EP1289558A2 - Combinaisons d'un antagoniste de recepteur d'endotheline et compose anti-epileptique presentant des proprietes analgesiques ou de soulagement de la douleur - Google Patents

Combinaisons d'un antagoniste de recepteur d'endotheline et compose anti-epileptique presentant des proprietes analgesiques ou de soulagement de la douleur

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Publication number
EP1289558A2
EP1289558A2 EP01939002A EP01939002A EP1289558A2 EP 1289558 A2 EP1289558 A2 EP 1289558A2 EP 01939002 A EP01939002 A EP 01939002A EP 01939002 A EP01939002 A EP 01939002A EP 1289558 A2 EP1289558 A2 EP 1289558A2
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EP
European Patent Office
Prior art keywords
benzo
dihydro
carboxylic acid
phenyl
dioxol
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.)
Withdrawn
Application number
EP01939002A
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German (de)
English (en)
Inventor
David James Dooley
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Warner Lambert Co LLC
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Warner Lambert Co LLC
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Publication date
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Publication of EP1289558A2 publication Critical patent/EP1289558A2/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention is directed to novel combinations effective for alleviating pain comprising a pain alleviating effective amount of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof, and one or two compounds selected from the group consisting of antiepileptic compounds having pain alleviating properties and analgesics, and to methods of treating or alleviating pain comprising administering effective amounts of said combinations to a mammal, including a human, in need of said treatment.
  • the invention also is directed to pharmaceutical compositions comprising said combinations.
  • Neurokinin 1 (NK ⁇ ) receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinins, and in particular of substance P, an important neurotransmitter in the transmission of pain.
  • the selective NKj receptor antagonist [2-( 1 H-indol-3 -yl)- 1 -methyl- 1 -( 1 -phenyl-ethylcarbamoyl)-ethyl] - carbamic acid benzofuran-2-ylmethyl ester, has been shown to block the maintenance of streptozotocin-induced static allodynia in the rat (Field et al., J. Pharmacol Exp. Ther. 1998;285 : 1226- 1232).
  • the endothelin receptor antagonist ABT-627 was found to attenuate pain in a rat model of diabetic neuropathy (Jarvis M.F. et al., Eur. J. Pharmacol. 2000;388:29-35).
  • the antihyperalgesic effects are maintained after chronic administration. This effect probably results from a block of ETA ⁇ receptors activated by endogenous endothelin- 1, leading to deficits in neurovascular blood flow and nerve conduction velocities.
  • Another endothelin receptor antagonist, BQ-123 was shown to alleviate pain in a mouse model of inflammation and hyperalgesia (Piovezan A.P. et al., Brit. J. Pharmacol.
  • Endothelin- 1 (ET-1), a potent vasoconstrictor, is a 21 amino acid bicyclic peptide that was first isolated from cultured porcine aortic endothelial cells.
  • Endothelin- 1 is one of a family of structurally similar bicyclic peptides which include ET-2, ET-3, vasoactive intestinal contractor (VIC), and the sarafotoxins (SRTXs).
  • NK j receptor antagonists such as capsaicin, heretofore used to treat pain or a disorder exhibiting a pain component can be used herein.
  • Specific NKj receptor antagonists that can be used herein are disclosed in United States
  • United States Patent No. 5,800,385 and WO 96/19233 are related and recite irrigation solutions comprised of anti-pain/anti-inflammation agents selected from: (1) serotonin receptor antagonists; (2) serotonin receptor agonists; (3) histamine receptor antagonists; (4) bradykinin receptor antagonists;
  • kallikrein inhibitors (6) tachykinin receptor antagonists, including neurokininj and neurokinin2 receptor subtype antagonists; (7) calcitonin gene- related peptide (CGRP) receptor antagonists; (8) interleukin receptor antagonists; (9) inhibitors of enzymes active in the synthetic pathway for arachadonic acid metabolites, including (a) phospholipase inhibitors, including PLA2 isoform inhibitors and PLC ⁇ isoform inhibitors, (b) cyclooxygenase inhibitors, and (c) lipoxygenase inhibitors; (10) prostanoid receptor antagonists including eicosanoid EP-1 and EP-4 receptor subtype antagonists and thromboxane receptor subtype antagonists; (11) leukotriene receptor antagonists including leukotriene B4 receptor subtype antagonists and leukotriene D4 receptor subtype antagonists; (12) opioid receptor agonists, including mu-opiate, delta opiate, and kappa opiate receptor
  • irrigation solutions comprised of anti-pain/anti-inflammation agents as described above and an anti-spasm agent selected from anti-pain/anti- inflammation agents which also serve as an anti-spasm agent such as serotonin receptor antagonists, tachykinin receptor antagonists, ATP-sensitive potassium channel openers, and calcium channel antagonists and agents utilized specifically for their anti-spasm properties such as endothelin receptor antagonists and the nitric oxide donors (enzyme activators).
  • WO 96/35453 recites methods of preventing/treating preterm labor, imminent abortion, dysmenorrhea, menstrual disorders (i.e., dysfunctional uterine bleeding, menorrhagia, breakthrough bleeding), preeclampsia of pregnancy which utilize an endothelin antagonist and/or an endothelin synthase (ECE) inhibitor which may be used in combination with a progestational agent (progestin), a cyclooxygenase inhibitor and/or a nitric oxide (NO) donor and/or NO substrate.
  • ECE endothelin synthase
  • a combination of pain alleviating compounds including an endothelin receptor antagonist with one, two, or three known compounds selected from the group consisting of antiepileptic compounds having pain alleviating properties and analgesics would provide benefits to patients in need of pain alleviating treatment not provided by administration of a higher dose of any single compound to achieve similar therapeutic benefit or by a combination of two or more pain alleviating compounds that did not include an endothelin receptor antagonist.
  • endothelin receptor antagonists when co-administered with compounds selected from the group consisting of antiepileptics having pain alleviating properties or analgesics, result in unexpected improved pain relief.
  • This finding is unexpected as the combination of an endothelin antagonist, which modulates diseases with a vascular component, and a pain alleviating agent to treat pain is not a combination that would have been obvious to one skilled in the medical arts at the time the invention was made. All that is required to practice the present invention is to administer a therapeutically effective amount of the invention combination from 1 to 6 times daily to a patient in need of treatment for alleviation of pain.
  • determination of dosage forms, amounts of the invention combinations, and routes of administration, selection of compounds for inclusion in the invention combination, and identification of patients in need of treatment is within the level of ordinary skill in the medical and pharmaceutical arts.
  • the present invention is combinations for alleviating pain.
  • the combinations comprise a pain alleviating effective amount of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and from 1 to 3 compounds independently selected from the group consisting of antiepileptic compounds having pain alleviating properties and analgesics, and pharmaceutically acceptable salts thereof.
  • antiepileptic compounds having pain alleviating properties are gabapentin and pregabalin.
  • Analgesics are selected from opioid analgesics and nonopioid analgesics.
  • Nonlimiting examples of nonopioid analgesics include NSAIDs, N-methyl-D- aspartate (NMDA) receptor antagonists, and neurokinin 1 (NKj) receptor antagonists.
  • antiepileptics having pain alleviating properties include those that have the following Formula I:
  • Rj is hydrogen or a lower alkyl
  • n is an integer of from 4 to 6
  • the cyclic ring is optionally substituted by lower alkyl or lower cycloalkyl, and the pharmaceutically acceptable salts thereof.
  • lower alkyl includes straight or branched chain alkyl groups of up to eight carbon atoms.
  • An especially preferred embodiment utilizes a compound of Formula I where Rj is hydrogen and n is 5, which compound is l-(aminomethyl)-cyclohexane acetic acid, known generically as gabapentin.
  • cyclic ring is substituted for example with alkyl such as methyl or ethyl
  • alkyl such as methyl or ethyl
  • preferred compounds of Formula I above, wherein the cyclic ring is substituted for example with alkyl such as methyl or ethyl include, but are not limited to (l-aminomethyl-3-methylcyclohexyl)acetic acid, (1-aminomethyl- 3-methylcyclopentyl)acetic acid, and (l-aminomethyl-3,4-dimethylcyclopentyl)- acetic acid.
  • antiepileptics having pain alleviating properties include those that are included in Formula II:
  • K ⁇ ⁇ is a straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or cycloalkyl having from 3 to 6 carbon atoms;
  • Rj2 1S hydrogen or methyl;
  • R ⁇ 3 is hydrogen, methyl, or carboxyl; or an individual diastereomeric or enantiomeric isomer thereof; or a pharmaceutically acceptable salt thereof.
  • the most preferred compound of Formula II is where R ⁇ 2 and Rj3 are both hydrogen, and Rj ⁇ is -(CH2) ⁇ -2"iC4H ⁇ . as an ( R), (S), or (R,S) isomer.
  • a more preferred embodiment of the invention utilizes 3-aminomethyl-5-methyl- hexanoic acid, and especially (S)-3-(aminomethyl)-5-methylhexanoic acid, now known generically as pregabalin.
  • Pregabalin is also known as "CI-1008" and "S-(+)-IBG.”
  • Another preferred compound is 3-(l-aminoethyl)-5-methylhexanoic acid.
  • Another preferred embodiment of the present invention includes an antiepileptic compound having pain alleviating properties of Formula
  • IIIG IIIH armaceutically acceptable salt thereof wherein: n is an integer of from 0 to 2; m is an integer of from 0 to 3; R is sulfonamide, amide, phosphonic acid, heterocycle, sulfonic acid, or hydroxamic acid; A' is a bridged ring selected from
  • Z ⁇ to Z4 are each independently selected from hydrogen and methyl; o is an integer of from 1 to 4; and p is an integer of from 0 to 2.
  • R cannot be sulfonic acid when m is 2 and n is 1 (Suman-Chaulan N. et al., European Journal of Pharmacology, 1993;244:293-301).
  • Another preferred embodiment of the present invention includes a compound of Formula III, IIIC, IIIF, IIIG, or IIIH selected from:
  • Another preferred embodiment of the present invention includes a compound of Formula III, IIIC, IIIF, IIIG, or IIIH, wherein preferred compounds are those wherein R is a sulfonamide selected from -NHSO2R ⁇ or -SO2NHR ⁇ wherein Ri 5 is straight or branched alkyl or trifluoromethyl.
  • Another preferred embodiment of the present invention includes a compound of Formula III, IIIC, IIIF, IIIG, or IIIH, wherein especially preferred is N-[2-(l-aminomethyl-cyclohexyl)-ethyl]-methanesulfonamide.
  • Another preferred embodiment of the present invention includes a compound of Formula III, IIIC, IIIF, IIIG, or IIIH, wherein other preferred compounds are those wherein R is a phosphonic acid, -PO3H2.
  • Another preferred embodiment of the present invention includes a compound of Formula III, IIIC, IIIF, IIIG, or IIIH, wherein especially preferred are (1 -aminomethyl-cy clohexy lmethy l)-phosphonic acid and (2-aminomethyl- 4-methyl-pentyl)-phosphonic acid.
  • Another preferred embodiment of the present invention includes a compound of Formula III, IIIC, IIIF, IIIG, or IIIH, wherein other preferred compounds are those wherein R is a heterocycle selected from:
  • Another preferred embodiment of the present invention includes a compound of Formula III, IIIC, IIIF, IIIG, or IIIH, wherein especially preferred are C-[l-(lH-tetrazol-5-ylmethyl)cyclohexyl]-methylamine and 4-methyl-2- (lH-tetrazol-5-ylmethyl)-pentylamine.
  • An especially preferred embodiment of the present invention includes a compound of Formula III wherein: m is an integer of from 0 to 2; p is an integer of 2; and
  • Ri is hydrogen, straight or branched alkyl of from 1 to 6 carbon atoms or phenyl
  • R2 is straight or branched alkyl of from 1 to 8 carbon atoms, straight or branched alkenyl of from 2 to 8 carbon atoms, cycloalkyl of from 3 to 7 carbon atoms, alkoxy of from 1 to 6 carbon atoms,
  • Ri is straight or branched alkyl of from 1 to 6 carbon atoms or phenyl when R ⁇ is methyl.
  • Ri is hydrogen, and R ⁇ is alkyl.
  • Another preferred embodiment includes a compound of Formula IV wherein Ri is methyl, and R ⁇ is alkyl. Still another preferred embodiment includes a compound of Formula IV wherein R* is methyl, and R ⁇ is methyl or ethyl.
  • (3S,5R)-3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid Preferred is a combination of the invention comprising an endothelin antagonist that antagonizes both the ET ⁇ and ET ⁇ receptor subtypes. Preferred is a combination of the invention comprising an endothelin antagonist that is selective for the ET ⁇ receptor subtype.
  • R a and R c are each 1 to 5 substituents and Rfo is from 1 to 4 substituents independently selected from: hydrogen, alkyl of from 1 to 7 carbons, alkenyl of from 2 to 7 carbons, alkynyl of from 2 to 7 carbons, cycloalkyl of from 3 to 8 carbons, phenyl, C(O)-phenyl, methylenedioxy, ethylenedioxy, OR, NRR l 5 SRi, NO 2 , N 3 , COR, CO 2 R,
  • R and R ⁇ axe each independently selected from hydrogen, alkyl of from 1 to 6 carbon atoms, alkenyl of from 2 to 7 carbon atoms, alkynyl of from 2 to 7 carbon atoms, cycloalkyl of from 3 to 8 carbon atoms, phenyl or benzyl wherein the phenyl or benzyl ring is substituted by one or more hydrogen, methoxy, and methylenedioxy substituents;
  • R d is H, CO 2 R, SO 3 R, PO3R, B(OH) 2 , CONRRi, SO 2 NRR ⁇ , C(O)NHSO 2 R ⁇ ,
  • X is (CH 2 ) n , O, NR, or S(O) n .
  • n 0 to 4.
  • R a is hydrogen, alkyl of 1-4 carbon atoms or cycloalkyl, phenyl or naphthyl, in which the phenyl or naphthyl group is substituted by methylenedioxy and further unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, OR,
  • R ⁇ is as defined above and R2 is hydrogen, alkyl of 1-6 carbon atoms, CF3, -CF2CF3, phenyl or benzyl in which phenyl or the phenyl portion of the benzyl group is unsubstituted or substituted by one or more substituents as defined above;
  • Re is S(O)p-phenyl, in which p is 0, 1 or 2, and phenyl is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, OR, NRR 1 , SR, NO 2 , N3, COR, CO 2 R, CONRR 1 , SO2NRR 1 , SO 2 R, CN, CF 3 , CF 2 CF 3 , CHO, OCOCH3.
  • B(OH) 2 methylenedioxy, NH(CH 2 ) m CO 2 R, S(CH 2 ) m CO R, O(CH 2 ) m CO 2 R,
  • the endothelin receptor antagonist is 4-(7-ethyl-l,3-benzodioxol-5-yl)-2- [2-(trifluoromethyl)phenyl]-2H-l ,2-dihydro-l ,2-benzothiazine-3 -carboxylic acid, 1,1-dioxide, or a pharmaceutically acceptable salt thereof.
  • the endothelin receptor antagonist is 4-(7-ethyl-l,3-benzodioxol-5-yl)-2- [2-(trifluoromethyl)phenyl] -2H- 1 ,2-dihydro- 1 ,2-benzothiazine-3 -carboxylic acid, 1,1-dioxide, potassium salt.
  • the endothelin receptor antagonist is 4-(3,5-dimethyl-phenyl)-l,l-dioxo-2-(2- trifluoromethyl-phenyl)- 1 ,2-dihydro-l ⁇ -benzo [e] [ 1 ,2]thiazine-3 -carboxylic acid, or a pharmaceutically acceptable salt thereof.
  • the endothelin receptor antagonist is 4-(3,5-dimethyl-phenyl)-l,l-dioxo-2-(2- trifluoromethyl-phenyl)- 1 ,2-dihydro- 1 ⁇ -benzo [e] [1 ,2]thiazine-3 -carboxylic acid.
  • This compound is also known as 4-(7-ethyl-benzo[l,3]dioxol-5-yl)-l,l- dioxo-2-(2 -trifluoromethyl-phenyl)- 1 ,2-dihydro- 1 ⁇ -benzofe] [ 1 ,2]thiazine-3 - carboxylic acid, potassium salt.
  • endothelin antagonist is selected from:
  • the combination is comprised of compounds of Formula I, II, or III.
  • the combination will contain the compound gabapentin, pregabalin, or 3-(l-aminomethyl-cyclohexylmethyl)-4H-[l,2,4]oxadiazol-5-one hydrochloride.
  • the antiepileptic compounds having pain alleviating properties is gabapentin and pregabalin.
  • the endothelin receptor antagonist is selected from: 4-(3 ,5-Dimethyl-phenyl)- 1 , 1 -dioxo-2-(2-trifluoromethyl-phenyl)- 1 ,2- dihydro- 1 ⁇ -benzo [e] [ 1 ,2]thiazine-3 -carboxylic acid;
  • the endothelin receptor antagonist is 4-(7-ethyl-l,3-benzodioxol-5-yl)-2-[2- (trifluoromethyl)phenyl]-2H-l ,2-dihydro-l ,2-benzothiazine-3 -carboxylic acid, 1,1-dioxide, potassium salt, and the analgesic is an antiepileptic compound having pain alleviating properties named gabapentin.
  • the endothelin receptor antagonist is 4-(7-ethyl-l,3-benzodioxol-5-yl)-2-[2- (trifluoromethyl)phenyl]-2H- 1 ,2-dihydro-l ,2-benzothiazine-3 -carboxylic acid, 1,1-dioxide, potassium salt, and the analgesic is an antiepileptic compound having pain alleviating properties named pregabalin.
  • the endothelin receptor antagonist is 4-(7-ethyl-l,3-benzodioxol-5-yl)-2-[2- (trifluoromethyl)phenyl]-2H-l,2-dihydro-l,2-benzothiazine-3-carboxylic acid, 1,1-dioxide, potassium salt
  • the analgesic is an antiepileptic compound having pain alleviating properties named 3-(l-aminomethyl-cyclohexylmethyl)-4H- [l,2,4]oxadiazol-5-one hydrochloride.
  • endothelin receptor antagonist is selected from:
  • Pentazocine Nalbuphine; Butorphanol; Hydromorphone; and Naloxone.
  • Preferred is a novel combination of a pain alleviating effective amount of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and from 1 to 3 compounds independently selected from the group consisting of antiepileptic compounds having pain alleviating properties and analgesics, and pharmaceutically acceptable salts thereof, wherein the analgesic is a nonopioid analgesic.
  • Preferred is a novel combination of the invention wherein the analgesic is an NSAID.
  • analgesic is an NSAID selected from: Naproxen; Naproxen sodium;
  • Ibuprofen Acetaminophen; Aspirin; Sulindac; Tolmetin;
  • Piroxicam Mefenamic acid; Phenylbutazone; Fenoprofen; Ketoprofen;
  • 2-imino-4-thiazolidinone methanesulfonate (1:1). Still more preferred is a novel combination of the invention wherein the endothelin receptor antagonist is selected from: 4-(3 ,5-Dimethyl-phenyl)- 1 , 1 -dioxo-2-(2-trifluoromethyl-phenyl)- 1 ,2- dihydro- 1 ⁇ -benzo [e] [ 1 ,2]thiazine-3 -carboxylic acid;
  • Acetaminophen Aspirin; Sulindac; Tolmetin; Piroxicam;
  • Mefenamic acid Phenylbutazone; Fenoprofen; Ketoprofen; Suprofen;
  • analgesic is an NMDA receptor antagonist. More preferred is a novel combination of the invention wherein the analgesic is an NMDA receptor antagonist selected from: lH-Indole-2-carboxylic acid, 4,6-dichloro-3-[3-oxo-3-(phenylamino)-
  • endothelin receptor antagonist is selected from:
  • 4-(7-Ethyl-l,3-benzodioxol-5-yl)-2-[2-(trifluoromethyl)phenyl]-2H-l,2- dihydro-l,2-benzothiazine-3 -carboxylic acid, 1,1-dioxide, potassium salt and the analgesic is an NMDA receptor antagonist nonopioid analgesic selected from: lH-Indole-2-carboxylic acid, 4,6-dichloro-3-[3-oxo-3-(phenylamino)- 1-propenyl]-, (E)- (GV- 150526);
  • analgesic is an NKj receptor antagonist. More preferred is a novel combination of the invention wherein the analgesic is an N j receptor antagonist named:
  • endothelin receptor antagonist is selected from:
  • Preferred is a novel combination of a pain alleviating effective amount of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and from 1 to 3 compounds independently selected from the group consisting of antiepileptic compounds having pain alleviating properties and analgesics, and pharmaceutically acceptable salts thereof, wherein one compound is an antiepileptic compound having pain alleviating properties and one compound is an analgesic. More preferred is a novel combination of the invention wherein one compound is an antiepileptic compound having pain alleviating properties and one compound is an opioid analgesic.
  • the endothelin receptor antagonist is selected from: 4-(3 ,5-Dimethyl-phenyl)- 1 , 1 -dioxo-2-(2-trifluoromethyl-phenyl)- 1 ,2- dihydro- 1 ⁇ -benzo [e] [ 1 ,2]thiazine-3 -carboxylic acid,
  • the antiepileptic compound having pain alleviating properties is selected from gabapentin, pregabalin, and 3 -(1 -aminomethy 1-cyclohexy lmethy 1)-4H- [l,2,4]oxadiazol-5-one hydrochloride; and the analgesic is a nonopioid analgesic selected from: Codeine;
  • Morphine Hydromorphone; Levorphanol; Methadone; Oxycodone; Hydrocodone; Pentazocine;
  • Nalbuphine Butorphanol; Hydromorphone; and Naloxone. More preferred is a novel combination of the invention wherein one compound is an antiepileptic compound having pain alleviating properties and one compound is a nonopioid analgesic.
  • endothelin receptor antagonist is selected from: 4-(3,5-Dimethyl-phenyl)-l,l-dioxo-2-(2-trifluoromethyl-phenyl)-
  • the antiepileptic compound having pain alleviating properties is selected from gabapentin, pregabalin, and 3 -(1-aminomethyl-cyclohexy lmethy 1)-4H- [l,2,4]oxadiazol-5-one hydrochloride; and the analgesic is a nonopioid analgesic selected from: Naproxen;
  • Naproxen sodium Ibuprofen; Acetaminophen; Aspirin; Sulindac;
  • (lS,2S)-l-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidine)- 1-propanol Preferred is a novel combination of a pain alleviating effective amount of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof and from 1 to 3 compounds independently selected from the group consisting of antiepileptic compounds having pain alleviating properties and analgesics, and pharmaceutically acceptable salts thereof, wherein one compound is an opioid analgesic and one compound is a nonopioid analgesic.
  • endothelin receptor antagonist is selected from:
  • nonopioid analgesic is selected from:
  • Another embodiment of the present invention is a pharmaceutical composition, comprising a pain alleviating effective amount of a combination of an endothelin antagonist, or a pharmaceutically acceptable salt thereof, and from 1 to 3 compounds independently selected from the group consisting of antiepileptic compounds having pain alleviating properties and analgesics, and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • Another embodiment of the present invention is a method of treating pain in a mammal suffering therefrom, comprising administering a pain alleviating effective amount of a combination of an endothelin antagonist, or a pharmaceutically acceptable salt thereof, and from 1 to 3 compounds independently selected from the group consisting of antiepileptic compounds having pain alleviating properties and analgesics, and pharmaceutically acceptable salts thereof.
  • an endothelin receptor antagonist which is 4-(7-ethyl- 1 ,3 -benzodio
  • an endothelin receptor antagonist which is 4-(7-ethyl-l,3-benzodioxol-5-
  • an endothelin receptor antagonist which is 4-(7-ethyl-l,3-benzo
  • Another embodiment of the present invention is a method of treating pain in a mammal suffering therefrom, comprising administering a pain alleviating effective amount of a pharmaceutical composition which comprises an endothelin antagonist, or a pharmaceutically acceptable salt thereof, and from 1 to 3 compounds independently selected from the group consisting of antiepileptic compounds having pain alleviating properties and analgesics, and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • a pharmaceutical composition which comprises an endothelin antagonist, or a pharmaceutically acceptable salt thereof, and from 1 to 3 compounds independently selected from the group consisting of antiepileptic compounds having pain alleviating properties and analgesics, and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • Figure 1 illustrates dose-response curves for gabapentin administered alone and the compound of formula (1) administered alone, expressed as the Pain Withdrawal Threshold (PWT) in grams of force of von Frey hairs measured at 1-hour postdose (the time point at which peak activity for each compound is observed), versus oral dose of compound administered in milligrams of compound per kilogram of rat body weight.
  • PWT Pain Withdrawal Threshold
  • Figure 2 illustrates the dose-response curves for a combination of gabapentin and the compound of formula (1) administered at a 1 :1 ratio
  • FIG. 1 illustrates the dose-response curves for a combination of gabapentin and the compound of formula (1) administered at a 3:1 ratio (weight/weight), respectively, expressed as the PWT in grams of force of von Frey hairs versus total oral dose of the combination administered in total milligrams of the combination per kilogram of body weight, and the dose-response curves of Figure 1.
  • Figure 3 illustrates the dose-response curves for a combination of gabapentin and the compound of formula (1) administered at a 3:1 ratio (weight/weight), respectively, expressed as the PWT in grams of force of von Frey hairs versus total oral dose of the combination administered in total milligrams of the combination per kilogram of body weight, and the dose-response curves of Figure 1
  • Figure 4 illustrates the dose-response curves for a combination of gabapentin and the compound of formula (1) administered at a 10:1 ratio (weight/weight), respectively, expressed as the PWT in grams of force of von F ⁇ -r_ecy hairs versus total oral dose of the combination administered in total milligrams of the combination per kilogram of body weight, and the dose-response curves of Figure 1.
  • the present invention is directed to novel combinations effective for alleviating pain comprising a pain alleviating effective amount of an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof, and one or two compounds selected from the group consisting of antiepileptic compounds having pain alleviating properties and analgesics, and to methods of treating or alleviating pain comprising administering effective amounts of said combinations to a mammal, including a human, in need of said treatment.
  • the invention also is directed to pharmaceutical compositions comprising said combinations.
  • a single endothelin receptor antagonist is combined with a single compound selected from the group consisting of antiepileptic compounds having pain alleviating properties, opioid analgesics, or nonopioid analgesics including NS AIDs, NMDA receptor antagonists, and NKj receptor antagonists.
  • Preferred combinations include, but are not limited to,
  • ET antagonist/opioid ET antagonist/morphine
  • ET antagonist/hydrocodone ET antagonist/oxycodone
  • ET antagonist/ibuprofen ET antagonist/naproxen
  • ET antagonist acetaminophen ET antagonist/gabapentin
  • ET antagonist/ pregabalin and ET antagonist/3 -( 1-aminomethyl-cyclohexy lmethy 1)-4H- [1 ,2,4]oxadiazol-5-one hydrochloride.
  • a single endothelin antagonist is combined with two or three, preferably two, compounds selected from the group consisting of NS AIDs, opioid analgesics, NMDA receptor antagonists, ,NK ⁇ receptor antagonists, or combinations thereof. While any endothelin antagonist disclosed herein can be combined with any two or three compounds selected from NSAID, opioid analgesic, NMDA receptor antagonists, NKi receptor antagonists, or combinations thereof, the preferred ET receptor antagonists are:
  • Preferred combinations include, but are not limited to, 4-(3 ,5-Dimethyl-phenyl)- 1 , 1 -dioxo-2-(2-trifluoromethyl-phenyl)- 1 ,2- dihydro-l ⁇ 6-benzo[e][l,2]thiazine-3-carboxylic acid/opioid/NSAID;
  • Preferred combinations include, but are not limited to, 4-(3 ,5 -Dimethyl-phenyl)- 1 , 1 -dioxo-2-(2-trifluoromethy 1-phenyl)- 1 ,2- dihydro-l ⁇ 6-benzo[e][l,2]thiazine-3-carboxylic acid/morphine/ibuprofen;
  • Preferred combinations include, but are not limited to,
  • Preferred combinations include, but are not limited to, 4-(3 ,5-Dimethyl-phenyl)- 1 , 1 -dioxo-2-(2-trifluoromethyl-phenyl)- 1 ,2- dihydro- 1 ⁇ -benzo[e] [ 1 ,2]thiazine-3 -carboxylic acid/oxycodone/acetaminophen; 4-(7-Ethyl-l,3-benzodiozol-5-yl)-2-[2-(trifluoromethyl)phenyl]-2H-l,2- dihydro- 1 ,2-benzothiazine-3 -carboxylic acid, 1 , 1 -dioxide/oxycodone/ acetaminophen; and
  • Preferred combinations include, but are not limited to,
  • Preferred combinations include, but are not limited to, 4-(3 ,5 -Dimethyl-phenyl)- 1 , 1 -dioxo-2-(2-trifluoromethyl-phenyl)- 1 ,2- dihydro- l ⁇ 6-benzo[e][l,2]thiazine-3-carboxylic acid/gabapentin or pregabalin/ hydrocodone;
  • Preferred combinations include, but are not limited to, 4-(3 ,5 -Dimethyl-phenyl)- 1 , 1 -dioxo-2-(2-trifluoromethyl -phenyl)- 1 ,2- dihydro- l ⁇ 6-benzo[e][ l,2]thiazine-3 -carboxy lie acid/gabapentin or pregabalin/oxyc ' odone; 4-(7-Ethyl- 1 ,3-benzodiozol-5-yl)-2-[2-(trifluoromethyl)phenyl]-2H- 1 ,2- dihydro- 1,2 -benzothiazine-3 -carboxylic acid, 1,1-dioxide/gabapentin or pregabalin/oxycodone; and
  • Preferred combinations include, but are not limited to, 4-(3,5-Dimethyl-phenyl)-l,l-dioxo-2-(2-trifluoromethyl-phenyl)-
  • Preferred combinations include, but are not limited to, 4-(3 ,5-Dimethyl-phenyl)- 1 , 1 -dioxo-2-(2-trifluoromethyl-phenyl)- 1 ,2- dihydro- l ⁇ 6-benzo[e][l, 2]thiazine-3 -carboxylic acid/gabapentin or pregabalin/ ibuprofen;
  • Preferred combinations include, but are not limited to, 4-(3 ,5-Dimethyl-phenyl)- 1 , 1 -dioxo-2-(2-trifluoromethyl-phenyl)- 1 ,2- dihydro- l ⁇ "-benzo[e][l, 2]thiazine-3 -carboxy lie acid/gabapentin or pregabalin/ naproxen; 4-(7-Ethyl-l,3-benzodiozol-5-yl)-2-[2-(trifluoromethyl)phenyl]-2H-l,2- dihydro-l,2-benzothiazine-3-carboxylic acid, 1,1-dioxide/gabapentin or pregabalin/naproxen; and
  • two or more antiepileptic compounds having pain alleviating properties are combined with an endothelin receptor antagonist and optionally NSAIDs, NMDA receptor antagonists, or NKj receptor antagonists, or combinations thereof.
  • any antiepileptics herein can be combined with any endothelin receptor antagonist and optionally with one or more compounds selected from NSAIDs, NMDA receptor antagonists, or NKj receptor antagonists, or combinations thereof
  • the preferred antiepileptic compounds having pain alleviating properties are chosen from the compounds of Formulas I, II, and III
  • the preferred ET antagonists are chosen from the compounds of Formulas V and VI.
  • Preferred combinations include, but are not limited to, gabapentin pregabalin/ET antagonist, gabapentin/pregabalin/ ET antagonist/NSAID, gabapentin/pregabalin/naproxen/ET antagonist, and gabapentin/pregabalin/ET antagonist/opioid. Any of the combinations disclosed herein can be used for treatment. The types of treatable pain experienced by mammals is varied and known to medical practitioners.
  • Nonlimiting examples of mammalian pain include centrally mediated pain, peripherally mediated pain, structural or soft tissue injury related pain, progressive disease related pain (i.e., oncology) and neuropathic pain states, all of which would include both acute (i.e., acute injury or trauma, pre- and postsurgical, headache such as a migraine), chronic (i.e., neuropathic pain conditions such diabetic peripheral neuropathy and posthepatic neuralgia), and inflammatory condition (i.e., osteo- or rheumatoid arthritis, sequela to acute injury or trauma) pain states.
  • acute i.e., acute injury or trauma, pre- and postsurgical, headache such as a migraine
  • chronic i.e., neuropathic pain conditions such diabetic peripheral neuropathy and posthepatic neuralgia
  • inflammatory condition i.e., osteo- or rheumatoid arthritis, sequela to acute injury or trauma
  • Nonlimiting examples of mammalian pain being treated are centrally mediated pain, peripherally mediated pain, structural or soft tissue pain, injury- related pain, progressive disease-related pain, or neuropathic pain.
  • Pain states include both acute (e.g., acute injury or trauma, pre- and postsurgical, headache such as migraine), chronic (e.g., pain from cancer, neuropathic pain conditions such as diabetic peripheral neuropathy and posthepatic neuralgia), and inflammatory conditions (e.g., osteo- or rheumatoid arthritis, sequela to acute injury or trauma).
  • mammal includes a human, dog, cat, cow, sheep, pig, and horse.
  • the phrase “effective amount” means the amount of a combination of the present invention that is effective for alleviating pain in a mammal suffering therefrom.
  • the phrase “therapeutically effective amount,” as used herein, means the same as the phrase “effective amount.”
  • co-administration is meant to include the administration of endothelin receptor antagonists before, during, or after administration of compounds selected from the group consisting of antiepileptics that demonstrate pain alleviating properties such as gabapentin and pregabalin, opioid analgesics, or nonopioid analgesics including NSAIDs, NMDA receptor antagonists, or NKj receptor antagonists.
  • One advantage of using the novel combinations described herein is the reduced severity and/or frequency of pain.
  • Another potential advantage is the overall improvement in pain control, which can include a reduction in the dosage and unwanted side effects in comparison to using higher doses of a single agent treatment to achieve a similar therapeutic effect.
  • the present invention is valuable because combination approaches to pain alleviation take advantage of the unique properties and mechanisms of action of two or more different drugs.
  • endothelin antagonists alleviate pain by a novel mechanism of action.
  • An endothelin antagonist, an antiepileptic compound having pain alleviating properties, and an analgesic each independently contribute to pain alleviating activity by distinct mechanisms of action, so a combination of an endothelin antagonist with one or more drugs selected from the group consisting of antiepileptic compound having pain alleviating properties and analgesics will be more effective at the same doses than any single drug administered by itself (i.e., show a synergistic effect).
  • endothelin receptor antagonist as used in this invention may be used interchangeably with the phrases endothelin antagonist or ET antagonist and are taken to mean the same.
  • a preferred endothelin receptor antagonist is 4-(7-ethyl-l ,3-benzodiozol-5-yl)-2-[2-(trifluoromethyl)phenyl]- 2H-1 ,2-dihydro- 1 ,2-benzothiazine-3 -carboxylic acid, 1,1-dioxide, and pharmaceutically acceptable salts thereof.
  • a preferred pharmaceutically acceptable salt thereof is the potassium salt.
  • Another preferred endothelin receptor antagonist is 4-(3 ,5-dimethyl-phenyl)- 1 , 1 -dioxo-2-(2-trifluoromethyl-phenyl)- l,2-dihydro-l ⁇ 6-benzo[e][l,2]-thiazine-3-carboxylic acid, and pharmaceutically acceptable salts thereof.
  • Analgesics used in this invention can be, for example, opioid analgesics or nonopioid analgesic compounds.
  • Nonopioid analgesics are generally defined to be those compounds that relieve pain without binding to opioid receptors.
  • Nonlimiting examples of nonopioid analgesics include NSAIDs such as acetaminophen, NMDA receptor antagonists, and NK ⁇ receptor antagonists.
  • Nonopioid analgesics are typically nonaddictive.
  • Nonlimiting examples of clinically validated analgesics include the following:
  • Opiate mu receptor agonists Opiate mu receptor agonists; Cyclooxygenase-2 (COX-2) inhibitors;
  • Sodium (Na+) channel blockers e.g., PN3, SNS, brain type III, SCN10A, and SCN3A;
  • Voltage-gated Calcium (Ca + 2) channel antagonists e.g., CACNA1B, CACNA1 A, and CACNA1E;
  • Alpha-2-adrenoceptor agonists and 5-HT1 A receptor antagonists.
  • preclinically validated analgesics include the following:
  • Cannabinoid receptor antagonists MAP kinase enzyme cascade inhibitors (e.g., MEK inhibitors);
  • GluR5 KA receptor antagonists mGluRl and mGluR5 receptor (Group I metabotrophic glutamate receptors) antagonists;
  • Muscarinic M4 and Mj receptor antagonists Muscarinic M4 and Mj receptor antagonists; Prostaglandin PGE2 (P ) receptor antagonists;
  • Opiate delta receptor agonists Opiate delta receptor agonists; and Adenosine kinase inhibitors.
  • Opioid analgesics are generally defined to be those compounds that relieve pain and bind to opioid receptors.
  • Opioid agonists and opioid agonist-antagonists are opioid analgesics and are addictive when administered to treat a mammal for pain.
  • Opioid antagonists are nonaddictive.
  • Nonlimiting examples of opioid analgesics include opiates, opiate derivatives, opioids, and their pharmaceutically acceptable salts.
  • opioid agonist analgesics include alfentanyl, alphaprodine, anileridine, bezitramide, codeine, dihydrocodeine, diphenoxylate, ethylmorphine, fentanyl, heroin, hydrocodone, hydromorphone, isomethadone, levomethorphan, morphine, neperidine, oxycodone, phenomorphan, phenoperidine, piritradide, pholcodine, proheptazoine, properidine, propiran, racemoramide, thebacon, trimeperidine, and the pharmaceutically acceptable salts thereof.
  • opioid agonist-antagonist analgesics include pentazocine, butorphanol, nalbuphine, buprenorphine, and the pharmaceutically acceptable salts thereof.
  • opioid antagonist analgesics include naloxone, naltrexone, and the pharmaceutically acceptable salts thereof.
  • neurokinin 1 receptor antagonist means nontoxic compounds that block or interfere with binding to the NK j receptor subtype.
  • NKj receptor antagonists that can be used herein are disclosed in United States Patent No. 5,594,022.
  • a more preferred NKj receptor antagonist is [2-(lH-indol-3-yl)-l-methyl-l-(l-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzofuran-2-ylmethyl ester.
  • N-methyl-D-aspartate receptor shall be understood to include all of the binding site subcategories associated with the NMDA receptor, e.g., the glycine-binding site, the phencyclidine (PCP)-binding site, etc., as well as the NMDA channel.
  • the invention herein contemplates the use of nontoxic substances that block or interfere with an NMDA receptor binding site.
  • NMDA receptor antagonists which can be used in the novel combinations are compounds that block or reduce the effects of NMDA at the NMDA subclass of neuronal glutamate receptors (nonlimiting examples include dextrorphan, dextromethorphan, and ketamine) or that block or interfere with the NMDA channel (e.g., a substance that blocks the magnesium or calcium channel).
  • the NMDA receptor antagonist is one which is specific for a subtype of NMDA receptor, those containing the NR2B subunit which are expressed in the forebrain (nonlimiting examples include
  • NMDA receptor antagonists acting at other sites of an NMDA receptor include, but are not limited to lH-indole-2-carboxylic acid, 4,6-dichloro-3-[3-oxo- 3-(phenylamino)-l-propenyl]-, (E)- (GV-150526) (a compound in preclinical development by Glaxo Wellcome), 1 -piperidineethanol, .alpha.-
  • NSAID as used to describe other compounds useful in the novel combination herein, is intended to be a nonsteroidal anti-inflammatory compound. NSAIDs are categorized by virtue of their ability to inhibit cyclooxygenase. Cyclooxygenase 1 and cyclooxygenase 2 are the two major isoforms of cyclooxygenase and most standard NSAIDs are mixed inhibitors of the two isoforms.
  • NSAIDs fall within one of the following five structural categories: (1) propionic acid derivatives, such as ibuprofen, naproxen, naprosyn, diclofenac, and ketoprofen; (2) acetic acid derivatives, such as tolmetin and sulindac; (3) fenamic acid derivatives, such as mefenamic acid and meclofenamic acid; (4) biphenyl carboxylic acid derivatives, such as diflunisal and flufenisal; and (5) oxicams, such as piroxim, peroxicam, sudoxicam, and isoxican.
  • Other useful NSAIDs include aspirin, acetaminophen, indomethacin, and phenylbutazone.
  • NSAID selectively inliibits cyclooxygenase-2 (COX-2). These compounds reduce pain and inhibit the inflammatory response without damaging the gastric mucosa, a common toxicity observed with the mixed inhibitors.
  • CT 3 (Channel); GR 253035 (Glaxo Wellcome); N-[6-[(2,4-Difluorophenyl)thio]-2,3-dihydro- 1 -oxo- 1 H-inden- 5-yl]methanesulfonamide (L 745337); L 748731 (Merck & Co); L 752860 (Merck & Co); (R)- 1 -[(4-bromophenyl)methyl]-5-methoxy-beta,2-dimethyl-lH-indole-
  • SD 8381 (Searle); and their pharmaceutically acceptable salts are examples of selective cyclooxygenase 2 inhibitors.
  • antiepileptic compound means a pharmaceutically active compound that treats disorders characterized by recurring attacks of motor, sensory, or psychic malfunction with or without unconsciousness or convulsive movement.
  • antiepileptic compound having pain alleviating properties means an antiepileptic compound as defined above which also alleviates pain in a mammal, including a human.
  • Many antiepileptic compound having pain alleviating properties are known such as, for example, the structural analogs of gamma-aminobutyric acid (GABA) or glutamic acid. Examples are gabapentin, pregabalin, and 3-(l -aminomethyl-cyclohexylmethyl)-4H-[l ,2,4]oxadiazol-5-one hydrochloride.
  • Gabapentin has been shown to possess pain alleviating properties in animal models of inflammation and neuropathic pains, and in particular to block the maintenance of streptozotocin-induced static allodynia in the rat (Field et al., J. Pharmacol. Exp. Ther. 1997;282:1242-1246). Since determination of pain alleviating activity of an antiepileptic compound in an animal model of pain alleviation is well known in the pharmaceutical arts, it is a simple matter to test any antiepileptic compound for pain alleviating properties.
  • Nonlimiting examples of antiepileptics having pain alleviating properties include gabapentin, pregabalin, 3-(l -aminomethyl-cyclohexylmethyl)-4H-[l ,2,4]oxadiazol-5-one hydrochloride, carbamazepine, lamotrigine, phenytoin, fosphenytoin, and analogues thereof.
  • the combinations of this invention may include any GABA analog.
  • GABA analogs to be utilized in the method of this invention are cyclic amino acids of Formula I. These are described in United
  • GABA analogs are described in PCT International Application No. WO 99/31074.
  • GABA analogs are novel compounds of formula (1A) and (IB)
  • n is an integer of from 0 to 2;
  • R is sulfonamide, amide, phosphonic acid, heterocycle, sulfonic acid, or hydroxamic acid;
  • A is hydrogen or methyl; and straight or branched alkyl of from 1 to 11 carbons, or -(CH 2 )l-4-Y-(CH2)o-4-phenyl wherein Y is -O-, -S-, -NR' 3 wherein:
  • R'3 is alkyl of from 1 to 6 carbons, cycloalkyl of from 3 to 8 carbons, benzyl or phenyl wherein benzyl or phenyl can be unsubstituted or substituted with from 1 to 3 substituents each independently selected from alkyl, alkoxy, halogen, hydroxy, carboxy, carboalkoxy, trifluoromethyl, and nitro.
  • GABA analogs are described in PCT International Application No. WO 99/31057. Such GABA analogs are novel compounds of formula (ID) and (IE)
  • n is an integer of from 0 to 2;
  • R is sulfonamide, amide, phosphonic acid, heterocycle, sulfonic acid, or hydroxamic acid;
  • X is -O-, -S-, -S(O)-, -S(O)2-, or NR'i wherein R' ⁇ is hydrogen, straight or branched alkyl of from 1 to 6 carbons, benzyl, -C(O)R'2 wherein R'2 is straight or branched alkyl of 1 to 6 carbons, benzyl or phenyl or -CO2R'3 wherein R'3 is straight or branched alkyl of from 1 to 6 carbons, or benzyl wherein the benzyl or phenyl groups can be unsubstituted or substituted by from 1 to 3 substituents selected from halogen, trifluoromethyl, and nitro.
  • GABA analogs are described in PCT International Application No. WO 98/17627. Such GABA analogs are novel compounds of formula
  • R is hydrogen or lower alkyl
  • R ⁇ is hydrogen or lower alkyl
  • X is -O-, -S-, -NR3- wherein
  • R3 is alkyl of from 1 to 6 carbons, cycloalkyl of from 3 to 8 carbons, benzyl or phenyl; wherein phenyl and benzyl can be unsubstituted or substituted with from 1 to 3 substituents each independently selected from alkyl, alkoxy, halogen, hydroxy, carboxy, carboalkoxy, trifluoromethyl, amino, and nitro.
  • substituents each independently selected from alkyl, alkoxy, halogen, hydroxy, carboxy, carboalkoxy, trifluoromethyl, amino, and nitro.
  • Other preferred GABA analogs are described in PCT International
  • GABA analogs are novel compounds of formulas (1), (2), (3), (4), (5), (6), (7), and (8)
  • R to Rjo are each independently selected from hydrogen or a straight or branched alkyl of from 1 to 6 carbons, benzyl, or phenyl; m is an integer of from 0 to 3; n is an integer of from 1 to 2; o is an integer of from 0 to 3; p is an integer of from 1 to 2; q is an integer of from 0 to 2; r is an integer of from 1 to 2; s is an integer of from 1 to 3; t is an integer of from 0 to 2; and u is an integer of from 0 to 1.
  • International patent applications WO 99/31074, WO 99/31057, WO 98/17627, and WO 99/61424 are herein inco ⁇ orated by reference.
  • Antiepileptic compounds having pain alleviating properties such as gabapentin and pregabalin are alpha-2-delta (gabapentin receptor) antagonists.
  • pain alleviating properties is generally defined herein to include the expressions “pain-suppressing,” “pain-reducing,” and “pain- inhibiting” as the invention is applicable to the alleviation of existing pain, as well as the suppression or inhibition of pain which would otherwise ensue from an imminent pain-causing event.
  • gabapentin is extremely well-tolerated and has been demonstrated to be virtually free of drug interactions.
  • alkyl means a straight or branched hydrocarbon radical having from 1 to 12 carbon atoms unless otherwise specified and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, allyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, and dodecyl.
  • lower alkyl means a straight or branched chain alkyl group of from 1 to 8 carbon atoms unless otherwise specified and includes, for example, methyl ethyl, isobutyl, pentyl, 3,3-dimethylhexyl, and 2-ethylpentyl.
  • alkenyl means a straight or branched hydrocarbon radical having from 2 to 12 carbon atoms unless otherwise specified and having at least one double bond in the carbon atom chain and includes, for example, 1-ethene, 1-propene, 2-methyl-l-propene, 1-butene, 2-butene, 1-pentene, 2-pentene, 2-methyl-l-butene, 3 -methyl- 1-butene, 3-methyl-2-butene, 1-hexene, 1-heptene, 1-octene, 1-nonene, 1-decene, 1-undecene, 1-dodecene, and the like.
  • alkynyl means a straight or branched hydrocarbon radical having from 2 to 12 carbon atoms unless otherwise specified and having at least one triple bond in the carbon atom chain and includes, for example, 1-ethyne, 1-propyne, 1-butyne, 3 -methyl- 1-butyne, 1-pentyne, 2-pentyne, 1-hexyne, and the like.
  • cycloalkyl means a saturated hydrocarbon ring which contains from 3 to 12 carbon atoms unless otherwise specified, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl.
  • lower cycloalkyl means a saturated hydrocarbon ring which contains from 3 to 8 carbon atoms unless otherwise specified and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • "Halogen” is fluorine, chlorine, bromine, or iodine.
  • analgesics including compounds of Formulas I through VI, are capable of further forming nontoxic pharmaceutically acceptable acid addition and/or base salts. All of these forms are within the scope of the present invention.
  • Pharmaceutically acceptable acid addition salts of the analgesics, antiepileptics having pain alleviating properties, and endothelin antagonists related to the invention include salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like
  • organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids,
  • Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.
  • salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S.M. et al, "Pharmaceutical Salts,” Journal of Pharmaceutical Science 1977;66:1-19).
  • the acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.
  • Pharmaceutically acceptable base addition salts are formed with metal cations, such as alkali and alkaline earth metal cations or amines such as organic amines.
  • metals used as cations are sodium, potassium, magnesium, calcium, and the like.
  • suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example Berge S.M., Supra., 1977).
  • the base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.
  • Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • the solvated forms, including hydrated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
  • Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R or S configuration.
  • the present invention includes all enantiomeric and epimeric forms as well as the appropriate diastereomeric mixtures thereof.
  • Jarvis et al. is one method used to test the pain alleviating effects of the combinations of the instant invention and is hereby inco ⁇ orated by reference (Jarvis M.F., Wessale J.L., Zhu C.Z., et al., Eur. J. Pharmacol.
  • a method for testing the novel combinations of the invention for pain alleviating activity in patients suffering from static or dynamic allodynia — forms of diabetic peripheral neuropathy — is described in Field M.J., Hughes J., Singh L., Pain 1999;80:391-398, which is hereby inco ⁇ orated by reference.
  • Diabetes was induced by a single i.p. injection of streptozocin at a dose of 50 mg/kg. Control animals received a similar administration of isotonic saline.
  • Static allodynia was measured using Semmes-Weinstein von Frey hairs (Stoelting, Wood Dale, IL). The animals were habituated to wire mesh bottom cages prior to the start of the experiment. Static allodynia was evaluated by application of von Frey hairs in ascending order of force (0.7, 1.2, 1.5, 2, 3.6, 5.5, 8.5, 11.8, 15.1, and 29 g) to the plantar surface of the rat's right hind paw. Each von Frey hair was applied to the paw for 6 seconds, or until a withdrawal response occurred. Once a withdrawal response was established, the paw was retested, starting with the next descending von Frey hair until no response occurred. The highest force of 29 g lifted the paw, as well as elicited a response, and thus represented the cut off point. The lowest amount of force required to elicit a response was recorded as PWT in grams. 4. Evaluation of dynamic allodynia
  • the animals are habituated to wire mesh bottom cages prior to the start of the experiment. Care is taken to perform this procedure in fully habituated rats that are not active to avoid recording general motor activity. Dynamic allodynia is assessed by lightly stroking the plantar suface of the rat's right hind paw with a cotton bud. Latency to paw withdrawal is noted. At least three measurements are taken at each time point. If no reaction is exhibited within 15 seconds, the procedure is terminated, and animals are assigned this withdrawal time. Thus 15 seconds effectively respresents no withdrawal. A withdrawal response is often accompanied by repeated flinching or licking of the paw. Animals are only selected for drug studies if they exhibit a withdrawal time of 8 seconds or less. 5.
  • the antiallodynic potential of a compound administered alone was examined in streptozocin-treated animals once dynamic and static allodynia had developed.
  • Baseline paw withdrawal thresholds to von Frey hairs or paw withdrawal latencies to a cotton bud) were determined on each test day before drug administration.
  • animals were re-evaluated using von Frey hairs (or cotton bud) at 0.5, 1, 2, and up to 4 hours.
  • the antiallodynic potential of a combination of the invention was then determined at the time point postdose that was expected to show peak activity for the combination.
  • Streptozocin was purchased from Aldrich (UK). All compounds were dissolved in normal saline and administered orally. Drug administrations were made in a volume of 1 mL/kg.
  • Vehicle-treated animals find the cotton bud stimulus innocuous throughout the dynamic allodynia studies.
  • Vehicle-treated animals had consistent blood glucose levels, similar to baseline values, throughout the experiment.
  • Streptozocin-treated animals had elevated blood glucose values from the first day of testing, Day 4 post-streptozocin dose.
  • Gabapentin was administered orally alone at doses of 10, 30, or 100 mg/kg of rat body weight, and PWT was determined at 1 hour postdose, the time point of peak activity for this compound. The results are illustrated in Figure 1 with the line " -. TEST 2
  • the compound of formula (1) was administered orally alone at doses of 3,
  • EXAMPLE 1 A combination of gabapentin and the compound of formula (1) at a 1:1 ratio, respectively, was administered orally at total doses (dose of gabapentin + dose of the compound of formula (1) of 2 mg/kg (1 mg/kg + 1 mg/kg, respectively), 6 mg/kg (3 mg/kg + 3 mg/kg, respectively), 20 mg/kg (10 mg/kg +
  • PWT was determined at 1 hour postdose. The results are illustrated in Figure 3 with the line ⁇ Bh. For comparison pu ⁇ oses, the results from Tests 1 and 2 are also illustrated in Figure 3.
  • Tests 1 and 2 and Examples 1 through 3 are illustrated in Figures 1 through 4 as described above. All data illustrated in the figures were determined at 1 hour postdose.
  • Figure 1 a dose-response curve for gabapentin administered alone shows that at a dose of 10 mg/kg, gabapentin had little or no effect on static allodynia, while at doses of 30 and 100 mg/kg, gabapentin effected essentially a complete reversal of static allodynia.
  • FIG. 1 Also in Figure 1 is a dose-response curve for the compound of formula (1) administered alone. This curve shows that at a dose of 3 mg/kg, the compound of formula (1) had little or no effect on static allodynia, while at doses of 10 and 30 mg/kg, the compound of formula (1) effected a partial (about 50%) reversal of static allodynia.
  • a dose-response curve for a combination of gabapentin and the compound of formula ( 1 ) administered at a ratio of 1 : 1 (weight: weight), respectively shows that at a total dose of 2 or 6 mg/kg, the combination had little or no effect on static allodynia, while at total doses of 20 or 40 mg/kg, the combination effected partial reversal of static allodynia. Also in Figure 2 for comparison pu ⁇ oses are the dose-response curves described for Figure 1.
  • a dose-response curve for a combination of gabapentin and the compound of formula (1) administered at a ratio of 3:1 (weigh weight), respectively shows that at a total dose of 4 mg/kg, the combination had little or no effect on static allodynia, while at total doses of 12 or 28 mg/kg, the combination effected partial reversal of static allodynia. Further at a total dose of 40 mg/kg, this combination effected a complete reversal of static allodynia. Also in Figure 3, for comparison pu ⁇ oses, are the dose-response curves described for Figure 1.
  • a dose-response curve for a combination of gabapentin and the compound of formula (1) administered at a ratio of 10:1 (weight: weight), respectively shows that at a total dose of 11 mg/kg, the combination had little or no effect on static allodynia, while at a total dose of 33 mg/kg, the combination effected partial reversal of static allodynia.
  • Figure 4 for comparison pu ⁇ oses are the dose-response curves described for Figure 1.
  • rat carrageenan-induced thermal hyperalgesia model may be used to determine pain alleviating effects as follows. Animals
  • Rats Male Sprague-Dawley rats (200-250 g, Sasco Laboratories) are used. Rats are group housed 5/cage on a 12-hour ligh dark cycle with free access to food and water. Rats receive only one dose of a drug or drug combination. All drugs are administered orally by gavage.
  • Dose-effect curves are first determined for (1) an endothelin antagonist by itself, (2) antiepileptic compound having pain alleviating properties by itself, and/or (3) an analgesic (e.g., naproxen) by itself.
  • the ED50 value and 95% confidence limits of each agent is determined, as is the time to peak effect.
  • dose effect curves are generated for the endothelin antagonist administered in a fixed dose ratio with the antiepileptic compound having pain alleviating properties and/or the analgesic; the drugs are administered so that their peak effects are coincident.
  • ED50 values and 95% confidence limits are then determined for the drugs in combination.
  • Carrageenan-induced thermal hyperalgesia Rats are acclimated to a testing chamber whose glass floor is maintained at 25°C. Thirty minutes later, a high intensity beam of light is focused through the glass on the ventral surface of each hindpaw, and the latency to reflex withdrawal of the paw from the light beam is measured to the nearest 0.1 second. This latency is termed the paw flick latency (PFL). Two measurements of PFL spaced 20 minutes apart are made for each paw, and the second measurement is taken as the baseline response latency. After determination of baseline PFL, 100 ⁇ L of 2% lambda-carrageenan is injected in the plantar surface of one hindpaw and the animal is returned to the testing chamber.
  • PFL paw flick latency
  • Dose- effect lines for each compound administered by itself are constructed using individual data and fitted with least squares linear regression analysis to determine ED50 values and 95% confidence limits.
  • a similar analysis is conducted for the compounds in combination using the total dose administered. Since parallel dose- effect lines are obtained for each compound administered by itself, and the combination of the invention, then a parallel line assay is conducted as described by Tallarida (Tallarida, 1992; Tallarida et al; 1989). This analysis compares the position of the experimentally-derived dose-effect line for the combination to the position of the theoretical dose-additive line.
  • a significant shift to the left or the right of the theoretical dose-additive line indicates that the compounds interact in a supra-additive (synergistic) or an infra-additive manner (antagonistic), respectively.
  • the amount of the active ingredients in the combinations will vary depending on the mammal to which the combinations are administered, the type of pain to be treated, other active ingredients present, etc. Generally, the amount of the endothelin receptor antagonist(s) and the other active compound(s) for a given composition and dosage form can be readily determined employing routine procedures.
  • the combinations of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms.
  • the combinations of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.
  • the combinations of the present invention can be administered by inhalation, for example, intranasally.
  • the combinations of the present invention can be administered transdermally.
  • the following dosage forms may comprise as the active components, a compound of Formula V or Formula VI, or a corresponding pharmaceutically acceptable salt thereof and from one to three compounds selected from the group consisting of antiepileptic compounds having pain alleviating properties and analgesics, or pharmaceutically acceptable salts thereof.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component(s).
  • the active component(s) is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from 5% to about 70% of the active combinations.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation" is intended to include the formulation of the active compound(s) with encapsulating material as a carrier providing a capsule in which the active component(s), with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component(s) is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component(s) in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component(s) in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component(s).
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • each active component in a unit dose preparation may be varied or adjusted from 1 to 1000 mg, preferably 10 to 100 mg according to the particular application and the potency of each active component.
  • the composition can, if desired, also contain other compatible therapeutic agents.
  • Co-administration of an endothelin receptor antagonist and from one to three compounds selected from the group consisting of antiepileptic compounds having pain alleviating properties and analgesics may comprise simultaneous or sequential administration of each pharmaceutically active compound that has been independently formulated by itself.
  • co-administration may comprise administration of an endothelin receptor antagonist and from one to three compounds selected from the group consisting of antiepileptic compounds having pain alleviating properties and analgesics wherein the pharmaceutically active compounds of the combination have been combined in a single formulation.
  • co-administration may comprise a combination of these two approaches wherein certain pharmaceutically active compounds are formulated together and others are independently formulated by themselves, and the formulations are administered simultaneously or sequentially.
  • the analgesics, antiepileptic compounds having pain alleviating properties, and endothelin antagonist compounds utilized in the pharmaceutical method of this invention can each be administered at the initial dosage of about 1 to about 100 mg/kg daily.
  • a daily dose range of about 1 to about 75 mg/kg is preferred.
  • a concentration range of the antiepileptic and/or analgesic between 1% and 99% and a complementary concentration range of endothelin antagonist compound between 99% and 1% of the 100% total of the combination of active ingredients is preferred.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art.
  • treatment is initiated with smaller dosages that are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstance is reached.
  • the total daily dosage may be divided and administered in portions during the day if desired.
  • the 1 ,2-benzothiazine-3-carboxylic acid, 1 , 1 -dioxide, potassium salt, gabapentin, lactose, and cornstarch (for mix) are blended to uniformity.
  • the cornstarch (for paste) is suspended in 200 mL of water and heated with stirring to form a paste.
  • the paste is used to granulate the mixed powders.
  • the wet granules are passed through a No. 8 hand screen and dried at 80°C.
  • the dry granules are lubricated with the 1% magnesium stearate and pressed into a tablet.
  • Such tablets can be administered to a human from one to four times a day for treatment of pain.

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Abstract

La présente invention est une nouvelle combinaison efficace pour soulager la douleur qui comprend une quantité efficace pour soulager la douleur d"un antagoniste de récepteur d"endothéline ou d"un sel pharmaceutiquement acceptable de celui-ci ainsi que 1 à 3 composants sélectionnés indépendamment dans le groupe constitué de composés anti-épileptiques présentant des propriétés analgésiques ou de soulagement de la douleur ainsi que leurs sels pharmaceutiquement acceptables et des compositions pharmaceutiques les comprenant. L"administration des antagonistes des récepteurs d"endothéline dans ces nouvelles combinaisons permet de mieux réduire la fréquence et l"intensité des douleurs. L"incidence des effets secondaires indésirables peut être réduite avec ces nouvelles combinaisons en comparaison aux doses plus importantes d"un agent de traitement unique, avec effet thérapeutique similaire. La présente invention comprend aussi des procédés pour utiliser des quantités efficaces des nouvelles combinaisons et compositions pharmaceutiques pour traiter la douleur chez les mammaliens, y compris l"homme.
EP01939002A 2000-05-31 2001-05-08 Combinaisons d'un antagoniste de recepteur d'endotheline et compose anti-epileptique presentant des proprietes analgesiques ou de soulagement de la douleur Withdrawn EP1289558A2 (fr)

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AU2001264570A1 (en) 2001-12-11
WO2001091736A2 (fr) 2001-12-06
WO2001091736A3 (fr) 2002-10-17
MXPA02010764A (es) 2003-03-10

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