3,4-dihydrobenzoxazine compounds and vanilloid receptor subtype 1 (vr1) inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to novel 3,4-dihydrobenzoxazine compounds of general formula [1] (where X denotes a nitrogen atom or CR3; R1 denotes a hydrogen atom or a halogen atom; R2 denotes a C1-6alkoxy group which can be substituted with 1-5 identical or different substitutes selected from a halogen atom and a hydroxyl group; and R3 denotes a halogen atom. However, R1 denotes a halogen atom when X denotes CR3). Said compounds are effective when treating diseases where activity of vanilloid receptors subtype 1 (VR1) is involved, e.g. pain.

EFFECT: more efficient use of pharmaceutical compositions based on said compounds, more effective treatment or pain killing.

19 cl, 4 tbl, 10 ex

 

The technical field

The present invention relates to novel 3,4-dihydroisoquinolin compounds that have inhibitory effects on the activity vanilloid receptor subtype 1 (VR1), and their pharmaceutically acceptable salts, pharmaceutical compositions comprising as active ingredient a specified compound or its pharmaceutically acceptable salt, and to a method of treatment and/or prevention of diseases, the occurrence of which involved vanilloid receptor subtype 1 (VR1), such as pain, acute pain, chronic pain, neuropathic pain, pain in rheumatoid arthritis, neuralgia, etc., in particular pain.

Prior art

Capsaicin, which is the main ingredient of red pepper, is an ingredient that causes a burning sensation, as well as the substance that causes pain. It was reported that many of nociceptive nerves, in particular semilinearly With fiber, have the sensitivity to capsaicin, and it is known that fibers selectively turn off when the introduction of capsaicin young rodents. It was also reported that there are many sites of action of capsaicin, distributed in the skin, cornea and mucous membrane of the mouth, and their distribution is also observed in muscles, joints and internal organs, in particular in the cardiovascular system is e, respiratory system and urinary system, and it is important for the activation of sensory nerves. In addition, sensitivity to capsaicin was observed in nerves proptional areas of the thalamus, and it is supposed to be involved in regulation of body temperature. The introduction of capsaicin leads to the observed depolarization of the incoming current of Na+and Ca2+in nociceptive nerves and to the separation of glutamic acid and neuropeptides (mainly substance P peptide associated with calcitonin gene) from the Central side end of the primary afferent fibers of the dorsal horn of the spinal cord. At the present time, when there was a specific binding activity of resiniferatoxin (RTX), which is almost similar to capsaicin effects, and was identified capsazepine as a competitive inhibitor, laboratorymy capsaicin is acting on the receptor protein (see Szallasi a, Blumberg P.M. (1999) Pharmacol. Rev. 51, 159-212 (non-patent document 1)).

Gene capsaicin receptor was cloned in 1997 (see, for example, Caterina M.J., Schumacher M.A., M. Tominaga, Posen T.A., Levine JD, Julius D. (1997) Nature 389, 816-824 (non-patent document 2)). By its amino acid sequence, it was assumed that he was an ion channel having sectarianly domain. Because capsaicin is in the structure manillow group, it refers to a type of van is lloydb along with its counterparts, such as RTX, and the cloned receptor was named vanilloid receptor subtype 1 (hereinafter referred to as VR1; this VR1 can also be called TRPV1 (transient receptor potential vanilloid 1)). Then was performed electrophysiological functional analysis using the method of fixation potential by ensuring the expression of VR1 oocytes Xenopus Laevis and human cultured cells, and found that VR1 is directly activated by capsaicin without the mediation of intracellular second informant (see, for example, Caterina M.J., Schumacher M.A., M. Tominaga, Posen T.A., Levine JD, Julius D. (1997) Nature 389, 816-824 (non-patent document 2)) and that VR1 is a non-selective cationic ion channel having a high permeability of Ca2+property outward rectification (see, for example, L.S. Premkumar, S. Agarwal, D. Steffen (2002) J. Physiol. 545, 107-117 (non-patent document 3)).

Although capsaicin is a substance that causes pain, it is used as analgesic remedy for reduction of pain in diabetic neuropathy or rheumatic neurosis (see, for example, Szallasi a, Blumberg P.M. (1999) Pharmacol. Rev. 51, 159-212 (non-patent document 1)). It is clear that this reduction is due to the phenomenon in which the end of a sensory nerve, exposed to capsaicin, stops responding on the nervous stimulus, that is sensibilizatsiya. Although it is believed that the mechanism of desensitization VR1 includes regulation mediated Ca2+the regulation, irrespective of capacity, regulate the activity of VR1 phosphorylation and dephosphorylation etc., many issues remain unclear.

Like capsaicin, heat and acid also cause pain, and it is known that sensitive to capsaicin nociceptive nerves respond to 2 or more types of stimulation. It was found that VR1 directly activated not only by capsaicin, but thermal stimulation of 43°C or more (see, for example, Yang D., R.W. Gereau 4th. (2002) J. Neurosci. 22, 6388-6393 (non-patent document 4)). The temperature of 43°C is largely consistent with a threshold temperature, which causes pain in humans and animals, suggesting that VR1 is involved in receiving nociceptive thermal stimulation.

Acidification occurs in the body in case of inflammation or ischemia and, as you know, it causes or increases pain (see, for example, Bevan s, Geppetti P. (1994) Trends Neurosci. 17, 509-512 (non-patent document 5)). It turned out that when the pH is outside of the cells is reduced within acidification, which occurs in the case of organ, VR1 can directly be activated one by acidification (proton), and it is assumed that VR1 represents the actual molecule that accepts stimulation acidification in the body, which is the origin of the result in the case of inflammation or ischemia (see, for example, Yang D., R.W. Gereau 4th. (2002) J. Neurosci. 22, 6388-6393 (non-patent document 4)).

Immunohistological analysis using specific antibodies confirmed that the number of demyelinating With fibers expressing VR1, is increased in inflamed areas compared with healthy region (see, for example, Carlton, S.M., R.E. Coggeshall (2001) Neurosci. Lett. 310, 53-56 (non-patent document 6)). Increased expression of VR1 in the submucosal plexus were indeed observed in inflammatory intestinal disease in humans (see, for example, Yiangou y, Facer p, Dyer N.H., C.L. Chan, C. Knowles, Williams N.S., Anand P. (2001) Lancet 357, 1338-1339 (non-patent document 7)). This increase in the number of VR1 expression causes peripheral sensitization in the fevered body and it is believed to affect the duration of inflammatory hyperalgesia.

It was also reported that extracellular ATP, bradykinin and nerve growth factor, which are substances associated with inflammation, increase the activity of VR1 (see, for example, Tominaga M., Wada M., Masu M. (2001) Proc. Natl. Acad. Sci. USA 98, 6951-6956 (non-patent document 8); X. Shu, L.M. Mendell (1999) Neurosci. Lett. 274, 159-162 (non-patent document 9)); Chuang H.H., Prescott E.D., Kong H., Shields, S., Jordt SE, Basbaum, A.I., Chao, M.V., Julius D. (2001) Nature 411, 957-962 (non-patent document 10), and Sugiura, T., Tominaga M., Katsuya h, Mizumura K. (2002) J. Neurophysiol. 88, 544-548 (non-patent document 11), and without a doubt it is believed that VR1 is involved in stimulating the AI pain and hypersensitivity to pain, including pain caused by inflammation (see, for example, Numazaki M., Tominaga, M. (2003) Biochemistry 75, 359-37 (non-patent document 12)).

The sensory nerve cells in mice with deficiency VR1 did not respond to stimulation by capsaicin, protons and heat. It is reported also that in the analysis of mouse actions with failure VR1 showed no painful reaction after injection of capsaicin and is not observed to reduce the sensitivity to thermal stimulation in inflammatory hyperalgesia (see, for example, Caterina M.J., Leffler a, Malmberg A.B., Martin WJ, Trafton j, Peterson-Zeitz K.R., Koltzenburg m, Basbaum, A.I., Julius D. (2000) Science 288, 306-313 (non-patent document 13) and L.B. Davis, J. Gray, M.J. Gunthorpe et al. (2000) Nature 405, 183-187 (non-patent document 14)). Thus, at the individual level analyses in mice with deficiency VR1 was also confirmed that VR1 acts as a receptor painful stimulation of the wide range.

In addition, as to the connection between vanilloid receptor subtype 1 (VR1) and diseases, it has been reported that a substance that inhibits the activity of VR1 can be used as a therapeutic agent for the treatment of various diseases.

In particular, in relation to a therapeutic agent against pain has a message that capsazepine, which is known as the VR1 antagonist, showed a significant analgesic effect in an experimental model (see, for example, Ikeda Y., Ueno, A., Naraba h, Oh-ishi S. (2001) Life Science 69, 2911-2919 (non-patent document 15)) and is likely to be used as a new therapeutic tool against pain, providing an inhibiting effect on the activity of VR1.

In relation to the high voltage of the bladder with frequent urination and urinary incontinence it was confirmed that the contractile function of the bladder in mice with deficiency VR1 is reduced, and there is a message stating that the connection with pharmacological mechanism of action similar to capsaicin, or the connection has inhibiting effect on VR1, i.e., the compound inhibiting the activity vanilloid receptor subtype 1 (VR1), can be applied to improve the function of the bladder, for example, as a therapeutic agent concerning the frequent urination, incontinence, and so on (see, for example, (2002) Nat. Neurosci. 5, 856-860 (non-patent document 16)).

In addition, in another reference it is reported that a substance having inhibitory effect on vanilloid receptor subtype 1 (VR1), in particular the VR1 receptor antagonist, can be used for prevention and treatment of diseases associated with VR1 activity, in particular sudden urinary incontinence, over active bladder, chronic pain, neuropathic pain, postoperative pain, pain in rheumatoid arthritis, neuralgia, is Europalia, hyperalgesia, nerve injury, ischemic symptom, neurodegenerative disorders, stroke, incontinence and inflammatory diseases (see, for example, document JP 2003-192673 (patent document 1)).

In addition, it is also known that disease-relevant activity vanilloid receptors may include pain, acute pain, chronic pain, neuropathic pain, postoperative pain, migraine, joint pain, neuropathy, nerve damage, diabetic nerve disease, neurodegenerative disease, neurogenic skin disorder, stroke, hypersensitive bladder syndrome, irritable bowel pathology of the respiratory organs, such as asthma and chronic obstructive pulmonary disease, irritation of skin, eyes or mucous membranes, fever, gastric ulcer and 12 duodenal ulcer, inflammatory bowel disease, inflammatory diseases, etc. (see, for example, JP 2004-506714 T2 (patent document 2)).

Accordingly, we can say that the compounds having antagonistic activity against vanilloid receptor subtype 1 (VR1), can be used as a therapeutic agent for the treatment of conditions that are involved With fiber, for example, without limitation, itching, allergic rhinitis, frequent urination and urinary incontinence by type redundantly and is active bladder, stroke, syndrome irritable bowel, respiratory diseases such as asthma and chronic obstructive pulmonary disease, dermatitis, mucositis, stomach ulcers and 12 duodenal ulcer, inflammatory bowel disease, etc. but also pain, acute pain, chronic pain, neuropathic pain, postoperative pain, migraine, joint pain, neuropathy, nerve damage, diabetic nerve disease, neurodegenerative disease, rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, neurogenic skin disorder, stroke, overweight, sudden incontinence, ischemic symptom, and inflammatory diseases, etc.

The following describes the connections that are perceived to be relatively similar to the famous antagonist vanilloid receptor subtype 1 (VR1), and the compound of the present invention.

Amides represented by the following General formula [A], [B] and [C]are disclosed in WO 03/068749 as compounds exhibiting antagonism against VR1 (patent document 3).

Connection urea represented by the following General formula [D], it is disclosed in document WO 03/080578 as compounds exhibiting antagonism against VR1 (patent document 4).

Hinkley-3'-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carbox ilat disclosed as compounds showing inhibitory effect against induced by capsaicin extravasation of plasma protein in the bladder, in the document WO 03/006019 (patent document 5).

Connection urea represented by the following General formula [E], disclosed in WO 03/053945 as compounds exhibiting antagonism against VR1 (patent document 6).

The connection represented by the following General formula [F], disclosed in WO 03/099284 as compounds exhibiting the activity of binding to VR1 (patent document 7).

However, these compounds differ from the compounds of the present invention according to the structure, and not found description, which involves the connection of the present invention.

For reference, the applicants have previously filed a patent application for the inhibitor VR1, represented by the following formula (PCT/JP 2005/013446 (patent document 8)):

[Non-patent document 1] Szallasi a, Blumberg P.M. (1999) Pharmacol. Rev. 51, 159-212

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

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

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

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

[Non-patent document 6] Carlton, S.M., R.E. Coggeshall (2001 Neurosci. Lett. 310, 53-56

[Non-patent document 7] Yiangou y, Facer p, Dyer N.H., C.L. Chan, C. Knowles, Williams N.S., Anand P. (2001) Lancet 357, 1338-1339

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

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

[Non-patent document 10] Chuang H.H., Prescott E.D., Kong H., Shields, S., Jordt SE, Basbaum, A.I., Chao, M.V., Julius D. (2001) Nature 411, 957-962

[Non-patent document 11] T. Sugiura, M. Tominaga, Katsuya h, Mizumura K. (2002) J. Neurophysiol. 88, 544-548

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

[Non-patent document 13] Caterina M.J., Leffler a, Malmberg A.B., Martin WJ, Trafton j, Peterson-Zeitz K.R., Koltzenburg m, Basbaum, A.I., Julius D. (2000) Science 288, 306-313

[Non-patent document 14] L.B. Davis, J. Gray, M.J. Gunthorpe 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 12] JP 2004-506714 T2

[Patent document 13] WO 03/068749

[Patent document 14] WO 03/080578

[Patent document 15] WO 03/006019

[Patent document 16] WO 03/053945

[Patent document 17] WO 03/099284

[Patent document 18] PCT/JP 2005/013446

Description of the invention

The problems to be resolved by the invention of

As analgesic currently used mainly narcotic analgesics (morphine etc), analgesics (NSAID (non-steroidal FR is vospalitelnye drugs)), etc. However, the use of narcotic analgesics severely limited due to development of resistance/dependence and other serious side effects. It is well known that the long introduction to non-narcotic analgesics often have disorders of the upper parts of the gastrointestinal tract and liver disorders and very desirable painkillers with a small number of side effects at higher obezbolivajuschem effect. In addition, there have not been found to be effective painkillers against diabetic neuropathic pain, post herpetic neuralgia and neuropathic pain such as trigeminal neuralgia, and while it is expected to develop effective analgesic about these disorders.

Similar to capsaicin compounds that act on VR1, consider how connections that develop analgesic effect based on the pharmacological mechanism entirely different from the mechanism of the existing painkillers (blockade sensitive to capsaicin sensitive nerves), and it is expected that due to their efficiency, they can be used as a therapeutic agent against neuropathic pain and pain that occurs when various conditions such as rheumatoid arthritis, against to the showing existing painkillers are ineffective.

The fact that the ultimate target of a variety of associated with inflammation substances is VR1, suggests the possibility that the agent, which acts on VR1, effective against a variety of inflammatory pain and interstitial cystitis, and hopes on him as a painkiller, which will replace the existing painkillers.

Therefore, the present invention is to create a new anesthetic, which is based on the pharmacological mechanism entirely different from the mechanisms of action of existing painkillers (blockade sensitive to capsaicin nerves), i.e. the inhibitor activity of VR1, and the creation of new compounds for the inhibition of the activity of VR1.

More specifically, the present invention is the creation of an inhibitor of the activity of VR1, having not only a high inhibitory activity against VR1, but also with high absorption and stability, the possibility of practical application which is higher than that of existing tools.

Another objective of the present invention is to develop a method of treatment and/or prevention of diseases involving activity vanilloid receptor subtype 1 (VR1), such as pain, chronic pain, neuropathic pain, pain when R is Motodrom arthritis, neuralgia, etc., in particular pain.

Means of resolving problems

As a result of intensive studies on the development of analgesic based on the new mechanism of action, which will replace the ordinary painkillers such as non-narcotic analgesics, pyrazolone analgesics, nephratonia analgesics and NSAID, applicants have discovered 3,4-dihydroisoxazole compound which has an excellent inhibitory activity against actions VR1 and has a much better absorption and stability, and have established the present invention. The present invention is described in more detail below.

1. 3,4-Dihydroisoxazole the connection represented by the following General formula [1]or its pharmaceutically acceptable salt:

where X denotes

(1) a nitrogen atom, or

(2) CR3;

R1means

(1) a hydrogen atom, or

(2) a halogen atom;

R2stands With1-6alkoxygroup, which may be substituted by same or different 1 to 5 substituents selected from the following groups:

(1) halogen atom, and

(2) a hydroxyl group; and

R3denotes a halogen atom (however, R1denotes a halogen atom when X represents CR3).

2. 3,4-Dihydroisoxazole compound according to claim 1, selected from the trail is a growing group of compounds or their pharmaceutically acceptable salts:

1) (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-(4-tert-butoxy-3,5-differenl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide,

2) (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-(3,5-debtor-4-isopropoxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide,

3) (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-(3,5-debtor-4-ethoxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide,

4) (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-[2-(2,2-dimethylpropylene)pyridine-5-yl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide,

5) (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-(2-tert-butoxypropan-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide,

6) (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-[2-(2,2,2-triptoreline)pyridine-5-yl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide,

7) (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-(2-isobutoxide-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide,

8) (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-[3,5-debtor-4-(2,2,2-triptoreline)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide,

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

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

3. Pharmaceutical composition comprising 3,4-dihydroisoxazole compound or its pharmaceutically acceptable salt according to claims 1 or 2, the pharmaceutically acceptable carrier.

4. Pharmaceutical composition comprising 3,4-dihydroisoxazole compound or its pharmaceutically acceptable salt according to claims 1 or 2 and a pharmaceutically acceptable carrier, for the treatment and/or prevention of a disease selected from pain, acute pain, chronic pain, neuropathic pain, pain in rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute herpetic neuralgia, post herpetic neuralgia, chronic herpetic neuralgia, postoperative pain, pain in cancer, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegenerative diseases, stroke, ischemic symptom, nerve injury, neurogenic skin disorder, inflammatory disease, pruritus, allergic rhinitis, stroke, syndrome, irritable bowel, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, stomach ulcers and 12 duodenal ulcer, inflammatory intestinal diseases, hypersensitivity of the bladder, frequent urination and urinary incontinence.

5. Pharmaceutical composition for treating and/or preventing pain, comprising 3,4-dihydroisoxazole compound or its pharmaceutically acceptable salt according to claims 1 or 2, and pharmaceutically acceptable but Icel.

6. The pharmaceutical composition according to claim 5, where the pain is an acute pain, chronic pain, neuropathic pain, pain in rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute herpetic neuralgia, post herpetic neuralgia, chronic herpetic neuralgia, postoperative pain, pain and cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy or neurodegenerative disease.

7. Inhibitor activity vanilloid receptor subtype 1 (VR1), including 3,4-dihydroisoxazole compound or its pharmaceutically acceptable salt according to claims 1 or 2 and a pharmaceutically acceptable carrier.

8. The method of treatment and/or prevention of a disease selected from pain, acute pain, chronic pain, neuropathic pain, pain in rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute herpetic neuralgia, post herpetic neuralgia, chronic herpetic neuralgia, postoperative pain, pain in cancer, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegenerative diseases, stroke, ischemic symptom, nerve injury, neurogenic skin Rosstroy the VA, inflammatory disease, pruritus, allergic rhinitis, stroke, syndrome, irritable bowel, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, stomach ulcers and 12 duodenal ulcer, inflammatory intestinal diseases, hypersensitivity of the bladder, frequent urination and urinary incontinence, characterized in that the method comprises the introduction of a pharmacologically effective amount of 3,4-dihydroisoxazole compound or its pharmaceutically acceptable salt according to claims 1 or 2.

9. The method of treatment and/or prevention of pain, wherein the method comprises the introduction of a pharmacologically effective amount of 3,4-dihydroisoxazole compound or its pharmaceutically acceptable salt according to claims 1 or 2.

10. The method of treatment and/or prevention of pain according to claim 9, where the pain is an acute pain, chronic pain, neuropathic pain, pain in rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute herpetic neuralgia, post herpetic neuralgia, chronic herpetic neuralgia, postoperative pain, pain and cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy or neurodegenerative disease.

11. Commercial packaging, including FA the pharmaceutical composition according to any one of p-6, and written instructions relating to the said pharmaceutical composition, which says that the specified composition can be applied or should be applied for the treatment and/or prevention of a disease selected from pain, acute pain, chronic pain, neuropathic pain, pain in rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute herpetic neuralgia, post herpetic neuralgia, chronic herpetic neuralgia, postoperative pain, pain in cancer, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegenerative diseases, stroke, ischemic symptom, nerve injury, neurogenic skin disorder, inflammatory disease, pruritus, allergic rhinitis, stroke, syndrome, irritable bowel, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, stomach ulcers and 12 duodenal ulcer, inflammatory intestinal diseases, hypersensitivity of the bladder, frequent urination and urinary incontinence.

12. The use of 3,4-dihydroisoxazole compound or its pharmaceutically acceptable salt according to claims 1 or 2 to obtain the pharmaceutical composition according to claim 4 for the treatment and/or prevention of a disease selected from pain, stop the pain Oh, chronic pain, neuropathic pain, pain in rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute herpetic neuralgia, post herpetic neuralgia, chronic herpetic neuralgia, postoperative pain, pain in cancer, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegenerative diseases, stroke, ischemic symptom, nerve injury, neurogenic skin disorder, inflammatory disease, pruritus, allergic rhinitis, stroke, syndrome, irritable bowel, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, stomach ulcers and 12 duodenal ulcer, inflammatory intestinal diseases, hypersensitivity of the bladder, frequent urination and urinary incontinence.

13. The use of 3,4-dihydroisoxazole compound or its pharmaceutically acceptable salt according to claims 1 or 2 to obtain a pharmaceutical composition for the treatment and/or prevention of pain in subparagraph 5 or 6.

14. The use of 3,4-dihydroisoxazole compound or its pharmaceutically acceptable salt according to clause 13, where the pain is an acute pain, chronic pain, neuropathic pain, pain in rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, the migration is ü, joint pain, acute herpetic neuralgia, post herpetic neuralgia, chronic herpetic neuralgia, postoperative pain, pain and cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy or neurodegenerative disease.

15. Drug, which includes a combination pharmaceutical composition comprising 3,4-dihydroisoxazole compound or its pharmaceutically acceptable salt according to claims 1 or 2 and a pharmaceutically acceptable carrier, one or more means selected from the group consisting of antiviral agents, antidepressant, anti-convulsants, anti-arrhythmic agents, local anesthetic, anesthetic, receptor antagonist N-methyl-D-aspartate, steroid adrenal cortex, neural blockade, non-steroidal anti-inflammatory analgesic drugs, antagonistic analgesic agonist α2-adrenaline receptor, medicines for external use, the antagonist of calcium channels, tools, opening potassium channels, and febrifuge.

16. The use of 3,4-dihydroisoxazole compound or its pharmaceutically acceptable salt according to claims 1 or 2 to obtain a medicinal product item 15.

17. The method of treatment is/or prevention of diseases, selected from pain, acute pain, chronic pain, neuropathic pain, pain in rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute herpetic neuralgia, post herpetic neuralgia, chronic herpetic neuralgia, postoperative pain, pain in cancer, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegenerative diseases, stroke, ischemic symptom, nerve injury, neurogenic skin disorder, inflammatory disease, pruritus, allergic rhinitis, stroke, syndrome, irritable bowel, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, ulceration ulcer and 12 duodenal ulcer, inflammatory intestinal diseases, hypersensitivity of the bladder, frequent urination and urinary incontinence, characterized in that one or more means selected from the group consisting of antiviral agents, antidepressant, anti-convulsants, anti-arrhythmic agents, local anesthetic, anesthetic, receptor antagonist N-methyl-D-aspartate, steroid adrenal cortex, neural blockade, non-steroidal anti-inflammatory analgesic drugs, antagonistic analgesic α 2-adrenaline receptor, medicines for external use, the antagonist of calcium channels, tools, opening potassium channels, and febrifuge, used in combination with a pharmaceutically effective amount of 3,4-dihydroisoxazole compound or its pharmaceutically acceptable salt according to claims 1 or 2.

18. The method of treatment and/or prevention of pain, wherein the method is used introduction 3,4-dihydroisoxazole compound or its pharmaceutically acceptable salt according to claims 1 or 2 in combination with induced stimulation analgesia selected from acupuncture, transcutaneous electro-acupuncture stimulation therapy, therapy by percutaneous electrical stimulation of the nerves, therapy silver spike point (SSP)therapy by stimulation of peripheral nerves, therapy electrical spinal cord stimulation, electroconvulsive therapy, laser therapy and low-frequency therapy.

19. The method of treatment and/or prevention of postoperative neuralgia, characterized in that 3,4-dihydroisoxazole compound or its pharmaceutically acceptable salt according to claims 1 or 2 is entered after executing surgical operations selected from the removal of the scar tissue, cryosurgical neurosurgical intervention, excision of peripheral nerves, and the cross section of the dorsal roots of the spinal cord, sympathectomy, and the destruction of the entrance area dorsal roots of the spinal cord, cordotomy and excision of the frontal lobe.

Advantages of the invention

3,4-Dihydroisoxazole compound of the present invention effectively inhibits the activity vanilloid receptor subtype 1 (VR1), and therefore it is effective for treatment and/or prevention of diseases such as pain, acute pain, chronic pain, neuropathic pain, pain in rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute post herpetic neuralgia, post herpetic neuralgia, chronic herpetic neuralgia, postoperative pain, pain and cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegenerative disease, stroke, ischemic symptom, nerve damage, neurogenic skin disorder, inflammatory disease, pruritus, allergic rhinitis, stroke, syndrome, irritable bowel, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, stomach ulcers and 12 duodenal ulcer, inflammatory bowel disease, bladder hypersensitivity, frequent urination type excessively active bladder and urinary incontinence by type excessively active mocemulobaze.

In particular, it is effective as a therapeutic agent and a prophylactic against diseases accompanied by pain condition, such as pain, acute pain, chronic pain, neuropathic pain, pain in rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute post herpetic neuralgia, post herpetic neuralgia, chronic herpetic neuralgia, postoperative pain, pain and cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy and neurodegenerative disease. In addition, are also effects due to a mechanism different from the mechanism of action of conventional analgesics.

3,4-Dihydroisoxazole compound of the present invention represented by the above General formula [1], not only has a pronounced inhibitory effect on the activity of VR1, but also counteracts oxidative metabolism and has an excellent effect on the duration of the inhibitory effect. The compound of the present invention, furthermore, has properties such as high absorption and/or high resistance to the action of gastric juice. The experts could not predict such effects.

Therefore, a new connection for infusion is to him the invention is likely to find practical application as a drug.

The best way of carrying out the invention

The following are the definitions of each term used in the present description.

"C1-6alkyl group" represents a linear or branched alkyl group having from 1 to 6 carbon atoms, preferably "C1-4alkyl group. "C1-6alkyl group, in particular, includes methyl group, ethyl group, through the group, isopropyl group, boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group, pentelow group, isopentyl group, tert-pentelow group, hexoloy group, etc. "C1-4alkyl group" represents a linear or branched alkyl group having from 1 to 4 carbon atoms, and specifically includes methyl group, ethyl group, through the group, isopropyl group, boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group, etc.

"Halogen atom" is a fluorine atom, chlorine atom, bromine atom or iodine atom, and preferred are a fluorine atom and a chlorine atom, and particularly preferred is a fluorine atom.

"C1-6alkoxygroup is alkoxygroup, in which the alkyl part is a "C1-6alkyl group" of the above definitions. In particular, he shall include a methoxy group, ethoxypropan, propoxylate, isopropoxy, butoxypropyl, isobutoxy, sec-butoxypropyl, tert-butylacrylate, pentyloxy, isopentylamine, 2-methylbutoxy, neopentylglycol, 1-ethylpropoxy, hexyloxy, 4-methylpentylamino, 3-methylpentylamino, 2-methylpentylamino, 1-methylpentylamino, 3,3-Dimethylbutane, 2,2-Dimethylbutane, 1,1-Dimethylbutane, 1,2-dimethylbutyramide, 1,3-Dimethylbutane, 2,3-Dimethylbutane, 2-ethylbutane etc.

"C1-6alkoxygroup, which may be substituted by 1-5 atoms of halogen, represents, in addition to the above "C1-6alkoxygroup", halogenlampe, in which "C1-6alkyl group, a part of the1-6alkoxygroup, substituted by 1-5, preferably 1-3, preferably 3 and same or different halogen atoms, preferably equal to 3 halogen atoms. In particular, this halogenlampe includes formatexpr, dipterocarp, cryptometer, bromoethoxy, chlorotoxin dichloromethoxy, 2-chlorethoxyfos, 1,2-declarationthree, 2,2-declarationthree, trichlormethiazide, 2-floridacheap, 2,2,2-triptracker, 2,2,2-trichlorethene, 4-formatexpr etc.

"C1-6ALCO is a sigroup, which may be substituted by 1-5 hydroxy groups, is, in addition to the above "C1-6alkoxygroup", alkoxygroup, in which "C1-6alkoxygroup", part of the1-6alkoxygroup, substituted by 1-5, preferably 1-2, preferably 1 hydroxyl group. In particular, this alkoxygroup, substituted hydroxyl group, includes hydroxyethoxy, 2-hydroxyethoxy, 1-hydroxyethoxy, 3-hydroxypropoxy, 4-hydroxybutyrate, 5-hydroxyphenylacetate, 6-hydroxyhexyloxy, 2-hydroxy-2-methylpropoxy, 1,1-dimethyl-2-hydroxyethyloxy etc.

In General formula [1], preferred examples of especially preferred examples of each of the following symbol. However, the present invention is not limited to them.

[Preferred R1]

R1denotes a hydrogen atom or a halogen atom. Halogen atom and this document represents preferably a fluorine atom or a chlorine atom, particularly preferably a fluorine atom.

However, R1preferably denotes a hydrogen atom when X represents a nitrogen atom, and R1denotes a halogen atom, particularly preferably a fluorine atom when X represents CR3.

Preferable and R3and R1denote a fluorine atom. More specifically, R1has, after the respective values:

R1means

(1) a hydrogen atom, or

(2) a halogen atom,

preferably

1) a hydrogen atom, or

(2) the fluorine atom

(however, R1preferably means

fluorine atom,

when X represents CR3).

[Preferred R2]

R2stands With1-6alkoxygroup, which may be substituted by same or different 1 to 5 substituents selected from a halogen atom and a hydroxyl group, preferably1-6alkoxygroup, which may be substituted by 1-3 halogen atoms, or 1-3 hydroxyl groups.

In the present invention "1-6alkoxygroup" can mean alkoxygroup in which the alkyl group is a linear or alkoxygroup in which the alkyl group is branched.

The preferred "C1-6alkoxygroup" means2-5alkoxygroup, which may be branched. In particular, it includes ethoxypropan, isopropoxy, isobutoxy, tert-butoxypropyl, 2,2-dimethylpropanoyl etc.

"C1-6alkoxygroup, which may be substituted by 1-3 halogen atoms"is, in addition to the above1-6alkoxygroup,1-6alkoxygroup substituted by 1-3 halogen atoms. With1-6alkoxygroup substituted by 1-3 halogen atoms, not only at the o 1-6alkoxygroup, substituted by same or different 1 to 3 halogen atoms, preferably the same 1 to 3 halogen atoms, particularly preferably 1 to 3 fluorine atoms. In particular, it includes 2,2,2-triptracker, 2,2,2-trichlorethene, 2,2,2-tribometer, 2,2,2-triacetoxy, etc. are Particularly preferred With1-6alkoxygroup substituted by 1-3 halogen atoms", is a2-5alkoxygroup, substituted by 1-3 fluorine atoms. In particular, it includes 2,2,2-triptracker etc.

"C1-6alkoxygroup, which may be substituted by 1-3 hydroxyl groups, is, in addition to the above1-6alkoxygroup,1-6alkoxygroup, substituted by 1-3 hydroxyl groups, preferably 1 hydroxyl group, With1-6alkoxygroup, substituted by 1-3 hydroxyl groups, preferably represents C2-5alkoxygroup, substituted 1 hydroxyl group. In particular, it includes 2-hydroxy-2-methylpropoxy, 2-hydroxy-1,1-dimethylaminopropyl etc.

[Preferred R3]

R3denotes a halogen atom. The halogen atom in the present invention is preferably a fluorine atom or a chlorine atom, particularly preferably a fluorine atom. Particularly preferably and R3and R1mean and the ohms of fluoride.

[Preferred R1and R2when X is a nitrogen atom]

When X is a nitrogen atom, preferably R1means a hydrogen atom, and R2means1-6alkoxygroup, which may be substituted by same or different 1 to 3 halogen atoms.

Particularly preferably, R1means a hydrogen atom, and R2means1-6alkoxygroup, which can be substituted by the same 3 halogen atoms. Preferably R1means a hydrogen atom, and R2means tert-butoxypropyl, isobutoxy, 2,2,2-triptracker or 2,2-dimethylpropanoyl.

[Preferred R1R2and R3when X is CR3]

When X is CR3preferred R1and R3are R1and R3that means the same or different halogen atoms, particularly preferably identical halogen atoms.

Preferable and R3and R1mean fluorine atoms.

When X is CR3preferred R2means2-5alkoxygroup, such as ethoxypropan, isopropoxide, isobutoxy, tert-butoxypropyl, 2,2-dimethylpropanoyl etc.; C1-6alkoxygroup substituted by 1-3 halogen atoms, preferably fluorine atoms such as 2,2,2-Tr is veracocha, 2,2,2-trilobitomorpha, 2,2,2-tribromopropane, 2,2,2-triacetoxy, etc.; or (C1-6alkoxygroup, substituted by 1 or 2 hydroxyl groups, such as 2-hydroxy-2-methylpropoxy, 2-hydroxy-1,1-dimethylaminopropan etc.

More specifically, when X is CR3, R1and R3means are preferably identical or different halogen atoms, particularly preferably fluorine atoms, and R2means preferably1-6alkoxygroup, which may be substituted by same or different 1 to 3 substituents selected from a fluorine atom and a hydroxyl group, more specifically ethoxypropan, tert-butoxypropyl, isopropoxy, 2,2,2-triptracker, 2-hydroxy-2-methylpropoxy or 2-hydroxy-1,1-dimethylaminopropyl.

"Pharmaceutically acceptable salt" in the present invention can be any type of salt until it forms a salt with the compound represented by the above General formula [1], and can be obtained by interacting, for example, inorganic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid or Hydrobromic acid; organic acid such as oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, is kasna acid, triperoxonane acid, gluconic acid, ascorbic acid, methylsulfonate acid, p-toluensulfonate acid, benzolsulfonat acid or benzylmalonate acid; or an amino acid such as lysine, arginine or alanine. Gidrirovannoe compound, hydrate and MES of each connection are also included in the present invention.

In addition, there are various isomers of the compounds represented by the above General formula [1]. For example, there are E-isomer and Z-isomer as geometric isomers, and when there is an asymmetric carbon atom, there are enantiomers and diastereoisomers as stereoisomers based on them, and there may be tautomers. Therefore, all these isomers and their mixtures are included in the scope of the present invention. In addition, the present invention also encompasses proletarienne compounds of these compounds and compounds metabolites as equivalent compounds, except compound represented by the above General formula [1].

"Prodrug" is a derivative of the compound of the present invention, having a group that can be destroyed chemically or metabolically, and upon introduction into a living organism as the result of chemical modification is transformed into a compound that has activity as Lakers the governmental funds and shows the original pharmacological effect; it also includes complexes and salts that are not linked by covalent bond.

The prodrug is used to improve absorption after oral administration or target area target. Parts subject to modification for the formation of prodrugs include reactive functional groups such as hydroxyl group and amino group in the compound of the present invention. Specific examples of the modifying group for a hydroxyl group include acetyl group, propionyl group, isobutyryl group, pivaloyl group, benzoyloxy group, 4-methylbenzoyl group, dimethylcarbamoyl group, alphagroup etc. Specific examples of the modifying group for the amino group include hexylberberine group, 3-methylthio-1-(acetylamino)propelleronline group, 1-sulfo-1-(3-ethoxy-4-hydroxyphenyl)methyl group, methyl-(5-methyl-2-oxo-1,3-dioxol-4-ilen) group, etc.

"Pharmaceutical composition" comprises a combination drug with other drugs, etc. except the so-called "composition", which includes the drug as the active ingredient and combine with it the agent, etc. it is Obvious that the pharmaceutical composition of the present invention can be used in combination with any other drug is rest, while this is allowed in the field of medicine. So you can say that the pharmaceutical composition is a pharmaceutical composition for combined use with other drugs.

"Pain" means any type of pain condition, regardless of status (for example, whether it is a dull pain or a sharp pain, chronic or acute, and so on), regardless of what disease causes pain (for example, regardless of whether it occurs pain as a result of rheumatic fever or caused by cancer and so on). Therefore, used in this document, the term "pain" includes, in addition to the so-called "pain, acute pain, chronic pain, neuropathic pain, pain in rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute herpetic neuralgia, post herpetic neuralgia, chronic herpetic neuralgia, postoperative pain, pain and cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy and neurodegenerative disease.

"Inhibitor activity vanilloid receptor subtype 1 (VR1)" means a substance that inhibits the function vanilloid receptor subtype 1 as ion channel and eliminates or reduces their activity. In particular, it includes the t antagonist vanilloid receptor subtype 1, etc. Antagonist vanilloid receptor subtype 1 means a substance that inhibits the effect of the agonist, acting on vanilloid receptors subtype 1, by inhibiting the function vanilloid receptor subtype 1 as ion channel. The inhibitor of the present invention should not compete with the agonist, but may also inhibit the function of VR1 as ion channel. In particular, agonists that act on vanilloid receptors subtype 1, include capsaicin, a derivative of capsaicin, acid stimulation (proton), thermal stimulation, and so on, the inhibitor activity vanilloid receptor subtype 1 (VR1) can be a substance that inhibits the input current of CA2+in the cell, caused by agonistic stimulation of capsaicin, acid stimulation (proton) or thermal stimulation.

The pharmaceutical composition of the present invention can enter the human and other mammals (mice, rats, hamsters, rabbits, cats, dogs, cows, horses, sheep, monkeys and so on). Therefore, the pharmaceutical composition of the present invention can also be used as a medicine for animals other than man.

When the compound of the present invention is used as a pharmaceutical preparation, it can be mixed with the usual f is macological acceptable carrier, excipient, diluent, filler, baking powder, stabilizer, preservative, buffer, emulsifier, perfume, coloring agent, sweetening agent, a thickener, a corrector of adverse effects, an agent that promotes dissolution, and other additional agents, in particular water, vegetable oil, alcohol such as ethanol or benzyl alcohol, hydrocarbons such as polyethylene glycol, glyceryltrinitrate, gelatin, lactose and starch, magnesium stearate, talc, lanolin, petrolatum, etc. for the manufacture of a medicinal product in such form, as a tablet, pill, powder, granule, suppository, means for injections, eye drops, liquid drug, encapsulated tool, toffee, spray tool, elixir, suspension, emulsion and syrup for systemic or local injection of an oral or parenteral route.

Although the dose varies depending on age, body weight, condition, therapeutic effect, the route of administration, etc. it is normally administered to adults in the range from 0.01 mg to 1 g per dose, from 1 to several times per day in the form of oral medication or injectable medication, such as a solution for intravenous injection, etc.

"Prevention" is a so-called prevention means, for example, preventive hearth is the beginning of neuralgia or chronic neuralgia. In relation to pain specifically included preventive suppression of the acute herpetic neuralgia, start-herpetic neuralgia, transition in post herpetic neuralgia from acute herpetic pain, chronic herpetic neuralgia, early post-operative pain, chronic post-operative pain, the onset of symptoms of pain in cancer, chronic pain in cancer, the onset of symptoms of inflammatory pain, the beginning of interstitial cystitis, chronic inflammatory pain, early post-traumatic neuralgia or chronic post-traumatic neuralgia.

"The drug, which includes a combination" means a drug, characterized in that it is a preparative form containing a pharmaceutical composition comprising the compound [1] or its pharmaceutically acceptable salt according to the present invention and the pharmaceutical composition or agent, subject to Association with the composition of the present invention, and the drug is different in that it is a kit comprising a pharmaceutical composition comprising the compound [1] or its pharmaceutically acceptable salt according to the present invention and the pharmaceutical composition or agent, subject to Association with HDMI is the function of the present invention, moreover, the drug is different in that it is a kit comprising a pharmaceutical composition comprising the compound [1] or its pharmaceutically acceptable salt according to the present invention and the pharmaceutical composition or agent, subject to Association with the composition of the present invention, and is respectively the same or different routes of administration, etc.

The compound and pharmaceutical composition of the present invention can be used in combination with one or more other funds in accordance with the method commonly present in conventional medical institutions. When used in combination medicinal product subject to application, can be administered simultaneously or separately at time intervals. Although there are various compounds that can be used in combination with the compound of the present invention, especially preferred are antiviral agent, an antidepressant, an anticonvulsant drug, an antiarrhythmic drug, a local anesthetic, an analgesic drug, receptor antagonist N-methyl-D-aspartate, steroid adrenal cortex, neural blockade, non-steroidal anti-inflammatory analgesic, narcotic analgesics, antagonistic analgesic agonist α2-adrenaline the s receptor, remedy for pain stimulation, drugs for exterior use, calcium channel antagonist, tool that opens potassium channels, and febrifuge.

Antiviral agent, in particular, includes vidarabine, acyclovir, ganciclovir, zidovudine, didanosine, amantadine, and idoxuridine, interferon, etc.

Antidepressant, in particular, includes amitriptyline, imipramine, clomipramine, trimipramine, lofepramine, dosulepin, desipramin, amoxapine, nortriptyline, fluoxetine, fluvoxamine, maprotiline, mianserin, setiptiline, trazodone etc.

Anticonvulsant drug, in particular, include gabapentin, pregabalin, phenobarbital, primidone, phenytoin, mephenytoin, Nirvana, ethotoin, trimethadione, ethosuximide, acetylphenyl, carbamazepine, zonisamide, acetazolamide, diazepam, clonazepam, nitrazepam, diphenylhydantoin, valproate acid, baclofen, etc.

Antiarrhythmic drug, in particular, include quinidine, disopyramide, procainamide, aymalin, primulin, cibenzoline, lidocaine, meksiletin, aprindine, sonicaid, phenytoin, flecainide, polkaing, propafenone, propranolol, amiodarone, verapamil, bepridil, etc.

Local anesthetic, in particular, includes lidocaine, meksiletin, cocaine, procaine, bupivacaine, mepivacaine, prilocaine, tetracaine, dibucaine, ethylaminomethyl, etc.

p> Painkiller, in particular, includes the benzodiazepine, diazepam, midazolam, thiopental, thiamylal, propofol, baclofen, droperidol, Sufentanil, etc. receptor Antagonist N-methyl-D-aspartate, in particular, includes ketamine, dextromethorphan, memantine, amantadine, etc.

Steroid adrenal cortex, in particular, includes cortisol, cortisone, prednisolone, triamcinolone, dexamethasone, betamethasone, paramethasone, fluotsinolon acetonide, fluocinonide, beclometasone, fludrocortisone, etc.

Nerve blockade, in particular, includes the blockade of the stellate ganglion, the epidural blockade of the ganglion, the ganglion blockade of the brachial plexus, nerve root blockade, blockade of the thoracic/lumbar sympathetic ganglion, the blockade of the trigger point, the subarachnoid blockade of the ganglion, the trigeminal nerve blockade, blockade of sympathetic nerves, local infiltration blockade, the blockade of peripheral nerves, etc.

Non-steroidal anti-inflammatory analgesic, in particular, include celecoxib, rofecoksib, etodolac, meloxicam, nimesulide, diclofenac sodium, mefenamico acid, zaltoprofen, loxoprofen sodium, sulindac, nabumetone, diflunisal, piroxicam, ibuprofen, naproxen, fenoprofen, acetylsalicylic acid, tolmetin, indomethacin, flurbiprofen, oxaprozin, Ketoprofen, movetalk, acetaminophen, Ketorolac, some the cancer, nitrospira, cuprofen, ampiroxicam, tiaramide, epirizole etc.

Narcotic analgesics, in particular, include morphine, fentanyl, oxycodone, methadone, codeine, cocaine, pethidine, opium, ipecac etc.

Antagonistic analgesic, in particular, includes Pentagon, buprenorphine, nalorfin, cyclazocine, butorphanol, etc.

Agonist α2-adrenaline receptor, in particular, includes clonidine, dexmedetomidine, tizanidine, guanfacine, guanabenz etc.

Medicinal preparation for external use, in particular, includes capsaicinoids cream, etc.

Febrifuge, in particular, includes diclofenac sodium, mefenamico acid, loxoprofen sodium, ibuprofen, acetylsalicylic acid, indomethacin, acetaminophen, etc.

The way stimulation analgesia, in particular, includes acupuncture, transcutaneous electro-acupuncture stimulating therapy, therapy by percutaneous electrical stimulation of the nerves, therapy silver spike point (SSP)therapy by stimulation of peripheral nerves, therapy electrical spinal cord stimulation, electroconvulsive therapy, laser therapy and low-frequency therapy, etc.

In addition, the compound of the present invention may be used in accordance with the General method is typically performed in the field, through the introduction after the implementation of the Oia surgery to prevent or treat pain. Although various surgical operations can be performed in combination with the compound of the present invention, particularly preferred are the excision of the scar tissue, cryosurgery nerve, excision of peripheral nerve excision of the dorsal roots of the spinal cord, sympathectomy, the destruction of the input zone of the dorsal roots of the spinal cord and resection of the frontal lobe.

Although the use of the compounds according to the present invention has been described mainly in the form of application for the prevention or treatment of pain, the compound of the present invention can be used in the States in which involved With fiber, such as irritation, allergic rhinitis, frequent urination and urinary incontinence by type excessively active bladder syndrome, irritable bowel, respiratory diseases such as asthma and chronic obstructive pulmonary disease, dermatitis, mucositis, stomach ulcers and 12 duodenal ulcer, inflammatory intestinal diseases, etc.

Further specifically describes a method for obtaining compounds of the present invention represented by the General formula [1], however, it should be understood that the present invention is not limited to these methods of getting.

Therefore, the compound of the present invention can be synthesized in accordance with the following method and obtain a or b, but it can be obtained in the following examples and with reference to these methods. Obtaining the compounds of the present invention, the order of interactions can appropriately be changed. It can be performed starting from the considered rational reaction stage or replacement parts. For example, the compound (X) can be entered before the introduction of compound (II), and this order can be reversed. With regard to the formation of 3,4-dihydroisoxazole, the reaction of the closure ring can be performed for the formation of this heterokonta before the introduction of compound (II) and/or compound (X) or, alternatively, the reaction of the closure ring can be performed for the formation of this heterokonta after administration of compound (II) and/or compound (X). Protecting and Unprotecting can be appropriately performed when the compound has a reactive functional group. To enhance the development of the reaction, it is possible to use reagents other than illustrated.

The course of the next way to obtain is a typical example of the production method, but obtaining compounds of the present invention is not specifically limited in the following way. Each connection received at each of the stages can be extracted and cleaned in the usual way, but depending on the specific case of the compounds is their possible use in the next stage without isolation and purification.

1. The method of receiving As:

(where R represents carboxyl protective group (in this document carboxyl protective group is carboxyl protective group commonly used in the field of synthetic organic chemistry, and includes, for example, methyl group, ethyl group, through the group, tert-boutelou group, benzyl group, para-methoxybenzyloxy group, and so on), and forms an ester which is easily gives the carboxylic acid by hydrolysis or catalytic hydrogenation. X' and X” are the same or different, and each represents a halogen atom, such as chlorine - or bromine - or sulfonyloxy, such as 3-nitrobenzenesulfonamide, p-toluensulfonate, benzolsulfonate, p-bromobenzosulfonyl, methysulfonylmethane or triftormetilfullerenov. R' represents a protective group of a phenolic hydroxyl group, which can be easily removed by hydrolysis or catalytic hydrogenation (protective group of a phenolic hydroxyl group is a protective group of a phenolic hydroxyl group generally used in the field of synthetic organic chemistry, and includes, for example, methoxymethyl group, methoxyethoxymethyl group, benzyl group, the pet-boutelou group, tetrahydropyranyloxy group, acetyl group, etc). R” represents a protective group of hydroxyl group, which can be easily removed by hydrolysis or catalytic hydrogenation (protective group of hydroxyl group is a protective group of hydroxyl group generally used in the field of synthetic organic chemistry, and includes, for example, methoxymethyl group, methoxyethoxymethyl group, benzyl group, tetrahydropyranyloxy group, acetyl group, etc). Every other character has the values defined above).

The first stage

This is the first stage of obtaining compound (III) catalyzed by palladium amination reaction Buchwald/Hartwig of the compounds (I) and compound (II).

The compound (III) can be obtained by the interaction of the compound (I) with compound (II) in toluene, 1,4-dioxane, tetrahydrofuran or similar compounds, or in a mixed solvent of these compounds using a palladium catalyst, such as a mixture of palladium acetate and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, bis(diphenylphosphino)ferienparadies chloride (II) or Tris(dibenzylideneacetone)dipalladium together with a base such as sodium carbonate, tribalistas (K3PO4), potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate or tert-piperonyl potassium, when the fact is the temperature value from 20°C to the boiling temperature under reflux, preferably at a temperature from 60°C to the boiling temperature under reflux for 5 hours to 96 hours, preferably for from 8 hours to 48 hours.

The second stage

This stage is the removal of R' of the compound (III) and obtain the compound (IV).

For example, when R' represents methoxymethyl group, benzoyloxymethyl group, methoxyethoxymethyl group, tert-boutelou group, tetrahydropyranyloxy group or acetyl group, the compound (IV) can be obtained by the interaction of the compound (III) without solvent or in water, methanol, ethanol, propanol, tetrahydrofuran, etc. or a mixed solvent of these compounds, using an acid such as hydrochloric acid or triperoxonane acid at a temperature from 0°C to the boiling temperature under reflux, preferably from 0 to 50°C for from 0.5 hour to 24 hours, preferably from 0.5 hour to 8 hours.

When R' denotes a benzyl group, etc. that the compound (IV) can be obtained by reaction in methanol, ethanol, propanol, tetrahydrofuran or a solvent, a mixture of these compounds, in the presence of a catalyst of palladium-on-coal, etc., using hydrogen or ammonium formate at a temperature of from about 0°C. to the boiling temperature under reflux, preferably from about 20°C to the boiling temperature under reflux for 0.5 hour to 96 hours, preferably from 1 hour to 48 hours.

Third stage

This stage represents the stage of obtaining the compound (VI) interaction of the compound (IV) and compound (V) in basic terms.

Compounds (VI) can be obtained by the interaction of the compounds (IV) and compound (V), i.e. gildenhard, glycidylmethacrylate, glycidylether etc. in chloroform, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, ethyl acetate, methanol, water or the solvent, a mixture of these compounds, in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or triethylamine, at temperatures from 0°C to the boiling temperature under reflux, preferably 0 to 60°C for from 0.5 hour to 24 hours.

The fourth stage

This stage is the conversion of compound (VI) to the compound (VII) in basic terms.

The compound (VII) can be obtained by the interaction of the compounds (VI) in chloroform, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, ethyl acetate, or in a solvent, a mixture of these compounds, in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or triethylamine, at temperatures from 0°C to the boiling temperature under reflux, preferably 0 to 60°C for from 0.5 hour to 24 hours.

This stage is designed to remove R from the compound (VII) and obtain the compounds (VIII).

For example, when R denotes a methyl group, ethyl group, through the group, and so on, then the compound (VIII) can be obtained by hydrolysis of compound (VII) in water, methanol, ethanol, propanol, tetrahydrofuran, etc. or in a solvent, a mixture of these compounds, using a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate or sodium carbonate, at temperatures from -20°C to the boiling temperature under reflux, preferably from 20°C to the boiling temperature under reflux for 0.5 hour to 24 hours preferably from 0.5 hour to 8 hours.

For example, when R represents tert-boutelou group, the compound (VIII) can be obtained by the interaction of the compounds (VII) without solvent or in water, methanol, ethanol, propanol, tetrahydrofuran, etc. or in a solvent, a mixture of these compounds, such as hydrochloric acid or triperoxonane acid, at a temperature from 0°C to the boiling temperature under reflux, preferably from 0 to 50°C for from 0.5 hour to 24 hours, preferably from 0.5 hour to 8 hours.

When R is a benzyl group, a para-methoxybenzyloxy group, etc., the compound (VIII) can be obtained is Samadashvili compounds (VII) in methanol, ethanol, propanol, tetrahydrofuran, etc. or in a solvent, a mixture of these compounds using hydrogen or ammonium formate in the presence of a catalyst of palladium-on-carbon, etc. at a temperature from about 0°C. to the boiling temperature under reflux, preferably from 20 to 50°C for from 0.5 hour to 96 hours, preferably from 1 hour to 48 hours.

Sixth stage

This stage is designed to protect the hydroxyl group of the compound (VIII) and obtain the compounds (IX).

For example, when R denotes an acetyl group, the compound (IX) can be obtained by the interaction of the compound (VIII) in chloroform, tetrahydrofuran, toluene, ethyl acetate, pyridine or without solvent, using acetylchloride or acetic anhydride in the presence or in the absence of a base, such as pyridine or triethylamine, at temperatures from 0°C to the boiling temperature under reflux, preferably from 0 to 50°C for from 0.5 hour to 24 hours, preferably from 0.5 hour to 8 hours.

When R” denotes tetrahydropyranyloxy group, the compound (IX) can be obtained by the interaction of the compound (VIII) in chloroform, tetrahydrofuran, toluene, ethyl acetate, or without solvent, using 2,3-dihydropyran, in the presence of an acidic catalyst such as p-toluensulfonate acid or chloride in the of aroda, at a temperature of from 0°C. to the boiling temperature under reflux, preferably from 0 to 50°C for from 0.5 hour to 24 hours, preferably from 0.5 hour to 8 hours.

When R” denotes methoxymethyl group, methoxyethoxymethyl group or benzyl group, the compound (IX) can be obtained by the interaction of the compound (VIII) in a solvent such as tetrahydrofuran or N,N-dimethylformamide, using methoxymethane, methoxyethoxymethyl, benzylchloride or benzylbromide, in the presence of a base such as sodium hydride or diisopropylamide lithium, at a temperature from 0°C to the boiling temperature under reflux, preferably from 0 to 50°C for from 0.5 hour to 24 hours, preferably from 0.5 hour to 8 hours.

The seventh stage

This stage is intended to obtain compound (XI) by the condensation reaction of compound (IX) and compound (X).

For example, when the condensation reaction is performed using a condensing agent, the compound (IX) interacts with the compound (X) in N,N-dimethylformamide, methylene chloride, chloroform, etc. or in a solvent, a mixture of these compounds, using a condensing agent, such as dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, at temperatures from -20°C to the boiling point inverse Ho what adalnikam preferably from 0 to 50°C for from 1 hour to 48 hours, preferably from 1 hour to 24 hours to obtain the compound (XI). In this case, it is possible to add additives such as hydroxybenzotriazole or N-hydroxyestrone acid.

When the condensation reaction goes through an acid chloride of the acid, the compound (IX) reacts with thionyl chloride, oxalylamino etc. in chloroform, methylene chloride, tetrahydrofuran, etc. or in a solvent, a mixture of these compounds, to obtain acid chloride (IX), and it interacts with the compound (X) in toluene, chloroform, tetrahydrofurane or in a solvent, a mixture of these compounds, in the presence of a base such as triethylamine or pyridine, at temperatures from -20°C to the boiling temperature under reflux, preferably from 0 to 40°C within 0.5 hour to 24 hours, preferably from 0.5 hours to 12 hours to obtain the compound (XI).

The eighth stage

This stage is designed to remove the protective group of the hydroxyl group of the compound (XI) and obtain the compounds represented by the General formula [1].

For example, when R denotes an acetyl group, the compound represented by the General formula [1]can be obtained by the interaction of the compound (XI) in tetrahydrofuran, ethanol, methanol, isopropanol, water or solvent, a mixture of these compounds, in risotti Foundation, such as lithium hydroxide, sodium hydroxide, potassium hydroxide or potassium carbonate, at temperatures from -20°C to the boiling temperature under reflux, preferably from 0 to 40°C for from 0.5 hour to 24 hours, preferably from 0.5 hours to 12 hours.

When R” denotes methoxymethyl group, methoxyethoxymethyl group, tetrahydropyranyloxy group or acetyl group, the compound represented by the General formula [1]can be obtained by reaction of the compound (XI) without solvent or in water, methanol, ethanol, propanol, tetrahydrofuran, etc. or in a solvent, a mixture of these compounds, using an acid such as hydrochloric acid or triperoxonane acid, at a temperature from 0°C to the boiling temperature under reflux, preferably from 0 to 50°C for from 0.5 hour to 24 hours, preferably from 0.5 hours up to 8 hours.

When R” denotes a benzyl group, the compound represented by the General formula [1]can be obtained by the interaction of the compound (XI) in methanol, ethanol, propanol, tetrahydrofuran, etc. or in a solvent, a mixture of these compounds using hydrogen or ammonium formate, in the presence of a catalyst of palladium-on-carbon, etc. at a temperature from about 0°C. to the boiling temperature under reflux FAV is preferably from 20 to 50°C for from 0.5 hour to 96 hours, preferably from 1 hour to 48 hours.

Therefore, compounds represented by the above General formulas (I) to (XI), can be used as intermediates for obtaining compounds of the present invention represented by the General formula [1].

2. The method of obtaining In:

This method of obtaining compounds of the present invention represented by the General formula [1], which is obtained directly from compound (VIII) without protection of the hydroxyl group.

(wherein each symbol has the same meaning as defined above).

The compound of the present invention represented by the General formula [1]can be obtained by the interaction of the compound (VIII) with compound (X) in N,N-dimethylformamide, methylene chloride, chloroform, etc. or in a solvent, a mixture of these compounds, using a condensing agent, such as dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, at temperatures from -20°C to the boiling temperature under reflux, preferably from 0 to 50°C for from 1 hour to 48 hours, preferably from 1 hour to 24 hours. In this case, it is possible to add additives such as hydroxybenzotriazole or N-hydroxyestrone acid.

3. The way to obtain

Salt of the compounds of the present invention, the pre is submitted to the General formula [1], can be obtained in accordance with a customary method, for example, in the following way:

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, simple diethyl ether, simple diisopropyl ether, toluene, n-hexane, n-heptane or in a solvent, a mixture of these compounds) and add solid undiluted or diluted dissolved form (using as solvent dilution, for example, water, methanol, ethanol, isopropyl alcohol, acetone, 2-butanone, tetrahydrofuran, ethyl acetate, isobutyl acetate, simple diethyl ether, simple, diisopropyl ether, toluene, n-hexane, n-heptane or the solvent, a mixture of these compounds), hydrocyclone (for example, hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonic acid, econsultancy acid, p-toluensulfonate acid, benzosulfimide acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulphonic acid, fumaric acid or maleic acid and so on), and the mixture can be stirred or left to stand at a temperature of from -20°C. to the boiling point of reverse refrigerator, prepost is positive from 0 to 50°C for from 1 hour to 48 hours, preferably from 1 hour to 24 hours, to obtain a salt of the compound of the present invention represented by the General formula [1].

EXAMPLES

Further, the connection of the present invention will be specifically described with reference to examples. However, the present invention is not limited to these examples. Along with the receipt of each connection is described by its NMR data.

Example 1-1

Obtain (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-(4-tert-butoxy-3,5-differenl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide

The first stage

Obtain methyl 3-nitrosalicylic

3-nitrosalicylic acid (500 g) dissolved in methanol (2.25 liters)add concentrated sulfuric acid (0.25 l) and the mixture is refluxed for 22 hours. The reaction solution is cooled on ice and the precipitated solid is collected by filtration and dried to obtain specified in the connection header (517,3 g).

(400 MHz, DMSO-d6): of 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).

The second stage

Obtain methyl 2-(2-methoxyethoxy)metiloksi-3-nitrobenzoate

Methyl 3-nitrosalicylic (516,3 g)obtained in the preceding stage, dissolved in N,N-dimethylformamide (2.0 l), add potassium carbonate (362 g), then added with stirring 1 chloromethoxy-2-metoxi is an (0,329 l) under ice cooling and the mixture is stirred at room temperature for 1 hour. The reaction solution is partitioned between water and ethyl acetate, an ethyl acetate layer is washed with water and then concentrated, receiving specified in the header connection (706,9 g).

(400 MHz, DMSO-d6): 3,22 (s, 3H), 3,41-of 3.43 (m, 2H), 3,65-3,68 (m, 2H), a 3.87 (s, 3H), 5,16 (s, 2H), 7,47 (t, J=7.9 Hz, 1H), of 8.06 (DD, J=7,9, 1.8 Hz, 1H), 8,11 (DD, J=7,9, 1.8 Hz, 1H).

The third stage

Obtain methyl 3-amino-2-(2-methoxyethoxy)methoxybenzoate

Methyl 2-(2-methoxyethoxy)metiloksi-3-nitrobenzoate (704,5 g)obtained in the preceding stage, dissolved in ethyl acetate (1 l) and tetrahydrofuran (1 l)add 5% palladium-on-carbon (water content 50%) (35 g) and the mixture is stirred for 4 hours in hydrogen atmosphere. The resulting reaction solution is filtered and the filtrate is concentrated and receiving specified in the header connection (617,7 g).

(400 MHz, DMSO-d6): 3,24 (s, 3H), 3.46 in-of 3.48 (m, 2H), 3,78-with 3.79 (m, 5H), to 4.98 (s, 2H), 5,16 (s, 2H), 6,84-6,84 (m, 1H), 6,88-6,91 (m, 2H).

The fourth stage

Obtain methyl 3-(5-picoline-2-yl)aminosalitsilata

The cesium carbonate (415 g), palladium acetate (8.8 g), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (25 g), methyl 3-amino-2-(2-methoxyethoxy)methoxybenzoate (200 g)obtained in the previous phase, and 2-chloro-5-picoline (103 g) are added to a toluene (1 l) in that order and stirred at 100°C for 2 days. The reaction solution is filtered and the filtrate concentrated. To the residue is added methanol (500 ml) is 6 N hydrochloric acid (200 ml), the mixture is refluxed and stirred for 0.5 hour. To the reaction solution was added activated charcoal (25 g), the mixture is stirred for 1 hour and then filtered. To the filtrate was added 1 N potassium citrate (2 l) and the precipitated crystalline product is collected by filtration (218 g). The crystals are collected by filtration, dissolved in ethyl acetate (1 l)is added silica gel (100 g) and the mixture is stirred at room temperature and then filtered. The filtrate is concentrated. The residue is recrystallized with acetone:water (2:1) (2 l) and the crystal is filtered and dried to obtain specified in the connection header (128 g).

(400 MHz, DMSO-d6): to 2.18 (s, 3H), 3,92 (s, 3H), 6.89 in (t, J=8.0 Hz, 1H),? 7.04 baby mortality (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 stage

Obtain methyl (R)-2-(oxiran-2-yl)metiloksi-3-(5-picoline-2-yl)aminobenzoate

Methyl 3-(5-picoline-2-yl)aminosalitsilata (139,5 g)obtained in the previous phase, and (R)-glycidylether (139,7 g) dissolved in dimethyl sulfoxide (700 ml), add potassium carbonate (74,6 g) and the mixture is stirred at room temperature for 1 hour. To the reaction solution was added ethyl acetate (1 l) and the mixture filtered. The filtrate is washed with water, then dried on anhydrous sodium sulfate and then concentrated. The residue is suspended in 2-prop is zero (400 ml) and the suspension is stirred at room temperature and crystallized. The crystal is collected by filtration and dried to obtain specified in the connection header (124 g).

(400 MHz, DMSO-d6): are 2.19 (s, 3H), was 2.76 (sq, J=2,6 Hz, 1H), 2,86 (DD, J=5.0 and 4.3 Hz, 1H), 3,40-to 3.41 (m, 1H), 3,86 (s, 3H), 3,93 (sq, 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), from 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 Hz, 1H), 8,19 (s, 1H), 8,53 (DD, J=8,2, 1.8 Hz, 1H).

Sixth stage

Obtain (S)-methyl 4-(5-picoline-2-yl)-3-hydroxymethyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxylate

Methyl (R)-2-(oxiran-2-yl)metiloksi-3-(5-picoline-2-yl)aminobenzoate (124 g)obtained in the preceding stage, dissolved in N,N-dimethylacetamide (1,24 l), add potassium carbonate (81,8 g) and the mixture was stirred at 100°C for 2 hours. The reaction solution is divided between water and ethyl acetate and an ethyl acetate layer washed with water, then dried over anhydrous magnesium sulfate and concentrated, obtaining specified in the header connection (142,1 g).

(400 MHz, DMSO-d6): of 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-to 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-to 7.18 (m, 2H), 7,35 (d, J=8,2 Hz, 1H), 7,53 (d, J=8,4 Hz, 1H), 8,15 (s, 1H).

The seventh stage

Obtain (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxylic acid

(S)-methyl 4-(5-picoline-2-yl)-3-hydroxymethyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxylate (142 g)obtained in the previous phase, astonaut in methanol (700 ml), add 4 N sodium hydroxide (150 ml), the mixture is refluxed and stirred for 2 hours. The reaction solution is concentrated and neutralized 6 N hydrochloric acid and then extracted with ethyl acetate, an ethyl acetate layer washed with water, dried over anhydrous magnesium sulfate and then concentrated. To the residue is added ethyl acetate (50 ml) and simple diisopropyl ether (400 ml) and the precipitated solid filtered and dried to obtain specified in the connection header (101,6 g).

(400 MHz, DMSO-d6): of 2.23 (s, 3H), 3,38 (t, J=9.9 Hz, 1H)and 3.59 (DD, J=10,6, 5.7 Hz, 1H), 3,98 (DD, J=10,8, and 2.6 Hz, 1H), 4,37-4,39 (m, 1H), 4,55 (DD, J=10,9, 1.2 Hz, 1H), 5,14 (users, 1H), PC 6.82 (t, J=7.9 Hz, 1H), 7,16-to 7.18 (m, 2H), to 7.32 (DD, J=8,2, 1.5 Hz, 1H), 7,53 (DD, J=8,4, 2.4 Hz, 1H), 8,14-to 8.14 (m, 1H), 12,66 (users, 1H).

The eighth stage

Obtain (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-(4-tert-butoxy-3,5-differenl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide

(S)-4-(5-picoline-2-yl)-3-hydroxymethyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxylic acid (400 mg)obtained in the preceding stage, dissolved in N,N-dimethylformamide (2 ml). Add 4-tert-butoxy-3,5-diptiranjan (268 mg), 1-hydroxybenzotriazole (204 mg), and hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (281 mg) are added in that order and the mixture is stirred over night at room temperature. To the reaction solution was added water easymany solution of sodium bicarbonate and then extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated. The residue is purified by chromatography on silica gel (hexane:ethyl acetate = 4:3) to obtain specified in the title compound (364 mg).

Example 1-2

Obtain (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-(3,5-debtor-4-isopropoxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide

(S)-4-(5-picoline-2-yl)-3-hydroxymethyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxylic acid (400 mg)obtained in the seventh stage of the example 1-1, dissolved in N,N-dimethylformamide (2 ml). 3,5-Debtor-4-isopropoxyaniline (249 mg), 1-hydroxybenzotriazole (204 mg), and hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (281 mg) are added in that order and the mixture is stirred over night at room temperature. To the reaction solution was added water and a saturated solution of sodium bicarbonate and then extracted with ethyl acetate. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated. The residue is purified by chromatography on silica gel (hexane:ethyl acetate = 4:3) to obtain specified in the title compound (332 mg).

Example 1-3

Obtain (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-(3,5-debtor-4-ethoxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide

()-4-(5-picoline-2-yl)-3-hydroxymethyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxylic acid (400 mg), received on the seventh stage of the example 1-1, dissolved in N,N-dimethylformamide (2 ml). 3,5-Debtor-4-ethoxyaniline (230 mg), 1-hydroxybenzotriazole (204 mg), and hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (281 mg) are added in that order and the mixture is stirred over night at room temperature. Add water and a saturated solution of sodium bicarbonate and then extracted with ethyl acetate. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated. The residue is purified by chromatography on silica gel (hexane:ethyl acetate = 5:4) to obtain specified in the title compound (358 mg).

Example 1-4

Obtain (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-[2-(2,2-dimethylpropylene)pyridine-5-yl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide

(S)-4-(5-picoline-2-yl)-3-hydroxymethyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxylic acid (300 mg)obtained in the seventh stage of the example 1-1, dissolved in N,N-dimethylformamide (3 ml). Hydrochloride 5-amino-2-(2,2-dimethylpropylene)pyridine (253 mg), triethylamine (0,14 ml) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (211 mg) are added in that order and the mixture is stirred over night at room temperature. To the reaction solution was added water and a saturated solution of sodium bicarbonate and then extracted with er what racedata. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated. The residue is purified by chromatography on silica gel to obtain specified in the title compound (340 mg).

Example 1-5

Obtain (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-(2-tert-butoxypropan-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide

(S)-4-(5-picoline-2-yl)-3-hydroxymethyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxylic acid (148 mg)obtained in the seventh stage of the example 1-1, dissolved in N,N-dimethylformamide (5 ml). 5-Amino-2-tert-butoxypropan (82 mg) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (103 mg) are added in that order and the mixture is stirred over night at room temperature. To the reaction solution was added water and a saturated solution of sodium bicarbonate and then extracted with ethyl acetate. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated. The resulting residue is purified by chromatography on silica gel (hexane:ethyl acetate = 1:1) to obtain specified in the title compound (94 mg).

Example 1-6

Obtain (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-[2-(2,2,2-triptoreline)pyridine-5-yl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide

(S)-4-(5-picoline-2-yl)-3-hydroxymethyl-,4-dihydro-2H-benzo[1,4]oxazin-8-carboxylic acid (150 mg), received on the seventh stage of the example 1-1, dissolved in N,N-dimethylformamide (1.5 ml). Hydrochloride 5-amino-2-(2,2,2-triptoreline)pyridine (114 mg), triethylamine (0,07 ml) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (105 mg) are added in that order and the mixture is stirred over night at room temperature. To the reaction solution was added water and a saturated solution of sodium bicarbonate and then extracted with ethyl acetate. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated. The resulting residue is purified by chromatography on silica gel (hexane:ethyl acetate = 1:1) to obtain specified in the title compound (154 mg).

Example 1-7

Obtain (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-(2-isobutoxide-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide

(S)-4-(5-picoline-2-yl)-3-hydroxymethyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxylic acid (388 mg)obtained in the seventh stage of the example 1-1, dissolved in N,N-dimethylformamide (4 ml). Hydrochloride 5-amino-2-isobutoxide (262 mg), triethylamine (of 0.18 ml) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (272 mg) are added in that order and the mixture is stirred over night at room temperature. To the reaction solution was added water and a saturated solution of hydrocarbon the sodium and then extracted with ethyl acetate. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated. The resulting residue is purified by chromatography on silica gel (hexane:ethyl acetate = 1:1) to obtain specified in the title compound (402 mg).

Example 1-8

Obtain (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-[3,5-debtor-4-(2,2,2-triptoreline)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide

The first stage

Obtain (S)-3-acetoxymethyl-4-(5-picoline-2-yl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxylic acid

(S)-4-(5-picoline-2-yl)-3-hydroxymethyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxylic acid (24,1 g)obtained in the seventh stage of the example 1-1, was dissolved in tetrahydrofuran (240 ml). Add 4-(dimethylamino)pyridine (9.8 g) and acetic anhydride (7,6 ml) and the mixture is stirred at room temperature for 0.5 hours. The reaction solution was separated between ethyl acetate and a solution of dilute acetic acid, and an ethyl acetate layer washed with water, then dried over anhydrous magnesium sulfate and concentrated. Simple diisopropyl ether is added to the concentrated residue and the precipitated crystal is collected by filtration and dried to obtain specified in the connection header (23,33 g).

(400 MHz, DMSO-d6) to 1.99 (s, 3H), of 2.23 (s, 3H), 4,03-4,11 (m, 2H), 4,18-is 4.21 (m, 1H), 4,48 (d, J=11,25 Hz, 1H), 4.72 in-4,74 (m, 1H), 6,86 DD, J=to 7.61, to 7.61 Hz, 1H), 7,17-7,20 (m, 2H), 7,33 (DD, J=8,16, to 0.88 Hz, 1H), 7,54 (DD, J=8,49, 2,32 Hz, 1H), 8,15 (d, J=1,54 Hz, 1H), 12,64 (users, 1H).

The second stage

Obtain (S)-3-acetoxymethyl-4-(5-picoline-2-yl)-N-[3,5-debtor-4-(2,2,2-triptoreline)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide

(S)-3-acetoxymethyl-4-(5-picoline-2-yl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxylic acid (400 mg)obtained in the preceding stage, dissolved in tetrahydrofuran (4 ml), add thionyl chloride (is 0.102 ml) with stirring under ice cooling, and the mixture is stirred for 1.5 hours. The reaction solution is concentrated and the residue diluted with tetrahydrofuran (4 ml). Add triethylamine (0,245 ml) and 3,5-debtor-4-(2,2,2-triptoreline)aniline (267 mg) under stirring at room temperature and the mixture is stirred for 0.5 hour. The reaction solution is divided between water and ethyl acetate and an ethyl acetate layer was washed with a saturated solution of sodium chloride, then dried over anhydrous magnesium sulfate and concentrated, obtaining specified in the header connection (749 mg).

(400 MHz, DMSO-d6) to 1.99 (s, 3H), of 2.25 (s, 3H), 4,12-4,16 (m, 2H), 4,22-of 4.25 (m, 1H), to 4.52 (d, J=11,25 Hz, 1H), 4.75 V-of 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=at 8.60 Hz, 1H), was 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).

The third stage

Obtain (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-[3,5-debtor-4-(2,2,2-triptoreline)phenyl]-3,4-dihyd the on-2H-benzo[1,4]oxazin-8-carboxamide

(S)-3-acetoxymethyl-4-(5-picoline-2-yl)-N-[3,5-debtor-4-(2,2,2-triptoreline)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide (749 mg)obtained in the preceding stage, dissolved in methanol (4 ml), add 4 N sodium hydroxide (0.35 ml) and the mixture is stirred at room temperature for 0.5 hour. The reaction solution is concentrated and then is divided between water and ethyl acetate and obtained an ethyl acetate layer was washed with a saturated solution of sodium chloride, then dried over anhydrous magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel to obtain specified in the title compound (340 mg).

Example 1-9

Obtain (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-[3,5-debtor-4-(2-hydroxy-2-methylpropyloxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide

The first stage

Obtain (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-(3,5-debtor-4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide

(S)-4-(5-picoline-2-yl)-3-hydroxymethyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxylic acid (900 mg)obtained in the seventh stage of the example 1-1, dissolved in N,N-dimethylformamide (4.5 ml). Add 3,5-debtor-4-hydroxyanisol (330 mg), and hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (630 mg) in that order and the mixture is stirred over night at room temperature. To the reaction solution on billaut water and a saturated solution of sodium bicarbonate and then extracted with ethyl acetate. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried over anhydrous solution of magnesium sulfate and then concentrated. The residue is purified by chromatography on silica gel (hexane:ethyl acetate = 1:1) to obtain specified in the title compound (550 mg).

(400 MHz, DMSO-d6) to 2.25 (s, 3H), 3,44-of 3.46 (m, 1H), 3,63-the 3.65 (m, 1H), 4,05-4,08 (m, 1H), 4,39-to 4.41 (m, 1H), 4,60 (d, J=9,74 Hz, 1H), 5,15 (users, 1H), 6.89 in (DD, J=7,88, 7,88 Hz, 1H), 7,10 (DD, J=7,65, of 1.62 Hz, 1H), 7,21 (d, J=8.35 Hz, 1H), 7,34 (DD, J=8,12, of 1.62 Hz, 1H), 7,46-7,49 (m, 2H), 7,56 (DD, J=8,35, to 1.86 Hz, 1H), 8,17 (DD, J=1,16, 1,16 Hz, 1H), to 9.91 (users, 1H), 10,23 (s, 1H).

The second stage

Obtain (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-(3,5-debtor-4-(ethoxycarbonylmethoxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide

(S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-(3,5-debtor-4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide (459 mg)obtained in the preceding stage, dissolved in N,N-dimethylformamide (4.5 ml). Add potassium carbonate (150 mg) and ethylbromoacetate (180 mg) and the mixture was stirred at 60°C for 3 hours. The reaction solution is divided between water and ethyl acetate. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated. The residue purified by chromatography on silica gel (hexane:ethyl acetate = 2:3) to obtain specified in the title compound (310 mg).

(400 MHz, DMSO-d6) to 1.21 (t,J=7,06 Hz, 3H), 2,24 (s, 3H), 3.43-3.45 points (m, 1H), 3,60-the 3.65 (m, 1H), 4.04 the-4,08 (m, 1H), 4,16 (sq, J=7,06 Hz, 2H), to 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 in (DD, J=7,83, 7,83 Hz, 1H), was 7.08 (DD, J=7,50, 1,32 Hz, 1H), 7,20 (d, J=at 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), accounted for 10.39 (s, 1H).

The third stage

Obtain (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-[3,5-debtor-4-(2-hydroxy-2-methylpropyloxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide

(S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-(3,5-debtor-4-(ethoxycarbonylmethoxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide (310 mg)obtained in the preceding stage, dissolved in tetrahydrofuran (3.1 ml) and added dropwise motility (0,98 M solution in tetrahydrofuran) (3,7 ml) under stirring conditions cooling with ice and then stirred for 1.5 hours. The reaction solution was poured into 5% citric acid solution and extracted with ethyl acetate. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated. The residue is purified by chromatography on silica gel (hexane:ethyl acetate = 1:3) to obtain specified in the title compound (72 mg).

Example 1-10

Obtain (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-[3,5-debtor-4-(1,1-dimethyl-2-hydroxyethyloxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide

The first stage

Obtain (S)-4-(5-picoline-2-yl)3-hydroxymethyl-N-[3,5-debtor-4-(1-etoxycarbonyl-1-methyl)ethoxyphenyl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide

(S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-(3,5-debtor-4-hydroxyphenyl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide (780 mg)obtained in the first stage of example 1-9, dissolved in dimethyl sulfoxide (7.8 ml). Add potassium carbonate (240 mg) and ethyl-2-bromo-2-methylpropionate (0,279 ml) and the mixture was stirred at 80°C for 1 hour. The reaction solution is divided between water and ethyl acetate. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated. The residue is purified by chromatography on silica gel (hexane:ethyl acetate = 1:1) to obtain specified in the title compound (740 mg).

(400 MHz, DMSO-d6) to 1.24 (t, J=7,19 Hz, 4H), for 1.49 (s, 6H), of 2.25 (s, 3H), 3,44-of 3.46 (m, 1H), 3,63-3,66 (m, 1H), 4,06-4.09 to (m, 1H), 4,17 (sq, J=7,11 Hz, 2H), 4,39-to 4.41 (m, 1H), 4,60 (d, J=10,20 Hz, 1H), 5,15 (t, J=5,57 Hz, 1H), 6.90 to (DD, J=7,88, 7,88 Hz, 1H), to 7.09 (DD, J=7,42, 1.39 Hz, 1H), 7,22 (d, J=8,81 Hz, 1H), 7,35 (DD, J=8,12, of 1.62 Hz, 1H), 7,53-EUR 7.57 (m, 3H), 8.17-a 8,17 (m, 1H), 10,47 (s, 1H).

The second stage

Obtain (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-[3,5-debtor-4-(1-carboxy-1-methyl)ethoxyphenyl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide

(S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-(3,5-debtor-4-(1-etoxycarbonyl-1-methyl)ethoxyphenyl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide (740 mg)obtained in the preceding stage, dissolved in ethanol (7.4 ml). Add 4 N sodium hydroxide solution (0,38 ml) and the mixture is stirred at those who tell night at room temperature. The reaction solution was poured into 5% citric acid solution and extracted with tetrahydrofuran. The layer of tetrahydrofuran, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated, getting mentioned in the title compound (586 mg).

(400 MHz, DMSO-d6) 1,45 (s, 6H), of 2.25 (s, 3H), of 3.45 (DD, J=becomes 9.97, becomes 9.97 Hz, 1H), 3,63-to 3.64 (m, 1H), 4,06-4,08 (m, 2H), to 4.38-to 4.41 (m, 1H), 4,59 (d, J=10,20 Hz, 1H), 6.90 to (DD, J=7,88, 7,88 Hz, 1H), to 7.09 (DD, J=7,65, of 1.62 Hz, 1H), 7,21 (d, J=8,81 Hz, 1H), 7,35 (DD, J=8,12, of 1.62 Hz, 1H), 7,53-7,56 (m, 3H), 8,17 (DD, J=1,16, of 0.58 Hz, 1H), 10,45 (s, 1H), 12,94 (users, 1H).

The third stage

Obtain (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-[3,5-debtor-4-(1,1-dimethyl-2-hydroxyethyloxy)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide

The triethylamine (0,191 ml), ethylchloride (0,131 ml) and then the suspension of (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-[3,5-debtor-4-(1-carboxy-1-methyl)ethoxyphenyl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide (586 mg)obtained at the previous step in tetrahydrofuran (5,9 ml), added to a tetrahydrofuran (3 ml) under stirring conditions cooling with ice and the mixture stirred at room temperature for 1 hour. The reaction solution is cooled on ice and add sodium borohydride (43 mg) and methanol (5,9 ml). The reaction solution was poured into 10% solution of ammonium chloride and extracted with ethyl acetate. An ethyl acetate layer was washed with saturated of restoranlarda sodium, dried over anhydrous magnesium sulfate and then concentrated. The residue is purified by chromatography on silica gel (hexane:ethyl acetate = 2:1) to obtain specified in the title compound (136 mg).

Chemical structure and NMR data of the compounds obtained in examples 1-1 - 1-10 shown in table 1 and table 2.

Table 1
ExampleChemical structureNMR
1-1(400 MHz, DMSO-d6) to 1.32 (s, 9H), 2,24 (s, 3H), 3,44-3,47 (m, 1H), 3,62-3,63 (m, 1H), 4.04 the-4,06 (m, 1H), 4 39 (t, J=7,28 Hz, 1H), 4,59 (d, J=10,37 Hz, 1H), 5,11 (t, J=5,40 Hz, 1H), 6.89 in (DD, J=7,94, 7,94 Hz, 1H), was 7.08 (DD, J=7,39, 1,21 Hz, 1H), 7,20 (d, J=scored 8.38 Hz, 1H), 7,33 (DD, J=8,27, 1,43 Hz, 1H), 7,51-EUR 7.57 (m, 3H), 8,16 (d, J=2,43 Hz, 1H), the 10.40 (s, 1H).
1-2(400 MHz, DMSO-d6) of 1.29 (d, J=6,03 Hz, 6H), and 2.26 (s, 3H), 3.45 points-of 3.48 (m, 1H), 3,64-3,66 (m, 1H), 4,08 (DD, J=10,67, 2,32 Hz, 1H), 4,29 is 4.35 (m, 1H), 4,39-to 4.46 (m, 1H), br4.61 (d, J=10,20 Hz, 1H), 5,15 (t, J=5,57 Hz, 1H), 6.90 to (DD, J=7,88, 3,94 Hz, 1H), 7,11 (DD, J=7,65, of 1.62 Hz, 1H), 7,22 (d, J=8.35 Hz, 1H), 7,35 (DD, J=8,35, 1.39 Hz, 1H), 7,54-EUR 7.57 (m, 3H), 8,17 (d, J=2,32 Hz, 1H), 10,41 (s, 1H).
1-3 (400 MHz, DMSO-d6) of 1.30 (t, J=of 6.96 Hz, 3H), of 2.25 (s, 3H), 3,44-of 3.46 (m, 1H), 3,62-to 3.64 (m, 1H), 4,11 (sq, J=of 6.96 Hz, 3H), 4,39-to 4.41 (m, 1H), 4,59 (d, J=10,20 Hz, 1H), 5,15 (t, J=5,57 Hz, 1H), 6.90 to (DD, J=7,88, 7,88 Hz, 1H), to 7.09 (DD, J=7,65, of 1.62 Hz, 1H), 7,21 (d, J=8,81 Hz, 1H), 7,35 (DD, J=8,35, 1.39 Hz, 1H), 7,53-7,58 (m, 3H), 8,17 (d, J=2,32 Hz, 1H), 10,41 (s, 1H).
1-4(400 MHz, DMSO-d6) 0,99 (s, 9H), 2,24 (s, 3H), 3,44 (dt, J=15,0, a 5.3 Hz, 1H), 3,60-3,66 (m, 1H), 3,93 (s, 2H), 4,07 (DD, J=10,9, and 2.6 Hz, 1H), and 4.40 (s, 1H), 4,60 (d, J=9.7 Hz, 1H), 5,14 (t, J=5.6 Hz, 1H), 6,83-of 6.90 (m, 2H), 7,13 (DD, J=7,5, 1.5 Hz, 1H), 7,20 (d, J=8.6 Hz, 1H), 7,32 (DD, J=8,2, 1.5 Hz, 1H), 7,55 (DD, J=9,0, 2.6 Hz, 1H), 8,02 (DD, J=8,9, 2.7 Hz, 1H), 8,16 (d, J=2.6 Hz, 1H), 8,48 (d, J=2.1 Hz, 1H), 10,15 (s, 1H).
1-5(400 MHz, DMSO-d6) of 1.52 (s, 9H), 2,24 (s, 3H), 3,44 (dt, J=14,8, and 5.2 Hz, 1H), 3,60-3,66 (m, 1H), 4,06 (DD, J=11,0, 2.7 Hz, 1H), and 4.40 (t, J=7,3 Hz, 1H), 4,60 (d, J=9.7 Hz, 1H), 5,14 (t, J=5.6 Hz, 1H), of 6.71 (d, J=8,8 Hz, 1H), to 6.88 (t, J=7.8 Hz, 1H), 7,12 (DD, J=7,7, and 1.6 Hz, 1H), 7,20 (d, J=8,3 Hz, 1H), 7,32 (DD, J=8,1, 1,6 Hz, 1H), 7,55 (DD, J=8,8, 2.1 Hz, 1H), 7, 99 (DD, J=8,8, 2.8 Hz, 1H), 8,16 (d, J=2.3 Hz, 1H), 8,44 (d, J=2.3 Hz, 1H), 10,13 (s, 1H).
1-6(400 MHz, DMSO-d6) 2,24 (s, 3H), 3,44 (TD, J=9,9, 6.0 Hz, 1H), 3,60-3,66 (m, 1H), 4,07 (DD, J=10,9, 2.8 Hz, 1H), and 4.40 (t, J=6,8 Hz, 1H), 4,60 (d, J=10.0 Hz, 1H), equal to 4.97 (sq, J=9.1 Hz, 2H), 5,14 (t, J=5.6 Hz, 1H), 6.89 in(t, J=7.9 Hz, 1H), 7,01 (d, J=8,8 Hz, 1H), 7,13 (DD, J=7,5, 1.5 Hz, 1H), 7,20 (d, J=8.6 Hz, 1H), 7,33 (DD, J=8,2, 1.5 Hz, 1H), 7,55 (DD, J=8,8, 2.1 Hz, 1H), 8,12 (DD, J=8,9, 2.7 Hz, 1H), 8,16 (d, J=2.3 Hz, 1H), 8,56 (d, J=2.3 Hz, 1H), 10,28 (s, 1H).
1-7(400 MHz, DMSO-d6) to 0.97 (d, J=6,7 Hz, 6H), 1,97-2,07 (m, 1H), 2,24 (s, 3H), of 3.45 (dt, J=15,0, and 5.2 Hz, 1H), 3,60-3,66 (m, 1H), 4,01 (d, J=6,7 Hz, 2H), 4,07 (DD, J=10,8, 2.4 Hz, 1H), and 4.40 (t, J=7,4 Hz, 1H), 4,60 (DD, J=10,9, and 0.9 Hz, 1H), 5,13 (t, J=5.6 Hz, 1H), for 6.81-6.90 to (m, 2H), 7,13 (DD, J=7,5, 1.5 Hz, 1H), 7,20 (d, J=8,3 Hz, 1H), 7,32 (DD, J=8,1, 1,6 Hz, 1H), 7,55 (DD, J=8,6, and 2.1 Hz, 1H), 8,02 (DD, J=8,9, 2.7 Hz, 1H), 8,16 (d, J=2,3 Hz, 1H), 8,48 (d, J=2.3 Hz, 1H), 10,14 (s, 1H).

Table 2
1-8(400 MHz, DMSO-d6) and 2.26 (s, 3H), 3,44-of 3.46 (m, 1H), 3,61-3,66 (m, 1H), 4,07 (DD, J=10,90, 2.55 Hz, 1H), 4,39-and 4.40 (m, 1H), 4,59 (d, J=10,20 Hz, 1H), 4,77 (sq, J=8,97 Hz, 2H), 5,14 (t, J=5,57 Hz, 1H), 6.90 to (DD, J=7,88, 7,88 Hz, 1H), 7,10 (DD, J=7,42, 1.39 Hz, 1H), 7,21 (d, J=8.35 Hz, 1H), 7,35 (DD, J=8,35, 1.39 Hz, 1H), 7,56-to 7.61 (m, 3H), 8,17 (d, J=1,16 Hz, 1H), 10,47 (s, 1H).
1-9(400 MHz, DMSO-d6) to 1.22 (s, 6H), of 2.25 (s, 3H), 3,40-of 3.48 (m, 1H), 3,61-3,66 (m, 1H), 3,80 (s, 2H), 4,07 (DD, J=10,90, 2.55 Hz, 1H), 4,39-and 4.40 (m, 1H), 4,58-br4.61 (m, 2H), 5,14 (t, J=5,57 Hz, 1H), 6.90 to (DD, J=7,88, 7,88 Hz, 1H), 7,09 (DD, J=7,88, 1.9 Hz, 1H), 7,21 (d, J=8,81 Hz, 1H), 7,34 (DD, J=8,12, of 1.62 Hz, 1H), 7,52-7,56 (m, 3H), 8,17 (d, J=2,32 Hz, 1H), accounted for 10.39 (s, 1H).
1-10(400 MHz, DMSO-d6) to 1.22 (s, 6H), of 2.25 (s, 3H), 3.46 in-3,48 (m, 3H), 3,61-3, 66 (m, 1H), 4,07 (DD, J=10,90, 2.55 Hz, 1H), 4,39-and 4.40 (m, 1H), 4,59 (d, J=10,20 Hz, 1H), is 4.93 (t, J=6,03 Hz, 1H), 5,14 (t, J=5,57 Hz, 1H), 6.90 to (DD, J=7,88, 3,94 Hz, 1H), was 7.08 (DD, J=7,65, of 1.62 Hz, 1H), 7,21 (d, J=8,81 Hz, 1H), 7,35 (DD, J=8,12, of 1.62 Hz, 1H), 7,53-7,56 (m, 3H), 8,17 (d, J=2,32 Hz, 1H), 10,43 (s, 1H).

Example test

Below will be described the analysis to assess the inhibiting VR1 compounds of the present invention.

The analysis was designed to assess thein vitroinhibitory effect of one of VR1 agonists at the entrance of CA2+in cells caused by proton (example test [1])was subjected to the test of metabolic stability in human liver S9 (example test [2]), test in vitro permeability through the membrane (Sample test [3]) and test for stability in solution 1 according to the Pharmacopoeia of Japan (the example test [4]), using the compound of the present invention and compounds of the comparative examples shown below in table 3. Compounds of comparative examples were obtained in accordance with the production method, described in the document PCT/JP2005/013446.

Table 3

An example of testing [1]: Inhibition of the input With the 2+in cells:

Inhibitory effect of VR1 activity was evaluated by measuring the capture of CA2+cells.

Cells of rat glioma (C6BU1), stably expressing human VR1, suspended in 20 mm MES buffer (pH 6.8, containing 20 mm morpholinepropanesulfonic (hereinafter referred to as MES), 115 mm NaCl, 5 mm KCl, 1 mm MgCl2and 14 mm D-glucose) to obtain the density of cells 1×106cells/ml of suspension was added a solution of fluorescent dye Fura 2-AM (Dojindo Corporate, Cat. No. 343-05401) to bring its concentration to 5 μm. Then added this amount of Pluronic F-127 (Wako Pure Chemical Industries, Ltd., Cat. No. P6866)so that its content was 0.1%. Then the suspension was incubated at 37°C for 30 minutes. The cells were collected and washed twice 20 mm MES buffer. Cells are again suspended with obtaining the density of cells 5×105cells/ml 500-μl portion of the suspension was placed in a cuvette (MC MEDICAL, INC., Cat. No. SSR3121), to which was added 10 μl of 20 mm MES buffer containing 250 mm CaCl2to enable the CA2+in cells. At the same time also added 5 μl of a solution of test compounds (in the range from 100 μm to 10 nm in DMSO) to ensure that its final concentration in the range from 1 μm to 0.1 nm. Alternative 5 µl DMSO was added as a control to ensure a final concentration of 1% DMSO. 10 minutes after these additions suspend the Yu was placed in intracellular ionomer (CAF-110; JASCO). Cells stimulated protons by adding 50 μl of 20 mm MES buffer at pH 1.1 to establish the pH of the suspension at the level of 5.7. The activity of the test compounds was determined as the difference between the minimum fluorescence intensity before stimulation with agonist and its maximum after stimulation. The value of the IC50received as a percentage share of inhibition of the test compound compared to control.

Example test [2] test metabolic stability in human liver S9

Human liver S9 (final concentration: 2 mg protein/ml) suspended in 100 mm potassium phosphate buffer (pH 7.4, containing β-nicotinamide adenindinucleotide 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 then mixed with the test compound dissolved in DMSO. The mixture is incubated at 37°C for 0 and 60 minutes and then was added acetonitrile containing formic acid (final concentration of 0.1%). Test connection (uncharged) in the supernatant after centrifugation was measured using high-performance liquid chromatography/mass spectrometry (LC/MS). Residual ratio (%) was calculated by the measured value in accordance with the following equation:

Residual ratio (%) = (number of tested compounds on the Les 60 minutes incubation/number of tested compounds at 0 minute incubation) × 100

Example test [3] test in vitro permeability across membranes

10 mm DMSO Solution of test compound was diluted with Hanks buffer (pH 6.5), 25 μm to prepare a solution of the test compound. 300 µl of the apical buffer (Hanks buffer (pH 6.5)and 1 ml basolateral buffer (4.5% Hanks buffer containing BSA (pH 7.4)are added respectively to the apical side (the side of the mucosa) and basolateral side (serosal side) cells SASO (cells cultured for 6 days after sowing), sown in a Cup to test permeability (analytical device WASOUT HTS Caco2: BD Biosciences), and pre-incubated at 37°C for 20 minutes, followed by measurement of transepithelial electrical resistance. Each buffer with the apical side and basolateral side was removed by aspiration. Then, accordingly to the apical side and basolateral side was added 300 μl of test compound and 1 ml basolateral buffer and incubated at 37°C for 2 hours under stirring at 60 rpm Then performed the sampling of each of the apical side and basolateral side and the sample was added acetonitrile and centrifuged. Test the connection (uncharged) in the supernatant was measured using high-performance liquid chromatography/tandem the th mass spectrometry (LC/MS/MS: Quantum, Thermo Quest).

The membrane permeability coefficient (Papp) was calculated in accordance with the following equation:

Papp (cm/sec) = (dx/dt)/(A×C0)

(where dx represents the number of tested compounds (uncharged) basolateral side after incubation, dt denotes the time of incubation, And denotes the surface area of the cell membrane and0denotes the initial concentration of the test compound on the apical side.)

An example of testing [4] the test on the stability in solution 1 according to the Pharmacopoeia of Japan

The test compound was dissolved in a mixed solution of CH3CN and the solution 1 in the Pharmacopoeia of Japan (volume ratio 3:7) and brought in a vial for HPLC and the concentration of 0.05 mm. The test compound was measured by HPLC at 40°C in 0 and 8 hours. The measured value at 0 hours was defined as 100% to determine the residual ratio of the tested connections after 8 hours.

In this document "solution 1 in the Pharmacopoeia of Japan" is a solution in which 21 ml of concentrated hydrochloric acid was added to 6 g of sodium chloride and then brought up to a volume of 3 l of distilled water.

Results inhibitory effect against the entrance of CA2+cells (example test [1]), test metabolic stability in human liver S9 (example test [2]) in order to test the permeability of membranes in vitro(example test [3]) is shown below in tables 4-6.

Table 4
An example is a Comparative exampleChemical structureInhibition VR1 IC50(nm)The residual value after passing through a human liver S9 (%)Membrane permeability Papp (×10-6cm/sec)
Example
1-1
0,02490,88,59
Example
1-2
0,03865,320,96
Example
1-3
0,24to 59.626,93
Example
1-4
0,01939,730,25
Example
1-5
0,6682,238,07
Example
1-6
0,1591,837,53
Example
1-7
0,1450,437,94

Table 5
Example
1-8
0,03891,513,61
Example
1-9
0,5477,350,36
Example
1-10
0,6992,2to 39.22
Cf. example 13 86,327,1
Cf. example 21,390,124,2
Cf. example 31889,425,6
Cf. example 45,292,55,3
Cf. example 542,064,97,9

Table 6
Cf. example 60,377,321,1
Cf. example 70,455,118,2
Cf. example 8 762,9to 43.1
Cf. example 90,1265,919,4
Cf. example 100,0482,36,7
Cf. example 110,3666,7of 40.3
Cf. example 120,0354,510,4
Cf. example 130,12for 91.328,6

[1]Discussion of test results the inhibition input CA2+cells (example test [1])

The value of the IC50compounds of examples 1-1 through 1-10, included in the compound of the present invention represented by the General formula is [1], constituted, as shown in tables 4-6, respectively 0024 nm, 0,038 nm, 0,024 nm, 0,019 nm, of 0.66 nm to 0.15 nm, 0.14 nm, 0,038 nm, of 0.54 nm, and 0.69 nm, and the average value of the IC50these 10 compounds was 0.25 nm.

In particular, the compounds of examples 1-1, 1-2, 1-4 and 1-8 had a value IC50accordingly 0,024, 0,038, and 0,019 0,038 nm, and they had an excellent inhibitory effect on the activity of VR1.

On the other hand, the value of the IC50compounds of comparative examples 1-13 were as shown in tables 4-6, respectively 3 nm, 1.3 nm, 18 nm and 5.2 nm, 42,0 nm, 0.3 nm, 0.4 nm, 7 nm, 0,12 nm of 0.04 nm to 0.36 nm to 0.03 nm and 0.12 nm, and the average value of the IC50these 13 compounds of the comparative examples was 5.99 nm.

As described above, the compound of the present invention possessed inhibitory activity is approximately 24 times higher than the activity of the compounds of comparative examples from the point of view of the average value of the IC50.

[2] Discussion of test results the metabolic stability in human liver S9 (example testing [2]

The residual ratio of the compounds of examples 1-1 through 1-10, included in the compound of the present invention represented by the General formula [1], after passing through a human liver S9 were as shown in tables 4-6, respectively 90,8%, 65,3%, 59,6%, 39,7%, 82,2%, 91,8%, 50,4%, 91,5%, 77,3% and 92.2%, and the average residual ratio of 10 compounds the donkey passing through the human liver S9 was 74%.

In particular, the compounds of examples 1-1, 1-6, 1-8 and 1-10 had a residual ratio of 90% or higher and showed a significant high residual ratio, i.e. the visible high metabolic stability in liver S9. Therefore, these compounds can be used as an excellent drug that can counteract oxidative metabolism and have a lasting effect.

On the other hand, the residual ratio of the compounds of comparative examples 1 to 13 after passing through the human liver S9, as shown in tables 4-6, respectively 86,3%, 90,1%, 89,4%, 92,5%, 64,9%, 77,3%, 55,1%, 62,9%, 65,9%, 82,3%, 66,7%, 54,5% and 91.3%, and the average residual correlation of these 13 compounds of the comparative examples was 75%.

[3] the Discussion of the test results on the permeability of membranesin vitro(example test [3])

Membrane permeabilityin vitrocompounds of examples 1-1 through 1-10, included in the compound of the present invention represented by the General formula [1], respectively 30,25×10-6, 38,07×10-6, 37,53×10-6, 37,94×10-6, 13,61×10-6, 50,36×10-6and to 39.22×10-6from the point of view of values Papp (cm/sec), and average Papp (cm/sec) of these 10 compounds was 30,35×10-6.

In particular, the compounds of examples 1-2 1-10 had membrane permeability of 10×10-6(cm/sec) is more and showed a very high membrane permeability. These compounds have superior properties as drugs because they not only have a high value IC50but also have higher absorption, which is also very useful for use as a medicine.

On the other hand, the values of Papp (cm/sec) compounds of comparative examples 1 to 13 was as shown in tables 4-6, respectively 27,1×10-6, and 24.2×10-6, of 25.6×10-6, 5,3×10-6that is 7.9×10-6, 21,1×10-6of 18.2×10-6, 43,1×10-6, and 19.4×10-6, of 6.7×10-6that , 40.3×10-6, 10,4×10-6and 28.6×10-6and the average Papp (cm/sec) of these 13 compounds of the comparative examples was 21,38×10-6.

As described above, the compound of the present invention had the membrane permeability is about 1.4 times higher than the compounds of the comparative examples in terms of averages Papp.

[4] Discussion the results of the test on the stability in solution 1 according to the Pharmacopoeia of Japan (the example test [4]):

In the test of stability in solution 1 according to the Pharmacopoeia of Japan's remaining share 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, respectively, 100 and 101%. On the other hand, the residual ratio of the compound of comparative example 13 was 62.1%.

Since before alagaesia, that solution 1 Pharmacopoeia of Japan has a pH of pH of gastric acid, in General, it is known that the stability it indicates resistance to gastric juice.

Therefore, these compounds compared with the compound of comparative example 13 can be used as drugs due to their resistance to gastric juice.

[5] Summary:

(1) Relative value IC50

In accordance with the document (J. Pharmacol. Exp. Ther. 2003 Jul; 306 (1): 377-86), it is known that VSTS, which is known as a substance inhibiting the activity of VR1, has inhibitory activity (the value of the IC50), a component of several nm. In addition, applicants also confirmed in tests that the value of the IC50: WSTS is several nm.

All values IC50compounds of the present invention, in particular compounds represented in these examples 1-1 through 1-10, constitute less than 1 nm.

On the other hand, of the compounds of comparative examples 7 compounds of comparative examples 6, 7, 9, 10, 11, 12 and 13, had a magnitude IC50less than 1 nm. However, these 7 compounds of the comparative examples were not necessarily satisfactory in respect of all of the indicators examined, because they had residual ratio of less than 80% in the test metabolic stability in liver S9, and/or values of Papp MenuItem 10×10 -6corresponding membrane permeability, or had a lower resistance to gastric juice.

(2) Relative metabolic stability in human liver S9

Metabolic stability is an important requirement for drugs, preferred drugs, having the metabolic stability of 80% or higher. The compounds of examples 1-1, 1-6, 1-8 and 1-10 had a residual value after passing through the liver 90% or higher and showed a very high residual ratio after passing through the liver, i.e. very 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. However, the compounds of comparative examples 1, 2, 3 and 4 had values IC501 nm or above and have not been satisfactory in light of the inhibitory activity. The compounds of comparative example 10 had a value of Papp of 6.7×10-6that is unsatisfactory in relation to membrane permeability. In addition, the compound of comparative example 13 had a lower resistance in the gastric juice and was not acceptable.

(3)In respect of the test membrane permeability

In relation to membrane permeability dial on the right is briteney had membrane permeability of about 1.4 more than the compounds of the comparative examples in terms of averages Papp, as described above. In particular, the compounds of examples 1-4, 1-5, 1-6, 1-7, 1-9, and 1-10 had a high membrane permeability of 30×10-6or higher from the viewpoint of the Papp values.

On the other hand, the compounds of comparative examples 8 and 11 had high membrane permeability. However, the connection of comparative example 8 had a value IC507 nm, corresponding inhibitory activity, and was not satisfactory in light of the inhibitory activity. In addition, the compound of comparative example 11 had a remaining portion after passing through the human liver S9 66,7%, which serves as an indicator of metabolic stability, and not necessarily suitable as a drug.

(4)Characteristics of the compounds of the present invention from the viewpoint of chemical structure

When comparing the compound of comparative example 11 and the compound of example 1-2, they differ in that the first has only the fluorine atom in the phenyl group, while the latter has 2 fluorine atom. The latter is the value of the IC50about 10 times higher than that of the first.

When comparing the compound of comparative example 8 and the compound of example 1-6, they differ in that the first has triptorelin group as is the " for pyridine, while the latter has 2,2,2-triptracker. The latter has a higher remaining portion after passing through the liver S9, which is about 1.5 times higher than the first, and its value IC50approximately 50 times higher than that of the first connection.

When compared to the compounds of comparative examples 7 and 9 and the compound of example 1-8, the compound of example 1-8 with 2 fluorine atom and one 2,2,2-triptracker as substituents for the phenyl group, differs from others in that the compound of comparative example 7 has only one triptorelin group and the fact that the compound of comparative example 9 has a fluorine atom and one triptorelin group. However, the compound of example 1-8 has a higher remaining portion after passing through the liver S9, which is about 1.4 to 1.7 times more compounds of comparative examples 7 and 9, and the higher the value of the IC50approximately 3-11 times more such compounds of comparative examples 7 and 9.

When comparing the compound of comparative example 13 and the compound of example 1-1, they differ in that the first has only one fluorine atom in the phenyl group, while the latter has 2 fluorine atom. The latter is the value of the IC50that is about 5 times greater than that of the first connection. This result could not be expected even specialists in this is blast.

Compounds represented by the General formula [1], in particular the compounds of examples 1-1 through 1-10, are compounds having a high inhibitory activity on VR1, and high metabolic stability in liver S9 and/or high membrane permeability.

Therefore, the compounds of examples 1-1 through 1-10 represented by the General formula [1], can be used not only as a drug with high activity as inhibitors VR1, but they can also be used as medicines, is able to counteract oxidative metabolism and has a long lasting effect, as well as having high absorbability.

Therefore, these compounds can be used not only as a drug with high efficacy as inhibitors VR1, but also expected them to practical use as medicines, is able to counteract oxidative metabolism and has a long lasting effect, as well as having high absorbability.

Industrial applicability

3,4-Dihydroisoxazole compound of the present invention effectively inhibits vanilloid receptor subtype 1 (VR1), and therefore it is effective for treatment and/or prevention of diseases such as pain, acute pain, chronic is th pain neuropathic pain, pain in rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute herpetic pain, post herpetic neuralgia, chronic herpetic neuralgia, postoperative pain, pain and cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegenerative disease, stroke, ischemic symptom, nerve damage, neurogenic skin disorder, inflammatory disease, pruritus, allergic rhinitis, stroke, syndrome, irritable bowel, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, stomach ulcers and 12 duodenal ulcer, inflammatory bowel disease the hypersensitivity of the bladder, frequent urination type excessively active bladder and urinary incontinence by type excessively active bladder.

1. 3,4-Dihydroisoxazole the connection represented by the following General formula [1]or its pharmaceutically acceptable salt:

where X denotes
(1) a nitrogen atom, or
(2) CR3;
R1does
(1) a hydrogen atom, or
(2) halogen;
R2represents C1-6alkoxygroup, which may be substituted by same or different 1 to 5 substituents selected from the following groups is:
(1) halogen atom, and
(2) a hydroxyl group; and
R3denotes a halogen atom (however, R1denotes a halogen atom when X represents CR3).

2. 3,4-Dihydroisoxazole compound according to claim 1, selected from the following group of compounds or their pharmaceutically acceptable salts:
1) (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-(4-tert-butoxy-3,5-differenl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide,
2) (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-(3,5-debtor-4-isopropoxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide,
3) (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-(3,5-debtor-4-ethoxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide,
4) (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-[2-(2,2-dimethylpropylene)pyridine-5-yl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide,
5) (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-(2-tert-butoxypropan-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide,
6) (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-[2-(2,2,2-triptoreline)pyridine-5-yl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide,
7) (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-(2-isobutoxide-5-yl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide,
8) (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-[3,5-debtor-4-(2,2,2-triptoreline)phenyl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-carboxamide,
9) (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-[3,5-debtor-4-(2-hydroxy-2-methylpropyloxy)phenyl]-3,4-dihydro-2H-benzo [1,4]oxazin-8-carbox the amide and
10) (S)-4-(5-picoline-2-yl)-3-hydroxymethyl-N-[3,5-debtor-4-(1,1-dimethyl-2-hydroxyethyloxy)phenyl]-3,4-dihydro-2H-benzo [1,4]oxazin-8-carboxamide.

3. 3,4-Dihydroisoxazole compound according to claim 1, represented by the following formula or its pharmaceutically acceptable salt.

4. 3,4-Dihydroisoxazole compound according to claim 1, represented by the following formula or its pharmaceutically acceptable salt.

5. 3,4-Dihydroisoxazole compound according to claim 1, represented by the following formula or its pharmaceutically acceptable salt.

6. 3,4-Dihydroisoxazole compound according to claim 1, represented by the following formula or its pharmaceutically acceptable salt.

7. 3,4-Dihydroisoxazole compound according to claim 1, represented by the following formula or its pharmaceutically acceptable salt.

8. Pharmaceutical composition having inhibitory activity against vanilloid receptor subtype 1 (VR1), including 3,4-dihydroisoxazole compound or its pharmaceutically acceptable salt according to any one of claims 1 to 7, and a pharmaceutically acceptable carrier.

9. Pharmaceutical composition having inhibitory activity against vanilloid receptors a confirmation is PA 1 (VR1), for the treatment and/or prevention of a disease selected from pain, acute pain, chronic pain, neuropathic pain, pain in rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute herpetic neuralgia, post herpetic neuralgia, chronic herpetic neuralgia, postoperative pain, pain in cancer, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegenerative disease, cerebral apoplexy, ischemic symptom, nerve injury, neurogenic skin disorder, inflammatory disease, pruritus, allergic rhinitis, apoplexy, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, stomach ulcers and 12 duodenal ulcer, inflammatory intestinal diseases, hypersensitivity of the bladder, frequent urination and urinary incontinence, including 3,4-dihydroisoxazole compound or its pharmaceutically acceptable salt according to any one of claims 1 to 7, and a pharmaceutically acceptable carrier.

10. Pharmaceutical composition having inhibitory activity against vanilloid receptor subtype 1 (VR1), for the treatment and/or prevention of pain, including 3,4-dihydroisoxazole connection or farmacevtichesky acceptable salt according to any one of claims 1 to 7, and pharmaceutically acceptable carrier.

11. The pharmaceutical composition of claim 10, where the pain is an acute pain, chronic pain, neuropathic pain, pain in rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute herpetic neuralgia, post herpetic neuralgia, chronic herpetic neuralgia, postoperative pain, pain and cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy or neurodegenerative disease.

12. Inhibitor activity vanilloid receptor subtype 1 (VR1), including 3,4-dihydroisoxazole compound or its pharmaceutically acceptable salt according to any one of claims 1 to 7, and a pharmaceutically acceptable carrier.

13. The method of treatment and/or prevention of a disease selected from pain, acute pain, chronic pain, neuropathic pain, pain in rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute herpetic neuralgia, post herpetic neuralgia, chronic herpetic neuralgia, postoperative pain, pain in cancer, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegenerative disease, cerebral stroke, eremites the first symptom, nerve injury, neurogenic skin disorder, inflammatory disease, pruritus, allergic rhinitis, apoplexy, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, stomach ulcers and 12 duodenal ulcer, inflammatory intestinal diseases, hypersensitivity of the bladder, frequent urination and urinary incontinence, characterized in that the method comprises the introduction of a pharmacologically effective amount of 3,4-dihydroisoxazole compound or its pharmaceutically acceptable salt according to any one of claims 1 to 7.

14. The method of treatment and/or prevention of pain, wherein the method comprises the introduction of a pharmacologically effective amount of 3,4-dihydroisoxazole compound or its pharmaceutically acceptable salt according to any one of claims 1 to 7.

15. The method of treatment and/or prevention of pain at 14, where pain is an acute pain, chronic pain, neuropathic pain, pain in rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute herpetic neuralgia, post herpetic neuralgia, chronic herpetic neuralgia, postoperative pain, pain and cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy or neurode generative disease.

16. Commercial package comprising the pharmaceutical composition according to any one of p-11, having inhibitory activity against vanilloid receptor subtype 1 (VR1), and written instructions relating to the said pharmaceutical composition, which says that the specified composition can be applied or should be applied for the treatment and/or prevention of a disease selected from pain, acute pain, chronic pain, neuropathic pain, pain in rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute herpetic neuralgia, post herpetic neuralgia, chronic herpetic neuralgia, postoperative pain, pain in cancer, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegenerative diseases, stroke, ischemic symptom, nerve injury, neurogenic skin disorder, inflammatory disease, pruritus, allergic rhinitis, cerebral stroke, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, stomach ulcers and 12 duodenal ulcer, inflammatory intestinal diseases, hypersensitivity of the bladder, frequent urination and urinary incontinence.

17. The use of 3,4-dihydrobenzo the new compound or its pharmaceutically acceptable salt according to any one of claims 1 to 7 to obtain the pharmaceutical composition according to claim 9, possessing inhibitory activity against vanilloid receptor subtype 1 (VR1), for the treatment and/or prevention of a disease selected from pain, acute pain, chronic pain, neuropathic pain, pain in rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute herpetic neuralgia, post herpetic neuralgia, chronic herpetic neuralgia, postoperative pain, pain in cancer, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy, neurodegenerative disease, cerebral apoplexy, ischemic symptom, nerve injury, neurogenic skin disorder, inflammatory disease, pruritus, allergic rhinitis, apoplexy, irritable bowel syndrome, asthma, chronic obstructive pulmonary disease, dermatitis, mucositis, stomach ulcers and 12 duodenal ulcer, inflammatory intestinal diseases, hypersensitivity of the bladder, frequent urination and urinary incontinence.

18. The use of 3,4-dihydroisoxazole compound or its pharmaceutically acceptable salt according to any one of claims 1 to 7 to obtain the pharmaceutical composition having inhibitory activity against vanilloid receptor subtype 1 (VR1), for the treatment and/or prevention of the Oli of claim 10.

19. The use of 3,4-dihydroisoxazole compound or its pharmaceutically acceptable salt p, where pain is an acute pain, chronic pain, neuropathic pain, pain in rheumatoid arthritis, neuralgia, neuropathy, hyperalgesia, migraine, joint pain, acute herpetic neuralgia, post herpetic neuralgia, chronic herpetic neuralgia, postoperative pain, pain and cancer pain, inflammatory pain, interstitial cystitis, posttraumatic neuralgia, diabetic neuropathy or neurodegenerative disease.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: disclosed compounds have activity and selectivity towards the GABA A receptor subunit α5. In formula I , R1 denotes hydrogen, halogen, phenyl, a 6-member heterocycyl with 2 heteroatoms selected from N, O, a 5-member heteroaryl with 1-2 heteroatoms selected from S, N, cyano, lower alkyl, -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-N(R)2, -(CH2)n-O-lower alkyl or -(CH2)n-OH; equals 0, 1 or 2; R denotes hydrogen or lower alkyl; R2 denotes C3-C7-cycloalkyl, phenyl, 5-6-member heteroaryl with 1 heteroatom selected from N, S or a 9-10-member bicyclic heteroaryl with 1-3 heteroatoms selected from N, which are possibly substituted with one or more substitutes selected from a group comprising halogen, cyano, nitro, oxo group, lower alkyl, lower alkyl substituted with a halogen, lower alkoxy, lower alkoxy substituted with a halogen, -C(O)O-lower alkyl, lower alkylsulphonyl, -NRaRb, -C(O)-NRaRb, -C(O)-(6-member heterocyclyl with 2 heteroatoms selected from N, O), benzyloxy, 6-member heterocyclyl with 1-2 heteroatoms selected from N, S, O, possibly substituted with hydroxy, 1-2 oxo-groups, halogen or lower alkyl, or selected from a 5-6-member heteroaryl with 1-3 heteroatoms selected from N, possibly substituted with lower alkyl; Ra and Rb independently denote hydrogen, lower alkylsulphonyl, -C(O)H, -(CH2)n-N(R)2, -(CH2)n-O-lower alkyl, -(CH2)n-S-lower alkyl, -(CH2)n-S(O)2-lower alkyl, (5-member heteroaryl with 1 heteroatom selected from S)-sulphonyl, lower alkyl, -(CH2)n-(5-6-member heterocyclyl with 1 heteroatom selected from O, N), possibly substituted with lower alkyl, oxo group, or denotes -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-(5-6-member heteroaryl with 1-2 heteroatoms selected from N), possibly substituted with an oxo group, -(CH2)n-OH, -(CO)-R', where R' denotes C3-C7-cycloalkyl, a 5-member heteroaryl with 1 heteroatom selected from S, or lower alkyl; R' denotes a phenyl or a 6-member heteroaryl with 1 heteroatom selected from N which are possibly substituted with a halogen or lower alkyl, optionally substituted with a halogen. The invention also relates to a medicinal agent containing one or more compounds of formula I and use of the disclosed compounds to prepare a medicinal agent.

EFFECT: high effectiveness of derivatives.

16 cl, 145 ex

Iap inhibitors // 2425838

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where R3 has any

of the formulae , where R1 is selected from

,

where each R2 independently denotes hydrogen, halogen, C1-C8alkyl, C1-C8alkoxy- C1-C8alkyl, C1-C8alkoxy; R4 denotes a five- or six-member monocyclic ring system, having two heteroatoms selected from O, N and S, such as pyrazinyl, isoxazole or thiazolyl, each of which can be optionally substituted with one or more of the following substitutes: C1-C8alkyl or C1-C8alkoxy; R5 and R6 independently denote hydrogen or C1-C8alkyl; R7 and R8 together form a cyclopentyl ring; R9 independently denotes C1-C8alkyl; R9a independently denotes C1-C8alkylcarbonyl or phenylcarbonyl; R10 denotes hydrogen; R11 independently denotes C1-C8alkyl or C1-C8alkoxy; R12 denotes hydrogen or -COOR17; R13 independently denotes hydrogen, phenyl and a 6-member heteroaryl containing one heteroatom selected from N; R17 denotes hydrogen; R23 denotes (a) C1-C8alkyl, phenyl, a 5-member heteroaryl containing 1-2 heteroatoms selected from S and N, where any phenyl or heteroaryl residue is optionally substituted with a halogen, C1-C8alkyl or C1-C8alkoxy; R24 denotes C1-C8alkyl; R27 denotes H, C1-C8alkyl, C1-C8alkoxy, O-phenyl, S-phenyl; R29 denotes -(CH2)w-COOR17; where w=0; R31 denotes hydrogen; and pharmaceutically acceptable salts thereof. The invention also relates to a method of producing the disclosed compounds, a pharmaceutical composition, having dual acting ATI and ETA receptor antagonist properties, containing the disclosed compound as an active component, use of the compound in preparing a medicinal agent and methods of treating arterial hypertension.

EFFECT: high effectiveness of the compounds.

8 cl, 1 dwg, 39 ex

Heterocompound // 2425832

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or pharmaceutically acceptable salt thereof, where symbols assume the following values; ring denotes

or , X denotes a single bond, -CH2-, -NR3-, -O-, -S-, R1 denotes a halogen; phenyl; pyridyl; (C3-C8)cycloalkyl; or (C1-C6) alkyl or (C2-C6) alkenyl, each of which can contain a halogen, -CONH2, phenyl or (C3-C8)cycloalkyl as a substitute, R2 denotes CN, -O-(C1-C6)alkyl, -C(=O)H, halogen; or (C1-C6)alkyl, which can be substituted with a halogen or -OH, R3 can form morpholino or 1-pyrrolidinyl together with R1 and nitrogen, and when X denotes a single bond, R1 and R2 can jointly form a 5-member ring and additionally contain -(C1-C6)alkyl as a substitute, R4 denotes the following ring: , , , , , , , , , , or , where any one of the bonds in the ring is linked to an oxazole ring, R5 denotes -H, (C1-C6)alkyl, which can be substituted by not less than one group selected from: -C(=O)NRXRY, -NHRX and -ORX- (C2-C6)alkenyl-; -C(=O)H; -C(=O)NRXRY, RX and RY can be identical or different and denote -H; or (C1-C6)alkyl. The invention also relates to a pharmaceutical composition based on said compounds, having SlP1 agonist activity.

EFFECT: compounds and compositions can be used in medicine for preventing and treating rejection during organ transplant, bone marrow or tissue transplant and autoimmune diseases.

16 cl, 84 tbl, 198 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrazole derivatives of general formula I

and pharmaceutically acceptable salts thereof, where n equals 1 or 2, m equals 0, 1 or 2, A contains in the ring a group selected from -CR1=, -CR2=, -CR3=, -CR4= and -CR5=, where 0 or 1 in these groups is replaced with N, R1, R2, R3, R4 and R5 are independently selected from a group comprising hydrogen, hydroxy, halogen, cyano, cyano(C1-C6)alkyl, C4-C6 heterocycloalkyl-C0-alkyl, where the said heterocycloalkyl contains 1-2 heteroatoms selected from nitrogen and oxygen atoms, C5heteroaryl-(C0-C4)alkyl, where the said heteroaryl contains 1-4 heteroatoms selected from nitrogen atoms, -XSO2R11, -XSO2NR11R12, -XSO2NR11C(O)R12, -XC(NR11)NR11OR12, -XCR11=NOR12, -XC(O)R11, -XC(O)OR11, -XNR11R12, -XC(O)NR11R12, -XOC(O)NR11R12, -XNR11C(O)NR11R12, -XNR11XOR12; -XN(XOR12)2, -XNR11XC(O)OR12 -XNR11XNR11C(O)R12 -XNR11XNR11R12, -XNR11C(O)R12, where each X is independently selected from a group comprising a chemical bond and C1-C4alkylene, each R11 is selected from a group comprising hydrogen and C1-C6alkyl, and R12 is selected from a group comprising hydrogen, C1-C6alkyl and phenyl, or R11 and R12 together with a nitrogen atom to which R11 and R12 are bonded form C6heterocycloalkyl. Said heteroaryl or heterocycloalkyl in R1, R2, R3, R4 or R5 optionally contains one substitute selected from a group comprising hydroxyl, cyano, C1-C6alkyl, hydroxyl(C1-C6)alkyl and carboxy, R6 and R7 independently denote hydrogen, R8 is selected from a group comprising C1-C6alkyl, halogen(C1-C3)alkyl, -CH2OR8a and -COOR8a or two R8 groups bonded to different carbon atoms, together form a (C1-C2)alkyl bridge, or two R8a groups bonded to one carbon atom form a (C3-C8)cycloalkyl group, where R8a is selected from a group comprising hydrogen and C1-C6alkyl, R9 is selected from a group comprising phenyl and C6heteroaryl, where the said heteroaryl contains 1-2 heteroatoms selected from nitrogen atoms, and C9heteroaryl, where the said heteroaryl contains 1-2 heteroatoms selected from nitrogen and oxygen atoms, where the said phenyl or heteroaryl in R9 is optionally substituted with 1-2 substitutes independently selected from a group comprising halogen, cyano, hydroxy, C1-C3alkyl, halogen(C1-C3)alkyl, hydroxy(C1-C3)alkyl, -C(O)R13, -C(O)NR13R14, where each of R13 and R14 is independently selected from a group comprising hydrogen and C1-C6alkyl, R10 denotes hydrogen, Y and Z are independently selected from a group comprising CR20 and N, where R20 denotes hydrogen, provided that compounds of formula I do not include compounds of formula II, which are described in claim 1, and provided that compounds of formula I do not include compounds which are: 1-(4-fluorophenyl)-4-((3-phenyl-1H-pyrazol-4-yl)methyl)piperazine, 1- ((3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-4-(4-(trifluoromethyl)-(pyridin-2- yl)piperazine, 1-((3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-4-(5-(trifluoromethyl)-(pyridin-2-yl)piperazine and 1-((3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-4-(5-fluoropyridin-2-yl)piperazine. The invention also relates to specific compounds obtained.

EFFECT: novel pyrazole derivatives which can be used in treating diseases or disorders which are mediated by disrupted activation of the said compound are obtained.

8 cl, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to aryl-isoxazole-4-yl-imidazole derivatives of formula I and to their pharmaceutically acceptable acid addition salts. The compounds of the present invention exhibit GABA A α5 receptor binding site activity and selectivity. In general formula I

each of R1-R3 independently represents hydrogen atom or halogen atom; R4 represents hydrogen atom, lower alkyl, C3-C7cycloalkyl, -(CH2)n-O-lower alkyl or hydroxy substituted lowest alkyl; R5 represents -(CH2)m-phenyl or -(CH2)m-(5-6-members heteroaryl with 1-2 heteroatoms independently seected from N, O) which optionally substituted by one or more substitutes selected from a group consisting of halogen atom, cyano, nitro, lower alkyl, lower alkoxy, lower alkylsulphanyl, lower alkyl substituted by halogen atom, -C(O)-lower alkyl, -C(O)-O-lower alkyl, -NH-C(O)-O-lower alkyl or -C(O)-NH-R' where R' represents the lower alkynyl or hydroxy substituted lower alkyl, or represents -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-(6-members heterocyclyl with 1-2 heteroatoms selected from N, O), -(CH2)n-(5-6-members heteroaryl with 1-2 heteroatoms selected from N, O) or -(CH2)n-phenyl optionally substituted by halogen atom; R6 represents hydrogen atom, -C(O)H, -(CH2)n-O-lower alkyl, -C(O)O-lower alkyl, lower alkyl substituted by hydroxy or halogen atom, or represents C3-C7-cycloalkyl, phenyl, or represents -(CH2)n-O-CH2-phenyl optionally substituted by halogen atom or lower alkyl, or represents -(CH2)n-O-CH2-(6-members heteroaryl with 1 heteroatom selected from N) optionally substituted by lower alkyl or lower alkyl substituted by halogen atoms, or represents -(CH2)n-NH-(CH2)o-(6-members heterocyclyl with 2 heteroatoms selected from N; n means 0, 1, 2 or 3; m means 0 or 1; o means 1, 2 or 3.

EFFECT: presented preparation of a drug containing one or more compound of formula I and application of the compounds for preparing the drug.

31 cl, 168 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

, where the dotted line in the 6-member nitrogen-containing ring Z of formula (I) (said ring Z consists of ring atoms numbered 1 to 6) indicates that a double bond is either present in the 3,4-position of the ring Z of formula (I), or a double bond is absent in ring Z of formula (I); and where the double bond may be present in the 3,4-position of the ring Z of formula (I); or: the double may be absent in ring Z of formula (I) if: i) X denotes N or N+-O-, or ii) V denotes -O-CH2-Q-, or iii) W denotes para-substituted phenyl or para-substituted pyridinyl, and V denotes pyrrolidinyl of formula:

X denotes CH, N, or N+-O-; W denotes para-substituted phenyl or para-substituted pyridinyl; V denotes -O-CH2-Q-, where Q is bonded with a group U of formula (I), or V denotes pyrrolidinyl of formula:

U denotes mono-, di-, tri- or tetra-substituted aryl, where the substitutes are independently selected from C1-7-alkyl and halogen; Q denotes a five-member heteroaryl with two or three heteroatoms independently selected from O and N; R1 denotes C1-7-alkyl or cycloalky; R2 denotes halogen or C1-7-alkyl; R3 denotes halogen or hydrogen; R4 denotes C1-7-alkyl-O-(CH2)0-4-CH2-; R'R"N-(CH2)0-4-CH2-, where R' and R" are independently selected from a group consisting of hydrogen, C1-7-alkyl (optionally substituted with one-three fluorine atoms), cyclopropyl (optionally substituted with one-three fluorine atoms), cyclopropyl- C1-7-alkyl (optionally substituted with one-three fluorine atoms) and -C(=O)-R"', where R'" denotes C1-4-alkyl, C1-4-alkoxy, -CH2-CF3, or cyclopropyl; or R12NH-C(=O)·(O)0-1-(CH2)0-4-, where R12 denotes C1-4-alkyl or cyclopropyl; and n equals 0; and salts thereof. The invention also relates to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds having inhibiting effect on renin.

21 cl, 112 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where R1 is a phenyl group (said phenyl group is substituted with one or more C1-6alkyl groups, one C1-3alkyl group (said C1-3alkyl group is substituted with one or more halogen atoms), one C1-3alkoxy group (said C1-3alkoxy group is substituted with one or more halogen atoms) or one or more halogen atoms), R2 is a C1-3alkyl group, R3 is a phenyl group (said phenyl group is substituted with one or more substitutes selected from a group comprising halogen atoms or a (C=O)R5' group (where R5' is NR6'R7', (where R6' is a hydrogen atom, and R7' is a C1-6alkyl group substituted with a hydroxyl group))), a thienyl group (said thienyl group is substituted with one or more substitutes selected from a group comprising hydrogen atoms and a (C=O)R5 group (where R5 is NR6R7 (where R6 is a hydrogen atom or a C1-3alkyl group, and R7 is a C1-6alkyl group (said C1-6alkyl group can be substituted with one or more hydroxyl groups, one C1-3alkoxy group or a 5-6-member aromatic heterocyclic group containing 1-2 heteroatoms selected from oxygen or nitrogen (where the 5-6-member aromatic heterocyclic group can be substituted with one or more C1-3alkyl groups, one or more C1-3alkoxy groups, and in case of a 5-6-member aromatic heterocyclic group containing one nitrogen atom, can be in be in form of N-oxides)), a pyridyl group, or overall NR6R7 is a nitrogen-containing heterocyclic group which is a 5-6-member hetero-monocyclic group which contains one or two nitrogen atoms and can additionally contain on oxygen atom (said nitrogen-containing heterocyclic group can be substituted with one or more hydrogen atoms, one or more C1-6alkyl group, one or more hydroxyl groups)) or C1-6alkyl group (said C1-6alkyl group can be substituted with one or more halogen atoms and is substituted with one cyano group))), and R4 is a hydrogen atom or to a pharmaceutically acceptable salt of said compound. The invention also relates to a medicinal agent for preventing or treating diseases, in which activation of the thrombopoietin receptor is effective, based on said compounds.

EFFECT: obtaining novel compounds and agents based thereon, which can be used in medicine to increase the number of thrombocytes.

33 cl, 7 tbl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted oxazole derivatives of general formula I. The disclosed compounds have affinity to the µ-opioid receptor. In general formula I

, n equals 0, 1 or 2, R1 denotes a phenyl residue bonded through a C1-C3alkyl chain, R2 denotes phenyl or thienyl, each of which is unsubstituted or mono-substituted with F or Cl, R3 and R4 independently denote a saturated, branched or straight C1-C6alkyl, phenyl or a phenyl residue bonded through a C1-C3akyl chain, or R3 and R4 together form an unsubstituted five-, six- or seven-member saturated ring which can optionally contain an extra heteroatom selected from a group comprising O or NR9, where R9 denotes phenyl or a phenyl residue bonded through a C1-C3alkyl chain, any of which is unsubstituted or mono-substituted with a substitute selected from a group comprising F, Cl, Br, I and O-C1-C6alkyl, where the ring can be optionally condensed with a phenyl ring, R5 and R6 independently denote a saturated, branched or straight C1-C6alkyl, R7 and R8 independently denote a saturated, branched or straight unsubstituted C1-C6alkyl or a phenyl residue bonded through a C1-C3alkyl chain, or R7 and R8 together form an unsubstituted or mono- or disubstituted five-, six- or seven-member saturated ring, where the substitutes are selected from a group comprising C1-C6alkyl or a phenyl residue bonded through a C1-C3alkyl chain, where the ring can optionally contain an extra heteroatom selected from a group comprising S, O and NR10, where R10 denotes a phenyl or a phenyl residue bonded through a C1-C3alkyl chain, any of which can be unsubstituted or mono-substituted with O-C1-C6alkyl. The invention also relates to methods of producing the disclosed compounds, a medicinal agent containing at least one substituted oxazole derivative of formula I, use of the compounds to prepare a medicinal agent.

EFFECT: improved properties.

13 cl, 1 tbl, 150 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula I ; or to its pharmaceutically acceptable salts where n represents 0, 1 or 2; Y1 represents a bond or a group C(O); Y2, represents a bond, the groups C(O) or S(O)2; R1 represents hydrogen, halogen, cyano, C1-2alkyl; R2 represents hydrogen, halogen, cyano, C1-4alkyl, C1-3alkoxy, halogen-substituted-C1-3alkyl, halogen-substituted-C1-3alkoxyl, C6aryl-C0alkyl, tetrazolyl, C3-6cycloalkyl-C0alkyl, C6-7heterocycloalkyl-C0-4alkyl where 1 or 2 carbon atoms in the ring are substituted by the groups selected from -O-, -NH-, -S(O) and -SO2-; and phenoxy groups; where said aryl and heterocycloalkyl groups R2 can be substituted by 1 or 2 radicals independently selected from C1-6alkyl; R3 represents hydrogen, halogen, cyano, C1-3alkoxy or halogen-substituted-C1-2alkyl group and a group -NR6aR6b where R6a and R6b are independently selected from hydrogen and C1-4alkyl; R4 represents hydrogen, halogen, cyano, C1-3alkoxy or halogen-substituted-C1-2alkyl group; R5 represents hydrogen or C1-3alkyl group; L represents a bivalent radical selected from ; ; ; ; ; ; ; ; ; ; ; ; and ; where asterisks the junctions of Y2 and R2; where any bivalent radical L can be substituted by 1 or 2 radicals independently selected from halogen, hydroxy, cyano, C1-4alkyl, C1-4alkyl carbonylamino, C1-4alkoxy, C1-4alkoxycarbonyl, halogen-substituted - C1-4alkyl, C1-3alkylsulfonyl, C1-3alkylsulfonyl-amino, cyano-substituted - C1-4alkyl and halogen-substituted -C1-4alkoxy radicals. Also, the invention refers to a method of Hedgehog path inhibition in a cell and to a method of undesired cell proliferation inhibition which involves the interaction of the compound of formula I and the cell.

EFFECT: new substituted imidazole derivatives which can be effective in treatment of some types of cancer are prepared.

13 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: disclosed compounds have activity and selectivity towards the GABA A receptor subunit α5. In formula I , R1 denotes hydrogen, halogen, phenyl, a 6-member heterocycyl with 2 heteroatoms selected from N, O, a 5-member heteroaryl with 1-2 heteroatoms selected from S, N, cyano, lower alkyl, -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-N(R)2, -(CH2)n-O-lower alkyl or -(CH2)n-OH; equals 0, 1 or 2; R denotes hydrogen or lower alkyl; R2 denotes C3-C7-cycloalkyl, phenyl, 5-6-member heteroaryl with 1 heteroatom selected from N, S or a 9-10-member bicyclic heteroaryl with 1-3 heteroatoms selected from N, which are possibly substituted with one or more substitutes selected from a group comprising halogen, cyano, nitro, oxo group, lower alkyl, lower alkyl substituted with a halogen, lower alkoxy, lower alkoxy substituted with a halogen, -C(O)O-lower alkyl, lower alkylsulphonyl, -NRaRb, -C(O)-NRaRb, -C(O)-(6-member heterocyclyl with 2 heteroatoms selected from N, O), benzyloxy, 6-member heterocyclyl with 1-2 heteroatoms selected from N, S, O, possibly substituted with hydroxy, 1-2 oxo-groups, halogen or lower alkyl, or selected from a 5-6-member heteroaryl with 1-3 heteroatoms selected from N, possibly substituted with lower alkyl; Ra and Rb independently denote hydrogen, lower alkylsulphonyl, -C(O)H, -(CH2)n-N(R)2, -(CH2)n-O-lower alkyl, -(CH2)n-S-lower alkyl, -(CH2)n-S(O)2-lower alkyl, (5-member heteroaryl with 1 heteroatom selected from S)-sulphonyl, lower alkyl, -(CH2)n-(5-6-member heterocyclyl with 1 heteroatom selected from O, N), possibly substituted with lower alkyl, oxo group, or denotes -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-(5-6-member heteroaryl with 1-2 heteroatoms selected from N), possibly substituted with an oxo group, -(CH2)n-OH, -(CO)-R', where R' denotes C3-C7-cycloalkyl, a 5-member heteroaryl with 1 heteroatom selected from S, or lower alkyl; R' denotes a phenyl or a 6-member heteroaryl with 1 heteroatom selected from N which are possibly substituted with a halogen or lower alkyl, optionally substituted with a halogen. The invention also relates to a medicinal agent containing one or more compounds of formula I and use of the disclosed compounds to prepare a medicinal agent.

EFFECT: high effectiveness of derivatives.

16 cl, 145 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof , where D denotes phenyl; n equals 0; A, B and Q denote hydrogen; Z is selected from a group comprising a bond, straight C1-3alkylene; R1 is selected from a group comprising hydrogen, C1-10alkyl, C3-8cycloalkyl, benzyl, a 6-member monocyclic, 9-10-member bicyclic aromatic carbon-containing ring system and a spiro-ring system of formula (V): where X1 and X3 denote O; and where the said alkyl, cycloalkyl or benzyl from the R1 group is optionally substituted with 1-3 substitutes selected from a group comprising C1-3alkyl, cyano, phenyl, wherein the said phenyl is optionally substituted with 1-3 substitutes selected from halogen. The invention also relates to compounds of formulae .

Values of radicals of the said compounds are given in the claim. The invention also relates to a pharmaceutical composition having ORL1 receptor or µ opioid receptor inhibiting properties, containing an effective amount of the disclosed compound, a method of curing pain and a method of modulating pharmacological response from the opioid receptor, including the ORL1 or µ opioid receptor.

EFFECT: improved method.

41 cl, 5 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula as well as separate enantiomers, diastereomers, racemic mixures and pharmaceutically acceptable salts thereof, having mitotic kinesin KSP inhibiting activity, as well as inhibitory action on tumour cells, use thereof in preparing a medicinal agent and a pharmaceutical composition based on said compounds. In said formula, R denotes Z-NR2R3, Z-OH, Ar1 and Ar2 independently denote a phenyl which, if needed, is substituted with one or more groups independently selected from: F, CI, Br, I, OH, Z denotes an alkylene having 1-6 carbon atoms which, if needed, is substituted with C1-6alkyl, and R1 assumes values given in the claim.

EFFECT: improved method.

16 cl, 3 dwg, 124 ex

Iap inhibitors // 2425838

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

Heterocompound // 2425832

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or pharmaceutically acceptable salt thereof, where symbols assume the following values; ring denotes

or , X denotes a single bond, -CH2-, -NR3-, -O-, -S-, R1 denotes a halogen; phenyl; pyridyl; (C3-C8)cycloalkyl; or (C1-C6) alkyl or (C2-C6) alkenyl, each of which can contain a halogen, -CONH2, phenyl or (C3-C8)cycloalkyl as a substitute, R2 denotes CN, -O-(C1-C6)alkyl, -C(=O)H, halogen; or (C1-C6)alkyl, which can be substituted with a halogen or -OH, R3 can form morpholino or 1-pyrrolidinyl together with R1 and nitrogen, and when X denotes a single bond, R1 and R2 can jointly form a 5-member ring and additionally contain -(C1-C6)alkyl as a substitute, R4 denotes the following ring: , , , , , , , , , , or , where any one of the bonds in the ring is linked to an oxazole ring, R5 denotes -H, (C1-C6)alkyl, which can be substituted by not less than one group selected from: -C(=O)NRXRY, -NHRX and -ORX- (C2-C6)alkenyl-; -C(=O)H; -C(=O)NRXRY, RX and RY can be identical or different and denote -H; or (C1-C6)alkyl. The invention also relates to a pharmaceutical composition based on said compounds, having SlP1 agonist activity.

EFFECT: compounds and compositions can be used in medicine for preventing and treating rejection during organ transplant, bone marrow or tissue transplant and autoimmune diseases.

16 cl, 84 tbl, 198 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to aryl-isoxazole-4-yl-imidazole derivatives of formula I and to their pharmaceutically acceptable acid addition salts. The compounds of the present invention exhibit GABA A α5 receptor binding site activity and selectivity. In general formula I

each of R1-R3 independently represents hydrogen atom or halogen atom; R4 represents hydrogen atom, lower alkyl, C3-C7cycloalkyl, -(CH2)n-O-lower alkyl or hydroxy substituted lowest alkyl; R5 represents -(CH2)m-phenyl or -(CH2)m-(5-6-members heteroaryl with 1-2 heteroatoms independently seected from N, O) which optionally substituted by one or more substitutes selected from a group consisting of halogen atom, cyano, nitro, lower alkyl, lower alkoxy, lower alkylsulphanyl, lower alkyl substituted by halogen atom, -C(O)-lower alkyl, -C(O)-O-lower alkyl, -NH-C(O)-O-lower alkyl or -C(O)-NH-R' where R' represents the lower alkynyl or hydroxy substituted lower alkyl, or represents -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-(6-members heterocyclyl with 1-2 heteroatoms selected from N, O), -(CH2)n-(5-6-members heteroaryl with 1-2 heteroatoms selected from N, O) or -(CH2)n-phenyl optionally substituted by halogen atom; R6 represents hydrogen atom, -C(O)H, -(CH2)n-O-lower alkyl, -C(O)O-lower alkyl, lower alkyl substituted by hydroxy or halogen atom, or represents C3-C7-cycloalkyl, phenyl, or represents -(CH2)n-O-CH2-phenyl optionally substituted by halogen atom or lower alkyl, or represents -(CH2)n-O-CH2-(6-members heteroaryl with 1 heteroatom selected from N) optionally substituted by lower alkyl or lower alkyl substituted by halogen atoms, or represents -(CH2)n-NH-(CH2)o-(6-members heterocyclyl with 2 heteroatoms selected from N; n means 0, 1, 2 or 3; m means 0 or 1; o means 1, 2 or 3.

EFFECT: presented preparation of a drug containing one or more compound of formula I and application of the compounds for preparing the drug.

31 cl, 168 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted oxazole derivatives of general formula I. The disclosed compounds have affinity to the µ-opioid receptor. In general formula I

, n equals 0, 1 or 2, R1 denotes a phenyl residue bonded through a C1-C3alkyl chain, R2 denotes phenyl or thienyl, each of which is unsubstituted or mono-substituted with F or Cl, R3 and R4 independently denote a saturated, branched or straight C1-C6alkyl, phenyl or a phenyl residue bonded through a C1-C3akyl chain, or R3 and R4 together form an unsubstituted five-, six- or seven-member saturated ring which can optionally contain an extra heteroatom selected from a group comprising O or NR9, where R9 denotes phenyl or a phenyl residue bonded through a C1-C3alkyl chain, any of which is unsubstituted or mono-substituted with a substitute selected from a group comprising F, Cl, Br, I and O-C1-C6alkyl, where the ring can be optionally condensed with a phenyl ring, R5 and R6 independently denote a saturated, branched or straight C1-C6alkyl, R7 and R8 independently denote a saturated, branched or straight unsubstituted C1-C6alkyl or a phenyl residue bonded through a C1-C3alkyl chain, or R7 and R8 together form an unsubstituted or mono- or disubstituted five-, six- or seven-member saturated ring, where the substitutes are selected from a group comprising C1-C6alkyl or a phenyl residue bonded through a C1-C3alkyl chain, where the ring can optionally contain an extra heteroatom selected from a group comprising S, O and NR10, where R10 denotes a phenyl or a phenyl residue bonded through a C1-C3alkyl chain, any of which can be unsubstituted or mono-substituted with O-C1-C6alkyl. The invention also relates to methods of producing the disclosed compounds, a medicinal agent containing at least one substituted oxazole derivative of formula I, use of the compounds to prepare a medicinal agent.

EFFECT: improved properties.

13 cl, 1 tbl, 150 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula (I) in which A means a group of formula or in which * specifies a carbon atom binding site of a pyridinyl ring, and # specifies the a carbon atom binding site of a phenyl ring, R1 means an amino group or a methyl-carbonylamino group, R2 means hydrogen, R3 means hydrogen, R4 means hydrogen, R5 means hydrogen or halogen, R6 means hydrogen or halogen, R7 means hydrogen, R8 means hydrogen, or one of its salts, its solvate or solvate of its salts, to a method of preparing it, to an agent for treatment and/or prevention of viral infections, on the basis of this compound. Also, the invention refers to the application of the compound of formula I for preparing the agent and to the method of viral infection control.

EFFECT: new arylsulfonamides which can are effective as antiviral agents, preferentially for cytomegalovirus control are prepared and described.

9 cl, 5 ex, 2 tbl, 1 dwg

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula , where R1 represents aryl, heteroaryl or (C5-C6)-cycloalkyl, each of which has an optional substitute halogen or (C1-C6)-alkyl; R2 represents hydrogen or (C1-C4)-alkyl; R3 represents -P(=O)-(alkoxy)2 or Y1Y2N-SO2-, cycloalkyl, aryl, heteroaryl, heterocyclyl, cycloalkenyl, each of which has an optional substitute: halogen, hydroxy, carboxy, Y1Y2N-, Y1Y2NC(=O)-, Y1Y2N-SO2, R7-SO2-NR6-, R7-C(=O)-NR6-, or alkyl, alkoxy, alkoxycarbonyl, each of which has an optional substitute halogen, -P(=O)-(alkoxy)2, Y1Y2NC(=O)-, Y1Y2N-SO2-, R7 -SO2-NR6 -, aryl or heteroaryl and when R3 is cycloalkyl, cycloalkenyl, heterocyclyl, it also optionally substituted by oxo; L1 represents a bond or (C1-C6)-alkylene, which is optionally substituted by -P(=O)-(alkoxy)2; R4, R5 and R6 are hydrogen, R7 represents alkyl; both Y1 and Y2 independently is hydrogen, alkyl which has an optional substitute: hydroxy, amino, alkylamino, dialkylamino, alkoxy, cycloalkyl, or Y1 and Y2 together with nitrogen atom whereto attached form heterocyclyl which optionally contains one more heteroatoms selected from oxygen, nitrogen or sulphur where heterocyclyl has an optional substitute alkyl or oxo; provided when L1 represents a bond, R3 is not optionally substituted by phenyl, optionally substituted by naphthyl, optionally substituted by benzoimidazolyl, optionally substituted by benzothiazolyl or optionally substituted by tetrazolyl; or to its pharmaceutically acceptable salt, and also to a pharmaceutical composition including a compound of formula I.

EFFECT: there are produced and described new compounds which can be effective in treating allergic or inflammatory disorders, particularly such disorders, as allergic rhinitis, asthma or chronic obstructive pulmonary disease.

25 cl, 118 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where R1 is a 3-7-member carbocyclic ring and n is a number ranging from 1 to 8, and the rest of the radicals are described in the claim.

EFFECT: possibility of using such compounds and compositions in therapy as metabotropic glutamate receptor modulators.

33 cl, 367 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, in particular, to pharmaceutics, and deals with pharmaceutical composition, which contains as acting substance therapeutically efficient amount of hydrochloride of 3-(3,4,5-tromethoxybenzoyloxyimino)-8-methyl-8-azabicylo [3,2,1] octane (tropoxin), and as auxiliary substances, at least, one, selected from the group, which includes starch, lactose, microcrystalline cellulose (MCC), ludipress, sodium phosphate twice-substituted, polyvinylpyrrolidone, methylcellulose, carboxymethylcellulose and its sodium salt, oxypropylcellulose, oxypropylmethylcellulose, mannite, sorbite, and, if necessary, stearic acid and/or its salt and/or aerosil Novel composition is represented in two specific versions. Composition is made in form of solid dosed medication, preferably, in form of tablet. Solid dosed drug forms in accordance with invention satisfy all demands of State Pharmacopoeia currently in force.

EFFECT: compositions by invention easily release acting substance, which ensures its high bioavailability.

10 cl, 4 tbl, 7 ex

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