EP2421535A1 - Pipérazinyl azétidinyl amides hétéroaromatiques et aromatiques en tant qu'inhibiteurs de la monoacylglycérol lipase - Google Patents

Pipérazinyl azétidinyl amides hétéroaromatiques et aromatiques en tant qu'inhibiteurs de la monoacylglycérol lipase

Info

Publication number
EP2421535A1
EP2421535A1 EP10714829A EP10714829A EP2421535A1 EP 2421535 A1 EP2421535 A1 EP 2421535A1 EP 10714829 A EP10714829 A EP 10714829A EP 10714829 A EP10714829 A EP 10714829A EP 2421535 A1 EP2421535 A1 EP 2421535A1
Authority
EP
European Patent Office
Prior art keywords
compound
isobutyl
iss
cyclohexylmethyl
disorder
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP10714829A
Other languages
German (de)
English (en)
Inventor
Christopher M. Flores
Marina I. Nelen
Erica L. Nulton
Stephen Prouty
Matthew Todd
Sui-Po Zhang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Pharmaceutica NV
Original Assignee
Janssen Pharmaceutica NV
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.)
Filing date
Publication date
Application filed by Janssen Pharmaceutica NV filed Critical Janssen Pharmaceutica NV
Publication of EP2421535A1 publication Critical patent/EP2421535A1/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • 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
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy

Definitions

  • the present invention is directed to the use of a compound of formula (I) as herein defined for the treatment, amelioration and / or prevention of an MGL disorder in a subject, including a mammal and/or human, in which the disease, syndrome, or condition is affected by MGL.
  • Cannabis sativa has been used for the treatment of pain for many years.
  • ⁇ 9 - tetrahydrocannabinol is a major active ingredient from Cannabis sativa and an agonist of cannabinoid receptors (Pertwee, Brit J Pharmacol, 2008, 153, 199-215).
  • Two cannabinoid G protein-coupled receptors have been cloned, cannabinoid receptor type 1 (CB 1 , Matsuda et al, Nature, 1990, 346, 561-4) and cannabinoid receptor type 2 (CB 2 , Munro et al, Nature, 1993, 365, 61-5).
  • CBi is expressed centrally in brain areas, such as the hypothalamus and nucleus accumbens, as well as peripherally in the liver, gastrointestinal tract, pancreas, adipose tissue and skeletal muscle (Di Marzo et al, Curr Opin Lipidol, 2007, 18, 129-140).
  • CB 2 is predominantly expressed in immune cells, such as monocytes (Pacher et al, Amer J Physiol, 2008, 294, Hl 133-H1134), and, under certain conditions, also in the brain (Benito et al, Brit J Pharmacol, 2008, 153, 277-285) and in skeletal (Cavuoto et al, Biochem Biophys Res Commun, 2007, 364, 105-110) and cardiac (Hajrasouliha et al, Eur J Pharmacol, 2008, 579, 246-252) muscle.
  • MGL inhibitors are potentially useful for the treatment of pain, inflammation and CNS disorders (Di Marzo et al, Curr Pharm Des, 2000, 6, 1361-80; Jhaveri et al, Brit J Pharmacol, 2007, 152, 624-632; McCarberg Bill et al, Amer J Ther, 2007, 14, 475- 83), as well as glaucoma and disease states arising from elevated intraocular pressure (Njie, Ya Fatou; He, Fang; Qiao, Xhuanhong; Song, Zhoa-Hui, Exp. Eye Res., 2008, 87(2): 106-14).
  • the present invention is directed to a method for treating, ameliorating or preventing a disease, syndrome, condition or disorder that is affected by the inhibition of MGL (such as pain, the diseases that lead to such pain, inflammation and CNS disorders) comprising, consisting of and / or consisting essentially of administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula (I)
  • R 2 is 4-methoxyphenyl; a compound wherein W is N, R 1 is H, v — ' is , X-Y-Z is - CH-C(R 2 )-N(R 3 )-, R 2 is isobutyl, and R 3 is isobutyl;
  • X-Y-Z is -CH-C(R 2 )-N(R 3 )-, R 2 is phenoxymethyl, and R 3 is 2,2-dimethylpropyl;
  • X-Y-Z is -CH-C(R 2 )-N(R 3 )-, R 2 is phenyl, and R 3 is 2,2-dimethylpropyl;
  • R 2 is 4-methylphenyl and R 3 is methoxy-methyl-carbonyl;
  • R 2 is n-propyl and R 3 is cyclohexylmethyl; and enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof.
  • the present invention is further directed to the use of a compound of formula (I) as herein defined, for the preparation of a medicament or pharmaceutical composition for the treatment, amelioration or prevention of a disease, syndrome, condition or disorder that is affected by the inhibition of MGL, in a subject in need thereof.
  • C 1 -Ce alkylcarbonyl refers to a group of the formula:
  • substituents and substitution patterns on the compounds of formula (I) can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • terapéuticaally effective amount refers to an amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation or partial alleviation of the symptoms of the disease, syndrome, condition, or disorder being treated.
  • composition is intended to encompass a product comprising the specified ingredients in therapeutically effective amounts, as well as any product that results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • “ameliorating” and the like shall include the management and care of a subject or patient (preferably mammal, more preferably human) for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present invention to prevent the onset of the symptoms or complications, alleviate the symptoms or complications, or eliminate the disease, condition, or disorder.
  • the terms “preventing” and “prevention” shall include (a) reduction in the frequency of one or more symptoms; (b) reduction in the severity of one or more symptoms; (c) the delay or avoidance of the development of additional symptoms; and / or (d) delay or avoidance of the development of the disorder or condition.
  • a subject in need of thereof shall include any subject or patient (preferably a mammal, more preferably a human) who has experienced or exhibited at least one symptom of the disorder, disease or condition to be prevented.
  • a subject in need thereof may additionally be a subject (preferably a mammal, more preferably a human) who has not exhibited any symptoms of the disorder, disease or condition to be prevented, but who has been deemed by a physician, clinician or other medical professional to be at risk of developing said disorder, disease or condition.
  • the subject may be deemed at risk of developing a disorder, disease or condition (and therefore in need of prevention or preventive treatment) as a consequence of the subject's medical history, including, but not limited to, family history, pre-disposition, co-existing (comorbid) disorders or conditions, genetic testing, and the like.
  • MGL inhibitor is intended to encompass a compound that interacts with MGL to substantially reduce or eliminate its catalytic activity, thereby increasing the concentrations of its substrate(s).
  • MGL-modulated is used to refer to the condition of being affected by the modulation of the MGL enzyme including the condition of being affected by the inhibition of the MGL enzyme, such as, for example, pain and the diseases that lead to such pain, inflammation and CNS disorders.
  • the term "affect" or "affected” when referring to a disease, syndrome, condition or disorder that is affected by inhibition of MGL shall imply a reduction in the frequency and / or severity of one or more symptoms or manifestations of said disease, syndrome, condition or disorder; and / or imply the prevention of the development of one or more symptoms or manifestations of said disease, syndrome, condition or disorder or the development of the disease, condition, syndrome or disorder.
  • the compounds of formula (I) are useful in methods for treating, ameliorating and / or preventing a disease, a syndrome, a condition or a disorder that is affected by the inhibition of MGL.
  • Such methods comprise, consist of and/or consist essentially of administering to a subject, including an animal, a mammal, and a human in need of such treatment, amelioration and / or prevention, a therapeutically effective amount of a compound of formula (I), or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof.
  • the compounds of formula (I) are useful for treating, ameliorating and / or preventing pain; diseases, syndromes, conditions, or disorders causing such pain; inflammation and / or CNS disorders.
  • the compounds of formula (I) are useful for treating, ameliorating and / or preventing inflammatory pain, inflammatory hypersensitivity conditions and / or neuropathic pain, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), as herein defined.
  • inflammatory pain examples include pain due to a disease, condition, syndrome, disorder, or a pain state including inflammatory bowel disease, visceral pain, migraine, post operative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint pain, abdominal pain, chest pain, labor, musculoskeletal diseases, skin diseases, toothache, pyresis, burn, sunburn, snake bite, venomous snake bite, spider bite, insect sting, neurogenic bladder, interstitial cystitis, urinary tract infection, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, postmastectomy pain syndrome, menstrual pain, endometriosis, pain due to physical trauma, headache, sinus headache, tension headache, or arachnoiditis.
  • inflammatory hyperalgesia is inflammatory hyperalgesia / hypersensitivity.
  • inflammatory hyperalgesia include a disease, syndrome, condition, disorder, or pain state including inflammation, osteoarthritis, rheumatoid arthritis, back pain, joint pain, abdominal pain, musculoskeletal diseases, skin diseases, post operative pain, headaches, toothache, burn, sunburn, insect sting, neurogenic bladder, urinary incontinence, interstitial cystitis, urinary tract infection, cough, asthma, chronic obstructive pulmonary disease, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, enteritis, irritable bowel syndrome, inflammatory bowel diseases including Crohn's Disease, ulcerative colitis, urinary incontinence, benign prostatic hypertrophy, cough, asthma, rhinitis, nasal hypersensitivity, itch, contact dermititis and / or dermal allegy and chronic obstructive pulmonary disease.
  • the present invention is directed to a method for treating, ameliorating and / or preventing inflammatory visceral hyperalgesia in which a enhanced visceral irritability exists, comprising, consisting of, and/or consisting essentially of the step of administering to a subject in need of such treatment a therapeutically effective amount of a compound, salt or solvate of formula (I).
  • the present invention is directed to a method for treating inflammatory somatic hyperalgesia in which a hypersensitivity to thermal, mechanical and/or chemical stimuli exists, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof.
  • a further embodiment of the present invention is directed to a method for treating, ameliorating and / or preventing neuropathic pain.
  • a neuropathic pain include pain due to a disease, syndrome, condition, disorder, or pain state including cancer, neurological disorders, spine and peripheral nerve surgery, brain tumor, traumatic brain injury (TBI), spinal cord trauma, chronic pain syndrome, fibromyalgia, chronic fatigue syndrome, lupus, sarcoidosis, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, central pain, neuropathies associated with spinal cord injury, stroke, amyotrophic lateral sclerosis (ALS),
  • TBI traumatic brain injury
  • fibromyalgia chronic fatigue syndrome
  • lupus sarcoidosis
  • peripheral neuropathy bilateral peripheral neuropathy, diabetic neuropathy, central pain, neuropathies associated with spinal cord injury, stroke, amyotrophic lateral sclerosis (ALS),
  • ALS amyotrophic lateral sclerosis
  • Parkinson's disease multiple sclerosis, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, bony fractures, oral neuropathic pain, Charcot's pain, complex regional pain syndrome I and II (CRPS IZII), radiculopathy, Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome, optic neuritis, postfebrile neuritis, migrating neuritis, segmental neuritis,
  • Gombault's neuritis neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngial neuralgia, migrainous neuralgia, idiopathic neuralgia, intercostals neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, postherpetic neuralgia, causalgia, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbital neuralgia, trigeminal neuralgia, vulvodynia, or vidian neuralgia.
  • neuropathic cold allodynia which can be characterized by the presence of a neuropathy-associated allodynic state in which a hypersensitivity to cooling stimuli exists.
  • neuropathic cold allodynia include allodynia due to a disease, condition, syndrome, disorder or pain state including neuropathic pain (neuralgia), pain arising from spine and peripheral nerve surgery or trauma, traumatic brain injury (TBI), trigeminal neuralgia, postherpetic neuralgia, causalgia, peripheral neuropathy, diabetic neuropathy, central pain, stroke, peripheral neuritis, polyneuritis, complex regional pain syndrome I and II (CRPS I/II) and radiculopathy.
  • neuropathic pain neuralgia
  • TBI traumatic brain injury
  • trigeminal neuralgia postherpetic neuralgia
  • causalgia peripheral neuropathy
  • diabetic neuropathy central pain
  • stroke peripheral neuritis
  • polyneuritis complex regional pain syndrome I and II
  • the present invention is directed to a method for treating, ameliorating and / or preventing neuropathic cold allodynia in which a hypersensitivity to a cooling stimuli exists, comprising, consisting of, and/or consisting essentially of the step of administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I) or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof.
  • the present invention is directed to a method for treating, ameliorating and / or preventing CNS disorders.
  • CNS disorders include anxieties, such as social anxiety, post-traumatic stress disorder, phobias, social phobia, special phobias, panic disorder, obsessive-compulsive disorder, acute stress, disorder, separation anxiety disorder, and generalized anxiety disorder, as well as depression, such as major depression, bipolar disorder, seasonal affective disorder, post natal depression, manic depression, and bipolar depression.
  • the present invention is directed to methods of treating, ameliorating and / or preventing a disorder, syndrome, condition or disease that is affected by the inhibition of MGL, comprising, consisting of or consisting essentially of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I)
  • the disease, syndrome, condition or disorder that is affected by inhibition of MGL is selected from the group consisting of pain, inflammatory pain, inflammatory hypersensitivity conditions and neuropathic pain, as herein defined.
  • the present invention is directed to treating, ameliorating or preventing a disease, syndrome, condition or disorder that is affected by inhibition of MGL, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (Ia)
  • the present invention is directed to treating, ameliorating or preventing a disease, syndrome, condition or disorder that is affected by inhibition of MGL, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (Ib)
  • the present invention is directed to treating, ameliorating or preventing a disease, syndrome, condition or disorder that is affected by inhibition of MGL, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (Ic)
  • R 1 , W, and -X-Y-Z- are as herein defined.
  • the present invention is directed to treating, ameliorating or preventing a disease, syndrome, condition or disorder that is affected by inhibition of MGL, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound selected from the group consisting of [l-(2,2-Dimethyl-propyl)-2-phenoxymethyl-lH-indol-5-yl]-[3-(4-pyridin-2-yl- piperazin-l-yl)-azetidin-l-yl]-methanone; (Compound #1) (2-Cyclohexyl-benzooxazol-6-yl)- [3 -(4-pyridin-2-yl-piperazin- 1 -yl)-azetidin- 1 - yl]-methanone; (Compound #2)
  • the present invention is directed to treating, ameliorating or preventing a disease, syndrome, condition or disorder that is affected by inhibition of MGL, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound selected from the group consisting of (2-Cyclohexyl-benzooxazol-6-yl)- [3 -(4-pyridin-2-yl-piperazin- 1 -yl)-azetidin- 1 - yl]-methanone; (Compound #2)
  • the present invention is directed to treating, ameliorating or preventing a disease, syndrome, condition or disorder that is affected by inhibition of MGL, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound selected from the group consisting of (2-Cyclohexyl-benzooxazol-6-yl)- [3 -(4-pyridin-2-yl-piperazin- 1 -yl)-azetidin- 1 - yl]-methanone; (Compound #2)
  • the present invention is directed to the use of any single compound or subset of compounds selected from the compounds listed in Tables 1-3 below, or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof; for the treatment, amelioration or prevention or a disease, syndrome, condition or disorder that is affected by the inhibition of MGL, in a subject in need thereof.
  • the compounds of formula (I) of the present invention are as listed in Tables 1-3, below.
  • the present invention is directed to treating, ameliorating or preventing a disease, syndrome, condition or disorder that is affected by inhibition of MGL, wherein the disease, syndrome, condition or disorder that is affected by inhibition of MGL is selected from the group consisting of inflammatory pain and neuropathic pain; comprising administering to a subject in need thereof (including a mammal and / or human), a therapeutically effective amount of a compound of formula (I)
  • the present invention is directed to treating, ameliorating or preventing inflammatory pain; comprising administering to a subject in need thereof (including a mammal and / or human), a therapeutically effective amount of a compound of formula (I)
  • the inflammatory pain is selected from the group as herein defined; and enantiomers, diastereomers, solvates and pharmaceutically acceptable salt thereof.
  • the inflammatory pain is selected from the group consisting of visceral pain and inflammatory hyeralgesia, preferably visceral pain.
  • the present invention is directed to treating, ameliorating or preventing inflammatory hyperalgesia, comprising administering to a subject in need thereof (including a mammal and / or human), a therapeutically effective amount of a compound of formula (I) selected from the group as herein defined; and enantiomers, diastereomers, solvates and pharmaceutically acceptable salt thereof.
  • the inflammatory hyperalgesia is ulcerative colitis.
  • the present invention is directed to treating, ameliorating or preventing neuropathic pain, comprising administering to a subject in need thereof (including a mammal and / or human), a therapeutically effective amount of a compound of formula (I)
  • the neuropathic pain is neuropathic cold allodynia.
  • salts of compounds of formula (I) refer to non-toxic "pharmaceutically acceptable salts.” Other salts may, however, be useful in the preparation of compounds of formula (I) or of their pharmaceutically acceptable salts thereof.
  • Suitable pharmaceutically acceptable salts of compounds of formula (I) include acid addition salts which can, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and salts formed with suitable organic ligands, such as quaternary ammonium salts.
  • representative pharmaceutically acceptable salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N- methylglucamine ammonium salt, oleate, pam
  • acids and bases that may be used in the preparation of pharmaceutically acceptable salts include acids such as acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(lS)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D- glucoronic acid, L-gluta
  • Embodiments of the present invention include prodrugs of compounds of formula (I).
  • such prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the required compound.
  • the term “administering” encompasses the treatment or prevention of the various diseases, conditions, syndromes and disorders described with the compound specifically disclosed or with a compound that may not be specifically disclosed, but which converts to the specified compound in vivo after administration to a patient.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • the compounds according to embodiments of this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention. The skilled artisan will understand that the term compound as used herein, is meant to include solvated compounds of Formula (I).
  • the processes for the preparation of the compounds according to certain embodiments of the invention give rise to mixture of stereoisomers
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
  • One embodiment of the present invention is directed to a composition, including a pharmaceutical composition, comprising, consisting of, and/or consisting essentially of the (+)-enantiomer of a compound of formula (I) wherein said composition is substantially free from the (-)-isomer of said compound.
  • substantially free means less than about 25 %, preferably less than about 10 %, more preferably less than about 5 %, even more preferably less than about 2 % and even more preferably less than about 1 % of the (-)-isomer calculated as o . . . . (mass (+) - enantiomer)
  • compositions including a pharmaceutical composition, comprising, consisting of, and consisting essentially of the (-)-enantiomer of a compound of formula (I) wherein said composition is substantially free from the (+)-isomer of said compound.
  • substantially free from means less than about 25 %, preferably less than about 10 %, more preferably less than about 5 %, even more preferably less than about 2 % and even more preferably less than about 1 % of the (+)-isomer calculated as n, , ⁇ , • (mass (-) - enantiomer) - ⁇
  • any of the processes for preparation of the compounds of the various embodiments of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective
  • compositions comprising compounds of formula (I) and at least one pharmaceutically acceptable carrier, pharmaceutically acceptable excipient, and/or pharmaceutically acceptable diluent.
  • the compounds of formula (I) may be admixed with any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilizing agent(s), and combinations thereof.
  • Solid oral dosage forms such as tablets or capsules, containing the compounds of the present invention may be administered in at least one dosage form at a time, as appropriate. It is also possible to administer the compounds in sustained release formulations.
  • Additional oral forms in which the present inventive compounds may be administered include elixirs, solutions, syrups, and suspensions; each optionally containing flavoring agents and coloring agents.
  • compounds of formula (I) can be administered by inhalation (intratracheal or intranasal) or in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
  • inhalation intratracheal or intranasal
  • a suppository or pessary or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
  • they can be incorporated into a cream comprising, consisting of, and/or consisting essentially of an aqueous emulsion of polyethylene glycols or liquid paraffin.
  • an alternative means of administration includes transdermal administration by using a skin or transdermal patch.
  • compositions of the present invention can also be injected parenterally, for example intracavernosally, intravenously, intramuscularly, subcutaneously, intradermally or intrathecally.
  • the compositions will also include at least one of a suitable carrier, a suitable excipient, and a suitable diluent.
  • compositions of the present invention are best used in the form of a sterile aqueous solution that may contain other substances, for example, enough salts and monosaccharides to make the solution isotonic with blood.
  • compositions of the present invention may be administered in the form of tablets or lozenges, which can be formulated in a conventional manner.
  • compositions containing at least one of the compounds of formula (I) can be prepared by mixing the compound(s) with a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, and/or a pharmaceutically acceptable excipient according to conventional pharmaceutical compounding techniques.
  • a pharmaceutically acceptable carrier e.g., benzyl alcohol, benzyl ether, benzyl ether, benzyl ether, benzyl ether, sulfate, a pharmaceutically acceptable excipient, etc.
  • the carrier, excipient, and diluent may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral, etc.).
  • suitable carriers, excipients and diluents include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like;
  • suitable carriers, excipients and diluents include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
  • Solid oral preparations also may be optionally coated with substances, such as, sugars, or be enterically -coated so as to modulate the major site of absorption and disintegration.
  • the carrier, excipient and diluent will usually include sterile water, and other ingredients may be added to increase solubility and preservation of the composition.
  • injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives, such as solubilizers and preservatives.
  • a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition thereof includes a dose range from about 0.1 mg to about 3000 mg, or any amount or range therein, in particular from about 1 mg to about 1000 mg, or any amount or range therein, more particularly, from about 10 mg to about 500 mg, or any amount or range therein, of ingredient compound of formula (I) in a regimen of about 1 to 4 times per day for an average (70 kg) human; although, it is apparent to one skilled in the art that the therapeutically effective amount for a compound of formula (I) will vary as will the diseases, syndromes, conditions, and disorders being treated.
  • a pharmaceutical composition is preferably provided in the form of tablets containing about 0.01, about 10, about 50, about 100, about 150, about 200, about 250, and about 500 milligrams of a compound of formula (I).
  • a compound of formula (I) may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three and four times daily.
  • Optimal dosages of a compound of formula (I) to be administered may be readily determined and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease, syndrome, condition, or disorder.
  • factors associated with the particular subject being treated including subject age, weight, diet and time of administration, will result in the need to adjust the dose to achieve an appropriate therapeutic level and desired therapeutic effect.
  • the above dosages are thus exemplary of the average case. There can be, of course, individual instances wherein higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • a compound of formula (I) may be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art whenever use of a compound of formula (I) is required for a subject in need thereof.
  • Representative compounds of the present invention may be synthesized in accordance with the general synthetic methods described below and illustrated in the schemes that follow. Since the schemes are an illustration, the invention should not be construed as being limited by the specific chemical reactions and specific conditions described in the schemes and examples.
  • the various starting materials used in the schemes are commercially available or may be prepared by methods well within the skill of persons versed in the art. The variables are as defined herein and within the skill of persons versed in the art.
  • DIPEA or DIEA Diisopropylethylamine
  • HBTU O-B enzotriazole-N,N,N ' ,N ' -tetramethy 1- uronium-hexafluoro-phosphate
  • HEPES 4-(2-Hydroxyethyl)-l-piperazineethane sulfonic acid
  • TEA Triethylamine
  • TFA Trifluoroacetic Acid
  • THF Tetrahydrofuran
  • the compounds of Formula (I) of the present invention may be prepared according to the process as outlined in Scheme 1, below.
  • a suitably substituted compound of formula (V), a known compound or compound prepared by known methods is reacted with a suitably substituted compound of formula (VI), wherein PG 1 is a suitably selected nitrogen protecting group such as -CH(phenyl) 2 , benzyl, t-butyl, methyl, and the like, preferably -CH(phenyl) 2 , a known compound or compound prepared by known methods; in the presence of an organic base such as DIPEA, pyridine, and the like (preferably not TEA); in an organic solvent such as acetonitrile, THF, DCM, and the like; preferably at a temperature in the range of from about 50 0 C to about 90 0 C; to yield the corresponding compound of formula (VII).
  • PG 1 is a suitably selected nitrogen protecting group such as -CH(phenyl) 2 , benzyl, t-butyl, methyl, and the like, preferably -CH(phenyl) 2 ,
  • the compound of formula (VII) is de-protected according to known methods, to yield the corresponding compound of formula (VIII).
  • PG 1 is - CH(phenyl) 2
  • the compound of formula (VII) is de-protected by reacting with 1- chloroethyl chloroformate, in an organic solvent such as dichloromethane, and then refluxed in an organic solvent such as methanol, to yield the corresponding compound of formula (VIII).
  • the compound of formula (VIII) is reacted with a suitably substituted compound of formula (IX), wherein LG 1 is selected from the group consisting of - C(O)Cl and C(O)OH, and wherein LG 1 is bound at the desired bonding position on benzene ring of the the benzo-fused portion of the compound of formula (IX), a known compound or compound prepared by known methods, in the presence of a suitably selected coupling agent such as HATU, HBTU, DCC, and the like; in the presence of a suitably selected organic base such as DIPEA, TEA, pyridine, and the like; in an organic solvent such as acetonitrile, DMF, DCM, and the like; to yield the corresponding compound of formula (I).
  • a suitably substituted compound of formula (IX) wherein LG 1 is selected from the group consisting of - C(O)Cl and C(O)OH, and wherein LG 1 is bound at the desired bonding position on benzene
  • Methanesulfonyl chloride (0.152 mL, 1.9 mmol) was added dropwise to a solution of (2-cyclohexyl-benzooxazol-6-yl)-(3 -hydroxy-azetidin- 1 -yl)-methanone (0.48 g, 1.6 mmol) and DIPEA (0.558 mL, 3.2 mmol) in DCM (20 mL) at -40 0 C under nitrogen. Immediately following the addition, the cooling bath was removed and the mixture slowly warmed to room temperature. The resulting mixture was then washed with water, dried using magnesium sulfate, filtered, and the solvent removed under reduced pressure.
  • Compounds #2 through 28 may be similarly prepared according to the procedures as described in Example 1, above and substituting suitably selected and / or substituted reagents, starting materials and purification methods known to those skilled in the art.
  • Example 2 (in vitro Assay); MGL Enzyme Activity Assay All rate-based assays were performed in black 384-well polypropylene PCR microplates (Abgene) in a total volume of 30 ⁇ L. Substrate 4-methylumbelliferyl butyrate (4MU-B, Sigma) and purified mutant MGL enzyme (mut-MGLL 11-313 L179S Ll 86S) were diluted separately into 20 mM PIPES buffer (pH 7), containing 150 mM NaCl, and 0.001% Tween 20.
  • MU-B 4-methylumbelliferyl butyrate
  • mut-MGLL 11-313 L179S Ll 86S purified mutant MGL enzyme
  • Compounds of Formula (I) were pre-dispensed (50 nL) into the assay plate using a Cartisian Hummingbird (Genomic Solutions, Ann Arbor, MI) prior to adding 4MU-B (25 ⁇ L of 1.2X solution, final concentration of 10 ⁇ M) followed by enzyme (5 ⁇ L of a 6X solution, final concentration of 5 nM) to initiate the reaction. Final compound concentrations ranged from 17 to 0.0003 ⁇ M.
  • the fluorescence change due to 4MU-B cleavage was monitored with excitation and emission wavelengths of 335 and 440 nm, respectively, and a bandwidth of 10 nm (Safire 2 , Tecan) at 37°C for 5 min.
  • IC50 values for compounds of Formula (I) were determined using Excel from a fit of the equation to the concentration- response-plot of the fractional activity as a function of inhibitor concentration.
  • ThermoFluor (TF) assay is a 384-well plate-based binding assay that measures thermal stability of proteins (Pantoliano, M. W., Petrella, E. C, Kwasnoski, J. D., Lobanov, V. S., Myslik, J., Graf, E., Carver, T., Asel, E., Springer, B. A., Lane, P., and Salemme, F. R. JBiomol Screen 2001, 6, 429-40; Matulis, D., Kranz, J. K.,
  • TF dye used in all experiments was 1,8-ANS (Invitrogen: A-47).
  • Screening compound plates contained 100% DMSO compound solutions at a single concentration.
  • compounds were arranged in a pre-dispensed plate (Greiner Bio-one: 781280), wherein compounds were serially diluted in 100% DMSO across 11 columns within a series. Columns 12 and 24 were used as DMSO reference and contained no compound.
  • the compound aliquots 50 nL were robotically pre-dispensed directly into black 384-well polypropylene PCR microplates (Abgene: TF-0384/k) using the Cartesian Hummingbird liquid handler (Genomic Solutions, Ann Arbor, MI). .
  • Fluorescence emission of the entire 384-well plate was detected by measuring light intensity using a CCD camera (Sensys, Roper Scientific) filtered to detect 500 ⁇ 25 nm, resulting in simultaneous and independent readings of all 384 wells. A single image with 20-sec exposure time was collected at each temperature, and the sum of the pixel intensity in a given area of the assay plate was recorded versus temperature and fit to standard equations to yield the T 1n .
  • CCD camera Sensys, Roper Scientific
  • HeLa cells were homogenated with a Polytron in 10 ml (about 400 million cells) HEPES buffer (HEPES 20 mM, pH 7.4, NaCl 125 mM, EDTA 1 mM, KCl 5 mM, Glucose 20 mM).
  • HEPES buffer pH 7.4, NaCl 125 mM, EDTA 1 mM, KCl 5 mM, Glucose 20 mM.
  • MGL inhibitor MGL inhibitor for 15 min to block MGL activity
  • the HEPES buffer solution was incubated with calcium (10 mM) for 20 min.
  • the total reaction volume was 5 ml.
  • the reactions were stopped by 6 mL organic solvent extraction (2: 1 chloroform/methanol).
  • Methoxy arachidonyl fluorophosphonate (MAFP) was used as positive control.
  • %MAFP (Compound 2-AG/MAFP 2-AG) x 100.
  • 100 mg of the compound #1, prepared as in Example 1 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.

Abstract

L'invention porte sur des composés, des compositions et des procédés pour traiter des maladies, syndromes, des états pathologiques et des troubles qui sont affectés par l'inhibition de la MGL, y compris la douleur. Ces composés sont représentés par la Formule (I) ci-après, dans laquelle R1, W et (a) sont définis présentement.
EP10714829A 2009-04-22 2010-04-22 Pipérazinyl azétidinyl amides hétéroaromatiques et aromatiques en tant qu'inhibiteurs de la monoacylglycérol lipase Withdrawn EP2421535A1 (fr)

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WO2013049289A1 (fr) * 2011-09-30 2013-04-04 Janssen Pharmaceutica Nv Inhibiteurs de monoacylglycérol lipase pour le traitement de maladies métaboliques et de troubles apparentés
WO2014100834A1 (fr) * 2012-12-21 2014-06-26 The Regents Of The University Of California Méthodes et compositions pour le traitement de la toxicité du cyanure et de sulfure d'hydrogène
EP3087067B1 (fr) * 2013-12-26 2018-10-24 Takeda Pharmaceutical Company Limited Composés 4-(pipérazin-1-yl)-pyrrolidin-2-one comme inhibiteurs de la monoacylglycérol lipase (magl)
WO2016158956A1 (fr) * 2015-03-30 2016-10-06 武田薬品工業株式会社 Composé hétérocyclique
US10463753B2 (en) 2016-02-19 2019-11-05 Lundbeck La Jolla Research Center, Inc. Radiolabeled monoacylglycerol lipase occupancy probe
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CA3076477A1 (fr) 2017-09-29 2019-04-04 Takeda Pharmaceutical Company Limited Compose heterocyclique
EP3717477B1 (fr) 2017-11-28 2022-07-20 F. Hoffmann-La Roche AG Nouveaux composés hétérocycliques
TW201930300A (zh) * 2017-12-15 2019-08-01 瑞士商赫孚孟拉羅股份公司 新雜環化合物
EP3856178A1 (fr) * 2018-09-28 2021-08-04 Janssen Pharmaceutica NV Modulateurs de la monoacylglycérol lipase

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