EP3846813A1 - Compositions analgésiques - Google Patents

Compositions analgésiques

Info

Publication number
EP3846813A1
EP3846813A1 EP19858445.0A EP19858445A EP3846813A1 EP 3846813 A1 EP3846813 A1 EP 3846813A1 EP 19858445 A EP19858445 A EP 19858445A EP 3846813 A1 EP3846813 A1 EP 3846813A1
Authority
EP
European Patent Office
Prior art keywords
dcuka
pain
treatment
pain threshold
mechanical
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP19858445.0A
Other languages
German (de)
English (en)
Other versions
EP3846813A4 (fr
Inventor
Boris Tabakoff
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lohocla Research Corp
Original Assignee
Lohocla Research Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US16/125,252 external-priority patent/US10391088B2/en
Application filed by Lohocla Research Corp filed Critical Lohocla Research Corp
Publication of EP3846813A1 publication Critical patent/EP3846813A1/fr
Publication of EP3846813A4 publication Critical patent/EP3846813A4/fr
Pending legal-status Critical Current

Links

Classifications

    • 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]
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • NSAIDs non steroidal anti-inflammatory drugs
  • anticonvulsants include muscle relaxants and antidepressants
  • drugs targeting voltage-sensitive calcium channels include NSAIDs, anticonvulsants, muscle relaxants and antidepressants, as well as drugs targeting voltage-sensitive calcium channels (gabapentin and pregabalin)
  • NSAIDs non steroidal anti-inflammatory drugs
  • gabapentin and pregabalin drugs targeting voltage-sensitive calcium channels
  • these treatments provide limited relief (Lunn et al., 2014; Moore et al., 2014; Schreiber et al., 2015; Smith et al., 2012; Sofat et al., 2017; Lozada, et al., 2008).
  • NSAIDs the next most popular drugs, after opioids, for treatment of chronic pain
  • side effects including stomach problems (such as bleeding, ulcer, and stomach upset), renal failure, high blood pressure or cardiac problems, fluid retention, rashes, or other allergic reactions (Marcum and Hanlon 2010).
  • a third category of drugs to treat chronic pain are the more recently introduced blockers of the 5-HT and NE reuptake systems (Smith et al., 2012; Sofat et al., 2017).
  • 5-HT/NE reuptake inhibitors also present a series of side effects including nausea, G.I. disturbances, fatigue but difficulty sleeping.
  • Target selection is a key feature of chronic pain drug development efforts, and most programs have used the approach of targeting a single target/site, such as a receptor, which has been the approach of choice of the pharmaceutical industry for many years (Ramsay et al., 2018).
  • targeting a single molecular entity to control a complex physiological system has resulted in agents with limited efficacy (Bozic et al., 2013).
  • perceptions have changed, in part due to the design of effective multi- target drugs for treatment of schizophrenia, viral infections, asthma, cardiovascular disease, neurodegenerative disease and cancer (Ramsay et al., 2018).
  • Such drugs produce partial inhibition of more than one target within a network, rather than total inhibition of a single target (Zimmerman et al., 2007; Millan, 2014; Talevi, 2015).
  • VSNaCs peripheral voltage-sensitive sodium channels
  • the tetrodotoxin-sensitive Navl.7 channel is located along the projections and cell bodies of the slowly conducting nociceptive neurons, and its role in both acute and chronic pain has been clearly demonstrated by genetic manipulation in animals and by naturally-occurring genetic mutations in humans (Black et al., 2004; Wang et al., 2011; Lawrence, 2012).
  • the Navl.7 channel has been particularly linked to pain associated with inflammation, and its upregulation contributes to the increased generation and conduction of action potentials in chronic pain syndromes (Eijkelkamp et al., 2012).
  • the activity of the Navl.7 channel can amplify generator potentials and promote the activation of other sensory neuron VSNaCs including the tetrodotoxin-resistant Navl.8 channel (Dib-Hajj et al., 2007; Choi & Waxman, 2011).
  • the Navl.8 channel has been linked to development of both inflammatory and neuropathic pain conditions.
  • the upregulation of the activity of the Navl.7 and Navl.8 channels in peripheral sensory neurons constitutes a common component of induction and maintenance of chronic pain syndromes (Wang et al., 2011; Theile & Cummins, 2011; Laedermann et al., 2015).
  • NMDA receptors are therefore involved in both the initiation and amplification of a pain sensation and its transmission into the CNS. Upregulation of NMDA receptors is seen both in peripheral neurons and spinal cord after sensory nerve damage, and this upregulation is thought to contribute to chronic neuropathic pain (Petrenko et al., 2003).
  • GluN2B (NR2B) subunit-containing NMDA receptors plays the most important role in development and maintenance of chronic pain syndromes (Karlsson et al., 2002; Iwata et al., 2007; Gaunitz et al., 2002; Wilson et al., 2005).
  • a medication that can simultaneously inhibit Navl.7 and Navl.8 channel activity, as well as inhibit the activity of NMDA receptors (particularly those that contain the GluN2B subunit), can be of benefit both in preventing the
  • N-substituted-4-ureido-5,7-dichloro-2-carboxy (or carboxyester) quinolines in combination with opioids, NE/5-HT reuptake inhibitors or NSAIDs are effective in treatment and prevention of chronic neuropathic pain in humans.
  • Analgesic compositions embodying the present invention contain an aminoquinoline compound together with an opioid, a NE/5-HT reuptake inhibitor, a non-steroidal anti inflammatory drug (NS AID), or a combination thereof.
  • the aminoquinoline compound potentiates bioactivity of opioids, agents that block the uptake of serotonin (5-HT) and norepinephrine (NE), and NSAIDs.
  • co-administration of the aminoquinoline compound allows for a lower dose of the opioid, NE or 5HT reuptake blocker, or NS AID to be used for a desired analgesic (antihyperalgesic) effect.
  • the aminoquinoline compound when administered early in the course of development of chronic pain, can present the development of chronic pain and/or exacerbation of chronic pain syndrome.
  • R 1 is H, C 2 -C 4 alkyl, C 2 -C 4 alkenyl, halo, ZV, or N(R 10 )(R U ).
  • R 2 is H, C C 4 alkyl, C 2 -C 4 alkenyl, halo, Z 2 R 12 , N(R 13 )(R 14 ), or C C 4 alkyl substituted with one or more moiety selected from the group consisting of C 4 -C 4 alkyl, C 2 -C 4 alkenyl, halo, Z 3 R 15 , N(R 16 )(R 17 ); each R 3 , R 4 , R 5 , and R 6 independently is H, C 4 -C 4 alkyl, C 2 -C 4 alkenyl, halo, Z 3 R 18 , or N(R 19 )(R 20 );
  • X 1 is N or CH; each R 7 and R 8
  • Ci-C 6 alkyl independently is H, Ci-C 6 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, aryl, or Ci-C 6 alkyl substituted with one or more moiety selected from the group consisting of Ci-C alkyl,
  • each R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , and R 23 independently is H, Ci-C alkyl, or Ci-C alkyl substituted with one or more moiety selected from the group consisting of C 4 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, halo, heteroaryl, Z 5 R 24 , and
  • R 1 is Z 4 R 9
  • R 9 is H or Ci-C 2 alkyl
  • each of R 3 and R 5 is halo
  • X 1 is N
  • each of R 4 and R 6 is H
  • at least one of R 7 and R 8 is not a phenyl, alkoxy- substituted phenyl, or Ci-C 6 alkyl group.
  • X and X each independently is halo, and each of X , R , R , R and R are as defined in Formulas (I) and (II) described above, with the proviso that when R 9 is H or Ci-C 2 alkyl, and
  • X I is N, then at least one of R 7 and R 8 is not a phenyl or alkoxy-substituted phenyl group.
  • each of X 2 , X 3 , R 1 , R 7 , and R 8 are as defined in Formulas (I) and (II) above.
  • each R 9 is H or C 1 -C 4 alkyl
  • each X 2 and X 3 independently is an electron withdrawing group (preferably halogen or nitro).
  • Non-limiting examples of compounds of the general Formula (VI) are derivatives of the 2-carboxy-quinolines, e.g., (N, N-dibutyl)-4-ureido-5,7-dichloro-2-carboxy-quinoline (BCUKA), (N,N-diphenyl)-4-ureido-5,7-dichloro-2-carboxy-quinoline (DCUKA), and the like.
  • the di-substituted-4-ureido-5,7-dichloro-2-carboxy-quinoline compounds of Formula (VI) possess affinity for some or all of the following: Navl.7, Navl.8, and NMDA receptors. These compounds possess beneficial activity in treating chronic pain syndromes arising from degenerative joint pain (e.g., osteoarthritis) and inflammatory and mechanical damage to peripheral nerves, effectively ameliorating mechanical or thermal
  • the (4-amino)-5,7-dichloro-2- carboxy-quinoline methyl or ethyl ester is acetylated at the 4-amino position with a disubstituted carbamoyl chloride to form a (N, N-disubstituted)-4-ureido-5,7-dichloro-2- carboxy-quinoline ester.
  • Fig. 2 graphically illustrates the treatment of cisplatin-induced neuropathic pain by DCUKA (50 mg/kg).
  • DCUKA 50 mg/kg
  • rats treated with the cancer chemotherapy agent cisplatin
  • the cisplatin treatment reduces the mechanical pain threshold
  • DCUKA treatment reverses this effect and increases the mechanical pain threshold toward control levels.
  • the data show the ratio of the mechanical pain threshold after cisplatin or cisplatin plus DCUKA treatment to the pre-cisplatin treatment mechanical pain threshold.
  • Fig. 6 shows the results of a meta analysis of experiments to determine the dose dependent effect of DCUKA to reverse CFA-induced neuropathic pain.
  • Fig. 9 graphically illustrates the treatment by DCUKA of osteoarthritic pain.
  • Rats were treated with monoiodoacetic acid (MIA), which initiates an inflammatory reaction.
  • MIA monoiodoacetic acid
  • Cartilage damage and degradation leads to chronic neuropathic pain, which is reflected in the lower mechanical pain threshold in comparison to baseline, measured in animals that received no MIA or drug.
  • DCUKA reversed the mechanical pain threshold in a dose- dependent manner.
  • the data show the ratio of the mechanical pain threshold after MIA or MIA plus DCUKA treatment to the mechanical pain threshold in animals that received no MIA or drug.
  • Fig. 10A shows graphically that administration of DCUKA enhances the ability of morphine to reverse CFA-induced neuropathic pain.
  • Fig. 10B shows graphically that administration of DCUK-OEt enhances the ability of morphine to reverse CFA-induced neuropathic pain.
  • Fig. 10C shows results of i sob olographic analysis that demonstrates that DCUK-OEt significantly decreased the half-maximal effective dose of morphine needed to reverse pain.
  • Fig. 11 illustrates that DCUKA potentiates the ability of oxycodone to reverse CFA- induced neuropathic pain.
  • Fig. 12 illustrates that DCUKA potentiates the ability of methadone to reverse CFA- induced neuropathic pain.
  • Fig. 13 illustrates that DCUKA potentiates the ability of tramadol to reverse MIA- induced osteoarthritic (neuropathic) pain.
  • Fig. 15 illustrates that DCUKA potentiates the ability of diclofenac to reverse CFA- induced neuropathic pain.
  • Fig. 16 illustrates graphically that administration of DCUKA following CFA injection prevents the development of CFA-induced neuropathic pain, measured by changes in the mechanical pain threshold.
  • Fig. 17 illustrates graphically that administration of DCUKA simultaneously with the cancer chemotherapy agent cisplatin prevents the development of cisplatin-induced neuropathic pain, measured by changes in the mechanical pain threshold.
  • analgesic compositions described herein are well suited for treatment of chronic (neuropathic) pain syndrome.
  • the methods described herein comprise treating a subject in need of pain relief (e.g., a human or animal patient) with the aminoquinoline containing compositions that also include an opioid, a NE/5-HT reuptake inhibitor, and/or a non-steroidal anti-inflammatory drug (NS AID).
  • a subject in need of pain relief e.g., a human or animal patient
  • the aminoquinoline containing compositions that also include an opioid, a NE/5-HT reuptake inhibitor, and/or a non-steroidal anti-inflammatory drug (NS AID).
  • Opioids suitable for use in the analgesic compositions include the opiates, i.e., the naturally occurring plant alkaloids such as morphine, codeine, papaverine, thebaine, and the like; the semi-synthetic opioids such as oxycodone, diamorphine, dihydrocodeine, and the like; as well as the synthetic opioids such as the phenylpyridine derivatives, e.g., 6-amino-5- (2,3,5-trichlorophenyl)-pyridine-2-carboxylic acid methylamide, and the like; the phenylpiperidine derivatives, e.g., fentanyl, sulfentanil, alfentanil, and the like; the morphinan derivatives, e.g., levorphanol, butorphanol, and the like; the diphenylheptane derivatives, e.g., methadone, propoxyphene, and the like; the benzomorph
  • Multitarget drugs suitable for use in analgesic compositions include drugs that act at the opiate receptor and/or at monoamine reuptake transporters, i.e., tramadol, and the like.
  • NS AIDs suitable for use in analgesic compositions include aspirin, the acetic acid derivatives such as indomethacin, sulindac, etodolac, tolmetin, ketorolac, nabumetone, diclofenac, and the like, the propionic acid derivatives such as ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, and the like, the enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, and the like, the fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, and the like, as well as the
  • Illustrative NS AID salts suitable for use in the present compositions are the pharmaceutically acceptable salts of the aforementioned acetic acid derivatives, e.g., indomethacin salts such as indomethacin sodium, indomethacin meglumine, and the like, the tolmetin salts such as tolmetin sodium, and the like, ketorolac salts such as ketorolac tromethamine, and the like, diclofenac salts such as diclofenac sodium, diclofenac diethylamine, diclofenac epolamine, and the like, as well as pharmaceutically acceptable salts of the aforementioned propionic acid derivatives, e.g., ibuprofen salts such as ibuprofen lysine, ibuprofen methylglucamine, and the like, naproxen salts such as naproxen piperazine naproxen sodium, and the like, fenoprofen salts such as
  • aminoquinoline compounds of Formula (I), (II), (III), (IV), (V) and (VI) can be prepared by any convenient method known to those skilled in the art.
  • U.S. Patent No. 6,962,930 to Tabakoff et al. and U.S. Patent No. 7,923,458 to Tabakoff which are incorporated herein by reference in their entirety, describe the preparation of certain quinoline compounds analogous to those of the present invention, which readily can be adapted to the preparation of the desired aminoquinoline compounds.
  • Scheme 1 provides a general scheme for preparing aminoquinoline compounds of Formula (I) and structurally related or analogous compounds from a 4-amino-substituted quinoline Compound (A), in which the R substituents are the same as those in Formula (I).
  • Compound (A) is reacted with an activated acylating Compound (B), comprising a leaving group (LG) that is reactive toward aromatic amino groups, to form a compound of Formula (I).
  • activated acylating Compound (B) comprising a leaving group (LG) that is reactive toward aromatic amino groups
  • LG leaving group
  • Substituted quinoline compounds having an amino group in the 4-position of the quinoline ring structure, such as Compound (A), having various substitution patterns on the quinoline ring system, and the preparation thereof, are well known to those of ordinary skill in the chemical arts.
  • Protective groups such as those disclosed in Protective Groups in Organic Synthesis , 3rd Ed., Green and Wuts, Eds., John Wiley & Sons, Inc.
  • aminoquinoline compound refers to compounds as set forth in Formulas (I), (II), (III), (IV), (V) and (VI) as described herein.
  • the aminoquinoline compounds are useful for chronic pain and a variety of other conditions.
  • alkyl as used herein is directed to a saturated hydrocarbon group (designated by the formula C n H 2n+i ) which is straight-chained, branched or cyclized (“cycloalkyl”) and which is unsubstituted or substituted, i.e., has had one or more of its hydrogens replaced by another atom or molecule.
  • Aryl designates either the 6-carbon benzene ring or the condensed 6-carbon rings of other aromatic derivatives (see, e.g., Hawley's Condensed Chemical Dictionary (13 ed.), R. J. Lewis, ed., J. Wiley & Sons, Inc., New York (1997)).
  • Aryl groups include, without limitation, phenyl and naphthyl.
  • Halide and halo refer to a halogen atom including fluorine, chlorine, bromine, and iodine.
  • Substituent groupings e.g., Ci -6 alkyl, are known, and are hereby stated, to include each of their individual substituent members, e.g., Ci alkyl, C 2 alkyl, C 3 alkyl and C 4 alkyl.
  • Prodrugs are any covalently bonded carriers which release the active parent drug of the aminoquinoline compounds in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of the aminoquinoline compounds of the present invention are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo , including by enzymatic conversion, to the parent compounds.
  • Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively.
  • Examples or prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the aminoquinoline compounds of the present invention, and the like. Compounds that function effectively as prodrugs of the
  • aminoquinoline compounds of the present invention may be identified using routine techniques known in the art.
  • prodrug derivatives see, for example, (a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology , Vol. 42, p. 309-396, edited by K. Widder et al. (Academic Press, 1985); (b) A Textbook of Drug Design and Development , edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5
  • the invention includes metabolites of the aminoquinoline compounds, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.
  • the instant invention provides pharmaceutical compositions which contain a pharmaceutically effective amount of the aminoquinoline compound together with an opioid or NSAID in a pharmaceutically acceptable carrier (e.g., a diluent, complexing agent, additive, excipient, adjuvant and the like).
  • a pharmaceutically acceptable carrier e.g., a diluent, complexing agent, additive, excipient, adjuvant and the like.
  • the aminoquinoline compositions can be present for example in a salt form, a micro-crystalline form, a nano-crystalline form, a co- crystalline form, a nanoparticulate form, a mirocparticulate form, and/or an amorphous form.
  • the carrier can be an organic or inorganic carrier that is suitable for external, enteral or parenteral applications.
  • composition dosage forms suitable for buccal or sublingual administration include lozenges comprising the analgesic agents in a flavored base, such as sucrose, acacia, or tragacanth; pastilles comprising the aminoquinoline compound in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • the pharmaceutical composition dosage forms for topical administration can include penetration enhancing agents, if desired.
  • the additives, excipients, and the like typically will be included in the compositions of topical oral administration within a range of concentrations suitable for their intended use or function in the composition, and which are well known in the pharmaceutical formulation art.
  • the analgesic agents are present in the compositions within a therapeutically useful and effective concentration range, as determined by routine methods that are well known in the medical and pharmaceutical arts.
  • the filter cake was suspended in water (50 ml) to which saturated sodium carbonate solution ( ⁇ 5 ml) was added to pH 10, causing thickening of the suspension.
  • the resultant solid was collected by filtration, washed with cold water and dried under vacuum (40 °C) to give the target aminoquinoline (5) as an off-white solid (1.82 g, 6.71 mmol).
  • Cisplatin was administered intraperitoneally on days 1 (2 mg/kg), 4 (1 mg/kg), 8 (2 mg/kg) and 12 (2 mg/kg) (7mg/kg total dose). Cisplatin was prepared daily and 2 ml of 0.9% saline was administered subcutaneously after each cisplatin injection. On day 14, the mechanical pain threshold was measured, and rats received vehicle (canola oil/gelatin), DCUKA (50 mg/kg), BCUKA (50 mg/kg) or gabapentin (30 mg/kg, a dose equimolar to DCUKA and BCUKA). One and two hours later, the mechanical pain threshold was again tested.
  • Bodnar RJ (2000) Supraspinal circuitry mediating opioid antinociception: antagonist and synergy studies in multiple sites. J Biomed Sci 7: 181-194.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Des compositions analgésiques comprennent une aminoquinoline conjointement avec un opioïde, un anti-inflammatoire non stéroïdien (AINS), un inhibiteur de recapture de NE/5-HT, ou une combinaison de ceux-ci. L'aminoquinoline potentialise la bioactivité des opioïdes, des AINS et des inhibiteurs de recapture de NE/5-HT.
EP19858445.0A 2018-09-07 2019-09-04 Compositions analgésiques Pending EP3846813A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US16/125,252 US10391088B2 (en) 2014-06-20 2018-09-07 Analgesic compositions
PCT/US2019/049457 WO2020051182A1 (fr) 2018-09-07 2019-09-04 Compositions analgésiques

Publications (2)

Publication Number Publication Date
EP3846813A1 true EP3846813A1 (fr) 2021-07-14
EP3846813A4 EP3846813A4 (fr) 2022-06-01

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EP19858445.0A Pending EP3846813A4 (fr) 2018-09-07 2019-09-04 Compositions analgésiques

Country Status (3)

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EP (1) EP3846813A4 (fr)
JP (1) JP7406266B2 (fr)
WO (1) WO2020051182A1 (fr)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070087977A1 (en) * 2004-11-16 2007-04-19 Wendye Robbins Methods and compositions for treating pain
MX2010005680A (es) * 2007-11-23 2010-12-21 Protect Pharmaceutical Corp Composiciones de tapentadol.
CA3164826C (fr) * 2014-06-20 2026-03-17 Lohocla Research Corporation Agents thérapeutiques multifonctionnels à base d'aminoquinoline

Also Published As

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EP3846813A4 (fr) 2022-06-01
WO2020051182A1 (fr) 2020-03-12
JP2022501419A (ja) 2022-01-06
JP7406266B2 (ja) 2023-12-27

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