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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
  • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

• the present invention is related to safrole ⁇ /-acylhydrazone derivatives. More specifically, the present invention is related to 6-nitro- ⁇ P-arylmethyldene- 1 ,3-benzodioxol-5-carbohydrazide derivatives, substituted or not, and its isosterics, having anti-inflammatory and/or analgesic properties acting on the central nervous system, also having antioxidant properties, particularly useful in the treatment of acute and chronic inflammatory diseases and/or central hyperalgesia. It also refers to a preparation process and pharmaceutical compositions containing the same.
• Inflammation is a reaction of the vascularized tissue to injury, characterized by the extravasation of liquid and cells from the blood to the interstitial space. This constitutes an important defense mechanism, the ultimate purpose of which is to protect the organism from the initial causal agent of the cellular injury (micro-organisms, toxins) and from the consequences of the injury (cells and necrotic tissue).
• Inflammation may be classified as acute or chronic. Acute inflammation lasts a relatively short time, from minutes to hours or for some days, and its main characteristics are: edema, leading to the exudation of plasmatic proteins, and the migration of leukocytes (mainly neutrophils) to the injured tissue.
• leukocytes mainly neutrophils
• Chronic inflammation is the sum of the organism's reactions as a result of the persistence of the aggressive agent, differing from acute inflammation by its long duration and by the absence or scarce evidence of the classic signs of inflammation.
• the migration of leukocytes to the site of inflammation is of vital importance, bearing in mind their role in the combat against the aggressive agents. They have the capacity to phagocyte and destroy aggressive agents, such as bacteria and antigens, besides degrading the tissue.
• Leukocytic margination is the process by which leukocytes migrate from the blood column in the veins to occupy the periphery. Next, they adhere to the endothelium, moving to the endothelial surface (rolling phenomenon) and finally migrate through the venule wall, traversing the endothelial cells.
• the whole process of leukocyte migration depends on the release of chemotactic substances, which guide the movement of these cells by forming a concentration gradient.
• neutrophils predominate at the injury site, being substituted by monocytes within 24 to 48 hours.
• the chemotactic agents arachidonic acid (AA)) metabolites and cytokines
• AA arachidonic acid
• cytokines as components of the complementary system, are responsible for attracting these cells to the inflamed site, and are also responsible for increasing the inflammatory stimulus.
• the macrophage is crucial in chronic inflammation due to the large number of substances produced once it is activated.
• the presence of the aggressive agent causes the release of chemical mediators of inflammation, the main role of which is the modulation of the entire inflammatory process.
• mediators are of plasma origin or are produced by the ceils involved in the inflammatory process.
• the main mediators include vasoactive amines (histamine and serotonin), the hypotensor cynins (bradykinin), the complementary system, the coagulation system, the cytokines (IL-1 and TNF), the chemokynes, nitric oxide and eicosanoids. Pain can be defined as an unpleasant sensorial and emotional experience associated with potential or already occurred tissue damage, or described in terms of this pathology. It is one of the body's warning mechanisms designed to produce reactions that allow the individual to eradicate the aggressive agent, thus avoiding consequential tissue damage. Pain can be classified into three types: acute or physiological pain, chronic or inflammatory pain and neuropathic pain.
• the high intensity stimuli capable of producing pain stimulate the nociceptors, present in the periphery of the skin, muscles, articulations and viscera, transmitting painful impulses via non- myelinic C fibers and myelinized A ⁇ fibers to the dorsal horn of the spinal chord.
• the information of pain is then conveyed along the central nervous system by the spinal chord, traversing the spinothalamic tract until it reaches the thalamus.
• Neurons of the second order perform synapsis with the neurons of the third order in the ventral portion of the thalamus, transmitting the impulse to the cerebral cortex, when the sensation of pain is then perceived.
• Descending tracts of the central nervous system are able to modulate the transmission of pain impulses in the dorsal horn, acting by monoaminergic mechanisms, involving the activation of ct 2 -adrenergic and serotoninergic receptors.
• Around ten to fifteen neuromodulators or neurotransmitters have been said to be involved in the nociceptive tracts, acting both on the backbone and in the ascending and descending tracts in the processing of pain.
• a tissue injury caused by stimuli of a chemical, physical or biological nature promote the release of pro-algesic chemical mediators at the site, such as serotonin, bradykinin, histamine, ATP, various monoamines, cytokines, chemokines, growth factors, excitory aminoacids and prostaglandins.
• pro-algesic chemical mediators such as serotonin, bradykinin, histamine, ATP, various monoamines, cytokines, chemokines, growth factors, excitory aminoacids and prostaglandins.
• the stimulation of the nociceptores by the action of the chemical mediators induces a process of amplification of the response in the neurons of the dorsal horn, producing a sensibilization of the central nervous system in a phenomenon called wind-up.
• the vasodilatation and the action of the chemical mediators at the site of the issue injury induce a stimulation not only of the local nocicepetors, but also of those present in the areas surrounding the injury, thus promoting the onset of the phenomenon of secondary hyperalgesia or referred pain, where the sensation of pain is felt in places other than those where the tissue injury really occurred.
• Neuropathic pain is the result of an injury to the nervous tissue associated to trauma, surgery, amputation and radiation or with certain types of diseases such as herpes zoster, multiple sclerosis, arthritis and diabetes.
• the post-herpetic neuralgia and diabetic neuropathy are two very common neuropathic syndromes.
• This injury to the nervous fibers promotes an atypical (ectopic) stimulation of these fibers, inducing the processes of hyperexcitability and central sensibilization of the neurons of the dorsal horn, resulting in the phenomena of hyperalgesia and allodynia.
• Acetylsalicylic acid just like indomethacin, ketoprofen, piroxicam and diclophenaco are part of the class of substances called non-steroidal antiinflammatory drugs (NSAIDs), and has been used clinically for many years.
• NSAIDs non-steroidal antiinflammatory drugs
• the analgesic and anti-inflammatory properties of these drugs are related to the inhibition of the prostaglandin endoperoxide synthase enzyme (PGHS) or cyclooxygenase (COX), reducing the production of the prostaglandins that, as seen earlier, are intimately related to the maintenance of the inflammatory processes, in the genesis of pain and platelet homeostasis.
• PGHS prostaglandin endoperoxide synthase enzyme
• COX cyclooxygenase
• Said NSAIDs are competitive inhibitors in the cyclooxigenase site of the PGHS, without modulating the peroxidase function. Since then, the search for new selective NSAIDs for COX-2 has become an important therapeutic strategy. The synthesis of various compounds having selective inhibitory activity for COX-2 has been described, and these new molecules have anti-inflammatory activity, but without causing gastrotoxic effects in various preclinical and clinical trials.
• three selective COX-2 drugs are on the market: celecoxib, etoricoxib and lumiracoxib. Rofecoxib and valdecoxib were recently withdrawn from the market because they increased the risk of myocardial infarction
• AAS is the most widely used clinical anti-platelet drug It is capable of irreversibly acetylating the hydroxyl residues of serine 529 in the COX-1 expressed on the platelet, preventing the link of AA to the active site of the enzyme
• Other NSAIDs reversibly compete with the AA for the link to the COX site
• the platelets have no nucleus and have low protein synthesis capacity
• 5-LO inhibitors are a significant strategy Zileuton, a selective 5- LO inhibitor, is available on the market and has been used in anti-asthmatic therapy.
• COX inhibitors induce side effects in patients with asthma by increasing the production of leukotrienes caused by a greater availability of arachidonic acid for metabolization via the 5-LO pathway.
• dual COX/5-LO inhibitors leading to compounds having increased effectiveness and fewer adverse effects compared to the NSAIDs.
• the dual inhibitors are therapeutically promising due to their anti-inflammatory effect with a greater scope of action than those of the classic NSAIDS, inhibiting both the production of inflammatory mediators deriving from 5-LO and the COX/5-LO.
• Various chemically distinct compounds have been described as dual COX/5-LO inhibitors, including BW-755c, CBS1108, ML3000 and tepoxalin.
• thalidomide was approved for the treatment of lepromas, multiple myeloma and rheumatoid arthritis, due to its capacity to modulate the biosynthesis of cytokines such as TNF- ⁇ .
• Clinical tests show various other candidates as cytokine modulating drugs having different action mechanisms, but which ultimately reduce the biosynthesis of cytokines.
• PDE-4 phosphodiesterase-4
• p38 mitogen-activated (p38 MAPK) protein inhibitors such as SB203580, BIRB796 and VX-745
• TNF- ⁇ (TACE) converting enzyme inhibitors such as marimastat
• KB (NF-KB) nuclear factor modulators such as acanthoic acid, parthelenolide and ergolide.
• CB2 peripheral canabinoid receptors
• the purpose of the present invention is to provide alternative therapeutic strategies to those resulting from the use of the anti-inflammatory and/or analgesic drugs currently available.
• the difficulties found with the anti-inflammatory and/or analgesic molecules available to-date are solved, since the molecules of the present invention inhibit cellular migration and edema, induce central analgesia and have antioxidant properties, without causing gastro-irritant effects.
• One of the purposes of the present invention is, therefore, to provide anti-inflammatory and/or analgesic molecules acting on the central nervous system with antioxidant properties, which are useful in the reversal of acute and/or chronic inflammation in mammals, preferably humans.
• Another purpose of the present invention is to provide anti-inflammatory and/or analgesic pharmaceutical compositions acting on the central nervous system with antioxidant properties, which are useful in reversing acute and chronic inflammation and/or for the treatment of central hyperalgesia in mammals, preferably humans.
• the pharmaceutical compositions of the present invention can be administered in a wider variety of presentation forms, resulting in benefits for the user and greater production flexibility. Accordingly, another purpose of the present invention is to provide alternatives for the limitations in administration of pharmaceutical compositions for the treatment of acute and chronic inflammatory diseases and/or central hyperalgesia.
• the molecules of the present invention have different synthesis pathways from other currently used to treat acute and chronic inflammatory diseases and/or central hyperalgesia, and it is easier to prepare drugs under these conditions.
• Another purpose of this present invention in preparing a drug for the treatment of inflammatory disturbances and/or hyperalgesia in mammals, is to provide the use of 6-nitro-/V-arylmethyldene-1 ,3-benzodioxol-5- carbohydrazides derivatives, substituted or not, its isosterics and/or pharmaceutically acceptable salts, solvates or hydrates.
• an additional purpose of the present invention is to provide methods to product the antiinflammatory and/or analgesic molecules listed herein.
• One of the purposes of I O the present invention is to disclose means of preparing n-acylhydrazone antiinflammatory and analgesic derivatives having antioxidant properties.
• Figure 1 Shows the structures of the classic NSAIDS (Acetylsalicylic acid, Indomethacin, Ketoprofen, Paracetamol, Piroxicam and Diclophenaco).
• FIG. 2 - Shows the structures of the selective PGHS-2 inhibitors 20 (Celecoxib, Lumiracoxib, Rofecoxib, Valdecoxib and Etoricoxib).
• Figure 3 Shows the structures of the 5-LO and dual COX/5-LO inhibitors (Zileuton, BW-755c, CBS1108, ML3000 and Tepoxalin).
• Figure 4 - Shows the structures of the PDE-4 inhibitors (Thalidomide, Rolipram, Nitraquazone, Theophiline and Ariflo).
• FIG. 6 Shows the structures of the TACE and NF- ⁇ B modulating inhibitors (Marimastat, Acanthoic acid, Parthenolide and Ergolide).
• the main structural characteristic of these new derivatives is the ⁇ /-acylhydrazone standard, this being the pharmacophoric group involved in recognizing the pharmacological target of action; besides the other aromatic subunits, acting as secondary pharmacophoric groups, having biophoric characteristics (electronic and hydrophoic), needed for recognition by the pharmacological action target of action, by way of van der Waals interactions between the aromatic ring and similar sites.
• the new compounds described in this invention belong to the class of derivatives of the 6-nitro-/V-arylmethyldene-1,3-benzodioxol-5-carbohydrazide nucleus and its isosterics, of general structure (I):
• R is hydrogen, alkyl, cycloalkyl, phenyl-W, furyl, thiophenyl, pyridyl, pyrimidinyl, pyrrolyl, thiazolyl, quinazolyl or isoquinolyl;
• W is hydrogen, ortho-a ⁇ ky ⁇ , ortho-cyc ⁇ oa ⁇ ky ⁇ , orf/70-alkoxyl, orf/70-cycloalkoxyl, ortr/o-thioxyl, orf/70-aryoxyl, ortr/o-sulphones, orf/70-sulphates, ortho- sulphoxides, or#?o-sulphonates, orf/70-sulphonamides, ortho-ammo, ortho- amide, orf/70-halates, orf/70-carboalkoxyl, orf/70-carbothioaikoxyl, ortho- trihaloalkane, ortho-cyan, ortr/o-nitro,
• the new compounds of formula (I) were obtained in good to excellent chemical yields, using the synthetic methodology described herein, which is characterized by having few stages, providing high yields, based on commercially available compounds, qualifying this synthetic methodology for industrial use.
• the compounds of the present invention were planned by way of converging syntheses, using classic reactions such as:
• the compounds of formula (I) of the present invention can be prepared using a method comprising the stages of:
• RMN 1 H (200MHz, DMSO-Cf 6 , TMS) ⁇ (ppm): 6,34 (s, 2H, H-2); 7,32 (s, 1 H, H- 4); 7,74 (s, 1 H, H-7); 10,09 (s, 1H, -CHO).
• IV ( ⁇ ma ⁇ , KBr) ⁇ (cm '1 ): 1682, 1518, 1368, 1336, 1126, 1119.
• reaction mixture continued to be stirred for 1.5 hours, whereupon it was noted that the start aldehyde had been totally consumed.
• 1OmL of solution saturated with sodium bisulphite was added, and it was noted that the chestnut color disappeared.
• the mixture was vacuum filtered and the solid was washed with 3OmL of methanol.
• the I O filtrate was evaporated under reduced pressure and recrystallized in ethanol/water.
• RMN 1 H (200MHz, CDCI 3 , TMS) ⁇ (ppm): 3,89 (s, 3H, OCH 3 ); 6,18 (s, 2H, H-7); 15 7,03 (s, 1 H, H-4); 7,38 (s, 1 H, H-2).
• RMN 1 H (200MHz, DMSO-Cf 6 , TMS) ⁇ (ppm): 4,42 (s, 2H, NH 2 ); 6,26 (s, 2H, H- 2); 7,03 (s, 1 H, H-4); 7,64 (s, 1H, H-7); 9,59 (s, 1 H, NH).
• IV ( ⁇ max , KBr) ⁇ (cm "1 ): 3336, 3199, 3120, 1670, 1519, 1502, 1475, 1328, 1257, 1030, 880.
• RMN 13 C (50MHz, DMSO-Cf 6 , TMS) ⁇ (ppm): 104,40 (C-2); 104,68 (C-7); 105,45 30 (C-4); 108,52 (C-3"); 108,86 (C-3"); 112,49 (C-4"); 112,72 (C-4"); 128,57 (C-5);
• 6-nitro-/V'-(2-pyridnylmethyldene)-1,3-benzodioxol-5-carbohydrazide Yellow solid; 0.264g (84%); m.p. 184-185°C.
• RMN 13 C (50MHz, DMSO-Cf 6 , TMS) ⁇ (ppm): 107,64 (C-2); 108,66 (C-7); 11 1 ,79 (C-5); 122,69 (C-6"); 123,68 (C-6"); 127,97 (C-4"); 128,25 (C-4"); 131 ,23 (C-6);
• RMN 13 C (50MHz, DMSO-Cf 6 , TMS) ⁇ (ppm): 107,64 (C-2); 107,79 (C-7); 108,61 (C-7); 111 ,74 (C-4); 112,04 (C-4); 124,33 (C-2",6”); 124,89 (C-2",6”); 131 ,04 (C-5); 131 , 16 (C-5); 144,74 (C-1”); 144,98 (C-1 "); 145,39 (C-4 1 ); 148,96 (C-4'); 152,13 (C-3",5 M ); 152,46 (C-3",5"); 153,39 (C-6); 153,45 (C-6), 155,52 (C-1a); 155,94 (C-3a); 165,53 (C-1'); 171 ,54 (C-f).
• 11 ,54 (s, 1 H 1 H-2 ⁇ ); 11 ,60 (s, 1 H, H-2'Z); 11 ,62 (s, 1 H, H-2'E).
• the randomly chosen compounds were analyzed by RMN 1 H and 13 C, in addition to IV-FT.
• the new compounds of formula (I) was spectroscopically characterized and pharmalogically evaluated in in vivo and in vitro studies, with a view to determining the anti-inflammatory, analgesic and antioxidant profiles of the compounds.
• the animal models used in in vivo studies were carrageenan- induced mouse paw edema to investigate the anti-inflammatory profile; formalin-induced hyperalgesia in mice, and the hot plate test on mice to investigate the analgesic profile.
• the in vitro studies comprised a DPPH radical scavenging assay in order to investigate the antioxidant profile. The results obtained showed high anti-inflammatory, analgesic and antioxidant activities.
• LASSBio-881 was not able to inhibit the inflammatory phase
• LASSBio-881 The pharmacological results provided by LASSBio-881 in the hot plate test in mice corroborate its central mechanism of analgesic action, and LASSBio-881 is capable of increasing the animal's latency time under thermal
• the radical scavenging effect was noted for the radical diphenylpycrylidrazine (DPPH). A decreased concentration was noted in the latter by UV-visible absorbance reading. Particularly the compound LASSBio- 881 (100 ⁇ M) was capable of stabilizing the radical by 35%.
• LASSBio-881 as a candidate for an anti-inflammatory drug, having central analgesic activity and antioxidant properties, proving to be useful in the treatment of acute and chronic inflammatory diseases in mammals, preferably humans.
• LASSBio- 881 can be useful in treating central hyperalgesic processes associated to
• tissue injury, inflammation or tumor growth in mammals preferably humans.
• the compounds tested were administered orally, in a dose of 300 ⁇ mol/kg, using a 5% Arabic gum solution as vehicle.
• One hour after administration was administered orally, in a dose of 300 ⁇ mol/kg, using a 5% Arabic gum solution as vehicle.
• the edema was induced by subplantar injection of carrageenan 1% (1000 ⁇ g/paw). A solution of NaCI 0.9% (0.1 ml/paw) was administered in the opposite side paw. A reading was taken 3 hours after the subplantar administration of carrageenan by using a plethysmograph attached to a continual-flow peristaltic pump. The edema was expressed by the volume
• the formalin assay consists of subplantar administration of formaldehyde
• the pain stimulus is then characterized for the time during which the animal continues to lick the paw that received the irritation stimulus.
• the formalin assay is characterized by having two distinct phases. The first phase (0-5 minutes after injecting formalin) is characterized by a so-called neurogenic phase, that is, having a particularly
• the second phase (15-30 minutes after injecting formalin) is the so-called inflammatory phase in which mass production of inflammatory mediators such as prostaglandins occurs, being inhibited by classic NSAIDs such as acetylsalicylic acid and selective COX-2 inhibitors such ( ⁇ >5 as nimesulid.
• classic NSAIDs such as acetylsalicylic acid
• selective COX-2 inhibitors such ( ⁇ >5 as nimesulid.
• the central analgesic activity of the compounds was evaluated using the hot plate exposure test (55 ⁇ 0.1 )°C, using Swiss mice of both sexes weighing 30 between 18-25g and kept without food for a period of eight hours.
• the animals were place on a hot plate and their response to the thermal stimulation (withdrawal and licking of paw) were timed. A first reading was taken for adaptation of the animals and subsequently a control reading. The animals that did not respond to the hot plate stimulus for over 10 seconds were discarded. The derivatives were then administered orally in doses of 100, 300 and 500 ⁇ mol/kg. Four readings were taken at 30-minutes intervals after oral administration of the compounds. 5

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• 2006
  • 2006-05-15 BR BRPI0601885-8A patent/BRPI0601885A/pt not_active Application Discontinuation
• 2007
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