UA119003C2 - 1-arylaminomethyl-4-phenyl-5,6,7,8-tetrahydro-2,2a, 8a-triazacycloplopent [c, d] azulenes exhibiting analgesic activity - Google Patents

Abstract

1-arylaminomethyl-4-phenyl-5,6,7,8-tetrahydro-2,2a, 8a-triazacyclopenta [c, d] azulenes exhibiting analgesic activity. The invention relates to pharmaceutical chemistry and medicine. The initial evaluation of analgesic activity was performed on a model of thermal nociceptive stimulation ("hot plate"). The studies were performed on white non-linear female mice breeding in the vivarium of the Institute of Pharmacology and Toxicology of the National Academy of Medical Sciences of Ukraine weighing 20 ± 2 g. The animals were kept on a standard diet, received food and water ad libitum. It is shown that in the model of thermal nociceptive stimulation the claimed compounds significantly outweigh the comparator - ketorolac. Thus, the activity of compounds 3a, 3b, 3d and 3e in the hot plate test is 117.51, 156.41, 214.56 and 174.30% of the change in the latent period of the reaction while in ketorolac only 100.25%. All this can be the basis for the creation of a new analgesic.

Description

of Medical Sciences of Ukraine" with a weight of 20:12 g. The animals were kept on a standard food ration, received food and water ai Irisht.

It is shown that on the model of thermal nociceptive stimulation, the declared compounds are significantly superior to the comparison drug - ketorolac. Thus, the activity of compounds Za, ZB, Za and Ze in the "hot plate" test is 117.51, 156.41, 214.56 and 174.30 95 changes in the latent period of the reaction, while ketorolac only has 100.25 95. All this can become the basis for creating a new analgesic agent .

The invention belongs to pharmaceutical chemistry and medicine, in particular to the preparation of biologically active 1-arylaminomethyl-4-phenyl-5,6,7,68-tetrahydro-2,2a, va-triazacyclopenta!|c, «|azulenes of the formula: you Mr

Kk de K, K1 - H, CHz, OSN», SI, Vg, which show analgesic activity and can become the basis for the development of new analgesic agents.

Despite the rather wide arsenal of modern analgesics, the problem of pain treatment remains relevant in modern pharmacology, and is due to a noticeable increase in patients with severe pain syndrome. Non-narcotic (non-opioid) analgesics, such as analgin, paracetamol, ketorolac, or their combination with narcotic analgesics with low activity, such as codeine, dihydrocodeine, etc., are used for minor pain and pain of moderate intensity. (11.

On the one hand, pain is considered as the most important protective and adaptive mechanism, on the other hand, it is the cause of suffering, sometimes long and unbearable. Thus, more than 70 95 of the population of developed countries complain of acute and chronic headaches, about 2095 of the adult population and up to 60-80 95 of the elderly are limited in their active lifestyle due to the pain accompanying deforming osteoarthritis. Despite the large arsenal of pharmacological agents, in 30-70 95 patients, it will not be possible to completely stop postoperative pain (|2, 3) and may be accompanied by the development of various, including severe, undesirable side reactions, which reduces the quality of life of patients and in most cases limits them application |41.

We chose ketorolac as a comparison drug. It is known that in patients with acute trauma, ketorolac is more effective than morphine, its effect is longer, and the number of side effects is less.

Ketorolac is not inferior in effectiveness to the opioid analgesic meperidine for biliary colic. No significant difference was found in the effectiveness of ketorolac and combined analgesic (codeine and paracetamol) in patients with lower back pain. The comparative effectiveness of ketorolac and morphine and meperidine was also after arthroscopic interventions. Ketorolac is more effective than lonoxicam for dental operations, otolaryngological interventions (5-91). (o; (c)

M

M / on

From Keterolak formula.

The therapeutic potential of ketorolac has been proven for all branches of emergency medicine, in terms of the degree of analgesia it exceeds other non-steroidal anti-inflammatory drugs and belongs to the first-line drugs for the short-term treatment of severe pain syndrome (10-12.

At the same time, one should not ignore the side effects of ketorolac - nausea, vomiting, dyspepsia, anorexia, abdominal pain, erosive-ulcerative lesions of the PCT, bleeding, ulcer perforation, diarrhea, constipation, acute pancreatitis, stomatitis, gastritis, esophagitis, dysfunction of the liver, drowsiness, euphoria, headache, anxiety, paresthesias, bradycardia, bronchospasm, bleeding from a postoperative wound, decreased blood coagulation rate, hematomas, female infertility, allergic reactions, hearing loss, visual impairment, etc. (111.

The invention patent is based on the task of finding new biologically active non-steroidal compounds with analgesic activity.

The task is solved by the fact that 1-arylaminomethyl-4-phenyl-5,6,7,8-tetrahydro-2,2a, va-triazacyclopentai|s, "azulenes zZach-i" are proposed as new biologically active compounds.

Claimed 1-arylaminomethyl-4-phenyl-5,6,7,8-tetrahydro-2,2a, va-triazacyclopentais,

Physazulenes Za-i were obtained in high yield during the condensation of Z-arylaminomethyl-b,7,8,9-

tetrahydro-5H-(1,2,Altriazolo|4,3-a|azepines Ta-i with phenacyl bromide and subsequent cyclization of the corresponding intermediate quaternary salts 2 a-i in 5 95 Mahon solution (Fig. 1):

M--Mm Ve

H v1 / M RISOSNOVgG.

M -- - - -" (c) M-M H 1 / Ж A in M 1 a-i in 2 a-i

In cheon and Mm--m H 1 pa

M in with a-and where 1, 2, Za) B-B-H, B) B-4-CHn", E, -H, c) K-4-SI, B/-H, a) B- 4-Vg, V.-H, is) B-2-OSN", V:-H,

In B8-2-OSN»z. B/-4-OSN", 9) B-2-OSN", VI-5-OSN 5, i) B-2-SNz, Vi-5-0Ї.

Fig. 1. Synthesis scheme of 3-arylaminomethyl-(b, 7,8,9-tetrahydro-BN-(1,2,4Igriazolo|4,3-a|azepines 4 a-i)

Examples of specific implementation.

Example 1

Synthesis of 1-phenylaminomethyl-4-phenyl-5,6,7,8-tetrahydro-2,2a, va-triazacyclopentai|c, "Chazulene

By. To a solution of 2.42 g (0.01 mol) of 3-phenylaminomethyl-b, 7,8,9-tetrahydro-BN-(1,2,4|triazolo4,3-a|azepine Ta in 60 ml of ethyl acetate was added with stirring 1.99 g (0.01 mol) of abromoacetophenone. The reaction mixture was refluxed for 1 hour, evaporated to a dry residue, 40 ml of 5 95 Mahon solution was added and the reaction mixture was boiled

From an hour. After cooling, the resulting precipitate was filtered, washed with water, and dried.

Crystallized from benzene. Yield 1.88 g (55 95). Tpl.-235-237 "S. Found, 90: M 16.2. Sg2Na2Na.

Calculated, 95: M 16.4. NMR "H (5, m.ch., OM5O-a4b): 1.56 (m, 2H, CH"), 1.67 (m, 2H, CH"), 1.75 (m, 2H, Snae) , 2.84 (m, 2H, CH"), 3.90 (d, 2H, CH"), 6.53 (t, 1H, MH), 7.22 (c, 1H, 3-CH), 6 ,54-7,55 (m,

TONE, SeNkSenNv).

Example 2 1-"(Para-tolyl)uaminomethyl-4-phenyl-5,6,7,8-tetrahydro-2,2a, va-triazacyclonenta|c, F"|azulene

Zr was obtained similarly to example 1 from 2.56 g (0.01 mol) of 3-(para-tolyl)aminomethyl-b,7,8,9-tetrahydro-5H-(1,2,A|gri-azolo|4 ,3-aiazepine ZB and 1.99 g (0.01 mol) of a-bromoacetophenone.

Crystallized from benzene. Yield 1.89 g (53 95). Tll- 183-185 "S. Found, 90: M 15.5. C2zNgaMy.

Calculated, 95: M 15.7. NMR "H (b, m.ch., OM5O-dv): 1.92 (m, 2H, CH"), 2.02 (m, 2H, SnNae), 2.14 (s,

ЗН, СНвз), 2.75 (m, 2Н, СНае), 4.02 (m, 2Н, СнНе»), 4.37 (d, 2Н, СнНе), 6.02 (t, 1Н, МН), 6.64 and 6.91 (d-d,

AN, SeNa), 7.18 (c, 111, 3-CH), 6.54-7.55 (m, 5H, SeNb).

Example C 1-(2-Chlorophenyl)aminomethyl-4-phenyl-5,6,7,8-tetrahydro-2,2a,va-triazacyclopentayl,

Zo 4|azulene Zc was obtained similarly to example 1 from 2.77 g (0.01 mol) of 3-(4-chlorophenyl)aminomethyl-b6,7,8,9-hetrahydro-5H-(11,2,4|griazolo |4,3-a|azepine Zc and 1.99 g (0.01 mol) of a-bromoacetophenone. Crystallized from benzene. Yield 2.22 g (59 95). M.p. 174-175 76.

Found, 95: M 14.8. Сг2НаиСИМа. Calculated, 95: M 14.9. NMR 1H (b, m.ch., OM5O-av): 2.00 (m, 2H, CH"), 2.08 (m, 2H, SnHe), 2.82 (m, 2H, СНе), 4 ... 6.96 (c, 1H, 3-CH), 7.09-7.39 (m, 5H, SveNv).

Example 4

1-(4-Bromophenyl)aminomethyl-4-phenyl-5,6, 7,8-tetrahydro-2,2a, va-triazacyclopentai|c,

Fazulen Za was obtained similarly to example 1 from 3.21 g (0.01 mol) of 3-(4-bromophenyl)aminomethyl-b,7,8,9-tetrahydro-5H-(1,2,4|griazolo|4, 3-a|azepine Za and 1.99 g (0.01 mol) of a-bromoacetophenone. Crystallized from benzene. Yield 2.65 g (63 90). Tll- 165-166 76.

Found, 95: M 13.5. Sg2NaiVIiMa. Calculated, 90: M 13.3. NMR "H (5, m.ch., OM5O-4v): 1.97 (m,

AN, СНеСНХ), 2.76 (m, 2Н, СНе), 4.01 (m, 2Н, СН»), 4.39 (d, 2Н, СнНе), 6.53 (t, 1Н, МН), 6.70 and 7.24 (d-d, 4H, SeNa), 7.20 (c, 1H, 3-CH), 7.16-7.47 (m, 5H, SeNv).

Example 5 1--2-Methoxyphenyl)aminomethyl-4-phenyl-5,6,7,8-tetrahydro-2,2a,va-triazacyclopentayl!|c,

Fazulen Ze was obtained similarly to example 1 from 2.72 g (0.01 mol) of 3-(2-methoxyphenyl)aminomethyl-b,7,8,9-tetrahydro-5H-(1,2,4|triazolo|4, 3-a|azepine Ze and 1.99 g (0.01 mol) of a-bromoacetophenone. Crystallized from benzene. Yield 1.90 g (51 95). Tll- 182-183 76.

Found, 90: M 15.3. SgzNgaMaO. Calculated, 90: M 15.0, NMR "H (b, m.ch., OM5O-av): 1.93 (m, 2H,

CH»), 2.03 (m, 2H, CH»), 2.75 (m, 2H, SnNae), 3.81 (s, ЗН, OSН»), 4.04 (m, 2Н, СнНх») . 3-CH).

Example 6 1-(2',4-Dimethoxyphenyl)aminomethyl-4-phenyl-5,6,7,8-tetrahydro-2,2a,va-triazacyclopentais, "Ch|azulene C was obtained similarly to example 1 of 3 .02 g (0.01 mol) 3-(2',4-dimethoxyphenyl)aminomethyl-b,7,8,9-tetrahydro-5H-I/1,2,4)griazolo|4,3-a|azepine ZI and 1.99 g (0.01 mol) of α-bromoacetophenone. Crystallized from benzene. Yield 1.93 g (48 95). Tpl. - 180-182 "S. Found, 95: M 13.7. SgaNoveMaO". Calculated, 90: M 13.9. NMR "H (b, m.ch., OM5O-yv): 1.92 ( m, 2H, СНе"), 2.01 (m, 2Н, Снае), 2.74 (m, 2Н, СНе"), 3.64 (с, ЗН, OSНЗ), 3.79 (с, ЗН, ОСНЗ3), 4.03 (m, 2Н, СНе"), 4.39 (d, 2Н, СНе), 5.17 (t, 1Н, МН), 6.39-7.43 (m, 8Н, СеНз - SeNb), 7.18 (c, 1H, 3-CH).

Example 7 1-(2,5-Dimethoxyphenyl)aminomethyl-4-phenyl-5,6,7,8-tetrahydro-2,2a, vatriazacyclopentais, "Ch|azulene 39 was obtained similarly to example 1 from 3, 02 g (0.01 mol) 3-(2,5'-dimethoxyphenyl)aminomethyl-b,7,8,9-tetrahydro-5H-I(1,2,4)griazolo|4,3-a|azepine Zd and 1.99 g (0.01 mol) of α-bromoacetophenone. Crystallized from benzene. Yield 2.25 g (56 95). Tpl.- 168-170 S. Found, 95: M 14.1. Cg4Na6MaOg Calculated, 95: M 13.9. H NMR (5, m.ch., OM5O-dbv):

Koo) 1.92 (m, 2H, SnNae), 2.01 (m, 2H, Sn"), 2.75 (m, 2H, CHg"), 3.63 (c, 311, OSN"), 3 ... ...

Example 8 1-(2'-Methyl-5'-chlorophenyl)aminomethyl-4-phenyl-5,6,7 8-tetrahydro-2,2a,va-triazacyclopentais, "azulene Zi was obtained similarly to example 1 of 2 .91 g (0.01 mol) 3-(21-methyl-5'-chlorophenyl)aminomethyl-b,7,8,9-tetrahydro-5H-(1,2,4|griazolo|4,3-a| of azepine Z and 1.99 g (0.01 mol) of α-bromoacetophenone. Crystallized from benzene. Yield 1.96 g (50 95). M.p. 176-177 76.

Found, 95: M 14.6. SgzNgzSIMy. Calculated, 95: M 14.3. NMR "H (b, m.ch., OM5O-av): 1.94 (m, 2H,

CH»), 2.02 (m, 2H, SnNa»), 2.21 (s, ЗН, СН), 2.76 (m, 2Н, СНг»), 4.05 (m, 2Н, SnNa») . ),

Example 9

The primary assessment of analgesic activity was carried out on a thermal ("hot plate") model

P2) Y. The research was carried out on white non-linear female mice bred in the vivarium of the State University "Institute of Pharmacology and Toxicology of the National Academy of Medical Sciences of Ukraine" with a weight of 202 g. The animals were kept on a standard diet, received food and water a

Accepted

Test substances (the test substance and the comparison substance ketorolac) were administered to animals in a test dose of 25 mg/kg of body weight intragastrically using a water-alcohol mixture (595 alcohol) with the addition of 595 tween-20 as an emulsifier. The volume of the obtained water-alcohol emulsion that was administered to the animals did not exceed 0.2 ml per animal.

In the "hot plate" test on the Noi-riage teitzeg device (to Vabiie, Italy), testing was performed on mice (5 in a group), in which the initial value of the latent period of the paw "licking" reaction did not exceed 20 s. The latent period of the reaction in seconds was measured after 1 hour. after the introduction of test substances. The percentage of change to the initial latent period of the reaction in each group was calculated.

Statistical processing of the obtained results was carried out according to the Student's method.

Changes at P«e0.05 were considered reliable.

Table

Analgesic activity of IETO385-IETO0399 compounds in the "hot plate" test

Percentage of change

Substance, code Dose, mg/k pato U

Note: "P" 0.05

Thus, it is shown that on the model of thermal nociceptive stimulation, the claimed compounds are significantly superior to the comparison drug - ketorolac. Thus, the activity of compounds Za, ZB, Za and Ze in the "hot plate" test is 117.51, 156.41, 214.56 and 174.30 95 changes in the latent period of the reaction, while ketorolac - only 100.25 95. All this can become the basis for the creation of a new analgesic agent.

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Pharmacist. - 2007. - Mo. 11. - P. 38-41. 5 Voueg K., Meropaia R., 2oeii5 T. A pomei! Toptiiaiop oi Keigoias oteiNatipe og ipigapazai! adtipiviganop: Rgesiipisa! zaieiiu emaIchayop. Yippee 9). Tohisoi - 2010. - Mo29 (5). - R. 467-478. b. SaItei U., Evieme S., Voada 5. eyi aYi. ApaYdevzis eMNesi oi ipiga-apisciag Keogoias ip Kpeye appgozsoru: sotragizop oi togrpipe apa ryrimasaipe. Kpee Z!ig9 5rogiv Tgtashtayo! ApNgozs. - 2004. - Me12. - R. 552-555. 7. Ippez S.0., Sigo5Kegtu R., MMogpidop "y. oh oh Keiogoias megzy5 aseiatiporpep-sodevipe ip She etegdapsu deraitepi oi ascie raip. ) Yetegu Mea. - 1998. - Mo. 16. - R. 549-556. 8. Maiia S, Siagsia 5., Miyipao A. ei ai. Mitevziiide: 25 Ueagz5 Iaieg. Mipegua Mea. - 2010. - Me101 (4). - R. 285-293. 9. Mescige 0.A., Zapaeegz K., Nepagiske 5.0. Sotragizop oi Keyugoias apa orioid apaiIdevisv ip rosioregaiime ASI. hesopvigysip oshraiyepi raiip sopigo//ApNgozsoru. - 1993. - Me9.- R. 653-661. 10. Belovol A.N. Nonsteroidal anti-inflammatory drug!: focus on ketorolac /

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Claims (1)

FORMULA OF THE INVENTION 1-Arylaminomethyl-4-phenyl-5,6,7,8-tetrahydro-2,2a,va-triazacyclopenta!|c,«|azulenes: ytM- m bak vi nm Z Kk de В, В:-Н, СН», OSN;», SI, Vig, which exhibit analgesic activity.