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Title:
USE OF (R)-9-(2,5-DIFLUOROPHENETHYL)-4-ETHYL-2-METHYL-1-OXA-4,9-DIAZASPIRO[5.5]UNDECAN-3-ONE FOR THE TREATMENT OF NOCICEPTIVE PAIN, NEUROPATHIC PAIN, OSTEOARTHRITIS PAIN AND CANCER PAIN, WHILE HAVING REDUCED SIDE EFFECTS COMPARED TO OPIOIDS
Document Type and Number:
WIPO Patent Application WO/2021/018824
Kind Code:
A1
Abstract:
The present invention relates (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9- diazaspiro[5.5]undecan-3-one, or a pharmaceutical acceptable salt thereof, for use in the treatment of nociceptive pain, neuropathic pain, osteoarthritis pain or cancer pain, while showing no tolerance after repeated administration and having reduced undesirable side effects as compared to strong opioids.

Inventors:
FERNANDEZ-PASTOR BEGOÑA (ES)
VIDAL-TORRES ALBA (ES)
CARCOLE-ESTRADA MIREIA (ES)
MALDONADO-LOPEZ RAFAEL (ES)
VELA-HERNANDEZ JOSE-MIGUEL (ES)
MERLOS ROCA MANUEL (ES)
ZAMANILLO CASTANEDO DANIEL (ES)
Application Number:
PCT/EP2020/071096
Publication Date:
February 04, 2021
Filing Date:
July 27, 2020
Export Citation:
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Assignee:
ESTEVE PHARMACEUTICALS SA (ES)
International Classes:
A61K31/537; A61P29/00
Domestic Patent References:
WO2015185209A12015-12-10
WO2019076475A12019-04-25
WO2017016669A12017-02-02
WO2015185207A12015-12-10
WO2015185209A12015-12-10
WO2017016669A12017-02-02
Other References:
NEES T A ET AL: "Pharmacological treatment of osteoarthritis-related pain", SCHMERZ, DER, SPRINGER VERLAG, BERLIN, DE, vol. 33, no. 1, 11 April 2018 (2018-04-11), pages 30 - 48, XP036700949, ISSN: 0932-433X, [retrieved on 20180411], DOI: 10.1007/S00482-018-0286-6
TURK DCWILSON HDCAHANA A: "Treatment of chronic non-cancer pain", LANCET, vol. 377, 2011, pages 2226 - 2235, XP055117246, DOI: 10.1016/S0140-6736(11)60402-9
GOLDBERG DSMCGEE SJ: "Pain as a global public health priority", BMC PUBLIC HEALTH, vol. 11, 2011, pages 770, XP021110362, DOI: 10.1186/1471-2458-11-770
"Progress in Pain Research and Management", vol. 25, 2003, IASP PRESS, article "Opioids and Pain Relief: A Historical Perspective"
BALLANTYNE J.C.SHIN N.S.: "Efficacy of opioids for chronic pain: a review of the evidence", CLIN J PAIN, vol. 24, no. 6, 2008, pages 469 - 78
MARTINEZ-NAVARRO M.MALDONADO R.BANOS J.E.: "Why mu-opioid agonists have less analgesic efficacy in neuropathic pain?", EUR J PAIN, vol. 23, no. 3, 2019, pages 435 - 54
DICKENSON, A.H.SUZUKI, R.: "Opioids in neuropathic pain: Clues from animal studies", EUR J PAIN, vol. 9, 2005, pages 113 - 6, XP004767581, DOI: 10.1016/j.ejpain.2004.05.004
ALLOUCHE S.NOBLE F.MARIE N.: "Opioid receptor desensitization: mechanisms and its link to tolerance", FRONT PHARMACOL., vol. 5, 2014, pages 280
DECOSTERD I: "Spared nerve injury: an animal model of persistent peripheral neuropathic pain", PAIN, vol. 87, no. 2, 2000, pages 149 - 158
Attorney, Agent or Firm:
MARTIN, Roberto (ES)
Download PDF:
Claims:
Claims:

1. (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9- diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of nociceptive pain, neuropathic pain, osteoarthritis pain or cancer pain.

2. (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9- diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of nociceptive pain, neuropathic pain, osteoarthritis pain or cancer pain, while reducing the undesirable side effects selected from opioid- induced respiratory depression, tolerance, dependence (withdrawal), emesis and intestinal transit inhibition (constipation).

3. (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9- diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use according to claims 1 or 2, while reducing respiratory depression.

4. (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9- diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use according to claims 1 or 2, while reducing tolerance.

5. (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9- diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use according to claims 1 or 2, while reducing dependence.

6. (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9- diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use according to claims 1 or 2, while reducing withdrawal.

54

7. (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9- diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use according to claims 1 or 2, while reducing emesis.

8. (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9- diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use according to claims 1 or 2, while reducing gastrointestinal transit inhibition.

Description:
USE OF (R)-9-(2,5-DIFLUOROPHENETHYL)-4-ETHYL-2-METHYL-1-OXA-4,9- DIAZASPIRO[5.5]UNDECAN-3-ONE FOR THE TREATMENT OF NOCICEPTIVE PAIN, NEUROPATHIC PAIN, OSTEOARTHRITIS PAIN AND CANCER PAIN, WHILE HAVING REDUCED SIDE EFFECTS COMPARED TO OPIOIDS

FIELD OF THE INVENTION

The present invention relates (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9- diazaspiro[5.5]undecan-3-one, or a pharmaceutical acceptable salt thereof, for use in the treatment of nociceptive pain, neuropathic pain, osteoarthritis pain or cancer pain, while showing no tolerance after repeated administration and having reduced undesirable side effects as compared to strong opioids.

BACKGROUND

The adequate management of pain constitutes an important challenge, since currently available treatments provide in many cases only modest improvements, leaving many patients unrelieved [Turk DC, Wilson HD, Cahana A. Treatment of chronic non-cancer pain. Lancet 377, 2226-2235 (2011)]. Pain affects a big portion of the population with an estimated prevalence of around 20% and its incidence, particularly in the case of chronic pain, is increasing due to the population ageing. Additionally, pain is clearly related to comorbidities, such as depression, anxiety and insomnia, which lead to important productivity losses and socio-economic burden [Goldberg DS, McGee SJ. Pain as a global public health priority. BMC Public Health. 1 1 , 770 (2011)]. Existing pain therapies include non-steroidal anti-inflammatory drugs (NSAIDs), opioid agonists, calcium channel blockers and antidepressants, but they are much less than optimal regarding their safety ratio. All of them show a limited benefit-risk balance, with secondary effects precluding their use, especially in chronic settings.

As mentioned before, there are few available therapeutic classes for the treatment of pain, and strong opioids are among the most effective, especially when addressing severe pain states. They act through three different types of opioid receptors (mu, kappa and delta) which are transmembrane G-protein coupled receptors (GPCRs). Still, the main analgesic action is attributed to the activation of the m-opioid receptor (or mu-opioid receptor or MOR). However, the general administration of MOR agonists is limited due to their important side effects, such as constipation, respiratory depression, tolerance, emesis and dependence [Meldrum, M.L. (Ed.). Opioids and Pain Relief: A Historical Perspective. Progress in Pain Research and Management, Vol 25. IASP Press, Seattle, 2003] Additionally, MOR agonists are not optimal for the treatment of chronic pain as indicated by the diminished effectiveness of opioids against chronic pain conditions [Ballantyne J.C., Shin N.S. Efficacy of opioids for chronic pain: a review of the evidence. Clin J Pain 24(6):469-78 (2008)]. This is especially proven for chronic pain conditions of neuropathic origin, in comparison to its high potency against acute pain [Martinez- Navarro M., Maldonado R., Banos J.E. Why mu-opioid agonists have less analgesic efficacy in neuropathic pain? Eur J Pain 23(3):435-54 (2019)]. The finding that chronic pain can lead to MOR down-regulation may offer a molecular basis for the relative lack of efficacy of opioids in long-term treatment settings [Dickenson, A.H., Suzuki, R. Opioids in neuropathic pain: Clues from animal studies. Eur J Pain 9, 113-6 (2005)]. Moreover, prolonged treatment with opioids (i.e., MOR agonists including morphine, oxycodone, hydrocodone, fentanyl, etc) may result in tolerance to its analgesic effects [Allouche S., Noble F., Marie N. Opioid receptor desensitization: mechanisms and its link to tolerance. Front Pharmacol. 18;5:280 (2014], most likely due to treatment-induced MOR down- regulation, internalization and other regulatory mechanisms. Opioid tolerance, defined by decreased analgesic efficacy of opioid analgesics after repeated and prolonged use, is a significant clinical problem limiting adequate treatment of pain with opioids, the most effective analgesics available today. Chronic pain conditions require repeated use of opioid analgesics to maintain a desired analgesic level during the period when pain persists. However, as the analgesic tolerance to chronically used opioids significantly diminishes their analgesic effectiveness, increased doses are constantly necessary to maintain the desired analgesic level and sufficiently control pain. Unfortunately, opioids at high doses cause several severe side effects and are fatal at extreme doses. Opioid tolerance, combined with the side effects at high opioid doses, significantly limits the clinical use of opioid analgesics to efficiently and sufficiently control pain, resulting in a possible forced termination of opioid treatment and replacement by other less effective alternatives, leaving chronic pain patients under-treated.

As a consequence of long-term opioid treatment, substantial increases in dosing may be needed in order to maintain a clinically satisfactory pain relief, but the narrow therapeutic window of MOR agonists may finally results in unacceptable side effects and poor patient compliance. Alternatively, addiction phenomena (i.e., compulsive use and a dependence on opioids) may arise.

As mentioned previously, opioids are among the most potent analgesics but they are also responsible for various adverse effects which seriously limit their use.

Accordingly, there is a need to find compounds exerting outstanding analgesic activity in the treatment of chronic pain following repeated administration and a better safety and benefit-risk balance compared to strong opioids. Some of the side effects known to be associated to strong opioids are e.g. respiratory depression, tolerance, dependence (withdrawal), emesis and intestinal transit inhibition (constipation).

Alkyl derivatives of 1-oxa-4,9-diazaspiro undecane compounds are such promising ligands. These compounds and their synthesis are disclosed and claimed in WO 2015185209.

Alkyl derivatives of 1-oxa-4,9-diazaspiro undecane compounds bind to the m-opioid receptor and the sigma-1 receptor. They display strong analgesic activity in the treatment of acute and chronic pain conditions. The compounds have the structural formula:

In particular, (7?)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9- diazaspiro[5.5]undecan-3-one (COMPOUND A) is one of such promising analgesic multimodal ligands.

(R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9- diazaspiro[5.5] undecan-3-one (COMPOUND A) is a new compound that behaves as a partial agonist at the m-opioid receptor and as an antagonist at the sigma-1 receptor.

COMPOUND A has a molecular weight of 353.1 Da and a p a of 7.9. The structural formula of the compound is:

(R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-dia zaspiro[5.5] undecan-3-one

(COMPOUND A) (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-dia zaspiro[5.5]undecan-3-one (COMPOUND A) is a first-in-class, multimodal (m-opioid and sigma-1 activity) new chemical entity that has first demonstrated strong analgesic activity in the treatment of acute and chronic pain, including nociceptive pain, neuropathic pain, osteoarthritis pain or cancer pain, with no tolerance after repeated administration and a reduced undesirable side effects as compared to strong opioids.

On the other side, COMPOUND B, which corresponds to the compound of example 136 in the PCT published patent application WO2017016669, is also a multimodal (m-opioid partial agonist and sigma-1 antagonist) new chemical entity that has been used for comparison with COMPOUND A on its activity with osteoarthritis pain.

BRIEF DESCRIPTION OF THE INVENTION

In the present invention, after an extensive research, it has been surprisingly found and demonstrated that (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9- diazaspiro[5.5]undecan-3-one exerts outstanding analgesic activity in the treatment of nociceptive pain, neuropathic pain, osteoarthritis pain or cancer pain following repeated administration and a better benefit-risk balance compared to strong opioids, with improved safety profile as it regards to respiratory depression, tolerance, dependence (withdrawal), emesis and intestinal transit inhibition (constipation).

Thus, the present invention relates to (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1- oxa-4,9-diazaspiro[5.5]undecan-3-one or a pharmaceutically acceptable salt thereof, for use in the treatment of nociceptive pain, neuropathic pain, osteoarthritis pain or cancer pain, while showing no tolerance after repeated administration and having reduced undesirable side effects (respiratory depression, dependence (withdrawal), emesis and intestinal transit inhibition (constipation) as compared to strong opioids. DETAILED DESCRIPTION OF THE INVENTION

The application relates in a first aspect to (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl- 1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of nociceptive pain.

The application thus also relates in this aspect to a method for treating nociceptive pain, the method comprising administering to the subject a therapeutically effective dose of (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-dia zaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

The application relates in another aspect to (R)-9-(2,5-difluorophenethyl)-4-ethyl-2- methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of nociceptive pain, having reduced opioid-related undesirable side effects consisting of respiratory depression, tolerance, dependence (withdrawal), emesis and intestinal transit inhibition (constipation).

The application relates in another aspect to a method for treating nociceptive pain, having reduced opioid-related undesirable side effects consisting of respiratory depression, tolerance, dependence (withdrawal), emesis and intestinal transit inhibition (constipation), the method comprising administering to the subject a therapeutically effective dose of (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9- diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of nociceptive pain, having reduced opioid-related respiratory depression.

In a preferred embodiment the application relates to a method for treating nociceptive pain, having reduced opioid-related respiratory depression, the method comprising administering to the subject a therapeutically effective dose of (R)- 9-(2,5- difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5 ]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of nociceptive pain, having reduced opioid-related tolerance.

In a preferred embodiment the application relates to a method for treating nociceptive pain, having reduced opioid-related tolerance, the method comprising administering to the subject a therapeutically effective dose of (R)-9-(2,5-difluorophenethyl)-4-ethyl-2- methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of nociceptive pain, having reduced opioid-related dependence (withdrawal).

In a preferred embodiment the application relates to a method for treating nociceptive pain, having reduced opioid-related dependence (withdrawal), the method comprising administering to the subject a therapeutically effective dose of (R)- 9-(2,5- difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5 ]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of nociceptive pain, having reduced opioid-related emesis.

In a preferred embodiment the application relates to a method for treating nociceptive pain, having reduced opioid-related emesis, the method comprising administering to the subject a therapeutically effective dose of (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl- 1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of nociceptive pain, having reduced opioid-related gastrointestinal transit inhibition (constipation).

In a preferred embodiment the application relates to a method for treating nociceptive pain, having reduced opioid-related gastrointestinal transit inhibition (constipation), the method comprising administering to the subject a therapeutically effective dose of (R)-9- (2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspir o[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

The application relates in another aspect to (R)-9-(2,5-difluorophenethyl)-4-ethyl-2- methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of nociceptive pain, having reduced undesirable side effects consisting of respiratory depression, tolerance, dependence (withdrawal), emesis and intestinal transit inhibition (constipation), compared to strong opioids.

The application relates in another aspect to a method for treating nociceptive pain, having reduced undesirable side effects consisting of respiratory depression, tolerance, dependence (withdrawal), emesis and intestinal transit inhibition (constipation), compared to strong opioids, the method comprising administering to the subject a therapeutically effective dose of (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa- 4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of nociceptive pain, while reducing respiratory depression compared to strong opioids.

In a preferred embodiment the application relates to a method for treating nociceptive pain, while reducing respiratory depression compared to strong opioids, the method comprising administering to the subject a therapeutically effective dose of (R)- 9-(2,5- difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5 ]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of nociceptive pain, while reducing tolerance compared to strong opioids.

In a preferred embodiment the application relates to a method for treating nociceptive pain, while reducing tolerance compared to strong opioids, the method comprising administering to the subject a therapeutically effective dose of (R)- 9-(2,5- difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5 ]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of nociceptive pain, while reducing dependence (withdrawal) compared to strong opioids.

In a preferred embodiment the application relates to a method for treating nociceptive pain, while reducing dependence (withdrawal) compared to strong opioids, the method comprising administering to the subject a therapeutically effective dose of (R)- 9-(2,5- difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5 ]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of nociceptive pain, while reducing emesis compared to strong opioids.

In a preferred embodiment the application relates to a method for treating nociceptive pain, while reducing emesis compared to strong opioids, the method comprising administering to the subject a therapeutically effective dose of (R)- 9-(2,5- difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5 ]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of nociceptive pain, while reducing gastrointestinal transit inhibition (constipation) compared to strong opioids.

In a preferred embodiment the application relates to a method for treating nociceptive pain, while reducing gastrointestinal transit inhibition (constipation) compared to strong opioids, the method comprising administering to the subject a therapeutically effective dose of (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9- diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

The application relates in a first aspect to (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl- 1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of neuropathic pain.

The application thus also relates in this aspect to a method for treating neuropathic pain, the method comprising administering to the subject a therapeutically effective dose of (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-dia zaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

The application relates in another aspect to (R)-9-(2,5-difluorophenethyl)-4-ethyl-2- methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of neuropathic pain, having reduced opioid-related undesirable side effects consisting of respiratory depression, tolerance, dependence (withdrawal), emesis and intestinal transit inhibition (constipation).

The application relates in another aspect to a method for treating neuropathic pain, having reduced opioid-related undesirable side effects consisting of respiratory depression, tolerance, dependence (withdrawal), emesis and intestinal transit inhibition (constipation), the method comprising administering to the subject a therapeutically effective dose of (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9- diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of neuropathic pain, having reduced opioid-related respiratory depression.

In a preferred embodiment the application relates to a method for treating neuropathic pain, having reduced opioid-related respiratory depression, the method comprising administering to the subject a therapeutically effective dose of (R)- 9-(2,5- difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5 ]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of neuropathic pain, having reduced opioid-related tolerance.

In a preferred embodiment the application relates to a method for treating neuropathic pain, having reduced opioid-related tolerance, the method comprising administering to the subject a therapeutically effective dose of (R)-9-(2,5-difluorophenethyl)-4-ethyl-2- methyl-1 -oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of neuropathic pain, having reduced opioid-related dependence (withdrawal).

In a preferred embodiment the application relates to a method for treating neuropathic pain, having reduced opioid-related dependence (withdrawal), the method comprising administering to the subject a therapeutically effective dose of (R)- 9-(2,5- difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5 ]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of neuropathic pain, having reduced opioid-related emesis.

In a preferred embodiment the application relates to a method for treating neuropathic pain, having reduced opioid-related emesis, the method comprising administering to the subject a therapeutically effective dose of (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl- 1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of neuropathic pain, having reduced opioid-related gastrointestinal transit inhibition (constipation).

In a preferred embodiment the application relates to a method for treating neuropathic pain, having reduced opioid-related gastrointestinal transit inhibition (constipation), the method comprising administering to the subject a therapeutically effective dose of (R)- 9- (2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspir o[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

The application relates in another aspect to (R)-9-(2,5-difluorophenethyl)-4-ethyl-2- methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of neuropathic pain, having reduced undesirable side effects consisting of respiratory depression, tolerance, dependence (withdrawal), emesis and intestinal transit inhibition (constipation), compared to strong opioids.

The application relates in another aspect to a method for treating neuropathic pain, having reduced undesirable side effects consisting of respiratory depression, tolerance, dependence (withdrawal), emesis and intestinal transit inhibition (constipation), compared to strong opioids, the method comprising administering to the subject a therapeutically effective dose of (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa- 4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of neuropathic pain, while reducing respiratory depression compared to strong opioids.

In a preferred embodiment the application relates to a method for treating neuropathic pain, while reducing respiratory depression compared to strong opioids, the method comprising administering to the subject a therapeutically effective dose of (R)- 9-(2,5- difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5 ]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of neuropathic pain, while reducing tolerance compared to strong opioids.

In a preferred embodiment the application relates to a method for treating neuropathic pain, while reducing tolerance compared to strong opioids, the method comprising administering to the subject a therapeutically effective dose of (R)- 9-(2,5- difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5 ]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of neuropathic pain, while reducing dependence (withdrawal) compared to strong opioids.

In a preferred embodiment the application relates to a method for treating neuropathic pain, while reducing dependence (withdrawal) compared to strong opioids, the method comprising administering to the subject a therapeutically effective dose of (R)- 9-(2,5- difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5 ]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of neuropathic pain, while reducing emesis compared to strong opioids.

In a preferred embodiment the application relates to a method for treating neuropathic pain, while reducing emesis compared to strong opioids, the method comprising administering to the subject a therapeutically effective dose of (R)- 9-(2,5- difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5 ]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of neuropathic pain, while reducing gastrointestinal transit inhibition (constipation) compared to strong opioids.

In a preferred embodiment the application relates to a method for treating neuropathic pain, while reducing gastrointestinal transit inhibition (constipation) compared to strong opioids, the method comprising administering to the subject a therapeutically effective dose of (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9- diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

The application relates in a first aspect to (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl- 1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of osteoarthritis pain.

The application thus also relates in this aspect to a method for treating osteoarthritis pain, the method comprising administering to the subject a therapeutically effective dose of (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-dia zaspiro[5.5]undecan-3- one, or a pharmaceutically acceptable salt thereof.

The application relates in another aspect to (R)-9-(2,5-difluorophenethyl)-4-ethyl-2- methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of osteoarthritis pain, having reduced opioid-related undesirable side effects consisting of respiratory depression, tolerance, dependence (withdrawal), emesis and intestinal transit inhibition (constipation).

The application relates in another aspect to a method for treating osteoarthritis pain, having reduced opioid-related undesirable side effects consisting of respiratory depression, tolerance, dependence (withdrawal), emesis and intestinal transit inhibition (constipation), the method comprising administering to the subject a therapeutically effective dose of (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9- diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of osteoarthritis pain, having reduced opioid-related respiratory depression.

In a preferred embodiment the application relates to a method for treating osteoarthritis pain, having reduced opioid-related respiratory depression, the method comprising administering to the subject a therapeutically effective dose of (R)- 9-(2,5- difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5 ]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of osteoarthritis pain, having reduced opioid-related tolerance.

In a preferred embodiment the application relates to a method for treating osteoarthritis pain, having reduced opioid-related tolerance, the method comprising administering to the subject a therapeutically effective dose of (R)-9-(2,5-difluorophenethyl)-4-ethyl-2- methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of osteoarthritis pain, having reduced opioid-related dependence (withdrawal).

In a preferred embodiment the application relates to a method for treating osteoarthritis pain, having reduced opioid-related dependence (withdrawal), the method comprising administering to the subject a therapeutically effective dose of (R)- 9-(2,5- difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5 ]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of osteoarthritis pain, having reduced opioid-related emesis.

In a preferred embodiment the application relates to a method for treating osteoarthritis pain, having reduced opioid-related emesis, the method comprising administering to the subject a therapeutically effective dose of (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl- 1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of osteoarthritis pain, having reduced opioid-related gastrointestinal transit inhibition (constipation).

In a preferred embodiment the application relates to a method for treating osteoarthritis pain, having reduced opioid-related gastrointestinal transit inhibition (constipation), the method comprising administering to the subject a therapeutically effective dose of (R)-9- (2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspir o[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

The application relates in another aspect to (R)-9-(2,5-difluorophenethyl)-4-ethyl-2- methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of osteoarthritis pain, having reduced undesirable side effects consisting of respiratory depression, tolerance, dependence (withdrawal), emesis and intestinal transit inhibition (constipation), compared to strong opioids.

The application relates in another aspect to (R)-9-(2,5-difluorophenethyl)-4-ethyl-2- methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt

1 7 thereof, for use in the treatment of nociceptive pain, neuropathic pain, osteoarthritis pain or cancer pain, while reducing the undesirable side effects selected from opioid- induced respiratory depression, tolerance, dependence (withdrawal), emesis and intestinal transit inhibition (constipation).

The application relates in another aspect to a method for treating osteoarthritis pain, having reduced undesirable side effects consisting of respiratory depression, tolerance, dependence (withdrawal), emesis and intestinal transit inhibition (constipation), compared to strong opioids, the method comprising administering to the subject a therapeutically effective dose of (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa- 4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of osteoarthritis pain, while reducing respiratory depression compared to strong opioids.

In a preferred embodiment the application relates to a method for treating osteoarthritis pain, while reducing respiratory depression compared to strong opioids, the method comprising administering to the subject a therapeutically effective dose of (R)- 9-(2,5- difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5 ]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of osteoarthritis pain, while reducing tolerance compared to strong opioids.

In a preferred embodiment the application relates to a method for treating osteoarthritis pain, while reducing tolerance compared to strong opioids, the method comprising administering to the subject a therapeutically effective dose of (R)- 9-(2,5- difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5 ]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of osteoarthritis pain, while reducing dependence (withdrawal) compared to strong opioids.

In a preferred embodiment the application relates to a method for treating osteoarthritis pain, while reducing dependence (withdrawal) compared to strong opioids, the method comprising administering to the subject a therapeutically effective dose of (R)- 9-(2,5- difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5 ]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of osteoarthritis pain, while reducing emesis compared to strong opioids.

In a preferred embodiment the application relates to a method for treating osteoarthritis pain, while reducing emesis compared to strong opioids, the method comprising administering to the subject a therapeutically effective dose of (R)- 9-(2,5- difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5 ]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of osteoarthritis pain, while reducing gastrointestinal transit inhibition (constipation) compared to strong opioids.

In a preferred embodiment the application relates to a method for treating osteoarthritis pain, while reducing gastrointestinal transit inhibition (constipation) compared to strong opioids, the method comprising administering to the subject a therapeutically effective dose of (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9- diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

The application relates in a first aspect to (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl- 1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer pain.

The application thus also relates in this aspect to a method for treating cancer pain, the method comprising administering to the subject a therapeutically effective dose of (R)-9- (2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspir o[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

The application relates in another aspect to (R)-9-(2,5-difluorophenethyl)-4-ethyl-2- methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer pain, having reduced opioid-related undesirable side effects consisting of respiratory depression, tolerance, dependence (withdrawal), emesis and intestinal transit inhibition (constipation).

The application relates in another aspect to a method for treating cancer pain, having reduced opioid-related undesirable side effects consisting of respiratory depression, tolerance, dependence (withdrawal), emesis and intestinal transit inhibition (constipation), the method comprising administering to the subject a therapeutically effective dose of (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9- diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer pain, having reduced opioid- related respiratory depression.

In a preferred embodiment the application relates to a method for treating cancer pain, having reduced opioid-related respiratory depression, the method comprising administering to the subject a therapeutically effective dose of (R)- 9-(2,5- difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5 ]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer pain, having reduced opioid- related tolerance.

In a preferred embodiment the application relates to a method for treating cancer pain, having reduced opioid-related tolerance, the method comprising administering to the subject a therapeutically effective dose of (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl- 1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer pain, having reduced opioid- related dependence (withdrawal).

In a preferred embodiment the application relates to a method for treating cancer pain, having reduced opioid-related dependence (withdrawal), the method comprising administering to the subject a therapeutically effective dose of (R)- 9-(2,5- difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5 ]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer pain, having reduced opioid- related emesis.

In a preferred embodiment the application relates to a method for treating cancer pain, having reduced opioid-related emesis, the method comprising administering to the subject a therapeutically effective dose of (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl- 1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer pain, having reduced opioid- related gastrointestinal transit inhibition (constipation).

In a preferred embodiment the application relates to a method for treating cancer pain, having reduced opioid-related gastrointestinal transit inhibition (constipation), the method comprising administering to the subject a therapeutically effective dose of (R)-9- (2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspir o[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

The application relates in another aspect to (R)-9-(2,5-difluorophenethyl)-4-ethyl-2- methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer pain, having reduced undesirable side effects consisting of respiratory depression, tolerance, dependence (withdrawal), emesis and intestinal transit inhibition (constipation), compared to strong opioids.

The application relates in another aspect to a method for treating cancer pain, having reduced undesirable side effects consisting of respiratory depression, tolerance, dependence (withdrawal), emesis and intestinal transit inhibition (constipation), compared to strong opioids, the method comprising administering to the subject a therapeutically effective dose of (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa- 4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof. In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer pain, while reducing respiratory depression compared to strong opioids.

In a preferred embodiment the application relates to a method for treating cancer pain, while reducing respiratory depression compared to strong opioids, the method comprising administering to the subject a therapeutically effective dose of (R)- 9-(2,5- difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5 ]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer pain, while reducing tolerance compared to strong opioids.

In a preferred embodiment the application relates to a method for treating cancer pain, while reducing tolerance compared to strong opioids, the method comprising administering to the subject a therapeutically effective dose of (R)- 9-(2,5- difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5 ]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer pain, while reducing dependence (withdrawal) compared to strong opioids.

In a preferred embodiment the application relates to a method for treating cancer pain, while reducing dependence (withdrawal) compared to strong opioids, the method comprising administering to the subject a therapeutically effective dose of (R)- 9-(2,5- difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5 ]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer pain, while reducing emesis compared to strong opioids.

In a preferred embodiment the application relates to a method for treating cancer pain, while reducing emesis compared to strong opioids, the method comprising administering to the subject a therapeutically effective dose of (R)-9-(2,5-difluorophenethyl)-4-ethyl-2- methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment the application relates to (R)-9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer pain, while reducing gastrointestinal transit inhibition (constipation) compared to strong opioids.

In a preferred embodiment the application relates to a method for treating cancer pain, while reducing gastrointestinal transit inhibition (constipation) compared to strong opioids, the method comprising administering to the subject a therapeutically effective dose of (R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9- diazaspiro[5.5]undecan-3-one, or a pharmaceutically acceptable salt thereof.

DEFINITIONS

AUC: Area under the concentration-time curve. It represents the total drug exposure across time. AUC is proportional to the total amount of drug absorbed by the body. C max : C max is the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administrated and before the administration of a second dose.

Half maximal effective dose (ED50): The Half maximal effective dose is the drug dose producing 50% of a maximal effect; or alternatively the dose producing the desired effect in 50% of the population. It is also sometimes abbreviated as the ED50, meaning "effective dose for 50% of the population".

Respiratory rate (RR): The respiratory rate is the rate at which breathing occurs. This is usually measured in breaths per minute.

Tidal volumen (TV): Tidal volume has been described as the volume of air that is transported into and out of the lungs with each respiratory cycle. Tidal volume is measured in milliliters and ventilation volumes are estimated based on a patient's ideal body mass.

Respiratory depression: respiratory depression occurs when ventilation is inadequate to perform needed gas exchange. By definition it causes an increased concentration of carbon dioxide and respiratory acidosis.

Drug tolerance: Drug tolerance is a pharmacological concept describing subjects' reduced response to a drug following its repeated use.

Drug dependence: drug dependence is an adaptive state that develops from repeated drug administration, and which results in withdrawal upon cessation of drug use.

Withdrawal: Drug withdrawal is the group of symptoms that occur upon the abrupt discontinuation or decrease in intake of medications or recreational drugs.

Tail flick: The tail-flick test is a test of nociception used in rats and mice. The noxious stimulus is usually radiant heat on the tail or tail immersion in hot water, and the response is a flick of the tail.. Nociceptive pain: Nociceptive pain is caused by stimulation of sensory nerve fibers that respond to stimuli approaching or exceeding harmful intensity (nociceptors), and may be classified according to the mode of noxious stimulation. It can be somatic or visceral. Somatic pain happens when pain receptors in tissues, such as muscles, bone, or skin, are activated. Visceral pain happens when internal organs are injured or inflamed.

Neuropathic pain: Neuropathic pain is caused by damage or disease affecting any part of the nervous system involved in bodily feelings (the somatosensory system). Neuropathic pain may be divided into peripheral, when it affects to peripheral nerves, or central when damage occurs in CNS areas.

Osteorathritis pain: Osteorathritis pain is caused by a type of joint disease that results from breakdown of joint cartilage and underlying bone. The most common symptoms are joint pain and stiffness.

Cancer pain: Cancer pain is caused by the tumour pressing on bones, nerves or other organs in the body. Sometimes pain is due to cancer treatment.

DESCRIPTION OF THE FIGURES

Figure 1. Acute nociceptive and neuropathic pain (spared nerve injury-induced mechanical allodynia): Effect of COMPOUND A in comparison to morphine and oxycodone in rats.

Figure 2. Respiratory depression (whole body plethysmography): Effect of COMPOUND A in comparison to oxycodone on minute volume (MV) in rats.

Figure 3. Protocol for assessment of nociceptive tolerance.

Figure 4. Analgesic tolerance: Effect of acute versus repeated administration of COMPOUND A in comparison to oxycodone on nociception in rats. Figure 5. Protocol for assessment of withdrawal symptoms.

Figure 6. Figure 6. Dependence (withdrawal): Effect repeated administration of COMPOUND A in comparison to morphine in mice.

Figure 7. Emesis and nausea: Effect of COMPOUND A in comparison to morphine in ferrets.

Figure 8. Intestinal transit inhibition: Effect of COMPOUND A in comparison with oxycodone and morphine in rats.

Figure 9. Osteoarthritis pain (mechanical allodynia): Effect of repeated administration of COMPOUND A in comparison to oxycodone and morphine in rats.

Figure 10. Osteoarthritis pain (mechanical allodynia): Effect of COMPOUND A and B after acute (A) and repeated (B-C) administration in mice

Figure 11. Bone cancer pain (mechanical allodynia): Effect of COMPOUND A after repeated administration in comparison with morphine in rats.

EXPERIMENTAL PART

LIST OF ABBREVIATIONS

2

EXAMPLES

Example 1. Acute nociceptive and neuropathic pain: Effect of single administration of COMPOUND A in comparison with morphine and oxycodone

The effect of single administration of COMPOUND A, morphine and oxycodone in rats was assayed in acute mechanical (Paw Pressure Test; PPT) and thermal (Tail-Flick test; TF) nociceptive models as well as in the spared nerve injury (SNI) model of neuropathic pain ( Decosterd I, et al. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain. 2000; 87(2): 149-158).

The spared nerve injury (SNI) model mimics human neuropathic pain related to peripheral nerve injury and it is useful to study the major clinical manifestations of neuropathic pain. It produces a robust, reliable and long-lasting neuropathic pain-related behaviour (e.g, mechanical allodynia). The SNI procedure comprised an axotomy and ligation of the tibial and common peroneal nerves leaving the sural nerve intact. Opioid analgesics are less effective reducing pain in neuropathic than in nociceptive pain models, in agreement with their limited efficacy for the treatment of neuropathic pain in the clinical practice.

Experimental design:

The paw withdrawal response to mechanical pressure stimulation and the tail-flick response to thermal (heat) stimulation was evaluated in the nociceptive PPT and TF models, respectively. As it regards to the neuropathic pain model (SNI), rats were briefly anaesthetised and the common peroneal and the tibial nerves were cut and tight-ligated. Mechanical allodynia was assessed by determination of the paw withdrawal threshold to von Frey filaments stimulation. The behavioural evaluation was performed 14 days after surgery.

Increasing doses of COMPOUND A, morphine or oxycodone were systemically administered by i.p. route and the dose of the drug producing 50% of the maximal effect (ED50) was calculated.

Results:

Systemic treatment with COMPOUND A, morphine or oxycodone by i.p. route exerted dose-dependent antinociceptive effects in mechanical (PPT) and thermal (TF) nociceptive models and significantly reversed SNI-induced mechanical allodynia. ED50 values are shown in the table included in Figure 1.

Conclusion COMPOUND A had a potency similar to oxycodone and greater than morphine in nociceptive pain models (PPT and TF), but it reversed spared nerve injury- induced mechanical allodynia in rats with higher potency than morphine and oxycodone, comparable to that in nociceptive pain models, which indicates that, unlike opioids such as morphine and oxycodone, its analgesic efficacy is not diminished in chronic neuropathic pain conditions.

Example 2. Respiratory depression: Effect of single administration of COMPOUND

A in comparison with oxycodone

The aim of this study was to evaluate the effects of COMPOUND A and oxycodone on respiratory function in rats, measuring the respiratory rate (RR), tidal volume (TV) and minute volume (MV) on whole body plethysmography in rats.

Experimental design:

The respiratory function of wistar rats (75-1 OOg at arrival, Charles River, France) was evaluated using a whole body plethysmography for unrestrained rats system and controlled by Fine PointeTM software (Data Sciences International). For acclimation, the rats were placed into the plethysmography chambers at least 30 min prior to the test. Before the administration, basal respiratory parameters were measured continuously for 15 min. Afterwards, the administration of COMPOUND A and oxycodone was done and the animals returned to the plethysmography chambers. Respiratory parameters were measured continuously for 60 min and grouped for every 5 min.

Results:

COMPOUND A induced a respiratory depression after i.p. administration of 10 and 20 mg/kg. The analysis of the AUCo^o showed a significant effect at 10 and 20 mg/kg on RR (data not shown) and MV (Figure 2) and no changes TV (data not shown). The effect reached a plateau of -30% reduction, with no differences between the 10 and 20 mg/kg dose. At 1.25 and 5 mg/kg no changes were observed in any of the respiratory parameters. Oxycodone 5 and 10 mg/kg showed a significant decrease in RR and MV in comparison with the control group. A significant effect on RR was also detected in animals treated at 2.5 mg/kg, and a transient effect was observed at 1.25 mg/kg. The analysis of AUCo^o showed a clear dose-response decrease in RR (data not shown) and MV (Figure 2), with a -50% reduction at 10 mg/kg and no apparent plateau.

Conclusion :

The degree of respiratory depression was slightly lower for COMPOUND A than for oxycodone.

COMPOUND A showed less efficacy and potency than oxycodone in inducing respiratory depression.

Example 3. Tolerance: Effect of COMPOUND A in comparison with oxycodone

The effect of repeated COMPOUND A and oxycodone administration was evaluated on acute nociception (Paw Pressure Test = PPT) in rats.

Experimental design:

Rats received vehicle (HPMC), COMPOUND A (5 g/kg, i.p.) or oxycodone (4 g/kg, i.p.) twice daily for 3 days. This induction dose was a dose producing about 60-80% of antinociception in nociceptive models when acutely administered. The paw withdrawal response to mechanical pressure stimulation was assessed in the nociceptive PPT model. The following experimental groups were evaluated:

- Control group (vehicle + vehicle group): animals that were repeated-treated with HPMC and on day 4 received HPMC.

- COMPOUND A acute group (vehicle + COMPOUND A group): animals that were repeated-treated with HPMC and on day 4 received COMPOUND A (5 mg/kg, i.p.).

- Oxycodone acute group (vehicle + oxycodone group): animals that were repeated- treated with HPMC and on day 4 received oxycodone (4 mg/kg, i.p.). - COMPOUND A repeated administered group (COMPOUND A + COMPOUND A group): animals that were repeated-treated with COMPOUND A (5 mg/kg i.p.) and on day 4 received COMPOUND A (5 mg/kg i.p.).

- Oxycodone repeated administered group (oxycodone + oxycodone group): animals that were repeated-treated with oxycodone (4 mg/kg i.p.) and on day 4 received oxycodone (4 mg/kg, i.p.).

On day 4, after COMPOUND A or oxycodone administration the PPT was performed (Figure 3).

Results:

In the PPT, systemic administration of COMPOUND A (5 mg/kg, i.p.) effectively reduced mechanical nociception following both acute and repeated administration to rats. No statistically significant differences in the mechanical antinociceptive response between both treatment groups (acute and repeated) were observed, indicating that repeated administration did not induce tolerance to the analgesic effect of COMPOUND A. Systemic administration of oxycodone (4 mg/kg, i.p.) also reduced mechanical nociception but its effect was markedly reduced when repeatedly administered (compared to the acute administration) to rats, indicating the development of tolerance to its analgesic effect (Figure 4).

Conclusion:

Unlike oxycodone, repeated administration of COMPOUND A did not induce tolerance to its antinociceptive effect in rats.

Example 4. Dependence (withdrawal): Effect of COMPOUND A in comparison with morphine

The effect of repeated COMPOUND A and morphine administration on physical dependence (withdrawal symptoms) was evaluated in mice.

vy Experimental design:

Mice received vehicle (HPMC), COMPOUND A (10 mg/kg, i.p.) or morphine (14 g/kg, i.p.) twice daily for 3 days. Dependence was measured as incidence/severity of withdrawal symptoms precipitated by naloxone. The following experimental groups were evaluated:

- Control group (vehicle + vehicle group): animals that were repeated-treated with HPMC and on day 4 received HPMC.

- COMPOUND A acute group (vehicle + COMPOUND A group): animals that were repeated-treated with HPMC and on day 4 received COMPOUND A (10 mg/kg, i.p.).

- Morphine acute group (vehicle + oxycodone group): animals that were repeated- treated with HPMC and on day 4 received morphine (16 mg/kg, i.p.).

- COMPOUND A repeated administered group (COMPOUND A + COMPOUND A group): animals that were repeated-treated with COMPOUND A (10 mg/kg i.p.) and on day 4 received COMPOUND A (10 mg/kg, i.p.).

- Morphine repeated administered group (oxycodone + oxycodone group): animals that were repeated-treated with morphine (16 mg/kg i.p.) and on day 4 received morphine (16 mg/kg, i.p.).

Doses of COMPOUND A (10 mg/kg) and morphine (16 mg/kg) were chosen based on the equiefficacy in nociceptive model in mice.

On day 4, after COMPOUND A or morphine administration, animals received a single dose of the m-opioid antagonist naloxone (1 mg/kg, s.c.) to precipitate withdrawal. Then, the number of jumps and forepaw tremors (withdrawal symptoms) were evaluated

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Results:

Data from physical abstinence (naloxone-precipitated withdrawal) were expressed as number of jumps and forepaw tremors. In the vehicle control group a mean of 3 paw tremors and no jumps were observed. Naloxone (1 mg/kg, s.c.) induced 18 jumps and 38 paw tremors in mice acutely administered with COMPOUND A, and 18 jumps and 25 paw tremors in mice repeatedly administered with COMPOUND A, with no statistically significant differences between groups. On the other hand, naloxone (1 mg/kg, s.c.) induced 21 jumps and 24 paw tremors in acutely administered morphine mice but 52 jumps and 86 paw tremors in repeatedly administered morphine group, being differences statistically significant (Figure 6). Thus, repeated administration of morphine, but not of COMPOUND A, induced a statistically significant increase in the number of naloxone- precipitated withdrawal symptoms (jumps and paw tremors).

Conclusion:

Unlike morphine, withdrawal (naloxone-precipitated) symptoms indicative of physical dependence did not significantly develop following repeated COMPOUND A administration.

Example 5. Emesis and nausea: Effect of COMPOUND A in comparison with morphine

The effect of single administration of COMPOUND A and morphine was evaluated in ferrets.

Experimental design:

Male Putorius furo ferrets (Marshall Bioresources (North Rose, USA) were used in the study. Ferrets were administered by i.p. route with vehicle (0.5% HPMC), COMPOUND A at 0.5 and 1 mg/kg, or morphine (0.5 mg/kg, s.c.) and were then observed continuously for 4 h for emesis and nausea-like behaviours quantification. During that period, both episodes of retches and episodes of vomiting (abdominal contractions without or with expulsion of part of the gastro-intestinal content, respectively) were recorded. During the same period, nausea-like behaviours were also evaluated by studying the occurrence of a set of typical behaviours (licking, gagging, chewing, backward walking, head burying in cage shavings, wet dog shake, mouth clawing and prolonged typical ventral recumbency). Results:

Control animals administered with vehicle did not show any emetic response, neither retching nor vomiting episodes. Morphine (0.5 mg/kg, s.c.) clearly induced emetic responses during the 4 h period after the administration with 2.17 ± 0.60 retches and 1.17 ± 0.65 vomits. In contrast, COMPOUND A at 0.5 mg/kg and 1 mg/kg i.p. did not induce any emetic response.

Nausea-like total score (Figure 5) for vehicle-treated animals was 2.67 ± 1 .31 . In this experiment, the positive control morphine (0.5 mg/kg) was very potent and efficacious in inducing nausea-like behaviours, with a score of 12.5 ± 2.2. No differences compared to vehicle-treated animals were observed for any of the two doses (0.5 and 1 mg/kg) of COMPOUND A.

Conclusion:

COMPOUND A, contrarily to morphine, did not induce emesis or nausea in ferrets.

Example 6. Gastrointestinal transit: Effect of COMPOUND A in comparison with morphine and oxycodone

The inhibition of gastrointestinal transit (constipation) is a significant problem with all opioids. In humans, opioids induce constipation by inhibiting gastric emptying and reducing the peristalsis of the intestine. These effects are mainly mediated by m-opioid receptors.

The aim was to study the effect of effect of COMPOUND A, oxycodone and morphine on gastrointestinal motility in rats by measuring the passage of a charcoal meal through the gastrointestinal tract, which is a reliable and widely used method.

Experimental design:

Rats were administered by i.p. route with 0.5% HPMC (vehicle), COMPOUND A, oxycodone or morphine, and 30 min later, charcoal was given p.o. and the animals sacrificed 30 min after. The total length of the intestine and the progression through the intestine of the charcoal were measured. The percentage of total length was calculated.

Results:

Oxycodone induced a high degree of intestinal transit inhibition which was close to a full blockade at 10 mg/kg. In a similar way, but with lower potency, morphine reduced the intestinal transit 50% at 10 mg/kg. Conversely, COMPOUND A induced a low intestinal transit inhibition which was below 25% at 10 mg/kg. ED 50 values were 4.4, 10.3 and 17.4 mg/kg for oxycodone, morphine and COMPOUND A, respectively.

Conclusion:

COMPOUND A inhibited gastrointestinal transit in rats with less potency than oxycodone and morphine.

Example 7: Osteoarthritis pain: Effect of repeated administration of COMPOUND A in comparison with morphine and oxycodone (rat)

Osteoarthritis of the hip and knee are major causes of pain and locomotor disability worldwide. Monoiodoacetate (MIA) injection in the knee joint of the rat causes a condition resembling human osteoarthritis and leads to reduced withdrawal thresholds to mechanical stimuli, i.e. mechanical allodynia.

Osteoarthritis pain was induced by intraarticular (i.a.) injection of MIA in the right knee joint of rats and mechanical allodynia was assessed by paw withdrawal thresholds to von Frey filaments stimulation.

Experimental design:

Rats were injected with MIA (60 mI of a 40 mg/ml solution in 0.9% saline, corresponding to 2.4 mg/injection) into the right knee joint. Fourteen days after i.a. injection of MIA, a significant decrease in the withdrawal threshold to ipsilateral versus contralateral paw mechanical stimulation was observed, corresponding to ipsilateral allodynia.

Fourteen days after MIA injection, animals received COMPOUND A (0.5, 1.5 and 3 mg/kg s.c.) or vehicle (saline 0.9%, s.c.) administered twice a day for 28 days, and oxycodone (2.5 g/kg, i.p.), morphine (5 and 10 mg/kg, i.p.) or vehicle (HPMC 0.5%, i.p.), administered twice a day for 21 days. The animals that received COMPOUND A or saline were evaluated for mechanical allodynia on days 0, 3, 7, 10, 14, 21 and 28. On the other hand, the rats administered with oxycodone, morphine or HPCM 0.5% were tested on day 0, 3, 7, 10, 14 and 21. In all cases, the day 0 was considered as the first day of the pharmacological treatment, i.e. 14 days after i.a. MIA injection. Mechanical allodynia was evaluated using von Frey filaments. The test was performed before morning drug administration (baseline measurement; PRE) and 30 min after morning administration (POST).

Results

Systemic administration of COMPOUND A (0.5, 1.5 and 3 mg/kg s.c.) induced a dose- response reduction of MIA-induced mechanical hypersensitivity. The effect remained unchanged throughout the treatment period, showing absence of tolerance to the analgesic effect after 4 weeks of repeated administration. Oxycodone (2.5 mg/kg, i.p.) and morphine (5 and 10 mg/kg, i.p.) also produced a dose-dependent reduction of mechanical hypersensitivity, but their analgesic effect progressively diminished throughout the treatment period (i.e., repeated oxycodone and morphine administration induced tolerance), their antinociceptive effect being almost completely lost after 3 weeks of treatment.

Conclusion :

After single administration, COMPOUND A effectively reversed MIA-induced osteoarthritis pain, similar to oxycodone and morphine.

However, unlike oxycodone and morphine, repeated administration of COMPOUND A did not induce tolerance to its antinociceptive (i.e., antiallodinic) effect in the MIA-induced osteoarthritis pain model. Example 8: Osteoarthritis pain: Effect of repeated administration of COMPOUND A in comparison with COMPOUND B (mouse)

COMPOUND A and COMPOUND B are both multimodal drugs acting as partial agonists at the m-opioid receptor and as antagonists at the sigma-1 receptor.

Experimental Design:

To assess their therapeutic potential in chronic osteoarthritis pain, we evaluated the sensitivity in response to von Frey filament stimulation 30 min after drug administration on CD1 mice intra-articularly injected with MIA. To assess their analgesic effect, compouns were administered acutely and repeatedly for 2 weeks, twice a day by i.p. route.

Results:

The single administration of either COMPOUND A or COMPOUND B decreased MIA- induced mechanical allodynia 30 min after i.p. administration in a dose-dependent manner (Figure 10A). However, COMPOUND A revealed greater analgesic efficacy (ED50 « 6 mg/kg) than COMPOUND B (ED50 « 32 mg/kg), as reflected by a lower median effective dose. Thus, COMPOUND A was 5 times more potent than COMPOUND B alleviating osteoarthritis pain.

For the repeated treatment, doses showing equivalent acute antinociceptive effects (7 mg/kg for COMPOUND A and 50 mg/kg for COMPOUND B) were used. Mechanical allodynia was assessed with the von Frey test before (PRE) and 30 min after (POST) the first daily dose. The chronic treatment with COMPOUND A, but not with COMPOUND B, induced a recovery of the mechanical thresholds assessed before the daily administration of the drug (Figure 10B). In addition, the antiallodynic effect exert by COMPOUND A was maintained throughout the treatment period. In the case of COMPOUND B, the antiallodynic effect progressively declines with time. Altogether, these results indicate that tolerance develops for COMPOUND B but not for COMPOUND A.

Hence, the simultaneous blockade of sigma-1 and stimulation m-opioid receptor exerted by COMPOUND A, but not by COMPOUND B, induced an antiallodynic effect after acute and chronic administrations. Conclusions:

COMPOUND A shows greater potency than COMPOUND B in alleviatic osteoarthritis pain.

Tolerance to its analgesic effect develops when administering repeatedly COMPOUND B but not COMPOUND A.

Example 9: Cancer pain: Effect of repeated administration of COMPOUND A in comparison with morphine

Opioids are the most effective analgesics for the tratment of cancer pain. The model of bone caner pain is widely use to evaluate the analgesic effect of opioids in rats. After single administration, opioids effectively reduced mechanical allodynia induced by cancer pain in rats. However, after repeated administration, their analgesic activity is reduced due to the development of tolerance.

The aim of this study was to evaluate the antiallodynic effect of COMPOUND A and morphine after single and repeated administration in a model of bone cancer pain in rats.

Experimental design:

Rats were injected with MRMT-1 rat mammary gland carcinoma cells into the intramedullary cavity on day 0. Vehicle, morphine (1 mg/kg) and COMPOUND A (1.15 and 2.3 mg/kg) were administered subcutaneously (s.c.) twice daily for 14 consecutive days (from day 7 to day 20). Mechanical allodynia was evaluated prior to MRMT-1 injection (day -1 ; pre-MRMT-1), on day 6 (for randomization), and on days 7, 10, 14, 17, 20, and 21. Note that no treatment was administerd on day 21.

Results:

In the vehicle control group, the mechanical allodynia developed over time as compared to the day -1 basal values and was stable over day 10 to day 21 , indicating a progressive development of bone cancer pain (Figure 10). Repeated administrations of COMPOUND A significantly attenuated mechanical allodynia compared to vehicle control group during

*30 the treatment period. Notably, the analgesic activity of the COMPOUND A was maintained unchanged at the end of the treatment period at both tested doses (1.15 and 2.3 mg/kg). Morphine (1 mg/kg) markedly inhibited mechanical allodynia on days 7 and 10 but not at days 14, 17 and 20 when compared to the vehicle control, suggesting the development of tolerance to the analgesic effect of morphine.

Conclusion :

Unlike morphine, repeated administration of COMPOUND A did not induce tolerance to its antinociceptive (i.e., antiallodinic) effect on a bone cancer pain model.

Summary of the Experimental Part:

Efficacy endpoints:

• Analgesic potency in nociceptive pain: COMPOUND A had a potency similar to oxycodone and greater than morphine in nociceptive pain models following acute mechanical and thermal stimulation (Example 1). However, repeated administration of COMPOUND A results in higher efficacy as compared to oxycodone in nociceptive pain models (Example 3).

• Analgesic potency in neuropathic pain: COMPOUND A reversed nerve injury- induced pain behaviour (i.e., mechanical allodynia) with higher potency than morphine and oxycodone, comparable to that in nociceptive pain models, which indicates that, unlike opioids such as morphine and oxycodone, its analgesic efficacy is not diminished in chronic neuropathic pain conditions (Example 1). This is a differential finding in respect to opioids. Note that opioid analgesics are less effective in reducing pain in neuropathic than in nociceptive pain models, in agreement with their limited efficacy for the treatment of neuropathic pain in the clinical practice.

• Analgesic potency in mixed pain conditions (osteoarthritis pain and cancer pain):

Acute administration of COMPOUND A exerts similar efficacy and potency than morphine and oxycodone (osteoarthritis pain; Example 7) and morphine (bone cancer pain; Example 9). However, repeated administration of COMPOUND A results in higher efficacy as compared to oxycodone and/or morphine in these mixed, chronic pain models (Example 7 and 9).

• Tolerance: In contrast to oxycodone and morphine, repeated administration of COMPOUND A did not induce tolerance to its analgesic effect in rats as revealed both in nociceptive pain (Example 3) and in chronic osteoarthritis (Example 7 and 8) and bone cancer pain (Example 9) models. That is, contrary to morphine and oxycodone, the analgesic effect of COMPOUND A is maintained (it did not decreased) throughout the treatment period. This is a differential finding in respect to opioids. It is also a differential feature of COMPOUND A as COMPOUND B (another multimodal compound showing partial agonism at the m-opioid receptor and antagonism at the sigma-1 receptor) induces tolerance to its antinociceptive effect following repeated administration (Example 8). Note that tolerance, defined by a decreased analgesic efficacy of opioid analgesics after repeated and prolonged use, is a significant clinical problem limiting adequate treatment of pain with opioids. Note also that, because of tolerance, increased doses are constantly necessary to maintain the desired analgesic level and sufficiently control pain, and that, unfortunately, opioids at high doses cause several severe side effects and increase the risk for opioid dependence and addiction.

Safety endpoints:

• Respiratory depression: COMPOUND A induced less respiratory depression (with a plateau effect at -30%) than oxycodone (Example 2). Note that analgesic potency of COMPOUND A is comparable to oxycodone in nociceptive models and higher than oxycodone and morphine in neuropathic pain models (Example 1) and in chronic, repeated administration settings (Example 7 and 8), but COMPOUND A had less efficacy and potency than oxycodone in inducing respiratory depression. Opioid-induced respiratory depression is potentially life threatening and the cause of substantial morbidity and mortality. • Dependence: Unlike morphine, withdrawal (naloxone-precipitated) symptoms indicative of physical dependence did not significantly develop following repeated COMPOUND A administration (Example 4). Note that drug dependence is an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure and it is a key component of a substance use disorder.

• Nausea and vomiting: Contrarily to morphine, COMPOUND A did not induce emesis or nausea (Example 5). Note that nausea and vomiting are troublesome side effects of opioid therapy. Pro-emetic effects are common opioid-induced side effects and can be a barrier to optimal pain management.

• Constipation: COMPOUND A inhibited gastrointestinal transit with less potency than oxycodone and morphine (Example 6). Note that analgesic potency of COMPOUND A is comparable to oxycodone in nociceptive models and higher than oxycodone and morphine in neuropathic pain models (Example 1) and in chronic, repeated administration settings (Example 7 and 8), but COMPOUND A showed less efficacy and potency than morphine and oxycodone in inducing gastrointestinal transit inhibition. Opioid-induced constipation is a common side effect of opioids that may limit the adequate dosing of opioids for pain relief and reduce the quality of life of patients suffering from chronic pain.