USE OF 2-PHENYL-6-(1H-IMIDAZOL-1-YL) QUINAZOLINE FOR THE PREVENTION OF ABUSE AND OF SIDE EFFECTS OF AT LEAST ONE OPIOID

Abstract

The present invention relates to a compound of formula 2-phenyl-6-(1H-imidazol-1-yl) quinazoline (CR4056) or a pharmaceutically acceptable salt thereof for use in the prevention of abuse in an opioid non-addicted subject and other side effects of at least one opioid. The invention also relates to a composition or a pharmaceutical kit comprising a compound of formula 2-phenyl-6-(1Himidazol-1-yl) quinazoline (CR4056) or one of its pharmaceutically acceptable salts and at least one opioid for use in the prevention of abuse in an opioid non-addicted subject and other side effects of at least one opioid.

Claims

1-15. (canceled)

16. A method for the prevention of side effects to at least one opioid in a subject in need thereof, wherein said method comprises the step of administering to the subject a compound of formula 2-phenyl-6-(1H-imidazol-1-yl) quinazoline (CR4056) or a pharmaceutically acceptable salt thereof, wherein the side effects are selected from chronic constipation and sedation.

17. The method according to claim 16, wherein the prevention of side effects to at least one opioid occurs during a pharmacological pain therapy and consists in the co-administration of 2-phenyl-6-(1H-imidazol-1-yl) quinazoline (CR4056) or a pharmaceutically acceptable salt thereof with the at least one opioid.

18. The method according to claim 16, wherein the at least one opioid is a mu-opioid receptor (MOR) agonist selected from the group consisting of morphine, codeine, dextromethorphan, dextropropoxyphene, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine methadone, oxycodone, oxymorphone, and/or their pharmaceutically acceptable salts.

19. The method according to claim 18, wherein the at least one opioid is morphine or a pharmaceutically acceptable salt thereof.

20. The method according to claim 17, wherein the compound of formula 2-phenyl-6-(1H-imidazol-1-yl) quinazoline (CR4056) or a pharmaceutically acceptable salt thereof and/or the at least one opioid are administered by the oral or any topical or parenteral routes of administration.

21. The method according to claim 18, wherein the compound of formula 2-phenyl-6-(1H-imidazol-1-yl) quinazoline (CR4056) or a pharmaceutically acceptable salt thereof is administered in an amount in the range from 10 to 400 mg/die.

22. A method for the prevention of side effects to at least one opioid in a subject in need thereof, wherein said method comprises the step of administering to the subject a composition comprising a compound of formula 2-phenyl-6-(1H-imidazol-1-yl) quinazoline (CR4056) or a pharmaceutically acceptable salt thereof and at least one opioid, wherein the side effects are selected chronic constipation and sedation, wherein the compound of formula 2-phenyl-6-(1H-imidazol-1-yl) quinazoline (CR4056) or a pharmaceutically acceptable salt thereof is administered in an amount in the range from 10 to 400 mg/die.

23. The method according to claim 22, wherein the at least one opioid is a MOR agonist selected from the group consisting of morphine, codeine, dextromethorphan, dextropropoxyphene, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine methadone, oxycodone, oxymorphone, and/or their pharmaceutically acceptable salts.

24. The method according to claim 22, wherein the at least one opioid is morphine or a pharmaceutically acceptable salt thereof.

25. The method according to claim 22, wherein the composition comprises also pharmaceutically acceptable excipients suitable for the final form of administration.

26. A method for the prevention of side effects to at least one opioid in a subject in need thereof comprising the step of using simultaneously, sequentially or separately the elements of a pharmaceutical kit for the administration to said subject, said pharmaceutical kit comprising: one or more discrete units of the compound of formula 2-phenyl-6-(1Himidazol-1-yl) quinazoline (CR4056) or a pharmaceutically acceptable salt thereof and one or more discrete units of an opioid, wherein the side effects are selected from chronic constipation and sedation.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0050] FIG. 1 shows the effects of different doses of morphine (panel A), CR4056 (B), and their combination (C) on inflammatory pain induced by complete Freund adjuvant (CFA) (*P<0.05 and **P<0.01 vs control; statistical analysis of sham animals not performed);

[0051] FIG. 2 shows the effect of CR4056 on defecation in normal rats, in comparison to codeine alone and to the CR4056-codeine combination treatment (Data represent the mean faecal number±SEM (n=6 per group) evaluated 16 h after drug treatment);

[0052] FIG. 3 shows the effect of CR4056 on morphine-induced constipation in rats (The faecal number was evaluated 16 h after drug treatment. Panel A: Morphine (10 mg/kg) induced a significant decrease in faecal number (*P<0.05 vs vehicle). The co-treatment of morphine with an analgesic dose of CR4056 did not further reduce stool number in comparison with morphine alone. Panel B: morphine and CR4056 co-administered at non-analgesic doses per se (1 mg/kg) did not induce constipation in rats, although this combination exerts a synergistic full analgesic effect as described above);

[0053] FIG. 4 shows the dose-response sedative effect of morphine in the rodent open field test (panel A) and absence of sedation with low dose morphine combined with low dose CR4056 (panel B);

[0054] FIG. 5 shows the absence of sedation or of potentiation of sedation in the rodent open field test with different doses of morphine combined with low or full analgesic doses of CR4056;

[0055] FIG. 6 shows the effects of a sedative dose of morphine and its combination with CR4056 on sedation scores (panel A) and rotarod test (panel B);

[0056] FIG. 7 shows the effects of a low, non-sedative dose of morphine with or without CR4056 low or full analgesic doses on sedation scores (panel A) and rotarod test (panel B).

[0057] The features and advantages of the present invention will be evident from the following detailed description and from the embodiments provided by way of illustrative and non-limiting examples.

DETAILED DESCRIPTION OF THE INVENTION

[0058] The invention therefore relates to a compound of formula 2-phenyl-6-(1H-imidazol-1-yl) quinazoline (CR4056) or a pharmaceutically acceptable salt thereof for use in the prevention of abuse of at least one opioid in an opioid non-addicted subject. Preferably, the compound for use according to claim 1 wherein the prevention of the abuse according to the invention comprises the prevention of side effects to at least one opioid, more preferably selected from chronic constipation and a sedative effect, where the latter precedes and may predict the most dangerous opioid side effect consisting in respiratory depression.

[0059] According to the invention, the prevention of the abuse occurs during a pharmacological pain therapy and consists in the co-administration of 2-phenyl-6-(1H-imidazol-1-yl) quinazoline (CR4056) or a pharmaceutically acceptable salt thereof with the at least one opioid in an opioid non-addicted subject.

[0060] Preferably, the at least one opioid is a mu-opioid receptor (MOR) agonist selected from the group consisting of morphine, codeine, dextromethorphan, dextropropoxyphene, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine methadone, oxycodone, oxymorphone, and/or their pharmaceutically acceptable salts. More preferably, the at least one opioid is morphine or a pharmaceutically acceptable salt thereof.

[0061] During the pharmacological therapy of pain, the compound of formula 2-phenyl-6-(1H-imidazol-1-yl) quinazoline (CR4056) or a pharmaceutically acceptable salt thereof and/or the at least one opioid are preferably administered by the oral or any topical or parenteral routes of administration, including e.g. the transdermal, subcutaneous, intramuscular, intracerebroventricular, intrathecal, intranasal, inhaled, rectal routes.

[0062] During the pharmacological therapy of pain, the at least one opioid is in an amount which is suboptimal as analgesic per se, but able to be potentiated while devoid of abuse and/or some side effect liability.

[0063] In fact, the at least one opioid should be in an amount able to be potentiated to provide full or almost full analgesia, but devoid or almost devoid of abuse and some side effect liability. The weight ratio between the compound of formula 2-phenyl-6-(1H-imidazol-1-yl) quinazoline (CR4056) and the at least one opioid is depending on the analgesic potency, side effect profile and route of administration of the opioid: according to the present invention, it is deduced that it is generally possible to reduce the daily therapeutic dosage of an at least one opioid from 1 to over 5 folds compared with the use as monotherapy.

[0064] Preferably, the at least one opioid in an amount which is suboptimal per se is morphine or one of its pharmaceutically acceptable salts.

[0065] The compound of formula 2-phenyl-6-(1H-imidazol-1-yl) quinazoline (CR4056) or a pharmaceutically acceptable salt thereof is orally administered in an amount in the range from 10 to 400 mg/die.

[0066] In another aspect the invention relates to a composition comprising a compound of formula 2-phenyl-6-(1H-imidazol-1-yl) quinazoline (CR4056) or a pharmaceutically acceptable salt thereof and at least one opioid for use in the prevention of abuse of that opioid in an opioid non-addicted subject and of some side effects to that opioid, such as chronic constipation or a sedative effect. Preferably the composition comprises the at least one opioid in an amount which is suboptimal as analgesic per se, but able to be potentiated while devoid of abuse and/or some side effect liability, and the compound of formula 2-phenyl-6-(1H-imidazol-1-yl) quinazoline (CR4056) or a pharmaceutically acceptable salt thereof in an amount in the range from 10 to 400 mg/die.

[0067] In the composition according to the invention, the at least one opioid is a MOR agonist preferably selected from the group consisting of morphine, codeine, dextromethorphan, dextropropoxyphene, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine methadone, oxycodone, oxymorphone, and/or their pharmaceutically acceptable salts. More preferably, the at least one opioid is morphine or a pharmaceutically acceptable salt thereof.

[0068] The composition for the use can be formulated through a pharmaceutical form suitable for the desired administration. The composition for the use can therefore also comprise pharmaceutically acceptable excipients and technologies suitable for the final route of administration.

[0069] The pharmaceutical compositions for the use according to the invention can hence be prepared by adding to the compound CR4056, or a pharmaceutically acceptable salt thereof, and to the at least one opioid as selected, pharmacologically acceptable inactive ingredients such as excipients, binders, dispersants, colorants, humectants, commonly used for the preparation of tablets, capsules, pills, solutions, suspensions, emulsions in the case of oral administration. Isotonic solutions and other media are also contemplated which can be locally or parenterally administered, (including e.g. the transdermal, subcutaneous, intramuscular, intracerebroventricular, intrathecal, intranasal, inhaled, rectal routes).

[0070] All the pharmaceutical compositions for the uses described above can be prepared by methods known in the state of the art in relation to the specific administration route.

[0071] In another aspect the invention relates to a pharmaceutical kit comprising: [0072] one or more discrete units of the compound of formula 2-phenyl-6-(1Himidazol-1-yl) quinazoline (CR4056) or a pharmaceutically acceptable salt thereof and [0073] one or more discrete units of an opioid

[0074] for simultaneous, sequential or separate use in the prevention of abuse of that opioid in an opioid non-addicted subject.

[0075] Also for the kit for use of the invention the prevention of abuse comprises the prevention of side effects to at least one opioid, preferably selected from chronic constipation and a sedative effect.

[0076] Below are provided examples of embodiments of the present invention in an illustrative and not limiting fashion.

EXAMPLES

Example 1

[0077] CR4056 does not synergize with opioids on abuse Conditioned place preference (CPP) is a commonly used experimental paradigm that measures reward behaviours associated with drug abuse. This test exploits the tendency of rats to associate the environment where they are located with the effect of drugs administered during a conditioning period. The experiment was done in a wooden apparatus consisting of two lateral chambers (30×25 cm, length×width) with different visual and tactile properties and a central “neutral” chamber, smaller than the others (12×25 cm, length×width) with total white floor and walls. The lateral chambers had different decoration of walls (points or stripes) and different type of floor (smooth or rough). These differences can be recognized by rats, and thus associated with the effect of drug or vehicle treatment. All walls were 38.5 cm high. Four days before the preconditioning phase, the light/dark cycle was inverted; all phases of experiments were performed during the dark phase. On the preconditioning day (day 1), Wistar rats (Charles River) were placed in the neutral chamber and for 15 min they were free to explore all the environments of the apparatus (van der Kam E. L. et al. Pain, 2008, 136:373-379). The time spent in each chamber was recorded with a video tracking software (Ethovision XT 13, Noldus information technology). Rats that spent over 60% of time in one of two lateral chambers were not admitted to the conditioning phase: for admitted animals, the “preferred” chamber was therefore the one where a rat spent between 50% and 60% of time during preconditioning (while the “unpreferred” chamber was the opposite one). After preconditioning, rats were randomly assigned to the experimental groups (n=16). A total of 256 rats were used in this model. During the 2 days of the conditioning phase rats were treated with the test drug(s) (day 2) or vehicle (day 3). On the first conditioning day rats were treated with the test drug(s) and were confined in the preconditioning unpreferred lateral chamber (now defined paired chamber), with no access to the other chambers of the apparatus for 40 min. On the second day of conditioning rats were treated with vehicle and were located in the opposite chamber (unpaired chamber). The control group received vehicle in both chambers. CR4056 or its vehicle were administered 40 min before conditioning, whereas morphine or its vehicle were administered immediately before conditioning. There was no treatment on the test day (day 4), when rats were placed in the neutral chamber with the possibility to explore all chambers of the apparatus. The time spent in each chamber was recorded. A significant difference between the mean time spent in the paired vs the unpaired chamber on the test day suggests the potential for a drug to induce preference (i.e. to induce a rewarding effect and thus to exert an abuse liability) (Mueller D. et al., Behavioural Brain Research 2002, 136:389-397).

[0078] In this set of experiments, three doses of morphine were administered alone. Results are reported in Table 1 and show that morphine induced preference for the paired chamber in a dose dependent manner already after acute administration. Actually, 1 mg/kg of morphine did not induce preference while doses of 2.5 and 5 mg/kg induced a statistically significant difference of time spent by rats in the paired vs the unpaired chamber.

TABLE-US-00001 TABLE 1 “Conditioned Place Preference” (CPP): Effects of morphine, CR4056, and their combination after single administration Seconds Seconds in Seconds in in Paired Neutral Unpaired chamber chamber chamber Δ(P − %(P − Treatment (P) (N) (U) U) ± ES U) Saline 344 197 359  .sup. −15.2 ± 9.3 −2.3 Morphine 348 211 341   .sup. 7.6 ± 9.4 1.2 (1 mg/Kg) Morphine 411 198 291 120.5(*) ± 20.7 17.1 (2.5 mg/Kg) Morphine 358 276 266 132.1(*) ± 26.5 20.2 (5 mg/Kg) CR4056 (6 326 220 354 .sup. −5.6 ± 86 −0.5 mg/kg) + Saline CR4056 (6 340 213 347  .sup. −7.9 ± 9.9 −1.1 mg/kg) + Morphine (1 mg/kg) CR4056 (6 417 194 289   .sup.  128.1 ± 16.2(*) 18.1 mg/kg) + Morphine (5 mg/kg) (*)Paired t-test < 0.05

[0079] The bottom half of Table 1 reports the effects of CR4056 and of the co-administration of morphine with CR4056. The full analgesic dose of CR4056 (6 mg/kg) did not induce place preference alone and did not potentiate morphine either at the CPP inactive dose of 1 mg/kg or at the CPP active dose of 5 mg/kg morphine. In Table 2 are reported the results of conditioned place preference performed after repeated administrations. CR4056 (1 mg/kg) and morphine (1 mg/kg) alone or in co-administration were administered every other day. After 8 days of conditioning the test day was held as described above.

TABLE-US-00002 TABLE 2 “Conditioned Place Preference” (CPP): Effects of morphine and its combination with CR4056 after repeated administrations Seconds Seconds in Seconds in in Paired Neutral Unpaired chamber chamber chamber Δ(P − %(P − Treatment (P) (N) (U) U) ± ES U) Saline 321 253 326 −5 ± 12   −1 Morphine 390 215 295 95 ± 17 (*) +14 (1 mg/kg) CR4056 (1 331 246 323 8 ± 13  +1 mg/kg) + Morphine (1 mg/kg) (*): Paired t-test < 0.05

[0080] The results showed that 1 mg/kg of morphine (inactive after single conditioning) induced preference after repeated conditionings. There was, indeed, a significant preference for the paired chamber in rats treated with morphine 1 mg/kg alone. The co-administration of CR4056 and morphine, as already noted in the experiment with single conditioning, did not induce preference for the paired chamber.

[0081] Of note, 1 mg/kg of morphine is not analgesic per se and it is potentiated to full analgesia by the non-analgesic dose of 1 mg/kg CR4056: FIG. 1 depicts the known analgesic effects of CR4056, morphine and their combination in the inflammatory pain paradigm induced by CFA.

[0082] This set of experiments shows therefore that CR4056 does not potentiate experimental abuse liability of single dose morphine and can even prevent the development of abuse after repeated doses of morphine. This finding is surprisingly at variance with the known effects of CR4056 and other imidazoline-I2 agonists in potentiating morphine analgesia and, consequently, in preventing the development of tolerance and of withdrawal symptoms.

Example 2

[0083] CR4056 does not Synergize with Opioids on Opioid-Induced Constipation

[0084] To rule out the possibility that synergism existed for the typical adverse reactions to opioids, CR4056 was studied in a rodent model of opioid-induced constipation. Activation of mu-opioid receptors (MORs) in the gastrointestinal tract inhibits propulsive peristalsis, thus slowing intestinal transit. Opioid-induced constipation is common and can arise at any time during treatment, because tolerance develops to the analgesic effects and upper gastrointestinal motility effects, but not to colon motility effects (Akbarali H. I. et al. Neurogastroenterol Motil. 2014, 26:1361-1367).

[0085] The aim of the present experiment was to evaluate if a possible synergistic activity between CR4056 and morphine or codeine occurred on constipation, a typical adverse effect induced by opioids.

[0086] The experiments were conducted according to the procedure described by Harada et al. (J. Pharmacol. Exp. Ther. 2017, 362: 78-84). Wistar rats were used in this model. Fecal excretion was evaluated at the end of the dark phase of the light/dark cycle, when most activities and feeding of albino rats take place. Drugs were administered 2 h before the dark phase of the light/dark cycle, and the feces were collected and counted 16 h after drug treatment. In this experimental paradigm, CR4056 1 or 6 mg/kg was administered orally 15 min before morphine or codeine. A full analgesic dose of morphine (10 mg/kg subcutaneous) or codeine (12 mg/kg oral) were administered 15 minutes after CR4056 or vehicle.

[0087] The results obtained are shown in FIGS. 2 and 3.

[0088] FIG. 2 shows the effect of the administration of CR4056 6 mg/kg on defecation in comparison to codeine 12 mg/kg and to the CR4056-codeine combination treatment. Codeine alone induced a significant decrease in defecation compared with vehicle or CR4056. The co-administration of a full analgesic dose of CR4056 did not worsen codeine-induced constipation and thus did not show a synergistic or additive modulation of this opioid adverse effect.

[0089] FIG. 3 Panel A shows the effect on defecation of full analgesic doses of morphine and CR4056, 10 mg/kg or 6 mg/kg, respectively. Morphine significantly reduced faecal count (P<0.05 vs vehicle; Tukey's multiple comparisons test) and thus induced constipation. Under these experimental conditions, co-administration of CR4056 with morphine did not worsen opioid-induced constipation; rather there was a trend for improvement. Importantly, the low doses of CR4056 1 mg/kg and morphine 1 mg/kg that act synergistically in analgesia (see above), did not induce constipation when co-administered (FIG. 3, Panel B).

[0090] This set of experiments shows therefore that regardless of the dose administered, CR4056 did not worsen morphine or codeine-induced constipation. Most importantly, there was no constipation when the low doses of CR4056 and morphine were combined, despite the known synergistic analgesic effects described above.

Example 3

[0091] CR4056 does not Synergize with Opioids on Opioid-Induced Sedation

[0092] To confirm that there is no synergism also for other typical adverse reactions to opioids, CR4056 was studied in rodent models of opioid-induced sedation.

[0093] The so-called open field test was used as a first model and the experiments were performed according to the procedure described by Haleem and Nawaz (Pain, 2017, 18:19-28). Drugs were administered 60 min (CR4056 or its vehicle, p.o.) and 30 min (morphine or its vehicle, s.c.) before the open field test. The video tracking was performed using the software Ethovision XT 13 (Noldus Information Technology), to assess the “distance travelled” as the primary parameter of sedation in this model. The test was performed every day after 4 days of repeated treatment.

[0094] The second model consisted of the rotarod performance test for the evaluation of the impairment of motor coordination as a sedation effect (Chuck T. L. et al. Life Sci, 2006, 79:154-161). The rotarod paradigm consists of a rotating cylinder suspended above the floor, on which rodents try to stay in order to avoid falling to the ground. The test had a duration of 2 days. On day 1 each rat did four trials on the rotarod apparatus (Rota-Rod/RS, Panlab, Spain) at a constant speed of 5 rpm during the first and second trials, and of 10 rpm during the third and fourth trials. For each trial, the time of endurance on rotarod (latency) was recorded and the mean value (2 min.) was used as the cut-off during the selection day. The rats that passed the selection (80%, while 20% had to be discarded), were randomly assigned to the experimental groups on day 2. The apparatus was set to acceleration mode: the speed of rotation increased from 0 to 40 rpm in 5 min that was the cut-off of the experiment. Four trials were performed during the test day: the first one immediately before treatment, and the following trials 15, 30 and 45 min after treatment. Sedation consisted in a worsening of performance.

[0095] In addition, sedation was scored before each rotarod testing by the sedation rating scale. This scale consists of a panel of 8 parameters (ocular ptosis, head position, posture, muscle tone, spontaneous movements, exploration, righting reflex, corneal reflex) recorded by the operator after drug administration (Chuck T. L. et al. Life Sci, 2006, 79:154-161). At each time point, a score from 0 (maximum sedation) to 5 (absent sedation) was assigned to each of the 8 parameters. The sum of the scores produced the total score.

[0096] Results of these experiments are reported in the figures that follow.

[0097] FIG. 4A reports the effect of morphine on locomotor activity in the open field test. The results showed a clear sedative effect of morphine at doses higher than 5 mg/kg. Lower doses of morphine were not sedative and, in line with literature data in rodents (Nestler E. J. et al. Semin. Neurosci. 1997, 9: 84-93), there was a modest sensitization in the range 1-2.5 mg/kg, as reflected by increased locomotor activity over the 4 days of repeated treatment.

[0098] Notably, a low dose of 1 mg/kg CR4056 which is able to potentiate the analgesic effect of a low dose of morphine 1 mg/kg (see above) is not sedative per se and it is not able to potentiate this morphine low dose to exert a sedative effect (FIG. 4B).

[0099] FIG. 5 shows that CR4056 did not change the locomotor activity profile of non-sedative and sedative doses of morphine (2.5, 5 and 7.5 mg/kg in panels A, B, or C, respectively) at low or full analgesic doses (1 and 6 mg/kg, respectively). The results obtained from the sedation rating scale and rotarod test are reported in FIG. 6 (panels A and B). A dose of 10 mg/kg morphine was clearly sedative in these models compared with controls, and was therefore used for the evaluation of possible synergistic interactions with CR4056. Low and high doses of CR4056 (1 and 6 mg/kg, respectively) did not further worsen but even tended to improve the performance of rats treated with 10 mg/kg morphine, with a significant difference in sedation scores at the higher dose of CR4056.

[0100] As shown in FIG. 7, there were no significant changes in performance vs. control rats when morphine was administered at a non-sedative dose of 1 mg/kg, alone or in combination with different doses of CR4056.