# Patent

## Title
Inhibitor of analgesic tolerance

## Abstract

Provided are: an agent for suppressing an undesirable effect of an opioid-type analgesic (opioid), which comprises a compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof as an active ingredient; the agent for suppressing an undesirable effect of an opioid-type analgesic (opioid), wherein the undesirable effect of the opioid-type analgesic (opioid) is analgesic tolerance or constipation; the agent for suppressing an undesirable effect of an opioid-type analgesic (opioid), wherein the undesirable effect of the opioid-type analgesic (opioid) is analgesic tolerance; and the like.

## Background
TECHNICAL FIELD
The present invention relates to an agent for suppressing an undesirable effect (for example, analgesic tolerance, hyperalgesia, dependence, constipation, drowsiness, etc.) of an opioid-type analgesic (opioid), which comprises a compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof as an active ingredient, and the like.
BACKGROUND ART
An opioid is widely used for serious acute pain and chronic pain. It is known that an opioid shows a strong analgesic effect and also exhibits undesirable effect such as analgesic tolerance, hyperalgesia, constipation, dependence, and drowsiness (The Medical Clinics of North America, 2007, Vol. 91, p. 199). Conventionally, as a main method for treating and/or preventing analgesic tolerance or hyperalgesia caused by an opioid, increase in the dose of the opioid, opioid rotation, change of administration route, or the like has been performed. However, the increase in the dose of the opioid has a problem that the side effects of the opioid itself such as constipation, nausea, drowsiness, respiratory depression, confusion, and immunosuppression also become severe, and the critical effectiveness is decreased from the overall viewpoint. Further, as for the opioid rotation or change of administration route, there are not a few cases where the option to be taken is limited due to the site of pain or the past history of a patient (for example, nephropathy, hepatopathy, etc.).
As a method for reducing the undesirable effect of an opioid such as dependence, for example, there are reports as described below: (1) Oxytrex (“The Journal of Pain”, 2005, Vol. 6, p. 392) or Embeda (“Annual Meeting of The American Society of Anesthesiologists”, 2007, Abstract A1370), both of which are a mixed preparation of an opioid and an ultra-low dose of an opioid antagonist, reduces opioid physical dependence as compared with the single administration of an opioid; (2) methylnaltrexone improve constipation induced by the administration of an opioid (“The Annals of Pharmacotherapy”, 2007, Vol. 41, p. 984); (3) aminoguanidine suppresses analgesic tolerance and physical dependence of morphine (“European Journal of Pharmacology”, 2006, Vol. 540, pp. 60-66); (4) finasteride suppresses analgesic tolerance and physical dependence of morphine (“Hormones and Behavior”, 2007, Vol. 51, p. 605); (5) an N-methyl-D-aspartic acid (NMDA) receptor antagonist suppresses analgesic tolerance and dependence of opioid (“Naunyn-Schmiedeberg's Archives of Pharmacology”, 2000, Vol. 361, p. 425; “The Clinical Journal of Pain”, 2000, Vol. 16, pp. S73-9); (6) a GM1 ganglioside inhibitor suppresses analgesic tolerance and physical dependence of morphine and the like (US 2004-0087607); (7) 3,7-dimethyl-1-propargylxanthine (DMPX), which is an adenosine receptor antagonist, suppresses psychological dependence of morphine (see Non-patent document 1); (8) DMPX suppresses psychological dependence of heroine (see Non-patent document 2 and Patent document 1); (9) 8-(3-chlorostyryl) caffeine (CSC) suppresses psychological dependence of morphine (see Non-patent document 3); (10) ZM241385, which is an adenosine receptor antagonist, affects an excitatory postsynaptic current induced by DAMGO, which is one of the opioid peptides (see Non-patent document 4); and (11) SCH59261 and CSC, both of which are an adenosine receptor antagonist, suppress physical dependence of morphine (see Non-patent document 8).
On the other hand, it is known that adenosine is widely distributed in the body and exhibits various physiological effects on the central nervous system, cardiac muscle, kidney, smooth muscle, and the like via its receptors (see Non-patent document 5).
For example, it is known that an adenosine A1 antagonist has defecation promoting activity (see Non-patent document 6). It is also known that the adenosine A2A receptors are involved particularly in the central nervous system, and an adenosine A2A receptor antagonist is known to be useful as a therapeutic agent for, for example, Parkinson's disease and the like (see Non-patent document 7). Further, a composition comprising an adenosine A2A receptor antagonist and an opioid for treating restless legs syndrome (RLS) and the like are also known (see Patent documents 2 and 3). Further, a method for alleviating chronic consumption of abused drugs such as ethanol or an opioid using an adenosine A2A receptor antagonist (see Patent documents 1 and 4), a method for treating a disease with chronic musculoskeletal pain (see Patent document 5) and the like are known. Furthermore, it is also known that an adenosine A2B receptor antagonist is useful as a therapeutic agent for constipation (see Patent document 6).
As a compound having an adenosine A2A receptor antagonistic activity, for example, compounds represented by the following formulae (IA), (IB), (IC), (ID), (IIA), (IIIA), (IIIB), (IIIC), (IVA), (V), (VIA), (VII), (VIII), and the like are known (see Patent documents 7 to 13, and Non-patent documents 9 to 11).










PRIOR ART DOCUMENTS
Patent Documents


    Patent document 1: WO 2006/009698
    Patent document 2: WO 2007/047293
    Patent document 3: WO 2007/038212
    Patent document 4: WO 2006/059713
    Patent document 5: WO 2005/094885
    Patent document 6: WO 01/080893
    Patent document 7: U.S. Pat. No. 5,587,378
    Patent document 8: WO 00/17201
    Patent document 9: WO 2005/063743
    Patent document 10: WO 2002/055524
    Patent document 11: WO 2003/011864
    Patent document 12: WO 2006/032273
    Patent document 13: WO 2002/055083


Non-Patent Documents


    Non-patent document 1: “European Journal of Pharmacology”, 1999, Vol. 383, p. 107
    Non-patent document 2: “Proceedings of the National Academy of Sciences of the United States of America”, 2006, Vol. 103, p. 7877
    Non-patent document 3: “Research Communications in Alcohol and Substances of Abuse”, 1997, Vol. 18, p. 141
    Non-patent document 4: “Neuroscience Letters”, 2005, Vol. 376, p. 102
    Non-patent document 5: “Nature Reviews Drug Discovery”, 2006, Vol. 5, p. 247
    Non-patent document 6: “Jpn. J. Pharmacol.”, 1995, Vol. 68, p. 119
    Non-patent document 7: “Progress in Neurobiology”, 2007, Vol. 83, p. 332
    Non-patent document 8: “Naunyn-Schmiedeberg's Archives of Pharmacology”, 2003, Vol. 368, p. 113
    Non-patent document 9: “European Journal of Pharmacology”, 1994, Vol. 267, p.
    Non-patent document 10: “Bioorganic 85 Medicinal Chemistry Letters”, 2007, Vol. 17, p. 1376
    Non-patent document 11: “Journal of Medicinal Chemistry”, 1993, Vol. 36, p.


SUMMARY OF THE PRESENT INVENTION
Problems that the Present Invention is to Solve
An object of the present invention is to provide an agent for suppressing an undesirable effect (for example, analgesic tolerance, hyperalgesia, constipation, dependence, drowsiness, etc.) of an opioid, which comprises a compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof as an active ingredient, and the like.
Means for Solving the Problems
The present invention relates to the following (1) to (93).

    (1) An agent for suppressing an undesirable effect of an opioid, which comprises a compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof as an active ingredient.
    (2) The agent according to (1), wherein the undesirable effect is analgesic tolerance, hyperalgesia, constipation, dependence, or drowsiness.
    (3) The agent according to (1), wherein the undesirable effect is analgesic tolerance or constipation.
    (4) The agent according to (1), wherein the undesirable effect is analgesic tolerance.
    (5) The agent according to any one of (1) to (4), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by any one of the following formulae (I) to (VIII).









    (Wherein, R1 represents a hydrogen atom or methyl; R2 and R3 may be the same or different, and each represents methyl, ethyl, propyl, butyl, or isopropyl; R4, R5, and R6 may be the same or different, and each represents a hydrogen atom, methyl, ethyl, methoxy, ethoxy, a fluorine atom, a chlorine atom, or a bromine atom; R7 represents methyl, ethyl, propyl, butyl, or 3-methylbutyl, or any of these groups substituted by hydroxy; R8 represents phenyl, pyridyl, pyrimidinyl, or 5,6-dihydro-2H-pyridylmethyl, or any of these groups substituted by 1 to 3 substituents selected from a chlorine atom, methyl, ethyl, methoxy, and ethoxy; R9 represents pyridyl or tetrahydropyranyl; R10 and R11 may be the same or different, and each represents a hydrogen atom, a fluorine atom, or 2-methoxyethoxy; and R12 represents methyl, ethyl, propyl, or butyl.)
    (6) The agent according to any one of (1) to (4), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (I).






    (Wherein, R1, R2, R3, R4, R5, and R6 have the same definitions as described above, respectively.)
    (7) The agent according to any one of (1) to (4), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (II).






    (Wherein, R7 has the same definition as described above.)
    (8) The agent according to any one of (1) to (4), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (III).






    (Wherein, R8 and R9 have the same definitions as described above, respectively.)
    (9) The agent according to any one of (1) to (4), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (IA), (IB), (IC), (ID), (IIA), (IIIA), (IIIB), (MC), (IVA), (V), (VIA), (VII), or (VIII).









    (10) The agent according to any one of (1) to (4), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (IA) or (IB).






    (11) The agent according to any one of (1) to (4), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (IIA), (IIIA), (MB), or (IIIC).






    (12) The agent according to any one of (1) to (11), wherein the opioid is selected from the group consisting of anileridine, opium, ampromide, allylprodine, alphaprodine, alfentanil, isomethadone, ethylmethylthiambutene, ethylmorphine, ethoheptazine, etonitazene, eptazocine, endorphin, enkephalin, oxycodone, oxymorphone, clonitazene, ketobemidone, cocaine, codeine, cylmorphan, diamorphone, dioxaphetylbutyrate, didezocine, dinorphine, dihydrocodeine, dihydromorphine, dipipanone, dimethylthiambutene, dimenoxadol, dimepheptanol, sufentanil, tilidine, dextromoramide, desomorphine, tramadol, narceine, nalorphine, nalbuphene, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, papaveretum, hydrocodone, hydroxypethidine, hydromorphone, piminodine, piritramide, fentanyl, phenazocine, phenadoxone, phenoperidine, phenomorphan, butorphanol, buprenorphine, properidine, propoxyphene, propheptazine, promedol, heroin, bezitramide, berzylmorphine, pentazocine, myrophine, methadone, metazocine, metopon, meptazinol, meperidine, morphine, levallorphan, levophenalofentanil, levorphanol, and remifentanil.
    (13) The agent according to any one of (1) to (11), wherein the opioid is morphine, fentanyl, or oxycodone.
    (14) The agent according to any one of (1) to (11), wherein the opioid is morphine.
    (15) A therapeutic and/or preventive agent for pain, which comprises (a) a compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof and (b) an opioid in combination.
    (16) A therapeutic and/or preventive agent for pain, which comprises the following (a) and (b) as active ingredients, both of which are to be administered simultaneously or separately at an interval: (a) a compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof; and (b) an opioid.
    (17) The agent according to (15) or (16), wherein the pain is selected from the group consisting of nociceptive pain, cancer pain, dorsolumbar pain, postoperative pain, herpes zoster pain, osteoarticular pain, dorsolumbar pain, rheumatic joint pain, pain accompanying osteoarthritis, fibromyalgia, myofascial pain, visceral pain, inflammatory pain, neuropathic pain, entrapment neuropathy, postherpetic neuralgia, diabetic pain, neurological low back pain, pain after infection with AIDS virus, post-spinal cord injury pain, and trigeminal neuralgia.
    (18) The agent according to any one of (15) to (17), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by any one of the following formulae (I) to (VIII).









    (Wherein, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 have the same definitions as described above, respectively.)
    (19) The agent according to any one of (15) to (17), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (I).






    (Wherein, R1, R2, R3, R4, R5, and R6 have the same definitions as described above, respectively.)
    (20) The agent according to any one of (15) to (17), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (II).






    (Wherein, R7 has the same definition as described above.)
    (21) The agent according to any one of (15) to (17), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (III).






    (Wherein, R8 and R9 have the same definitions as described above, respectively.)
    (22) The agent according to any one of (15) to (17), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (IA), (IB), (IC), (ID), (IIA), (IIIA), (IIIB), (IIIC), (IVA), (V), (VIA), (VII), or (VIII).









    (23) The agent according to any one of (15) to (17), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (IA) or (IB).






    (24) The agent according to any one of (15) to (17), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (IIA), (IIIA), (IIIB), or (IIIC).






    (25) The agent according to any one of (15) to (24), wherein the opioid is selected from the group consisting of anileridine, opium, ampromide, allylprodine, alphaprodine, alfentanil, isomethadone, ethylmethylthiambutene, ethylmorphine, ethoheptazine, etonitazene, eptazocine, endorphin, enkephalin, oxycodone, oxymorphone, clonitazene, ketobemidone, cocaine, codeine, cylmorphan, diamorphone, dioxaphetylbutyrate, didezocine, dinorphine, dihydrocodeine, dihydromorphine, dipipanone, dimethylthiambutene, dimenoxadol, dimepheptanol, sufentanil, tilidine, dextromoramide, desomorphine, tramadol, narceine, nalorphine, nalbuphene, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, papaveretum, hydrocodone, hydroxypethidine, hydromorphone, piminodine, piritramide, fentanyl, phenazocine, phenadoxone, phenoperidine, phenomorphan, butorphanol, buprenorphine, properidine, propoxyphene, propheptazine, promedol, heroin, bezitramide, berzylmorphine, pentazocine, myrophine, methadone, metazocine, metopon, meptazinol, meperidine, morphine, levallorphan, levophenalofentanil, levorphanol, and remifentanil.
    (26) The agent according to any one of (15) to (24), wherein the opioid is morphine, fentanyl, or oxycodone.
    (27) The agent according to any one of (15) to (24), wherein the opioid is morphine.
    (28) A kit, which comprises (a) a first component containing a compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof and (b) a second component containing an opioid.
    (29) The kit according to (28), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by any one of the following formulae (I) to (VIII).









    (Wherein, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 have the same definitions as described above, respectively.)
    (30) The kit according to (28), wherein the compound having adenosine A2A, receptor antagonistic activity is a compound represented by the following formula (I).






    (Wherein, R1, R2, R3, R4, R5, and R6 have the same definitions as described above, respectively.)
    (31) The kit according to (28), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (II).






    (Wherein, R7 has the same definition as described above.)
    (32) The kit according to (28), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (III).






    (Wherein, R8 and R9 have the same definitions as described above, respectively.)
    (33) The kit according to (28), wherein the compound having adenosine A2A, receptor antagonistic activity is a compound represented by the following formula (IA), (IB), (IC), (ID), (IIA), (IIIA), (IIIB), (IIIC), (IVA), (V), (VIA), (VII), or (VIII).









    (34) The kit according to (28), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (IA) or (IB).






    (35) The kit according to (28), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (IIA), (IIIA), (IIIB), or (IIIC).






    (36) The kit according to any one of (28) to (35), wherein the opioid is selected from the group consisting of anileridine, opium, ampromide, allylprodine, alphaprodine, alfentanil, isomethadone, ethylmethylthiambutene, ethylmorphine, ethoheptazine, etonitazene, eptazocine, endorphin, enkephalin, oxycodone, oxymorphone, clonitazene, ketobemidone, cocaine, codeine, cylmorphan, diamorphone, dioxaphetylbutyrate, didezocine, dinorphine, dihydrocodeine, dihydromorphine, dipipanone, dimethylthiambutene, dimenoxadol, dimepheptanol, sufentanil, tilidine, dextromoramide, desomorphine, tramadol, narceine, nalorphine, nalbuphene, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, papaveretum, hydrocodone, hydroxypethidine, hydromorphone, piminodine, piritramide, fentanyl, phenazocine, phenadoxone, phenoperidine, phenomorphan, butorphanol, buprenorphine, properidine, propoxyphene, propheptazine, promedol, heroin, bezitramide, berzylmorphine, pentazocine, myrophine, methadone, metazocine, metopon, meptazinol, meperidine, morphine, levallorphan, levophenalofentanil, levorphanol, and remifentanil.
    (37) The kit according to any one of (28) to (35), wherein the opioid is morphine, fentanyl, or oxycodone.
    (38) The kit according to any one of (28) to (35), wherein the opioid is morphine.
    (39) A pharmaceutical composition, which comprises (a) a compound represented by any one of the following formulae (I) to (VIII) or a pharmaceutically acceptable salt thereof and (b) an opioid.









    (Wherein, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 have the same definitions as described above, respectively.)
    (40) A pharmaceutical composition, which comprises (a) a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof and (b) an opioid.






    (Wherein, R1, R2, R3, R4, R5, and R6 have the same definitions as described above, respectively.)
    (41) A pharmaceutical composition, which comprises (a) a compound represented by the following formula (II) or a pharmaceutically acceptable salt thereof and (b) an opioid.






    (Wherein, R7 has the same definition as described above.)
    (42) A pharmaceutical composition, which comprises (a) a compound represented by the following formula (III) or a pharmaceutically acceptable salt thereof and (b) an opioid.






    (Wherein, R8 and R9 have the same definitions as described above, respectively.)
    (43) A pharmaceutical composition, which comprises (a) a compound represented by the following formula (IA), (IB), (IC), (ID), (IIA), (IIIA), (MB), (IIIC), (IVA), (V), (VIA), (VII), or (VIII) or a pharmaceutically acceptable salt thereof and (b) an opioid.









    (44) A pharmaceutical composition, which comprises (a) a compound represented by the following formula (IA) or (IB) or a pharmaceutically acceptable salt thereof and (b) an opioid.






    (45) A pharmaceutical composition, which comprises (a) a compound represented by the following formula (IIC), (IIIA), (IIIB), or (IIIC) or a pharmaceutically acceptable salt thereof and (b) an opioid.






    (46) The pharmaceutical composition according to any one of (39) to (45), wherein the opioid is selected from the group consisting of anileridine, opium, ampromide, allylprodine, alphaprodine, alfentanil, isomethadone, ethylmethylthiambutene, ethylmorphine, ethoheptazine, etonitazene, eptazocine, endorphin, enkephalin, oxycodone, oxymorphone, clonitazene, ketobemidone, cocaine, codeine, cylmorphan, diamorphone, dioxaphetylbutyrate, didezocine, dinorphine, dihydrocodeine, dihydromorphine, dipipanone, dimethylthiambutene, dimenoxadol, dimepheptanol, sufentanil, tilidine, dextromoramide, desomorphine, tramadol, narceine, nalorphine, nalbuphene, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, papaveretum, hydrocodone, hydroxypethidine, hydromorphone, piminodine, piritramide, fentanyl, phenazocine, phenadoxone, phenoperidine, phenomorphan, butorphanol, buprenorphine, properidine, propoxyphene, propheptazine, promedol, heroin, bezitramide, berzylmorphine, pentazocine, myrophine, methadone, metazocine, metopon, meptazinol, meperidine, morphine, levallorphan, levophenalofentanil, levorphanol, and remifentanil.
    (47) The pharmaceutical composition according to any one of (39) to (45), wherein the opioid is morphine, fentanyl, or oxycodone.
    (48) The pharmaceutical composition according to any one of (39) to (45), wherein the opioid is morphine.
    (49) A method for suppressing an undesirable effect of an opioid, which comprises administering an effective amount of a compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof.
    (50) The method according to (49), wherein the undesirable effect is analgesic tolerance or constipation.
    (51) The method according to (49), wherein the undesirable effect is analgesic tolerance.
    (52) The method according to any one of (49) to (51), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by any one of the following formulae (I) to (VIII).









    (Wherein, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 have the same definitions as described above, respectively.)
    (53) The method according to any one of (49) to (51), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (I), (II), or (III).






    (Wherein, R1, R2, R3, R4, R5, R6, R7, R8, and R9 have the same definitions as described above, respectively.)
    (54) The method according to any one of (49) to (51), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (IA), (IB), (IC), (ID), (IIA), (IIIA), (IIIB), (IIIC), (IVA), (V), (VIA), (VII), or (VIII).









    (55) The method according to any one of (49) to (54), wherein the opioid is selected from the group consisting of anileridine, opium, ampromide, allylprodine, alphaprodine, alfentanil, isomethadone, ethylmethylthiambutene, ethylmorphine, ethoheptazine, etonitazene, eptazocine, endorphin, enkephalin, oxycodone, oxymorphone, clonitazene, ketobemidone, cocaine, codeine, cylmorphan, diamorphone, dioxaphetylbutyrate, didezocine, dinorphine, dihydrocodeine, dihydromorphine, dipipanone, dimethylthiambutene, dimenoxadol, dimepheptanol, sufentanil, tilidine, dextromoramide, desomorphine, tramadol, narceine, nalorphine, nalbuphene, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, papaveretum, hydrocodone, hydroxypethidine, hydromorphone, piminodine, piritramide, fentanyl, phenazocine, phenadoxone, phenoperidine, phenomorphan, butorphanol, buprenorphine, properidine, propoxyphene, propheptazine, promedol, heroin, bezitramide, berzylmorphine, pentazocine, myrophine, methadone, metazocine, metopon, meptazinol, meperidine, morphine, levallorphan, levophenalofentanil, levorphanol, and remifentanil.
    (56) The method according to any one of (49) to (54), wherein the opioid is morphine.
    (57) A method for treating and/or preventing pain, which comprises administering an effective amount of (a) a compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof and (b) an effective amount of an opioid in combination.
    (58) A method for treating and/or preventing pain, which comprises administering an effective amount of (a) a compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof and (b) an effective amount of an opioid simultaneously or separately at an interval.
    (59) The method according to (57) or (58), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by any one of the following formulae (I) to (VIII).









    (Wherein, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 have the same definitions as described above, respectively.)
    (60) The method according to (57) or (58), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (I), (II), or (III).






    (Wherein, R1, R2, R3, R4, R5, R6, R7, R8, and R9 have the same definitions as described above, respectively.)
    (61) The method according to (57) or (58), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (IA), (IB), (IC), (ID), (IIA), (IIIB), (IIIC), (IVA), (V), (VIA), (VII), or (VIII).









    (62) The method according to any one of (57) to (61), wherein the opioid is selected from the group consisting of anileridine, opium, ampromide, allylprodine, alphaprodine, alfentanil, isomethadone, ethylmethylthiambutene, ethylmorphine, ethoheptazine, etonitazene, eptazocine, endorphin, enkephalin, oxycodone, oxymorphone, clonitazene, ketobemidone, cocaine, codeine, cylmorphan, diamorphone, dioxaphetylbutyrate, didezocine, dinorphine, dihydrocodeine, dihydromorphine, dipipanone, dimethylthiambutene, dimenoxadol, dimepheptanol, sufentanil, tilidine, dextromoramide, desomorphine, tramadol, narceine, nalorphine, nalbuphene, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, papaveretum, hydrocodone, hydroxypethidine, hydromorphone, piminodine, piritramide, fentanyl, phenazocine, phenadoxone, phenoperidine, phenomorphan, butorphanol, buprenorphine, properidine, propoxyphene, propheptazine, promedol, heroin, bezitramide, berzylmorphine, pentazocine, myrophine, methadone, metazocine, metopon, meptazinol, meperidine, morphine, levallorphan, levophenalofentanil, levorphanol, and remifentanil.
    (63) The method according to any one of (57) to (61), wherein the opioid is morphine.
    (64) Use of a compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof for the manufacture of a suppressant of an undesirable effect of an opioid.
    (65) The use according to (64), wherein the undesirable effect is analgesic tolerance or constipation.
    (66) The use according to (64), wherein the undesirable effect is analgesic tolerance.
    (67) The use according to any one of (64) to (66), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by any one of the following formulae (I) to (VIII).









    (Wherein, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 have the same definitions as described above, respectively.)
    (68) The use according to any one of (64) to (66), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (I), (II), or (III).






    (Wherein, R1, R2, R3, R4, R5, R6, R7, R8, and R9 have the same definitions as described above, respectively.)
    (69) The use according to any one of (64) to (66), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (IA), (IB), (IC), (ID), (IIA), (IIIA), (IIIB), (IIIC), (IVA), (V), (VIA), (VII), or (VIII).









    (70) The use according to any one of (64) to (69), wherein the opioid is selected from the group consisting of anileridine, opium, ampromide, allylprodine, alphaprodine, alfentanil, isomethadone, ethylmethylthiambutene, ethylmorphine, ethoheptazine, etonitazene, eptazocine, endorphin, enkephalin, oxycodone, oxymorphone, clonitazene, ketobemidone, cocaine, codeine, cylmorphan, diamorphone, dioxaphetylbutyrate, didezocine, dinorphine, dihydrocodeine, dihydromorphine, dipipanone, dimethylthiambutene, dimenoxadol, dimepheptanol, sufentanil, tilidine, dextromoramide, desomorphine, tramadol, narceine, nalorphine, nalbuphene, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, papaveretum, hydrocodone, hydroxypethidine, hydromorphone, piminodine, piritramide, fentanyl, phenazocine, phenadoxone, phenoperidine, phenomorphan, butorphanol, buprenorphine, properidine, propoxyphene, propheptazine, promedol, heroin, bezitramide, berzylmorphine, pentazocine, myrophine, methadone, metazocine, metopon, meptazinol, meperidine, morphine, levallorphan, levophenalofentanil, levorphanol, and remifentanil.
    (71) The use according to any one of (64) to (69), wherein the opioid is morphine.
    (72) Use of (a) a compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof and (b) an opioid in combination for the manufacture of a therapeutic and/or preventive agent for pain.
    (73) Use of the following (a) and (b) for the manufacture of a therapeutic and/or preventive agent for pain: (a) a compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof; and (b) an opioid, both of which are to be administered simultaneously or separately at an interval.
    (74) The use according to (72) or (73), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by any one of the following formulae (I) to (VIII).









    (Wherein, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 have the same definitions as described above, respectively.)
    (75) The use according to (72) or (73), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof.






    (Wherein, R1, R2, R3, R4, R5, R6, R7, R8, and R9 have the same definitions as described above, respectively.)
    (76) The use according to (72) or (73), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (IA), (IB), (IC), (ID), (IIA), (IIIA), (IIIB), (IIIC), (IVA), (V), (VIA), (VII), or (VIII).









    (Wherein, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 have the same definitions as described above, respectively.)
    (77) The use according to any one of (72) to (76), wherein the opioid is selected from the group consisting of anileridine, opium, ampromide, allylprodine, alphaprodine, alfentanil, isomethadone, ethylmethylthiambutene, ethylmorphine, ethoheptazine, etonitazene, eptazocine, endorphin, enkephalin, oxycodone, oxymorphone, clonitazene, ketobemidone, cocaine, codeine, cylmorphan, diamorphone, dioxaphetylbutyrate, didezocine, dinorphine, dihydrocodeine, dihydromorphine, dipipanone, dimethylthiambutene, dimenoxadol, dimepheptanol, sufentanil, tilidine, dextromoramide, desomorphine, tramadol, narceine, nalorphine, nalbuphene, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, papaveretum, hydrocodone, hydroxypethidine, hydromorphone, piminodine, piritramide, fentanyl, phenazocine, phenadoxone, phenoperidine, phenomorphan, butorphanol, buprenorphine, properidine, propoxyphene, propheptazine, promedol, heroin, bezitramide, berzylmorphine, pentazocine, myrophine, methadone, metazocine, metopon, meptazinol, meperidine, morphine, levallorphan, levophenalofentanil, levorphanol, and remifentanil.
    (78) The use according to any one of (72) to (76), wherein the opioid is morphine.
    (79) A compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof for use in suppressing an undesirable effect of an opioid.
    (80) The compound or a pharmaceutically acceptable salt thereof according to (79), wherein the undesirable effect is analgesic tolerance or constipation.
    (81) The compound or a pharmaceutically acceptable salt thereof according to (79), wherein the undesirable effect is analgesic tolerance.
    (82) The compound or a pharmaceutically acceptable salt thereof according to any one of (79) to (81), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by any one of the following formulae (I) to (VIII).









    (Wherein, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 have the same definitions as described above, respectively.)
    (83) The compound or a pharmaceutically acceptable salt thereof according to any one of (79) to (81), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (I), (II), or (III).






    (Wherein, R1, R2, R3, R4, R5, R6, R7, R8, and R9 have the same definitions as described above, respectively.)
    (84) The compound or a pharmaceutically acceptable salt thereof according to any one of (79) to (81), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (IA), (IB), (IC), (ID), (IIA), (IIIA), (IIIB), (IIIC), (IVA), (V), (VIA), (VII), or (VIII).









    (85) The compound or a pharmaceutically acceptable salt thereof according to any one of (79) to (84), wherein the opioid is selected from the group consisting of anileridine, opium, ampromide, allylprodine, alphaprodine, alfentanil, isomethadone, ethylmethylthiambutene, ethylmorphine, ethoheptazine, etonitazene, eptazocine, endorphin, enkephalin, oxycodone, oxymorphone, clonitazene, ketobemidone, cocaine, codeine, cylmorphan, diamorphone, dioxaphetylbutyrate, didezocine, dinorphine, dihydrocodeine, dihydromorphine, dipipanone, dimethylthiambutene, dimenoxadol, dimepheptanol, sufentanil, tilidine, dextromoramide, desomorphine, tramadol, narceine, nalorphine, nalbuphene, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, papaveretum, hydrocodone, hydroxypethidine, hydromorphone, piritramide, fentanyl, phenazocine, phenadoxone, phenoperidine, phenomorphan, butorphanol, buprenorphine, properidine, propoxyphene, propheptazine, promedol, heroin, bezitramide, berzylmorphine, pentazocine, myrophine, methadone, metazocine, metopon, meptazinol, meperidine, morphine, levallorphan, levophenalofentanil, levorphanol, and remifentanil.
    (86) The compound or a pharmaceutically acceptable salt thereof according to any one of (79) to (84), wherein the opioid is morphine.
    (87) A combination of (a) a compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof and (ID) an opioid for use in treating and/or preventing pain.
    (88) A combination of (a) a compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof and (b) an opioid for simultaneous or separate-at-an-interval use in treating and/or preventing pain.
    (89) The combination according to (87) or (88), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by any one of the following formulae (I) to (VIII).









    (Wherein, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 have the same definitions as described above, respectively.)
    (90) The combination according to (87) or (88), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (I), (II), or (III).






    (Wherein, R1, R2, R3, R4, R5, R6, R7, R8, and R9 have the same definitions as described above, respectively.)
    (91) The combination according to (87) or (88), wherein the compound having adenosine A2A receptor antagonistic activity is a compound represented by the following formula (IA), (IB), (IC), (ID), (IIA), (IIIA), (IIIC), (IVA), (V), (VIA), (VII), or (VIII).









    (92) The combination according to any one of (87) to (91), wherein the opioid is selected from the group consisting of anileridine, opium, ampromide, allylprodine, alphaprodine, alfentanil, isomethadone, ethylmethylthiambutene, ethylmorphine, ethoheptazine, etonitazene, eptazocine, endorphin, enkephalin, oxycodone, oxymorphone, clonitazene, ketobemidone, cocaine, codeine, cylmorphan, diamorphone, dioxaphetylbutyrate, didezocine, dinorphine, dihydrocodeine, dihydromorphine, dipipanone, dimethylthiambutene, dimenoxadol, dimepheptanol, sufentanil, tilidine, dextromoramide, desomorphine, tramadol, narceine, nalorphine, nalbuphene, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, papaveretum, hydrocodone, hydroxypethidine, hydromorphone, piminodine, piritramide, fentanyl, phenazocine, phenadoxone, phenoperidine, phenomorphan, butorphanol, buprenorphine, properidine, propoxyphene, propheptazine, promedol, heroin, bezitramide, berzylmorphine, pentazocine, myrophine, methadone, metazocine, metopon, meptazinol, meperidine, morphine, levallorphan, levophenalofentanil, levorphanol, and remifentanil.
    (93) The combination according to any one of (87) to (91), wherein the opioid is morphine.


The Effects of the Present Invention
According to the present invention, an agent for suppressing an undesirable effect (for example, analgesic tolerance, hyperalgesia, constipation, dependence, drowsiness, etc.) of an opioid, which comprises a compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof as an active ingredient, and the like can be provided.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph showing the effect of Compound (IA) on analgesic tolerance of morphine according to Test Example 1 of the present invention. The vertical axis represents response latency (sec) and the horizontal axis represents time (h) after administration.
FIG. 2 is a graph showing the effect of Compound (IA) on morphine-induced constipation according to Test Example 2 of the present invention. The vertical axis represents the amount (number) of stools. The bars from left to right represent the results of normal group, morphine administration group, Compound (IA) administration group, and combination administration group, respectively.



DESCRIPTION OF EMBODIMENTS
The compound having adenosine A2A receptor antagonistic activity of the present invention or to be used in the present invention is not particularly limited as long as it is a compound having adenosine A2A receptor antagonistic activity, however, preferred examples include compounds having selective antagonistic activity against adenosine A2A receptors.
Specifically, for example, a compound represented by any one of the following formulae (I) to (VIII) or a pharmaceutically acceptable salt thereof is preferred:







wherein, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 have the same definitions as described above, respectively.

More specifically, for example, a compound represented by the following formula (IA), (IB), (IIA), (IIIA), (IIIB), (IIIC), (IVA), (V), (VIA), (VII), or (VIII); or a pharmaceutically acceptable salt thereof is preferred.







Further more preferably, for example, a compound represented by the following formula (IA) or (IB), or a pharmaceutically acceptable salt thereof is illustrated.




Further, for example, a compound represented by the following formula (IIA) or a pharmaceutically acceptable salt thereof is also preferred.




Still further, for example, a compound represented by the following formula (IIIA), (IIIB), or (IIIC) or a pharmaceutically acceptable salt thereof is also preferred.




The compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof of the present invention or to be used in the present invention include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like.
The acid addition salts of the compound having adenosine A2A receptor antagonistic activity of the present invention or to be used in the present invention include, for example, inorganic acid salts such as hydrochloride, sulfate, hydrobromide, nitrate, and phosphate; and organic acid salts such as acetate, mesilate, succinate, maleate, fumarate, citrate, and tartrate. The pharmaceutically acceptable metal salts thereof include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; aluminum salts, zinc salts, and the like. The pharmaceutically acceptable ammonium salts thereof include, for example, salts of ammonium, tetramethylammonium, and the like. The pharmaceutically acceptable organic amine addition salts thereof include, for example, addition salts of morpholine, piperidine, and the like. The pharmaceutically acceptable amino acid addition salts thereof include, for example, addition salts of glycine, phenylalanine, lysine, aspartic acid, glutamic acid, and the like.
The compounds having adenosine A2A receptor antagonistic activity or pharmaceutically acceptable salts thereof of the present invention or to be used in the present invention can be produced according to conventionally known methods, respectively. For example, Compound (I) can be produced by the method described in WO 94/01114, U.S. Pat. No. 5,587,378, J. Med. Chem. 1993, 36, 1333-1342, or the like. Compound (II) can be produced by the method described in WO 00/17201 or the like. Compound (III) can be produced by the method described in WO 2005/063743 or the like. Compound (IV) can be produced by the method described in WO 2001/092264 or the like. Compound (V) can be produced by the method described in WO 2002/055524 or the like. Compound (VI) can be produced by the method described in WO 2003011864 or the like. Compound (VII) can be produced by the method described in WO 2006/032273 or the like. Compound (VIII) can be produced by the method described in WO 2002/055083 or the like.
Some compounds having adenosine A2A receptor antagonistic activity of the present invention or to be used in the present invention may exist in the form of stereoisomers such as geometric isomers and optical isomers, tautomers, or the like. In the agent for suppressing an undesirable effect of an opioid, therapeutic and/or preventive agent for pain, the kit, the pharmaceutical composition, the method for suppressing an undesirable effect of an opioid, the method for treating and/or preventing pain, the use for the manufacture of an agent for suppressing an undesirable effect of an opioid, the use for the manufacture of a therapeutic and/or preventive agent for pain, and the combination of the present invention, any of all possible isomers including the above-mentioned isomers and mixtures thereof can be used, and the compounds having adenosine A2A receptor antagonistic activity of the present invention include all possible isomers including the above-mentioned isomers and mixtures thereof.
In the case where the salt of the compound having adenosine A2A receptor antagonistic activity of the present invention or to be used in the present invention is desired to be obtained, when the respective compounds are obtained in the form of a salt, the compounds may be purified as it is, and when the respective compounds are obtained in the free form, the salt may be obtained by dissolving or suspending each compound in an appropriate solvent and adding an acid or a base thereto, followed by isolation and purification.
Further, some compounds having adenosine A2A receptor antagonistic activity or pharmaceutically acceptable salts thereof of the present invention or to be used in the present invention may exist in the form of an adduct with water or any of various solvents. Any of these adducts can also be used in the agent for suppressing an undesirable effect of an opioid, the therapeutic and/or preventive agent for pain, the kit, the pharmaceutical composition, the method for suppressing an undesirable effect of an opioid, the method for treating and/or preventing pain, the use for the manufacture of an agent for suppressing an undesirable effect of an opioid, the use for the manufacture of a therapeutic and/or preventive agent for pain, and the combination of the present invention.
Examples of the opioid to be used in the present invention include drugs which act on the opioid receptor to exhibit analgesic activity, and specific examples thereof include anileridine, opium, ampromide, allylprodine, alphaprodine, alfentanil, isomethadone, ethylmethylthiambutene, ethylmorphine, ethoheptazine, etonitazene, eptazocine, endorphin, enkephalin, oxycodone, oxymorphone, clonitazene, ketobemidone, cocaine, codeine, cylmorphan, diamorphone, dioxaphetylbutyrate, didezocine, dinorphine, dihydrocodeine, dihydromorphine, dipipanone, dimethylthiambutene, dimenoxadol, dimepheptanol, sufentanil, tilidine, dextromoramide, desomorphine, tramadol, narceine, nalorphine, nalbuphene, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, papaveretum, hydrocodone, hydroxypethidine, hydromorphone, piminodine, piritramide, fentanyl, phenazocine, phenadoxone, phenoperidine, phenomorphan, butorphanol, buprenorphine, properidine, propoxyphene, propheptazine, promedol, heroin, bezitramide, berzylmorphine, pentazocine, myrophine, methadone, metazocine, metopon, meptazinol, meperidine, morphine, levallorphan, levophenalofentanil, levorphanol, remifentanil, and the like. Preferred examples thereof include morphine, fentanyl, oxycodone, and the like, and more preferred examples thereof include morphine and the like. These may be used alone or in combination.
Some of these opioids may exist in the form of a pharmaceutically acceptable salt (the pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like, and examples thereof include inorganic acid salts such as hydrochloride, sulfate, hydrobromide, nitrate, and phosphate; organic acid salts such as acetate, mesilate, succinate, maleate, fumarate, citrate, and tartrate; alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; metal salts such as aluminum salts and zinc salts; ammonium salts such as ammonium salts and tetramethylammonium salts; organic amine addition salts of morpholine, piperidine, and the like; amino acid addition salts of glycine, phenylalanine, lysine, aspartic acid, glutamic acid, and the like; and the like), a hydrate thereof, or the like. Any of these can also be used in the therapeutic and/or preventive agent for pain, the kit, the pharmaceutical composition, the method for treating and/or preventing pain, the use for the manufacture of a therapeutic and/or preventive agent for pain, and the combination of the present invention.
Further, the opioids illustrated above can be obtained as commercially available products or by producing them according to conventionally known methods.
The agent for suppressing an undesirable effect of an opioid and a compound having adenosine A2A receptor antagonistic activity of the present invention can be used, for example, in combination with any of the above-mentioned opioids, and also, the agent for suppressing an undesirable effect of an opioid, the kit, the pharmaceutical composition, the method for suppressing an undesirable effect of an opioid, and the combination of the present invention can be used for, for example, the treatment and/or prevention of pain. The pain for which the agent for suppressing an undesirable effect of an opioid, the therapeutic and/or preventive agent for pain, the kit, the pharmaceutical composition, the method for suppressing an undesirable effect of an opioid, the method for treating and/or preventing pain, the compound having adenosine A2A receptor antagonistic activity, and the combination of the present invention can be used is not particularly limited, however, examples thereof include pain for which an opioid has been conventionally used for the treatment and/or prevention (for example, chronic pain, etc.), and specific examples thereof include nociceptive pain, neuropathic pain, and the like. More specific examples thereof include nociceptive pain, cancer pain, dorsolumbar pain, pain accompanying traumatic cervical syndrome, traumatic pain, postoperative pain, burn pain, delivery pain, herpes zoster pain, headache, migraine, osteoarticular pain, dorsolumbar pain, rheumatic joint pain, pain accompanying osteoarthritis, fibromyalgia, myofascial pain, visceral pain, inflammatory pain, neuropathic pain, entrapment neuropathy, phantom limb pain, persistent postoperative pain, persistent post-traumatic pain, postherpetic neuralgia, diabetic pain, neurological low back pain, pain after infection with AIDS virus, post-stroke thalamic pain, post-spinal cord injury pain, trigeminal neuralgia, glossopharyngeal neuralgia, and the like, and preferred examples thereof include nociceptive pain, cancer pain, dorsolumbar pain, postoperative pain, herpes zoster pain, osteoarticular pain, dorsolumbar pain, rheumatic joint pain, pain accompanying osteoarthritis, fibromyalgia, myofascial pain, visceral pain, inflammatory pain, neuropathic pain, entrapment neuropathy, postherpetic neuralgia, diabetic pain, neurological low back pain, pain after infection with AIDS virus, post-spinal cord injury pain, trigeminal neuralgia, and the like.
The undesirable effect of an opioid of the present invention refers to symptoms, side effects, and the like, which are problematic when an opioid such as morphine, fentanyl, or oxycodone is administered, and examples thereof include symptoms caused by administering an opioid such as analgesic tolerance, hyperalgesia, dependence, constipation, vomiting, anorexia, drowsiness, wobble, respiratory depression, anxiety, pruritus, paralytic ileus, yawning, sneezing, lacrimation, perspiration, nausea, stomachache, mydriasis, headache, insomnia, delirium, tremor, general myalgia, general joint pain, respiratory distress, withdrawal syndrome, shortness of breath, slow respiration, irregular respiration, abnormal respiration, confusion, pulmonary atelectasis, bronchial spasm, laryngeal edema, toxic megacolon, arrhythmia, change in blood pressure, facial flushing, dizziness, restlessness, excitement, visual accommodation disorder, dry mouth, rash, urination disorder, and intracranial hypertension. By the agent for suppressing an undesirable effect of an opioid or the method for suppressing an undesirable effect of an opioid of the present invention, for example, the above-mentioned symptoms or the like caused by administrating an opioid can be treated and/or prevented. Among them, analgesic tolerance, hyperalgesia, dependence, constipation, vomiting, anorexia, drowsiness, wobble, respiratory depression, anxiety, pruritus, paralytic ileus, and the like, preferably analgesic tolerance, hyperalgesia, dependence, constipation, vomiting, anorexia, drowsiness, and the like, more preferably analgesic tolerance, hyperalgesia, dependence, constipation, and the like, further more preferably analgesic tolerance, hyperalgesia, constipation, and the like, still further more preferably analgesic tolerance, constipation, and the like can be treated and/or prevented.
As for the compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof to be used in the agent for suppressing an undesirable effect of an opioid and the method for suppressing an undesirable effect of an opioid of the present invention, the above-mentioned compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof can be administered alone as it is, however, in general, it is preferably provided as any of various pharmaceutical preparations. Further, such a pharmaceutical preparation is used for animals or humans.
The pharmaceutical preparations related to the agent for suppressing an undesirable effect of an opioid and the method for suppressing an undesirable effect of an opioid of the present invention can contain a compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof as an active ingredient alone or as a mixture with any other active ingredients for any other treatments. Further, these pharmaceutical preparations are produced by mixing the active ingredient with one or more pharmaceutically acceptable carriers (for example, a diluent, a solvent, an excipient, etc.) and then subjecting the mixture to any method well known in the technical field of pharmaceutics.
As for the administration route, it is preferred to use the most effective administration route for the treatment, and examples thereof include oral administration and parenteral administration such as intravenous administration and transdermal administration.
Examples of the dosage form include tablets, injections, suppositories, patches, and the like.
Suitable dosage form for oral administration, for example, a tablet and the like can be produced by using an excipient such as lactose, a disintegrator such as starch, a lubricant such as magnesium stearate, a binder such as hydroxypropyl cellulose, or the like.
Suitable dosage form for parenteral administration, for example, an injection and the like can be produced by using a diluent, a solvent, etc. such as a salt solution, a glucose solution, or a mixed solution of brine and a glucose solution. Also, a suppository, a patch, and the like can be produced by conventionally known methods.
The doses and the frequencies of administration of the compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof may vary depending on its dosage form; type; potency; dose and/or dosage form of an opioid used; age and body weight of a patient; nature or seriousness of the symptom to be treated; and the like. However, in the oral administration, in general, a dose of 0.01 to 1000 mg, preferably 0.05 to 100 mg is administered to an adult patient once or several times a day. In the parenteral administration such as intravenous administration, in general, a dose of 0.001 to 1000 mg, preferably 0.01 to 100 mg is administered to an adult patient once or several times a day. However, these doses and frequencies of administration vary depending on the various conditions described above.
The (a) compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof and the (b) opioid to be used in the pharmaceutical composition, the therapeutic and/or preventive agent for pain, the method for treating and/or preventing pain, the use for the manufacture of a therapeutic and/or preventive agent for pain, or the combination of the present invention can be used or administered as a single preparation (combination preparation) or as a combination of a plurality of preparations as long as, for example, the formulation is performed along with a pharmaceutically acceptable carrier so that these respective active ingredients are incorporated therein. In particular, a combination of two or more preparations is preferred. When these active ingredients are used or administered as a combination of a plurality of preparations, these active ingredients can be used or administered simultaneously or separately at an interval. Incidentally, these preparations are preferably used in the form of, for example, a tablet, an injection, a suppository, a patch, or the like.
The ratio of the doses (weight/weight) of the (a) compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof and the (b) opioid may be appropriately adjusted according to the combination of the (a) compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof and the (b) opioid used, the respective potencies of the (a) compound having adenosine A receptor antagonistic activity or a pharmaceutically acceptable salt thereof and the (b) opioid, or the like, however, specifically, the ratio is between 1/100000 ((a) compound having adenosine A2A, receptor antagonistic activity or a pharmaceutically acceptable salt thereof/(b) opioid) and 1000/1, preferably between 1/50000 and 500/1, more preferably between 1/6000 and 100/1, further more preferably between 1/4000 and 15/1, still further more preferably between 1/1000 and 10/1, and most preferably between 1/100 and 10/1.
When these active ingredients are administered as a combination of a plurality of preparations, for example, (a) a first component containing a compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof and (b) a second component containing an opioid are separately formulated into preparations and prepared as a kit, and the respective components can be administered simultaneously or separately at an interval to the same subject through the same administration route or different administration routes using this kit.
As the kit, for example, a kit comprising contents and two or more containers (for example, vials, bags, etc.) whose material, shape, and so on are not particularly limited as long as the containers do not cause degeneration of the components which are the contents due to external temperature or light nor cause elution of chemical components from the containers during storage, and having a form which enables the administration of the above first and second components which are the contents through separate routes (for example, tubes, etc.) or the same route is used. Specific examples thereof include tablet kits, injection kits, and the like.
As described above, the pharmaceutical composition, the therapeutic and/or preventive agent for pain, or the combination of the present invention can be used, administered, or produced as a single preparation or a combination of a plurality of preparations as long as it is obtained by formulating the (a) compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof and the (b) opioid into a preparation so that the respective active ingredients are incorporated therein. The therapeutic and/or preventive agent for pain and the like are preferably in a unit dosage form suitable for oral administration such as a tablet or parenteral administration such as an injection, a suppository, or a patch.
These preparations are produced by mixing the respective active ingredients with one or more pharmaceutically acceptable carriers (for example, a diluent, a solvent, an excipient, etc.) other than these active ingredients, and then subjecting the mixture to any method well known in the technical field of pharmaceutics.
Suitable for oral administration, for example, tablets and the like can be produced by using an excipient such as lactose, a disintegrator such as starch, a lubricant such as magnesium stearate, a binder such as hydroxypropyl cellulose, and the like.
Suitable for parenteral administration, for example, an injection and the like can be produced by using a diluent, a solvent, etc. such as a salt solution, a glucose solution, or a mixed liquid of brine and a glucose solution. Also, a suppository, a patch, and the like can be produced by conventionally known methods.
In the case where the (a) compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof and the (b) opioid are used or administered as a combination of a plurality of preparations for the above-mentioned purpose, the doses and the frequencies of administration of the respective active ingredients may vary depending on potencies of the respective active ingredients, dosage form, age, body weight, and symptom of a patient, and the like. However, in general, the (a) compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof and the (b) opioid are preferably administered at the following doses per day, respectively.
In the case of oral administration in the form of, for example, tablets, the (a) compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof and the (b) opioid are administered at doses of 0.1 to 1000 mg and 0.1 to 10000 mg, preferably 0.1 to 500 mg and 0.1 to 5000 mg, more preferably 0.5 to 500 mg and 1 to 3000 mg, further more preferably 0.5 to 300 mg and 1 to 2000 mg, respectively, to an adult patient generally once or several times a day simultaneously or separately at an interval.
In the case of parenteral administration in the form of, for example, an injection and the like, the (a) compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof and the (b) opioid are administered at doses of 0.1 to 1000 mg and 0.1 to 10000 mg, preferably 0.1 to 500 mg and 0.1 to 5000 mg, more preferably 0.5 to 500 mg and 1 to 3000 mg, further more preferably 0.5 to 300 mg and 1 to 2000 mg, respectively, to an adult patient generally once or several times a day simultaneously or separately at an interval.
Further, in the case where the (a) compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof and the (b) opioid are used or administered as a single preparation for the above-mentioned purpose, the doses and the frequencies of administration may vary depending on potencies of the respective active ingredients; dosage form; age, body weight, and symptom of a patient; and the like. However, it is preferred that the respective active ingredients are formulated into a single preparation at the same doses as in the above-mentioned case where the respective active ingredients are used and administered as a combination of a plurality of preparations and the resulting single preparation is used or administered.
However, these doses and frequencies of administration vary depending on the above-mentioned various conditions.
Next, the suppressing effect of the compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof on an undesirable effect of an opioid, and the effect of the administration of the (a) compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof and the (b) opioid in combination will be specifically described in the Test Examples.
TEST EXAMPLE 1
Suppressing Activity of Compound (I) on Morphine Analgesic Tolerance
Experimental Materials and Methods
1. Used Animals
Male ddY mice (3 to 4 weeks old, Japan SW, Inc.) having a body weight of 19 to 25 g were used, and the animals were maintained under the following conditions: 19 to 25° C. room temperature, 30 to 70% humidity, and 12-h light and dark cycle (light period: from 7 a.m. to 7 p.m., dark period: from 7 p.m. to 7 a.m.) until they were subjected to the experiment. Food and water were provided ad libitum.
2. Used Agents and Preparation Methods
Hereinafter, the test was performed under the instructions of narcotics researchers in accordance with the narcotic handling rule each time morphine was used. Morphine was dissolved in physiological saline at a concentration of 0.6 mg/mL and subcutaneously administered at a dose of 6 mg/kg. Compound (IA) was suspended in 0.5% methyl cellulose (0.5% MC) at a concentration of 1 mg/mL and orally administered at a dose of 10 mg/kg.
3. Determination of Analgesic Activity
Nociceptive pain was determined by a hot plate method. Each mouse was placed on a hot plate apparatus (35100, Ugo Basile, Comerio, VA, Italy) set to 53° C., and the time (latency) until an escape response (paw-licking, -biting, -shaking, or jumping) was evoked was determined to be a pain threshold. In the experiment, animals having a response latency of 6 to 16 seconds before the first drug administration were used. Further, in order to minimize the damage to the site of stimulation, the cut-off time was set to 45 seconds. The analgesic activity was evaluated by determining the response latency at 30, 60, and 120 minutes after drug administration on the last day of repeated drug administration (on day 7).
4. Statistical Processing
The experimental results were expressed as mean±standard error. The statistical analysis was performed using a statistical analysis software SAS (SAS Institute Inc., Cary, N.C., USA). Comparison between two groups was performed using a Wilcoxn rank sum test. A p-value of less than 0.05 was considered to be a significant difference.
5. Experimental Results
The results are shown in FIG. 1. In the group in which morphine was repeatedly administered for 7 days (repeated morphine administration group: twice a day, one-time administration only on day 7), the response latency was significantly and markedly decreased as compared with that of the single morphine administration group (physiological saline was repeatedly administered twice a day for 6 days, and morphine was administered only on day 7), and the development of analgesic tolerance was observed. In the repeated combination administration group in which Compound (IA) was orally administered at 30 minutes before administration of morphine, a decrease in analgesic activity was not observed as compared with the single morphine administration group, and the development of analgesic tolerance was prevented. Incidentally, in the group in which Compound (IA) was repeatedly administered alone (repeated Compound (IA) administration group), the effect on the response latency was not observed.
From the above test, it was confirmed that Compound (IA) has a suppressing effect on morphine analgesic tolerance. From this, it was considered that the development of analgesic tolerance following chronic opioid administration can be prevented by using Compound (I) and an opioid in combination.
TEST EXAMPLE 2
Suppressing Activity of Compound (I) on Morphine-Induced Constipation
Experimental Materials and Methods
1. Used Animals
Male ddY mice (5 weeks old, Japan SLC, Inc.) having a body weight of 23 to 27 g were used, and the animals were maintained under the following conditions: 19 to 25° C. room temperature, 30 to 70% humidity, and 12-h light and dark cycle (light period: from 7 a.m. to 7 p.m., dark period: from 7 p.m. to 7 a.m.) until they were subjected to the experiment. Food and water were provided ad libitum. At the time of collection of fecal pellets, food and water were not provided.
2. Used Agents and Preparation Methods
Morphine was dissolved in physiological saline at a concentration of 0.3 mg/mL and subcutaneously administered at a dose of 3 mg/kg. Compound (IA) was suspended in 0.5% MC at a concentration of 1 mg/mL and orally administered at a dose of 10 mg/kg.
3. Determination of Suppressing Activity on Constipation
On the day of the test, the tails of the mice were numbered for identification, and the body weight of each mouse was measured. On the basis of the measured body weight, 0.5% MC or Compound (IA) was orally administered. At 30 minutes after administration of 0.5% MC or Compound (IA), physiological saline or morphine was subcutaneously administered, and collection of fecal pellets was started. The fecal pellets were collected at 3 hours after administration of morphine. The amount of feces was evaluated by counting the number of the fecal pellets.
4. Statistical Processing
The experimental results were expressed as mean±standard error. The statistical analysis was performed using a statistical analysis software SAS (SAS Institute Inc., Cary, N.C., USA). Comparison between two groups was performed using a Wilcoxn rank sum test. A p-value of less than 0.05 was considered to be a significant difference.
5. Experimental Results
The results are shown in FIG. 2. In the morphine administration group, the number of fecal pellets was significantly decreased as compared with the normal group, and constipation was observed. In the combination administration group in which Compound (IA) was orally administered at 30 minutes before administration of morphine, the number of fecal pellets was significantly increased as compared with the morphine administration group, and a suppressing activity on constipation was observed. Further, in the Compound (IA) administration group in which only Compound (IA) was administered and the combination administration group in which morphine and Compound (IA) were administered, diarrhea was not induced.
From the above test, it was confirmed that Compound (IA) has a suppressing effect on morphine-induced constipation. That is, it was considered that Compound (I) improves morphine-induced constipation and that constipation caused by administration of an opioid can be improved by using Compound (I) and an opioid in combination.
TEST EXAMPLE 3
Suppressing Activity of Compound (III) on Morphine Analgesic Tolerance
Experimental Materials and Methods
1. Used Animals
Male ddY mice (3 to 4 weeks old, Japan SLC, Inc.) having a body weight of 19 to 25 g were used, and the animals were maintained under the following conditions: 19 to 25° C. room temperature, 30 to 70% humidity, and 12-h light and dark cycle (light period: from 7 a.m. to 7 p.m., dark period: from 7 p.m. to 7 a.m.) until they were subjected to the experiment. Food and water were provided ad libitum.
2. Used Agents and Preparation Methods
Hereinafter, the test was performed under the instructions of narcotics researchers in accordance with the narcotic handling rule each time morphine was used. Morphine was dissolved in physiological saline at a concentration of 0.6 mg/mL and subcutaneously administered at a dose of 6 mg/kg. Compound (IIIB) was suspended in 0.5% MC at a concentration of 0.3 mg/mL and orally administered at a dose of 3 mg/kg. Compound (IIIC) was suspended in 0.5% MC at a concentration of 0.1 mg/mL and orally administered at a dose of 1 mg/kg.
3. Determination of Analgesic Activity
Nociceptive pain was determined by a hot plate method. Each mouse was placed on a hot plate apparatus (35100, Ugo Basile, Comerio, VA, Italy) set to 53° C., and the time (latency) until an escape response (paw-licking, -biting, -shaking, or jumping) was evoked was determined to be a pain threshold. In the experiment, animals having a response latency of 6 to 16 seconds before the first drug administration were used. Further, in order to minimize the damage to the site of stimulation, the cut-off time was set to 45 seconds. The analgesic activity was evaluated by determining the response latency before drug administration, and at 30, 60, and 120 minutes after drug administration, on the last day of repeated drug administration (on day 7).
4. Statistical Processing
The experimental results were expressed as mean±standard error. The statistical analysis was performed using a statistical analysis software SAS (SAS Institute Inc., Cary, N.C., USA). Comparison between two groups was performed using a Wilcoxn rank sum test. A p-value of less than 0.05 was considered to be a significant difference.
5. Experimental Results
The results are shown in Tables 1 and 2.







TABLE 1







Effect of Compound (IIIB) on Morphine Analgesic


Tolerance (Response Latency (sec))










Pre value




(before drug
ΔChange



administration
(Latency at each time point − Pre value)











Latency (sec)
on last day)
0.5 h
1 h
2 h





Single morphine
11.4 ± 0.8
21.9 ± 1.9 
11.8 ± 1.1 
2.9 ± 0.9


administration






group






Repeated morphine
 9.3 ± 0.6
 11.4 ± 1.3 **
 8.5 ± 0.8 *
3.4 ± 0.7


administration






group






Repeated
 9.6 ± 0.3
18.2 ± 1.2 ##
13.5 ± 0.8 ##
4.8 ± 0.7


combination






administration






group






Repeated Compound
10.7 ± 0.7
0.1 ± 0.5 
−0.1 ± 0.4  
0.4 ± 1.2


(IIIB) administration






group





** P < 0.01,


* P < 0.05 [Single morphine administration group vs. Repeated morphine administration group]


## P < 0.01 [Repeated morphine administration group vs. Repeated combination administration group]













TABLE 2







Effect of Compound (IIIC) on Morphine Analgesic


Tolerance (Response Latency (sec))










Pre value




(before drug
ΔChange



administration
(Latency at each time point − Pre value)











Latency (sec)
on last day)
0.5 h
1 h
2 h





Single morphine
10.7 ± 0.7
20.2 ± 1.9  
6.3 ± 1.7
2.3 ± 0.5


administration






group






Repeated morphine
10.8 ± 0.7
  7.7 ± 1.3 **
3.7 ± 1.0
1.7 ± 0.7


administration






group






Repeated
10.9 ± 0.7
16.1 ± 2.4 #
  9.3 ± 1.6 #
1.9 ± 0.9


combination






administration






group






Repeated Compound
12.4 ± 1.0
−2.2 ± 1.3 
−1.0 ± 0.7 
−1.0 ± 0.9 


(IIIC) administration






group





** P < 0.01 [Single morphine administration group vs. Repeated morphine administration group]


# P < 0.05 [Repeated morphine administration group vs. Repeated combination administration group]






In the group in which morphine was repeatedly administered for 7 days (repeated morphine administration group: twice a day, one-time administration only on day 7), the response latency was significantly and markedly decreased as compared with that of the single morphine administration group (physiological saline was repeatedly administered twice a day for 6 days, and morphine was administered only on day 7), and the development of analgesic tolerance was observed. In the repeated combination administration group in which Compound (IIIB) or (IIIC) was orally administered at 30 minutes before administration of morphine (repeated combination administration group: Compound (IIIB) or (IIIC) was administered at 30 minutes before each administration of morphine in repeated morphine administration group), a decrease in analgesic activity was not observed as compared with the single morphine administration group, and the development of analgesic tolerance was prevented. Incidentally, in the group in which Compound (IIIB) or (IIIC) was repeatedly administered alone (repeated Compound (IIIB) administration group, repeated Compound (IIIC) administration group), the effect on the response latency was not observed.
From the above test, it was confirmed that Compounds (MB) and (IIIC) have a suppressing effect on morphine analgesic tolerance. From this, it was considered that the development of analgesic tolerance following chronic opioid administration can be prevented by using Compound (III) such as Compound (IIIB) or (IIIC) and an opioid in combination.
TEST EXAMPLE 4
Suppressing Activity of Compounds (IC) and (ID) on Morphine Analgesic Tolerance
The effect of Compounds (IC) and (ID) on morphine analgesic tolerance was studied. The experiment was performed in the same manner as in Test Example 3. Compounds (IC) and (ID) were used at a dose of 10 mg/kg, respectively. The results are shown in Table 3. In the statistical analysis, comparison between two groups was performed using a Wilcoxn rank sum test, and comparison among multi-groups was performed using a Kruskal-Wallis test.







TABLE 3







Effect of Compounds (IC) and (ID) on Morphine


Analgesic Tolerance (Response Latency (sec))










Pre value




(before drug
ΔChange



administration
(Latency at each time point − Pre value)











Latency (sec)
on last day)
0.5 h
1 h
2 h





Single morphine
12.8 ± 1.5
19.5 ± 2.0 
6.4 ± 1.5
−0.8 ± 1.5 


administration






group






Repeated morphine
10.5 ± 1.4
 7.5 ± 1.3 **
  1.7 ± 1.5 **
1.2 ± 1.4


administration






group






Repeated
11.4 ± 1.2
16.0 ± 1.8 ##
5.1 ± 1.7
0.9 ± 1.3


combination






administration






group (Compound






(IC) and morphine)






Repeated
12.2 ± 1.4
14.3 ± 1.7 ##
  5.1 ± 1.3 #
−0.1 ± 1.4 


combination






administration






group (Compound






(ID) and morphine)






Repeated Compound
 9.8 ± 0.8
1.0 ± 0.7 
3.3 ± 1.2
1.7 ± 0.7


(IC) administration






group






Repeated Compound
 9.5 ± 0.7
2.1 ± 0.8 
2.3 ± 1.3
2.5 ± 0.9


(ID) administration






group





** P < 0.01 [Single morphine administration group vs. Repeated morphine administration group]


## P < 0.01, # P < 0.05 [Repeated morphine administration group vs. Repeated combination administration group]






In the group in which morphine was repeatedly administered for 7 days (repeated morphine administration group: twice a day, one-time administration only on day 7), the response latency was significantly and markedly decreased as compared with the single morphine administration group (physiological saline was repeatedly administered twice a day for 6 days, and morphine was administered only on day 7), and the development of analgesic tolerance was observed. In the repeated combination administration group in which Compound (IC) or (ID) was orally administered at 30 minutes before administration of morphine (repeated combination administration group: Compound (IC) or (ID) was administered at 30 minutes before each administration of morphine in repeated morphine administration group), the degree of the decrease in response latency was smaller as compared with that of the repeated morphine administration group, and the development of analgesic tolerance was prevented. Incidentally, in the group in which Compound (IC) or (ID) was repeatedly administered alone (repeated Compound (IC) administration group, repeated Compound (ID) administration group), the effect on the response latency was not observed.
From the above test, it was confirmed that Compounds (IC) and (ID) have a suppressing effect on morphine analgesic tolerance. From the results of this test and Test Example 1, it was considered that the development of analgesic tolerance following chronic opioid administration can be prevented by using Compound (I) such as Compound (IA), (IB), (IC), or (ID) and an opioid in combination.
TEST EXAMPLE 5
Suppressing Activity of Compounds (IIA), (VIA), and (VII) on Morphine Analgesic Tolerance
The effect of Compounds (IIA), (VIA), and (VII) on morphine analgesic tolerance was studied. The experiment was performed in the same manner as in Test Example 3. Compounds (IIA), (VIA), and (VII) were used at doses of 100 mg/kg, 30 mg/kg, and 60 mg/kg, respectively. The results are shown in Table 4. In the statistical analysis, comparison between two groups was performed using a Wilcoxn rank sum test, and comparison among multi-groups was performed using a Kruskal-Wallis test.







TABLE 4







Effect of Compounds (IIA), (VIA), and (VII) on Morphine


Analgesic Tolerance (Response Latency (sec))










Pre value




(before drug
ΔChange



administration
(Latency at each time point − Pre value)











Latency (sec)
on last day)
0.5 h
1 h
2 h





Single morphine
8.8 ± 0.6
16.8 ± 2.7
10.4 ± 2.2 
8.8 ± 0.6


administration






group






Repeated morphine
9.1 ± 0.9
  7.3 ± 1.2 *
5.4 ± 1.3
2.7 ± 0.8


administration






group






Repeated
8.2 ± 0.5
12.8 ± 1.9
6.4 ± 1.7
2.4 ± 1.2


combination






administration






group (Compound






(IIA) and morphine)






Repeated
8.6 ± 1.1
13.0 ± 2.4
7.6 ± 1.7
1.9 ± 1.3


combination






administration






group (Compound






(VIA) and morphine)






Repeated
8.2 ± 0.5
12.8 ± 2.1
7.8 ± 1.3
1.8 ± 0.8


combination






administration






group (Compound






(VII) and morphine)






Repeated Compound
9.9 ± 0.6
−0.8 ± 1.0
−0.7 ± 1.0 
0.0 ± 0.6


(VII) administration






group






Repeated Compound
9.7 ± 1.1
−0.8 ± 1.3
0.2 ± 2.1
−0.2 ± 1.1 


(VIA) administration






group






Repeated Compound
9.0 ± 0.7
 1.2 ± 1.5
1.7 ± 1.4
0.9 ± 1.1


(IIA) administration






group





* P < 0.05 [Single morphine administration group vs. Repeated morphine administration group]






In the group in which morphine was repeatedly administered for 7 days (repeated morphine administration group: twice a day, one-time administration only on day 7), the response latency was significantly and markedly decreased as compared with that of the single morphine administration group (physiological saline was repeatedly administered twice a day for 6 days, and morphine was administered only on day 7), and the development of analgesic tolerance was observed. In the repeated combination administration group in which Compound (IIA), (VIA), or (VII) was orally administered at 30 minutes before administration of morphine (repeated combination administration group: Compound (IIA), (VIA), or (VII) was administered at 30 minutes before each administration of morphine in repeated morphine administration group), the degree of the decrease in response latency was smaller as compared with that of the repeated morphine administration group, and the development of analgesic tolerance was prevented. Incidentally, in the group in which Compound (IIA), (VIA), or (VII) was repeatedly administered alone (repeated Compound (IIA) administration group, or repeated Compound (VIA) administration group, repeated Compound (VII) administration group), the effect on the response latency was not observed.
From the above test, it was confirmed that Compounds (IIA), (VIA), and (VII) have a suppressing effect on morphine analgesic tolerance. From the results of this test, it was considered that the development of analgesic tolerance following chronic opioid administration can be prevented by using Compound (II) such as Compound (IIA), Compound (VI) such as Compound (VIA), or Compound (VII) and an opioid in combination.
TEST EXAMPLE 6
Suppressing Activity of Compounds (IVA) and (VIII) on Morphine Analgesic Tolerance
The effect of Compounds (IVA) and (VIII) on morphine analgesic tolerance was studied. The experiment was performed in the same manner as in Test Example 3. Compounds (IVA) and (VIII) were used at a dose of 30 mg/kg, respectively. The results are shown in Table 5. In the statistical analysis, comparison between two groups was performed using a Wilcoxn rank sum test, and comparison among multi-groups was performed using a Kruskal-Wallis test.







TABLE 5







Effect of Compounds (IVA) and (VIII) on Morphine


Analgesic Tolerance (Response Latency (sec))










Pre value




(before drug
ΔChange



administration
(Latency at each time point − Pre value)











Latency (sec)
on last day)
0.5 h
1 h
2 h





Single morphine
12.4 ± 1.0
18.0 ± 2.2 
6.8 ± 1.3 
1.9 ± 1.0


administration group






Repeated morphine
12.0 ± 1.1
 6.8 ± 1.3 **
 3.1 ± 1.0 **
0.4 ± 0.9


administration group






Repeated combination
11.7 ± 0.9
14.9 ± 1.6 ##
8.3 ± 0.4 ##
0.7 ± 1.1


administration group






(Compound (IVA) and






morphine)






Repeated combination
12.3 ± 0.8
13.6 ± 1.6 ##
7.8 ± 0.8 ##
1.1 ± 0.8


administration group






(Compound (VIII) and






morphine)






Repeated Compound
12.6 ± 1.2
0.5 ± 0.6 
−0.4 ± 1.0    
−0.5 ± 1.4 


(IVA) administration






group






Repeated Compound
12.1 ± 1.1
−0.5 ± 0.9  
0.1 ± 0.9 
−1.1 ± 1.1 


(VIII) administration






group





** P < 0.01, * P < 0.05 [Single morphine administration group vs. Repeated morphine administration group]


## P < 0.01, # P < 0.05 [Repeated morphine administration group vs. Repeated combination administration group]






In the group in which morphine was repeatedly administered for 7 days (repeated morphine administration group: twice a day, one-time administration only on day 7), the response latency was significantly and markedly decreased as compared with that of the single morphine administration group (physiological saline was repeatedly administered twice a day for 6 days, and morphine was administered only on day 7), and the development of analgesic tolerance was observed. In the repeated combination administration group in which Compound (IVA) or (VIII) was orally administered at 30 minutes before administration of morphine (repeated combination administration group: Compound (IVA) or (VIII) was administered at 30 minutes before each administration of morphine in repeated morphine administration group), the degree of the decrease in response latency was smaller as compared with that of the repeated morphine administration group, and the development of analgesic tolerance was prevented. Incidentally, in the group in which Compound (IVA) or (VIII) was repeatedly administered alone (repeated Compound (IVA) administration group, or repeated Compound (VIII) administration group), the effect on the response latency was not observed.
From the above test, it was confirmed that Compounds (IVA) and (VIII) have a suppressing effect on morphine analgesic tolerance. From the results of this test, it was considered that the development of analgesic tolerance following chronic opioid administration can be prevented by using Compound (IV) such as Compound (IVA) or Compound (VIII) and an opioid in combination.
TEST EXAMPLE 7
Suppressing Activity of Compound (IA) on Oxycodone Analgesic Tolerance
Experimental Materials and Methods
1. Used Animals
Male ddY mice (3 to 4 weeks old, Japan SLC, Inc.) having a body weight of 18 to 23 g were used, and the animals were maintained under the following conditions: 19 to 25° C. room temperature, 30 to 70% humidity, and 12-h light and dark cycle (light period: from 7 a.m. to 7 p.m., dark period: from 7 p.m. to 7 a.m.) until they were subjected to the experiment. Food and water were provided ad libitum.
2. Used Agents and Preparation Methods
Hereinafter, the test was performed under the instructions of narcotics researchers in accordance with the narcotic handling rule each time oxycodone was used. Oxycodone was prepared at a concentration of 2 mg/mL using distilled water for injection and orally administered at a dose of 20 mg/kg. Compound (IA) was suspended in 0.5% MC at a concentration of 1 mg/mL and orally administered at a dose of 10 mg/kg.
3. Determination of Analgesic Activity
Nociceptive pain was determined by a hot plate method. Each mouse was placed on a hot plate apparatus (MK-350B, MUROMACHI KIKAI CO., LTD.) set to 53° C., and the time (latency) until an escape response (paw-licking, -biting, -shaking, or jumping) was evoked was determined to be a pain threshold. In the experiment, animals having a response latency of 6 to 16 seconds before the first drug administration were used. Further, in order to minimize the damage to the site of stimulation, the cut-off time was set to 45 seconds. The analgesic activity was evaluated by determining the response latency at 30, 60, and 120 minutes after drug administration on the last day of repeated drug administration (on day 4).
4. Statistical Processing
The experimental results were expressed as mean±standard error. The statistical analysis was performed using a statistical analysis software SAS. Comparison between two groups was performed using a Wilcoxn rank sum test. A p-value of less than 0.05 was considered to be a significant difference.
5. Experimental Results
The results are shown in Table 6.







TABLE 6







Effect of Compound (IA) on Oxycodone Analgesic


Tolerance (Response Latency (sec))










Pre value




(before drug
ΔChange



administration
(Latency at each time point − Pre value)











Latency (sec)
on last day)
0.5 h
1 h
2 h





Single oxycodone
11.7 ± 1.0
17.5 ± 4.2
11.8 ± 2.0
6.9 ± 2.4


administration group






Repeated oxycodone
12.4 ± 1.1
  5.9 ± 3.4 *
   2.7 ± 2.3 **
  0.1 ± 1.3 **


administration group






Repeated combination
11.9 ± 0.7
13.5 ± 2.6
 6.0 ± 1.6
2.2 ± 1.6


administration group






Repeated Compound
11.9 ± 1.2
−0.2 ± 1.7
−0.4 ± 2.2
−0.1 ± 2.2 


administration group





** P < 0.01, * P < 0.05 [Single oxycodone administration group vs. Repeated oxycodone administration group]






In the group in which oxycodone was repeatedly administered for 4 days (repeated oxycodone administration group: twice a day, one-time administration only on day 4), the response latency was significantly and markedly decreased as compared with that of the single oxycodone administration group (distilled water for injection was repeatedly administered twice a day for 3 days, and oxycodone was administered only on day 4), and the development of analgesic tolerance was observed. In the repeated combination administration group in which Compound (IA) was orally administered at 30 minutes before administration of oxycodone, the degree of the decrease in response latency was smaller as compared with that of the repeated oxycodone administration group, and the development of analgesic tolerance was prevented. Incidentally, in the group in which Compound (IA) was repeatedly administered alone (repeated Compound (IA) administration group), the effect on the response latency was not observed.
From the above test, it was confirmed that Compound (IA) has a suppressing effect on oxycodone analgesic tolerance.
It is known that Compound (IA) has potent and selective adenosine A2A receptor antagonistic activity (Eur. J. Pharmacol., 1994, 267(3), 335). Also, it is well known that Compounds (I) to (VIII) each have adenosine A2A receptor antagonistic activity (for example, Nature Reviews 2006, 5, 247, J. Med. Chem., 1993, 36, 1333, U.S. Pat. No. 5,587,378, WO 00/17201, WO 2005/063743, Bioorg. Med. Chem. Lett. 2007, 17, 1376, WO 2002/055524, WO 2003/011864, WO 2006/032273, WO 2002/055083, etc.).
Accordingly, from Test Examples 1 and 3 to 7, it was considered that a compound having adenosine A2A receptor antagonistic activity (for example, Compounds (I) to (VIII)) or a pharmaceutically acceptable salt thereof has a suppressing effect on opioid analgesic tolerance.
Further, from the above Test Example 2, it was considered that a compound having adenosine A2A receptor antagonistic activity (for example, Compounds (I) to (VIII)) or a pharmaceutically acceptable salt thereof improves constipation induced by an opioid such as morphine, and that constipation caused by administration of an opioid can be improved by using a compound having adenosine A2A receptor antagonistic activity (for example, Compounds (I) to (VIII)) or a pharmaceutically acceptable salt thereof and an opioid in combination.
That is, from the above Test Examples 1 to 7, it is considered that the undesirable effect (for example, analgesic tolerance, constipation, etc.) of an opioid can be suppressed by using a compound having adenosine A2A receptor antagonistic activity (for example, Compounds (I) to (VIII)) or a pharmaceutically acceptable salt thereof and an opioid in combination. Further, it is expected that an increase in the dose of an opioid can be prevented by using a compound having adenosine A2A receptor antagonistic activity (for example, Compounds (I) to (VIII)) or a pharmaceutically acceptable salt thereof and an opioid in combination, and as a result, it is considered that the undesirable effect (for example, drowsiness, wobble, respiratory depression, hallucination, anxiety, pruritus, etc.) of an opioid due to an increase in the dose of the opioid can be suppressed. That is, it is considered that use of a compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof and an opioid in combination is useful for the treatment and/or prevention of pain in which an undesirable effect of an opioid is reduced. Accordingly, the therapeutic and/or preventive agent for pain and the method for treating and/or preventing pain of the present invention are effective particularly in patients in which the useful effect of an opioid itself cannot be sufficiently achieved due to the undesirable effect (for example, analgesic tolerance, constipation, etc.) of an opioid such as morphine.
Hereinafter, the aspects of the present invention will be more specifically described with Examples, however, the scope of the present invention is not limited to these Examples.
EXAMPLE 1
Tablets having the following composition are prepared according to the conventional manner. Compound (IA) (40 g), lactose (286.8 g), and potato starch (60 g) are mixed, and then a 10% aqueous solution of hydroxypropyl cellulose (120 g) is added thereto. The resulting mixture is kneaded, granulated, dried, and sized according to the conventional manner, whereby granules for tableting are prepared. Magnesium stearate (1.2 g) is added thereto and mixed therewith, and the resulting mixture is tableted using a tableting machine (RT-15, manufactured by Kikusui Seisakusho Ltd.) with a punch having a diameter of 8 mm, whereby tablets (containing 20 mg of the active ingredient per tablet) are obtained.







TABLE 7





Formulation



















Compound (IA)
20
mg



Lactose
143.4
mg



Potato starch
30
mg



Hydroxypropyl cellulose
6
mg



Magnesium stearate
0.6
mg




200
mg









EXAMPLE 2
Tablets having the following composition are prepared in the same manner as in Example 1.







TABLE 8





Formulation



















Compound (IB)
20
mg



Lactose
143.4
mg



Potato starch
30
mg



Hydroxypropyl cellulose
6
mg



Magnesium stearate
0.6
mg




200
mg









EXAMPLE 3
Tablets having the following composition are prepared in the same manner as in Example 1.







TABLE 9





Formulation



















Compound (IIA)
20
mg



Lactose
143.4
mg



Potato starch
30
mg



Hydroxypropyl cellulose
6
mg



Magnesium stearate
0.6
mg




200
mg









EXAMPLE 4
Tablets having the following composition are prepared in the same manner as in Example 1.







TABLE 10





Formulation



















Compound (IIIA)
20
mg



Lactose
143.4
mg



Potato starch
30
mg



Hydroxypropyl cellulose
6
mg



Magnesium stearate
0.6
mg




200
mg









EXAMPLE 5
Tablets having the following composition are prepared in the same manner as in Example 1.







TABLE 11





Formulation



















Compound (IIIB)
20
mg



Lactose
143.4
mg



Potato starch
30
mg



Hydroxypropyl cellulose
6
mg



Magnesium stearate
0.6
mg




200
mg









EXAMPLE 6
Tablets having the following composition are prepared in the same manner as in Example 1.







TABLE 12





Formulation



















Compound (IIIC)
20
mg



Lactose
143.4
mg



Potato starch
30
mg



Hydroxypropyl cellulose
6
mg



Magnesium stearate
0.6
mg




200
mg









EXAMPLE 7
Tablets having the following composition are prepared in the same manner as in Example 1.







TABLE 13





Formulation



















Compound (IVA)
20
mg



Lactose
143.4
mg



Potato starch
30
mg



Hydroxypropyl cellulose
6
mg



Magnesium stearate
0.6
mg




200
mg









EXAMPLE 8
Tablets having the following composition are prepared in the same manner as in Example 1.







TABLE 14





Formulation



















Compound (V)
20
mg



Lactose
143.4
mg



Potato starch
30
mg



Hydroxypropyl cellulose
6
mg



Magnesium stearate
0.6
mg




200
mg










EXAMPLE 9
Tablets having the following composition are prepared in the same manner as in Example 1.







TABLE 15





Formulation



















Compound (VIA)
20
mg



Lactose
143.4
mg



Potato starch
30
mg



Hydroxypropyl cellulose
6
mg



Magnesium stearate
0.6
mg




200
mg










EXAMPLE 10
Tablets having the following composition are prepared in the same manner as in Example 1.







TABLE 16





Formulation



















Compound (VII)
20
mg



Lactose
143.4
mg



Potato starch
30
mg



Hydroxypropyl cellulose
6
mg



Magnesium stearate
0.6
mg




200
mg










EXAMPLE 11
Tablets having the following composition are prepared in the same manner as in Example 1.







TABLE 17





Formulation



















Morphine
20
mg



Lactose
143.4
mg



Potato starch
30
mg



Hydroxypropyl cellulose
6
mg



Magnesium stearate
0.6
mg




200
mg










EXAMPLE 12
Tablets having the following composition are prepared according to the conventional manner. Compound (IA) (40 g), morphine (40 g), lactose (246.8 g), and potato starch (60 g) are mixed, and then a 10% aqueous solution of hydroxypropyl cellulose (120 g) is added thereto. The resulting mixture is kneaded, granulated, dried, and sized according to the conventional manner, whereby granules for tableting are prepared. Magnesium stearate (1.2 g) is added thereto and mixed therewith, and the resulting mixture is tableted using a tableting machine (RT-15, manufactured by Kikusui Seisakusho Ltd.) with a punch having a diameter of 8 mm, whereby tablets (containing 20 mg of Compound (IA) and 20 mg of morphine per tablet) are obtained.







TABLE 18





Formulation



















Compound (IA)
20
mg



Morphine
20
mg



Lactose
123.4
mg



Potato starch
30
mg



Hydroxypropyl cellulose
6
mg



Magnesium stearate
0.6
mg




200
mg










EXAMPLE 13
Tablets having the following composition are prepared in the same manner as in Example 12.







TABLE 19





Formulation



















Compound (IB)
20
mg



Morphine
20
mg



Lactose
123.4
mg



Potato starch
30
mg



Hydroxypropyl cellulose
6
mg



Magnesium stearate
0.6
mg




200
mg










EXAMPLE 14
Tablets having the following composition are prepared in the same manner as in Example 12.







TABLE 20





Formulation



















Compound (IIA)
20
mg



Morphine
20
mg



Lactose
123.4
mg



Potato starch
30
mg



Hydroxypropyl cellulose
6
mg



Magnesium stearate
0.6
mg




200
mg










EXAMPLE 15
Tablets having the following composition are prepared in the same manner as in Example 12.







TABLE 21





Formulation



















Compound (IIIA)
20
mg



Morphine
20
mg



Lactose
123.4
mg



Potato starch
30
mg



Hydroxypropyl cellulose
6
mg



Magnesium stearate
0.6
mg




200
mg










EXAMPLE 16
An injection having the following composition is prepared according to the conventional manner. Compound (IB) (1 g) is added to distilled water for injection and mixed therewith. Hydrochloric acid and an aqueous solution of sodium hydroxide are further added thereto to adjust the pH of the mixture to 7, and distilled water for injection is added thereto to make the total amount 1000 mL. The obtained mixed liquid is aseptically filled in glass vials in an amount of 2 mL per vial, whereby injections (containing 2 mg of the active ingredient per vial) are obtained.







TABLE 22





Formulation



















Compound (IB)
2
mg










Hydrochloric acid
appropriate amount



Aqueous solution of sodium hydroxide
appropriate amount



Distilled water for injection
appropriate amount










2.00
mL










EXAMPLE 17
An injection having the following composition is prepared in the same manner as in Example 16.







TABLE 23





Formulation



















Compound (IVA)
2
mg










Hydrochloric acid
appropriate amount



Aqueous solution of sodium hydroxide
appropriate amount



Distilled water for injection
appropriate amount










2.00
mL










EXAMPLE 18
An Injection having the following composition is prepared in the same manner as in Example 16.







TABLE 24





Formulation



















Morphine
2
mg










Hydrochloric acid
appropriate amount



Aqueous solution of sodium hydroxide
appropriate amount



Distilled water for injection
appropriate amount










2.00
mL










EXAMPLE 19
An injection having the following composition is prepared according to the conventional manner. Compound (IB) (1 g) and morphine (1 g) are added to distilled water for injection and mixed therewith. Hydrochloric acid and an aqueous solution of sodium hydroxide are further added thereto to adjust the pH of the mixture to 7, and distilled water for injection is added thereto to make the total amount 1000 mL. The obtained mixed liquid is aseptically filled in glass vials in an amount of 2 mL per vial, whereby injections (containing 2 mg of Compound (IB) and 2 mg of morphine per vial) are obtained.







TABLE 25





Formulation



















Compound (IB)
2
mg



Morphine
2
mg










Hydrochloric acid
appropriate amount



Aqueous solution of sodium hydroxide
appropriate amount



Distilled water for injection
appropriate amount










2.00
mL










EXAMPLE 20
An injection having the following composition is prepared in the same manner as in Example 19.







TABLE 26





Formulation



















Compound (IB)
2
mg



Heroin
2
mg










Hydrochloric acid
appropriate amount



Aqueous solution of sodium hydroxide
appropriate amount



Distilled water for injection
appropriate amount










2.00
mL










EXAMPLE 21
An injection having the following composition is prepared in the same manner as in Example 19.







TABLE 27





Formulation



















Compound (IVA)
2
mg



Heroin
2
mg










Hydrochloric acid
appropriate amount



Aqueous solution of sodium hydroxide
appropriate amount



Distilled water for injection
appropriate amount










2.00
mL










EXAMPLE 22
An injection having the following composition is prepared in the same manner as in Example 19.







TABLE 28





Formulation



















Compound (V)
2
mg



Heroin
2
mg










Hydrochloric acid
appropriate amount



Aqueous solution of sodium hydroxide
appropriate amount



Distilled water for injection
appropriate amount










2.00
mL










Industrial Applicability

According to the present invention, an agent for suppressing an undesirable effect of an opioid-type analgesic (opioid), which comprises a compound having adenosine A2A receptor antagonistic activity or a pharmaceutically acceptable salt thereof as an active ingredient, and the like can be provided.
Description of Reference Numerals and Signs


    1. FIG. 1
    -♦-: Single morphine administration group
    -▴-: Repeated morphine administration group
    -●-: Repeated combination administration group
    -▪-: Repeated Compound (IA) administration group
    **: P<0.01 [Single morphine administration group vs. Repeated morphine administration group (Wilcoxn rank sum test)]
    ##: P<0.01 [Repeated morphine administration group vs. Repeated combination administration group (Wilcoxn rank sum test)]
    #: P<0.05 [Repeated morphine administration group vs. Repeated combination administration group (Wilcoxn rank sum test)]
    2. FIG. 2
    **: P<0.01 (Wilcoxn rank sum test)

## Claims

1. A method for suppressing an undesirable effect of an opioid, which comprises administering an effective amount of a compound represented by at least one of formulae (I) to (VIII), or a pharmaceutically acceptable salt thereof:






in which R1 represents a hydrogen atom or methyl; R2 and R3 independently represent methyl, ethyl, propyl, butyl or isopropyl; R4, R5 and R6 independently represent a hydrogen atom, methyl, ethyl, methoxy, ethoxy, a fluorine atom, a chlorine atom or a bromine atom; R7 represents methyl, ethyl, propyl, butyl or 3-methylbutyl, each of which is optionally substituted with hydroxy; R8 represents phenyl, pyridyl, pyrimidinyl or 5,6-dihydro-2H-pyridylmethyl, each of which is optionally substituted with 1 to 3 substituents selected from the group consisting of a chlorine atom, methyl, ethyl, methoxy and ethoxy; R9 represents pyridyl or tetrahydropyranyl; R10 and R11 independently represent a hydrogen atom, a fluorine atom or 2-methoxyethoxy; and R12 represents methyl, ethyl, propyl or butyl, wherein
said undesirable effect is analgesic tolerance.

2. The method according to claim 1, wherein the opioid is selected from the group consisting of anileridine, opium, ampromide, allylprodine, alphaprodine, alfentanil, isomethadone, ethylmethylthiambutene, ethylmorphine, ethoheptazine, etonitazene, eptazocine, endorphin, enkephalin, oxycodone, oxymorphone, clonitazene, ketobemidone, cocaine, codeine, cylmorphan, diamorphone, dioxaphetylbutyrate, didezocine, dinorphine, dihydrocodeine, dihydromorphine, dipipanone, dimethylthiambutene, dimenoxadol, dimepheptanol, sufentanil, tilidine, dextromoramide, desomorphine, tramadol, narceine, nalorphine, nalbuphene, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, papaveretum, hydrocodone, hydroxypethidine, hydromorphone, piminodine, piritramide, fentanyl, phenazocine, phenadoxone, phenoperidine, phenomorphan, butorphanol, buprenorphine, properidine, propoxyphene, propheptazine, promedol, heroin, bezitramide, berzylmorphine, pentazocine, myrophine, methadone, metazocine, metopon, meptazinol, meperidine, morphine, levallorphan, levophenalofentanil, levorphanol, and remifentanil.

3. The method according to claim 1, wherein the opioid is morphine.

4. The method according to claim 1, wherein the compound is represented by at least one of formula (IA), (IB), (IC), (ID), (IIA), (IIIA), (IIIB), (IIIC), (IVA), (V), (VIA), (VII) or (VIII), or a pharmaceutically acceptable salt thereof:

5. The method according to claim 1, wherein the compound is represented by at least one of formula (IA) or (IB), or a pharmaceutically acceptable salt thereof:

6. The method according to claim 1, wherein the compound is represented by formula (IIIC), or a pharmaceutically acceptable salt thereof:

7. The method according to claim 4, wherein the opioid is selected from the group consisting of anileridine, opium, ampromide, allylprodine, alphaprodine, alfentanil, isomethadone, ethylmethylthiambutene, ethylmorphine, ethoheptazine, etonitazene, eptazocine, endorphin, enkephalin, oxycodone, oxymorphone, clonitazene, ketobemidone, cocaine, codeine, cylmorphan, diamorphone, dioxaphetylbutyrate, didezocine, dinorphine, dihydrocodeine, dihydromorphine, dipipanone, dimethylthiambutene, dimenoxadol, dimepheptanol, sufentanil, tilidine, dextromoramide, desomorphine, tramadol, narceine, nalorphine, nalbuphene, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, papaveretum, hydrocodone, hydroxypethidine, hydromorphone, piminodine, piritramide, fentanyl, phenazocine, phenadoxone, phenoperidine, phenomorphan, butorphanol, buprenorphine, properidine, propoxyphene, propheptazine, promedol, heroin, bezitramide, berzylmorphine, pentazocine, myrophine, methadone, metazocine, metopon, meptazinol, meperidine, morphine, levallorphan, levophenalofentanil, levorphanol, and remifentanil.

8. The method according to claim 4, wherein the opioid is morphine.

9. The method according to claim 5, wherein the opioid is selected from the group consisting of anileridine, opium, ampromide, allylprodine, alphaprodine, alfentanil, isomethadone, ethylmethylthiambutene, ethylmorphine, ethoheptazine, etonitazene, eptazocine, endorphin, enkephalin, oxycodone, oxymorphone, clonitazene, ketobemidone, cocaine, codeine, cylmorphan, diamorphone, dioxaphetylbutyrate, didezocine, dinorphine, dihydrocodeine, dihydromorphine, dipipanone, dimethylthiambutene, dimenoxadol, dimepheptanol, sufentanil, tilidine, dextromoramide, desomorphine, tramadol, narceine, nalorphine, nalbuphene, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, papaveretum, hydrocodone, hydroxypethidine, hydromorphone, piminodine, piritramide, fentanyl, phenazocine, phenadoxone, phenoperidine, phenomorphan, butorphanol, buprenorphine, properidine, propoxyphene, propheptazine, promedol, heroin, bezitramide, berzylmorphine, pentazocine, myrophine, methadone, metazocine, metopon, meptazinol, meperidine, morphine, levallorphan, levophenalofentanil, levorphanol, and remifentanil.

10. The method according to claim 5, wherein the opioid is morphine.

11. The method according to claim 6, wherein the opioid is selected from the group consisting of anileridine, opium, ampromide, allylprodine, alphaprodine, alfentanil, isomethadone, ethylmethylthiambutene, ethylmorphine, ethoheptazine, etonitazene, eptazocine, endorphin, enkephalin, oxycodone, oxymorphone, clonitazene, ketobemidone, cocaine, codeine, cylmorphan, diamorphone, dioxaphetylbutyrate, didezocine, dinorphine, dihydrocodeine, dihydromorphine, dipipanone, dimethylthiambutene, dimenoxadol, dimepheptanol, sufentanil, tilidine, dextromoramide, desomorphine, tramadol, narceine, nalorphine, nalbuphene, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, papaveretum, hydrocodone, hydroxypethidine, hydromorphone, piminodine, piritramide, fentanyl, phenazocine, phenadoxone, phenoperidine, phenomorphan, butorphanol, buprenorphine, properidine, propoxyphene, propheptazine, promedol, heroin, bezitramide, berzylmorphine, pentazocine, myrophine, methadone, metazocine, metopon, meptazinol, meperidine, morphine, levallorphan, levophenalofentanil, levorphanol, and remifentanil.

12. The method according to claim 6, wherein the opioid is morphine.