EA044367B1 - BENZODIAZEPINE-BASED PRODUCT WITH ACTIVITY ON NEUROPATHIC PAIN - Google Patents

Description

Field of technology

The invention relates to the prevention and/or treatment of neuropathic pain.

In this scenario, treatment strategies should interfere with both systems by combining an AChe enzyme inhibitor capable of improving cholinergic tone with an NMDA receptor antagonist capable of resisting glutamate-induced neurodegeneration. However, this combination of therapies has several disadvantages. In addition to resistance to the administration of individual drugs, an additional problem for older patients suffering from AD and their caregivers is that the different pharmacokinetics of the respective drugs may have different pharmacodynamics. In practice, hospitals will not welcome combination therapy with two different ADME (Administration, Distribution, Metabolism, and Excretion) curves.

An alternative and new approach to two-drug combinations is two drugs that can act on multiple pharmacological targets, called multi-target drugs (MTDs).

The strategy of targeting two or more proteins simultaneously with a simple compound can provide superior therapeutic effects (Cavalli A, Bolognesi ML, Minarini A, Rosini M, Tumiatti V, Recanatini M, Melchiorre C. Multi-target-directed ligands to combat neurodegenerative diseases J Med Chem 2008, 51, 347-72) (Zimmerman GR, Lehar J, Keith CT. Multi-target therapeutics; when the whole is greater than the sum of the parts. Drug Discov Today 2007, 12, 34-42) (Morphy R, Ranlovic, Z. Fragments, network biology and designing multiple ligands. Drug Discov Today 2007, 12, 156-60). This may be explained by a number of potential benefits provided by the use of MTD relative to cocktails or multicomponent medications. The advantages of MTD relative to cocktails can be summarized as follows: 1) reduced variability in clinical development, given that predicting the pharmacokinetics of a single compound is much easier than for a cocktail, overcoming the problem of different bioavailability, pharmacokinetics and metabolism; 2) pharmacodynamic safety; 3) increased efficacy due to the synergistic effect of inhibition of multiple therapeutic targets, and 4) increased safety with reduced secondary effects of consuming drug cocktails (reduced risks due to drug-drug interactions); This is especially true in drug metabolism, where competition between different drugs for the same metabolic enzyme affects their toxicity.

Another important benefit is a simplified therapeutic regimen with improved compliance capabilities, and this is especially important for older Alzheimer's patients and their caregivers (Small, G, Dubois In A review of compliance to treatment in Alzheimer's disease: potential benefits of a transdermal patch. Curr Med Res Opin 2007, 23, 2705-13). An important aspect in this regard is that patients with Alzheimer's disease are susceptible to a wide range of medical conditions (comorbidities), which include hypertension, vascular disease and diabetes, which can often be comorbid. Thus, the problems associated with the use of multiple pharmaceutical agents in the elderly population have been recognized as critical in recent years. These problems mainly involve drug interactions, which occur more frequently in this population due to the coexistence of chronic diseases and organ failure. It cannot be assumed that two drugs that are safe on their own will also be safe when combined, especially in the elderly population. In addition, the number of drugs administered simultaneously should be reduced as much as possible, since advanced age is an unpredictable risk factor for any drug treatment (Turnheim, K. When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp. Geront 2006, 38, 843-853). Because MTDs are particularly preferred over multidrug therapies due to the complexity of interactions between multifunctional drugs, comorbidities, altered pharmacodynamic sensitivities, and altered pharmacokinetics in the elderly. Clinical use of MTD may also simplify the therapeutic regimen (Youdim, M.B., and Buccafusco, J.J. (2005) CNS Targets for multi-functional drugs in the treatment of Alzheimer's and Parkinsons diseases J. Neural Transm 112, 519-537). Compliance with prescribed medication regimens is important for effective treatment.

Multiple epidemiological studies have shown that chronic pain is widespread, with significant impacts on public health, healthcare and social services (Torrance N, Smith BH. Bennett Ml, Lee AJ. The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey J Pain 2006;7:281-289 (Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, Hansson P, Hughes R, Nurmikko T, Serra J. Redefinition of neuropathic pain and a grading system for clinical use: consensus statement on clinical and research diagnostic criteria. Neurology 2008;70:16301635). In particular, it has been estimated that chronic pain with neuropathic content affects approximately 7-8% of the general population, and the therapies available to treat them are still unsatisfactory (Torrance N, Smith BH. Bennett Ml, Lee AJ. The epidemiology of chronic pain of predominantly neuro

- 1 044367 pathic origin. Results from a general population survey. J Pain 2006; 7:281-289) (van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N. Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain 2014; 155:654-62) (Bennett Ml, Rayment C, Hjermstad M, Aass N, Caraceni A, Kaasa S. Prevalence and aetiology of neuropathic pain in cancer patients: A systematic review. Pain 2012;153:359-365). NP is seen as a symptom of neurodegeneration, so it is logical to consider neuroprotection as a strategy to prevent its onset, combat its progression, and even reverse the neural damage leading to these symptoms of chronic pain (Bordet T and Pruss RM. Targeting neuroprotection as an alternative approach to preventing and treating neuropathic pain Neurotherapeutics 2009;6:648-662). Neuroprotection includes modalities that support neuronal survival or function in the context of pathological stress (traumatic, toxic, ischemic or metabolic events). Thus, today, the treatment of most peripheral and central NP neuropathies (painful diabetic neuropathy, distal polyneuropathy, sensory distal due to HIV and antiretroviral therapy, peripheral neuropathies caused by chemotherapy, postherpetic neuralgia, MS pain and pain after stroke, etc. .) are aimed at this area (Bordet T and Pruss RM. Targeting neuroprotection as an alternative approach to preventing and treating neuropathic pain. Neurotherapeutics 2009; 6:648-662) (Flatters SJL, Bennett GJ. Studies of peripheral sensory nerves in paclitaxel- induced painful peripheral neuropathy: Evidence for mitochondrial dysfunction. Pain 2006; 122: 245-257) (Jaggi AS, Singh N. Mechanisms in cancer-chemotherapeutic drugs-induced peripheral neuropathy. Toxicology 2012; 291: l-9). Particular attention is paid to glutamatergic dysfunction, nitro-oxidative stress, mitochondrial dysfunction, apoptosis, trophic factors, neuroinflammation and changes in intact fibers caused by neurodegeneration (Bordet T and Pruss RM. Targeting neuroprotection as an alternative approach to preventing and treating neuropathic pain. Neurotherapeutics 2009 ; 6:648-662) (DeLeo JA, Sorkin LS, Watkins LR, editors. Immune and glial regulation of pain. Seattle: IASP Press; 2007) (Park ES, Gao X, Chung JM, Chung K. Levels of mitochondrial reactive oxygen species increase in rat neuropathic spinal dorsal horn neurons. Neuroscience Letters 2006;391:108-111). Biologists have proposed the development of new methods of treating pain based on the participation of the electron transport chain in ATP-dependent neuropathies (Joseph EK, Levine JD. Mitochondrial electron transport in models of neuropathic and inflammatory pain. Pain 2006; 121:105-114) (Joseph EK, Levine JD. Multiple PKCεdependent mechanisms mediating mechanical hyperalgesia. Pain 201 O; 150:17-21). Mitochondrial dependence of nerve growth factor-induced mechanical hyperalgesia has also been noted (Chu C, Levine E, Gear RW, Bogen O, Levine JD. Mitochondrial dependence of nerve growth factor-induced mechanical hyperalgesia. Pain 2011; 152:1832-1837 ).

Consistent with these ideas, multiple immune mediators involved in Wallerian degeneration (WD), which occurs when nerve fiber continuity is disrupted, have been proposed as new targets for NP drug treatment (Debovy P. Wallerian degeneration and peripheral nerve conditions for both Lingor P, Koch JC, Tanges L, Bahr M. Axonal degeneration as a therapeutic target in the CNS. Cell Tissue Res 2012; 349:289- 311). Roles played by neuroimmune activation, microglia-neuronal signaling, and oxidative stress have also been recognized in enhancing transmission after nerve injury (Berger JV, Knaepen L, Janssen SPM, Jaken RJP, Marcus MAE, Joosten EAJ, Deumens R. Cellular and molecular insights into neuropathy-induced pain hypersensitivity for mechanismbased treatment approaches. Brain Research Reviews 2011; 67: 282-310) (De Leo J.A, Tawfik VL, La CroixFralish ML. The tetrapartite synapse: Path to CNS sensitization and chronic pain. Pain 2006;122: 17-21) (Austin PJ, Moalem-Taylor G. The neuro-immune balance in neuropathic pain: Involvement of inflammatory immune cells, immune-like glial cells and cytokines Journal of Neuroimmunology 201 O; 229:26-50) (Salvemini D , Little JW, Doyle T, Neumann WL. Roles of reactive oxygen and nitrogen species in pain. Free Radical Biology &Medicine 2011;51:951-966).

Consequently, new strategies aimed at neuroprotection and, in particular, neuroinflammation for the treatment of NP are currently in the research and development stage (Bordet T and Pruss RM. Targeting neuroprotection as an alternative approach to preventing and treating neuropathic pain. Neurotherapeutics 2009 ; 6:648-662) (Stavniichuk R, Drel VR, Shevalye H, Maksimchyk Y, Kuchmerovska TM, Nadler JL, Obrosova IG. Baicalein alleviates diabetic peripheral neuropathy through inhibition of oxidative-nitrosative stress and p38 MAPK activation. Experimental Neurology 2011; 203:106-113).

Aging and neurological and psychiatric disorders cause neuronal damage and death. Among the common and relevant changes in the nervous system, we have included, but are not limited to, neuronal degeneration, ischemia, inflammation, immune responses, trauma, and cancer. As a result, neurons may die within minutes or hours, or they may survive the initial injury in a damaged state, activating neurodegeneration and ultimately leading to cell death as well.

Given the importance of the nervous system in generating basic motor skills and sensation, there is interest in finding a therapeutic agent to protect the nervous system.

Neuroprotective action is aimed at preserving, restoring, healing or regenerating

- 2 044367 nervous system, its cells, structure and function (Vajda et al 2002, J Clin Neurosci 9:4-8). One of the goals of neuroprotection is to prevent or minimize the impact of the initial damage to the nervous system or to prevent or minimize the consequences of endogenous or exogenous noxious processes that cause damage to axons, neurons, synapses and dendrites.

Neuroprotection is a mechanism and strategy used to protect against neuronal damage or CNS degeneration resulting from chronic neurodegenerative disease (Alzheimer's, Parkinson's disease). The goal of neuroprotection is to limit dysfunction/death following CNS injury and attempt to preserve as much integrity as possible for cellular interactions in the brain, resulting in intact neural function.

The concept of neuroprotection has been applied to chronic brain diseases as well as acute neurological conditions, given that some of the underlying mechanisms affecting the CNS are similar to these conditions. Neurodegenerative disorders include AD, PO, Huntington's disease, and amyotrophic lateral sclerosis. Neuroprotection has been considered as the mechanism of action of the drug used to treat these conditions.

There is a wide range of neuroprotective products available or under investigation, and some products could potentially be used for more than one disease, given that many mechanisms of damage to neural tissues are similar. Products with neuroprotective effects are grouped into the following categories: free radical scavengers, antiextoxin agents, apoptosis (programmed cell death) inhibitors, anti-inflammatory agents, neurotrophic factors, metal ion chelators, ion channel modulators, and gene therapy.

Oxygen free radicals have been demonstrated to be associated with protein denaturalization, enzyme inactivation, and DNA damage, leading to lipid peroxidation of cell membranes and ultimately cell death in neurodegenerative diseases.

Research in both animal and human models shows that loss of balance among oxidant species generated by brain metabolism and antioxidant defense mechanisms causes what is called oxidative stress, where these defense systems become less effective and disrupted.

Generally speaking, treatment strategies are often based on modulating one factor of the proposed lesion. Although we may observe that these treatments are beneficial in very limited animal models, it is less likely that they would demonstrate effectiveness in more complex human disorders with higher severity of lesions in a genetically diverse population (Faden and Stoica, 2007. Arch Neurol 64: 794-800). To a large extent, given the proposed mechanisms of neuronal death, such as oxidative stress, mitochondrial dysfunction, added proteins, apoptosis and inflammation (oudim, M.B., and Buccafusco, J.J. (2005) CNS Targets for multifunctional drugs in the treatment of Alzheimer's and Parkinsons diseases J Neural Transm 112, 519-537), they are as complex as they are varied, we would need single compounds that have multi-target effects on multiple mechanisms of injury.

The compound (3-ethoxycarbonyl-2-methyl-4-(2-nitrophenyl)-4,11-dihydro-1H-pyrido[2,3-b][1,25]benzodiazepine) (JM-20), which is described in Cuban patent document CU23879, according to its chemical structure, may have an effect on cardiovascular, cerebrovascular and other diseases associated with the central nervous system.

Surprisingly, researchers have found that compound JM-20 has a significant therapeutic effect on the central nervous system, preferably for the treatment of neuropathic pain.

Thus, the essence of the present invention is based on the use of JM-20 and its chemical products, which are preferably used in the treatment of neuropathic pain.

Although the potential utility of JM-20 has been noted in the literature, its potential as a therapeutic drug for neuropathic pain has not been established.

As a further aspect of the present invention, the compound of general formula III (JM20), its salts, hydrates, crystalline forms, enantiomers, isomers, metabolites, physiologically tested prodrugs can be administered in mixtures with at least one vehicle, diluent and/or carrier, chemically inert, non-toxic, hereinafter recognized as excipients included in the proposed drug compositions.

Drug compositions are provided for any liquid, solid or semi-solid composition, they can be administered orally, bucopharyngeal, sublingually, parenterally, for example: intramuscularly, intravenously, intradermally or subcutaneously, topically, transdermally, tracheally, bronchially, nasally, pulmonaryly, rectally or others suitable routes of administration.

The drug compositions described will contain suitable excipients for each formulation. The compositions are usually prepared using methods existing in the art. Excipients are selected according to their chosen drug form according to the route by which they will be administered.

The compound of general formula III (JM-20), its salts, hydrates, crystalline forms, enantiomers, isomers, metabolites, prodrugs for administration thereof to humans may be contained in pharmaceutically acceptable dosage forms, which include, but are not limited to, these forms release: tablets (including sublingual, coated and chewable), hard and soft capsules (including microcapsules, nanoparticles and pellets), solutions (oral drops, syrups), parenteral solutions, transdermal patches, implants and other retard systems, ointments (creams and gels), nasal sprays, mucoadhesives, suppositories, suspensions, powders to be diluted or added to food, among other dosage forms included in the present invention.

Using known technological processes of the prior art, JM-20, its salts, hydrates, crystalline forms, enantiomers, isomers, metabolites, prodrugs, can be formulated into dosage forms adapted for their administration, mixed with excipients such as liquid, solid excipients or semi-solids consisting of organic and inorganic substances, natural or synthetic. Some of these include: solid fillers, diluents, agglutinating agents, solvents, emulsions, lubricants, disintegrants, glidants, flavors, dyes, pigments, polymers, sweeteners, plasticizers, absorption enhancers, penetration enhancers, surfactants, co-surfactants, special oils and/or buffer systems that impart physical, chemical and/or biological stability to the active compounds or their physiologically acceptable salts.

Some excipients used in dosage forms containing a compound of general formula III or its products, without limitation to the use of other excipients, are: starches, lactase, cellulose and its products, sucrose, sorbitol, mannitol and other sugars, talc, colloidal silicon dioxide, carbonates, magnesium oxides, calcium phosphates, titanium dioxide, polyvinylpyrrolidone, povidone, gelatin, milk proteins, citrates, tartrates, alginates, dextran, ethylcellulose, cyclodextrins, silicon elastomers, polysorbates, amylopectin, parabens, animal and vegetable oils, propylene glycol , sterilized water, mono- or polyhydric alcohols such as glycerin, magnesium stearate, calcium stearate, sodium stearyl fumarate, sodium lauryl sulfate, glycerin and polyethylene glycol waxes, among others.

Solid oral dosage forms such as tablets, microgranules, nanoparticles, pellets, reconstituted powders or capsules containing a compound of general formula III or salts thereof, enantiomeric forms and redox products of the present invention can be used for immediate or modified release.

The selected form of the medicinal product according to the present invention is a tablet containing, as its active pharmaceutical ingredient, a compound of general formula III or its salts, hydrates, crystalline forms, enantiomers, isomers, metabolites, prodrugs, obtaining a mixture with microcrystalline cellulose, corn starch, crospovidone, adding dissolved polyvinylpyrrolidone and sodium lauryl sulfate to obtain granulate, which is dried in a complete fluidized bed process and mixed with magnesium stearate and talc, then the tablets are obtained using a rotary die system for their production, finally the tablets are coated with hydroxypropyl cellulose, polyethylene glycol 4000, titanium dioxide and color suspension.

By coating the tablets we achieve an attractive final appearance and avoid unpleasant taste; this is achieved by a taste masking agent such as methacrylic acid copolymer, ethylcellulose, methylhydroxypropylcellulose or other polymers. Tablets can be produced either by the wet granulation method shown above or by the direct compression method using direct compression auxiliaries and reducing the number of steps in the tableting phase, provided that low doses are used.

Tablets may be modified release and they may contain the compound of general formula III or its products in microgranules, nanoparticles or matrix systems using excipients such as: polyethylene oxide, hydroxypropylcellulose 2910, magnesium stearate, sodium chloride, red iron oxide, cellulose acetate , polyethylene glycol 3350 and opadry.

According to the present invention, drug compositions may contain pharmaceutically acceptable polymers that are permeable, biodegradable and water insoluble to control its release profile, thereby obtaining modified release (immediate, delayed or controlled) dosage forms. These polymers can be used to coat tablets, microbeads, capsules in the preparation of nanoparticles, as release matrices in pellets, tablets, granules or mixtures with other excipients included in any other dosage form specified in the present invention.

For oral administration, other suitable pharmaceutical compositions are hard capsules, soft capsules and pharmaceutical powders, the compound of general formula III or salts thereof, enantiomeric forms and physiologically acceptable oxidation-reduction products thereof can be dosed in the form of hard gelatin or cellulose capsules, for example containing inside a mixture of the active pharmaceutical ingredient with commonly used excipients in solid form, such as those described for tablets; the specified mixture can be obtained by dry method, wet granulation, extrusion, tableting, in the form of microcapsules or microtablets. For soft gelatin capsule doses, conventional methods of manufacture are used and these may involve admixing the compound of general formula III or its salts, hydrates, crystalline forms, enantiomers, isomers, metabolites, prodrugs with vegetable oils, fat or other similar vehicles suitable for their use. education.

In the case of pharmaceutical powders, they can be prepared by simply mixing the compound of general formula III (JM-20) or its salts, enantiomeric forms and physiologically acceptable prodrug products thereof with excipients, suspending agents, sweeteners, flavorings and preservatives. Although the present invention also uses atomization drying method at inlet temperatures of 100-150°C and outlet temperatures of 50-90°C to obtain powders, auxiliary substances such as dextran, polyethylene glycol 4000 and sodium lauryl sulfate, among others, are used to improve solubility of the active pharmaceutical ingredient for its proper administration into the body in solutions, or adding it to foods such as juices.

For rectal administration, the compound of general formula III (JM-20) or its salts, hydrates, crystalline forms, enantiomers, isomers, metabolites, physiologically acceptable prodrugs can be dosed in the form of suppositories, foams or rectal solutions for microenemas, which may contain a mixture of active compounds with a base of neutral solid fat (Witespol 45) or some other similar media suitable for their composition; sorbitan monooleate, polysorbate 20, wax emulsifier, anhydrate colloidal silicone, sodium meta-bisulfite, disodium edate, methyl parahydroxyl benzoate, sodium phosphates, macrogol 300, glycerin, water, propane, isobutene and n-butane.

For liquid oral administration, the compound of general formula III (JM-20) or its salts, hydrates, crystalline forms, enantiomers, isomers, metabolites, physiologically acceptable prodrugs can be formulated as syrups, elixirs, concentrated drops or suspensions with a pharmaceutically acceptable vehicle such as a mixture ethanol, glycerin, propylene glycol and/or polyethylene glycol, among others, carboxymethylcellulose or other thickeners; it may contain coloring, flavoring, sweetener (sucralose, aspartame, cyclamate, stevia) and preservative (parabens, benzoates). These liquid dosages can be prepared by diluting the powdered pharmaceutical compositions with a suitable diluent prior to use.

For parenteral administration, the compound of general formula III (JM-20) or its salts, hydrates, crystalline forms, enantiomers, isomers, metabolites, physiologically acceptable prodrugs can be formulated as solutions for injection. These solutions may contain stabilizing, preservative and/or buffering ingredients.

In the present invention, the active pharmaceutical ingredient is in 69% ethanol solution, benzoic alcohol, propylene glycol, benzoic acid, sodium benzoate, sodium hydroxide, water for injection; other excipients can also be used, such as polyethylene glycol 400, sodium citrate and citric acid.

Solutions for parenteral administration which contain a compound of general formula 111 (JM 20) or its salts, hydrates, crystalline forms, enantiomers, isomers, metabolites, physiologically acceptable prodrugs, can also be prepared by diluting the dry pharmaceutical composition (lyophilized) with a suitable diluent before use, including the use of excipients such as mannitol, polysorbate 80, sodium chloride and others.

For subcutaneous administration, the compound of general formula III (JM 20) or its salts, hydrates, crystalline forms, enantiomers, isomers, metabolites, physiologically acceptable prodrugs can be dosed as implants using excipients such as silicon elastomers and anhydrate colloidal silicone, although for Other pharmaceutical polymers can be used to make pellets.

For transdermal administration, the compound of general formula III (JM 20) or its salts, hydrates, crystalline forms, enantiomers, isomers, metabolites, physiologically acceptable prodrugs can be formulated in the form of patches; in this case, the active pharmaceutical ingredient is contained in a support of acrylic polymer, ethanol, light liquid paraffin, isopropyl palmitate, polyethylene terephthalate, ethylene vinyl acetate solution and a silicone layer within a peel-off layer (with a nominal release rate of 15 mg/day, over a surface area of 12.75 ^cm2 ) .

Implementation examples

Preparation of the synthetic intermediate, 1,4-dihydropyridine 5-formate.

Compound II is obtained based on the transformation of I through phosphorus oxychloride, in dry dimethylformamide, a mixture of which is then added in proportions 3-9 times to dissolve I in dichloromethane or chloroform and aged at a temperature of 20-60°C for 15-20 hours (Fig. 1).

The resulting product is then subjected to basic hydrolysis, followed by extraction with chloroform or dichloromethane, purification by washing and drying.

Compound I is prepared by a multicomponent reaction in one step, where 2-nitrobenzene aldehyde, Meldrum's acid, ethyl acetoacetate and ammonium acetate are mixed in equimolar quantities, in

- 5 044367 acetic acid as a solvent and subjected to reflux for 7-10 hours. After this, the mixture is poured into water and the resulting precipitate is purified by recrystallization in ethanol.

Preparation of compound III.

Compound IIa or IIb obtained above is reacted with orthophenylenediamine in absolute ethanol to give compound III (JM-20), which can be prepared to form various salts, depending on the conditions and reagents used.

Preparation of compound III from IIa.

To prepare compound III (JM-20), we started with an ethanol solution of compound Ha and added equimolar amounts of orthophenylenediamine, in absolute ethanol as solvent, with stirring. Equimolar amounts or larger amounts (1 to 2 equivalents) of triethylamine (Figure 2, Method A) were added to the reaction mixture, maintaining stirring, or sufficient amounts (1 to 1.5 equivalents) of sodium hydroxide were added by controlled dripping and with continuous stirring of the reaction mixture ( Fig. 2, method B).

Preparation of compound III from IIb.

To prepare compound III (JM-20), we started with compound IIb in ethanol solution and added equimolar amounts of orthophenylenediamine, in absolute ethanol as solvent, with stirring. Equimolar amounts or larger amounts (1-2 equivalents) of triethylamine (Figure 3, Method A) were added to the reaction mixture, maintaining stirring, or sufficient amounts (1-1.5 equivalents) of sodium hydroxide were added by controlled dripping and with continuous stirring of the reaction mixture ( Fig. 3, method B).

The structure of the isomer of compound JM20 is shown in FIG. 4.

Preparation of compound III in the form of halohydrate salts.

The corresponding hydrochloride or hydrobromide salts of III (halohydrates JM-20) were prepared from IIa or IIb, respectively, with or without the use of a catalyst. When the appropriate hydrogen acid was added in suitable catalytic amounts (5-25 mol%), a catalytic process occurred which reduced the reaction time and slightly reduced the reaction yield (Fig. 5).

JM20 hydrochloride (IIIa) was suitably prepared from IIa and when suitable amounts of HCl were added, a catalytic reaction occurred. Compound JM-20 can also be prepared as hydrobromide (IIIb) from IIb (Figure 5), with bromide being a better target group than chloride, the intramolecular nucleophilic substitution reaction is facilitated, giving a fast and efficient reaction to produce JM-20 in in the form of hydrobromide.

Preparation of compound III in the form of fumarate salt.

Fumarate salt JM-20 (IIIc) is prepared from the hydrochloride or hydrobromide of III by adding monosodium fumarate to a solution of IIIa or IIIb, stirring with a magnetic stirrer for 2-5 hours (Fig. 6) and its subsequent precipitation by adding ethanol in suitable quantities.

The precipitate corresponding to fumarate IIIc is suitably filtered and washed, purified and then placed in a temperature controlled dryer under reduced pressure.

Preparation of compound III in the form of phosphate salt.

Phosphate salt JM-20 (IIId) can be prepared in a manner similar to that described above from IIa or IIb by adding equimolar amounts of phosphoric acid at the beginning of the reaction or by adding phosphoric acid to IIIa or IIIb in ethanol solution with stirring (Fig. 7 ).

Preparation of compound III in the form of sulfate salt.

JM-20 sulfate (IIIf) can be prepared from IIa or IIb or from the halohydrates IIIa or IIIb as shown in FIG. 8.

Obtaining the composition in tablet form.

Each 120.00 mg tablet contains:

Component Quantity Function JM 20 40.00 mg Active ingredient Corn starch 23.00 mg Disintegrant Polyvinylpyrrolidone K-25 4.00 mg Agglutinin Monohydrated lactase 50.50 mg Filler Magnesium stearate 1.50 mg Lubricant Colloidal silicon dioxide 1.00 mg Lubricant

- 6 044367

Ethanol class e* 12.00 µl Solvent Deionized water 12.00 µl Solvent

*Evaporates during the drying process.

Brief description of the technological process.

1. Sift the active ingredient, cornstarch and lactase through a 20 mesh sieve.

2. Weigh all components of the composition according to the quantities established in the formula.

3. For the agglutinin solution, pour a mixture of water and class C ethyl alcohol into a metal container with a steam jacket, add polyvinylpyrrolidone and shake until completely dissolved.

4. Add the active ingredient, corn starch and lactase (internal phase components) into the mixer. Mix for 15 minutes.

5. Add the agglutinin solution slowly using a peristaltic pump, adjusting to the required humidity level with water and grade C ethyl alcohol (1:1) if necessary. Grind in a mill on low speed.

6. Dry the granulate in a fluidized bed. After 10 minutes, take a typical sample of the granulate, degranulate it and test for its residual moisture; the specified humidity should be between 0.8 and 1.2%.

7. Mix the dry granulate with lubricants for 10 minutes.

8. In a high-speed centrifuge, compress the mixture using a 6.4 mm (1/4 PBR) flat, bevel and groove punch to obtain tablets with the following parameters:

Weight: 120.0 mg ±10%

Height: 2.6±0.10mm

Hardness: 4.0 ± 1 kg-s

Brittleness: less than 1%

Preparation of the composition for oral drops.

Each ml (20 drops) contains:

Component Quantity Function JM-20 40.0 mg Active ingredient Propylene glycol 300.0 mg Solvent medium Kollidon 25 160.0 mg Viscosity control agent Sodium saccharinate 12.5 mg Sweetener Ponceau S, acid red 0.05 mg Dye Lemon acid 5.535 mg pH stabilizer Dehydrated sodium citrate 20.0 mg pH stabilizer Ethanol 100.0 mg Solvent medium Methylparaben 1.8 mg Preservative a.t. Propylparaben 0.2 mg Preservative a.t. Liquid strawberry flavor (soluble) 20.0 mg Flavoring Purified water (sufficient quantity) 1.0 ml Wednesday

Brief description of the technological process.

1. Measure the pH and conductivity of purified water at the time of product manufacture.

2. Pour propylene glycol into the reactor.

3. Dissolve sodium saccharin in purified water in a stainless steel auxiliary tank with an appropriate container.

4. Turn on Kollidon 25, adding it a little at a time, stirring for at least 30 minutes until it completely disappears.

5. Stir and apply heat to the preparation, maintaining the temperature at 40-50°C for 30 minutes.

- 7 044367

6. Add the active component to the result of the first stage in small portions, maintaining constant stirring for 30 minutes.

7. Remove heat and wait until the drug reaches room temperature: 30±2°C.

8. Dissolve methylparaben and propylene glycol in grade C ethyl alcohol in a auxiliary beaker or stainless steel container with a suitable container, stirring constantly until completely dissolved.

9. Add instant liquid strawberry flavoring to the results of the previous step and mix until completely homogeneous.

10. Add the results of the previous step slowly into the reactor vessel, stirring it constantly and vigorously.

11. Dissolve citric acid and dehydrated sodium citrate in a suitable stainless steel beaker or container, stirring after each addition until completely dissolved.

12. Slowly add the results of the previous step into the reactor container, stirring it constantly and vigorously.

13. Dissolve Ponceau S, acid red in purified water in a glass or stainless steel container with a suitable container, stir until completely dissolved and administer the drug.

14. Remove the previously prepared volume of water. Stir until smooth.

15. Test that the pH is maintained at 4.0-6.0.

16. Carry out final filtration; test organoleptic characteristics.

17. Bottle the final preparation in x 15 ml amber glass bottles with 15.0±1.0 ml of solution and cap properly using caps with drip reducers for oily products.

Obtaining an injection composition.

Each flask (2 ml) JM-20 contains:_________________________________

Component each ml contains Quantity per dose Unit of measurement Function JM-20 5.0 mg 10.0 mg Active ingredient Cremofor ELP 527.0 mg 1054.0 mg Wednesday Hydrochloric acid 1N sufficient amount - - Not pH adjustable Absolute alcohol sufficient quantity 1.0 ml 2.0 ml solvent *Nitrogen sufficient amount - -

1. Check that the reactor is completely dry after sterilization; if not, wash it with dehydrated alcohol.

2. Prepare a solution of 1 N hydrochloric acid to adjust the pH.

3. Add one part Cremofor ELP and dehydrated alcohol to the reactor. Mix at 420 rpm.

4. Weigh the active ingredient and add portions of the dehydrated alcohol to the beaker containing it; disperse it with a glass stirrer and add it to the reactor; repeat this operation until all the active ingredients have been swept away and all the dehydrated alcohol has been used.

5. Maintain stirring in the reactor for 60 minutes at 420 rpm until the active ingredient is completely dissolved.

6. Add the rest of Cremofor ELP, sweeping up the remainder with dehydrated alcohol, stirring for 10 minutes at 420 rpm.

7. Determine the pH of the solution and bring it with 1 N hydrochloric acid to 5.0-6.0.

8. Add volume of solution by adding dehydrated alcohol. Stir for 5 minutes at 420 rpm.

9. Take 10 ml of solution and send it to the laboratory to control the process (assessment and pH)

10. Check that the filling and nitriding systems are installed correctly.

11. Carry out an integrity check on the Sartobran P MidiCaps filter, porosity (0.45+0.2 µm) with dehydrated alcohol.

12. After completing process control, increase the reactor pressure with nitrogen (0.7-1.0 bar) to push the solution through the Sartobran P filter cartridge with a porosity of 0.45 µm +0.2 µm. Fill and seal the flasks to obtain 2.2 ml doses of solution.

Tonic pain.

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We studied the effects of JM-20 (10, 20, 40 mg/kg, p.o.) on pain behavior in a tonic pain model (5% formaldehyde test) in rats. (Dubuisson D, Dennis SG. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine and brain-stem stimulation in rats and cats. Pain

1977;4:161-174).

The results are shown in Fig. 9 A, 9 V and 10.

Neuropathic pain.

We investigated the effect of JM-20 in a model of permanent sciatic nerve stenosis (CCl), an NP model (Bennett Ml, Rayment C, Hjermstad M, Aass N, Caraceni A, Kaasa S. Prevalence and aetiology of neuropathic pain cancer in patients: A systematic review Pain 2012;153:359-365).

The results are shown in Fig. 11-15.

Carrageenan-induced peritonitis.

We subsequently designed various experiments in a rodent model of SA-induced peritonitis to investigate the possible anti-inflammatory activity of JM-20 under these conditions.

The results are shown in Fig. 16 A-E.

Claims (1)

Application of compound formula III (JM-20) in the treatment of neuropathic pain. Scheme for obtaining IIa and IIb