WO2020051182A1 - Compositions analgésiques - Google Patents

Compositions analgésiques Download PDF

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Publication number
WO2020051182A1
WO2020051182A1 PCT/US2019/049457 US2019049457W WO2020051182A1 WO 2020051182 A1 WO2020051182 A1 WO 2020051182A1 US 2019049457 W US2019049457 W US 2019049457W WO 2020051182 A1 WO2020051182 A1 WO 2020051182A1
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Prior art keywords
dcuka
pain
treatment
pain threshold
mechanical
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PCT/US2019/049457
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English (en)
Inventor
Boris Tabakoff
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Lohocla Research Corporation
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Priority claimed from US16/125,252 external-priority patent/US10391088B2/en
Application filed by Lohocla Research Corporation filed Critical Lohocla Research Corporation
Priority to JP2021537448A priority Critical patent/JP7406266B2/ja
Priority to EP19858445.0A priority patent/EP3846813A4/fr
Publication of WO2020051182A1 publication Critical patent/WO2020051182A1/fr

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    • 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

  • the present invention relates to analgesic compositions containing aminoquinoline compounds together with opioids, norepinephrine/serotonin reuptake inhibitors and/or non steroidal anti-inflammatory drugs (NSAIDs)
  • opioids norepinephrine/serotonin reuptake inhibitors
  • non steroidal anti-inflammatory drugs NSAIDs
  • opiates have many adverse effects, including tolerance/hyperalgesia, which results in dose escalation, and the development of opiate addiction (Chou et al., 2015). Additional side effects of high dose, chronic administration of opiates include constipation, sleep-disordered breathing, fractures, hypothalamic-pituitary-adrenal dysregulation, and overdose, as well as effects on the cardiovascular and immune systems (Baldini et al., 2012).
  • 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 of X 2 , X 3 , R 7 , R 8 and R 9 are as defined in Formulas (I) and (II) above.
  • R 7 is alkyl, cycloalkyl, aminoalkyl or phenyl
  • R 8 is H, alkyl, cycloalkyl, aminoalkyl, or phenyl
  • R 7 and R 8 are phenyl.
  • Particularly preferred for use in the present analgesic compositions are compounds of Formula (VI) in free acid form, free base form, or as a pharmacologically acceptable addition salt wherein:
  • R 7 is alkyl (preferably a 3 to 6 carbon alky), or phenyl
  • R 8 is alkyl (preferably a 3 to 6 carbon alkyl), or phenyl;
  • 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).
  • Administration of the analgesic compositions can be by oral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal or buccal routes.
  • 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
  • Compounds of Formula (VI) can be prepared by amidation of a 5,7- dichloroquinolone-2-carboxylate intermediate (e.g., obtainable by Michael addition of 3,5- dichloroaniline to dimethyl acetylene dicarboxylate, followed by thermal cyclization of the resultant aryl maleate) with chlorosulfonyl isocyanate to generate (4-amino)-5,7-dichloro-2- carboxy-quinoline ethyl ester (a key intermediate), which can be functionalized through reactions with relevant electrophiles.
  • a reactive urea intermediate is prepared through the reaction of a primary amine with
  • 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.
  • the (N, N-disubstituted)-4-ureido-5,7-dichloro-2- carboxy-quinoline-ester can be hydrolyzed to an (N, N-disubstituted)-4-ureido-5,7-dichloro- 2-carboxy-quinoline.
  • DCUKA and DCUK-OEt each exhibit affinity for Navl .7 and Navl .8, and DCUKA also exhibits affinity for the NMD A receptor.
  • DCUK-OEt can also act as a pro-drug for DCUKA, with ester hydrolysis by carboxylesterase 1 occurring after in vivo administration.
  • Fig. 1 graphically illustrates that DCUK-OEt can act as a pro-drug for DCUKA.
  • rats were administered DCUK-OEt orally in a suspension of a spray-dried dispersion formulation, the data show that the levels of DCUKA in blood depended on the dose of DCUK-OEt that was administered.
  • the peak level of DCUKA is ⁇ 3 mM after the dose of 50 mg/kg of DCUK-OEt, and ⁇ 11 mM after the dose of 100 mg/kg of DCUK-OEt.
  • 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. 3 graphically illustrates a comparison of the effects of equimolar doses of DCUKA, BCUKA and gabapentin to reverse cisplatin-induced neuropathic pain, measured by changes in the mechanical pain threshold.
  • Fig. 4 graphically illustrates the reversal by DCUKA (50 mg/kg) of neuropathic pain induced by treatment of rats with Complete Freund’s Adjuvant (CFA). CFA treatment of the rat’s paw induces inflammation and reduces the mechanical pain threshold.
  • DCUKA treatment reverses the reduction in the mechanical pain threshold in CFA-treated rats and returns the threshold toward the baseline level.
  • the data show the ratio of the mechanical pain threshold after CFA or CFA plus DCUKA treatment to the mechanical pain threshold prior to CFA treatment.
  • Fig. 5 illustrates a comparison of the effect of DCUKA (50 mg/kg) and BCUKA (50 mg/kg) to reverse neuropathic pain induced by treatment of rats with CFA.
  • the data show the ratio of the mechanical pain threshold after CFA treatment, or CFA plus DCUKA or BCUKA treatment, to the baseline (pre-CFA) 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. 7 graphically illustrates the treatment by DCUKA (50 mg/kg) of pain caused by diabetic neuropathy. Rats were treated with streptozotocin (STZ) to induce diabetes, which reduced the mechanical pain threshold in comparison to baseline (pre-STZ treatment). DCUKA treatment reversed the mechanical pain threshold to baseline. The data show the ratio of the mechanical pain threshold after STZ or STZ plus DCUKA treatment to the pre- STZ mechanical pain threshold.
  • STZ streptozotocin
  • Fig. 8 shows the results of a meta-analysis of experiments to determine the dose- dependent effect of DCUKA to reverse STZ-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. 14 illustrates that DCUKA potentiates the ability of aspirin to reverse STZ- induced neuropathic pain (diabetic neuropathy).
  • 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.
  • Heteroaryl rings are aromatic rings including at least one carbon atom in the ring and one or more, typically from 1-4, atoms forming the ring is an atom other than a carbon atom, i.e., a heteroatom (typically O, N or S).
  • Heteroaryl includes, without limitation: morpholinyl, piperazinyl, piperidinyl, pyridyl, pyrrolidinyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, indolinyl, indolyl-4,7-dione, l,2-dialkyl-indolyl, l,2-dimethyl-indolyl, and 1,2- dialkyl-indolyl-4,7-dione.
  • Alkoxy means -OR where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, 2-propoxy and the like.
  • Alkenyl means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenyl, propenyl, and the like.
  • Alkynyl means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e.g., ethynyl, propynyl, and the like.
  • 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.
  • “Substituted” means that one or more hydrogen atoms on the designated atom is/are replaced with a selection from the indicated group, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound.
  • Pharmaceutically acceptable salts are materials in which the parent compound (e.g., an aminoquinoline compound of Formula (I)) or some other therapeutic agent or excipient is modified by making acid or base salts thereof.
  • Examples of pharmaceutically-acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, or alkali or organic salts of acidic residues such as carboxylic acids.
  • Pharmaceutically acceptable salts include the
  • non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • Pharmaceutically acceptable salts are those forms of compounds, suitable for use in contact with the tissues of human beings and animals without causing excessive toxicity, irritation, allergic response, or other problems or complication, commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salt forms of the aminoquinoline compounds provided herein are synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts are prepared, for example, by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.
  • nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in Remington's Pharmaceutical Sciences , 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is incorporated herein by this reference.
  • 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 also includes solvates, metabolites, and pharmaceutically acceptable salts of the aminoquinoline compounds.
  • solvate refers to an aggregate of a molecule with one or more solvent molecules.
  • A“metabolite” is a pharmacologically active product produced through in vivo metabolism in the body of a specified compound or salt thereof. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound.
  • 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.
  • aminoquinoline compositions of the present invention can be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, liposomes, suppositories, intranasal sprays, solutions, emulsions, suspensions, aerosols, targeted chemical delivery systems, and any other form suitable for such use, which are well known in the pharmaceutical formulation arts.
  • Non-limiting examples of carriers that can be used include water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, com starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, liquid or aerosol form.
  • auxiliary, stabilizing, thickening and coloring agents and perfumes can be used.
  • the pharmaceutical compositions comprise at least one aminoquinoline compound as described herein in combination with an opioid, NE- or 5HT uptake inhibitor and/or a NS AID and a pharmaceutically acceptable carrier, vehicle, or diluent, such as an aqueous buffer at a physiologically acceptable pH (e.g., pH 7 to 8.5), a polymer-based nanoparticle vehicle, a liposome, and the like.
  • a pharmaceutically acceptable carrier such as an aqueous buffer at a physiologically acceptable pH (e.g., pH 7 to 8.5), a polymer-based nanoparticle vehicle, a liposome, and the like.
  • the pharmaceutical compositions can be delivered in any suitable dosage form, such as a liquid, gel, solid, cream, or paste dosage form.
  • the compositions can be adapted to give sustained release of the
  • the pharmaceutical compositions include, but are not limited to, those forms suitable for oral, rectal, nasal, topical, (including buccal and sublingual), transdermal, vaginal, parenteral (including intramuscular, intraperitoneal, subcutaneous, and intravenous), spinal (epidural, intrathecal), and central (intracerebroventricular)
  • compositions can, where appropriate, be conveniently provided in discrete dosage units.
  • the pharmaceutical compositions of the invention can be prepared by any of the methods well known in the pharmaceutical arts. Some preferred modes of administration include intravenous (iv), topical, subcutaneous, oral and spinal.
  • iv intravenous
  • topical topical
  • subcutaneous oral
  • spinal spinal
  • the aminoquinoline compound generally will be administered the subject at a dosage in the range of about 1 milligram of aminoquinoline compound per kilogram of body mass (mg/kg) to about 200 mg/kg.
  • the administered dosage should be sufficient to provide a concentration of aminoquinoline compound in the subject of about 100 nanomolar (nM) to about 100 micromolar (mM).
  • compositions suitable for oral administration include capsules, cachets, or tablets, each containing a predetermined amount of one or more of the aminoquinoline compounds, as a powder or granules.
  • the oral composition is a solution, a suspension, or an emulsion.
  • the aminoquinoline compound containing analgesic compositions can be provided as a bolus, electuary, or paste.
  • Tablets and capsules for oral administration can contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, colorants, flavoring agents, preservatives, or wetting agents.
  • the tablets can be coated according to methods well known in the art, if desired.
  • Oral liquid preparations include, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs.
  • the compositions can be provided as a dry product for constitution with water or another suitable vehicle before use.
  • Such liquid preparations can contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and the like.
  • the additives, excipients, and the like typically will be included in the compositions for 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.
  • compositions for parenteral, spinal, or central administration can be provided in unit dose form in ampoules, pre-filled syringes, small volume infusion, or in multi-dose containers, and preferably include an added preservative.
  • the compositions for parenteral administration can be suspensions, solutions, or emulsions, and can contain excipients such as suspending agents, stabilizing agents, and dispersing agents.
  • the additives, excipients, and the like typically will be included in the compositions for parenteral 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 aminoquinoline compounds are included in the compositions within a therapeutically useful and effective concentration range, as determined by routine methods that are well known in the medical and
  • compositions for topical administration to the epidermis can be formulated as ointments, creams, lotions, gels, or as a
  • transdermal patch Such transdermal patches can contain penetration enhancers such as linalool, carvacrol, thymol, citral, menthol, t-anethole, and the like.
  • Ointments and creams can, for example, include an aqueous or oily base with the addition of suitable thickening agents, gelling agents, colorants, and the like.
  • Lotions and creams can include an aqueous or oily base and typically also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, coloring agents, and the like.
  • Gels preferably include an aqueous carrier base and include a gelling agent such as cross-linked polyacrylic acid polymer, a derivatized polysaccharide (e.g., carboxymethyl cellulose), and the like.
  • a gelling agent such as cross-linked polyacrylic acid polymer, a derivatized polysaccharide (e.g., carboxymethyl cellulose), and the like.
  • the additives, excipients, and the like typically will be included in the
  • compositions for topical administration to the epidermis 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.
  • 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.
  • analgesic agents are provided in a solid or semisolid
  • compositions of rectal administration can be provided as unit dose suppositories.
  • Suitable carriers or vehicles include cocoa butter and other materials commonly used in the art.
  • the additives, excipients, and the like typically will be included in the compositions of rectal administration within a range of
  • compositions of the present invention suitable for vaginal
  • compositions suitable for vaginal administration can be delivered in a liquid or solid dosage form.
  • the additives, excipients, and the like typically will be included in the compositions of vaginal 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.
  • Analgesic compositions suitable for intra-nasal administration are also encompassed by the present invention.
  • Such intra-nasal compositions comprise, in addition to the analgesic agents, a delivery vehicle and a suitable device to deliver a liquid spray, dispersible powder, or drops.
  • Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilizing agents, or suspending agents.
  • Liquid sprays are conveniently delivered from a pressurized pack, an insufflator, a nebulizer, or other convenient means of delivering an aerosol comprising the
  • Pressurized packs comprise a suitable propellant such as
  • compositions for administration by inhalation or insufflation can be provided in the form of a dry powder composition, for example, a powder mix of the analgesic agents and a suitable powder base such as lactose or starch.
  • a powder mix of the analgesic agents and a suitable powder base such as lactose or starch.
  • Such powder composition can be provided in unit dosage form, for example, in capsules, cartridges, gelatin packs, or blister packs, from which the powder can be administered with the aid of an inhalator or insufflator.
  • the additives, excipients, and the like typically will be included in the compositions of intra-nasal 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.
  • Methods for alleviating chronic pain comprise administering to a patient suffering from one of the aforementioned conditions an effective amount of an aminoquinoline compound together with an opioid and/or a NSAID and/or 5-HT/NE uptake inhibitor.
  • the analgesic composition is administered parenterally or enterally.
  • the dosage of the effective amount of the aminoquinoline compounds can vary depending upon the age and condition of each individual patient to be treated. Suitable dosages of the aminoquinoline compound typically range about 1 mg/kg to about 200 mg/kg, and the aminoquinoline compound can be administered together with an opioid, NSAID and/or 5- HT/NE uptake inhibitor at one tenth to the full recommended dose of a particular compound. Such dosages can be administered one or more times a day, one or more times a week, one or more times per month, and the like.
  • the terms “reducing”, “inhibiting”, “blocking”, “preventing”, “alleviating”, “relieving”, and “antagonist” when referring to a composition mean that the compound brings down the occurrence, severity, size, volume, or associated symptoms of a condition, event, or activity by at least about 7.5%, 10%, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 27.5%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, or 100% compared to how the condition, event, or activity would normally exist without application of the composition comprising the compound.
  • enhancing”, “upregulating”, “improving”, “activating” and “agonist”, when referring to a compound mean that the compound increases the occurrence or activity of a condition, event, or activity by at least about 7.5%, 10%, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 27.5%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 750%, or 1000% compared to how the condition, event, or activity would normally exist without application of the composition.
  • DCUKA to increase potency of opioids/NSAIDs/5-HT and NE reuptake inhibitors.
  • MME Malphine Milligram Equivalents
  • DCUKA or DCUK-OEt (which acts as a prodrug for DCUKA)
  • morphine increases the potency of morphine by 4-5 fold.
  • addition of DCUKA or DCUK-OEt to the pain treatment allows the analgesic dose to be reduced in the same manner as the reduction of the morphine dose when morphine is given with DCUKA/DCUK-OEt.
  • the dose of another analgesic when given with DCUKA can be calculated by the following formula:
  • Dose of opioid analgesic daily dose of morphine used in a similar situation ⁇ MME ⁇ A factor based on the increase in opioid potency as a result of addition of DCUKA or DCUK-OEt.
  • the MME for the opioid of interest in this case oxycodone
  • the use of rating scales is important in this regard (Schneider et al., 2003).
  • a singular dose of morphine can vary between 10 and 30 mg and such doses are taken 6 times daily (i.e., 60-180 mg/day); (3) the factor by which the dose of opioid can be decreased by addition of DCUKA to the dosing regimen for pain.
  • the dose of DCUKA can vary between 150 - 450 mg given 2-3 times per day. If DCUKA is administered as such, the dose of the opioid that is used can be lowered by a factor of 4-5 (this factor is determined based on data in Figure 11 and 12.
  • the pain treatment specialist should closely monitor the patient to adjust dosing as necessary for the comfort of the patient. This can be accomplished by increasing the dose of opioid or DCUKA within the recommended ranges.
  • Methadone given for control of pain is usually titrated upward over a six-week period and the lower dose given with DCUKA can be titrated accordingly.
  • DCUKA daily dose of DCUKA and/or opioid can be incrementally increased (an increment would involve a 25-50% increase in daily dose of DCUKA or opioid).
  • the factor by which the dose of NSAID can be reduced when given together with DCUKA is in the range of about 5 to about 6.
  • DCUKA and its prodrug can increase the potency of opioids and NSAIDs
  • DCUK-OEt can increase the potency of opioids and NSAIDs
  • a downward adjustment of the daily doses of opioids and NSAIDs results in lowering of side effects while maintaining pain relief.
  • Derivatives of kynurenic acid containing a tertiary ureido group including 5,7- dichloro-4-(3,3-diphenylureido)quinoline-2-carboxylic acid (DCUKA, 7a), may be synthesized, as previously described (Snell et ak, 2000) through the use of a reactive carbamoyl chloride intermediate (6a-b).
  • DCUKA 5,7- dichloro-4-(3,3-diphenylureido)quinoline-2-carboxylic acid
  • Dimethyl anilinomaleate (3, 3.50 g, 11.5 mmol) was added portion-wise to diphenyl ether (70 ml) at 250 °C. The temperature of the resulting solution was maintained at 250 °C for 2 hours, before being cooled to room temperature and diluted with hexanes (100 ml).
  • Chlorosulfonyl isocyanate (1.20 ml, 13.8 mmol) was added to a slurry of quinoline carboxylate (4, 2.50 g, 9.19 mmol) in anhydrous MeCN (35 ml) at room temperature. The mixture was brought to reflux for 1.5 hours, at which point the heating was stopped and a 1.0M solution of HC1 in anhydrous MeOH (20 ml) was added. The reaction mixture was allowed to cool to room temperature with stirring until a precipitate formed after 1 hour. The precipitate was removed via filtration, washed with MeCN, and air dried.
  • 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).
  • Carbamoyl chlorides are limited in their commercial availability, and, furthermore, are characterized by high reactivity, especially to hydrolysis, and subsequent poor stability. This is particularly evident in the case of mono-n-substituted carbamoyl chlorides. Therefore, in order to prepare mono-n-substituted analogues of kynurenic acid it was advantageous to utilize alternative carbamoyl cation equivalents, with attenuated reactivity.
  • Carbamoyl imidazoles e.g. 9a-d
  • n-Butylamine (8a, 100 m ⁇ , 74 mg, 1.01 mmol) in DCM (1 ml) was added to a solution of CDI (0.197 g, 1.21 mmol) in DCM (5 ml) at 0 °C, before the reaction mixture was allowed to warm to RT and stirred overnight.
  • the solution was diluted with DCM (10 ml) washed with water (2 x 10 ml) and brine (10 ml), dried (Na 2 S0 4 ) and evaporated to dryness to give the target carbamoyl imidazole (9a) as a colorless oil (115 mg, 0.69 mmol).
  • N-(3-(Dimethylamino)propyl)-lH-imidazole-l-carboxamide (9b) was prepared from 3-dimethylaminopropylamine (8b) as described in synthesis phase V.
  • tert-Butyl (3-(lH-imidazole-l-carboxamido)propyl)carbamate (9c) was prepared from tert- butyl (3-aminopropyl)carbamate (8c) as described in synthesis phase V.
  • tert-Butyl (3-(lH-imidazole-l-carboxamido)propyl)(methyl)carbamate (9d) was prepared from A 7 -(3-aminopropyl)-A 7 -methylcarbamic acid tert- butyl ester (8d) as described in synthesis phase V.
  • the absorption peak values (in ppm) found in the 1H NMR spectrum performed in CDCI 3 were 1.49 (9H, s), 1.74-1.80 (2H, br), 2.87 (3H, s), 3.35-3.43 (4H, m), 7.09 (1H, s), 7.53 (1H, s), 8.11 (1H, br), 8.25 (1H, s).
  • TFA (173 pL, 2.25 mmol) was added to a solution of Boc-protected amine (10c, 103 mg, 0.23 mmol) in DCM (4 ml). After stirring at room temperature for 16 hours, the solvent was removed under reduced pressure and the residue was purified directly by reverse phase chromatography (C18, 1 : 1 H 2 0:MeCN) to give the TFA salt form of 4-(3-(3- aminopropyl)ureido)-5,7-dichloroquinoline-2-carboxylic acid (lOd) as a white solid (64 mg, 0.14 mmol).
  • DCUKA 5,7-dichloro-4-(3,3-diphenylureido)quinoline-2- carboxylic acid
  • Applied Biosystems Sciex 4000 (Applied Biosystems; Foster City, CA) equipped with a Shimadzu HPLC (Shimadzu Scientific Instruments, Inc.; Columbia, MD) and Leap auto-sampler (LEAP Technologies; Carrboro, NC) was used.
  • Liquid chromatography employed an Agilent Technologies, Zorbax extended-Cl8 250 x 4.6 mm, 5 micron column equipped with a column guard at 40 °C with a flow-rate of 0.6 mL/min.
  • the mobile phase consisted of A: 10 mM (NH40Ac), 0.1% formic acid in H20, and B: 50:50 ACN:MeOH.
  • the chromatography method used was: 95% A for 2.0 min; ramped to 95% B at 7.0 min and held for 9.0 min, lastly, brought back to 95% A at 18.0 min and held for 2.0 min (20.0 min total run time).
  • Compounds were monitored via electro-spray ionization positive ion mode (ESI+) using the following conditions: i) an ion-spray voltage of 5500 V; ii) temperature, 450°C; iii) curtain gas (CUR; set at 10) and Collisionally Activated Dissociation (CAD; set at 12) gas were nitrogen; iv) Ion Source gas one (GS1) and two (GS2); v) entrance potential was set at 10 V; vi) quadruple one (Ql) and (Q3) were set on Unit resolution; vii) dwell time was set at 200 msec; and viii) declustering potential (DP), collision energy (CE), and collision cell exit potential (CXP) are voltages (V).
  • FIG. 1 graphically illustrates that DCUK-OEt can serve as a pro-drug for DCUKA after in vivo administration. Data are plotted as mean ⁇ SD values from 3-4 rats per group (data from one outlier at 60 min after the 100 mg/kg dose is not included). 50 mg/kg or 100 mg/kg of DCUK-OEt, prepared as a spray-dried dispersion formulation with the polymer HPMCAS-MG, was administered as an HPMC suspension by gavage to 4 rats per group. Blood was obtained from the jugular vein at the indicated times, and DCUKA levels were determined by LC-MS/MS analysis. The results show the blood levels of DCUKA obtained after administration of DCUK-OEt. DCUK-OEt was only detectable after the 100 mg/kg dose.
  • DCUK-OEt The highest levels of DCUK-OEt were 0.49 pM and 0.24 pM at 60 minutes after DCUK-OEt administration, and 0.08 pM at 90 minutes after DCUK-OEt administration. Levels of DCUK-OEt were below the limit of detection in the fourth rat in the group. In contrast, as shown in Figure 1, DCUKA levels reached approximately 3 pM after 50 mg/kg of DCUK-OEt, and approximately 11 pM after 100 mg/kg of DCUK-OEt.
  • EXAMPLE 3 Treatment of Neuropathic Pain by DCUKA, BCUKA and DCUK-OEt.
  • DCUKA DCUKA
  • BCUKA DCUK-OEt
  • neuropathic pain measured as mechanical or thermal pain, induced by cisplatin (cancer chemotherapy), Complete Freund’s Adjuvant (CFA) (inflammatory pain), or diabetes (streptozotocin-induced pain) or monoiodoacetate (MIA) (osteoarthritic pain).
  • CFA Complete Freund’s Adjuvant
  • MIA monoiodoacetate
  • DCUKA D-a- Tocopherol polyethylene glycol 1000 succinate
  • TPGS 1000 D-a- Tocopherol polyethylene glycol 1000 succinate
  • DCUK-OEt 2.5 g was weighed out into a clean glass beaker and TPGS 1000 (47.5. ml) was slowly added. The mixture was homogenized for 2-3 minutes to produce a creamy white aqueous suspension. This suspension was encapsulated into Torpac capsules (Torpac, Fairfield, NJ) and delivered orally to rats with a Torpac capsule syringe (Wempe et ak, 2012).
  • Cisplatin Sigma- Aldrich, St. Louis, MO
  • Streptozotocin Sigma- Aldrich
  • 20 mM sodium citrate buffer, pH 4.5
  • Complete Freund’s Adjuvant CFA
  • Sodium Mono-iodoacetate was obtained from Sigma-Aldrich and was dissolved in saline.
  • Rats were housed in an AAAL AC-accredited facility with regulated lighting, temperature and humidity. Pain was tested using an electronic von Frey anesthesiometer (IITC Life Science), Woodland Hills, CA). Rats were placed in suspended chambers with a metal mesh floor and were allowed to acclimate for approximately 20 minutes. Mechanical stimuli were applied to the mid-plantar surface of the hind paw(s). Two different methods were used. In the first, a set of von Frey filaments with different strength ranges (g) was used, and filaments of increasing strength were applied to the paw. The force generated with each filament application was displayed on the electronic sensor. Each filament was applied five times, until a paw withdrawal response occurred (“flinch” after filament application).
  • the pressure (force in g) at paw withdrawal (paw withdrawal threshold) was recorded by an electronic transducer. Five measurements were taken per test, and the average value was calculated. In both methods, to avoid sensitization, a three-minute interval was imposed between measurements.
  • Cisplatin was dissolved in 0.9% saline (1 mg/ml) and injected into the tail vein in a volume of 1.5 or 2.5 ml/kg of body weight. The intravenous injection of cisplatin was followed by an injection of the same amount of saline (Joseph and Levine, 2009). The cisplatin doses were 1.5 or 2.5 mg/kg in individual experiments.
  • Cisplatin was dissolved in 0.9% saline and administered by intraperitoneal injection on days 1, 4, 8 and 12.
  • the cisplatin doses were 2 mg/kg, 1 mg/kg, 2 mg/kg and 2 mg/kg, respectively, for a total dose of 7 mg/kg.
  • a fresh solution of cisplatin was prepared every day before injection, and 0.9% saline (2 ml) was injected subcutaneously after the cisplatin injection (to avoid nephrotoxicity).
  • rats were tested for baseline pain sensitivity (mechanical pain threshold) prior to any cisplatin treatment.
  • identification number was used as a repeated measure as there are multiple measurements on one animal, including pre and post treatment and left and right paw. All models were tested for equal variances among treatment groups (Barlett’s test for homogeneity of variances) and normality (Kolmogorov-Smirnov goodness of fit test). If the data did not pass these assumptions, we adjusted accordingly in the mixed model. Some analyses used Fisher’s LSD post hoc tests to compare statistical significance (p-value ⁇ 0.05) between the different treatment doses and all analyses used Fisher’s LSD post hoc tests to compare statistical significance between treatment group and the baseline value. Experiments were included in the meta-analysis if they met the following
  • 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.
  • rats Fourteen days after the first STZ treatment, rats were given vehicle (canola oil/gelatin) or various doses of DCUKA orally, and the mechanical pain threshold was tested at various times after these treatments. Data are presented as the ratio of the mechanical pain threshold following DCUKA treatment to the baseline mechanical pain threshold (measured on the same paw).
  • the mechanical pain threshold was tested at 90 minutes after drug administration. At the end of testing, blood was taken from the tail vein for determination of DCUKA levels by LC-MS/MS analysis. Data are presented as the ratio of the mechanical pain threshold following DCUKA treatment to the mechanical pain threshold determined in animals with no drug or MIA treatment.
  • FIG. 2 illustrates that DCUKA (50 mg/kg) treatment reverses neuropathic pain caused by treatment of rats with the cancer chemotherapeutic agent, cisplatin. Combined results from six experiments are shown. Treatment means ⁇ 1 SEM plotted. *P-value ⁇ 0.0001 compared to control (0 mg/kg DCUKA). In all experiments, rats were tested for baseline mechanical pain threshold prior to cisplatin treatment. Following cisplatin treatments described earlier, rats were given DCUKA, and one hour later, the mechanical pain threshold was again determined. The results show the ratio of the mechanical pain threshold measured at one hour after vehicle or DCUKA administration compared to the baseline (pre-cisplatin treatment) mechanical pain threshold.
  • Figure 3 graphically compares the effect of DCUKA (50 mg/kg), BCUKA (50 mg/kg) and gabapentin (Neurontin, 30 mg/kg) on neuropathic pain induced by the chemotherapeutic agent, cisplatin.
  • the mean mechanical pain threshold ⁇ 1 standard error is plotted for each treatment group and time. *P ⁇ 0.05 compared to the corresponding pre-treatment group. Rats were tested for baseline mechanical pain threshold prior to cisplatin treatment, and were treated with cisplatin as described earlier. Following cisplatin treatment the mechanical pain threshold was measured, and rats were given oral doses of vehicle, DCUKA, BCUKA, or gabapentin. The mechanical pain threshold was again measured at 1 and 2 hours after these treatments.
  • Data are the ratio of the mechanical pain threshold measured prior to DCUKA, BCUKA or gabapentin administration, and 1 and 2 hours later.
  • Cisplatin treatment alone (“pretreatment”) significantly reduced the mechanical pain threshold, compared to baseline, and DCUKA and BCUKA significantly reversed the drop in mechanical pain threshold.
  • FIG. 4 graphically illustrates that DCUKA treats the neuropathic pain induced by treatment of rats with Complete Freund’s Adjuvant (CFA) to produce an inflammatory response.
  • CFA Complete Freund’s Adjuvant
  • Figure 5 graphically illustrates a comparison of the effect of DCUKA (50 mg/kg) and BCUKA (50 mg/kg) to treat neuropathic pain produced by CFA treatment.
  • Mechanical pain threshold for each animal is represented by the ratio to baseline for the injected paw only. The mean mechanical pain threshold ⁇ 1 standard error is plotted for each treatment group. *P ⁇ 0.05 compared to vehicle. Baseline mechanical pain threshold was measured, and rats were treated with CFA as described earlier. Forty-eight hours later, rats were given vehicle (canola oil/gelatin), DCUKA or BCUKA, and one hour later the mechanical pain threshold was measured.
  • the mechanical pain threshold was again measured at 60 min after vehicle or DCUKA administration.
  • the requirements were: 1) CFA treatment produced at least a 25% decrease in the mechanical pain threshold; 2) the pain threshold was measured at 60 min after DCUKA or vehicle administration.
  • the dose-dependence of the effects of DCUKA on STZ-induced neuropathic pain was determined by a meta-analysis approach. Requirements for an experiment to be included in the meta-analysis were: 1) STZ treatment induced neuropathic pain, as measured by a decrease in mechanical pain threshold of at least 25%; 2) pain was measured 90 minutes after vehicle or DCUKA treatment. Four experiments that met these criteria were included in the meta-analysis.
  • Figure 8 shows the dose-dependence of the effect of DCUKA to treat STZ-induced neuropathic pain.
  • the data are reported as the ratio of the mechanical pain threshold after vehicle or DCUKA treatment to the baseline pain threshold measured on the same paw. *P ⁇ 0.05 compared to the vehicle treatment group..
  • STZ treatment induced approximately a 40% reduction in the pain threshold, and doses of DCUKA of 30 mg/kg and higher reversed the effect of STZ and increased the pain threshold back to the baseline level.
  • Figure 9 shows the dose-dependence of DCUKA to treat MIA-induced neuropathic pain.
  • the data are reported as the mean ⁇ SEM ratio of the mechanical pain threshold after vehicle (0 capsules) or DCUKA treatment (1 or 2 capsules), to the baseline pain threshold measured in animals not treated with MIA or drugs. *P ⁇ 0.05 compared to the vehicle group (ANOVA and post hoc comparisons).
  • DCUKA and DCUK-OEt Enhance the Effect of Morphine on CFA- Induced Neuropathic Pain.
  • Example 3 CFA treatment and measurement of mechanical pain threshold are described under Example 3.
  • mechanical pain threshold was tested at baseline.
  • vehicle, DCUKA or morphine, or the combination of DCUKA and morphine were injected 30 minutes prior to measurement of the mechanical pain threshold.
  • Figure 10A demonstrates that combining doses of DCUKA and morphine that in themselves, are ineffective in producing analgesia, results in a complete reversal of inflammation-induced chronic pain.
  • DCUKA Enhances the Effect of Oxycodone and Methadone to treat FA- Induced Neuropathic Pain.
  • Figure 12 demonstrates that DCUKA (1 capsule) potentiates the effect of methadone (1.5 or 3.5 mg/kg) to reduce inflammation-induced chronic pain.
  • Data are presented as the mean ⁇ SEM ratio of the mechanical pain threshold in the treated paw after drug or vehicle (VEH) treatment, to the mechanical pain threshold prior to treatment with Freund's adjuvant (FA).
  • *P ⁇ 0.05 compared to DCUKA/VEH or methadone 1.5 mg/kg alone; **P ⁇ 0.05 compared to DCUKA/VEFl or methadone 3.5 mg/kg alone; +P ⁇ 0.05 compared to VEH (n 8/group, ANOVA and post hoc comparisons).
  • the increased effect of the combination of DCUKA and methadone 1.5 mg/kg reflects a "positive combination effect” (Foucquier and Guedj, 2015).
  • the figure illustrates the "Highest Single Agent” approach, which reflects the fact that the effect of the drug combination is greater than the effects produced by its individual components.
  • the interrupted dotted line indicates the expected additive effects of 3.5 mg/kg methadone and DCUKA.
  • the increased effect of the drug combination above this line reflects a "positive combination effect.” (Foucquier and Guedj, 2015).
  • DCUKA Enhances the Effect of Tramadol to Treat MIA-Induced Neuropathic Pain.
  • Data are presented as the ratio of the mechanical pain threshold after drug treatment, to the non-MIA, non-drug treated baseline mechanical pain threshold. Data from two outliers in the DCUKA plus tramadol group were eliminated from the analysis. Animals with a blood level of DCUKA ⁇ 500 ng/ml, the level that had previously been found to be ineffective in reversing MIA-induced neuropathic pain, were deemed to have received a“low dose” of DCUKA. Data from these animals was used for analysis of differences among groups by l-way ANOVA and the Holm-Sidak test for all pairwise comparisons.
  • Figure 13 demonstrates that doses of DCUKA (1 capsule, where the blood level of DCUKA was ⁇ 500 ng/ml) and tramadol (5 mg/kg), which by themselves do not have a significant effect on mechanical pain threshold compared to vehicle, when combined, produce a significant reversal of the reduction of the pain threshold caused by MIA treatment.
  • Data are presented as mean ⁇ SEM of the ratio of mechanical pain threshold after treatment with low-dose DCUKA, low-dose (5 mg/kg) tramadol, or the combination of low dose DCUKA and low dose tramadol, to the pre-MIA treatment mechanical pain threshold. *P ⁇ 0.05 compared to all other groups (ANOVA and post hoc comparisons).
  • rats were tested for allodynia using a von Frey apparatus. Sixty minutes prior to testing, rats were divided into four groups. Group 1 received vehicle; Group 2 received DCUKA; Group 3 received aspirin; and Group 4 received a combination of DCUKA and aspirin.
  • Figure 14 demonstrates that doses of DCUKA (12.5 mg/kg) or aspirin (25 mg/kg) which by themselves do not have any significant effect on allodynia, when combined, completely reverse the hyper-responsiveness, i.e., return the pain threshold to the baseline level.
  • Rats were treated with Freund’s adjuvant and tested for mechanical pain as described in Examples 2 and 5. Groups of rats were given different doses of diclofenac on day 4 to determine appropriate doses for the experiment testing the combined effects of DCUKA and diclofenac. Different groups of rats were tested on day 4 after administration of a single capsule of DCUKA or low doses of diclofenac alone and in combination. Figure 15 shows that DCUKA potentiates the effect of diclofenac to reduce inflammation-induced chronic pain.
  • this figure illustrates the "Combination Subthreshold" approach, in which the combination of ineffective doses of drugs yields a significant effect.
  • the solid black line indicates the baseline mechanical pain threshold ratio in animals treated with Freund's adjuvant and vehicle. The increase above this line indicates the (non-significant) effect of DCUKA or Diclofenac 1.5 mg/kg alone.
  • the gray line indicates the expected additive effect of DCUKA and Diclofenac 1.5 mg/kg. The increased effect of the combination of DCUKA and Diclofenac 1.5 mg/kg, above the gray line, indicates a
  • Figure 16 shows that DCUKA can prevent the development of neuropathic pain caused by CFA.
  • Data show the ratio of the mechanical pain threshold at 60 hours after CFA treatment to the pre-CFA baseline mechanical pain threshold.
  • CFA treatment significantly reduced the pain threshold by approximately 70%.
  • Student's t-test is used to compare the pain threshold between group, and paired t-test is used to compare the pain threshold within group.
  • Figure 17 illustrates that repeated DCUKA treatments during the period between the administration of cisplatin and pain testing, prevented the development of pain in the rat cisplatin-induced neuropathic pain model.
  • Data are presented as mean ⁇ SEM of the mechanical pain threshold (paw withdrawal threshold). Injection of Cisplatin resulted in a significant decrease in mechanical pain threshold over days in the rats treated chronically with vehicle.
  • With repeated DCUKA treatments there was no statistically significant decrease of pain threshold compared to the pre-cisplatin baseline.
  • the results show that DCUKA has the ability to prevent the development of chemotherapy-induced neuropathic pain, when given after the administration of the chemotherapeutic agent.
  • Bodnar RJ (2000) Supraspinal circuitry mediating opioid antinociception: antagonist and synergy studies in multiple sites. J Biomed Sci 7: 181-194.
  • Osteoarthritis medication Analgesics, other, nonsteroidal anti-inflammatory. Medscape.
  • Lunn MP Hughes RA, Wiffen PJ (2014) Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia.

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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.
PCT/US2019/049457 2018-09-07 2019-09-04 Compositions analgésiques WO2020051182A1 (fr)

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Citations (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
US20170204064A1 (en) * 2014-06-20 2017-07-20 Lohocla Research Corporation Multifunctional aminoquinoline therapeutic agents
US20170216212A1 (en) * 2007-11-23 2017-08-03 Gruenenthal Gmbh Tapentadol compositions

Patent Citations (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
US20170216212A1 (en) * 2007-11-23 2017-08-03 Gruenenthal Gmbh Tapentadol compositions
US20170204064A1 (en) * 2014-06-20 2017-07-20 Lohocla Research Corporation Multifunctional aminoquinoline therapeutic agents

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* Cited by examiner, † Cited by third party
Title
See also references of EP3846813A4 *

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