Delta opioid receptor agonists for use in the treatment of pain

Abstract

The invention relates to diphenylmethylenepiperidine derivatives of formula (I), for use in the treatment or prevention of diseases or conditions that benefit from agonism of the delta opioid receptor, such as pain, neurological disorders, cardiovascular diseases, mental disorders, psychiatric disorders or behavioural disorders. The invention also relates to pharmaceutical compositions comprising such compounds, and to certain novel 4-diphenylmethylenepiperidine derivatives.

Description

[0001] DELTA OPIOID RECEPTOR AGONISTS FOR USE IN THE TREATMENT OF PAIN

[0002] TECHNICAL FIELD

[0003] The invention relates to diphenylmethylenepiperidine derivatives of formula (I), for use in the treatment or prevention of diseases or conditions that benefit from agonism of the delta opioid receptor, such as pain, neurodegenerative disorders, cardiovascular diseases and mental disorders. The invention also relates to pharmaceutical compositions comprising such compounds, and to certain novel diphenylmethylenepiperidine derivatives.

[0004] BACKGROUND

[0005] Physical pain is a typical sensory experience that may be described as the unpleasant awareness of a noxious stimulus or bodily harm. Individuals may experience pain by various daily hurts and aches, and sometimes through more serious injuries or illnesses. For scientific and clinical purposes, pain is defined by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”.

[0006] Pain is the most common symptom for which patients seek medical advice and treatment. Pain can be classified as acute or chronic. While acute pain is usually self-limited, chronic pain can persist for 3 months or longer and lead to significant changes in a patient's personality, lifestyle and functional ability, or overall quality of life (K. Foley, Chapter 27: “Pain”, in Cecil Textbook of Medicine, L. Goldman and J. Bennett eds., 21st ed., 2000). A survey of more than 45,000 people in 16 countries revealed that almost 20% of the European population suffers moderate or severe pain persisting for more than 6 months (Breivik et al., Eur. J. Pain 2006, vol. 10, p. 287-333). The impact of chronic pain can vary from mild discomfort to the worst possible pain, having a significant impact both on the patients and their families and social contacts.

[0007] There are many different types of chronic pain, including migraine, lower back pain, fibromyalgia and post-viral illness (e.g., shingles), but neuropathies and joint pain (such as arthritis and osteoarthritis) are particularly prominent. Central nervous system (CNS) related diseases such as Alzheimer’s disease, Parkinson’s disease and multiple sclerosis also have a high prevalenceof associated pain. The incidence of chronic pain increases with advancing of these diseases and is associated with and potentiated by depressive illness and loss of sleep.

[0008] Current analgesic therapies are only poorly effective and are associated with significant side effects, especially concerning chronic conditions. Opioids such as morphine, codeine and oxycodone have found widespread use in the treatment of severe acute and chronic pain. Opioids act through the opioid receptors, the family of G-protein coupled receptors (GPCRs) that mediate pain relief through both the central and peripheral nervous systems. Opioids are powerful drugs for treating moderate and severe pain, but due to the presence of opioid receptors in the central nervous system, the use of these drugs is hampered by side effects such as nausea, constipation and respiratory depression (Schein et al., Nat. Med. 2003, vol. 9, p. 1003-1008).

[0009] Four types of opioid receptors have been described, including the μ-opioid receptor (MOR), the κ-opioid receptor (KOR), the δ-opioid receptor (DOR), and the nociceptin opioid peptide receptor (NOP receptor) (Faouzi et al., Molecules 2020, vol. 25, 4257). While the μ-, κ- and δ-opioid receptors have an analgesia-inducing function, they also induce undesirable effects such as convulsions, depression and physical dependence. As opioids are either non-selective (acting on all three opioid receptor sub-types) or somewhat μ-opioid receptor-biased, they produce the full range of both beneficial and unwanted effects. The development of tolerance additionally limits their clinical efficacy. For at least these reasons, the prescription of conventional opioids for the management of chronic pain is not recommended (see e.g., the guideline of the UK’s National Institute for Health and Care Excellence (NICE), “Chronic pain (primary and secondary) in over 16s: assessment of all chronic pain and management of chronic primary pain”, 7 April 2021, https: / / www.nice.org.uk / guidance / ng193).

[0010] Delta opioid receptors have multiple roles in the central nervous system disorders, not only in pain but also in depression, anxiety, epilepsy, and stress; in gastrointestinal disorders such as in diarrhea, postoperative ileus, ulceration and irritable bowel syndrome; in inflammatory disorders such as in osteoarthritis and rheumatoid arthritis; and in respiratory disorders, alcoholism and obesity / binge eating. Selective delta opioid receptor agonists have therefore been considered as a potential means to relieve pain conditions and mental disorders such as depression and anxiety.It has been established that the activation of opioid receptors triggers two main transducing pathways, namely the β-arrestin 2 and / or the G-protein pathway. While agonism of the G-protein pathway will result in the useful (i.e., pain-relieving) properties of the opioid receptor, opioid receptor activation can also lead to recruitment of arrestin proteins which control receptor internalization (i.e., removal of the receptor away from the cell surface and termination of its action). Opioid receptor agonists retain full analgesic efficacy when the receptors remain on the cell surface. However, following receptor internalization, opioid receptor agonist-induced analgesia is abolished and complete behavioral desensitization is observed. It is therefore expected that G-biased agonists (that do not recruit arrestin proteins) will be devoid of the undesired properties of the opioid receptor. In the case of the delta opioid receptor, a G-biased agonist should separate convulsions from analgesia (Faouzi et al., Molecules 2020, vol. 25, 4257).

[0011] Selective delta opioid receptor agonists have been disclosed e.g. in WO 02 / 094786, WO 03 / 029215, WO 2016 / 099393 and WO 2016 / 099394. The compound PN6047 (see WO 2016 / 099393; Conibear et al., J. Pharmacol. Exp. Then 2020, vol. 372, p. 224-236) is currently in clinical studies. Also, a receptor agonist is disclosed in A / , A / -Diethyl-4-(phenylpiperidin-4-ylidenemethyljbenzamide: A Novel, Exceptionally Selective, Potent 3 Opioid Receptor Agonist with Oral Bioavailability and Its Analogues, Zhong-Yong Wei et. al. J. Med. Chem. 2000, 43, 3895-3905.

[0012] Despite improvements made during recent years, there is a continued need for novel pain therapies that are effective over prolonged periods with low risk for side-effects such as tolerance and convulsions.

[0013] DETAILED DESCRIPTION OF THE INVENTION

[0014] Phase I multiple ascending dose studies on the delta opioid receptor agonist PN6047 have revealed the major metabolites that are formed following oral administration of the compound. The dealkylated metabolite 3-[[4-(dimethylcarbamoyl)phenyl]-(piperidin-4-ylidene)methyl]-benzamide (referred to herein as “Compound 1 ”) was found present in human plasma at concentrations greater than 10% of the concentration of PN6047. Unexpectedly, this metabolite retains many of the properties of the parent compound: it is a highly selective delta opioid receptor agonist and has roughly the same potency as PN6047. Surprisingly, it has beendiscovered that the metabolite is a 1000-fold weaker ß-arrestin-2 recruiter than PN6047.

[0015] Compound 1 is therefore expected even less likely to induce tolerance and cause convulsions. Given its presence in toxicology testing of PN6047, Compound 1 is likely to be safe and well tolerated. It is therefore expected that Compound 1, and certain structurally related compounds, will be useful as G-biased delta opioid receptor agonists.

[0016] In a first aspect, therefore, the invention relates to a compound of formula (I)

[0017] O

[0018]

[0019] wherein

[0020] R1is selected from hydrogen or an alkyl, wherein said alkyl is preferably selected from methyl and ethyl; and

[0021] R2is selected from hydrogen, an alkyl or a hydroxy alkyl, wherein said alkyl preferably is selected from methyl and ethyl, wherein preferably said hydroxy alkyl is 2-hydroxyethyl; or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or condition that benefits from agonism of the delta-opioid receptor.

[0022] In some embodiments, R1and R2are each methyl.

[0023] In some embodiments, R1and R2are each ethyl.

[0024] In some embodiments, R1is methyl and R2is hydroxyethyl.

[0025] In some embodiments, R1is ethyl and R2is methyl or hydroxyethyl.

[0026] In a particular embodiment, the compound of formula (I) is selected from the group consisting of:

[0027] 3-[[4-(dimethylcarbamoyl)phenyl]-(piperidin-4-ylidene)methyl]benzamide;

[0028] 3-[[4-(diethylcarbamoyl)phenyl](piperidin-4-ylidene)methyl]benzamide;

[0029] 3-[[4-[ethyl(methyl)carbamoyl]phenyl]-(piperidin-4-ylidene)methyl]benzamide; and 3-[[4-[2-hydroxyethyl(methyl)carbamoyl]phenyl]-(piperidin-4-ylidene)methyl]benzamide; or a pharmaceutically acceptable salt thereof.In a more particular embodiment, the compound of formula (I) is 3-[[4-(dimethylcarbamoyl)phenyl]-(piperidin-4-ylidene)methyl]benzamide, or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In another embodiment, the compound of formula (I) is the hydrochloride salt of 3-[[4-(dimethylcarbamoyl)phenyl]-(piperidin-4-ylidene)methyl]benzamide.

[0030] In some embodiments, the disease or condition that benefits from agonism of the delta opioid receptor is pain, a neurological disorder, a cardiovascular disease, a mental disorder, a psychiatric disorder or a behavioural disorder.

[0031] In some embodiments, the pain is acute pain, chronic pain, neuropathic pain, cancer pain, visceral pain, diabetic pain, post-surgical pain, ischemic pain, inflammatory pain or chemotherapy-induced pain; or pain caused by diseases or conditions such as spinal cord injury, rheumatoid arthritis, osteoarthritis, low back pain, neck pain, fibromyalgia, migraine, opioid-induced hyperalgesia (OIH), opioid withdrawal syndrome (OWS), opioid withdrawal hyperalgesia, opioid overuse headache, shingles, hyperesthesia and other forms of hyperalgesia.

[0032] In some embodiments, the neurological disorder is stroke, Alzheimer’s disease, Parkinson’s disease, MS (multiple sclerosis), epilepsy or dementia (including frontal lobe dementia, Lewy body dementia and vascular dementia).

[0033] In some embodiments, the cardiovascular disease is ischemic heart disease or acute myocardial infarction, vascular ischemic pain or claudicatio intermittens.

[0034] In some embodiments, the mental disorder, psychiatric disorder or behavioural disorder is an anxiety disorder (including OCD (Obsessive-Compulsive disorder), panic disorder, trauma, PTSD (Post traumatic stress syndrome), GAD (Generalized Anxiety Disorder), SOC

[0035] (Social Anxiety Disorder), SAD (Schizophrenia)), or a substance use disorder (including alcohol, nicotine, opioid and other drug abuse or addiction) or a panic disorder, an impulsive control disorder, a personality disorder, a mood disorder (including depression, melancholia, bipolar disorder and MDD (major depressive disorder)), ADHD (attention deficit hyperactivity disorder), tic disorder or eating disorder (including anorexia, binge eating and bulimia).In some embodiments, the disease or condition that benefits from agonism of the delta opioid receptor is urinary incontinence, sensory hypersensitivity (including itch), lung edema, a gastrointestinal disorder (including irritable bowel syndrome and inflammatory bowel disease), or a disorder of the sympathetic nervous system, hypertension, or a respiratory disease (including COPD (chronic obstructive pulmonary disease) and cough, such as chronic cough).

[0036] The invention also relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a disease or condition that benefits from agonism of the delta opioid receptor.

[0037] The invention also relates to a method for treatment or prevention of a disease or condition that benefits from agonism of the delta opioid receptor, comprising administering to a warm-blooded animal in need of such treatment or prevention, such as man, a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0038] Compound 1 and certain other compounds of formula (I) have previously been disclosed in WO 03 / 029215, WO 2016 / 099393 and WO 2016 / 099394, as intermediates in the preparation of delta opioid receptor agonists such as PN6047. Certain further compounds of formula (I) are novel. In another aspect, therefore, the invention also relates to a compound of formula (I')

[0039]

[0040] wherein

[0041] R1is ethyl; and

[0042] R2is selected from methyl and 2-hydroxyethyl;

[0043] or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, R1is ethyl and R2is methyl. In some embodiments, the R1is ethyl and R2is hydroxyethyl.In some embodiments, the compound of formula (I') is 3-[[4-[ethyl(methyl)carbamoyl]phenyl]-(piperidin-4-ylidene)methyl]benzamide, or a pharmaceutically acceptable salt thereof.

[0045] The preparation of certain compounds of formula (I') is disclosed in the experimental section.

[0046] A suitable pharmaceutically acceptable salt of a compound of formula (I) or (I1) is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic. Examples of acidaddition salts include halide salts (e.g., a hydrobromide or hydrochloride salt), or a salt with an organic acid which affords a physiologically acceptable anion, for example a salt with acetic acid, trifluoroacetic acid, lactic acid, succinic acid, tartaric acid, glutaric acid, maleic acid, fumaric acid or citric acid.

[0047] Pharmaceutical compositions

[0048] In another aspect, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. The excipients may e.g. include fillers, binders, disintegrants, glidants and lubricants. In general, pharmaceutical compositions may be prepared in a conventional manner using conventional excipients.

[0049] Examples of suitable fillers include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose (such as lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, dry starch, hydrolyzed starches and pregelatinized starch.

[0050] Examples of suitable binders include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (such as sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums (such as acacia gum and tragacanth gum), sodium alginate, cellulose derivatives (such as hydroxypropylmethylcellulose (“hypromellose”), hydroxypropylcellulose and ethylcellulose) and synthetic polymers (such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid copolymers and polyvinylpyrrolidone (povidone)).Examples of suitable disintegrants include, but are not limited to, dry starch, modified starch (such as (partially) pregelatinized starch, sodium starch glycolate and sodium carboxymethyl starch), alginic acid, cellulose derivatives (such as sodium carboxymethylcellulose, hydroxypropyl cellulose, and low substituted hydroxypropyl cellulose (L-HPC)) and cross-linked polymers (such as carmellose, croscarmellose sodium, carmellose calcium and cross-linked PVP (crospovidone)).

[0051] Examples of suitable glidants and lubricants include, but are not limited to, talc, magnesium stearate, calcium stearate, stearic acid, stearyl fumarate, glyceryl behenate, colloidal silica, aqueous silicon dioxide, synthetic magnesium silicate, fine granulated silicon oxide, starch, sodium lauryl sulfate, boric acid, magnesium oxide, waxes (such as carnauba wax), hydrogenated oil, polyethylene glycol, sodium benzoate, polyethylene glycol, and mineral oil.

[0052] In general, pharmaceutical compositions may be prepared in a conventional manner using conventional excipients. In some embodiments, the ingredients of the composition are mixed to a homogenous mixture and then formulated as tablets or capsules.

[0053] The homogenous mixture of the ingredients may be compressed into tablets using conventional techniques, such as rotary tablet press. Alternatively, the mixture may be wetted by the addition of a liquid, such as water and / or an appropriate organic solvent (e.g., ethanol or isopropanol), and thereafter granulated and dried. The granules obtained may then be compressed into tablets using conventional techniques. Tablets may be coated with one or more coating layers, e.g., enteric coating layers or coating layers for modified release of the active ingredient. Examples of modified release include delayed release, extended release, slow release, controlled release or sustained release of the active ingredient. The coating layers may comprise one or more coating agents, and may optionally comprise plasticizers and / or pigments (or colorants).

[0054] Example of suitable coating agents include, but are not limited to, cellulose-based polymers (such as ethylcellulose, hydroxypropylmethylcellulose (or hypromellose), hydroxypropylcellulose, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate), vinyl-based polymers (such as polyvinyl alcohol) and polymers based on acrylic acid and derivatives thereof (such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methylmethacrylate copolymers, aminoalkyl methacrylate copolymers, and polyacrylic acid / polymethacrylic acid copolymers).

[0055] Examples of suitable plasticizers include, but are not limited to, triethyl citrate, glyceryl triacetate, tributyl citrate, diethyl phthalate, acetyl tributyl citrate, dibutyl phthalate, dibutyl sebacate and polyethylene glycol.

[0056] Examples of suitable pigments include, but are not limited to, titanium dioxide, iron oxides (such as yellow, brown, red or black iron oxides) and barium sulfate.

[0057] Capsules (such as hard gelatine capsules) may comprise a powder mixture or small multiparticulates (such as granules, extruded pellets or minitablets) of the ingredients, or a liquid or semisolid formulation of the ingredients. For soft gelatine capsules, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may be admixed with, for example, a vegetable oil or polyethylene glycol.

[0058] Formulations for use in nasal administration or oral inhalation (e.g., nebulized solutions) may comprise an aqueous solution of a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with, for example, a suitable preservative such as benzalkonium chloride. Formulations for use in topical administration (e.g. an ointment or a cream) may comprise a compound of formula (I), or a pharmaceutically acceptable salt thereof, in admixture with, for example, an oil or a wax and a suitable preservative.

[0059] Dosages

[0060] The dosage required for the therapeutic or prophylactic treatment will depend on the route of administration, the severity of the disease, the age and weight of the patient and other factors normally considered by the attending physician, when determining the appropriate regimen and dosage level for a particular patient.

[0061] The amount of the compound to be administered will vary for the patient being treated, and may vary from about 1 μg / kg of body weight to about 50 mg / kg of body weight per day. A unit dose form, such as a tablet or capsule, will usually contain about 1 to about 250 mg of active ingredient, such as about 25 to about 200 mg, or such as about 50 to about 200 mg, or such as about 50 to about150 mg, e.g., about 50 mg, or about 75 mg, or about 100 mg, about 125 mg, or about 150 mg. The daily dose can be administered as a single dose or divided into one, two, three or more unit doses. An orally administered daily dose of a compound of formula (I) is preferably within about 5 to about 500 mg, more preferably within about 25 to about 500 mg, such as within about 50 to about 500 mg, such as within about 100 to about 500 mg, such as within about 200 to about 400 mg, or such as within about 250 to about 350 mg, e.g., about 250 mg, or about 300 mg, or about 350 mg.

[0062] Combination therapy

[0063] In some embodiments, a compound of formula (I), ora pharmaceutically acceptable salt thereof, may be administered in combination with at least one other therapeutically active agent, such as with one, two, three or more other therapeutically active agents. The compound of formula (I), or a pharmaceutically acceptable salt thereof, and the at least one other therapeutically active agent may be administered simultaneously, sequentially or separately. Therapeutically active agents that are suitable for combination with a compound of formula (I) include, but are not limited to, known active agents that are useful in the treatment of any of the aforementioned conditions, disorders and diseases.

[0064] In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with one or more other analgesic agents. Combinations of different analgesic agents (with different properties) are often used to achieve a balance of effects necessary for maintaining an anesthetic state (e.g. amnesia, analgesia, muscle relaxation and sedation). The one or more other analgesic agents may e.g., be an anesthetic agent, a hypnotic agent, an anxiolytic agent, a neuromuscular blocker, a neuropeptide receptor blocker or an opioid. Examples of such compounds include, but are not limited to, tricyclic antidepressants (e.g., amitriptyline), serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine), gabapentinoids (e.g., pregabalin), CGRP receptor antagonists (e.g., ubrogepant), benzodiazepines (e.g., diazepam) and ketamine.

[0065] In another embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with one or more other compounds that are useful in the treatment or prevention of pain. Examples of such compounds include, but are not limited to, opioid receptor agonists (e.g., buprenorphine and methadone) and opioid receptor antagonists (e.g., naloxone), cannabinoids (e.g., tetrahydrocannabinol), alpha-2 adrenoceptor agonists (e.g.,lofexidine), purinoceptor antagonists (e.g., gefapixant), transient receptor potential channel blockers (e.g., capsaicin), sodium channel blockers (e.g., lidocaine and lamotrigine), calcium channel blockers (e.g., pregabalin), and potassium channel blockers (e.g., retigabine).

[0066] Definitions

[0067] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0068] As used herein, the terms "effective amount” and “therapeutically effective amount” refer to a sufficient amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, that, following administration to a subject, will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic use is the amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.

[0069] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delayingthe onset of, or inhibitingthe progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.As used herein, the terms “subject,” “individual,” or “patient,” used interchangeably, refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human.

[0070] As used herein, the term “pharmaceutically acceptable” refers to those compounds, materials, compositions and / or dosage forms that are suitable for human pharmaceutical use and that are generally safe, non-toxic and neither biologically nor otherwise undesirable.

[0071] As used herein, the term "about" refers to a value or parameter herein that includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to "about 20" includes description of "20." Numeric ranges are inclusive of the numbers defining the range. Generally speaking, the term "about" refers to the indicated value of the variable and to all values of the variable that are within the experimental error of the indicated value (e.g., within the 95% confidence interval for the mean) or within 10 percent of the indicated value, whichever is greater.

[0072] The invention will now be described by the following examples which do not limit the invention in any respect. All cited documents and references are incorporated by reference.

[0073] EXPERIMENTAL SECTION

[0074] Preparation of compounds

[0075] The compounds of the invention can be prepared as a free base, or a pharmaceutically acceptable salt thereof, by the processes described below. Throughout the following description of such processes it is understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are for example described in Greene’s Protective Groups in Organic Synthesis by P. G. M Wutz and T. W. Greene, 4th Edition, John Wiley & Sons, Hoboken, 2006.

[0076] AbbreviationsDCM dichloromethane

[0077] DIPEA N,N-diisopropylethylamine

[0078] DME dimethoxyethane

[0079] DMF dimethylformamide

[0080] dppf 1,1’-bis(diphenylphosphino)ferrocene

[0081] EtOAc ethyl acetate

[0082] HATU hexafluorophosphate azabenzotriazole tetramethyl uranium, or (1- [bis(dimethylamino)methylene]-1 H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate)

[0083] rt room temperature

[0084] TFA trifluoroacetic acid

[0085] General methods

[0086] All solvents used were of analytical grade. Commercially available anhydrous solvents were routinely used for reactions. Starting materials were available from commercial sources or prepared according to literature procedures. Sodium 4-[bromo-(1-tert-butoxycarbonyl-piperidin-4-ylidene)methyl]benzoate may be prepared as described in WO 02 / 094786. Room temperature refers to 20 - 25 °C. Solvent mixture compositions are given as volume percentages or volume ratios.

[0087] Analytical HPLC-MS was performed using an Agilent 1100 series Liquid Chromatograph / Mass Selective Detector (MSD) (Single Quadrupole) equipped with an electrospray interface and a UV diode array detector. Analyses were performed using either an ACE C8 column (3.0 x 50 mm, 3 µm) with a gradient of acetonitrile in 0.1% aqueous TFA over 3 min and a flow rate of 1 mL / min, or an Xbridge C18 column (3.0 x 50 mm) with a gradient of acetonitrile in 10 mM ammonium bicarbonate over 3 min and a flow rate of 1 mL / min.

[0088] 1H NMR spectra were recorded on a Bruker AVANCE-III HD 400 MHz NMR instrument at 25 °C. The reported values for the chemical shifts 5 (ppm) were calibrated to the residual proton resonance signal of the deuterated solvent used (acetic acid-d4).

[0089] The prepared compounds were given IUPAC names generated from Biovia Draw. Commercial names or trivial names were used for the commercial starting materials and reagents.Example 1

[0090] Preparation

[0091]

[0092] 3-[[4-[ethyl(methyl)carbamoyl]phenyl]-(piperidin-4-ylidene)methyl]benzamide (“Compound 2”)

[0093] Step 1

[0094] tert-Butyl 4-[bromo-[4-[ethyl(methyl)carbamoyl]phenyl]methylene]piperidine-1 -carboxylate

[0095]

[0096] To a suspension of sodium 4-[bromo-(1-tert-butoxycarbonyl-piperidin-4-ylidene)methyl]benzoate (600 mg, 1.43 mmol) and HATU (655 mg, 1.72 mmol) in DMF (5 mL) was added DIPEA (0.5 mL, 2.87 mmol). The reaction mixture was stirred for 15 minutes at rt. N-methylethanamine (0.102 g, 1.72 mmol) was added and the reaction mixture was stirred at rt for 2 hours. EtOAc (10 mL) was added, and the mixture was washed with 1 M aq. HCl (10 mL), sat. aq. NaHCO3(10 mL) and brine (10 mL), then dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to afford the title compound (714 mg). Material was taken to the next step without any further purification.

[0097] MS (ES ) m / z 383 [M-tBu+H]+.

[0098] Step 2

[0099] tert-Butyl 4-[(3-carbamoylphenyl)-[4-[ethyl(methyl)carbamoyl]phenyl]methylene]-piperidine-1-carboxylate

[0100] NH2

[0101]

[0102] tert- Butyl 4-[bromo-[4-[ethyl(methyl)carbamoyl]phenyl]methylene]piperidine-1 -carboxylate (Step 1; 714 mg, 1.63 mmol) and (3-carbamoylphenyl)boronic acid (323 mg, 1.96 mmol) were dissolved in DME (25 ml), then 2 M aq. K2CO3(1.22 mL, 2.45 mmol) and Pd(dppf)Cl2: DCM complex (67 mg, 0.08 mmol) were then added under a nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 3.5 hours, then allowed to attain ambient temperature and left to stir overnight. DCM (100 mL) and water (100 mL) were added and the phases were separated. The aqueous phase was extracted with DCM (3 x 50 mL). The organic phases were combined, washed with brine (100 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to afford the title compound (646 mg, 1.35 mmol, 83% yield). Material was taken to the next step without any further purification.

[0103] MS (ES ) m / z 422 [M-tBu+H]+.

[0104] Step 3

[0105] 3-[[4-[Ethyl(methyl)carbamoyl]phenyl]-(piperidin-4-ylidene)methyl]benzamide

[0106] O

[0107]

[0108] tert-Butyl 4-[(3-carbamoylphenyl)-[4-[ethyl(methyl)carbamoyl]phenyl]methylene]piperidine-1-carboxylate (Step 2; 646 mg, 1.35 mmol) was dissolved in DCM (8 mL) and TFA (2 mL) was added. The reaction mixture was stirred at rt for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (20 mL) and the solution was washed with sat. aq. K2CO3(20 mL), dried over anhydrous MgSO4, filtered, and then concentrated to afford the title compound as a brown solid (316 mg, 0.84 mmol, 62% yield).

[0109] 1H NMR (400 MHz, Acetic acid-oL) δ 9.71 (s, 9H), 8.13-8.04 (m, 2H), 7.48-7.38 (m, 2H), 3.59 (dd, J = 6.7, 5.0 Hz, 2H), 3.45-3.35 (m, 2H), 2.68 (dd, J = 6.7, 5.1 Hz, 2H), 2.37-2.23 (m, 2H), 1.47 (s, 9H). MS (ES ) m / z 378 [M+H]+.

[0110] Example 2

[0111] Biological data

[0112] cAMP modulation assaycAMP modulation was assessed by Eurofins using a TR-FRET cAMP assay. Human DOR expressing CHO cell lines were expanded from freezer stocks according to standard procedures. Cells were seeded at the appropriate density in a total volume of 5 pL HBSS / 10mM HEPES containing 500pM IBMX into white walled, 384-well half area microplates shortly before testing. Cells were incubated with sample in the presence of an EC80forskolin concentration to induce response. Intermediate dilution of sample stocks was performed to generate 2X sample in assay buffer containing 2X EC80forskolin. 5 pL of 2X sample was added to cells and incubated at room temperature for 30 or 60 minutes. Final assay vehicle concentration was 1 %.

[0113] Compound activity was analyzed using CBIS data analysis suite (Chemlnnovation, CA). The percentage activity is calculated using the following formula:

[0114] % Activity = 100% x (1 - (mean RATIO of test sample - mean RATIO of MAX control) / (mean RATIO of vehicle control - mean RATIO of MAX control)).

[0115] Arrestin recruitment and DOR Internalization assay

[0116] Arrestin recruitment and DOR internalization were measured by Eurofins, using the PathHunter assay developed by DiscoveRx. The potency and efficacy of the compound of interest was determined and compared with a natural ligand response.

[0117] PathHunter cells were expanded from freezer stocks according to standard procedures. Cells were seeded in a total volume of 10 or 20 pL into white walled, 384-well microplates and incubated at 37°C for the appropriate time prior to testing.

[0118] Compounds and ligands were serially diluted to generate an intermediate 5X sample in assay buffer. 5 pL of 5X sample was added to cells and incubated at 37°C or room temperature for 1-16 hours depending on the target and assay. Final assay vehicle concentration was 1 %.

[0119] In parallel, EFC positive and negative control tests were performed to determine the maximal arrestin recruitment possible in the system. In the EFC positive control test, 5 pL of 10X EA reagent plus 5 pL of cell lysis buffer was added to 20 pL cells in assay buffer. In the EFC negative control test, 5 pL of 10X EA dilution buffer plus 5 pL of cell lysis buffer was added to 20 pL cells in assay buffer.

[0120] Assay signal was generated through a single addition of 15 pL PathHunter Detection reagent cocktail, followed by a 1-2 hour incubation at room temperature. Microplates were read following signal generation with a PerkinElmer EnvisionTM instrument for chemiluminescent signal detection.Biological data for Compound 1 are provided in table 1 below, in comparison with data for the previously known selective delta opioid receptor agonists SNC80, PN6047 and ARM390. Arrestin protein recruitment is thought to mediate DOR internalization leading to functional tolerance (an element of addiction) and a contribution towards of seizure activity. Thus, Compound 1 is a more than 100-fold weaker B-arrestin-2 recruiterthan SNC80, and about a 1000-fold weaker B-arrestin-2 recruiter than PN6047. As a G-biased agonist, Compound 1 is therefore likely to be non-addictive and not to cause seizures.Table 1

[0121] Compound Structure CAMP CAMP Arrestin Arrestin DOR Internalization DOR Internalization ICso (nM) Emax ECso (nM) Emax ECso (nM) Emax

[0122] / / z z — —

[0123] a V Voo

[0124] Compound 1 7.8 ± 0.6 0.73 ± 0.03 25.3 ± 1.6 0.08 ± 0.002 >1000 21.9 ± 3 Vo

[0125] 00 y

[0126] 00 V 0 TZ yZ Z— ^

[0127] 00 ( > TZ —

[0128] 00 / Z o—

[0129] P \o ■

[0130] SNC80 3.9 ± 0.3 0.77 ± 0.04 25.3 ± 0.94 0.53 ± 0.02 9.0 ± 0.8 167 ± 20

[0131] PN6047 0.93 ± 0.04 0.83 ± 0.04 5.1 ± 5 0.31 ± 0.01 2.9 ± 2 95.2 ± 5

[0132] ARM390 5.7 ± 0.6 0.74 ± 0.05 30.4 ± 1.0 0.46 ± 0.02 nd nd

[0133]

[0134] Emax: the maximum effect that can be expected from the compound: nd: not determined

[0135] c

[0136] z—

[0137] /

Claims

CLAIMS1. A compound of formula (I)OwhereinR1is selected from hydrogen or an alkyl, wherein said alkyl is preferably selected from methyl and ethyl; andR2is selected from hydrogen, an alkyl or a hydroxy alkyl, wherein said alkyl preferably is selected from methyl and ethyl, wherein preferably said hydroxy alkyl is 2-hydroxyethyl; or a pharmaceutically acceptable salt thereof,for use in the treatment or prevention of a disease or condition that benefits from agonism of the delta opioid receptor.

2. The compound for use accordingto claim 1, wherein R1and R2are each methyl.

3. The compound for use according to claim 1, which is selected from the group consisting of3-[[4-(dimethylcarbamoyl)phenyl]-(piperidin-4-ylidene)methyl]benzamide;3-[[4-(diethylcarbamoyl)phenyl](piperidin-4-ylidene)methyl]benzamide; 3-[[4-[ethyl(methyl)carbamoyl]phenyl]-(piperidin-4-ylidene)methyl]benzamide; and 3-[[4-[2-hydroxyethyl(methyl)carbamoyl]phenyl]-(piperidin-4- ylidene)methyl]benzamide;or a pharmaceutically acceptable salt thereof.

4. The compound for use according to claim 1, which is 3-[[4-(dimethylcarbamoyl)phenyl]- (piperidin-4-ylidene)methyl]benzamide, or a pharmaceutically acceptable salt thereof.

5. The compound for use according to claim 1, which is the hydrochloride salt of 3-[[4- (dimethylcarbamoyl)phenyl]-(piperidin-4-ylidene)methyl]benzamide.

6. The compound for use accordingto claim 1, wherein the disease or condition that benefits from agonism of the delta opioid receptor is pain, a neurological disorder, a cardiovascular disease, a mental disorder, a psychiatric disorder or a behavioural disorder.

7. The compound for use according to claim 6, wherein the pain is acute pain, chronic pain, neuropathic pain, cancer pain, visceral pain, diabetic pain, post-surgical pain, ischemic pain, inflammatory pain or chemotherapy-induced pain; or pain caused by diseases or conditions such as spinal cord injury, rheumatoid arthritis, osteoarthritis, low back pain, neck pain, fibromyalgia, migraine, opioid-induced hyperalgesia (OIH), opioid withdrawal syndrome (OWS), opioid withdrawal hyperalgesia, opioid overuse headache, shingles, hyperesthesia and other forms of hyperalgesia.

8. The compound for use according to claim 6, wherein the neurological disorder is stroke, Alzheimer’s disease, Parkinson’s disease, MS (multiple sclerosis), epilepsy or dementia (including frontal lobe dementia, Lewy body dementia and vascular dementia).

9. The compound for use according to claim 6, wherein the cardiovascular disease is ischemic heart disease, acute myocardial infarction, vascular ischemic pain or claudicatio intermittens.

10. The compound for use according to claim 6, wherein the mental disorder, psychiatric disorder or behavioural disorder is an anxiety disorder (including OCD (Obsessive- Compulsive disorder), panic disorder, trauma, PTSD, GAD, SOC and SAD), or a substance use disorder (including alcohol, nicotine, opioid and other drug abuse or addiction) or a panic disorder, an impulsive control disorder, a personality disorder, a mood disorder (including depression, melancholia, bipolar disorder and MDD (major depressive disorder)), ADHD (attention deficit hyperactivity disorder), tic disorder or eating disorder (including anorexia, binge eating and bulimia).

11. The compound for use according to claim 1, wherein the disease or condition that benefits from agonism of the delta opioid receptor is urinary incontinence, sensory hypersensitivity (including itch), lung edema, a gastro-intestinal disorder (including irritable bowel syndrome and inflammatory bowel disease), or a disorder of the sympathetic nervous system, hypertension, or a respiratory disease (including COPD (chronic obstructive pulmonary disease) and cough, such as chronic cough).

12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I)OwhereinR1is selected from hydrogen or an alkyl, wherein said alkyl is preferably selected from methyl and ethyl; andR2is selected from hydrogen, an alkyl or a hydroxy alkyl, wherein said alkyl preferably is selected from methyl and ethyl and wherein preferably said hydroxy alkyl is 2- hydroxyethyl;or a pharmaceutically acceptable salt thereof,and one or more pharmaceutically acceptable excipients.

13. A compound of formula (I')OwhereinR1is ethyl; andR2is selected from methyl and 2-hydroxyethyl;or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 13, wherein R1is ethyl and R2is methyl.

15. The compound according to claim 13, which is 3-[[4- [ethyl(methyl)carbamoyl]phenyl]-(piperidin-4-ylidene)methyl]benzamide, or a pharmaceutically acceptable salt thereof.

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