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WO2023033679A1 - Benzamides à substitution méthoxy(azacycloalkyl) utilisés en tant que modulateurs du récepteur 1 associé à une amine trace (taar1) - Google Patents

Benzamides à substitution méthoxy(azacycloalkyl) utilisés en tant que modulateurs du récepteur 1 associé à une amine trace (taar1) Download PDF

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WO2023033679A1
WO2023033679A1 PCT/RU2022/050270 RU2022050270W WO2023033679A1 WO 2023033679 A1 WO2023033679 A1 WO 2023033679A1 RU 2022050270 W RU2022050270 W RU 2022050270W WO 2023033679 A1 WO2023033679 A1 WO 2023033679A1
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disorder
ylmethoxy
piperidin
disease
compound
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WO2023033679A4 (fr
Inventor
Raul Radikovich GAINETDINOV
Andrey Sergeevich GERASIMOV
Aleksey Yurievich LUKIN
Nikolay Ilyich ZHURILO
Mikhail Yurievich KRASAVIN
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<<excellena Research And Development>> <<excellena>> LLC LLC
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<<excellena Research And Development>> <<excellena>> LLC LLC
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    • 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
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4462—Non condensed piperidines, e.g. piperocaine only substituted in position 3
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61P3/08—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
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms

Definitions

  • the present invention relates to (azacycloalkyl)methoxy-substituted benzamides 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 P-phenyl ethylamine (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. 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. Altered levels of trace amines have also been found in patients suffering from attention deficit hyperactivity disorder (ADHD), Parkinson’s disease, and some other brain diseases [Lindemann & Hoener, 2005], Therefore, it is believed that the identification of new ligands for TA receptors could lead to the development of therapeutics targeting this new neuromodulatory system.
  • ADHD attention deficit hyperactivity disorder
  • Parkinson Parkinson’s disease
  • some other brain diseases [Lindemann & Hoener, 2005]
  • 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 T AAR 1 -knockout mouse strain
  • 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.
  • the present inventors have surprisingly found that (azacycloalkyl)methoxy-substituted benzamides 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 (azacycloalkyl)methoxy-substituted benzamides, 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 the compound of formula 1, or a pharmaceutically acceptable salt thereof, where n is 0, 1 or 2; m is 0 if n is 2, or m is 1 if n is 0 or 1;
  • R 1 and R 2 are independently: hydrogen atom
  • Ci-Cio alkyl optionally substituted with C3-C10 cycloalkyl
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 5- or 6- membered saturated heterocyclyl containing 1 nitrogen atom and optionally substituted with C1-C10 alkyl; or R 1 and R 2 together with the nitrogen atom to which they are attached form a 6- membered saturated heterocyclyl containing 1 nitrogen atom and 1 heteroatom selected from oxygen, sulfur and nitrogen.
  • the present invention provides the method for producing the compound of formula 1 comprising
  • step (b) contacting the compound of formula 5 obtained in step (a) with amines of general formula R'R ⁇ H followed by removal of the protective tert-butoxycarbonyl group to form 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 present invention provides the 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 use of the 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 a 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.
  • alkyl refers to straight or branched chain saturated hydrocarbon radicals containing 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, even more preferably 1 to 4 carbon atoms.
  • Examples of Ci-Cio alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl and tertbutyl.
  • cycloalkyl means a monovalent saturated carbocyclic group containing 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, which can be monocyclic, bicyclic or polycyclic.
  • Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and etc.
  • heterocyclyl or «heterocyclic» means an aromatic or non-aromatic saturated or partially saturated monocyclic or polycyclic system containing 3 or more atoms in the cycle of which one or more atom(s) is/are a heteroatom such as, but not limited to, N, O, S.
  • heterocyclyl is 5-10 membered heterocyclyl, preferably 5-6 membered heterocyclyl.
  • heterocyclic groups contain 1 or 2 heteroatoms selected from N, O, S.
  • Heterocyclyl may have one or more substituents such as Ci- Cio alkyl, C3-C10 cycloalkyl.
  • Nitrogen and sulfur atoms within heterocyclyl can be oxidized to N-oxide, S-oxide or S-dioxide.
  • heterocyclyls include piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and etc.
  • An example of substituted heterocyclyl is piperidinyl substituted with C1-C10 alkyl.
  • the term «optionally substituted» group refers to a substituted or unsubstituted group and means that said group may be substituted at one or more positions with 1-3 substituents.
  • the terms «optionally substituted» and «substituted or unsub stituted» may be used interchangeably.
  • compounds of the present invention may exhibit properties of tautomerism, conformational isomerism, geometric isomerism and/or optical isomerism. Since the depicted formulas in the specification and claims may represent only one of the possible tautomeric, conformational isomeric, optical isomeric or geometric isomeric forms, it should be understood that the present invention encompasses any tautomeric, conformational isomeric, optical isomeric and/or geometric isomeric forms of compounds having one or more uses described herein, as well as mixtures of these different forms.
  • «pharmaceutically acceptable» is meant substances that are not biologically or otherwise undesirable, for example, a substance can be incorporated in a pharmaceutical composition administered to a subject without causing any undesirable biological effects or harmful interaction with any of other components of the composition containing the same.
  • 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.
  • the terms «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.
  • 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. arresting the development of clinical symptoms; and/or (iii) alleviating a disease, i.e. causing regression of clinical symptoms or their severity.
  • 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 or buccal dosage form; aerosols; implants; dosage form for topical, transdermal, subcutaneous, intramuscular, intravenous, intranasal, intraocular or rectal administration.
  • the most convenient route of administration is commonly oral using a normal daily dosage regimen which can be adjusted depending on disease severity and patient’s response.
  • an active ingredient is usually mixed with a carrier having the necessary binding capacity in suitable proportions and compressed into the desired shape and size.
  • 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., in 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. In particular, base salts can be specially prepared from the purified free base of the claimed compound and a suitable organic or inorganic acid.
  • salts obtained in this manner are 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. Pharm. Sci., 1977, 66: 1-19).
  • the present invention relates to (azacycloalkyl)methoxy-substituted benzamides exhibiting properties of a trace amine receptor TAAR1 agonist, i.e. compounds of general formula 1 or pharmaceutically acceptable salts thereof, where n is 0, 1 or 2; m is 0 if n is 2, or m is 1 if n is 0 or 1;
  • R 1 and R 2 are independently: hydrogen atom
  • Ci-Cio alkyl optionally substituted with C3-C10 cycloalkyl
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 5- or 6- membered saturated heterocyclyl containing 1 nitrogen atom and optionally substituted with C1-C10 alkyl; or R 1 and R 2 together with the nitrogen atom to which they are attached form a 6- membered saturated heterocyclyl containing 1 nitrogen atom and 1 heteroatom selected from oxygen, sulfur and nitrogen.
  • R 1 and R 2 cannot simultaneously be hydrogen.
  • R 1 and R 2 are simultaneously hydrogen.
  • R 1 is hydrogen and R 2 is Ci-Cio alkyl, preferably Ci-Ce alkyl.
  • R 1 is hydrogen and R 2 is C3-C10 cycloalkyl, preferably C3-C8 cycloalkyl.
  • R 1 and R 2 together with the nitrogen atom to which they are attached form pyrrolidinyl, piperidinyl or morpholinyl.
  • R 1 and R 2 together with the nitrogen atom to which they are attached form pyrrolidinyl or piperidinyl substituted with C1-C10 alkyl.
  • the amide group within benzene ring of the compound of formula 1 is located at para- or meta-position relative to the methoxy substituent.
  • 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 approximately 0.1 mg to approximately 1000 mg, preferably approximately 1 mg to approximately 800 mg, more preferably approximately 10 mg to approximately 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.
  • the excipient is typically present in the composition in an amount of approximately 1 wt.% to approximately 99 wt.%, preferably approximately 5 wt.% to approximately 98 wt.%, more preferably approximately 15 wt.% to approximately 95 wt.% of the total weight of the composition.
  • the amount of excipient present in the inventive composition is selected from the following: at least approximately 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 using 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 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 therapeutically effective amount of the compound of formula 1 or a pharmaceutically acceptable salt thereof is approximately 0.1 mg/day to 1000 mg/day, preferably approximately 1 mg/day to approximately 800 mg/day, more preferably approximately 10 mg/day to approximately 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, a cognitive disorder, a metabolic disorder, a neurological and a 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, and cardiovascular disorder.
  • ADHD attention deficit hyperactivity disorder
  • ADHD attention deficit hyperactivity disorder
  • psychosis schizophrenia
  • 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, and cardiovascular disorder.
  • the present invention provides the 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 formula 1 or a pharmaceutically acceptable salt thereof comprising:
  • step (b) contacting the compound of formula 5 obtained in step (a) with amines of general formula R 1 R 2 NH followed by removal of the protective tert-butoxycarbonyl group to form the compound of formula 1, where n, m, R 1 and R 2 are as defined above for the compound of formula 1.
  • contacting an ester of hydroxybenzoic acid with the compound of formula 3 in step (a) is carried out in the presence of triphenylphosphine (PPhs) and diisopropyl azodi carboxylate (DIAD) at room temperature.
  • Phs triphenylphosphine
  • DIAD diisopropyl azodi carboxylate
  • step (b) conversion of the compound of formula 5 obtained in step (a) to the corresponding amide by contacting its with amines of general formula R 1 R 2 NH in step (b) is carried out in the presence of N,N’ -carbonyl diimidazole (CDI) at room temperature.
  • CDI N,N’ -carbonyl diimidazole
  • An ester of hydroxybenzoic acid is alkyl ester of ortho-, meta-, or para-hydroxybenzoic acid.
  • an ester of hydroxybenzoic acid is ethyl ester of para- or meta-hydroxybenzoic acid.
  • amines of general formula R 1 R 2 NH are selected from the group including piperidine, 4-methylpiperidine, isopropylamine, cyclopropylamine, morpholine, pyrrolidine.
  • 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 scheme below:
  • Example 5 Preparation of m orpholino[4-(piperi din-3 -ylmethoxy)phenyl]methanone hydrochloride (1.4, TRX-0004). It was obtained as colorless crystals.
  • Example 7 Preparation of (4-m ethylpiperi din- l-yl)[3-(piperi din-3 - ylmethoxy)phenyl]methanone hydrochloride (1.6, TRX-0006). It was obtained as colorless crystals.
  • Example 14 Preparation of morpholino[4-(piperidin-4-ylmethoxy)phenyl]methanone hydrochloride (1.13, TRX-0013). It was obtained as colorless crystals.
  • Example 15 Preparation of (4-methylpiperidin-l-yl)[4-(piperidin-4-ylmethoxy)- phenyl]methanone hydrochloride (1.14, TRX-0014). It was obtained as colorless crystals.
  • Example 20 Construction of expression plasmids, TAAR and stably transfected cell lines.
  • the pchTAARl 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 Gas-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 Gas-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
  • pchTAARl 3-5 pg
  • pcEPAC 3-5 pg
  • Lipofectamine 2000 Invitrogen
  • the same amount of «empty» pcDNA3.1(+) vector was used as a negative control instead of the pchTAARl 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 pl of PBS buffer containing Ca 2+ and Mg 2+ ions, 10 pl of 2 mM IBMX solution (Sigma) and 10 pl of 50 pM 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 pM were added and incubated for another 5 minutes at room temperature.
  • 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 and circadian rhythm disorder, and cardiovascular disorder.
  • TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity. Proc Natl Acad Sci U S A 108, 8485-8490.

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Abstract

La présente invention concerne des benzamides à substitution méthoxy (Azacycloalkyl) de formule générale 1 et leurs sels pharmaceutiquement acceptables qui sont des modulateurs du récepteur 1 associé à l'amine de trace (TAAR1). La présente invention concerne également le procédé de production des composés de formule 1, sur leur base et l'utilisation desdits composés et d'une composition pharmaceutique pour le traitement d'une maladie, d'un trouble ou d'un état induit par des récepteurs TAAR1 à l'état de trace tels que des troubles mentaux, des troubles cognitifs, des troubles métaboliques, des maladies neurologiques et neurodégénératives.
PCT/RU2022/050270 2021-09-01 2022-09-01 Benzamides à substitution méthoxy(azacycloalkyl) utilisés en tant que modulateurs du récepteur 1 associé à une amine trace (taar1) Ceased WO2023033679A1 (fr)

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