RU2711968C1 - Analgesic agent - Google Patents

Abstract

FIELD: chemistry.SUBSTANCE: invention relates to use of substituted pyrrolo[3,4-b]quinolindione of general formula 1 and a pharmaceutically acceptable salt thereof, having analgesic activity, for preparing a pharmaceutical composition suitable for use as an analgesic agent. In formula 1R=Ph, n-MeCH, n-ClCH; R=H, Me, Et, halogen; R=H, Me, CHOH; X=O, NH, NMe; Z=(CH)n, where n=0, 1, 2, or Z=CHOCH.EFFECT: disclosed is an analgesic agent.1 cl, 2 tbl, 4 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 pyrrolo [3,4-b] quinolinedione of general formula 1, their salts or compositions based on them and which can find use for the treatment of people and animals as an anesthetic

where R ¹ = Ph, n-MeC ₆ H ₄ , n-ClC ₆ H ₄

R ² = H, Me, Et, halogen,

R ³ = H, Me, CH ₂ OH

X = 0, NH, NMe

Z = 0, 1, 2, 8, CH ₂ OCH ₂ ,

their salts and compositions based on them as an analgesic.

Effect: obtained compounds, including those not previously described, having analgesic activity in the test "hot plate", which suggests the possibility of their use in medicine as an analgesic.

In the treatment of conditions accompanied by acute or chronic pain, a number of difficulties arise. One of them is the imperfection of existing drugs. Currently, NSAIDs, amine reuptake inhibitors, opioids and antiepileptics with undesirable effects are used to relieve pain. When creating new tools, companies are trying to increase efficiency, avoid adverse reactions and eliminate addiction [A.S. Yekkirala, D.P. Roberson, B.P. Bean, C.J. Woolf. Nature Reviews Drag Discovery (2017), 16, 545-564].

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, physico-chemical and spectral characteristics of a number of compounds claimed in this patent are described [RF Patent 2381229, 2010.], their anti-tuberculosis activity is described [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 the present invention, is the pyrrolo [3,4-b] quinolinedione moiety containing substituents in various positions and without a substituent on the nitrogen atom. Compounds of the general formula 1 differ in structure from the class of known drugs - antibacterial fluoroquinolones.

Known [b] -annelated 4-quinolones with experimentally confirmed analgesic activity, or those for which we can assume an analgesic effect based on the action of these substances on biological targets on the basis of published data. So, for example: substituted pyrazolo [4,3-b] quinolinones 2 [Patent EP 1310498] are inhibitors of the protein kinase C enzyme, and can be used to treat / treat neuropathic pain, as well as acute and chronic pain associated with inflammation.

The effect on recombinant human α-, β2-, γ-protein kinases C of compounds 3 was established in experiments in vitro. The IC _{50 of} compounds 2 was 0.1-1 μmol.

The effectiveness of the compounds in neuropathic pain was evaluated in vivo in male SD rats. After ligature was applied to the sciatic nerve, tactile allodynia was tested using Frey's hairs on day 14. For the treatment of inflammation, it is proposed to use compounds 3 in doses of 0.06-2 mg / kg.

In addition, it is reported that 7-chloro-4-hydroxy-2- (2-pyridylethyl) -1,2,5,10-tetrahydropyridazino [4,5-b] quinoline-1,10-dionmethylsulfonate 3 exhibits analgesic activity [Patent WO2002026740].

For 7-chloro-4-hydroxy-2- (2-ciridylethyl) -1,2,5,10-tetrahydropyridazino [4,5-b] quinoline-1,10-dionmethylsulfonate 3, 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.V. 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]. 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.

The levorotatory enantiomer of compound 3 binds to the glycine receptor site with a much greater affinity than the dextrorotatory isomer (concentrations 190 and 3200 nmol / dm ^3, respectively). The authors suggest that not only methyl sulfonates, but also ethyl sulfonates, benzyl sulfonates, n-toluenesulfonates, as well as tartrates, citrates, chlorides, malonates, etc. will also exhibit analgesic activity [Patent WO 2002026740].

The analgesic activity for methyl sulfonate 3 (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, pain sensitivity at a dose of 200 mg / kg decreases by 83% in the first phase and by 72% in the second. [Patent WO2002026740].

Closest to the claimed technical solution in essence and according to the achieved results is compound 3, which is taken as a prototype of the invention.

The main disadvantage of the prototype is the lack of data on the toxicity of compound 3. In the literature there is evidence that substances that strongly block the activity of NMDA receptors may have undesirable side effects, such as hallucinations, fainting, fatigue, 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 a large number of side effects (D. Jamero, A. Borghol, N. Vo, F. Hawawini, USPharmacist 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 lack of toxicity data, it is not possible to draw conclusions about the degree of safety of compound 3 and its analogues and, with edovatelno, promising as analgesic agents.

The technical task of the invention is the expansion of the arsenal of analgesics, the search based on pyrrolo [3,4-b] quinolinedione for a new drug with analgesic activity and low toxicity, and comparable in analgesic properties with drugs used in medical practice.

The problem is solved using chemical compounds of the formula 1, exhibiting pronounced analgesic activity and having low toxicity.

The preparation of compounds 1 is realized by the reaction of nucleophilic addition of aliphatic diamines and amino-containing alcohols to 3-aroyl-4-oxo-1,4-dihydro-2-quinolinecarboxylic acid methyl esters [Botev AA. dis. ... cand. farm. sciences. Per. state farm. Academy, Perm, 2008; RF patent 2381229, 2010].

The advantages of the invention are:

1. High analgesic activity: at a dose of 0.05 mmol / kg, the lengthening of the latent period of the reaction to nociceptive stimulation reaches 198.5% compared with the control (example 1, table 1).

2. Low toxicity of substances: LD ₅₀ is in the range from 500 mg / kg to more than 1000 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).

3. 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 3-4.

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 s]

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 (for substances 1, 5, 6, 8, 10, 11, 16, 19, 23 - after 1 hour and after 2 hours) the animal was placed on an electrically heated to 50 ° C plate with a Plexiglas cylinder (19 cm in diameter and 30 cm high). The response time to nociceptive stimulation (licking or shaking of the 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 to the control group of animals and was calculated by the formula:

, где

where

t _at - response time to nociceptive stimulation in a group of animals that receive 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 performed 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 1000 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), no. 13, p. 47-51]. The LD50 of the drug for comparison of diclofenac sodium with intraperitoneal administration 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 used 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.

An analgesic based on compounds of formula 1 and pharmaceutical compositions based on it can have various forms of administration: oral, parenteral, rectal, etc.

Compositions for use can be prepared by any method and may contain the active ingredient in a mixture with non-toxic excipients (fillers, binders, loosening, antifriction substances, film-forming agents, odor, taste and color flavoring agents, prolongators, substances for creating a hydrophobic layer, plasticizers, solvents and etc.).

Compositions for oral administration can be represented by tablets, capsules, sachets, powders, granules, solution, aqueous and non-aqueous suspension and emulsion containing a certain amount of the active compound, as well as soft or hard gelatin capsules in which the active substance is mixed with excipients, for example such as calcium carbonate, starch, calcium phosphate, kaolin, or water, vegetable and petroleum jelly oils, respectively, but not limited to.

In addition, pharmaceutical compositions for oral administration can be represented by aqueous suspensions in which 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 vegetable oil — for example, sunflower, peanut, coconut, olive, or in mineral — such as liquid paraffin, and contain additional excipients. The compositions may also be emulsions containing auxiliary substances, 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 can be presented in topical form, for example, ointment, cream, aerosol, 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

pyrrolo [3,4-b] quinolinedione of the general formula 1 at a dose of 0.05 mmol / kg

* - p≤0.05

** - p≤0.1

EXAMPLE 2:

Toxicity of substituted pyrrolo [3,4-b] quinolinedione of general formula 1

EXAMPLE 3:

10-Bromo-12b-phenyl-1,2,3,4,7,12b-hexahydro-pyrimido [1 ', 2': 1,5] pyrrolo [3,4-b] quinoline-6,12-dione (compound 17 )

To 0.5 g (1.3 mmol) of 3-benzoyl-6-bromo-4-oxo-1,4-dihydroquinoline-2-carboxylic acid methyl ester dissolved in 40 ml of 1,4-dioxane was added 0.1 g (1.3 mmol) of propylene diamine. Boiled under reflux for 2 hours (control by TLC), evaporated in vacuo. The precipitate formed was filtered off and recrystallized from 1,4-dioxane. Yield 55%, mp> 300 ° C (dioxane). IR spectrum (liquid paraffin) ν, cm ^-1 : 3230, 3180, 3150, 3115 (NH), 1700 (С ⁶ = O), 1644 (С ¹² = O), 1604 (C = С). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ, ppm: 12.97 (s, 1H, NH), 8.11 (d, J = 2.4 Hz, 1H, 11-H), 7.83 (dd, J = 9.2 Hz, J = 2.4 Hz, 1H, 9-H), 7.74 (d, J = 8.4 Hz, 8-H), 7.58 (d, J = 7.2 Hz, 2H, 2'-H, 6'- H), 7.37-7.33 (m, 2Н, 3'-Н, 5'-Н), 7.28-7.27 (m, 1Н, 4'-Н), 4.29 (d, J = 12.8 Hz, 1H, 4-Н ), 2.98-2.87 (m, 2Н, 3-Н), 2.67-2.65 (m, 1Н, 4-Н), 1.50-1.48 (m, 2Н, 2-Н). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ, ppm: 169.7 (12-C), 161.2 (6-C), 140.5, 138.8, 136.5 134.8, 129.2, 128.2 (3'-C, 5 '-C), 127.6, 127.5 (2'-C, 6'-C), 127.2, 126.2, 121.9, 116.5, 78.5 (12b-C), 40.1 (2-C), 37.0 (4-C), 25.8 (3-C). Found (%): C, 58.65; H, 3.82; Br, 19.26; N, 10.00. C ₂₃ H ₂₃ N ₃ O ₂ . Calculated (%): C, 58.55; H, 3.93; Br, 19.48; N, 10.24.

EXAMPLE 4:

12b-Phenyl-8-ethyl-1,2,3,4,7,12b-hexahydro-pyrimido [1 ', 2': 1,5] pyrrolo [3,4-b] quinoline-6,12-dione (compound 18 ) Received similarly. Yield 55%, mp. 292-293 ° C (decomp.) (Acetonitrile). IR spectrum (KBr) ν, cm ^-1 : 3342, 3303 (NH), 1698 (С ⁶ = 0), 1636 (С ¹² 0), 1596 (C = С). NMR ¹ H (500 MHz, DMSO-d ₆ ) δ, ppm: 11.44 (s, 1H, NH), 7.94 (d, J = 8.1 Hz, 1H, 11-H), 7.59-7.57 (m, 2H, 2'-H, 6'-H), 7.54-7.52 (m, 1H, 9-H), 7.37-7.34 (m, 2H, 3'-H, 5'-H), 7.30-7.25 (m , 2Н, 10-Н, 4'-Н), 4.30 (d, J = 13.2 Hz, 1Н, 4-Н), 3.19-3.04 (m, 2Н, СН ₂ ), 2.97-2.87 (m, 2Н, 2 -H), 2.67-2.64 (m, 1H, 4-H), 1.54-1.48 (m, 2H, 3-H), 1.21 (t, J = 7.4 Hz, 3H, CH ₃ ). ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ, ppm: 171.3 (12-C), 167.6 (6-C), 161.2, 140.1, 137.7, 136.8, 133.9, 131.7, 128.3, 128.1 (3 '-С, 5'-С), 127.5 (2'-С, 6'-С), 127.5, 126.5, 123.7, 123.0, 90.3, 77.8 (12b-С), 40.1 (2-С), 36.8 (4 -C), 25.8 (3-C), 23.2 (CH ₂ ), 14.5 (CH ₃ ). Found (%): C, 72.89; H, 6.31; N, 11.45. C ₂₂ H ₂₁ N ₃ O ₂ * 0.2 C ₄ H ₈ O ₂ . Calculated (%): C, 72.77; H, 6.02; N, 11.23.

More synthetic examples are given in [RF Patent 2381229, 2010].

Claims (8)

The use of substituted pyrroloquinolinedione general formula 1

where R ¹ = Ph, n-MeC ₆ H ₄ , n-ClC ₆ H ₄ ; R ² = H, Me, Et, halogen; R ³ = H, Me, CH ₂ OH; X = O, NH, NMe; Z = (CH ₂ ) _n , where n = 0, 1, 2 and Z = CH ₂ OCH ₂ , or a pharmaceutically acceptable salt thereof having analgesic activity, for the preparation of a pharmaceutical composition suitable for use as an analgesic.