WO2021026377A1 - Composés contenant du lactame pour le traitement de la douleur - Google Patents

Composés contenant du lactame pour le traitement de la douleur Download PDF

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Publication number
WO2021026377A1
WO2021026377A1 PCT/US2020/045246 US2020045246W WO2021026377A1 WO 2021026377 A1 WO2021026377 A1 WO 2021026377A1 US 2020045246 W US2020045246 W US 2020045246W WO 2021026377 A1 WO2021026377 A1 WO 2021026377A1
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Prior art keywords
pain
compound
another embodiment
formula
hydrogen
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PCT/US2020/045246
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English (en)
Inventor
Lewis D. Pennington
James R. Woods
Hoan Huynh
Brian M. Aquila
Ingo Andreas Mugge
Yuan HU
Younggi Choi
Thomas Andrew Wynn
Baudouin Gerard
Todd Bosanac
Nicholas J. VANTANGOLI
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Alkermes, Inc.
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Publication of WO2021026377A1 publication Critical patent/WO2021026377A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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]
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • Opiates have been the subject of intense research since the isolation of morphine in 1805, and thousands of compounds having opiate or opiate-like activity have been identified.
  • Many opioid receptor-interactive compounds including those used for producing analgesia (e.g,, morphine) and those used for treating drug addiction (e.g,, naitrexone and cyclazocine) have been employed in human therapy.
  • the actions of endogenous opioids and opiates are mediated by three receptor types (m, d, and k receptors), which are coupled to different intracellular effector systems. [Berrocoso E. et. al., Current Pharmaceuticsl Design, 15(14) 2009, 1612-22].
  • agents that can modulate the actions of one or more of the opioid receptor types with selectivity and sensitivity are important to treat the various diseases and disorders regulated by the opioid system.
  • Compounds that bind to opioid receptors are likely to be usefui in the treatment of diseases and conditions modulated by opiate receptors.
  • provided herein are compounds useful for the treatment of pain in a subject in need thereof.
  • compounds of the Fomula !: or a pharmaceutically acceptable salt thereof are provided herein.
  • a pharmaceutical composition comprising a compound of any of Formula l, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier
  • a method of treating pain in a subject in need thereof comprising administering to the subject a compound of Formula l, or pharmaceutically acceptable salts thereof
  • the pain is inflammatory pain, thermal pain, acute pain, chronic pain, traumatic pain, chemical pain, ischemic pain, centrally mediated pain, peripherally mediated pain, prickling pain, visceral pain, progressive disease pain, musculoskeletal pain (e.g,, back pain, neck pain), post-surgical pain, bone pain (e g., osteoarthritis), nociceptive pain, or neuropathic pain
  • the pain is musculoskeletal pain (e.g , back pain, neck pain), post-surgical pain, or bone pain (e.g.
  • provided herein is a method of treating depression in a subject in need thereof comprising administering to the subject a compound of Formula l, or a pharmaceutically acceptable salt thereof.
  • a method of treating addiction in a subject in need thereof comprising administering to the subject a compound of Formula l, or a pharmaceutically acceptable salt thereof, in an embodiment, the addiction is drug addiction, in an embodiment, the addiction is opioid addiction. In another embodiment, the addiction is alcohol addiction.
  • compounds e.g., the compounds of Formula l, or pharmaceutically acceptable salts thereof, that are useful in the treatment of pain in a subject.
  • these compounds may modulate the m-opioid receptor.
  • the compounds provided herein are considered p-receptor agonists.
  • the compounds provided herein are useful in treatment of pain in a subject by acting as an agonist of the p-receptor. Definitions
  • the articles “a” and “an” refer to one or to more than one ⁇ i.e., to at least one) of the grammatical object of the article.
  • an element means one element or more than one element.
  • use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.
  • the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ⁇ 20% or ⁇ 10%, including ⁇ 5%, ⁇ 1%, and ⁇ 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods, As used to herein, the term “EC 50 ” refers to the concentration of a compound required to achieve an effect that is 50% of the maximal observed effect of a compound.
  • agonist refers to a compound that, when contacted with a target of interest (e.g., the m-opioid receptor) causes an increase in the magnitude of a certain activity or function of the target compared to the magnitude of the activity or function observed in the absence of the agonist.
  • a target of interest e.g., the m-opioid receptor
  • pain generally defined as physical suffering or discomfort caused by illness or injury, and can be thought of as encompassing inflammatory pain, thermal pain, acute pain, chronic pain, musculoskeletal pain, post-surgical pain, nociceptive pain, neuropathic pain, and the like.
  • depression can be generally defined as a mental condition characterized by feelings of severe despondency and dejection. “Depression” can also be referred to as major depression, clinical depression, major depressive illness, major affective disorder and unipolar mood disorder.
  • the depressive condition can be an anxiety disorder, a mental condition, recurrent depression, and the like.
  • addiction is generally defined as a chronic brain disease that causes compulsive drug seeking and use, or alcohol seeking and use.
  • Drug addicition can be opioid addiction ⁇ i.e,, opioid dependence), stimulant addiction, and the like.
  • the term "treat, “treated,” “treating, or “treatment” includes the diminishment or alleviation of at least one symptom associated or caused by the state, disorder or disease being treated.
  • the treatment comprises bringing into contact with the opioid receptor an effective amount of a compound of the invention for conditions related to pain, depression or addiction.
  • prevent means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or ail of the symptoms associated with the disorder or disease.
  • the term “patient,” Individual” or “subject” refers to a human or a non- human mammal.
  • Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals.
  • the patient, subject, or in di vidua! is human.
  • the terms “effective amount,” “pharmaceutically effective amount,” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired aiteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation,
  • the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biologicai effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • the term “pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its sail form.
  • pharmaceutically acceptable salts include, but are not limited to, minerai or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable saits of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • Such saits can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrlie are preferred.
  • pharmaceuticalaiiy acceptable salt Is not limited to a mono, or 1:1, salt.
  • pharmaceutically acceptable salt also includes bis-salis, such as a bis-hydrochloride salt Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed,, Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.
  • compositions refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.
  • the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrylng or transporting a compound useful within the invention within or to the patient such that it may perform its intended function.
  • a pharmaceutically acceptable material, composition or carrier such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrylng or transporting a compound useful within the invention within or to the patient such that it may perform its intended function.
  • Such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the patient.
  • materiais that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oii and soybean oil; glycols, such as propylene glycol; poiyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water;
  • “pharmaceutically acceptable carrier” also inciudes any and all coatings, antibacterial and antifungal agents, and absorption delaylng agents, and the like that are compatible with the activity of the compound useful within the invention, and are physiologicaliy acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions.
  • the “pharmaceuticaiiy acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention.
  • Other additional ingredients that may be included in the pharmaceuiicaf compositions used in the practice of the invention are known in the art and described, for example in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.
  • alkyl by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e,, C 1-6 alkyl means an alkyl having one to six carbon atoms) and includes straight and branched chains. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutl , tert-butyl, pentyl, neopentyl, and hexyl. Other examples of C 1 ⁇ C 6 ⁇ alkyl include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl.
  • alkoxy refers to the group -O-alkyl, wherein alkyl is as defined herein. Aikoxy Includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy and the like.
  • halo or “halogen” alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.
  • substituted means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.
  • R 1 is C 1 -C 6 alkyl or C 1 -C 4 alkoxy, wherein the C 1 - 6 akyl or C1-4 alkoxy is optionally substituted with 1 , 2, or 3 halogen;
  • R 2, R 3 , and R 4 are each, independently, selected from the group consisting of H, C 1- C 4 alkyl, G1-G4 alkoxy, hydroxy, and halogen, wherein the C 1- C 4 alkyl is optionally substituted by 1, 2, or 3 halogen;
  • R 5 Is H or C 1- C 4 alkyl
  • X is selected from the group consisting of OR a R b , 0, S, NR a , and C(» O);
  • R a and R 5 are each, independently, H or C 1- C 6 alkyl.
  • R 1 is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1 , 2, or 3 halogen atoms.
  • R 1 is C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with 1 , 2, or 3 halogen atoms.
  • R 1 is C 1-2 alkyl, wherein the C 1-2 alkyl is optionally substituted with 1 , 2, or 3 halogen atoms.
  • R 1 is C 2-4 alkyl, wherein the C 2-4 alkyl Is optionally substituted with 1, 2, or 3 halogen atoms.
  • R 1 is C 2-3 alkyl, wherein the C 2-3 alkyl is optionally substituted with 1 victim 2, or 3 halogen atoms.
  • R 1 is C 3-4 alkyl, wherein the C 3-4 alkyl is optionally substituted with 1 , 2, or 3 halogen atoms.
  • R 1 is methyl, wherein the methyl is optionally substituted with 1, 2, or 3 halogen atoms.
  • R 1 is ethyl, wherein the ethyl is optionally substituted with 1 , 2, or 3 halogen atoms.
  • R 1 is C 3 alkyl, wherein the C 3 alkyl is optionally substituted with 1 , 2, or 3 halogen atoms.
  • R 1 is C 4 alkyl, wherein the C 4 alkyl is optionally substituted with 1 , 2, or 3 halogen atoms.
  • R 1 is unsubstituted G 1-4 alkyl.
  • R 1 is unsubstituted C 1-3 aikyl.
  • R 1 is unsubstituted C 1-2 aikyl.
  • R 1 is unsubstituted C 2-4 aikyl. in another embodiment of Formula (l), R 1 is unsubstituted C 2-3 alkyl, in another embodiment of Formula (I), R 1 is unsubstituted C 3-4 alkyl.
  • R 1 Is unsubstituted methyl.
  • R 1 is unsubsiltuted ethyl.
  • R 1 is unsubstituted C 3 alkyl.
  • R 1 is unsubstituted C 4 alkyl.
  • R 1 is C 1-4 alkoxy, wherein the C « alkoxy is Optionally substituted with 1 , 2, or 3 haiogen atoms
  • R 1 is G 1-3 alkoxy, wherein the C 1-3 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms
  • R 1 Is C 1-2 alkoxy, wherein the C 1-2 alkoxy is optionally substituted with 1 , 2, or 3 haiogen atoms.
  • R 1 is C 2-4 alkoxy, wherein the C 2-4 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms in another embodiment of Formula (I), R 1 is C 2-3 alkoxy, wherein the C 2-3 alkoxy is optionally substituted with 1 , 2, or 3 halogen atoms.
  • R 1 is C 3-4 alkoxy, wherein the C 3-4 alkoxy is optionally substituted with 1 , 2, or 3 halogen atoms.
  • R 1 is methoxy, wherein the methoxy is optionally substituted with 1 , 2, or 3 haiogen atoms
  • R 1 is ethoxy, wherein the ethoxy is optionally substituted with 1 , 2, or 3 halogen atoms
  • R 1 Is C 3 alkoxy, wherein the C 3 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms.
  • R 1 is C 4 alkoxy, wherein the C 4 alkoxy is optionally substituted with 1 , 2, or 3 halogen atoms.
  • R 1 is unsubstituted C 1-4 alkoxy.
  • R 1 is unsubstituted C 1-3 alkoxy. in another embodiment of Formula (l), R 1 is unsubstituted C 1-2 alkoxy in another embodiment of Formula (I), R 1 is unsubstituted C 2-4 alkoxy.
  • R 1 Is unsubstituted C 2-3 alkoxy.
  • R 1 is unsubstituted C 3 -4 alkoxy.
  • R 1 is unsubstituted methoxy.
  • R 1 is unsubstituted ethoxy.
  • R 1 is unsubstituted C 3 alkoxy.
  • R 1 is unsubstituted C 4 alkoxy.
  • R 1 is -OCF 3, in another embodiment of Formula (I), R 1 is — OCH 2 CF 3. in another embodiment of Formula (I), R 2 , R3, and R 4 are each hydrogen.
  • R 2 and R 4 are each hydrogen.
  • R 2 - and R 3 are each hydrogen.
  • R 3 and R 4 are each hydrogen.
  • R 2 is hydrogen
  • R 3 is hydrogen
  • R 4 is hydrogen in another embodiment of Formula (I), R 2 is haiogen. in another embodiment of Formula (I), R 2 is fiuoro or chloro. in another embodiment of Formula (i), R 2 is fiuoro. in another embodiment of Formula (i), R 3 is chloro. in another embodiment of Formula (I), R 2 is CF 3 . in another embodiment of Formula (I), Rs is CF 3 H. in another embodiment of Formula (i), R 2 is CH 2 F. in another embodiment of Formula (i), R 3 is halogen. In another embodiment of Formula (i), R 3 is fluoro or chloro. In another embodiment of Formula (l), R 3 is fluoro. In another embodiment of Formula (l), R 3 is chloro.
  • R 3 is CF 3 . in another embodiment of Formula (l), R 3 is CF 2 H. in another embodiment of Formula (i), R 3 is CH 2 F. in another embodiment of Formula (l), R 4 Is halogen. in another embodiment of Formula (I), R 4 is fluoro or chloro. In another embodiment of Formula (l), R 4 is fluoro, In another embodiment of Formula :(l), R 4 is chloro. in another embodiment of Formula (I), R 4 is CF 3 . In another embodiment of Formula (l), R 4 is CF 2 H. in another embodiment of Formula (I), R 4 is CH 2 F. in another embodiment of Formula (I), R 3 is hydrogen, in another embodiment of Formula (I), R 3 is C 1- C 4 alkyl.
  • X is CR a R b. In another embodiment of Formula (i), X is O. In another embodiment of Formula (l), X is S, In another embodiment of Formula (l), X is NR 3 . In another embodiment of Formula (l), X is C(» O). in another embodiment of Formula (I), X is CR a R b ,, . O, or S. in another embodiment of Formula (I), X is CR a R b , . O, or NRa. in another embodiment of Formula (i), Rs is halogen, and R 3 and R 4 are each hydrogen, in another embodiment of Formula (i), R 3 is fluoro or chloro, and R 3 and R 4 are each hydrogen.
  • R 2 is fluoro, and R 3 and R 4 are each hydrogen. in another embodiment of Formula (l), R 2 is chloro, and R 3 and R 4 are each hydrogen. in another embodiment of Formula (l), R 2 is CF 3 , and R 3 and R 4 are each hydrogen. in another embodiment of Formula (I), R 2 is CF 2 H, and R 3 and R 4 are each hydrogen. in another embodiment of Formula (i), Rs is CH 2 F, and R 3 and R 4 are each hydrogen. in another embodiment of Formula (I), R 3 Is halogen, and R 2 and R 4 are each hydrogen. in another embodiment of Formula (l), R 3 is fluoro or chloro, and and R a . are each hydrogen. in another embodiment of Formula (I), R 3 is f!uoro, and R 2 and R 4 are each hydrogen.
  • R 3 is chloro, and R 3 and R 4 are each hydrogen.
  • R 3 is CF 3, and and R 4 are each hydrogen.
  • R 3 is CF 2 H, and R 2 and R 4 are each hydrogen.
  • R 3 is CH 2 F, and R 2 and R 4 are each hydrogen.
  • R 4 is halogen, and R 2 and R 3 are each hydrogen.
  • R 4 is fluoro or chloro, and R 2 and R 3 are each hydrogen.
  • R 4 is fluoro, and R 2 and R 2 are each hydrogen.
  • R 4 is chloro, and R 2 and R 3 are each hydrogen.
  • Rt is CFs, and and R 3 are each hydrogen.
  • R 4 is CF 2 H, and R 2 and R 3 are each hydrogen.
  • R 4 is CH 2 P, and R 2 and R 3 are each hydrogen.
  • R 1 is C 1-4 alkyl, R 2 is halogen, and R 3 and R 4 are each hydrogen.
  • R 1 is C 1-4 alkoxy, R 2 is halogen, and R 3 and R 4 are each hydrogen.
  • R 1 is C 1-4 alkyl
  • R 3 is fluoro or chloro
  • R 3 and R 4 are each hydrogen.
  • R 1 is C 1-4 alkoxy
  • R 2 Is fluoro or chloro
  • R 3 and R 4 are each hydrogen.
  • Rt is C 1-4 alkyl, R 2 is fluoro, and R 3 and R 4 are each hydrogen.
  • R 1 is C 1-4 alkoxy, R 2 is fluoro, and R 3 and R 4 are each hydrogen, in another embodiment of Formula (I), R 1 is C 1-4 alkyl, R 2 is chloro, and R 3 and R 4 are each hydrogen.
  • R 1 is C 1-4 alkoxy
  • R 2 is chloro
  • R 3 and R 4 are each hydrogen.
  • R 1 is C 1-4 alkyl, R 2 is CFs, and R 2 and R 4 are each hydrogen.
  • R 1 is C 1-4 alkoxy, R 2 is CFs, and R 3 and R 4 are each hydrogen.
  • R 1 is C 1-4 alkyl, R 2 is CF 2 H, and R 3 and R 4 are each hydrogen.
  • R 1 is C 1-4 aikyl, R 2 is CH 2 F, and R 3 and R 4 are each hydrogen.
  • R 1 is C 1-4 alkoxy, R 2 is CH 2 F, and R 3 and R, ; are each hydrogen.
  • R 1 is C 1-4 aikyl, R 3 is halogen, and R 2 and R 4 are each hydrogen.
  • R 1 is C 1.4 alkoxy, R 3 is halogen, and R 2 and R 4 are each hydrogen.
  • R 1 is C 1-4 aikyl, R 3 is fluoro or chloro, and R3 and R 1 are each hydrogen.
  • R 1 is C 1-4 alkoxy, R 3 is fluoro or eh loro, and R 2 and R 4 are each hydrogen.
  • R 1 is C 1-4 alkyl, R 3 is fluoro, and R 2 and R 4 are each hydrogen.
  • R 1 is C 1-4 alkoxy, R 3 is fluoro, and R 2 and R 4 are each hydrogen.
  • R 1 is C 1-4 alkyl
  • R 3 is chloro
  • R 2 and R 4 are each hydrogen.
  • R 1 is C 1-4 alkoxy, R3 is chloro, and R 2 and R 4 are each hydrogen.
  • R 1 is C 1-4 aikyl, R 3 is GF 3 , and R 2 and R 4 are each hydrogen.
  • R 1 is C 1-4 alkoxy, R 3 is CFs, and R 2 .
  • R 4 are each hydrogen, in another embodiment of Formula (i), R 1 is C 1-4 aikyl, R 2 is CFgH, and R 2 and R 4 are each hydrogen.
  • R 1 is C 1-4 alkoxy, R 3 is CFgH, and R 2 and R 4 are each hydrogen.
  • R 1 is C 1-4 aikyl, R 3 is CH 2 F, and R 2 and R 4 are each hydrogen.
  • R 1 is C 1-4 alkoxy, R 3 is CH 2 F, and R 2 and R 4 are each hydrogen.
  • R 1 is C 1-4 alkyl, R 4 is halogen, and and l3 ⁇ 4 are each hydrogen.
  • R 1 is C 1.4 alkoxy, R 4 is halogen, and R 2 and R 3 are each hydrogen.
  • R 1 is C 1-4 alkyl, R 4 is fluoro or chloro, and R3 and R s are each hydrogen.
  • R 1 is C 1-4 alkoxy, R 1 is fluoro or chloro, and R3 and R 3 are each hydrogen.
  • R 1 is C 1-4 alkyl, R 4 is fluoro, and R 2 and R 3 are each hydrogen.
  • R 1 is C 1-4 alkoxy, R 4 is fluoro, and R 2 and R 3 are each hydrogen.
  • R 1 is C 1-4 alkyl, R$ is chloro, and R 2 and R 3 are each hydrogen.
  • R 1 is C 1-4 alkoxy, R 1 Is chloro, and R 2 and R 3 are each hydrogen.
  • R 1 is C 1-4 alkyl, R 4 is CF 3, and R- and R 3 are each hydrogen.
  • R 1 is C 1.4 alkoxy, R 4 is CF 3, and R 2 and R 3 are each hydrogen.
  • R 1 is C 1-4 alkyl
  • R 4 is CF 2 H
  • R 2 and R 3 are each hydrogen.
  • R 1 is C 1-4 alkoxy, R 1 is CF 2 H, and R 2 and R 3 are each hydrogen.
  • R 1 is C 1-4 alkyl, R 4 is GHaF, and and R 3 are each hydrogen.
  • R 1 is C 1-4 alkoxy, R 3 is CH 2 F, and R 2 and R 3 are each hydrogen, in another embodiment of Formula (i), and R 3 are each halogen,
  • R 2 and R 3 are each fluoro or chloro. in another embodiment of Formula (l), R 3 and R 3 are each fluoro.
  • R 2 and R 3 are each chloro. in another embodiment of Formula (i), R 3 and R 4 are each halogen. in another embodiment of Formula (l), R 2 and R 4 are each fluoro or chloro. in another embodiment of Formula (l), R 2 and R 4 are each fluoro.
  • R 2 and R 4 are each chloro.
  • R 3 and R 4 are each halogen. in another embodiment of Formula (l), R 2 and R 4 are each fiuoro or chloro. in another embodiment of Formula (I), R 2 and R 2 are each fiuoro. in another embodiment of Formula (l), R 2 and R 3 are each chloro in another embodiment of Formula (I), R 3 and R 3 are each halogen, and FU is hydrogen. in another embodiment of Formula (l), R 2 and R 3 are each fiuoro or chloro, and R 4 is hydrogen. in another embodiment of Formula (I), R 2 .
  • R 3 are each fiuoro, and S3 ⁇ 4 is hydrogen, in another embodiment of Formula (l), and R 2 are each chloro, and R 4 is hydrogen in another embodiment of Formula (I), R 2 and R 4 are each halogen, and R 3 Is hydrogen in another embodiment of Formula (I), R 2 and R 4 are each fiuoro or chloro, and R 3 is hydrogen. in another embodiment of Formula (l), R 2 and R 4 are each fiuoro, and R 3 is hydrogen.
  • R 2 and R 4 are each chloro, and R 2 is hydrogen.
  • R 3 and R 4 are each halogen, and R 2 is hydrogen.
  • R 2 and !3 ⁇ 4. are each fiuoro or chloro, and R 2 is hydrogen.
  • R 2 and R 4 are each fiuoro, and R 2 Is hydrogen.
  • R 2 and R 4 are each chloro, and R 2 is hydrogen.
  • R 1 is C 1-4 alkyl
  • R 2 and R ;3 ⁇ 4 are each halogen
  • R 4 is hydrogen
  • R 1 is C 1-4 alkoxy
  • Rz and R 3 are each halogen
  • R 4 is hydrogen
  • R 1 is C 1-4 alkyl
  • R 2 and R 2 are each fiuoro or chloro
  • R 4 is hydrogen
  • R 1 is C 1-4 alkyl
  • R 2 and R 3 are each fiuoro
  • R 4 is hydrogen
  • R 1 is C 1-4 alkoxy
  • R 2 and R3 are each fiuoro
  • R 4 is hydrogen
  • R 1 is C 1-4 alkyl, R 2 and R 3 are each chloro, and R 4 is hydrogen.
  • R 1 Is C 1-4 alkoxy, R 2 and R 2 are each chloro, and R 4 is hydrogen.
  • R 1 is C 1-4 alkyl, R 3 and R 4 are each halogen, and R;i Is hydrogen.
  • R 1 is C 1-4 alkoxy, R 2 and R 4 are each halogen, and R 3 is hydrogen.
  • R 1 is C 1-4 alkyl, R 2 and R 4 are each fluoro or chloro, and R 3 is hydrogen.
  • R 1 is C 1-4 alkoxy, R 2 and R 4 are each fluoro or chloro, and R 3 is hydrogen.
  • R 1 is C 1-4 alkyl, R ; > and R 4 are each fluoro, and R 3 is hydrogen.
  • R 1 is C 1-4 alkoxy, R 2 and R 4 are each fluoro, and R 3 is hydrogen.
  • R 1 is C 1-4 alkyl
  • R 3 and R 3 are each chloro
  • R 3 is hydrogen
  • R 1 is C 1-4 alkoxy, R 2 and R 4 are each chloro, and R 3 Is hydrogen, in another embodiment of Formula (I), R 1 is C 1-4 alkyl, R 3 and R 4 are each halogen, and R 3 is hydrogen. in another embodiment of Formula (I), R 1 is C 1-4 alkoxy, R 3 and R 4 are each halogen, and R 3 is hydrogen.
  • R 1 is C 1-4 alkyl
  • R 3 and R 4 are each fluoro or chloro
  • R 3 is hydrogen
  • R 1 is C 1-4 alkoxy
  • R 3 and R 3 are each fluoro or chloro
  • R 3 is hydrogen
  • R 1 is C 1-4 alkox,y R 3 and R 4 are each fluoro, and R 3 is hydrogen.
  • R 1 is C 1-4 alkoxy, R 3 and R 4 are each fluoro, and R 3 is hydrogen.
  • R 1 is C 1-4 alkyl, R 3 and R 4 are each chloro, and R 3 is hydrogen.
  • R 1 is C 1-4 alkoxy, R 3 and R 4 are each chloro, and R 2 is hydrogen,
  • the disclosed compounds may possess one or more stereocenters, and each stereoeenter may exist independently in either the R or S configuration in one embodiment, compounds described herein are present in optically active or racemic forms it is to be understood that the compounds described herein encompass racemic, opticaiiy-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein.
  • Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from opticaiiy-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase, in one embodiment, a mixture of two or more isomers is utilized as the disclosed compound described herein. In another embodiment, a pure isomer is utilized as the disclosed compound described herein. In another embodiment, compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantloselective synthesis or separation of a mixture of enantiomers or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting exampie, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.
  • the disclosed compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.
  • Compounds described herein also include isotopicaily-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds described herein include and are not limited to 2 H, 3 H, n C, 13 C, 14 C, 36 Cl, 18 F, 123 i, l25 f, 13 N, 15 N, 15 O, 17 O, 18 O,
  • isotopicaiiy-labeled compounds are useful in drug or substrate tissue distribution studies, in another embodiment, substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements) in another embodiment, the compounds described herein include a 2 H (i.e., deuterium) isotope, in yet another embodiment, substitution with positron emitting isotopes, such as 11 C, 18 F, 1s O and 13 N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy isotopicaliy-iabeied compounds are prepared by any suitable method or by processes using an appropriate isotopically-iabeled reagent in place of the non- labeled reagent otherwise employed.
  • PET Positron Emission Topography
  • the compounds of the invention can be used in a method of treating a disease or condition in a subject, said method comprising administering to the subject a compound of the invention, or a pharmaceutical composition comprising a compound of the invention.
  • the compounds of the invention can be used to treat a disease or condition selected from the group consisting of pain, depression, or addiction in a subject in need thereof.
  • the compounds of the invention can be used to treat pain in a subject.
  • the pain is selected from inflammatory pain, thermal pain, acute pain, chronic pain, traumatic pain, chemical pain, ischemic pain, centrally mediated pain, peripherally mediated pain, prickling pain, visceral pain, progressive disease pain, musculoskeletal pain (e.g., back pain, neck pain), post-surgical pain, bone pain (e.g., osteoarthritis), nociceptive pain, or neuropathic pain
  • the pain is inflammatory pain, thermal pain, acute pain, chronic pain, or neuropathic pain
  • the pain is musculoskeletal pain (e.g., back pain, neck pain), post-surgical pain, or bone pain (e.g., osteoarthritis).
  • the pain is muscuioskeletal pain, in another embodiment, the pain is chronic pain. In another embodiment, the pain is chronic musculoskeletal pain. In another embodiment, the pain is chronic back pain in another embodiment, the pain is chronic lower back pain, in another embodiment, the pain is chronic neck pain. in yet another embodiment, the pain can be chronic pain, wherein the pain is chronic pain from headache, chronic pain from neuropathic conditions, chronic pain from post-stroke conditions or chronic pain from migraine.
  • the pain can be acute pain, wherein the pain is acute pain from acute injury, acute pain from trauma, or acute pain from surgery.
  • the pain can be neuropathic pain, wherein the pain is neuropathic pain from alcoholic polyneuropathy, phantom limb pain, chemotherapy, diabetic pain, pain from HIV infection or AIDS, multiple sclerosis, shingles, Parkinson's disease, spine surgery, or postherpetic neuralgia.
  • the pain can be inflammatory pain, wherein the pain is pain associated with arthritis such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, juvenile arthritis, or scapulohumeral periarthritis.
  • the compounds of the invention can be used to treat depression in a subject in need thereof.
  • depression refers to “clinical depression” or “major depressive disorder.”
  • the compounds of the invention can be used to treat a depressive condition in a subject in need thereof.
  • the depressive condition is depressed mood, diminshed concentration, insomnia, fatigue, loss of appetite, excessive guilt, and suicidal thoughts.
  • the depressive condition can be an anxiety disorder, wherein the anxiety disorder is generalized anxiety disorder, panic, or agoraphobia.
  • the depressive condition can be associated with a mental condition, wherein the mental condition is schizoaffective disorder, or seasonal affective disorder.
  • the depressive condition can be associated with chronic or recurrent depression.
  • the depressive condition can be depressed mood, loss of pleasure, loss of appetite, sleep disturbance, psychomotor changes, fatigue, or post-partum depression.
  • the depressive condition can be adjustment disorders with depressed mood, Asperger syndrome, attention deficit, bereavement, bipolar I disorder, bipolar IE disorder, borderline and personality disorder, cyclothymia and dysthymia, Dysthymic disorder, hyperactivity disorder, impulse control disorder, mixed mania, obsessive-compulsive personalty disorder (GCD), paranoid, seasons!
  • the compounds of the invention can be used to treat addiction in a subject in need thereof.
  • the addiction can be drug addiction or alcohoi addiction.
  • the drug addiction can be one or more of opioid addiction (i.e, opioid dependence) or stimulant addiction.
  • the opioid can be one or more of fentanyl, morphine, oxymorphone, buprenorphine, hydromorphone, oxycodone, hydrocodone, or the like.
  • the drug addiction can also be one or more of diamorphine (i.e, heroin), cocaine, nicotine, and amphetamine.
  • compounds of the invention can be used to treat a disease or condition in a subject, wherein the subject has a tolerance to opioid medication, the subject has a history of opioid dependency or abuse, the subject is at risk of opioid dependency or abuse, or in circumstances wherein it is desirable that the risk of opioid dependence, opioid addiction, or symptoms of opioid withdrawal in the subject is minimized.
  • the compounds of the invention can also be used to treat alcohol addiction, which can also be referred to as alcoholism, “Alcoholism” refers to an addictive disease or disorder characterized by an inability to control the intake of alcohol, i.e., a continued excessive or compulsive use of alcoholic drinks. Alcoholism may involve changes an individual’s ability to metabolize alcohol as well. Diagnosis of alcoholism can be made by psychiatric examination, in one aspect, the compounds provided herein are useful in treatment of pain by acting as an agonist of the m-opioid receptor, in one embodiment of the methods described herein, the subject is human.
  • composition comprising at least one compound of the invention, together with a pharmaceutically acceptable carrier.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.
  • a medical doctor e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceuticai composition required, For example, the physician or veterinarian could begin administration of the pharmaceutical composition to dose the disclosed compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of the disclosed compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle.
  • the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the disclosed compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compound ing/formulating such a disciosed compound for the treatment of pain, a depressive disorder, or drug addiction in a patient.
  • the compounds of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers.
  • the pharmaceutical compositions of the invention comprise a therapeutically effective amount of a disciosed compound and a pharmaceutically acceptable carrier.
  • the dose of a disclosed compound is from about 1 mg to about 1 ,000 mg. In some embodiments, a dose of a disclosed compound used in compositions described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 800 mg, or iess than about 300 mg, or less than about 200 mg, or iess than about 100 mg, or iess than about 50 mg, or less than about 20 mg, or less than about 10 mg.
  • a dose is about 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or about 600 mg.
  • Routes of administration of any of the compositions of the invention include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical.
  • the compounds for use in the invention may be formulated for administration by any suitable route, such as for oral or parenteral, for example, fransdermai, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethrai, vaginai (e.g., trans- and perivaginally), (intra)nasal and (trans)rectall, intravesical, intrapulmonary, intraduodenal, intragastrical intrathecal, subcutaneous, intramuscular, intradermai, intra-arterial, intravenous, intra bronchial, inhalation, and topical administration.
  • the preferred route of administration is oral.
  • suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, soiutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein.
  • compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of Inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets.
  • excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.
  • the tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.
  • the disclosed compounds may he formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose or continuous infusion.
  • Suspensions, soiutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing or dispersing agents may be used.
  • reaction conditions including buf not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application, it is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these vaiues and ranges, are meant to be encompassed within the scope of the present invention. Moreover, all vaiues that fail within these ranges, as weii as the upper or lower limits of a range of values, are also contemplated by the present application.
  • the aqueous layer was extracted with Ef 2 O ⁇ 3 x 20 mL). The mixture was neutralized to pH 8 with saturated Na 2 CO 3 (aq.). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na 2 SO 4 . After fiitration, the filtrate was concentrated under reduced pressure.
  • the resulting mixture was stirred for additional 2 h at -78 °C.
  • the reaction was monitored by LGMS.
  • the reaction was quenched by the addition of sat, NH 4 CI (aq.) (20 mL) at 0 °C.
  • the aqueous layer was extracted with EtOAc (3 x 100 mL), The combined organic layers were washed with brine (3x50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • NBS NBS
  • benzoylperoxide 0.52 g, 2.14 mmol, 0.1 equiv
  • CCl 4 100mL
  • 1 -bromo-5-fiuoro-2- methyl-3-nitro benzene 5.00 g, 21.4 mmol, 1 equiv
  • the ( 35 S]GTPyS assay measures the functional properties of a compound by quantifylng the level of G-protein activation foilowing agonist binding in studies using stably transfected ceils, and is considered to be a measure of the efficacy of a compound.
  • Membranes from CHO (Chinese Hamster Ovary) cells that stably expressed one type of the cloned human opioid receptor human were used in the experiments.
  • the assay buffer consisted of 50 mM Tris-HCi, pH 7.4, 3 mM MgCl 2 , 0.2 mM EQTA, 5 mM GDP, and 100 mM NaCI. CHO
  • membranes stably expressing the human p opioid receptor were pre- incubated with scintillation proximity assay beads from PerkinElmer ⁇ (WGA PVT SPA) for 30 minutes, at 8 mg membrane and 350 mg beads in a volume of 0.1 ml per reaction.
  • WGA PVT SPA scintillation proximity assay beads from PerkinElmer ⁇
  • 11 different concentrations of each test compound were incubated with the membrane-SPA bead mixture and a finai concentration of 0.020 nM [35S]GTPyS for 1.5 hours with gentle shaking. Reactions were then incubated for 5 hours.
  • Data are the mean EC 50 values ⁇ S.E.M and are shown in Table 1.

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Abstract

L'invention concerne des composés qui sont utiles dans le traitement de la douleur chez un sujet. L'invention concerne également une composition pharmaceutique comprenant des composés ou des sels pharmaceutiquement acceptables de ceux-ci, et un support pharmaceutiquement acceptable et des procédés de traitement de la douleur chez un sujet en ayant besoin.
PCT/US2020/045246 2019-08-07 2020-08-06 Composés contenant du lactame pour le traitement de la douleur WO2021026377A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080242693A1 (en) * 2003-10-15 2008-10-02 Targacept, Inc. Pharmaceutical Compositions and Methods for Relieving Pain and Treating Central Nervous System Disorders
US20100331310A1 (en) * 2008-02-13 2010-12-30 Fumihiro Ozaki Bicycloamine derivatives
US20180117012A1 (en) * 2016-10-31 2018-05-03 Teikoku Pharma Usa, Inc. Methods of Managing Pain Using Dexmedetomidine Transdermal Delivery Devices
WO2019152946A1 (fr) * 2018-02-05 2019-08-08 Alkermes, Inc. Composés pour le traitement de la douleur

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080242693A1 (en) * 2003-10-15 2008-10-02 Targacept, Inc. Pharmaceutical Compositions and Methods for Relieving Pain and Treating Central Nervous System Disorders
US20100331310A1 (en) * 2008-02-13 2010-12-30 Fumihiro Ozaki Bicycloamine derivatives
US20180117012A1 (en) * 2016-10-31 2018-05-03 Teikoku Pharma Usa, Inc. Methods of Managing Pain Using Dexmedetomidine Transdermal Delivery Devices
WO2019152946A1 (fr) * 2018-02-05 2019-08-08 Alkermes, Inc. Composés pour le traitement de la douleur

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