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WO2023218423A1 - Indazoles et leur utilisation dans des méthodes de traitement d'affections sensibles au 5-ht2 - Google Patents

Indazoles et leur utilisation dans des méthodes de traitement d'affections sensibles au 5-ht2 Download PDF

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WO2023218423A1
WO2023218423A1 PCT/IB2023/054940 IB2023054940W WO2023218423A1 WO 2023218423 A1 WO2023218423 A1 WO 2023218423A1 IB 2023054940 W IB2023054940 W IB 2023054940W WO 2023218423 A1 WO2023218423 A1 WO 2023218423A1
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compound
formula
hydrogen
optionally substituted
iii
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Graham Johnson
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Eleusis Therapeutics US Inc
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Eleusis Therapeutics US Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention features compositions and methods for treating 5-HT2 responsive conditions.
  • BACKGROUND OF THE INVENTION Significant interest in the therapeutic application of 5-HT2 receptor ligands has developed, based upon evidence of possible therapeutic effects in a wide array of 5-HT2 responsive conditions (e.g., mitigating or improving conditions and disorders via 5-HT2 receptor target modulation), including psychiatric conditions, pain disorders, immunological conditions, and neurological conditions.
  • 5-HT2 responsive conditions e.g., mitigating or improving conditions and disorders via 5-HT2 receptor target modulation
  • psychiatric conditions e.g., mitigating or improving conditions and disorders via 5-HT2 receptor target modulation
  • the present invention discloses a new chemotype class of ligands of the 5-HT2 receptors that have potent pharmacological properties. Also provided are methods of using the compounds or compositions of the invention, e.g., for treating an inflammatory or a neurological disorder in a subject in need thereof.
  • An aspect of the invention features a compound of any one of formulas (I)-(III), or a pharmaceutically acceptable salt or zwitterion, hydrate, ester, co-crystal or prodrug thereof: (II) wherein, X is N for formulae (I) and (II); and N(CH3) for formula (III); ; R 3 is hydrogen, OH, optionally substituted O-alkaryl, optionally substituted O-alkyl, OPO 3 H 2 , O-acyl, OCH3, OCH2CH3, ; R 9 is C2-7 heterocyclyl, optionally substituted C6-12 aryl, optionally substituted C7-14 alkaryl, optionally substituted C 3-10 alkheterocyclyl, or optionally substituted C 1-8 heteroalkyl; R 11 is H or methyl, the latter being in either the R or S stereochemical configuration; and R 12 is H, optionally substituted C 1 -C 8 alkyl, optionally substituted C2-7 heterocyclyl, optionally
  • R 12 when R 12 is H, R 3 is not OH.
  • formula (III) does not include the compound: Compound S)
  • above definition e.g. disclaiming Compounds (S)
  • the compound of formula (I) is selected from: , , or a phar
  • the compound of formula (I) is selected from: , or a In particular embodiments, the compound of formula (II) is selected from: , or a In , or a In a particular embodiment of formula (I), (II), or (III)
  • R 3 is: . , , , a halogen.
  • the halogen is F, Cl, Br, I, or At.
  • R 3 is hydrogen, OH, O-Benzyl, or OMe.
  • R 3 is OPO 3 H 2.
  • R 4 is hydrogen, or OCH 3 .
  • R 5 is hydrogen, or OH
  • R 9 is hydrogen, or CH3.
  • R 10 is hydrogen, or CH 3 .
  • R 11 is hydrogen, or CH 3 .
  • R 12 is hydrogen, or CH3.
  • compounds meeting the above definition may be referred to as compounds of formula (I)a or (III)a respectively.
  • a compound of formula (I)a wherein R 3 is OH or OCH 3 ; and R 10 is CH 3 .
  • R 3 is OH or OCH3; and R 10 is H.
  • a compound of formula (I)a wherein R 3 is OH; and R 10 is hydrogen or CH3.
  • a compound of formula (III)a wherein R 3 is OH, OCH 3 , or O-Benzyl; and R 12 is CH3.
  • a compound of formula (III)a wherein R 3 is OH or OCH 3 ; and R 12 is CH 3 .
  • R 3 is OH or O-Benzyl; and R 12 is H.
  • R 12 is hydrogen, R 3 is not OH.
  • the invention includes a composition of any of the preceding aspects (e.g., a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt or zwitterion or prodrug thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition can be formulated, e.g., for oral, intranasal, subcutaneous, intramuscular, parenteral, topical, intraocular or pulmonary administration.
  • Such a pharmaceutical composition may be formulated as an orally disintegrating tablet.
  • Such a composition may comprise an amorphous or crystalline form of any of the compounds of any of the aspects and/or embodiments disclosed herein.
  • the compound may be present as crystalline polymorphic form.
  • a method of treating 5-HT2 responsive conditions in a subject in need thereof including administering to the subject a therapeutically effective amount of the compound or the pharmaceutical composition of any of the preceding aspects.
  • the 5-HT2 responsive condition is an inflammatory or neurological disorder.
  • the 5-HT2 responsive condition is an inflammatory disorder selected from asthma, chronic obstructive pulmonary disease, neuroinflammation, rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes, inflammatory bowel disease, Crohn’s disease, multiple sclerosis, septicemia, conjunctivitis, Alzheimer’s disease, or any inflammatory condition described herein.
  • a method of treating a psychological condition in a subject in need thereof the method including administering to the subject a therapeutically effective amount of the compound or the pharmaceutical composition of any of the preceding aspects.
  • the psychological condition is depression, anxiety, addiction, post-traumatic stress disorder, an eating disorder, compulsive behavior, autism spectrum disorders, or any psychological condition described herein.
  • a method of treating chronic pain in a subject in need thereof including administering to the subject a therapeutically effective amount of the compound or the pharmaceutical composition of any of the preceding aspects.
  • the described composition of matter embodies a new chemotype class of ligands targeting the 5-HT2 receptors that offers structural differentiation from previously known chemotype ligand classes for these receptors, namely substituted phenethylamines, lysergamides, and tryptamines non exhaustively.
  • the compound can be administered by any suitable route of administration, e.g., orally, intranasally, or by inhalation.
  • the present compound or pharmaceutical composition thereof is administered by one or more of a variety of routes, including nasal, buccal, oral, by inhalation (e.g., as an oral spray, nebulizer, nasal spray, or aerosol), intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (e.g., by powders, ointments, creams, gels, lotions, and/or drops), mucosal, enteral, vitreal, intratumoral, sublingual; by intratracheal instillation, bronchial instillation, and/or through a portal vein catheter.
  • routes including nasal, buccal, oral, by inhalation (e.g., as an oral spray, nebulizer, nasal spray, or aerosol), intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular,
  • the composition is administered by systemic intravenous injection. In specific embodiments the composition is administered intravenously and/or orally.
  • a compound as described herein for use as a medicament optionally wherein the medicament is for the treatment of a condition disclosed herein (e.g. treating 5-HT2 responsive conditions).
  • a compound as described herein for the manufacture of a medicament optionally wherein the medicament is for the treatment of a condition disclosed herein (e.g. treating 5-HT2 responsive conditions).
  • Compound C for use in a method of treatment which selectively activates the 5-HT2A receptor subtype.
  • Compound F for use in a method of treatment which selectively activates the 5-HT2A receptor subtype.
  • Compound G for use in a method of treatment which selectively activates the 5-HT2A receptor subtype.
  • Compound O for use in a method of treatment which selectively activates the 5-HT2A receptor subtype.
  • Compound Q for use in a method of treatment which selectively activates the 5-HT2A receptor subtype.
  • substituents of compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure include each and every individual subcombination of the members of such groups and ranges.
  • C1-8 alkyl is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C 5 alkyl, C 6 alkyl, C 7 alkyl, and C 8 alkyl.
  • a phrase of the form “optionally substituted X” is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein the alkyl is optionally substituted”). It is not intended to mean that the feature “X” (e.g., alkyl) per se is optional.
  • the terms “alkyl” and the prefix “alk-” are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e., cycloalkyl, and combinations thereof. Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 6 ring carbon atoms, inclusive.
  • Exemplary cyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.
  • the C1-8 alkyl group may be substituted or unsubstituted.
  • Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, cyano, nitrilo, NH-acyl, amino, aminoalkyl, disubstituted amino, C 2-7 heterocyclyl, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
  • C 1-8 alkyls include, without limitation, methyl; ethyl; n-propyl; isopropyl; cyclopropyl; cyclopropylmethyl; cyclopropylethyl; n-butyl; iso-butyl; sec-butyl; tert-butyl; cyclobutyl; cyclobutylmethyl; cyclobutylethyl; n- pentyl; cyclopentyl; cyclopentylmethyl; cyclopentylethyl; 1-methylbutyl; 2-methylbutyl; 3-methylbutyl; 2,2- dimethylpropyl; 1-ethylpropyl; 1,1-dimethylpropyl; 1,2-dimethylpropyl; 1-methylpentyl; 2-methylpentyl; 3- methylpentyl; 4-methylpentyl; 1,1-dimethylbutyl; 1,2-dimethylbutyl; 1,3-dimethylbut
  • An alkylene is a divalent alkyl group.
  • C 2-8 alkenyl is meant a branched or unbranched hydrocarbon group containing one or more double bonds and having from 2 to 8 carbon atoms.
  • a C2-8 alkenyl may optionally include monocyclic or polycyclic rings, in which each ring desirably has from three to six members.
  • the C2-8 alkenyl group may be substituted or unsubstituted.
  • substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, cyano, nitrilo, NH-acyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
  • C2-8 alkenyls include, without limitation, vinyl; allyl; 2-cyclopropyl-1-ethenyl; 1-propenyl; 1-butenyl; 2-butenyl; 3-butenyl; 2-methyl-1- propenyl; 2-methyl-2-propenyl; 1-pentenyl; 2-pentenyl; 3-pentenyl; 4-pentenyl; 3-methyl-1-butenyl; 3- methyl-2-butenyl; 3-methyl-3-butenyl; 2-methyl-1-butenyl; 2-methyl-2-butenyl; 2-methyl-3-butenyl; 2-ethyl- 2-propenyl; 1-methyl-1-butenyl; 1-methyl-2-butenyl; 1-methyl-3-butenyl; 2-methyl-2-pentenyl; 3-methyl-2- pentenyl; 4-methyl-2-pentenyl; 2-methyl-3-pentenyl; 3-methyl-3-pentenyl; 2-methyl-3-pentenyl; 4-methyl-2-penteny
  • C2-8 alkenyl has a cis configuration around the double bond.
  • C 2-7 heterocyclyl is meant a stable 5- to 7-membered monocyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated, partially unsaturated, or unsaturated (aromatic), and which consists of 2 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclyl group may be substituted or unsubstituted.
  • substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxy, fluoroalkyl, perfluoralkyl, cyano, nitrilo, NH-acyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized.
  • the heterocyclic ring may be covalently attached via any heteroatom or carbon atom which results in a stable structure, e.g., an imidazolinyl ring may be linked at either of the ring-carbon atom positions or at the nitrogen atom.
  • a nitrogen atom in the heterocycle may optionally be quaternized.
  • Heterocycles include, without limitation, 1H-indazole, 2- pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H- quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazoly
  • Preferred 5 to 10 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, 1H- indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl.
  • Preferred 5 to 6 membered heterocycles include, without limitation, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl.
  • C6-12 aryl is meant an aromatic group having a ring system comprised of carbon atoms with conjugated ⁇ electrons (e.g., phenyl). The aryl group has from 6 to 12 carbon atoms.
  • Aryl groups may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members.
  • the aryl group may be substituted or unsubstituted.
  • Exemplary subsituents include alkyl, hydroxy, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, fluoroalkyl, carboxyl, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, monosubstituted amino, disubstituted amino, and quaternary amino groups.
  • C7-14 alkaryl is meant an alkyl substituted by an aryl group (e.g., benzyl, phenethyl, or 3,4- dichlorophenethyl) having from 7 to 14 carbon atoms.
  • C3-10 alkheterocyclyl is meant an alkyl substituted heterocyclic group having from 7 to 14 carbon atoms in addition to one or more heteroatoms (e.g., 3-furanylmethyl, 2-furanylmethyl, 3- tetrahydrofuranylmethyl, or 2-tetrahydrofuranylmethyl).
  • C1-8 heteroalkyl is meant a branched or unbranched alkyl, alkenyl, or alkynyl group having from 1 to 8 carbon atoms in addition to1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O, S, and P.
  • Heteroalkyls include, without limitation, tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates, sulfonamides, and disulfides.
  • a heteroalkyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has three to six members.
  • the heteroalkyl group may be substituted or unsubstituted.
  • substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, cyano, nitrilo, NH-acyl, amino, aminoalkyl, disubstituted amino, quaternary amino, C2-7 heterocyclyl, hydroxyalkyl, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
  • C1-8 heteroalkyls include, without limitation, methoxymethyl and ethoxyethyl.
  • halide is meant bromine, chlorine, iodine, or fluorine.
  • fluoroalkyl is meant an alkyl group that is substituted with one or more fluorine atoms.
  • carboxyalkyl is meant a chemical moiety with the formula -(R)-COOH, wherein R is selected from C 1-8 alkyl, C 2-7 heterocyclyl, C 6-12 aryl, C 7-14 alkaryl, C 3-10 alkheterocyclyl, or C 1-8 heteroalkyl.
  • hydroxyalkyl is meant a chemical moiety with the formula -(R)-OH, wherein R is selected from C1-8 alkyl, C2-7 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-8 heteroalkyl.
  • alkoxy is meant a chemical substituent of the formula -OR, wherein R is selected from C1-8 alkyl, C 2-7 heterocyclyl, C 6-12 aryl, C 7-14 alkaryl, C 3-10 alkheterocyclyl, or C 1-8 heteroalkyl.
  • aryloxy is meant a chemical substituent of the formula -OR, wherein R is a C 6-12 aryl group.
  • alkylthio is meant a chemical substituent of the formula -SR, wherein R is selected from C1-8 alkyl, C2-7 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-8 heteroalkyl.
  • arylthio is meant a chemical substituent of the formula -SR, wherein R is a C 6-12 aryl group.
  • quaternary amino is meant a chemical substituent of the formula -(R)-N(R’)(R’’)(R’’’) + , wherein R, R’, R’’, and R’’’ are each independently an alkyl, alkenyl, alkynyl, or aryl group.
  • R may be an alkyl group linking the quaternary amino nitrogen atom, as a substituent, to another moiety.
  • the nitrogen atom, N is covalently attached to four carbon atoms of alkyl and/or aryl groups, resulting in a positive charge at the nitrogen atom.
  • acyl is meant a chemical moiety with the formula R-C(O)-, wherein R is selected from C1-8 alkyl, C2-7 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, or C1-8 heteroalkyl.
  • prodrug means a compound (e.g., a drug precursor) that is transformed in vivo to yield a compound of the instant Formulas. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W.
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group to form an ester or methylenedioxy-linked ester.
  • Suitable prodrug esters can include, for example, phosphate esters or acyl esters.
  • the prodrug ester is selected from phosphate esters of formula —P(O)(OH) 2 , — P(O)(OH)(O)(C 1 -C 6 alkyl), —P(O)(O)(C 1 -C 6 alkyl) 2 , either as directly linked phosphate esters or methyleneoxy-linked phosphate esters; C1-C6-alkanoyloxymethyl esters, dimethylamino acid esters, and C1-C6-alkanoyl esters (e.g., acetate esters), either as directly linked alkanoyl esters or methyleneoxy- linked alkanoyl esters.
  • a refers to a condition that arises as a response to a stressful event or situation of an exceptionally threatening or catastrophic nature, which is likely to cause pervasive distress in an individual (e.g., natural or man-made disaster, combat, serious accident, witnessing the violent death of others, or being the victim of torture, terrorism, rape, or other crime).
  • acute stress disorder is an anxiety disorder that involves a very specific reaction following exposure to a traumatic event or stressor.
  • duration of acute stress disorder is shorter than that for PTSD, such that the symptoms are present for at least one, two, or three days, but no more than four, five, or six weeks.
  • administration or “administering” refers to a method of giving a dosage of a compound or pharmaceutical composition to a subject.
  • disthymia or “dysthymic disorder” is meant a chronically depressed mood that occurs for most of the day, more days than not, for at least two years.
  • the mood may be irritable rather than depressed, and the required minimum duration is one year.
  • any symptom-free intervals last no longer than 2 months.
  • at least two of the following additional symptoms are present: poor appetite or overeating, insomnia or hypersomnia, low energy or fatigue, low self-esteem, poor concentration, or difficulty making decisions, and feelings of hopelessness.
  • the symptoms cause clinically significant distress or impairment in social, occupational (or academic), or other important areas of functioning.
  • dysthymia The diagnosis of dysthymia is not made if: the individual has ever had a manic episode, a mixed episode, a hypomanic episode; has ever met the criteria for a cyclothymic disorder; the depressive symptoms occur exclusively during the course of a chronic psychotic disorder (e.g., schizophrenia); or if the disturbance is due to the direct physiological effects of a substance or a general medical condition. After the initial two-years of dysthymic disorder, major depressive episodes may be superimposed on the dysthymic disorder ("double depression"). Diagnostic and Statistical Manual of Mental Disorders (OSM IV), American Psychiatric Press, 4th Edition, I 994.
  • OSM IV Diagnostic and Statistical Manual of Mental Disorders
  • the term “generalized anxiety disorder” refers to a condition characterized by excessive anxiety and worry (i.e., apprehensive expectation). Typically, the excessive anxiety and worry occur on more days than not for a period of time (e.g., one, two, three, or four months or more).
  • the anxiety and worry can be associated with (i) restlessness, feeling keyed up, or on edge; and/or (ii) muscle tension.
  • the anxiety and worry can be associated with (a) a marked avoidance of situations in which a negative outcome could occur; (b) a marked time and effort preparing for situations in which a negative outcome could occur; (c) a marked procrastination in behavior or decision-making due to worries; and (d) repeatedly seeking reassurance due to worries.
  • the anxiety, worry, or physical symptoms can cause clinically significant distress or impairment in social, occupational, or other important areas of functioning in many, but not necessarily all individuals with GAD.
  • Obsessive compulsive disorder As used herein, the terms “obsessive compulsive disorder,” “OCD,” and “anxiety and obsessive- compulsive spectrum disorders” refer to a condition characterized by obsessions and/or compulsions. Obsessions are recurrent and persistent thoughts, urges, or images that are experienced, at some time during the disturbance, as intrusive and unwanted and that usually cause marked anxiety or distress in which the appetite individual attempts to ignore or suppress such thoughts, urges, or images, or to neutralize them with some other thought or action (i.e., by performing a compulsion).
  • Compulsions are repetitive behaviors (e.g., hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) that the person feels driven to perform in response to an obsession, or according to rules that must be applied rigidly.
  • the behaviors or mental acts are aimed at preventing or reducing anxiety or distress, or preventing some dreaded event or situation; however, these behaviors or mental acts either are not connected in a realistic way with what they are designed to neutralize or prevent or are clearly excessive.
  • the obsessions or compulsions are time consuming (for example, take more than 1 hour a day), or cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
  • the term “pharmaceutically acceptable salt” refers to those salts of the compounds described herein that are suitable for pharmaceutical use.
  • Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008.
  • the salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately, e.g., by reacting the free base of the compound with a suitable organic acid or inorganic acid.
  • Panic disorder includes both panic disorder with agoraphobia and panic disorder without agoraphobia. Subjects with this condition can exhibit one or both of the following: (i) a persistent concern or worry about additional panic attacks or their consequences (e.g., losing control, having a heart attack, going crazy); and/or (ii) significant maladaptive change in behavior related to the attacks (e.g., behaviors designed to avoid having panic attacks), which may include agoraphobic avoidance.
  • post traumatic stress disorder and “PTSD” refer to a condition that arises as a delayed and/or protracted response to a stressful event or situation (either short- or long- lasting) of an exceptionally threatening or catastrophic nature, which is likely to cause pervasive distress in an individual (e.g., natural or man-made disaster, combat, serious accident, witnessing the violent death of others, or being the victim of torture, terrorism, rape, or other crime).
  • Predisposing factors such as personality traits (e.g., compulsive, asthenic) or previous history of neurotic illness may lower the threshold for the development of the condition or aggravate its course, but they are neither necessary nor sufficient to explain its occurrence.
  • PTSD is a less frequent and more enduring consequence of psychological trauma than the more frequently seen acute stress response.
  • PTSD has been recognized in the past as railway spine, stress syndrome, shell shock, battle fatigue, traumatic war neurosis, and post-traumatic stress syndrome.
  • Diagnostic symptoms include re-experiencing original trauma(s), by means of flashbacks or nightmares; avoidance of stimuli associated with the trauma; and increased arousal, such as difficulty falling or staying asleep, anger, and hypervigilance.
  • Formal diagnostic criteria DSM-V, DSM-IV, and/or ICD-9 require that the symptoms last more than one month and cause significant impairment in social, occupational, or other important areas of functioning (e.g., problems with work and/or relationships).
  • Formal diagnostic criteria can include: (i) intrusion symptoms that are associated with the traumatic event (e.g., (a) spontaneous or cued recurrent, involuntary, and intrusive distressing memories of the traumatic event; (b) recurrent distressing dreams in which the content and/or affect of the dream is related to the event; (c) dissociative reactions (e.g., flashbacks) in which the individual feels or acts as if the traumatic event were recurring (such reactions may occur on a continuum, with the most extreme expression being a complete loss of awareness of present surroundings; (d) intense or prolonged psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event; and/or (e) marked physiological reactions to reminders of the traumatic event); (ii) persistent avoidance of stimuli associated with the traumatic event (e.g., (a) thoughts, feelings, or physical sensations that arouse recollections of the traumatic event; (b) activities, places, physical reminders, or times (
  • Formal diagnostic criteria can further include that the duration of disturbance is more than a certain period of time (e.g., one month, three months, or six months) and that the disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.
  • the condition may show a chronic course over many years and a transition to an enduring personality change.
  • the three main symptoms associated with PTSD are (1) “reliving” the traumatic event, such as flashbacks, nightmares, intrusive thoughts, and recollections, (2) avoidance behaviors and emotional numbing, and (3) hypersensitivity such as an inability to sleep, anxious feelings, overactive startle response, hyperarousal, hypervigilance, irritability, and outbursts of anger.
  • psychological disorder and “psychological condition” refer to a condition characterized by a disturbance in one’s emotional or behavioral regulation that reflects a dysfunction in the psychological, biological, or developmental processes underlying mental function.
  • Psychological disorders include, but are not limited to depressive disorders (major depression, treatment resistant depression, melancholic depression, atypical depression, or dysthymia), anxiety disorders (end of life anxiety, generalized anxiety disorder, panic disorder, social anxiety, post-traumatic stress disorder, acute stress disorder, obsessive compulsive disorder, or social phobia), addictions (e.g., substance abuse, e.g., alcoholism, tobacco abuse, or drug abuse)), eating disorders (e.g., anorexia nervosa, bulimia nervosa, and binge eating disorder) and compulsive behavior disorders (e.g., primary impulse-control disorders or obsessive-compulsive disorder).
  • depressive disorders major depression, treatment resistant depression, melancholic depression, atypical depression,
  • Psychological disorders can be any psychological condition associated with one or more symptoms, e.g., somatic symptoms (e.g., chronic pain, anxiety disproportionate to severity of physical complaints, pain disorder, body dysmorphia, conversion (i.e., loss of bodily function due to anxiety), hysteria, or neurological conditions without identifiable cause), or psychosomatic symptoms (e.g., back pain, fibromyalgia, migraines, and chronic fatigue syndrome).
  • somatic symptoms e.g., chronic pain, anxiety disproportionate to severity of physical complaints, pain disorder, body dysmorphia, conversion (i.e., loss of bodily function due to anxiety), hysteria, or neurological conditions without identifiable cause
  • psychosomatic symptoms e.g., back pain, fibromyalgia, migraines, and chronic fatigue syndrome.
  • Psychological disorders also include repetitive body-focused behaviors, such as tic disorders (e.g., Tourette's Syndrome, trichotillomania, nail-biting, temporomandibular disorder, thumb-sucking, repetitive oral-digital, lip-biting, fingernail biting, eye-rubbing, skin-picking, or a chronic motor tic disorder).
  • tic disorders e.g., Tourette's Syndrome, trichotillomania, nail-biting, temporomandibular disorder, thumb-sucking, repetitive oral-digital, lip-biting, fingernail biting, eye-rubbing, skin-picking, or a chronic motor tic disorder.
  • development of a psychological disorder is associated with or characterized by a prodromal symptom, such as depressed mood, decreased appetite, weight loss, increased appetite, weight gain, initial insomnia, middle insomnia, early waking, hypersomnia, decreased energy, decreased interest or pleasure, self-blame, decreased concentration, indecision, suicidality, psychomotor agitation, psychomotor retardation, crying more frequently, inability to cry, hopelessness, worrying/brooding, decreased self-esteem, irritability, dependency, self-pity, somatic complaints, decreased effectiveness, helplessness, and decreased initiation of voluntary responses.
  • a prodromal symptom such as depressed mood, decreased appetite, weight loss, increased appetite, weight gain, initial insomnia, middle insomnia, early waking, hypersomnia, decreased energy, decreased interest or pleasure, self-blame, decreased concentration, indecision, suicidality, psychomotor agitation, psychomotor retardation, crying more frequently, inability to cry, hopelessness, worrying/brooding, decreased self-esteem, irritability, dependency
  • Subjects with this condition typically exhibit a marked fear or anxiety about one or more social situations in which the person is exposed to possible scrutiny by others. Examples include social interactions (e.g., having a conversation), being observed (e.g., eating or drinking), or performance in front of others (e.g., giving a speech).
  • social interactions e.g., having a conversation
  • being observed e.g., eating or drinking
  • performance in front of others e.g., giving a speech.
  • an individual with this condition (i) fears that he or she will act in a way, or show anxiety symptoms that will be negatively evaluated (i.e., be humiliating, embarrassing, lead to rejection, or offend others); (ii) the social situations almost invariably provoke immediate fear or anxiety; (iii) the social situations are avoided or endured with intense fear or anxiety; and (iv) the fear or anxiety is out of proportion to the danger posed by the social situation.
  • an effective amount of a compound is, for example, an amount sufficient to prevent, slow down, or reverse the progression of the disorder or condition as compared to the response obtained without administration of the compound.
  • the terms “treat,” “treating,” or “treatment” refer to administration of a compound or pharmaceutical composition for a therapeutic purpose.
  • a disorder or use for “therapeutic treatment” refers to administering treatment to a patient already suffering from a disease to ameliorate the disease or one or more symptoms thereof to improve the patient’s condition (e.g., by reducing one or more symptoms of a 5-HT2 responsive condition, such as inflammation, depression, anxiety, Alzheimer’s disease, etc.).
  • a 5-HT2 responsive condition such as inflammation, depression, anxiety, Alzheimer’s disease, etc.
  • the term “therapeutic” includes the effect of mitigating deleterious clinical effects of certain inflammatory processes (i.e., consequences of the inflammation, rather than the symptoms of inflammation).
  • the methods of the invention can be used as a primary prevention measure, i.e., to prevent a condition or to reduce the risk of developing a condition.
  • Prevention refers to prophylactic treatment of a patient who may not have fully developed a condition or disorder, but who is susceptible to, or otherwise at risk of, the condition.
  • the methods of the invention can be used either for therapeutic or prophylactic purposes.
  • unipolar depression or “major depressive disorder” is meant a clinical course that is characterized by one or more major depressive episodes in an individual without a history of manic, mixed, or hypomanic episodes.
  • unipolar depression is not made if: manic, mixed, or hypomanic episodes develop during the course of depression; if the depression is due to the direct physiological effects of a substance; if the depression is due to the direct physiological effects of a general medical condition; if the depression is due to a bereavement or other significant loss ("reactive depression”); or if the episodes are better accounted for by schizoaffective disorder and are not superimposed on schizophrenia, schizophreniform disorder, delusional disorder, or psychotic disorder. If manic, mixed, or hypomanic episodes develop, then the diagnosis is changed to a bipolar disorder. Depression may be associated with chronic general medical conditions (e.g., diabetes, myocardial infarction, carcinoma, and stroke).
  • chronic general medical conditions e.g., diabetes, myocardial infarction, carcinoma, and stroke.
  • unipolar depression is more severe than dysthymia.
  • the essential feature of a major depressive episode is a period of at least two15 weeks during which there is either depressed mood or loss of interest or pleasure in nearly all activities. In children and adolescents, the mood may be irritable rather than sad.
  • the episode may be a single episode or may be recurrent.
  • the individual also experiences at least four additional symptoms drawn from a list that includes changes in appetite or weight, sleep, and psychomotor activity; decreased energy; feelings of worthlessness or guilt; difficulty thinking, concentrating, or making decisions; or recurrent thoughts of death or suicidal ideation, plans, or attempts. Each symptom must be newly present or must have clearly worsened compared with the person's pre-episode status.
  • the symptoms must persist for most of the day, nearly every day, for at least two consecutive weeks, and the episode must be accompanied by clinically significant distress or impairment in social, occupational (or academic), or other important areas of functioning (Diagnostic and Statistical Manual of Mental Disorders (OSM IV), American Psychiatric Press, 4th Edition, 1994). Diagnostic guidance for psychological disorders can be found, for example, in the ICD-10 (The ICD-10 Classification of Mental and Behavioral Disorders: Diagnostic Criteria for Research, Geneva: World Health Organization, 1993) and the DSM-V (American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) Arlington, VA.; American Psychiatric Association, 2013).
  • ICD-10 The ICD-10 Classification of Mental and Behavioral Disorders: Diagnostic Criteria for Research, Geneva: World Health Organization, 1993
  • DSM-V American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) Arlington, VA.; American Psychiatric Association, 2013).
  • the invention features compounds of formula (I), (II), or (III).
  • the compounds are useful for treating 5-HT2 responsive conditions (e.g., inflammation, pain, depression, anxiety, PTSD, and Alzheimer’s disease).
  • the compounds can be resistant to metabolism (e.g., by monoamineoxidase degradation in vivo), and can exhibit a longer in-vivo half-life and hence longer lasting pharmacological effect.
  • Serotonin also referred to as 5-hydroxytryptamine or 5-HT
  • 5-HT is a neurotransmitter that has been strongly implicated in the pathophysiology and treatment of a wide variety of neuropsychiatric disorders.
  • these fourteen separate 5-HT receptors have been grouped into seven (7) pharmacological subtypes, designated 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7.
  • pharmacological subtypes designated 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7.
  • the receptors are grouped pharmacologically as follows: 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3A, 5-HT3B, 5-HT4, 5-HT5A, 5-HT6, 5-HT7.
  • all but one are members of the G-protein coupled receptor superfamily.
  • Serotonin receptors 5-HT1A, 5-HT1B, and 5- HT1D inhibit adenylate cyclase, and 5-HT2 receptors activate phospholipase C pathways, stimulating breakdown of polyphosphoinositides.
  • the 5-HT2 receptor belongs to the family of rhodopsin-like signal transducers that are distinguished by a seven-transmembrane configuration and functional linkage to G- proteins.
  • the 5-HT3 receptor family includes ligand-gated ion channel receptors that have four putative TMDs.
  • Serotonin regulates a wide variety of sensory, motor, and behavioral functions in the mammalian CNS, including behaviors such as learning and memory, sleep, thermoregulation, motor activity, pain, sexual and aggressive behaviors, appetite, neuroendocrine regulation, and biological rhythms. Serotonin has also been linked to pathophysiological conditions such as anxiety, depression, obsessive-compulsive disorders, schizophrenia, suicide, autism, migraine, emesis, alcoholism and neurodegenerative disorders.
  • This biogenic amine neurotransmitter is synthesized by neurons of the brain stem that project throughout the CNS, with highest density in basal ganglia and limbic structures (Steinbusch, 1984, In: Handbook of Chemical Neuroanatomy 3:68-125, Bjorklund et al., Eds., Elsevier Science Publishers, B. V.).
  • lymphocytes express type 2A, type 2B, type 2C, type 6 and type 7 on resting cells (Ameisen et al., 1989, J. Immunol. 142:3171- 3179; Stefulj et al., 2000, Brain, Behavior, and Immunity 14:219-224) and that the type 1A and type 3 receptors are up-regulated upon activation (Aune et al., 1993, J. Immunol. 151:1175-1183; Meyniel et al., 1997, Immunol. Lett. 55:151-160; Stefulj et al., 2000, Brain, Behavior, and Immunity 14:219-224).
  • WO 03/106660 discloses the use of fluphenazine, an antagonist of 5- HT(1B/1D) and 5-HT(2C) receptors, for inhibiting proliferation and inducing cell death in lymphocytes.
  • the new chemotypes of the invention may be screened for activity at the various 5-HT subtypes or monoamine transporters as described in Example 2.
  • Compounds The invention features compounds of formula (I), (II), or (III).
  • compositions of any of the aforementioned compounds include tablets for oral use containing the compound in a mixture with non-toxic pharmaceutically acceptable excipients.
  • excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, sodium chloride, or lactose); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene
  • a pharmaceutically acceptable excipient is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% pure.
  • an excipient is approved for use in humans and for veterinary use.
  • an excipient is approved by United States Food and Drug Administration.
  • an excipient is pharmaceutical grade.
  • an excipient meets the standards of the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP), the British Pharmacopoeia, and/or the International Pharmacopoeia.
  • the pharmaceutical composition is prepared, packaged, and/or sold in a formulation suitable for pulmonary administration, e.g., via a nebulizer.
  • a formulation may include dry particles that include the active ingredient in the form of dry powders for administration using a device including a dry powder reservoir to which a stream of propellant may be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device including the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container.
  • compositions may be in the form of tablets and/or lozenges made using conventional methods, and may contain from 0.1% to 60% (w/w) active ingredient, the balance including an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein.
  • Pharmaceutical compositions for oral use may also be presented as chewable tablets, or as hard gelatin capsules in which the compound is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium phosphate, or kaolin), or as soft gelatin capsules wherein the compound is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent e.g., potato starch, lactose, microcrystalline cellulose, calcium phosphate, or kaolin
  • an oil medium for example, peanut oil, liquid paraffin, or olive oil.
  • Methods of treating 5-HT2 responsive conditions include administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the invention.
  • the exact amount of the compound or composition required for therapeutic effect can vary from subject to subject, depending on the species, age, weight, and general condition of the subject, the severity of the disease, the particular composition, its mode of administration, its mode of activity, and the like.
  • Pharmaceutical compositions in accordance with the present disclosure are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment.
  • compositions described herein may be administered to subjects, such as human patients or, alternatively, to other mammals, such as domesticated animals, cats, dogs, mice, or rats. Compositions described herein may be administered by any route.
  • the present compound or pharmaceutical composition thereof is administered by one or more of a variety of routes, including nasal, buccal, oral, by inhalation (e.g., as an oral spray, nasal spray, or aerosol), intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (e.g., by powders, ointments, creams, gels, lotions, and/or drops), mucosal, enteral, vitreal, intratumoral, sublingual; by intratracheal instillation, bronchial instillation, and/or through a portal vein catheter.
  • routes including nasal, buccal, oral, by inhalation (e.g., as an oral spray, nasal spray, or aerosol), intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intra
  • the composition is administered by systemic intravenous injection.
  • the composition is administered intravenously and/or orally.
  • a compound of the invention can be administered in a therapeutically effective amount (e.g., an amount that results in the desired therapeutic effect, e.g., within the therapeutic window between a dose sufficient to reduce inflammation and a dose that elicits a psychoactive effect (about a ten-fold difference)).
  • the compound is administered in an amount resulting in circulating drug plasma levels of less than 200 ng/mL (e.g., 0.5 to 200 ng/mL, e.g., 1 to 150 ng/mL, .5 to 100 ng/mL, or 10 to 50 ng/mL, e.g., 0.5 to 1 ng/mL, 1 to 2 ng/mL, 2 to 3 ng/mL, 3 to 4 ng/mL, 4 to 5 ng/mL, 5 to 10 ng/mL, 10 to 50 ng/mL, 50 to 100 ng/mL, 100 to 150 ng/mL, or 150 to 200 ng/mL, e.g., about 0.5 ng/mL, 1 ng/mL, 2 ng/mL, 5 ng/mL, 10 ng/mL, 20 ng/mL, 25 ng/mL, 50 ng/mL, 75 ng/mL, 100 ng/mL, e
  • the circulating drug plasma level of the compound is below the limit of detection (e.g., 0.1 ng/mL or less).
  • a therapeutically effective amount of the compound can be less than about 2000 ⁇ g/kg body weight (e.g., less than 1000 ⁇ g/kg, less than 500 ⁇ g/kg, less than 100 ⁇ g/kg, or less than 50 ⁇ g/kg body weight, e.g., from 100 to 2000 ⁇ g/kg body weight, e.g., from 100 to 500 ⁇ g/kg, from 500 to 1000 ⁇ g/kg, from 1000 to 1500 ⁇ g/kg, or from 1500 to 1000 ⁇ g/kg, e.g., about 500 ⁇ g/kg, about 1000 ⁇ g/kg, about 1500 ⁇ g/kg, or about 2000 ⁇ g/kg).
  • compositions in accordance with the present disclosure may be administered at dosage levels sufficient to deliver from about 0.0001 ⁇ g/kg to about 2 mg/kg, from about 0.01 ⁇ g/kg to about 500 ⁇ g/kg, from about 0.1 ⁇ g/kg to about 400 ⁇ g/kg, from about 0.5 ⁇ g/kg to about 30 ⁇ g/kg, from about 0.01 ⁇ g/kg to about 10 ⁇ g/kg, from about 0.1 ⁇ g/kg to about 10 ⁇ g/kg, from about 1 ⁇ g/kg to about 25 ⁇ g/kg, from about 25 ⁇ g/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.5 mg/kg, from about 1 mg/kg to about 2 mg/kg, or from about 1.5 mg/kg to about 2 mg/kg of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • the 5-HT2 responsive condition to be treated is a psychological condition.
  • the psychological condition may be any psychological condition described herein.
  • the psychological condition is depression, anxiety, addiction, post-traumatic stress disorder (PTSD), an eating disorder, or compulsive behavior.
  • the psychological condition may be depression.
  • the psychological condition may also be anxiety.
  • the anxiety may be experienced by a subject who is receiving palliative care or is enrolled in a hospice program.
  • the subject who is experiencing anxiety has symptoms such as hypervigilance, fatigue, racing thoughts, irritability, excessive worry, and/or fear.
  • a subject with a psychological condition may be diagnosed by a clinician, a physician, or a therapist.
  • the subject may be diagnosed with a psychological condition by evaluation of the subject’s symptoms by a physician, clinician, or therapist based on a physical examination.
  • a blood test may be used to evaluate blood concentration levels of certain biomarkers such as hormones, calcium, vitamin D, electrolytes, and iron in diagnosing depression.
  • a depression screening test may be performed by the physician, clinician, or therapist to aid in the diagnosis of depression.
  • the depression screening test may be the Patient Health Questionnaire-9 (PHQ-9), the Beck Depression Inventory (BDI), the Zung Self- Rating Depression Scale, the Center for Epidemiological Studies Depression Scale (CES-D), the Hamilton Rating Scale for Depression (HRSD), or the Montgomery-Asberg Depression Rating Scale (MADRS-C).
  • the methods described herein may be used to treat psychosomatic pain conditions.
  • the psychosomatic pain condition may be fibromyalgia, chronic fatigue, migraines, or back pain.
  • the patient is being treated for depression with a compound of formula (I), (II), or (III). The patient may have their symptoms of depression evaluated using a depression screening test.
  • the symptoms of depression may be evaluated by a clinician using the Clinical Global Impression (CGI) rating.
  • the depression screening test may be the Patient Health Questionnaire-9 (PHQ-9), the Beck Depression Inventory (BDI), the Zung Self-Rating Depression Scale, the Center for Epidemiological Studies Depression Scale (CES-D), the Hamilton Rating Scale for Depression (HRSD), and/or the Montgomery-Asberg Depression Rating Scale (MADRS).
  • the patient being treated for depression with a compound of formula (I) or (II) may have their symptoms of depression evaluated using the Montgomery- Asberg Depression Rating Scale (MADRS-C).
  • the patient evaluated using the MADRS-C by a clinician, physician, or third-party rater.
  • the patient may have their symptoms of anxiety evaluated using an anxiety screening test.
  • the anxiety screening test may be the Zung Self-Rating Anxiety Scale, the Hamilton Anxiety Scale, the Beck Anxiety Inventory, the Social Phobia Inventory, the Penn State Worry Questionnaire, the Yale- Brown Obsessive-Compulsive Scale, or the - General Anxiety Disorder-7.
  • the patient’s anxiety score using any one of these screening tests decreases in comparison to the patient’s score before receiving treatment.
  • the patient’s anxiety score using any one of the above screening tests decreases by 50% in comparison to the patient’s score before receiving treatment.
  • the patient meets fewer criteria for anxiety as described by the Diagnostic and Statistical Manual of Mental Disorders in comparison before receiving treatment.
  • the methods of the invention are used to treat psychological conditions, e.g., depression, anxiety, PTSD, an eating disorder, and compulsive behavior, by administering a compound of formula (I) or (II) as needed to treat the symptoms associated with the psychological condition.
  • Neurological Injuries e.g., depression, anxiety, PTSD, an eating disorder, and compulsive behavior
  • the 5-HT2 responsive condition to be treated is a neurological injury.
  • the neurological injury may be any neurological injury.
  • the neurological injury is a stroke, a traumatic brain injury, or a spinal cord injury.
  • the methods of treating a neurological injury described herein may reduce acute inflammation. In certain embodiments, hippocampal hyperactivity is reduced.
  • the methods described herein for treating a neurological injury may be administered in combination with a behavioral, physical, or speech therapy.
  • the methods of the invention are used to treat a neurological injury, e.g., stroke, traumatic brain injury, and spinal cord injury , by administering a compound of formula (I) or (II) as needed to pain, inflammation, and/or other symptoms associated with the neurological injury.
  • a neurological injury e.g., stroke, traumatic brain injury, and spinal cord injury
  • the 5-HT2 responsive condition to be treated is an inflammatory condition.
  • An inflammatory condition in a subject can be treated with a compound of formula (I), (II), (III) using the methods of the invention.
  • the inflammatory condition to be treated can be a lung inflammation (e.g., chronic obstructive pulmonary disease (COPD)), neuroinflammation (e.g., Alzheimer’s disease), chronic inflammation, rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes, inflammatory bowel disease, Crohn’s disease, conjunctivitis, multiple sclerosis, and/or septicemia.
  • inflammation is treated by administering a compound of formula (I), (II), or (III) as needed to treat (i) acute attacks of inflammation (e.g., inflammatory bowel disease), or (ii) chronic inflammatory conditions (e.g., arthritis).
  • a disorder or condition associated with cephalic pain can be treated with a compound of formula (I), (II), or (III) using the methods of the invention.
  • a disorder or condition associated with cephalic pain is a disorder or condition which has as one of its symptoms cephalic/head pain (e.g., headache).
  • disorders or conditions include trigeminal autonomic cephalalgias such as episodic and chronic cluster headache (CH), episodic and chronic paroxysmal hemicrania (PH), and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT).
  • disorders or conditions associated with cephalic pain include miscellaneous headache unassociated with a structural lesion, headache associated with a nonvascular intracranial disorder, headache associated with a non-cephalic infection, headache associated with a metabolic disorder, headache associated with a disorder of the cranium, neck, eyes, nose, sinuses, teeth, mouth, or other facial or cranial structure, nerve trunk pain and deafferentiation pain.
  • Example 1 Synthesis and characterization of Compounds (A)-(B). Compounds (A)-(B) can be synthesized according to Scheme 1 (details below). (B)
  • HATU (9.3 g, 24.4 mmol) was added to a mixture of 3-(tert-butoxycarbonyl(methyl) amino)propanoic acid (4.5 g, 22.2 mmol), N,O-Dimethylhydroxylamine hydrochloride (3.2 g, 33.2 mmol) and DIPEA (7.14 g, 55.4 mmol) in DMF (50 mL) at 0 °C. The mixture was stirred for 12 h at room temperature. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3 x 100 mL).
  • G ⁇ q-mediated calcium flux downstream of 5-HT2A receptor activation can be determined using HEK293 cells stably expressing the human 5-HT2A receptor.
  • Cells are seeded in DMEM supplemented with 10% fetal bovine serum, 100 units/mL penicillin, 100 mg/mL streptomycin, and 100 mg/mL ZeocinTM onto 96-well poly-D-lysine plates with clear bottoms (12,000 cells/well) and cultured at 37 ⁇ C. The following day, media is aspirated and replaced with serum-free DMEM for 12 h.

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Abstract

L'invention concerne des composés méthyléthanamine lié à l'indazole et azétidine lié à l'indazole comme ligands du récepteur 5-HT2 à petites molécules, et des compositions pharmaceutiques de ceux-ci utiles pour traiter des affections sensibles au 5-HT2, tels que l'arthrite, le diabète, l'inflammation et la dépression associées à la maladie d'Alzheimer. L'invention concerne également des procédés synthétiques de préparation de tels nouveaux composés indazole et des procédés d'utilisation des composés et/ou compositions de l'invention pour traiter des affections sensibles au 5-HT2 chez un sujet dont l'état le nécessite.
PCT/IB2023/054940 2022-05-12 2023-05-12 Indazoles et leur utilisation dans des méthodes de traitement d'affections sensibles au 5-ht2 Ceased WO2023218423A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022232233A1 (fr) * 2021-04-28 2022-11-03 Eleusis Therapeutics Us, Inc. Indoleazétidines et leur utilisation dans des procédés de traitement d'états sensibles à 5-ht2

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022232233A1 (fr) * 2021-04-28 2022-11-03 Eleusis Therapeutics Us, Inc. Indoleazétidines et leur utilisation dans des procédés de traitement d'états sensibles à 5-ht2

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM COMPOUND ANONYMOUS : "2-(1H-Indazol-3-yl)-N,Ndimethylethanamine", XP093110088, retrieved from PUBCHEM *
DATABASE PUBCHEM COMPOUND ANONYMOUS : "2-(1H-Indazol-3-yl)-Nmethylethanamine", XP093110094, retrieved from PUBCHEM *
DATABASE PUBCHEM COMPOUND ANONYMOUS : "3-[2-(methylamino)ethyl]-2Hindazol-4-ol", XP093110090, retrieved from PUBCHEM *
DATABASE PUBCHEM COMPOUND ANONYMOUS : "4-(Benzyloxy)-1h-indazole", XP093110096, retrieved from PUBCHEM *
DATABASE PUBCHEM COMPOUND ANONYMOUS : "N-(azetidin-3-yl)indazole", XP093110092, retrieved from PUBCHEM *
DATABASE PUBCHEM COMPOUND ANONYMOUS : "N-methyl-N-[(4-phenylmethoxy-2Hindazol-3-yl)methyl]butan-1-amine", XP093110097, retrieved from PUBCHEM *
DATABASE PUBCHEM COMPOUND ANONYMOUS ISABEL: "3-(azetidin-3-yl)-1H-indazole", XP093110098, retrieved from PUBCHEM *

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