WO2013062680A1 - Nouveaux composés et compositions à base de ceux-ci pour traiter des troubles du système nerveux - Google Patents

Nouveaux composés et compositions à base de ceux-ci pour traiter des troubles du système nerveux Download PDF

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Publication number
WO2013062680A1
WO2013062680A1 PCT/US2012/054898 US2012054898W WO2013062680A1 WO 2013062680 A1 WO2013062680 A1 WO 2013062680A1 US 2012054898 W US2012054898 W US 2012054898W WO 2013062680 A1 WO2013062680 A1 WO 2013062680A1
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compound
disease
disorder
condition
nervous system
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PCT/US2012/054898
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English (en)
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Leo BLEICHER
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Braincells, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C229/50—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms being part of the same condensed ring system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/14—All rings being cycloaliphatic
    • C07C2602/18—All rings being cycloaliphatic the ring system containing six carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the instant disclosure relates to a novel compound, methods synthesizing the compound, compositions containing the compound, and methods for using the compound to treat and/or prevent diseases and/or conditions of the central and peripheral nervous system.
  • mGluRs metabotropic glutamate receptors
  • mGluR2/3 Specific central and peripheral nervous system diseases, disorders and/or conditions linked to mGluR2/3 include depression, treatment resistant depression, anxiety, Alzheimer's disease, cognition, addiction, and Parkinson's disease.
  • Other disorders and conditions associated with metabotropic glutamate receptors (mGluRs) are cancers directly or indirectly linked to mGluR2/3, including but not limited to colon cancer and glioblastoma.
  • the present invention is directed to Compound 1 having the following structure and the use of this compound in a pharmaceutical formulation to treat and/or prevent diseases and/or conditions of the c
  • Compound 1 The chemical name for Compound 1 is (lR,2R,3R,5R,6R)-6-((((adamantane-l- carbonyl)oxy)methoxy)carbonyl)-2-amino-3-((3,4-dichlorobenzyl)oxy)-6- fluorobicyclo[3.1.0]hexane-2-carboxylic acid.
  • a compound and various compositions comprising the compound or a pharmaceutically acceptable salt, prodrug or other derivative thereof, for the prevention and/or treatment of diseases, disorders, conditions and injuries of the central and peripheral nervous systems.
  • the compound stimulates or increases neurogenesis.
  • the methods described are for treating neurodegenerative disorders, neurological trauma including brain or central nervous system trauma and/or recovery there from, psychosis, addiction, pain, learning and memory disorders and ischemia of the central and/or peripheral nervous systems and affective disorders, including depression and anxiety.
  • the methods described are useful for improving cognitive disorders associated with multiple sclerosis, dementia, Parkinson's disease and/or stroke.
  • the methods described are useful for treating cancer or tumors associated with mGluR2/3.
  • the cancer associated with mGluR2/3 is melanoma, colon cancer or glioblastoma.
  • Compound 1 is administered with at least one other active agent.
  • compositions comprising a prodrug of (lR,2R,3R,5R,6R)-2-amino-3-((3,4-dichlorobenzyl)oxy)-6-fluorobicyclo[3.1.0]hexane-2,6- dicarboxylic acid (Compound 2) with an oral bioavailability of at least about 35% when administered to a subject.
  • the oral bioavailability of the prodrug is between about 35% and about 50%.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers, diluents, or
  • the prodrug is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-oethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Also provided herein are methods for treating a disease, disorder or condition of the central and/or peripheral nervous system comprising administering a pharmaceutical composition comprising a prodrug of (lR,2R,3R,5R,6R)-2-amino-3-((3,4- dichlorobenzyl)oxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (Compound 2) with an oral bioavailabilty between about 30% and about 50% when administered to a subject.
  • a pharmaceutical composition comprising a prodrug of (lR,2R,3R,5R,6R)-2-amino-3-((3,4- dichlorobenzyl)oxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (Compound 2) with an oral bioavailabilty between about 30% and about 50% when administered to a subject.
  • the prodrug is (Compound 1), or a pharmaceutically acceptable salt or hydrate thereof.
  • the disease, disorder or condition is a mGluR 2/3-dependent or mGluR 2/3-mediated disease or condition.
  • the disease, disorder or condition is selected from the group consisting of Alzheimer's disease, schizophrenia, Parkinson's disease, anxiety, depression, treatment resistant depression, obsessive compulsive disorders, psychosis, addiction, epilepsy, insomnia, brain or central nervous system trauma and/or recover therefrom, ischemia of the central and/or peripheral nervous systems, pain, learning and memory disorders and cognitive and memory deficiencies due to disease or aging.
  • the disease, disorder or condition is a nervous system disorder related to cellular degeneration, a psychiatric condition, cognitive impairment, cellular trauma or injury, or another neurologically related condition.
  • the disease, disorder or condition is a cellular degeneration disease selected from the group consisting of a neurodegenerative disorder, a neural stem cell disorder, a neural progenitor cell disorder, an ischemic disorder or a combination thereof.
  • the neurodegenerative disorder is a degenerative disease of the retina, lissencephaly syndrome, or cerebral palsy.
  • the psychiatric condition is a neuropsychiatric disorder.
  • Figure 1 is a dose-response curve showing the effect of Compound 1
  • Figure 2 provides the rat PK profile of (lR,2R,3R,5R,6R)-2-amino-3-((3,4- dichlorobenzyl)oxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (Compound 2) after a 10 mg/kg oral dose of:
  • Figure 3 provides the rat PK profile of Compound 2 after a 10 mg/kg oral dose of Compound 1.
  • Figure 5 provides the human PK profile of Compound 2 after a 1 mg oral dose of Compound 1, Compound 3, Compound 4 and Compound 5, as adjusted based on the molecular weight of the Compound administered.
  • Figure 6 provides the human PK profile of Compound 2 after a 1 mg oral dose of Compound 1 , as adjusted based on the molecular weight of Compound 1.
  • Figure 7 provides a comparison of the human PK profile for Compound 2 after a 1 mg oral dose of Compound 1 and Compound 3, as adjusted based on the molecular weight of the Compound administered.
  • Figure 8 provides the human PK profile of Compound 2 after a 1 mg oral dose of Compound 1, Compound 3, Compound 4 and Compound 5.
  • Figure 9 provides the human PK profile of Compound 2 after a 1 mg oral dose of Compound 1.
  • Figure 10 provides a comparison of the human PK profile for Compound 2 after a 1 mg oral dose of Compound 1 and Compound 3.
  • Figure 11 provides the rat PK profile of Compound 2 after a 10 mg/kg oral dose of Compound 1 , as adjusted based on the molecular weight of Compound 1.
  • Figure 12 provides a comparison of the rat PK profile of Compound 2 after a 10 mg/kg oral dose of Compound 1 and Compound 3, as adjusted based on the molecular weight of the Compound administered.
  • the term "effective amount” or “therapeutically effective amount” refers to that amount of a compound described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below.
  • the therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • the term also applies to a dose that will induce a particular response in target cells, e.g. reduction of platelet adhesion and/or cell migration.
  • the specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
  • treatment or “treating,” or “palliating” or “ameliorating” is used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder.
  • the compositions may be
  • the treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, functional (self) evaluation, and/or any form of vision evaluation.
  • the "therapeutic effect" as used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above.
  • a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • co-administration encompass the administration of two or more agents to a subject so that both agents and/or their metabolites are present in the subject at the same time.
  • Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.
  • Subject refers to an animal, such as a mammal, for example a human.
  • the methods described herein can be useful in both human therapeutics and veterinary applications.
  • the patient is a mammal, and in some embodiments, the patient is human.
  • Prodrug is meant to indicate a compound that may be converted under
  • prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable.
  • a prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis.
  • prodrug is also meant to include any covalently bonded carriers, which release the active Compound in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of an active compound, as described herein may be prepared by modifying functional groups present in the active Compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
  • Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active Compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.
  • in vivo refers to an event that takes place in a subject's body.
  • in vitro refers to an event that takes places outside of a subject's body.
  • an in vitro assay encompasses any assay run outside of a subject assay.
  • In vitro assays encompass cell-based assays in which cells alive or dead are employed.
  • In vitro assays also encompass a cell-free assay in which no intact cells are employed.
  • a chiral center in the compound described herein includes all possible stereoisomers of the compound, including compositions comprising the racemic mixture of the two enantiomers, as well as compositions comprising each enantiomer individually, substantially free of the other enantiomer.
  • contemplated herein is a composition comprising the S enantiomer of a compound substantially free of the R enantiomer, or the R enantiomer substantially free of the S enantiomer. If the named compound comprises more than one chiral center, the scope of the present disclosure also includes compositions comprising mixtures of varying proportions between the diastereomers, as well as
  • compositions comprising one or more diastereomers substantially free of one or more of the other diastereomers.
  • substantially free it is meant that the composition comprises less than 25%, 15%, 10%>, 8%, 5%, 3%, or less than 1% of the minor enantiomer or
  • salts are meant to include salts of active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituent moieties found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • Organic and inorganic counter ions are well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride,
  • Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like.
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric with replacement of one or both protons, sulfamic, phosphoric with replacement of one or both protons, e.g.
  • orthophosphoric, or metaphosphoric, or pyrophosphoric and nitric and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, embonic, nicotinic, isonicotinic and amino acid salts, cyclamate salts, fumaric, toluenesulfonic, methanesulfonic, N-substituted sulphamic, ethane disulfonic, oxalic, and isethionic, and the like.
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxy
  • non-toxic salts include those derived from inorganic acids such as non toxic metals derived from group la, lb, Ila and lib in the periodic table.
  • inorganic acids such as non toxic metals derived from group la, lb, Ila and lib in the periodic table.
  • lithium, sodium, or potassium, magnesium, calcium, zinc salts, or ammonium salts such as those derived from mono, di and trialkyl amines.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts 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 acetonitrile. Lists of suitable salts are found in Remington s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, which is hereby incorporated by reference.
  • solvate means a compound, or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.
  • analog thereof in the context of the compounds disclosed herein includes diastereomers, hydrates, solvates, salts, prodrugs, and N-oxides or S-oxides of the compounds.
  • the present invention also includes isotopically labeled compounds, which are identical to those recited in the disclosure, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. These isotopically labeled compounds may show greater stability and/or may be used as imaging agents. Examples of isotopes that can be
  • incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, bromine and iodine such as 2 H, 3 H, n C, 13 C, 14 C, 15 N, n O, 17 0, 18 0, 31 P, 32 P, 35 S, 16 F, 18 F, 36 C1, 76 Br and 123 I respectively.
  • Neurogenesis is defined herein as proliferation, differentiation, migration and/or survival of a neural cell in vivo or in vitro.
  • the neural cell is an adult, fetal, or embryonic neural stem cell or population of cells.
  • the cells may be located in the central nervous system or elsewhere in an animal or human being.
  • the cells may also be in a tissue, such as neural tissue.
  • the neural cell is an adult, fetal, or embryonic progenitor cell or population of cells, or a population of cells comprising a mixture of stem cells and progenitor cells.
  • Neural cells include all brain stem cells, all brain progenitor cells, and all brain precursor cells.
  • Neurogenesis includes neurogenesis as it occurs during normal development, as well as neural regeneration that occurs following disease, damage or therapeutic intervention, such as by the treatment described herein.
  • a "neurogenic agent” is defined as a chemical agent or reagent that can promote, stimulate, or otherwise increase the amount or degree or nature of neurogenesis in vivo or ex vivo or in vitro relative to the amount, degree, or nature of neurogenesis in the absence of the agent or reagent.
  • treatment with a neurogenic agent increases neurogenesis if it promotes neurogenesis by about 5%, about 10%, about 25%, about 50%>, about 100%), about 500%>, or more in comparison to the amount, degree, and/or nature of neurogenesis in the absence of the agent, under the conditions of the method used to detect or determine neurogenesis.
  • Compound 1 is in a pharmaceutically acceptable formulation, that promotes, stimulates, or otherwise increases the amount or degree or nature of neurogenesis is a neurogenic agent.
  • neurogenesis modulators or “neurogenic modulating agents” are defined as an agent when used alone or in combination with one or more other agents induces a change in neurogenesis. In some embodiments, administering "neurogenic modulators" or
  • neurogenesis modulating agents changes neurogenesis in a target tissue and/or cell-type by about 20%, about 25%, about 30%, about 40%>, about 50%, about 75%, or about 90% or more in comparison to the absence of the combination.
  • neurogenesis is modulated by about 95% or by about 99% or more.
  • the modulation noted is an increase in neurogenesis.
  • stem cell or neural stem cell (NSC)
  • NSC neural stem cell
  • progenitor cell e.g., neural progenitor cell
  • neural progenitor cell refers to a cell derived from a stem cell that is not itself a stem cell. Some progenitor cells can produce progeny that are capable of differentiating into more than one cell type.
  • mGluR2 and/or mGluR3 refers to the metabotropic glutamate receptors (mGluRs) in Group II.
  • the compound disclosed herein is an mGluR2 and/or mGluR3 antagonist.
  • the chemical name for Compound 1 is (lR,2R,3R,5R,6R)-6-((((adamantane-l- carbonyl)oxy)methoxy)carbonyl)-2-amino-3-((3,4-dichlorobenzyl)oxy)-6- fluorobicyclo[3.1.0]hexane-2-carboxylic acid.
  • the Chemical Formula of Compound 1 is: C 27 H 30 CI 2 FNO 7 .
  • Compound 1 has an Exact Mass of 569.14. Also included in the invention described herein are analogs of Compound 1.
  • Compound 1 has a bioavailability of greater than about 10%. In some embodiments, the bioavailability of Compound 1 is between about 10% to about 30%, or about 20% to about 40%, or about 30% to about 50%, or about 40% to about 60%, or about 50%) to about 70%>, or about 60%> to about 90%>. In some specific embodiments the bioavailability of Compound 1 is greater than about 50%. In other specific embodiments, the bioavailability of Compound 1 is greater than about 60%. In yet other specific embodiments the bioavailability of Compound 1 is between about 80% and 90%. In still further embodiments, the bioavailability of Compound 1 is between about 40% and 50%.
  • Compound 1 provides a rapid onset of anti-depressant response when administered to a subject.
  • Compound 1 has a pharmacodynamic half-life of greater than 2 hours, greater than 4 hours, greater than 8 hours, greater than 24 hrs, greater than 2 days, greater than 4 days, greater than 7 days systemically.
  • the systemic pharmacodynamic half-life of Compound 1 is between 2 hours and 8 hours. In other embodiments, the systemic pharmacodynamic half-life of Compound 1 is between 2 days and 7 days.
  • Compound 1 has a pharmacodynamic half-life of greater than 2 hours, greater than 4 hours, greater than 8 hours, greater than 24 hrs, greater than 2 days, greater than 4 days, greater than 7 days in the brain. In some embodiments, the
  • pharmacodynamic half- life of Compound 1 in the brain is between 2 hours and 8 hours. In other embodiments, the pharmacodynamic half-life of Compound 1 in the brain is between 2 days and 7 days.
  • Compound 2 refers to a compound having the following structure:
  • Compound 2 has an Exact Mass of 377.02
  • Compound 4 has an Exact Mass of 427.02.
  • the scientific name for Compound 5 is (lR,2R,3R,5R,6R)-2-amino-3-(3,4- dichlorobenzyloxy)-6-((2,3-dihydro-lH-inden-5-yloxy) carbonyl)-6- fluorobicyclo[3.1.0]hexane-2-carboxylic acid.
  • the Chemical Formula of Compound 5 is: C24H22CI2FNO5.
  • Compound 5 has an Exact Mass of 493.09.
  • the compound of this invention used in the methods described herein is in the form of a pharmaceutical composition that includes at least one
  • pharmaceutically acceptable excipient includes any excipient known in the field as suitable for pharmaceutical applications. Suitable pharmaceutical excipients and formulations are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (19th ed.) (Genarro, ed. (1995) Mack Publishing Co., Easton, Pa.). Pharmaceutical carriers may be chosen by a skilled person based upon the intended mode of administration of compound.
  • the pharmaceutically acceptable carrier may include, for example, disintegrants, binders, lubricants, glidants, emollients, humectants, thickeners, silicones, flavoring agents, and/or water.
  • the compound may be incorporated with excipients and administered in the form of ingestible tablets, chewable tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, or any other form known in the pharmaceutical arts.
  • the pharmaceutical compositions may also be formulated in a sustained release or a delayed release form.
  • compositions are known in the art.
  • the compositions may be a quick release formulation.
  • An effective amount of a composition may vary based on a variety of factors, including but not limited to, the activity of the active compound, the physiological characteristics of the subject, the nature of the condition to be treated, and the route and/or method of administration.
  • the disclosed methods typically involve the administration in a dosage range of 0.001 mg/kg/day to 4000 mg/kg/day or in a dosage range of 0.05 to 500 mg/kg/day.
  • methods described herein allow treatment of indications with reductions in side effects, dosage levels, dosage frequency, treatment duration, tolerability, and/or other factors.
  • the disclosed neurogenic agent or pharmaceutical compositions are administered by any means suitable for achieving a desired effect.
  • Various delivery methods are known in the art and can be used to deliver the agent to a subject or to NSCs or progenitor cells within a tissue of interest. The delivery method will depend on factors such as the tissue of interest, the nature of the compound (e.g., its stability and ability to cross the blood-brain barrier), and the duration of the treatment, among other factors.
  • an osmotic minipump can be implanted to facilitate administration of the Compound into a neurogenic region, such as the lateral ventricle.
  • compounds can be administered by direct injection into the cerebrospinal fluid of the brain or spinal column, or into the eye. Administration to the eyes may also be in the form of ocular drops. Compounds can also be administered into the periphery (such as by intravenous or subcutaneous injection, oral or nasal delivery), and subsequently cross the blood-brain barrier.
  • the disclosed agents or pharmaceutical compositions are administered in a manner that allows them to cross the blood-brain barrier and in a non- limiting embodiment, contact the subventricular zone (SVZ) of the lateral ventricles and/or the dentate gyrus of the hippocampus.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral, inhalation, transdermal (topical), transmucosal, and rectal administration.
  • Intranasal administration generally includes, but is not limited to, inhalation of aerosol suspensions for delivery of compositions to the nasal mucosa, trachea and bronchioli.
  • the compound combinations are administered so as to either pass through or by-pass the blood-brain barrier.
  • Methods for allowing factors to pass through the blood-brain barrier are known in the art, and include minimizing the size of the factor, providing hydrophobic factors which facilitate passage, and conjugating the compound to a carrier molecule that has substantial permeability across the blood brain barrier.
  • the combination of compounds can be administered by a surgical procedure implanting a catheter coupled to a pump device.
  • the pump device can also be implanted or be extracorporally positioned.
  • Administration of the compound can be in intermittent pulses or as a continuous infusion.
  • Devices for injection to discrete areas of the brain are known in the art.
  • the Compound is administered locally to the ventricle of the brain, substantia nigra, striatum, locus ceruleous, nucleus basalis Meynert, pedunculopontine nucleus, cerebral cortex, and/or spinal cord by, e.g., injection.
  • Methods, compositions, and devices for delivering therapeutics, including therapeutics for the treatment of diseases and conditions of the CNS and PNS, are known in the art.
  • the delivery or targeting of a compound, to a neurogenic region, such as the dentate gyrus or the subventricular zone enhances efficacy and reduces side effects compared to known methods involving administration with the same or similar compounds.
  • the methods may comprise the use of one or more agents reported as anti-depressant agents.
  • Compound 1 may be coadministered with one or more reported anti-depressant agents known in the art.
  • Antidepressant agents known in the art include, but are not limited to, SSRIs, SNRIs, SSNRIs, triple uptake inhibitors, agents like dehydroepiandrosterone (DHEA) and DHEA Sulfate, Monoamine Oxidase inhibitors (MAO), Vlb antagonists, opioids, NMDA antagonists, Angiotensin modulators, Psychostimulants, Melatonin receptor agonists,
  • Muscarinic/acetylcholine receptor modulators Phosphodiesterase (PDE) inhibitors, Gama- aminobutyric acid (GAB A) receptor modulators, 5-Hydroxytryptamine receptor modulators (5HT), Peroxisome proliferatory-activated receptor (PPAR) modulators, Melatonergic Agonist/5-HT2C antagonists (such as agomelatine and related melatonin receptor 1& 2 modulators including BCI-952), and tricyclics.
  • PDE Phosphodiesterase
  • GAB A Gama- aminobutyric acid
  • 5HT 5-Hydroxytryptamine receptor modulators
  • PPAR Peroxisome proliferatory-activated receptor
  • Melatonergic Agonist/5-HT2C antagonists such as agomelatine and related melatonin receptor 1& 2 modulators including BCI-952
  • tricyclics such as agomelatine and related melatonin receptor 1& 2 modulators including BCI-952
  • Non-limiting examples of SSRI selective serotonine reuptake inhibitor
  • SSRI selective serotonine reuptake inhibitor
  • fluoxetine Prozac ®
  • citalopram Celexa
  • escitalopram Lexapro
  • fluvoxamine or fluvoxamine maleate CAS RN: 61718-82-9
  • Luvox ® paroxetine
  • Paxil ® paroxetine
  • Zoloft ® the compound nefazodone
  • Non-limiting examples of SNRI (selective norepinephrine reuptake inhibitors) useful in the combinations disclosed herein are reboxetine (Edronax ® ) and atomoxetine (Strattera ® ).
  • Non-limiting examples of SSNRI (selective serotonin & norepinephrine reuptake inhibitors) useful in the combinations disclosed herein are venlafaxine (Effexor ® ), and its reported metabolite desvenlafaxine, or duloxetine (Cymbalta ® ).
  • Non-limiting examples of serotonin, noradrenaline, and dopamine (triple uptake) inhibitors useful in the combinations disclosed herein are DOV 102,677, DOV 102,677, DOV 216,303, DOV 216,303, DOV 21,947, NS-2330 (CAS RN 402856-42-2), and NS 2359 (CAS RN 843660-54-8).
  • Non-limiting examples of tricyclic compounds useful in the combinations disclosed herein are amitriptyline, desipramine, doxepin, imipramine, and nortriptyline.
  • Non-limiting examples of psychostimulants useful in the combinations disclosed herein are dextroamphetamine and methylphenidate.
  • Non- limiting examples of MAO inhibitors useful in the combinations disclosed herein are selegiline (Emsam ® ); an ampakine such as CX516 (or Ampalex, CAS RN: 154235-83-3), CX546 (or l-(l,4-benzodioxan-6-ylcarbonyl)piperidine), and CX614 (CAS RN 191744-13-5) from Cortex Pharmaceuticals.
  • selegiline Emsam ®
  • an ampakine such as CX516 (or Ampalex, CAS RN: 154235-83-3), CX546 (or l-(l,4-benzodioxan-6-ylcarbonyl)piperidine), and CX614 (CAS RN 191744-13-5) from Cortex Pharmaceuticals.
  • Vlb antagonist useful in the combinations disclosed herein are SSR149415 ((2S,4R)-1 -[5-Chloro- 1 -[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxy- phenyl)-2-oxo-2,3-dihydro-lH-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine carboxamide).
  • NMDA antagonists and opioids including but not limited meperidine, Methadone, Dextropropoxyphene, Tramadol, Ketobemidone, Ketamine, dextromethorphan, phencyclidine and nitrous oxide
  • mGluR5 modulators including but not limited to Aricept, and muscarinic agonists/positive allosteric modulators (PAMs), more specifically Ml and M3.
  • PAMs muscarinic agonists/positive allosteric modulators
  • fluorinated pyrimidines including but not limited to flurouracil (5-FU) and alkylating agents, including but not limited to Temozolomide.
  • Compound 1 optionally in combination with one or more other agents, results in improved efficacy, fewer side effects, lower effective dosages, less frequent dosing, and/or other desirable effects relative to use of Compound 1 individually (such as at higher doses). In some embodiments, this is due to synergistic activities and/or the targeting of molecules and/or activities that are differentially expressed in particular tissues and/or cell-types.
  • Compound 1 alone or in the combinations contemplated herein, is useful as a pharmaceutical to treat and/or prevent diseases and/or conditions of the central and peripheral nervous system.
  • Compound 1 is administered to a subject in a pharmaceutical composition.
  • the compound and compositions described herein can be used to treat diseases, disorders, and conditions of the central and/or peripheral nervous systems (CNS and PNS, respectively) by administering Compound 1, optionally in combination with another therapeutic, including but not limited to an mGluR2 and/or mGluR3 antagonist and/or another agent (CNS, neurogenic, anti-astrogenic, anti-nausea, etc).
  • Compound 1 optionally in combination with another agent, may be any that results in a measurable relief of a disease condition like those described herein.
  • the method may be applied to maintain and/or stabilize cognitive function in the subject.
  • the cognitive impairment may be the result of chronic infection, toxic disorders, neurodegenerative disorders and combinations thereof.
  • kits for treating a subject suffering from cognitive impairment due to a non-disease state include administering to the subject a therapeutically effective amount of Compound 1 or Compound 1 in a
  • Non-limiting examples of non-disease states include cognitive impairment due to aging, chemotherapy and radiation therapy.
  • the invention described herein provides a novel method for treating a mental disorder with a therapeutically effective amount of Compound 1 or
  • the method may be used to moderate or alleviate the mental disorder in an animal or human subject.
  • a mental disorder include an anxiety disorder and/or a mood disorder including depression.
  • the method may be used to improve, maintain, or stabilize an affective disorder in a subject.
  • Disclosed herein are also methods for identifying an animal or human subject suffering from one or more diseases, disorders, or conditions, or a symptom thereof, and administering to the subject a therapeutically effective amount of Compound 1 or Compound 1 in a pharmaceutically acceptable formulation.
  • the disclosed methods include identification of a subject as in need of an increase in neurogenesis and administering a therapeutically effective amount of Compound 1 or Compound 1 in a pharmaceutically acceptable formulation.
  • the subject is a mammal, more preferably a human being.
  • Compound 1 is used to stimulate or increase neurogenesis in a cell or tissue in a subject.
  • the subject may have a condition affecting normal neurogenesis whereby stimulating or increasing neurogenesis improves the condition.
  • the cell or tissue to be treated may exhibit the effects of insufficient amounts of, inadequate levels of, or aberrant neurogenesis.
  • the cell or tissue exhibits decreased neurogenesis or is subject to an agent that decreases or inhibits neurogenesis.
  • the subject may be one that has a disease, condition or disorder which results in suppressed or decreased neurogenesis.
  • the subject is in need of neurogenesis and has been diagnosed with a disease, condition, or injury of the central or peripheral nervous system.
  • the subject has one or more chemical addictions or dependencies.
  • the aberrant neurogenesis may be attributed to epilepsy, or a condition associated with epilepsy as non-limiting examples.
  • an increase in neurogenesis would decrease or alleviate the aberrant neurogenic symptoms in the subject.
  • Non- limiting examples of symptoms that may be treated with the methods described herein include abnormal behavior, abnormal movement, hyperactivity, hallucinations, acute delusions, combativeness, hostility, negativism, withdrawal, seclusion, memory defects, sensory defects, cognitive defects, pain and tension.
  • abnormal behavior include irritability, poor impulse control, distractibility, and aggressiveness.
  • an improvement in the Hamilton depression scale (HAM- D) score for depression may be used to determine (such as quantitatively) or detect (such as qualitatively) a measurable level of improvement in the depression of a subject.
  • neurodegenerative disorders and neural diseases such as dementias (e.g., senile dementia, memory disturbances/memory loss, dementias caused by neurodegenerative disorders (e.g., Alzheimer's, Parkinson's disease, Parkinson's disorders, Huntington's disease (Huntington's Chorea), Lou Gehrig's disease, multiple sclerosis, Pick's disease, Parkinsonism dementia syndrome), progressive subcortical gliosis, progressive supranuclear palsy, thalmic degeneration syndrome, hereditary aphasia, amyotrophic lateral sclerosis, Shy-Drager syndrome, and Lewy body disease; vascular conditions (e.g., infarcts, hemorrhage, cardiac disorders); mixed vascular and Alzheimer's; bacterial meningitis; Creutzfeld- Jacob Disease; and Cushing's disease.
  • dementias e.g., senile dementia, memory disturbances/memory loss
  • dementias caused by neurodegenerative disorders e.g.,
  • the disclosed embodiments also provide for the treatment of a nervous system disorder related to neural damage, cellular degeneration, a psychiatric condition, cellular (neurological) trauma and/or injury (e.g., subdural hematoma or traumatic brain injury), toxic chemicals (e.g., heavy metals, alcohol, some medications), CNS hypoxia, or other neurologically related conditions.
  • a nervous system disorder related to neural damage e.g., cellular degeneration, a psychiatric condition, cellular (neurological) trauma and/or injury (e.g., subdural hematoma or traumatic brain injury), toxic chemicals (e.g., heavy metals, alcohol, some medications), CNS hypoxia, or other neurologically related conditions.
  • the disclosed compositions and methods may be applied to a subject or patient afflicted with, or diagnosed with, one or more central or peripheral nervous system disorders in any combination. Diagnosis may be performed by a skilled person in the applicable fields using known and routine methodologies which identify and/or distinguish these nervous
  • Non-limiting examples of nervous system disorders related to cellular degeneration include neurodegenerative disorders, neural stem cell disorders, neural progenitor cell disorders, degenerative diseases of the retina, and ischemic disorders.
  • an ischemic disorder comprises an insufficiency, or lack, of oxygen or angiogenesis, and non- limiting example include spinal ischemia, ischemic stroke, cerebral infarction, multi-infarct dementia. While these conditions may be present individually in a subject or patient, the disclosed methods also provide for the treatment of a subject or patient afflicted with, or diagnosed with, more than one of these conditions in any combination.
  • Non-limiting embodiments of nervous system disorders related to a psychiatric condition include neuropsychiatric disorders and affective disorders.
  • an affective disorder refers to a disorder of mood such as, but not limited to, depression, post- traumatic stress disorder (PTSD), hypomania, panic attacks, excessive elation, bipolar depression, bipolar disorder (manic-depression), and seasonal mood (or affective) disorder.
  • Non-limiting embodiments include schizophrenia and other psychoses, lissencephaly syndrome, anxiety syndromes, anxiety disorders, phobias, stress and related syndromes (e.g., panic disorder, phobias, adjustment disorders, migraines), cognitive function disorders, aggression, drug and alcohol abuse, drug addiction, and drug-induced neurological damage, obsessive compulsive behavior syndromes, borderline personality disorder, non-senile dementia, post-pain depression, post-partum depression, and cerebral palsy.
  • Examples of nervous system disorders related to cellular or tissue trauma and/or injury include, but are not limited to, neurological traumas and injuries, surgery related trauma and/or injury, retinal injury and trauma, injury related to epilepsy, cord injury, spinal cord injury, brain injury, brain surgery, trauma related brain injury, trauma related to spinal cord injury, brain injury related to cancer treatment, spinal cord injury related to cancer treatment, brain injury related to infection, brain injury related to inflammation, spinal cord injury related to infection, spinal cord injury related to inflammation, brain injury related to environmental toxin, brain injury related to substance abuse, and spinal cord injury related to environmental toxin.
  • Non-limiting examples of nervous system disorders related to other neurologically related conditions include learning disorders, memory disorders, age-associated memory impairment (AAMI) or age-related memory loss, autism, learning or attention deficit disorders (ADD or attention deficit hyperactivity disorder, ADHD), narcolepsy, sleep disorders and sleep deprivation (e.g., insomnia, chronic fatigue syndrome), cognitive disorders, epilepsy, injury related to epilepsy, and temporal lobe epilepsy.
  • AAMI age-associated memory impairment
  • ADD attention deficit hyperactivity disorder
  • narcolepsy sleep disorders and sleep deprivation (e.g., insomnia, chronic fatigue syndrome), cognitive disorders, epilepsy, injury related to epilepsy, and temporal lobe epilepsy.
  • diseases and conditions treatable by the methods described herein include, but are not limited to, hormonal changes (e.g., depression and other mood disorders associated with puberty, pregnancy, or aging (e.g., menopause)); and lack of exercise (e.g., depression or other mental disorders in elderly, paralyzed, or physically handicapped patients); infections (e.g., HIV); genetic abnormalities (Down syndrome);
  • hormonal changes e.g., depression and other mood disorders associated with puberty, pregnancy, or aging (e.g., menopause)
  • lack of exercise e.g., depression or other mental disorders in elderly, paralyzed, or physically handicapped patients
  • infections e.g., HIV
  • genetic abnormalities Down syndrome
  • metabolic abnormalities e.g., vitamin B12 or folate deficiency
  • hydrocephalus memory loss separate from dementia, including mild cognitive impairment (MCI), age-related cognitive decline, and memory loss resulting from the use of general anesthetics, chemotherapy, radiation treatment, post-surgical trauma, or therapeutic intervention
  • diseases of the of the peripheral nervous system including but not limited to, PNS neuropathies (e.g., vascular neuropathies, diabetic neuropathies, amyloid neuropathies, and the like), neuralgias, neoplasms, myelin-related diseases, etc.
  • the disclosed methods provide for the application of Compound 1, optionally in combination with another mGluR2 and/or mGluR3 agent and/or another neurogenic agent, to treat a subject or patient for a condition due to the anti-neurogenic effects of an opiate or opioid based analgesic.
  • an opiate or opioid based analgesic such as an opiate like morphine or other opioid receptor agonist
  • the administration of a compound, optionally in combination with a neurogenic agent, with an opiate or opioid based analgesic would reduce the anti-neurogenic effect.
  • the disclosed embodiments include a method of treating post operative pain in a subject or patient by combining administration of an opiate or opioid based analgesic with a compound, optionally in combination with an mGluR2 and/or mGluR3 agent and/or a neurogenic agent.
  • the analgesic may have been administered before, simultaneously with, or after the compound, alone or in combination with a neurogenic agent.
  • the analgesic or opioid receptor agonist is morphine or another opiate.
  • PNS peripheral nervous system
  • PNS neuropathies e.g., vascular neuropathies, diabetic neuropathies, amyloid neuropathies, and the like
  • neuralgias e.g., neoplasms and myelin-related diseases as non-limiting examples.
  • a compound of this invention is in the form of compositions that include at least one pharmaceutically acceptable excipient.
  • suitable pharmaceutical excipients and formulations are known in the art and are described, for example, in
  • Pharmaceutical carriers may be chosen by a skilled person based upon the intended mode of administration of an mGluR2 and/or mGluR3 agonist, antagonist, Negative Allosteric Modulators (NAM), Positive Allosteric Modulators (PAM) or allosteric agonist.
  • the pharmaceutically acceptable carrier may include, for example, disintegrants, binders, lubricants, glidants, emollients, humectants, thickeners, silicones, flavoring agents, and water.
  • the compound may be incorporated with excipients and administered in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, or any other form known in the pharmaceutical arts.
  • the pharmaceutical compositions may also be formulated in a sustained release form. Sustained release compositions, enteric coatings, and the like are known in the art. Alternatively, the compositions may be a quick release
  • methods of treatment disclosed herein comprise the step of administering to the subject or patient the compound, optionally in combination with another agent, for a time and at a concentration sufficient to treat the condition targeted for treatment.
  • the disclosed methods can be applied to individuals having, or who are likely to develop, disorders relating to neural degeneration, neural damage and/or neural
  • a method comprises selecting a population or sub- population of patients, or selecting an individual patient, that is more amenable to treatment and/or less susceptible to side effects than other patients having the same disease or
  • a sub-population of patients is identified as being more amenable to neurogenesis by taking a cell or tissue sample from prospective patients, isolating and culturing neural cells from the sample, and determining the effect of a compound, optionally in combination with a neurogenic agent, on the degree or nature of neurogenesis, thereby allowing selection of patients for which the compound or combination has a substantial effect on neurogenesis.
  • the selection step(s) results in more effective treatment for the disease or condition that known methods using the same or similar compounds.
  • ChesEik ! ⁇ nnuia C i; ; ;6 0.
  • CheHskaS ofmuia ⁇ 5; ⁇ 3 ⁇ 40
  • CheHskaS ofmuia C ; ; ! O0;
  • reaction mixture was stirred at 100°C (bath temperature) for 6h using Dean-Stark apparatus. After complete consumption of starting material by TLC, reaction mixture was diluted with water (15mL) and extracted with ethyl acetate (3 x 25mL). The combined organic layer was washed with water (1 x 20mL), brine (1 x 20mL), dried over Na 2 S0 4 and concentrated under reduced pressure to afford 2.8g of light yellow color liquid (Intermediate 2) which was used in the next step without further purification.
  • MGS0039 a Potent and Selective Group II Metabotropic Glutamate Receptor Antagonist With Antidepressant-Like Activity, 46 Neuropharmacology 457 (2004) and Nakazato et al., Synthesis, In Vitro Pharmacology, Structure- Activity Relationships, and Pharmacokinetics of 3-Alkoxy-2-Amino-6-Fluorobicyclo[3.1.01Hexane-2,6-Dicarboxylic Acid Derivatives as Potent and Selective Group II Metabotropic Glutamate Receptor Antagonists, 47 J. Med. Chem.
  • hNSCs Human neural stem cells
  • Results are shown in Figure 1, which shows dose response curves of neuronal differentiation after background media values are subtracted.
  • the data is presented as a percent of neuronal positive control.
  • the data indicates that (lR,2R,3R,5R,6R)-6- ((((adamantane-l-carbonyl)oxy)methoxy)carbonyl)-2-amino-3-((3,4-dichlorobenzyl)oxy)-6- fluorobicyclo[3.1.0]hexane-2-carboxylic acid promoted neuronal differentiation.
  • Compound 4, Compound 5 and Compound 1 were dosed at 10 mg/kg to fasted rats.
  • the dosing solution comprised the Compound being tested, 20%> 2-hydroxypropyl-beta- cyclodextrin ( ⁇ - ⁇ -CD) /0.03NHC1 in water. Following dosing of the compounds they were absorbed and metabolized in vivo to deliver Compound 2. Plasma samples were drawn and analyzed for Compound 2 (active drug).
  • the pharmacokinetic data for Compound 2 following 10 mg/kg administration in rat is provided in Figures 2, 3, 4, 11 and 12. This data is also provided in Table 1.
  • Human plasma protein (pooled from a minimum of 3 donors, mixed gender) containing sodium heparin was pH adjusted to 7.4 and the test compound added at ⁇ . The mixture was then subjected to equilibrium dialysis using a Teflon dual chamber microdialysis apparatus at 37°C for >22 hours. Warfarin was used as a positive control and the experiments were performed in duplicate. The supernatant from each compartment was then analyzed by LC-MS/MS for the amount of test compound, the amount of Compound 2 and warfarin. Calibration standards were prepared identically using matched matrix. The data is expressed as % protein bound.
  • the AUC of Compound 2 is increased by approximately 21% for Compound 4 and 28% for Compound 1 compared to Compound 3. In contrast, the AUC of Compound 2 is decreased by 72% after dosing with Compound 5 as compared to Compound 3.
  • the bioavailability of Compound 2 following Img of Compound 4 is shown in Table 6.
  • the bioavailability of Compound 1 is about 50% higher than Compound 4, the bioavailability Compound 4 is about the same as the bioavailability of Compound 3 and the bioavailability of Compound 5 is significantly reduced compared to the other three compounds.
  • Compound 4 dosing when compared to that obtained following dosing of Compound 3.
  • the increase in Cmax would be expected to result in higher initial brain concentrations and, as for rat, the brain drug concentration is expected to have a long half-life.

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Abstract

La présente invention concerne un nouveau composé, des procédés de synthèse du composé, des compositions contenant le composé, et des procédés d'utilisation du composé ou de la composition pour traiter et/ou prévenir des maladies et/ou des états du système nerveux central et périphérique.
PCT/US2012/054898 2011-10-25 2012-09-12 Nouveaux composés et compositions à base de ceux-ci pour traiter des troubles du système nerveux WO2013062680A1 (fr)

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WO2015175531A1 (fr) * 2014-05-12 2015-11-19 Steerwasher, Llc Compositions et méthodes pour le traitement de troubles dépressifs
WO2017183734A1 (fr) 2016-04-18 2017-10-26 Taisho Pharmaceutical Co., Ltd. Promédicament de dérivé d'acide aminé
WO2020018670A1 (fr) * 2018-07-17 2020-01-23 Board Of Regents, The University Of Texas System Composés utiles en tant qu'inhibiteurs de l'indoléamine 2,3-dioxygénase et/ou de la tryptophane dioxygénase
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015175531A1 (fr) * 2014-05-12 2015-11-19 Steerwasher, Llc Compositions et méthodes pour le traitement de troubles dépressifs
WO2017183734A1 (fr) 2016-04-18 2017-10-26 Taisho Pharmaceutical Co., Ltd. Promédicament de dérivé d'acide aminé
KR20180134892A (ko) 2016-04-18 2018-12-19 다이쇼 세이야꾸 가부시끼가이샤 아미노산 유도체의 전구약물
US10464884B2 (en) 2016-04-18 2019-11-05 Taisho Pharmaceutical Co., Ltd. Prodrug of amino acid derivative
US10689327B2 (en) 2016-04-18 2020-06-23 Taisho Pharmaceutical Co., Ltd. Prodrug amino acid derivative
US11173145B2 (en) 2017-01-17 2021-11-16 Board Of Regents, The University Of Texas System Compounds useful as inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan dioxygenase
WO2020018670A1 (fr) * 2018-07-17 2020-01-23 Board Of Regents, The University Of Texas System Composés utiles en tant qu'inhibiteurs de l'indoléamine 2,3-dioxygénase et/ou de la tryptophane dioxygénase
US11046649B2 (en) 2018-07-17 2021-06-29 Board Of Regents, The University Of Texas System Compounds useful as inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan dioxygenase

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