WO2016099394A1 - Nouveaux agonistes des récepteurs opiacés delta sélectifs utiles pour le traitement de la douleur, de l'anxiété et de la dépression - Google Patents

Nouveaux agonistes des récepteurs opiacés delta sélectifs utiles pour le traitement de la douleur, de l'anxiété et de la dépression Download PDF

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Publication number
WO2016099394A1
WO2016099394A1 PCT/SE2015/051364 SE2015051364W WO2016099394A1 WO 2016099394 A1 WO2016099394 A1 WO 2016099394A1 SE 2015051364 W SE2015051364 W SE 2015051364W WO 2016099394 A1 WO2016099394 A1 WO 2016099394A1
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WO
WIPO (PCT)
Prior art keywords
pain
compound
formula
mmol
treatment
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Application number
PCT/SE2015/051364
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English (en)
Inventor
Bengt Von Mentzer
Ingemar Starke
Peter Brandt
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Pharmnovo Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
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Publication of WO2016099394A1 publication Critical patent/WO2016099394A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • Novel selective delta-opioid receptor agonists useful for the treatment of pain, anxiety and depression.
  • the present invention is directed to novel compounds, to a process for their preparation, their use and pharmaceutical compositions comprising the novel compounds.
  • novel selective ⁇ -opioid receptor agonists are useful in therapy, and in particular for the treatment of pain, anxiety and depression.
  • Delta opioid receptors have been considered as a potential target to relieve pain conditions and depression and anxiety disorders.
  • Physical pain is a typical sensory experience that may be described as the unpleasant awareness of a noxious stimulus or bodily harm. Individuals experience pain by various daily hurts and aches, and sometimes through more serious injuries or illnesses.
  • 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”.
  • Pain is the most common symptom for which patients seek medical advice and treatment. Pain can be 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, functional ability or overall quality of life (K. M. Foley, Pain, in Cecil Textbook of Medicine 100-107, J. C. Bennett and F. Plum eds., 20th ed. 1996).
  • the types of pain are many and varied and include lower back pain, arthritis (especially osteoarthritis), headache (including migraine), fibromyalgia, nerve damage
  • Neurode neurode
  • neurological disease e.g. multiple sclerosis
  • post-viral illness e.g. shingles
  • CNS-related diseases such as Alzheimer's and Parkinson's have a high prevalence of associated pain. The incidence of chronic pain increases with advancing age and is associated with, and potentiated by depressive illness and loss of sleep.
  • DORs have multiple roles in the central nervous system disorders beside pain, such as depression, anxiety, epilepsy, and stress; gastrointestinal disorders such as diarrhea, postoperative ileus, ulceration, and irritable bowel syndrome and related inflammatory disorders such as osteoarthritis and rheumatoid arthritis, and others including respiratory, alcoholism and obesity/binge eating.
  • the current compounds can be used in the cure of many diseases.
  • opioids such as, codeine, dihydrocodeine (for mild to moderate pain) and oxycodone, tramadol etc. (for severe pain) are either non-selective, acting on all three opioid receptor sub-types or somewhat ⁇ receptor-biased and they produce the full range of both beneficial and unwanted effects.
  • Compounds of this invention show selective high potency for the ⁇ -opioid receptor (DOR).
  • DOR ⁇ -opioid receptor
  • the present invention provides a compound of formula (I)
  • R is selected from anyone of
  • a compound of formula I is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the compounds of formula I are used in pain therapy, such as treating acute pain, and chronic pain.
  • Compounds of the invention are highly potent and will retain analgesic potency on repeated administration.
  • Compounds of the invention will be useful in therapy, especially for the treatment of various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, osteoarthritis, fibromyalgia, migraine, visceral pain, diabetic pain, etc.
  • Compounds of the invention are useful for the treatment of urinary incontinence, various mental illnesses, cough, lung edema, various gastro-intestinal disorders (irritable bowel syndrome, irritable bowel disease), spinal injury and drug addiction, 120 including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension.
  • Compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts and organ transplants.
  • Compounds of the invention are useful in disease states where degeneration or 125 dysfunction of opioid receptors is present or implicated in that paradigm. This may involve the use of isotopically labeled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission
  • PET tomography
  • Compounds of the invention are useful as an analgesic agent for use during general 130 anesthesia and monitored anesthesia care.
  • Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anesthetic state (e.g. amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anesthetics, hypnotics, anxiolytics, neuromuscular blockers, neuropeptide receptor blockers and other opioids.
  • a further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of compound according to the formula I above, is administered to a patient in need of such treatment.
  • a pharmaceutical 145 composition comprising at least a compound of the formula I as an active
  • Example 1 d has been made by 1 ) de-protection of the 1 -nitrogen of compound III to 160 form compound VII, 2) reductive amination with 3-pyridinaldehvde to form compound VIII, and 3) coupling reaction with 3-aminocarbonylphenyl boronic acid.
  • HATU 1 -[Bis(dimethylamino)methylene]-1 /-/-1 ,2,3-triazolo[4,5-Jb]pyridinium 3-oxid hexafluorophosphate
  • Example IV ieri-Butyl 4-[(3-carbamoylphenyl)( ⁇ 4-[(2-hydroxyethyl)(methyl) 290 carbamoyl]phenyl ⁇ ) methylidene]piperidine-1 -carboxylate fe/f-Butyl 4-[bromo( ⁇ 4-[(2-hydroxyethyl)(methyl) carbamoyl] phenyl ⁇ )methylidene] piperidine-1 -carboxylate (1 .63 g, 3.0 mmol) was dissolved in a mixture of degassed 1 ,4-dioxane/H20 4/1 (30 ml_).
  • a method for treatment of a condition which method comprises administration of a therapeutically effective amount of the compound of formula I to a person suffering from, or susceptible to, such a condition.
  • the compounds of the invention will normally be administered via the oral, topical, parenteral, intravenous, intramuscular, subcutaneous, intra articular injection or in other injectable ways,
  • compositions inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable dosage form.
  • the compositions may be administered at varying doses.
  • Suitable daily doses of the compounds of the invention in therapeutically treatment of humans are about 0.0001 -100 mg/kg body weight, preferably 0.01 -10 mg/kg body weight.
  • Oral formulations are tablets or capsules which may be formulated by methods known to those skilled in the art to provide doses of the active compound in the range 365 of 0.007 mg to 700 mg for example 1 mg, 3 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg , 250 and 500 mg.
  • the optimum dosage and frequency of administration will depend on the particular condition being treated and its severity; the species of the patient; the age, sex, size and weight, diet, and general physical condition of the particular patient; brain/body 370 weight ratio; other medication the patient may be taking; the route of administration; the formulation; and various other factors known to physicians and others skilled in the art.
  • the compounds of the invention may be present in the pharmaceutical formulation in a concentration from 0.1 to 99.5%, such as from 0.5 to 95%, by weight of the total formulation.
  • the compound of the invention may be admixed with an
  • adjuvant or a carrier for example, lactose, saccharose, or sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the
  • a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
  • the compound of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets.
  • liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • such liquid preparations may contain coloring agents, flavoring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those
  • ⁇ -opioid receptors are coupled to inhibitory G proteins (Gi/o) which inhibit adenylyl cyclase activity, open K + channels and block Ca 2+ channels. They can also 405 couple, in an agonist-dependent manner to ⁇ -arrestin 2, which lead to
  • the Seltzer assessment is used to evaluate chronic pain. Thirty male CD1 mice (29- 37 g) are included in the study. They were obtained from Charles-River Ltd. and kept 420 in the Animal Facility of the Department of Pharmacology and Pharmacotherapy at the University of Pecs at 24-25 °C provided with standard chow and water ad libitum. All experimental procedures are carried out according to the 1998/XXVIII Act of the Hungarian Parliament on Animal Protection and Consideration Decree of Scientific Procedures of Animal Experiments (243/1988) and complied with the
  • mice with a minimum of 30% pre-injection hyperalgesia are included in the study.
  • the blood and the brain samples are taken 60 min after drug administration under 435 deep ketamin-xylazine anesthesia and sent for further analysis.
  • Blood (0.5-1 .5 ml) is taken by cardiac puncture to EDTA-containing tubes and centrifuged.
  • the plasma samples are stored at -70 ° C.
  • the whole brain with the cerebellum and the brainstem is dissected, put into Eppendorf tubes, immediately frozen in liquid nitrogen and they are stored at -70 ° C.
  • Rats are anaesthetized using 2.5% Isoflurane (Abbott, Maidenhead, UK) in oxygen with a flow rate of 1 L per minute.
  • the left leg is shaved and surgically prepared.
  • the medial collateral ligament is exposed and a section of it removed to expose the meniscus.
  • the meniscus is cut through its full thickness at the narrowest point.
  • left (ipsilateral) and right (contralateral) knees are assessed using an incapacitance meter (Linton Instruments UK) .
  • the change in hind paw weight distribution is defined as the difference in the amount of weight between the right contralateral control limb and the left ipsilateral treated limb divided by the sum of the weight right and left limbs x 100.
  • Hind paw withdrawal thresholds to mechanical stimulation are measured
  • Co-ordination the rotarod assessment is used to evaluate general coordinator behavior. It will be assessed by performance on the rotarod apparatus (Ugo Basile) on which mice will be trained for 3 days, each mouse receiving four training trials per day consisting of placing the mice for 2 min on a rod rotating at a speed of 475 up to 24 rpm, the latency to fall off the rotarod onto foam rubber padding being
  • Open field behavior the open field assessment is use to evaluate general social behavior. Animals will be placed within a standard Open field arena' and behavior 480 monitored by computer tracking (Ethovision) for up to 2 hours per day. Overall
  • locomotion will be measured and the time spent in the central part of the arena and in rearing will give an indication of anxiety-like behavior.

Abstract

Composé de formule I, destiné à être utilisé pour le traitement de la douleur, et composition pharmaceutique comprenant ledit composé.
PCT/SE2015/051364 2014-12-19 2015-12-17 Nouveaux agonistes des récepteurs opiacés delta sélectifs utiles pour le traitement de la douleur, de l'anxiété et de la dépression WO2016099394A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE1451612-4 2014-12-19
SE1451612 2014-12-19

Publications (1)

Publication Number Publication Date
WO2016099394A1 true WO2016099394A1 (fr) 2016-06-23

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002094783A1 (fr) * 2001-05-18 2002-11-28 Astrazeneca Ab Derives de 4-(phenyl-(piperidine-4-yl)-amino)-benzamide et leur utilisation dans le traitement de douleurs, de l'anxiete ou de troubles gastro-intestinaux
WO2003029215A1 (fr) * 2001-10-03 2003-04-10 Astrazeneca Ab Derives de 4(piperidin-4-yliden-(3-carbamoylphenyle)methyle) benzamide et leur utilisation dans le traitement de la douleur, de lesions spinales ou de troubles gastro-intestinaux
WO2004087663A1 (fr) * 2003-04-03 2004-10-14 Astrazeneca Ab Derives de diarylmethylidene piperidine, leurs preparations et leur utilisation
WO2004101520A1 (fr) * 2003-05-16 2004-11-25 Astrazeneca Ab Derives de diarylmethylidene piperidine et leur utilisation comme agonistes du recepteur opioide delta

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002094783A1 (fr) * 2001-05-18 2002-11-28 Astrazeneca Ab Derives de 4-(phenyl-(piperidine-4-yl)-amino)-benzamide et leur utilisation dans le traitement de douleurs, de l'anxiete ou de troubles gastro-intestinaux
WO2003029215A1 (fr) * 2001-10-03 2003-04-10 Astrazeneca Ab Derives de 4(piperidin-4-yliden-(3-carbamoylphenyle)methyle) benzamide et leur utilisation dans le traitement de la douleur, de lesions spinales ou de troubles gastro-intestinaux
WO2004087663A1 (fr) * 2003-04-03 2004-10-14 Astrazeneca Ab Derives de diarylmethylidene piperidine, leurs preparations et leur utilisation
WO2004101520A1 (fr) * 2003-05-16 2004-11-25 Astrazeneca Ab Derives de diarylmethylidene piperidine et leur utilisation comme agonistes du recepteur opioide delta

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