RU2634618C1 - Analgesic means - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: invention relates to an analgesic means in which individual substituted quinoline-4(1H)-ones of general formula 1

their salts or compositions based on them are active substances, and which can be used as an anesthetic to treat humans and animals, where R¹ = phenyl unsubstituted or substituted by one substituent selected from alkyl (C1-C4), alkoxy (OC1-OC4), halogen; phenyl substituted by two substituents selected from methyl, ethyl, methoxy, ethoxy or halogen; unsubstituted naphthyl, unsubstituted thienyl or thienyl substituted by one substituent selected from methyl or halogen; unsubstituted furyl, C4-alkyl, OMe; R²+R³ = =O, =NOMe, R⁴=H, COOMe, COOH; R⁵= H, Me; R^6th= H, Me, OMe, Et, halogen; R^7th= H, halogen, CN; R⁸= H, alkyl (C1-C4), halogen, CN.

EFFECT: expansion arsenal of anesthetic means.

2 tbl, 7 ex

Description

The invention relates to the field of medicine, veterinary medicine, pharmacy and pharmacology, in particular to an analgesic agent, the active substance in which may be individual substituted quinolin-4 (1H) -ones of general formula 1, their salts or compositions based on them and which may find application for treating people and animals as an anesthetic

,

,

where R ¹ = phenyl unsubstituted or substituted with one substituent selected from alkyl (C1-C4), alkoxy (OC1-OC4), halogen; phenyl substituted with two substituents selected from methyl, ethyl, methoxy, ethoxy or halogen; naphthyl unsubstituted, thienyl, unsubstituted or substituted with one substituent selected from methyl or halogen; furyl unsubstituted, C4 alkyl, OMe;

R ² + R ³ = = O, C = NOMe,

R ⁴ = H, COOMe, COOH;

R ⁵ = H, Me, R ⁶ = H, Me, OMe, Et, halogen,

R ⁷ = H, halogen, CN,

R ⁸ = H, alkyl (C1-C4), halogen, CN.

Technical result: compounds are obtained, including those not previously described, that have analgesic activity in the hot plate test, which suggests the possibility of their use in medicine as an analgesic.

The feeling of pain accompanies various situations associated with tissue damage or dysfunction, such as acute and chronic diseases, injuries, operations, etc. (nociceptive pain) or with somatosensory system dysfunction (neuropathic pain). For the relief of nociceptive pain, two groups of drugs are most often used: 1) non-narcotic analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) and 2) narcotic analgesics. Both groups of drugs have various side effects. Reception of opioid analgesics may be accompanied by the occurrence of physical and psychological dependence [S.E. Reisman Nature (2011), 458-459]. The use of NSAIDs is largely limited by their negative effect on the mucosa of the gastrointestinal tract (perforation, ulcerogenicity, bleeding), blood clotting disorders, renal failure with prolonged use, and cardiovascular complications [A. Cicconetti, A. Bartoli, F. Ripari, A. Ripari. Oral Surg Oral Med Oral Pathol Oral Radiol Endod (2004), 97 (2), 139-146; A.N. Mironov Guide to conducting preclinical studies of drugs. Part one. - M .: Grif and K, 2012. - 944 p.]. Side effects and lack of effectiveness of existing non-narcotic pain medications stimulate the search for new compounds with analgesic activity.

In the literature there is information about the synthesis, physico-chemical, spectral characteristics of some of the compounds represented by general formula 1, as well as their biological activity. So, the synthesis, physicochemical and spectral characteristics of a number of compounds claimed in this patent are described [A.A. Botev, O.P. Krasnykh, M.V. Tomilov, M.I. Vakhrin, E.B. Babushkina, T.F. Odegova. Bashkir Chemical Journal (2007), vol. 14, No. 3, 32-37; A.A. Botev, O.P. Krasnykh, I.V. Fefilova, E.B. Babushkina, P.A. Slepukhin. News of the Academy of Sciences. Chemical Series (2014), No. 3, 731-738; Boteva A.A. dis. ... cand. farm. sciences. Per. state farm. Academy, Perm, 2008], their antimicrobial activity is described [A.A. Botev, O.P. Krasnykh, M.V. Tomilov, M.I. Vakhrin, E.B. Babushkina, T.F. Odegova. Bashkir Chemical Journal (2007), vol. 14, No. 3, 32-37; Boteva A.A. dis. ... cand. farm. sciences. Per. state farm. Academy, Perm, 2008] and anti-tuberculosis [RF patent 2457208 C2, 2012; Boteva A.A. dis. ... cand. farm. sciences. Per. state farm. Academy, Perm, 2008].

However, information on the analgesic activity of any of the compounds described by formula 1 is not available in the literature, which does not allow us to talk about the possibility of obtaining drugs based on them with analgesic properties.

The central structural fragment in the compounds of general formula 1, the use of which is the object of this invention, is a 4-quinolone fragment containing substituents at positions 2 and 3 of the 4-quinolone system and not containing a substituent at the nitrogen atom. The compounds of general formula 1 differ in structure from the class of known drugs - antibacterial fluoroquinolones.

Compounds are known that contain a 4-quinolone fragment having experimentally confirmed analgesic activity, or for which an analgesic effect can be assumed due to literature data on the modulation by such compounds of the corresponding biological targets.

The glutamate receptors of the NMDA subtype are ligand-driven ion channels embedded in the cell membrane of neurons. NMDA receptor antagonists have been shown to be active in arresting neuropathic and inflammatory pain. Among the compounds containing the 4-quinolone fragment, substituted 2- (piperidin-1-carbonyl) quinolin-4 (1H) -ones 2 were found which showed antagonistic activity against NMDA with an IC _{50 of} 1.9-28.0 nmol / dm ³ concentrations in tests on cells [patent WO 2006010967]:

Efficacy as an analgesic for eight compounds has been confirmed in vivo (formalin test in mice). It was found that compounds 2 are effective in the second phase of the response to the introduction of formalin (20-25 minutes after chemical induction of pain). The ED _50, when administered orally, ranges from 0.46 mg / kg to more than 20 mg / kg.

Compounds 2 differ from the compounds described by formula 1 in that they do not have a substituent at position 3.

It is known that agonists of muscarinic M1 receptors are capable of producing an analgesic effect in the case of pain syndromes of various origins, including thermal, inflammatory and neuropathic types of pain. N-substituted 4-quinolones 3 are allosteric positive modulators of muscarinic M1 receptors, which was confirmed in experiments on cells expressing acetylcholine M1 or other muscarinic receptors. It was found that the EU ₅₀ compounds 3 in relation to the M1 subtype is 0.389-4,200 μmol / DM ³ [patent WO 2007100366]:

Compounds 3 differ from the compounds described by formula 1 in that they do not have a substituent at position 2 and have a substituent at position 1. In addition, the analgesic activity of compounds 3 is not confirmed in in vivo experiments.

The cannabinoid system plays an important role in modulating pain. Selective activators of type 2 cannabinoid receptors (CB2) exhibit an analgesic effect in models of pain associated with inflammation, nerve damage, tumor growth, etc. without significant effects on the central nervous system functions, which are more associated with the modulation of type 1 cannabinoid receptors.

4-Quinolone-3-carboxamides 4 were found to be selective modulators of type 2 cannabinoid receptors. The study of the structure-activity ratio for the class and further structural modification led to the discovery of a derivative with the highest affinity and selectivity as a ligand of CB2 receptors (R ¹ = n-pentyl, R ² = adamantyl, R ³ = H, R ⁴ = OMe) for which CB1, K _i > 10,000 nmol; CB2, K _i = 0.6 nmol). [S. Pasquini, L. Botta, T. Semeraro, C. Mugnaini, A. Ligresti, E. Palazzo, S. Maione, V. Di Marzo, F. Corelli J. Med. Chem. (2008), 51, 5075-5084; S. Pasquini, M. De Rosa, V. Pedani, C. Mugnaini, F. Guida, L. Luongo, M. De Chiaro, S. Maione, S. Dragoni, M. Frosini, A. Ligresti, V. Di Marzo , F. Corelli J. Med. Chem. (2011), 54, 5444-5453; PG Baraldi, G. Saponaro, AR Moorman, R. Romagnoli, D. Preti, S. Baraldi, E. Ruggiero, K. Varani, M. Targa, F. Vincenzi, PA Borea, MA Tabrizi. J. Med. Chem. (2012), 55, 6608-6623.]

Compound 4, where R ¹ = n-pentyl, R ² = adamantyl, R ³ = H, R ⁴ = OMe, was studied in vivo in a formalin test in mice and at a dose of 6 mg / kg significantly reduced the formalin-induced nociceptive response in seven control points of nine in the range of 20-60 minutes after administration of a chemical pain inducer, acting as an inverse agonist [S. Pasquini, M. De Rosa, V. Pedani, C. Mugnaini, F. Guida, L. Luongo, M. De Chiaro, S. Maione, S. Dragoni, M. Frosini, A. Ligresti, V. Di Marzo, F Corelli J. Med. Chem. (2011), 54, 5444-5453].

Compounds 4 differ from the compounds described by formula 1 in that they have no substituent at position 2 and have a substituent at position 1.

The closest to the claimed technical solution in essence and in the achieved results is the following analogue: 7-chloro-4-hydroxy-2- (2-pyridylethyl) -1,2,5,10-tetrahydropyridazino [4,5-b] quinoline- 1,10-Dionomethyl sulfonate 5 exhibiting analgesic activity [patent WO 2002026740].

The described analogue is adopted as a prototype of the invention.

For 7-chloro-4-hydroxy-2- (2-pyridylethyl) -1,2,5,10-tetrahydro-pyridazino [4,5-b] quinoline-1,10-dionmethyl sulfonate 5, its effect on NMDA receptors was established in vitro experiments [DG Brown, R.A. Urbanek, T.M. Bare, F.M. McLaren, C.L. Horchler, M. Murphy, G.B. Steelman, J.R. Empfield, J.M. Forst, K.J. Herzog, W. Xiao, M.C. Dyroff, C.-M. C. Lee, S. Trivedi, K.L. Neilson, R.A. Keith, Bioorg. Med. Chem. Lett. (2003), 13, 3553-3556; Patent EP 0736531 A1]. In this case, the levorotatory enantiomer binds to the glycine site of the receptor with a much greater affinity than the dextrorotatory isomer (190 nM and 3200 nM, respectively). The authors suggest that not only methyl sulfonates, but also ethyl sulfonates, benzyl sulfonates, p-toluenesulfonates, as well as tartrates, citrates, chlorides, malonates, etc., will also exhibit analgesic activity [patent WO 2002026740].

The analgesic activity for methyl sulfonate 5 (levorotatory isomer and for racemate) was confirmed in in vivo experiments in the formalin test. It was found that the levorotatory isomer reduces pain sensitivity in the first phase by 50% at a dose of 173 mg / kg (3.7 mmol / kg), and in the second phase at a dose of 65 mg / kg (1.4 mmol / kg). In the same phase, pain sensitivity decreases by 68% at a dose of 200 mg / kg (4.3 mmol / kg). For a racemate, the pain sensitivity at a dose of 200 mg / kg is reduced by 83% in the first phase and by 72% in the second [patent WO 2002026740].

The main disadvantages of the prototype:

1. The first group of disadvantages follows from the fact that the claimed molecule can have two optically active isomers, while only one optical isomer exhibits significant analgesic activity. Data on the activity of the dextrorotatory isomer in vivo are not provided.

When taking a dosage form containing a racemic mixture, the patient will have to take both isomers. This is often a rather big problem, because, for example, it is known that an inactive enantiomer can form a toxic metabolite in the body. In other cases, an inactive isomer may slow down or alter the metabolism of the active isomer. Enantiomers can exhibit different types of biological activity. [R. Silverman, Elsevier, AcademicPress, 2004, 617 pp.]

The development of a dosage form containing only the most biologically most active optical isomer includes the stages of separation of isomers and purification of one of them, development of an appropriate analytical method for quality control, which generally significantly increases the cost of the introduction of the drug and, as a result, the final product.

2. The second significant drawback of the prototype is the lack of data on the toxicity of compound 5. In the literature there is evidence that substances that expressly block the activity of NMDA receptors may have undesirable side effects, such as hallucinations, fainting, tiredness, dizziness, etc. Many drugs that are antagonists of NMDA receptors and created for the treatment of neurodegenerative diseases have been withdrawn from development in the clinical trials stage due to the large number of side effects [D. Jamero, A. Borghol, N. Vo, F. Hawawini, US Pharmacist http://www.medscape.com/viewarticle/744071_3; R. Sacco, J. DeRosa, E. Haley, B. Levin, P. Ordronneau, S. Phillips, T. Rundek, R. Snipes, J. Thompson. Glycine antagonist in neuroprotection for patients with acute stroke: GAIN Americas: a randomized controlled trial. JAMA 28: 1719-1728, 2001]. As a result of this, the lack of toxicity data does not allow us to draw conclusions about the degree of safety of compound 5 and its analogs and, therefore, its potential as an analgesic.

The technical task of the invention is to expand the arsenal of analgesics, search based on the structure of N-unsubstituted 4-quinolone for a new agent with analgesic activity, low toxicity and comparable analgesic properties with drugs used in medical practice.

The problem is solved by the use of chemical compounds of formula 1, which exhibit pronounced analgesic activity and have low toxicity.

The preparation of compounds 1 is realized by the known reaction of thermolysis of 1-aryl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylic acid methyl esters [A.A. Botev, O.P. Krasnykh, I.V. Fefilova, E.B. Babushkina, P.A. Slepukhin. News of the Academy of Sciences. Chemical Series, (2014), No. 3, 731-738; K. Mohri, A. Kanie, Y. Horiguchi, K. Isobe, Heterocycles, (1999), 51, 10, 2377-2384].

The advantages of the invention are:

1. The lack of requirements for the existence of an active component in the form of a pure optically active isomer, which eliminates paragraph 1 from the list of disadvantages of the prototype.

2. High analgesic activity: at a dose of 0.05 mmol / kg, the lengthening of the latent period of the reaction to nociceptive stimulation reaches 130% compared with the control (example 1, table 1).

3. Low toxicity of substances: LD ₅₀ is in the range from 500 mg / kg to more than 2000 mg / kg (example 2, table 2). This advantage eliminates paragraph 2 from the list of disadvantages of the prototype associated with the lack of data on toxicity. Moreover, the toxicity of the claimed compounds is significantly lower than that used in medicine diclofenac sodium (example 2, table 2).

4. Proven scheme for the production of substances, high yields, i.e. easy synthetic availability of substances of the formula 1.

Physicochemical constants and spectral data of representative representatives of compounds of structure 1 are shown in examples 3-7.

The biological activity of compounds 1 was studied by assessing acute toxicity and determining the analgesic activity in the test "hot plate" according to standard methods [A.N. Mironov. Guidelines for preclinical studies of drugs. Part one. - M .: Grif and K, 2012. - 944 p.].

The hot plate test was performed on a Hotplate 60200 series (TSE Systems, Germany). The substance was administered to outbred Sprague Dawley rats weighing 180-350 g intraperitoneally as a suspension in 2% starch mucus at a dose of 0.05 mmol / kg. The control group of animals received only starchy mucus. The reference drug (diclofenac) was administered in an equimolar dose. After 1 hour, the animal was placed on a plate with a Plexiglas cylinder (diameter 19 cm and height 30 cm), electrically heated to 50 ° C. The response time to nociceptive stimulation (licking or shaking paw, jumping) was recorded, while, regardless of the response, the maximum time the animal spent on the plate was 30 seconds to prevent inadvertent disturbance of the skin of experimental animals [European Convention for the Protection of Vertebrate Animals used for experiments or other scientific purposes. ETS N 123. Strasbourg, March 18, 1986 / European Convention for the Protection of Vertebrate Animals Used for Experimental and other Scientific Purposes. ETS 123. Strasbourg, 03/18/1986)].

Analgesic activity (AA) was expressed as an increase (in percent) in the response time to nociceptive stimulation in the group of animals that received the substance, compared with the control group of animals and was calculated by the formula:

AA,% = (t _in -t _k ) / t _k ,

Where

t _at - response time to nociceptive stimulation in a group of animals that received the substance,

t _k is the response time to nociceptive stimulation in the control group of animals that received 2% starch mucus.

The results were processed using the GraphPadPrism 6 program using the "Multiple t tests" method. The results of the study are presented in table 1.

The study of acute toxicity was carried out on outbred white mice of the CD-1 line weighing 27-38 grams. The test substances were administered intraperitoneally in 2% starch mucus. After administration of the test substances, the survival of the animals in the groups was evaluated with constant monitoring for 24 hours and subsequent general observation for 14 days. It was found that LD _{50 of the} claimed substances of formula 1 lies in the range from 500 to more than 2000 mg / kg (table 2).

The compounds belong to the 4th class of toxicity, i.e. are low toxic [K.K. Sidorov. Toxicology of new industrial substances. Moscow, (1973), issue 13, p. 47-51]. The LD ₅₀ of the comparison drug for diclofenac sodium when administered intraperitoneally to mice is 42-132 mg / kg [V.E. Koll, B.Ya. Syropyatov. M .: "Medicine", 1998. - 263 p.].

The analgesic can be made from one representative of the compounds described by formula 1, from a combination of two or more, from simple derivatives based on them, such as salts, which, when applied internally, will decompose to form compounds 1, as well as from compositions containing compounds of structure 1 with the addition of any other components used as excipients.

The pharmaceutical composition may be intended for various forms of administration, including, but not limited to, oral and parenteral administration. For example, compositions for oral administration can be presented including tablets, capsules, sachets containing a certain amount of active compound. Also, the composition may be presented as a powder, granules, solution, aqueous and non-aqueous suspension and emulsion.

Compositions for oral administration can be prepared by any of the known methods and may contain the active ingredient in a mixture with non-toxic excipients, such as fillers, binders, loosening, antifriction substances, film formers, odor, taste and color flavoring agents, prolongators, substances for creating a hydrophobic layer , plasticizers and solvents.

For tablets, these excipients may include excipients such as starch, glucose, sucrose, lactose, basic magnesium carbonate, magnesium oxide, sodium chloride, sodium bicarbonate, kaolin, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose sodium, calcium carbonate, calcium phosphate, glycine , dextrin, amylopectin, sorbitol, mannitol, pectin, etc. binders such as water, ethyl alcohol, starch paste, sugar syrup, polyvinyl alcohol, polyvinyl pyrrolidone, alginic acid, sodium alginate, gelatin, carboxymethyl cellulose solutions, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol and polyvinyl alcohol; baking powder - starch, pectin, gelatin, methyl cellulose, sodium carboxymethyl cellulose, amyl pectin, agar agar, alginic acid, potassium or sodium alginate, a mixture of sodium carbonate with citric or tartaric acid, tween-80, sugar, glucose, aerosil, etc. .

The composition for oral administration can be represented by soft or hard gelatin capsules, where the active substance is mixed with excipients, for example, calcium carbonate, starch, calcium phosphate, kaolin, or water, vegetable and petrolatum oils, respectively, but not limited to.

Other pharmaceutical compositions for oral administration include aqueous suspensions, where the active substance is mixed with inert excipients suitable for the preparation of an aqueous suspension. An oily suspension can be prepared by suspending the active substance in a vegetable oil, for example, sunflower, peanut, coconut, olive, or in a mineral, such as liquid paraffin, and contain additional excipients, the compositions can also be emulsions containing excipients, including including colorants and sweeteners.

The pharmaceutical composition may be a sterile injectable aqueous or oleaginous suspension or a powder for extemporaneous preparation of a sterile solution or suspension suitable for injection.

The pharmaceutical composition of the present invention may be presented in a topical form, for example, ointment, cream, spray, powder, lotion or the like, as well as any transdermal form. The pharmaceutical composition of the present invention may be in a form suitable for rectal administration and prepared using cocoa butter, paraffin, hydrogenated fats, gelatin, glycerin, polyethylene oxides and other substances used to prepare suppositories.

The invention is illustrated by the following examples.

EXAMPLE 1

Analgesic activity (AA) of substituted quinolin-4 (1H) -ones of general formula 1 at a dose of 0.05 mmol / kg

* - p <0.05

** - p <0.1

z - tested at a dose of 0.03 mmol / kg.

EXAMPLE 2

Toxicity of substituted quinolin-4 (1H) -ones of general formula 1

EXAMPLE 3

Methyl 3-benzoyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (compound 1)

Methyl 3-benzoyl-4,5-dioxo-1-phenyl-4,5-dihydro-1H-pyrrole-2-carboxylate was kept in absolute biphenyl oxide (or Dowtherm A) in the temperature range of 190-210 ° C for 10-40 min (monitoring of the reaction was carried out by TLC). The precipitate formed upon cooling was washed with petroleum ether (70-100 ° C), recrystallized from dioxane. [A.A. Botev, O.P. Krasnykh, I.V. Fefilova, E.B. Babushkina, P.A. Slepukhin. News of the Academy of Sciences. Chemical Series, 2014, No. 3, S. 731-738.] Yield 75%, mp. = 234-236 ° C (decomp.) (1,4-dioxane). IR spectrum, ν / cm ^-1 : 1741 (COO); 1673 (Bz); 1618 (C (4) = O). ¹ H NMR spectrum (500 MHz, DMSO-d ₆ ) δ ppm: 3.75 (s, 3H, OMe), 7.45 (dd, J = 8.1, 6.9, 1.1 Hz, 1H, 4'- H), 7.47-7.50 (m, 2H, 3'-H, 5'-H), 7.59-7.64 (m, 1H, 6-H), 7.77-7.81 (m, 1H, 7-H), 7.81- 7.85 (m, 2H, 2'-H, 6'-H), 8.00 (d, J = 8.0 Hz, 1H, 8-H), 8.07 (dd, J = 8.1, 1.5 Hz, 1H, 5- H), 12.40 (s, 1H, NH). ¹³ C NMR Spectrum (125 MHz, DMCO-d ₆ ): 53.40 (OMe); 119.57, 122.69, 124.62, 124.67, 125.53, 128.48, 128.54, 132.90, 133.08, 135.83, 137.19, 139.35; 161.92 (COO); 175.71 (C (4)); 193.90 (COPh).

EXAMPLE 4

Methyl 3-benzoyl-4-oxo-8-ethyl-1,4-dihydroquinoline-2-carboxylate (compound 10)

Received similarly. Yield 59%. Mp 170-172 ° (decomp.) (Acetonitrile). IR spectrum, ν / cm ^-1 : 3368 (NH); 1740 (COO); 1680 (Bz); 1620 C (4) = O, 1600 (C = C). ¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ ppm: 1.45 (t, J = 7.5 Hz, 3H, Me), 2.96 (q, J = 7.6 Hz, 2H, CH ₂ ), 3.77 (s, 3Н, OMe), 7.36 (dd, J = 8.2, 7.2 Hz, 1Н, 4'-Н), 7.42-7.46 (m, 2Н, 3'-Н, 5'-Н), 7.53-7.59 (m , 2Н, 6-Н, 7-Н), 7.91-7.93 (m, 2Н, 2'-Н, 6'-Н), 8.21 (d, J = 8.4 Hz, 1Н, 5-Н), 9.09 (s , 1H, NH). ¹³ C NMR spectrum (125 MHz, DMCO-d ₆ ): 13.9 (Me), 22.72 (CH ₂ ), 53.32 (OMe), 120.9, 122.9, 124.8, 126.0, 128.5 (C-2 ', C-6') 128.8 (С-3 ', С-5'), 132.3, 133.0, 136.8, 137.27, 139.1, 162.4 ( С ОО), 175.6 (С-4), 194.0 ( C OPh). Found (%): C, 71.61; H, 5.07; N, 4.18. C ₂₀ H ₁₇ NO ₄ . Calculated (%): C, 71.63; H, 5.11; N, 4.18.

EXAMPLE 5

Methyl 3-benzoyl-4-oxo-6-fluoro-1,4-dihydroquinoline-2-carboxylate (compound 14)

Received similarly. Yield 64%. Mp 241.4-242.5 ° C (decomp.) (Acetonitrile). IR spectrum, ν / cm ^-1 : 3355 (NH); 1744 (COO); 1680 (Bz); 1584 (C (4) = O, C = C). ¹ H NMR spectrum (500 MHz, DMSO-d ₆ ) δ ppm: 3.75 (s, 3H, OMe), 7.43-7.52 (m, 2H, 3'-H, 5'-H), 7.55-7.70 (m, 1H, 4'-H), 7.69-7.81 (m, 2H, 6-H, 7-H), 7.78-7.86 (m, 2H, 2'-H, 6'-H), 8.09 (d d, J = 9.1, 4.6 Hz, 1H, 5-H), 12.57 (s, 1H, NH). ¹³ C NMR spectrum (125 MHz, DMCO-d ₆ ): 53.47 (OMe), 108.65, 108.83, 121.83, 122.07, 122.27, 122.64, 122.70, 126.78, 126.83, 127.96, 128.52 (C-2 ', C-6' ), 128.58 (С-3 ', С-5'), 128.95, 132.19, 132.99, 135.95, 158.12, 160.07, 161.84 (СОО), 174.96 (С-4), 193.71 ( C OPh). Found (%): C, 66.46; H, 3.65; N, 4.37; F, 5.73. C ₁₈ H ₁₂ FNO ₄ . Calculated (%): C, 66.46; H, 3.72; N, 4.31, F, 5.84.

EXAMPLE 6

Methyl 3-thienoyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (compound 26)

To 2.50 g (8.7 mmol) of methyl (Z) -4-oxo-2- (phenylamino) -4- (2-thienyl) -2-butenoate in 15 ml of absolute chloroform was added 785 μl of oxalyl chloride. Boiled for 3 hours under reflux, protecting from atmospheric moisture (monitoring by TLC). Chloroform was distilled off, after adding 6 ml of Dowtherm A to the flask. It was kept at a temperature of 200-210 ° С for 15 minutes. The precipitate formed upon cooling was washed with hot petroleum ether and recrystallized from dioxane 2 times. Yield 18%. Mp 228.2-228.9 ° C (decomp.). IR spectrum, ν / cm ^-1 : 1755 (COO); 1675 (Bz); 1625 (C (4) = O, C = C). ¹ H NMR spectrum (500 MHz, DMSO-d ₆ ) δ ppm: 3.78 (s, 3H, OMe), 7.15 (dd, 1H, J = 4.8, 3.8 Hz, 4'-H), 7.43 -7.46 (m, 1H, 8-H), 7.57 (dd, 1H, J = 3.8, 1.1 Hz, 3'-H), 7.79 (dd, 1H, J = 8.5, 7.1, 1.4 Hz, 6-H), 7.99-8.01 (m, 2H, 5'-H, 7-H), 8.10 (m, 1H, 5-H), 12.37 (s, 1H, NH). ¹³ C NMR spectrum (125 MHz, DMCO-d ₆ ): 185.72 (СО), 175.40 (С-4), 161.82 (СОО), 144.59, 139.27, 135.80, 134.48, 134.06, 133.09, 128.40, 125.69, 124.79, 124.68 , 122.29, 119.61, 53.46 (OMe). Found (%): C, 61.26; H, 3.54; N, 4.45; S, 10.00. C ₁₆ H ₁₁ NO ₄ S. Calculated (%): C, 61.33; H, 3.54; N, 4.47, S, 10.23.

EXAMPLE 7

3-Benzoyl-4-oxo-1,4-dihydro-2-quinolinecarboxylic acid (compound 2)

1.3 mmol of methyl 3-benzoyl-4-oxo-1,4-dihydro-2-quinolinecarboxylate 1 in 1.5 ml of a 20% solution of sodium hydroxide in a 1: 1 water-methanol mixture was heated to boiling. After cooling, the solution was neutralized with sulfuric acid (1: 4). The precipitate was filtered off, washed with water, and dried. [A.A. Botev, O.P. Krasnykh, M.V. Tomilov, M.I. Vakhrin, E.B. Babushkina, T.F. Odegova. Bashkir chemical journal. 2007, t. 14, No. 3, p. 32-37.] Yield 93%, mp. 163-164 ° C (decomp.). IR spectrum, ν / cm ^-1 : 3444, 3346, 3257 (NH); 1726 (COO); 1664 (Bz); 1608 (C (4) = O, 1600 C = C). ¹ H NMR (500 MHz, DMSO-d ₆₎ δ ppm .: 7.40-7.45 (m, 1H, 4'-H), 7.46-7.49 (m, 2H, 3'-H, 5'-H ), 7.58-7.61 (m, 1H, 6-Н), 7.77 (dd, J = 8.5, 7.2, 1.4 Hz, 1Н, 7-Н), 7.79-7.83 (m, 2Н, 2'- H, 6'-H), 8.02 (d, 1H, J = 8.5 Hz, 8-H), 8.05 (dd, J = 8.0, 1.0 Hz, 5-H), 12.25 (s, 1H, NH) .

Claims (10)

The use of substituted quinolin-4 (1H) -ones of the general formula 1

, where R ¹ = phenyl unsubstituted or substituted with one substituent selected from alkyl (C1-C4), alkoxy (OC1-OC4), halogen; phenyl substituted with two substituents selected from methyl, ethyl, methoxy, ethoxy or halogen; naphthyl unsubstituted, thienyl, unsubstituted or substituted with one substituent selected from methyl or halogen; furyl unsubstituted, C4 alkyl, OMe; R ² + R ³ = = O, = NOMe, R ⁴ = H, COOMe, COOH; R ⁵ = H, Me, R ⁶ = H, Me, OMe, Et, halogen, R ⁷ = H, halogen, CN, R ⁸ = H, alkyl (C1-C4), halogen, CN, their salts and compositions based on them as an analgesic.