4-dihydrobenzoxazine compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 7. A method for treating and / or preventing pain, characterized in that the method uses administering a compound of -3,4-dihydrobenzoxazine or a pharmaceutically acceptable salt thereof as defined in any one of claims. 1 to 7 in combination with analgesia produced by selected acupuncture stimulation, transcutaneous electroacupuncture stimulation therapy, transcutaneous nerve electrical stimulation therapy, silver spike point (SSP) therapy "), peripheral nerve stimulation therapy, spinal cord electrical stimulation therapy, electroconvulsive therapy, laser therapy, and low frequency therapy. A method for the treatment and / or prevention of postoperative neuralgia, characterized in that a 3,4-dihydro-benzoxazine compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 7 is administered after a selected surgical procedure for scarectomy, nerve freezing, peripheral nerve excision, spinal cord dorsal root excision, sympathectomy, destruction of the spinal cord dorsal root entry zone. , cordotomy, and frontal lobe excision.