WO2023033681A1 - 2-(5-aryl-4 h-1,2,4-triazol-3-yl)éthanamines substituées utilisées comme modulateurs du récepteur 1 associé aux amines à l'état de traces (taar1) - Google Patents

2-(5-aryl-4 h-1,2,4-triazol-3-yl)éthanamines substituées utilisées comme modulateurs du récepteur 1 associé aux amines à l'état de traces (taar1) Download PDF

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WO2023033681A1
WO2023033681A1 PCT/RU2022/050272 RU2022050272W WO2023033681A1 WO 2023033681 A1 WO2023033681 A1 WO 2023033681A1 RU 2022050272 W RU2022050272 W RU 2022050272W WO 2023033681 A1 WO2023033681 A1 WO 2023033681A1
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triazole
ethanamine hydrochloride
disorder
phenyl
optionally substituted
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PCT/RU2022/050272
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English (en)
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WO2023033681A4 (fr
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Raul Radikovich GAINETDINOV
Andrey Sergeevich GERASIMOV
Aleksey Yurievich LUKIN
Anna Gennadievna BAHOLDINA
Mikhail Yurievich KRASAVIN
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Limited Liability Company «Excellena Research And Development» (Llc «Excellena»)
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Priority claimed from EA202192214 external-priority patent/EA043874B1/ru
Application filed by Limited Liability Company «Excellena Research And Development» (Llc «Excellena») filed Critical Limited Liability Company «Excellena Research And Development» (Llc «Excellena»)
Publication of WO2023033681A1 publication Critical patent/WO2023033681A1/fr
Publication of WO2023033681A4 publication Critical patent/WO2023033681A4/fr

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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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

Definitions

  • the present invention relates to substituted 2-(5-aryl-4H-1,2,4-triazol-3-yl)ethanamines or pharmaceutically acceptable salts thereof exhibiting properties of a trace amine receptor (TAAR1) agonist, a method for production thereof, a pharmaceutical composition on their basis and a use thereof.
  • TAAR1 trace amine receptor
  • Trace amines such as ⁇ -phenylethylamine (PEA), tyramine, tryptamine and octopamine are structurally similar to classical monoamines and play an important role in invertebrate physiology, but their functions in the body of mammals, where they are present in trace amounts, remain unknown. Determining the role of these amines and their receptors in mammalian physiology would explain many enigmas in pathology and pharmacology of monoaminergic synaptic transmission [Sotnikova et al., 2008]. In general, TAs are present in the CNS and function in parallel with monoaminergic pathways. TAs are structurally related, co- localized and recovered with biogenic amines and neurotransmitters.
  • PEA ⁇ -phenylethylamine
  • tryptamine tryptamine
  • octopamine are structurally similar to classical monoamines and play an important role in invertebrate physiology, but their functions in the body of mammals, where they are
  • TAs are thought to posses the neuromodulatory functions of classical neurotransmitters such as dopamine, serotonin and norepinephrine which levels are affected by all antidepressants and antipsychotics currently being used in clinical practice.
  • Dysfunctions in TA physiology have long been associated with schizophrenia and mood disorders.
  • Increased urine PEA levels, changes in tryptamine and tyramine metabolism, and changes in enzymes involved in the synthesis and catabolic pathways of these amines have been shown to be associated with schizophrenia.
  • PEA hypothesis was developed to explain causes underlining depression development which postulates that PEA deficiency is related to endogenous depression: pilot studies have shown that the use of this amine or its precursor reduces symptoms of depression.
  • TAAR1 is the most investigated receptor among TAARs which represents a new target for pharmacology of a wide range of mental, neurological and metabolic disorders, and substances acting on TAAR1 are already on the stage of clinical trials [Revel et al. 2011; Revel et al.2012; Berry et al., 2017].
  • TAAR1 is a proven target for endogenous TAs.
  • the TAAR1 gene is expressed in brain structures associated with mental disorders, in particular in those key areas where modulation of dopamine (ventral tegmental region) and serotonin (brainstem raphe nucleus) occurs, as well as in the amygdala, hypothalamus, nucleus accumbens, entorhinal and frontal cortex and subiculum. Therefore, even if the TA function is not impaired, neuromodulatory effects on monoaminergic pathways could predictably lead to improved mental health.
  • TAAR1-KO mice TAAR1-KO mice
  • Their use in studies has shown that TAAR1 agonists should be effective in the treatment of mental and a number of other disorders such as schizophrenia, depression, ADHD, drug abuse, Parkinson’s disease, sleep disorders by acting either directly or indirectly on monoaminergic pathways [Revel et al.2011; Revel et al.2012].
  • TAAR1 expression levels were also found in the pancreas, stomach and intestines, and preclinical studies have shown the efficacy of TAAR1 agonists in metabolic disorders such as obesity and diabetes. TAAR1 expression was also shown in leukocytes suggesting the involvement of this receptor in immunological processes [Lam et al., 2015]. Searches for new TAAR1 receptor modulators and their use as agents for the treatment of mental disorders, cognitive disorders, metabolic disorders, neurological and neurodegenerative diseases are very relevant.
  • substituted 2-(5-aryl-4H-1,2,4- triazol-3-yl)ethanamines exhibit properties of a trace amine receptor 1 (TAAR1) agonist and can be used to treat diseases mediated by trace amine receptors TAAR1. Therefore, the present invention relates to a number of substituted 2-(5-aryl-4H-1,2,4-triazol-3-yl)ethanamines, a method for production thereof, a pharmaceutical composition on their basis and a use of said compounds.
  • TAAR1 trace amine receptor 1
  • the present invention provides a compound of formula 1, 1 or a pharmaceutically acceptable salt thereof, where R is: ⁇ 6 - ⁇ 14 aryl optionally substituted with 1-2 substituents selected from the group consisting of: ⁇ 1 - ⁇ 10 alkyl optionally substituted with 1-3 halogen atoms, ⁇ 1 - ⁇ 10 alkoxy optionally substituted with 1-3 halogen atoms or ⁇ 6 - ⁇ 14 aryl optionally substituted with a halogen atom, ⁇ 6 - ⁇ 14 aryl optionally substituted with 1-2 substituents selected from the group including halogen and ⁇ 1 - ⁇ 10 alkoxy optionally substituted with 1-3 halogen atoms, halogen, amino group of formula -N(R 1 ) 2 where each R 1 is independently hydrogen or ⁇ 1 - ⁇ 10 alkyl, nitro group, and C 6 -C 14 aryloxy optionally substituted with ⁇ 1 - ⁇ 10 alkyl; or 5-membered heteroary
  • the present invention provides a method for producing the compound of formula 1 comprising the following steps: (a) obtaining the compound of formula 5 by a method selected from: contacting the compound of formula 4 with hydrazine hydrate; or heating the compound of formula 11: or the compound of formula 15: to the melting temperature of said compounds; (b) removing the tert-butoxycarbonyl protecting group, to produce the compound of formula 1 where values of R are as defined above.
  • the present invention provides a pharmaceutical composition for the treatment of disease, disorder or condition mediated by trace amine receptors TAAR1 comprising a therapeutically effective amount of the compound of formula 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
  • the present invention provides use of the compound of formula 1 or pharmaceutical composition described herein for the treatment of disease, disorder or condition mediated by trace amine receptors TAAR1.
  • the present invention provides a compound described herein for use in treating a disease, disorder or condition mediated by trace amine receptors TAAR1.
  • the present invention provides the use of a compound described herein for producing a drug for the treatment of disease, disorder or condition mediated by trace amine receptors TAAR1.
  • the present invention provides the method for treating a disease, disorder or condition mediated by trace amine receptors TAAR1 in a subject comprising administration of a therapeutically effective amount of the compound of formula 1 or pharmaceutical composition described herein to the subject.
  • the present invention also relates to a method for activating the trace amine receptor TAAR1 by contacting said receptor with the compound of formula 1.
  • ⁇ 1 - ⁇ 10 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl and tert- butyl.
  • cycloalkyl means a monovalent saturated carbocyclic group containing 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, which can be monocyclic or polycyclic.
  • Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and etc.
  • aryl refers to a cyclic aromatic hydrocarbon without heteroatoms.
  • Aryl groups include monocyclic, bicyclic and polycyclic ring systems and contain 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms, even more preferably 6 to 10 carbon atoms in the rings moieties of the groups.
  • Aryl groups include, but are not limited to, phenyl and naphthyl.
  • the term «aryl» means phenyl.
  • heteroaryl as used herein refers to mono- or polycyclic aromatic radicals containing 5 or more ring members of which one or more is/are a heteroatom selected from S, O or N, and the remaining ring atoms are carbon atoms.
  • the heteroaryl is 5-membered heteroaryl. In some embodiments of the invention, the heteroaryl contains 1 heteroatom selected from S, O or N. Heteroaryl includes, but is not limited to, thiophene, furan, or pyrrole.
  • the term «alkoxy» refers to -O-alkyl group where alkyl is as defined above. Examples of -O-alkyl group include, but are not limited to: methoxy, ethoxy, n-propyloxy, isopropyloxy, n- butyloxy, isobutyloxy, tert-butyloxy.
  • « ⁇ 1 - ⁇ 10 alkoxy» refers to -O-alkyl where alkyl is ⁇ 1 - ⁇ 10 alkyl.
  • the term «aryloxy» refers to -O-aryl group where aryl is as defined above. Examples of - O-aryl group include, but are not limited to: phenyloxy, naphthyloxy.
  • « ⁇ 6 - ⁇ 14 aryloxy» refers to -O-aryl where aryl is ⁇ 6 - ⁇ 14 aryl.
  • the term «halogen» refers to fluoride, bromide, chloride, and iodide.
  • the term «nitro group» refers to –NO 2 group.
  • amino group refers to the group of formula -NR1 2 where each R1, independently of each other, is hydrogen, alkyl or cycloalkyl, e.g., -NH 2 , methylamino, dimethylamino, diethylamino, cyclohexylamino, tert-butylamino or ethylamino.
  • optionally substituted group refers to a substituted or unsubstituted group and means that said group may be substituted at one or more positions with 1, 2, 3, 4 or 5 substituents.
  • the terms «optionally substituted» and «substituted or unsubstituted» may be used interchangeably.
  • substituting groups include, but are not limited to, alkyl, cycloalkyl, halogen, alkoxy group, aryl, nitro group, amino group.
  • substituting groups include, but are not limited to, alkyl, cycloalkyl, halogen, alkoxy group, aryl, nitro group, amino group.
  • the term «pharmaceutically acceptable» refers to an excipient, it is understood that the excipient meets the required standards of toxicological and manufacturing tests.
  • the term «subject» refers to an animal, such as a mammal (including human), that was or will be the subject of treatment, observation or experiment. «Subject» and «patient» may be used interchangeably unless indicated otherwise.
  • the methods described in this specification can be used in the treatment of human and/or in veterinary.
  • the subject is a mammal.
  • the subject is human.
  • the terms «therapeutically effective amount» and «effective amount» are used interchangeably and refer to the amount of a compound that is sufficient to conduct the treatment, as defined below, when administered to a patient (e.g., human) in need of such treatment, in one or more doses.
  • the therapeutically effective amount may vary depending on the disease to be treated, patient’s weight and/or age, disease severity or route of administration determined by the qualified physician prescribing a preparation or giving care.
  • treatment means administration of a compound described herein for the purpose of: (i) delaying disease onset, i.e. preventing the development or delaying clinical symptoms of a disease; (ii) inhibiting a disease, i.e.
  • excipient means pharmaceutically acceptable and pharmacologically compatible fillers, solvents, diluents, carriers, disintegrants, glidants, dispersants, preservatives, stabilizers, humectants, emulsifiers, suspending agents, thickeners, sweeteners, odorants, flavoring agents, antibacterial agents, lubricants, regulators of prolonged delivery, etc., the choice and ratio of which depend on the nature and method of prescription and dosage.
  • suspending agents examples include ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, as well as mixtures of these substances.
  • the protection against the action of microorganisms can be provided using a variety of antibacterial and antifungal agents such as parabens, chlorobutanol, sorbic acid and similar compounds.
  • the composition can also include isotonic agents such as sugars, sodium chloride and the like. Prolonged action of the composition can be provided by agents slowing down active ingredient absorption, e.g., aluminum monostearate and gelatin.
  • suitable carriers, solvents, diluents and delivery vehicles include water, ethanol, polyalcohols and mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate).
  • suitable carriers include water, ethanol, polyalcohols and mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate).
  • fillers include lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like.
  • disintegrants and dispersants include starch, alginic acid and its salts, silicates.
  • lubricants and glidants include magnesium stearate, sodium lauryl sulfate, talc and high molecular weight polyethylene glycol.
  • the pharmaceutical composition of the present invention may be formulated as an oral dosage form such as tablets, gelatin capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal dosage form, aerosols, implants, dosage form for topical, transdermal, subcutaneous, intramuscular, intravenous, intranasal, intraocular or rectal administration.
  • oral dosage form such as tablets, gelatin capsules, pills, powders, granules, chewing gums and oral solutions or suspensions
  • sublingual and buccal dosage form such as tablets, gelatin capsules, pills, powders, granules, chewing gums and oral solutions or suspensions
  • sublingual and buccal dosage form such as tablets, gelatin capsules, pills, powders, granules, chewing gums and oral solutions or suspensions
  • sublingual and buccal dosage form such as tablets, gelatin capsules, pills, powders, granules, chewing gums and oral solutions or suspensions
  • aerosols implants
  • Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, and the like. Tablets may contain colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like in addition to an active ingredient.
  • Liquid dosage forms suitable for oral administration are emulsions, syrups, elixirs and aqueous suspensions. They include solid dosage forms which are intended to be converted to liquid preparations immediately prior to use.
  • Emulsions can be prepared in solutions, e.g., aqueous solutions of propylene glycol, or may contain emulsifiers such as lecithin, sorbitol monooleate or acacia gum.
  • Aqueous suspensions can be prepared by dispersing a finely grinded active ingredient in water with viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well known suspending agents.
  • pharmaceutically acceptable salt means relatively non-toxic organic and inorganic salts of the compounds claimed in the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of compounds, or specially prepared.
  • base salts can be specially prepared from the purified free base of the claimed compound and a suitable organic or inorganic acid.
  • suitable organic or inorganic acid examples include hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valerates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates, mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like (a detailed description of properties of such salts is provided in Berge S.M., et al., Pharmaceutical Salts, J.
  • the present invention relates to substituted 2-(5-aryl-4H-1,2,4-triazol-3-yl)ethanamines exhibiting properties of a trace amine receptor TAAR1 agonist, i.e.
  • R is: ⁇ 6 - ⁇ 14 aryl optionally substituted with 1-2 substituents selected from the group consisting of: ⁇ 1 - ⁇ 10 alkyl optionally substituted with 1-3 halogen atoms, ⁇ 1 - ⁇ 10 alkoxy optionally substituted with 1-3 halogen atoms or ⁇ 6 - ⁇ 14 aryl optionally substituted with a halogen atom, ⁇ 6 - ⁇ 14 aryl optionally substituted with 1-2 substituents selected from the group including halogen and ⁇ 1 - ⁇ 10 alkoxy optionally substituted with 1-3 halogen atoms, halogen, amino group of formula -N(R 1 ) 2 where each R 1 is independently hydrogen or ⁇ 1 - ⁇ 10 alkyl, nitro group, and C 6 -C 14 aryloxy optionally substituted with ⁇ 1 - ⁇ 10 alkyl; or 5-membered heteroaryl containing 1 heteroatom selected from nitrogen, oxygen
  • R is ⁇ 6 - ⁇ 14 aryl, preferably ⁇ 6 - ⁇ 10 aryl, more preferably phenyl.
  • R is ⁇ 6 - ⁇ 14 aryl substituted with 1-2 substituents selected from optionally substituted ⁇ 1 - ⁇ 10 alkoxy.
  • unsubstituted ⁇ 1 - ⁇ 10 alkoxy is methoxy, ethoxy, propoxy or butoxy.
  • substituted ⁇ 1 - ⁇ 10 alkoxy is trifluoromethoxy.
  • substituted ⁇ 1 - ⁇ 10 alkoxy is methoxy substituted with ⁇ 6 - ⁇ 14 aryl optionally substituted with a halogen atom.
  • R is ⁇ 6 - ⁇ 14 aryl substituted with 1-2 substituents selected from optionally substituted C 6 -C 14 aryloxy.
  • ⁇ 6 - ⁇ 14 aryloxy is phenyloxy optionally substituted with ⁇ 1 - ⁇ 10 alkyl, preferably ⁇ 1 - ⁇ 4 alkyl.
  • R is ⁇ 6 - ⁇ 14 aryl substituted with 1-2 substituents selected from optionally substituted ⁇ 6 - ⁇ 14 aryl.
  • R is phenyl substituted with phenyl optionally substituted with 1-2 substituents selected from halogen or optionally substituted ⁇ 1 - ⁇ 10 alkoxy.
  • unsubstituted ⁇ 1 - ⁇ 10 alkoxy is methoxy, ethoxy, propoxy or butoxy.
  • substituted ⁇ 1 - ⁇ 10 alkoxy is trifluoromethoxy.
  • R is ⁇ 6 - ⁇ 14 aryl substituted with 1-2 substituents selected from optionally substituted ⁇ 1 - ⁇ 10 alkyl, preferably ⁇ 1 - ⁇ 4 alkyl.
  • ⁇ 1 - ⁇ 10 alkyl is methyl, ethyl, propyl, butyl. In another embodiment on the invention, substituted ⁇ 1 - ⁇ 10 alkyl is trifluoromethyl.
  • R is ⁇ 6 - ⁇ 14 aryl substituted with 1-2 substituents selected from fluoride, chloride or bromide.
  • R is ⁇ 6 - ⁇ 14 aryl substituted with an amino group. In a preferred embodiment of the invention, the amino group is selected from methylamino, dimethylamino or diethylamino. In another embodiment of the invention, R is ⁇ 6 - ⁇ 14 aryl substituted with a nitro group.
  • R is 5-membered heteroaryl containing 1 heteroatom selected from nitrogen, oxygen or sulfur.
  • the heteroaryl is thiophene.
  • the pharmaceutically acceptable salt is hydrochloride of the compound of formula 1.
  • the present invention provides a pharmaceutical composition for treating a disease, disorder or condition mediated by trace amine receptors TAAR1 comprising a therapeutically effective amount of the compound of formula 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
  • the compound of formula 1 or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 0.1 mg to about 1000 mg, preferably about 1 mg to about 800 mg, more preferably about 10 mg to about 600 mg.
  • the compound of formula 1 or a pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg or 1000 mg.
  • the excipient may be selected from the group including a pharmaceutically acceptable carrier, diluent, filler and solvent.
  • the amount of any individual excipient in the composition may vary depending on the role of excipient, requirements to the dosage of active agent components, and particular demands of the composition. However, the excipient is typically present in the composition in an amount of about 1 wt.% to about 99 wt.%, preferably about 5 wt.% to about 98 wt.%, more preferably about 15 wt.% to about 95 wt.% of the total weight of the composition. In general, the amount of excipient present in the inventive composition is selected from the following: at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or even 95% by weight.
  • the pharmaceutical composition of the present invention may be made as dosage forms selected from the group including tablets, powders, granules, pills, suspension, pellets, capsules, sachets and injectable solution.
  • the present invention provides the use of the compound of formula 1 or a pharmaceutically acceptable salt thereof or pharmaceutical composition described herein for the treatment of disease, disorder or condition mediated by trace amine receptors TAAR1.
  • the present invention provides a compound of formula 1, or a pharmaceutically acceptable salt thereof for use in the treatment of disease, disorder or condition mediated by trace amine receptors TAAR1.
  • the present invention provides use of the compound of formula 1 or a pharmaceutically acceptable salt thereof or pharmaceutical composition described herein for producing a drug for the treatment of disease, disorder or condition mediated by trace amine receptors TAAR1.
  • the present invention provides a method for treating disease, disorder or condition mediated by trace amine receptors TAAR1 in a subject comprising administration of a therapeutically effective amount of the compound of formula 1 or pharmaceutical composition described herein to the subject.
  • the therapeutically effective amount of the compound of formula 1 or a pharmaceutically acceptable salt thereof is about 0.1 mg/day to about 1000 mg/day, preferably about 1 mg/day to about 800 mg/day, more preferably about 10 mg/day to about 600 mg/day administered either as a single dose or as multiple doses.
  • multiple doses include two, three or four doses per day.
  • the dosage may be altered depending on patient’s age, body weight, susceptibility, symptom or compound efficacy.
  • said disease, disorder or condition mediated by trace amine receptors TAAR1 is selected from the group including a mental disorder, cognitive disorder, metabolic disorder, neurological and neurodegenerative disease.
  • said disease, disorder or condition mediated by trace amine receptors TAAR1 is selected from the group including depression, anxiety, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-induced disorder, psychosis, schizophrenia, obsessive-compulsive disorder, Parkinson’s disease, Alzheimer’s disease, epilepsy, migraine, high blood pressure, alcohol or drug abuse, nicotine addiction, eating disorder, diabetes, diabetes complications, obesity, dyslipidemia, disorders associated with energy consumption and expenditure, disorders associated with impaired body temperature homeostasis, sleep and circadian rhythm disorder, as well as cardiovascular disorder.
  • the present invention provides a method for activating the trace amine receptor TAAR1 by contacting said receptor with the compounds of formula 1.
  • the present invention provides a method for preparing the compound of general formula 1 or a pharmaceutically acceptable salt thereof comprising the following steps: (a) obtaining the compound of formula 5 by a method selected from: contacting the compound of formula 4 with hydrazine hydrate; or heating the compound of formula 11: or the compounds of formula 15: to the melting temperature of said compounds; (b) removing the tert-butoxycarbonyl protecting group, to obtain the compound of formula 1 where the values of R are as described in claim 1.
  • the method described above additionally comprises after step (a) the step of attaching the tetrahydropyranyl protecting group to the cyclic secondary nitrogen atom of the compound of formula 5, where R is phenyl substituted with halogen, followed by the Suzuki reaction, wherein step (b) further includes removing the tetrahydropyranyl protecting group.
  • step (b) further includes removing the tetrahydropyranyl protecting group.
  • N-acylated imino ether 4 is obtained by reacting poorly stable anhydride 2 with imino ether hydrochloride in alkaline medium; its treatment with hydrazine hydrate yields triazole 5. Removing the Boc-protection yields the desired compound 1.1.
  • Method B Synthesis of 1,2,4-triazole derivatives from amidrazones.
  • Keto ester 9 is obtained by reacting N-Boc-protected 3-aminopropanoic acid (6) with N- methylmorpholine (7) and isobutyl chloroformate (8) in inert atmosphere. Its interaction with amidrazones (10) yields compounds 11 which spontaneously cyclized to triazoles 5 when heated to their melting temperature. Deprotection of amino group is conducted in the final stage.
  • Method C Synthesis of triazole derivatives from imino ethers and 3-tert-butyl-(3- aminopropanehydrazide)carbamate. Compounds 11 are obtained in one step by reacting imino ether 3 with protected 3- aminopropanoic acid hydrazide 12.
  • Method D Synthesis of 1,2,4-triazoles from amidine and hydrazides. Compound 15 is obtained by reacting hydrazides 14 with amidine trifluoroacetate 13 in the presence of sodium methylate. The subsequent steps are carried out similarly to the method B.
  • Method E Synthesis of 1,2,4-triazole derivatives by the Suzuki reaction. In the first stage, the tetrahydropyranyl protection is attached to the cyclic secondary nitrogen atom. Next, protected compounds 17 are introduced into the Suzuki reaction, and the treatment of biaryl-substituted triazoles 18 by hydrochloric acid in dioxane led to the simultaneous removal of both protective groups.
  • Example 1 General procedure for obtaining the compounds of general formula 1. The procedure for obtaining the compounds of general formula 1 is shown in the diagrams above.
  • Step 2 The flask was purged with argon and added compound (6), tetrahydrofuran and 1.1 eq. of N-methylmorpholine.
  • the reaction mixture was cooled to -30°C and 1 eq. of isobutyl chloroformate was slowly added dropwise. Cooling was stopped 10 minutes after dropwise addition. When the temperature reached 0°C, the precipitate was quickly filtered off. 1 eq. of amidrazone was immediately added to the stock solution and left for 16 hours under stirring. The progress of the reaction was monitored by TLC (1% MeOH/CHCl 3 ). Next, the precipitate was filtered off.
  • reaction mixture was evaporated on a rotary evaporator and melted at a temperature of 180-200 °C in an oil bath with a reflux condenser. Purification was carried out using normal phase column chromatography on silica gel in the system ethyl acetate:light petroleum 1:1. The Boc-protecting group was removed with hydrochloric acid in dioxane.
  • Step 2 The flask was purged with argon, and 1 eq. of compound (17) in argon flow was dissolved in 30 ml of dioxane followed by addition of 3.5 ml of 20% sodium carbonate solution in distilled water and 2 eq. of boronic acid. In 15 minutes, 0.03 eq. of Pd(PPh 3 ) 4 and 0.03 eq. of PdCl 2 (PPh 3 ) 2 were added.
  • Boiling was conducted with a reflux condenser in argon flow for 3-4 hours. The progress of the reaction was monitored by TLC (2% MeOH/CHCl 3 ). Once the reaction has completed, the reaction mixture was extracted with ethyl acetate and successively with water and 5% potassium carbonate solution. The organic layer was passed through sodium sulfate and evaporated on a rotary evaporator. Purification was carried out using normal phase column chromatography on silica gel in the system ethyl acetate:light petroleum 1:1. THP- and Boc-protections were removed from the purified product with hydrochloric acid in dioxane. Example 2.
  • the pchTAAR1 expression vector containing the human TAAR1 receptor gene was obtained for conducting experiments.
  • the expression vector pcEPAC was used to explore changes in cAMP concentrations in cells in response to the action of various chemical compounds. It provides constitutive expression of the Rluc-EPAC-YFP fused gene, the product of which is a biosensor for monitoring the activation of G ⁇ s signaling pathway. It is based on cAMP-dependent factor EPAC1 (Exchange protein activated by cAMP 1) which changes its conformation in response to binding of cAMP molecule.
  • Donor (Rluc) and acceptor (YFP) molecules are located in close proximity in an inactive form, however, when the biosensor binds to cAMP they move significantly away from each other (Barak et al., 2008). Consequently, a decrease in resonance energy transfer from the donor to the acceptor is observed. This is expressed mathematically as the ratio between acceptor luminescence intensity (535 nm) and donor luminescence intensity (480 nm) or the so-called BRET ratio (BRET ratio). Therefore, upon activation of G ⁇ s signaling pathway, which occurs when the receptor under study is activated by a ligand, a decrease in the BRET ratio will be observed.
  • BRET HEK293T cell culture (ATCC#CRL-3216) was grown in DMEM medium (Gibco) containing 4.5 g/L glucose until about 70–90% confluence was reached.
  • DMEM medium Gibco
  • pchTAAR1 3– 5 ⁇ g
  • pcEPAC 3–5 ⁇ g
  • Lipofectamine 2000 Invitrogen
  • the same amount of «empty» pcDNA3.1(+) vector was used as a negative control instead of the pchTAAR1 vector to assess non-specific interaction.
  • the cells were removed from the dish, suspended in MEM medium without phenol red (Gibco) containing 2% of fetal bovine serum, and transferred to 96-well plate pretreated with 0.0001% poly-D-lysine solution at 100,000-150,000 cells per well. Cells were grown on plates for 24–48 hours. The culture medium was then carefully aspirated, and 70 ⁇ l of PBS buffer containing Ca 2+ and Mg 2+ ions, 10 ⁇ l of 2 mM IBMX solution (Sigma) and 10 ⁇ l of 50 ⁇ M coelenterazine h solution (Promega) were sequentially added to each well. The plate was incubated for 10 min at room temperature.
  • ligand solutions diluted from 0.1 nM to 10 ⁇ M were added and incubated for another 5 minutes at room temperature.
  • TAAR1 receptor activation by compounds 1.1 – 1.31 Therefore, it can be concluded based on the data obtained that the compounds of formula 1 according to the present invention have excellent agonistic activity on TAAR1 receptor and can be used to treat diseases mediated by trace amine receptors TAAR1 such as mental disorders, cognitive disorders, neurological and neurodegenerative diseases, schizophrenia, depression, bipolar disorder, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder, Parkinson’s disease, dementia (including Alzheimer’s disease), epilepsy, migraine, high blood pressure (hypertension), alcohol or drug abuse, nicotine addiction, obesity, diabetes, metabolic disorder, disorder associated with energy consumption and expenditure, disorder associated with impaired body temperature homeostasis, sleep and circadian rhythm disorder, and cardiovascular disorder.
  • ADHD attention deficit hyperactivity disorder
  • Parkinson’s disease dementia
  • epilepsy migraine, high blood pressure (hypertension)
  • alcohol or drug abuse nicotine addiction, obesity, diabetes, metabolic disorder, disorder associated with energy consumption and expenditure, disorder associated with impaired body temperature homeostasis, sleep
  • Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor.
  • Mol Pharmacol 60, 1181–1188. 3. Sotnikova, T. D., Zorina, O. I., Ghisi, V., Caron, M. G., & Gainetdinov, R. R. (2008). Trace amine associated receptor 1 and movement control. Parkinsonism Relat Disord 14(Suppl.2), S99–102. 4. Lindemann, L., & Hoener, M. C. (2005).

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Abstract

L'invention concerne des 2-(5-aryl-4H-1,2,4-triazol-3-yl)éthanamines substituées de formule générale 1 et leurs sels pharmaceutiquement acceptables qui sont des modulateurs du récepteur 1 associé aux amines à l'état de traces (TAAR1). L'invention concerne également le procédé de production des composés de formule 1, une composition pharmaceutique à base desdits composés et l'utilisation desdits composés et de la composition pharmaceutique pour le traitement d'une maladie, d'un trouble ou d'un état médié(e) par des récepteurs TAAR1, tel(le) que les troubles mentaux, les troubles cognitifs, les troubles métaboliques, les maladies neurologiques et neurodégénératives.
PCT/RU2022/050272 2021-09-01 2022-09-01 2-(5-aryl-4 h-1,2,4-triazol-3-yl)éthanamines substituées utilisées comme modulateurs du récepteur 1 associé aux amines à l'état de traces (taar1) WO2023033681A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008046757A1 (fr) 2006-10-19 2008-04-24 F. Hoffmann-La Roche Ag Aminométhyl-4-imidazoles
WO2008052907A1 (fr) 2006-11-02 2008-05-08 F. Hoffmann-La Roche Ag 2-imidazoles substitués en tant que modulateurs des récepteurs associés aux amines de trace
CA2856204A1 (fr) 2012-01-12 2013-07-18 F. Hoffmann-La Roche Ag Derives heterocycliques utilises comme recepteurs associes a des amines sous forme de trace (taar)
WO2013131018A1 (fr) * 2012-03-02 2013-09-06 Zalicus Pharmaceuticals Ltd. Inhibiteurs biaryle du canal sodique
WO2016016292A1 (fr) 2014-08-01 2016-02-04 F. Hoffmann-La Roche Ag Dérivés du 2-oxa -5-azabicyclo [2.2.1] heptan -3-yl

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008046757A1 (fr) 2006-10-19 2008-04-24 F. Hoffmann-La Roche Ag Aminométhyl-4-imidazoles
WO2008052907A1 (fr) 2006-11-02 2008-05-08 F. Hoffmann-La Roche Ag 2-imidazoles substitués en tant que modulateurs des récepteurs associés aux amines de trace
CA2856204A1 (fr) 2012-01-12 2013-07-18 F. Hoffmann-La Roche Ag Derives heterocycliques utilises comme recepteurs associes a des amines sous forme de trace (taar)
WO2013131018A1 (fr) * 2012-03-02 2013-09-06 Zalicus Pharmaceuticals Ltd. Inhibiteurs biaryle du canal sodique
WO2016016292A1 (fr) 2014-08-01 2016-02-04 F. Hoffmann-La Roche Ag Dérivés du 2-oxa -5-azabicyclo [2.2.1] heptan -3-yl

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
BERGE S.M ET AL.: "Pharmaceutical Salts", J. PHARM. SCI., vol. 66, 1977, pages 1 - 19, XP002675560, DOI: 10.1002/jps.2600660104
BOROWSKY, B.ADHAM, N.JONES, K. A.RADDATZ, R.ARTYMYSHYN, R.OGOZALEK, K. L.GERALD, C.: "Trace amines: Identification of a family of mammalian G protein-coupled receptors", PROC NATL ACAD SCI U S A, vol. 98, 2001, pages 8966 - 8971, XP002185201, DOI: 10.1073/pnas.151105198
BUNZOW, J. RSONDERS, M. SARTTAMANGKUL, S.HARRISON, L. M.ZHANG, G.QUIGLEY, D. IGRANDY, D. K.: "Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor", MOL PHARMACOL, vol. 60, 2001, pages 1181 - 1188, XP008008060
LAM V. M., ESPINOZA S., GERASIMOV A. S., GAINETDINOV R. R., SALAHPOUR A.: "In-vivo pharmacology of trace-amine associated receptor 1.", EUR. J. PHARMACOL., vol. 763, 2015, pages 136 - 142
LINDEMANN, L.HOENER, M. C.: "A renaissance in trace amines inspired by a novel GPCR family", TRENDS PHARMACOL SCI, vol. 26, 2005, pages 274 - 281, XP002498588, DOI: 10.1016/j.tips.2005.03.007
REVEL, F. G.MOREAU, J. L.GAINETDINOV, R. R.BRADAIA, A.SOTNIKOVA, T. DMORY, RHOENER, M. C: "TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity", PROC NATL ACAD SCI U S A, vol. 108, 2011, pages 8485 - 8490, XP055710233, DOI: 10.1073/pnas.1103029108
REVEL, F. G.MOREAU, J. L.GAINETDINOV, R. R.FERRAGUD, A.VELAZQUEZ-SANCHEZ, C.SOTNIKOVA, T. D.HOENER, M. C.: "Trace amine-associated receptor 1 partial agonism reveals novel paradigm for neuropsychiatric therapeutics", BIOL PSYCHIATRY, vol. 72, 2012, pages 934 - 942
SOTNIKOVA, T. D., ZORINA, O. I., GHISI, V., CARON, M. G., & GAINETDINOV, R. R.: "Trace amine associated receptor 1 and movement control", PARKINSONISM RELAT DISORD, vol. 14, 2008, pages 99 - 102

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