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WO2025019529A1 - Antagonistes du récepteur sérotoninergique 5-ht 2b, leurs compositions pharmaceutiques et leurs procédés d'utilisation - Google Patents

Antagonistes du récepteur sérotoninergique 5-ht 2b, leurs compositions pharmaceutiques et leurs procédés d'utilisation Download PDF

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WO2025019529A1
WO2025019529A1 PCT/US2024/038286 US2024038286W WO2025019529A1 WO 2025019529 A1 WO2025019529 A1 WO 2025019529A1 US 2024038286 W US2024038286 W US 2024038286W WO 2025019529 A1 WO2025019529 A1 WO 2025019529A1
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methyl
alkyl
cyclopropyl
salt
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Kenneth A. Jacobson
Dilip K. Tosh
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US Department of Health and Human Services
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/24—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one nitrogen and one sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00—Compounds containing boron, silicon or a metal, e.g. chelates or vitamin B12

Definitions

  • Serotonin or 5 -hydroxy tryptamine, 5-HT is a neurotransmitter of the peripheral and central nervous systems (PNS and CNS). 5-HT is associated with mood disorders such as depression and schizophrenia as well as in controlling food intake, gastrointestinal function, cardiovascular function, cell development, drug seeking behavior, and pain.
  • the serotonin receptor 2 (5-HTz) subfamily consists of three subtypes: 5-HTZA, 5-HT2B, and 5-HT2C.
  • the 5-HT2B receptor is found in both the peripheral and central nervous system.
  • the 5-HT2B receptor binds the neurotransmitter serotonin and mediates many of the central and peripheral physiologic functions of serotonin.
  • 5-HT2B receptors regulate serotonin release via the serotonin transporter, and are important both to normal physiological regulation of serotonin levels in blood plasma, and with the abnormal acute serotonin release produced by drugs such as MDMA.
  • Some of the effects of serotonin on the CNS include presynaptic inhibition, neuronal sensitization to tactile stimuli, mediation of some of the effects of hallucinogenic substituted amphetamines, and behavioral modifications. It has been contemplated that 5-HTZB receptor antagonists would be useful in cardioprotection, liver protection, and central nervous system activity.
  • the invention provides compounds and compositions for treating various disease conditions, including fibrosis of the lung, liver, skin, and coronary, pulmonary arterial hypertension, valvular heart disease, pain, cancer, autoimmune diseases, and neuropathic pain of diverse states by selectively antagonizing 5-HT2B receptors relative to 5-HT2C receptors.
  • the compounds of the invention advantageously, do not reduce body core temperature.
  • the invention also provides methods of treating such diseases by the use of these compounds and compositions.
  • the present invention provides a compound of formula (I) or formula (II), a salt thereof, or an optical isomer thereof. wherein, in the compound of formula (I),
  • R 1 is selected from the group consisting of ary l, arylalkyl, cycloalky l, cycloalkyl alky l, di-cycloalkylalkyl, di-bicycloalkyl, tricycloalkyl, alky l, (cycloalkyl)(alkyl)alkylenyl, and H, wherein the aryl, alkyl, and cycloalkyl moieties can be optionally substituted with one or more of alkyd, halo, and cyano groups;
  • R 2 is selected from the group consisting of H, halo, alky Ithio, arylalky Ithio, heteroaryl, tetrahydropyrrolyl, cyano, and thienylalkyny 1, wherein each of said moieties, other than H and halo, can be optionally substituted with one or more of alkyl, halo, and cyano groups; and
  • Figures 1A-1B depict reaction schemes to produce compounds in accordance with an aspect of the invention.
  • Figures 2A-2J depict calcium efflux values for certain compounds in accordance with an aspect of the invention.
  • Figure 3 depicts preferred substituents for providing affinity to 5-HT2B receptors in accordance with an aspect of the invention.
  • Figure 4 depicts a reaction scheme to prepare compounds 47, 48, 94, and 95 in accordance with an aspect of the invention.
  • Figure 5 depicts a reaction scheme to prepare compounds 49 and 50 in accordance with an aspect of the invention.
  • Figure 6A depicts a reaction scheme to prepare compounds 51 and 54 in accordance with an aspect of the invention.
  • Figure 6B depicts a reaction scheme to prepare compounds 87 and 103 in accordance with an aspect of the invention.
  • Figure 7 depicts a reaction scheme to prepare compound 40. which is a compound of formula (I) and depicted as MRS 8209.
  • Figure 8 depicts a reaction scheme for the synthesis of 4’-cyano and difluoromethyl (N)-methanocarba adenosine derivatives in accordance with an aspect of the invention.
  • Figure 9 depicts a reaction scheme for the synthesis of 4’-aryl modified (N)- methanocarba adenosine derivatives in accordance with an aspect of the invention.
  • Figure 10A depicts that compound 40 (MRS8209) in accordance with an aspect of the invention advantageously does not reduce core body temperature or locomotor activity in wild type male mice at a dose of 1 mg/kg ip.
  • Figure 10B depicts that compound 40 (MRS 8209) in accordance with an aspect of the invention advantageously failed to reduce core body temperature or locomotor activity in wild type male mice at a dose of 3 mg/kg ip.
  • Figure 12 depicts a scheme for molecular interactions of an antagonist of the invention with the 5-hydroxytryptamine receptor 2A.
  • the present invention provides a compound of formula (I) or formula (II), a salt thereof, or an optical isomer thereof, wherein, in the compound of formula (I),
  • R 1 is selected from the group consisting of aryl, arylalkyd, cycloalky 1, cycloalkyl alkyl, di-cycloalkylalkyl, di-bicycloalkyl, tricycloalkyl, alkyl, (cycloalkyl)(alkyl)alkylenyl, and H, wherein the aryl, alkyl, and cycloalkyl moieties can be optionally substituted with one or more of alkyl, halo, and cyano groups;
  • R 2 is selected from the group consisting of H, halo, alkylthio, arylalkylthio, heteroaryl, tetrahydropyrrolyl, cyano, and thienylalkynyl, wherein each of said moieties, other than H and halo, can be optionally substituted with one or more of alkyl, halo, and cyano groups; and
  • R 3 is selected from the group consisting of optionally substituted 5 -membered aromatic heterocyclyl, 3-alkyl-l,2,4-oxadiazol-5-yl, triazolylalkyl, cyano, alkydaminocarbonyl, alkylaminothiocarbonyl, alkydoxy carbonyl, alkydoxythiocarbonyl, hydroxyalkyl, monohaloalkyl, dihaloalkyd, cyanoalkyl, and cyanothioalkyl; and
  • R 1 is cycloalkyl or di-cycloalkylalkyl
  • R 2 is halo
  • X is NH, O, S, Se or CH 2 .
  • R 3 is COXR 4 or CSXR 4 , and R 4 is H, alkyl, or alkyloxy;
  • R 3 is CH2OH and R 1 is H, alkyl, di-cycloalkyl alkyl, or (cycloalkyl)(alkyl)alkylenyl, then R 2 is not chloro or H;
  • R 3 is alkylaminocarbonyl and R 1 is di-cycloalkyl alkyl, or (chloro substituted aryl)alkyl, then R 2 is not chloro;
  • the invention provides a compound, a salt, or an optical isomer according to formula (I), wherein the aryl moiety of aryl and arylalkyl in R 1 is phenyl, biphenyl, naphthyl, anthracenyl, or pyrenyl.
  • R 1 is phenyl optionally substituted with one or more of alkyd, halo, and cyano groups.
  • the invention provides a compound, salt, or optical isomer according to formula (I) as described above, wherein R 3 is an optionally substituted 5-membered aromatic heterocyclyl.
  • R 3 is selected from the group consisting of thienyl, furyl, oxadiazolyl, diazolyl, thiazolyl, triazolyl, pyrazolyl, and pyrrolyl, each of which is optionally substituted with halo, 6
  • R 3 can be 3-alkyl- l,2,4-oxadiazol-5-yl or triazolylalkyl.
  • the invention provides a compound, a salt, or an optical isomer according to formula (I), wherein R 1 is selected from the group consisting of phenyl, phenylalkyl, halophenyl, dihalophenyl, halobenzyl, C3-C8 cycloalkyl, di-C3-C8 cycloalkyl C3- C8 alkyl, and C3-C8 alkyl; R 2 is selected from the group consisting of chloro, bromo, iodo, C1- C8 alkylthio, aryl C1-C8 alkylthio, heteroaryl, thienylalkynyl, pyrrolidinyl, and halothienylalkynyl; and R 3 is selected from the group consisting of 3-methyl-l,2,4-oxadiazol- 5-yl, cyano, hydroxy C1-C8 alkyl, cyano C1-
  • the invention provides a compound, salt, or optical isomer according to formula (I), wherein R 1 is selected from the group consisting of di-cyclopropylmethyl, di- bicyclobutylmethyl, di-bicyclopentylmethyl, di-bicyclohexylmethyl, (isopropyl)(cyclopropyl)methyl, (cyclopropyl)(cyclobutyl)methyl, and dicyclopentylmethyl.
  • R 2 is selected from the group consisting of methylthio, chloro, and iodo.
  • the invention provides a compound, salt, or optical isomer according to formula (I), wherein R 3 is selected from the group consisting of 3- methyl-l,2,4-oxadiazol-5-yl, cyano, dihalomethyl, hydroxymethyl, cyanomethyl, methylaminocarbonyl, trizolylmethyl, and cyanothiomethyl.
  • the invention provides compounds of formula (I) with the following structures:
  • the invention provides a compound, salt, or optical isomer wherein:
  • R 1 is , R 2 is Cl, and R 3 is CH2OH;
  • R 1 is , R 2 is H. and R 3 is CH2OH;
  • R 1 is di(cyclopropyl)methyL
  • R 2 is Cl
  • R 3 is CHF2;
  • R 1 is isopropyl(cyclopropyl)methyl (R), R 2 is Cl, and R 3 is CHF2;
  • R 1 is (cyclopropyl)(cyclobuty l)methyl (R), R 2 is I, and R 3 is CHF2;
  • R 1 is (cyclopropyl)(cyclobutyl)methyl (5), R 2 is I, and R 3 is CHF2; R 1 is m-chlorobenzyl, R 2 is I. and R 3 is CHF2;
  • R 1 is H, R 2 is Cl, and R 3 is CN;
  • R 1 is methyl, R 2 is I, and R 3 is CN;
  • R 1 is n-propyl, R 2 is I, and R 3 is CN;
  • R 1 is isopropyl(cyclopropyl)methyl (R), R 2 is Cl, and R 3 is CN;
  • R 1 is isopropyl(cyclopropyl)methyl (R), R 2 is I, and R 3 is CN;
  • R 1 is (cyclobutyl)(cyclopropyl)methyl (R).
  • R 2 is I. and R 3 is CN;
  • R 1 is (cyclobutyl)(cyclopropyl)methyl (R), R 2 is I, and R 3 is CH2SCN;
  • R 1 is (cyclobutyl)(cyclopropyl)methyl ( ⁇ S), R 2 is I, and R 3 is CN;
  • R 1 is (cyclobutyl)(cyclopropyl)methyl (R), R 2 is I, and R 3 is CH2CN;
  • R 1 is (cyclopropyl)(cyclobutyl)methyl (S), R 2 is I, and R 3 is CH2CN;
  • R 1 is cyclopentyl, R 2 is I, and R 3 is CN;
  • R 1 is cyclopentyl, R 2 is I, and R 3 is CH2CN;
  • R 1 is 3-difluorocyclopentyl (R), R 2 is I, and R 3 is CN;
  • R 1 is 3-difluorocyclopentyl (R), R 2 is I, and R 3 is CH2CN;
  • R 1 is 3-difluorocyclopentyl (S), R 2 is I, and R 3 is CN;
  • R 1 is 3-difluorocyclopentyl (5), R 2 is I, and R 3 is CH2CN;
  • R 1 is , R 2 is I, and R 3 is CN;
  • R 1 is bicyclo [1.1.2] butyl, R 2 is I, and R 3 is CH2CN;
  • R 1 is m-chlorobenzyl, R 2 is I, and R 3 is CN;
  • R 1 is m-chlorobenzyl, R 2 is I, and R 3 is CH2CN;
  • R 1 is Me, R 2 is 5-Cl-thien-2-yl, and R 3 is CN;
  • R 1 is nPr, R 2 is 5-Cl-thien-2-yl, and R 3 is CN;
  • R 1 is Me.
  • R 2 is 5-Cl-thien-2-yl -ethynyl, and R 3 is CN;
  • R 1 is H, R 2 is S-CH 2 Ph, and R 3 is CH2OH;
  • R 1 is Me, R 2 is S-CH2PI1, and R 3 is CH2OH;
  • R 1 is Me, R 2 is S-CH2PI1, and R 3 is CH2CN;
  • R 1 is (cyclopropyl)(cyclobutyl)methyl, R 2 is Cl, and R 3 is COOCH2CH3;
  • R 1 is H.
  • R 2 is 1. and R 3 is CONHCH3;
  • R 1 is Me, R 2 is I, and R 3 is CONHCH3;
  • R 1 is phenylethyl, R 2 is I, and R 3 is CONHCH3;
  • R 1 is Me, R 2 is 5-Cl-thien-2-yl, and R 3 is CONHCH3; R 1 is nPr, R 2 is 5-Cl-thien-2-yl, and R 3 is CONHCH3;
  • R 1 is Me.
  • R 2 is 5-Cl-thien-2-yl-ethynyl, and R 3 is CONHCH3;
  • R 1 is nPr, R 2 is 4-pyridyl, and R 3 is CONHCH3;
  • R 1 is Me, R 2 is I, and R 3 is COOCH2CH3; or
  • R 1 is (cyclopropyl)(isopropyl)methyl
  • R 2 is 5-Cl-thien-2-yl-ethynyl
  • R 3 is
  • R 1 is Me.
  • the invention provides a compound, salt, or optical isomer according to formula (I), wherein:
  • R 1 is Me, R 2 is Cl-thienyl-ethynyl, and R 3 is CH2CN;
  • R 1 is c-Bu, R 2 is I; and R 3 is CH2OH;
  • R 1 is c-Bu, R 2 is I, and R 3 is CN;
  • R 1 is c-Hex, R 2 is I, and R 3 is CH2OH;
  • R 1 is c-Hex, R 2 is I. and R 3 is CN;
  • R 1 is (CH 2 )2cPr, R 2 is I, and R 3 is CH2OH;
  • R 1 is (CH 2 )2cPr, R 2 is I, and R 3 is CN;
  • R 1 is (CH 2 ) 2 cPr, R 2 is I, and R 3 is CH2CN;
  • R 1 is (CH2)2cPr, R 2 is I, and R 3 is CH2CI;
  • R 1 is (CH2)2cPr, R 2 is I, and R 3 is CChEt;
  • R 1 is (CH 2 )2cPr, R 2 is I, and R 3 is CONHCH3;
  • R 1 is (CH 2 ) 2 cPr, R 2 is I, and R 3 is CH2SH;
  • R 1 is Ph, R 2 is I, and R 3 is CH2OH;
  • R 1 is Ph, R 2 is I, and R 3 is CN;
  • R 1 is Ph, R 2 is I, and R 3 is CH2CN;
  • R 1 is Ph, R 2 is I, and R 3 is CChEt;
  • R 1 is Ph
  • R 2 is Cl-thienyl-ethynyl
  • R 3 is CONHCH3
  • R 1 is (cyclobutyl)(cyclopropyl)methyl, R 2 is Cl-thienyl-ethynyl, and R 3 is CH2OH;
  • R 1 is (CH2)sPh.
  • R 2 is Cl-thienyl-ethynyl.
  • R 3 is CChEt
  • R 1 is (3-F-Ph), R 2 is I, and R 3 is CH2OH;
  • R 1 is (3-F-Ph), R 2 is I, and R 3 is CN;
  • R 1 is (3,5-diCl-Ph), R 2 is I, and R 3 is CH2OH;
  • R 1 is (3,5-F-Ph), R 2 is I, and R 3 is CN; R 1 is NH-(3,4-diCl-Ph), R 2 is I, and R 3 is CH2OH;
  • R 1 is (3,4-diCl-Ph), R 2 is I. and R 3 is CN;
  • R 1 is (3-Cl-Bn), R 2 is I, and R 3 is CN;
  • R 1 is (3-Cl-Bn), R 2 is I, and R 3 is CChEt;
  • R 1 is (3-Cl-Bn), R 2 is Cl-thienyl-ethynyl, and R 3 is CH2CN;
  • R 1 is pyrrolyl, R 2 is I, and R 3 is CH2OH;
  • R 1 is H, R 2 is I, and R 3 is N ;
  • R 1 is tetrahydropyrrolyl, R 2 is I, and R 3 is N ; O r
  • R 1 is (cyclopropyl)(cyclobutyl) (R), R 2 is I, and R 3 is
  • the present invention also provides a compound, salt, or optical isomer according to formula (II), wherein R 1 is selected from the group consisting of cycloalkyd or di-cycloalkylalkyl; R 2 is halo; and R 3 is CH2OH or COOR 4 , wherein R 4 is alkyl, more particularly, a compound of formula
  • alkyl means a straight-chain or branched alkyd substituent containing from, for example, 1 to about 6 carbon atoms, preferably from 1 to about 4 carbon atoms, more preferably from 1 to 2 carbon atoms.
  • substituents include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-buty l, pentyd, isoamyl, hexyl, and the like.
  • cycloalkyl means a cyclic alkyd substituent containing from, for example, about 3 to about 8 carbon atoms, preferably from about 4 to about 7 carbon atoms, and more preferably from about 4 to about 6 carbon atoms.
  • substituents include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • the cyclic alkyl groups may be unsubstituted or further substituted with alkyl groups such as methyl groups, ethyl groups, and the like.
  • halo or “halogen,” as used herein, means a substituent selected from Group VIIA, such as, for example, fluorine, bromine, chlorine, and iodine.
  • a range of the number of atoms in a structure is indicated (e.g., a C1-C12. Ci-Cs, Ci-C 6 , C1-C4. or C2-C12, C2-C8. C2-C6, C2-C4 alkyl, alkenyl, or alkynyl). it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used.
  • a range of 1- 8 carbon atoms e.g., Ci-Cs
  • 1-6 carbon atoms e.g., C1-C6
  • 1-4 carbon atoms e.g., C1-C4
  • 1-3 carbon atoms e.g., C1-C3
  • 2-8 carbon atoms e.g., C2-C8
  • any chemical group e.g., alkyl, alkylamino, etc.
  • any sub-range thereof e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 1-9 carbon atoms, 1-10 carbon atoms, 1-11 carbon atoms.
  • 1-12 carbon atoms 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 2-9 carbon atoms, 2-10 carbon atoms, 2-11 carbon atoms, 2-12 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3- 6 carbon atoms, 3-7 carbon atoms, 3-8 carbon atoms, 3-9 carbon atoms, 3-10 carbon atoms, 3-11 carbon atoms, 3-12 carbon atoms, 4-5 carbon atoms.
  • the compound or salt of formula (I) or formula (II) can have at least one asymmetric carbon atom.
  • the compound or salt can exist in the racemic form, in the form of its pure optical isomers, or in the form of a mixture wherein one isomer is enriched relative to the other.
  • the inventive compounds when the inventive compounds have a single asymmetric carbon atom, the inventive compounds may exist as racemates, i.e., as mixtures of equal amounts of optical isomers, i.e., equal amounts of two enantiomers, or in the form of a single enantiomer.
  • single enantiomer is intended to include a compound that comprises more than 50% of a single enantiomer (i.e., enantiomeric excess more than 60%, more than 70%, more than 80%, more than 90%, or up to 100% pure enantiomer).
  • single diastereomer is intended to mean a compound that comprises more than 50% of a single diastereomer (i.e., diastereomeric excess more than 60%, more than 70%, more than 80%, more than 90%, or up to 100% pure diastereomer).
  • the optical isomers of the compounds of the invention in particular those of formula (I), have optical isomerism at the N 6 group, not the entire molecule.
  • 7? and S' in this disclosure refer to the optical isomerism at the N 6 group.
  • pharmaceutically acceptable salt is intended to include nontoxic salts 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.
  • nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • suitable salts are found in Remington ’s Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, and Berge, S. M., at al., Journal of Pharmaceutical Science, 66, 1-19 (1977).
  • Suitable bases include inorganic bases such as alkali and alkaline earth metal bases, e.g., those containing metallic cations such as sodium, potassium, magnesium, calcium and the like.
  • suitable bases include sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate.
  • Suitable acids include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, benzene sulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, maleic acid, tartaric acid, fatty acids, long chain fatty acids, and the like.
  • Preferred pharmaceutically acceptable salts of inventive compounds having an acidic moiety include sodium and potassium salts.
  • Preferred pharmaceutically acceptable salts of inventive compounds having a basic moiety include hydrochloride and hydrobromide salts.
  • the compounds of the present invention containing an acidic or basic moiety are useful in the form of the free base or acid or in the form of a pharmaceutically acceptable salt thereof.
  • solvate refers to a molecular complex wherein the solvent molecule, such as the cry stallizing solvent, is incorporated into the crystal lattice. When the solvent incorporated in the solvate is water, the molecular complex is called a hydrate.
  • Pharmaceutically acceptable solvates include hydrates, alcoholates such as methanolates and ethanolates, acetonitrilates and the like. These compounds can also exist in polymorphic forms.
  • the present invention further provides a pharmaceutical composition comprising a compound of formula (I) or (II), salt, or optical isomer thereof, as described above and a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount, e.g., a therapeutically effective amount, including a prophylactically effective amount, of one or more of the aforesaid compounds, or salts thereof, of the present invention.
  • the pharmaceutically acceptable carrier can be any of those conventionally used and is limited only by chemico-physical considerations, such as solubility and lack of reactivity with the compound, and by the route of administration. It will be appreciated by one of skill in the art that, in addition to the following described pharmaceutical compositions; the compounds of the present invention can be formulated as inclusion complexes, such as cyclodextrin inclusion complexes, or liposomes.
  • compositions described herein for example, vehicles, adjuvants, excipients, or diluents, are well known to those who are skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one which is chemically inert to the active compounds and one which has no detrimental side effects or toxicity under the conditions of use.
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) pow ders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
  • Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Capsule forms can be of the ordinary' hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch.
  • Tablet forms can include one or more of lactose, sucrose, mannitol, com starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
  • Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
  • the compounds of the present invention alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation. These aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.
  • Formulations suitable for parenteral administration include aqueous and non- aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, glycerol ketals, such as 2,2-dimethyl-l,3-dioxolane- 4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxy methylcellulose, or emulsifying agents and other
  • Oils which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, com, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
  • suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and poly oxy ethylene-polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-beta-aminopropionates, and 2-alkyl-imidazoline quaternary 7 ammonium salts, and (3) mixtures thereof.
  • the parenteral formulations will typically contain from about 0.5 to about 25% by weight of the active ingredient in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity 7 of surfactant in such formulations ranges from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • HLB hydrophile-lipophile balance
  • parenteral formulations can be presented in unit-dose or multi- dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use.
  • sterile liquid carrier for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • the compounds of the present invention may be made into injectable formulations.
  • the requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy’ Practice, J. B. Lippincott Co., Philadelphia, Pa., Banker and Chalmers, eds., pages 238-250 (1982), wdASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986).
  • Topical formulations including those that are useful for transdermal drug release, are w ell-know n to those of skill in the art and are suitable in the context of the invention for application to skin.
  • Topically applied compositions are generally in the form of liquids, creams, pastes, lotions and gels. Topical administration includes application to the oral mucosa, which includes the oral cavity, oral epithelium, palate, gingival, and the nasal mucosa.
  • the composition contains at least one active component and a suitable vehicle or carrier. It may also contain other components, such as an anti-irritant.
  • the carrier can be a liquid, solid or semi-solid.
  • the composition is an aqueous solution.
  • the composition can be a dispersion, emulsion, gel, lotion or cream vehicle for the various components.
  • the primary vehicle is water or a biocompatible solvent that is substantially neutral or that has been rendered substantially neutral.
  • the liquid vehicle can include other materials, such as buffers, alcohols, glycerin, and mineral oils with various emulsifiers or dispersing agents as known in the art to obtain the desired pH. consistency and viscosity. It is possible that the compositions can be produced as solids, such as powders or granules. The solids can be applied directly or dissolved in water or a biocompatible solvent prior to use to form a solution that is substantially neutral or that has been rendered substantially neutral and that can then be applied to the target site.
  • the vehicle for topical application to the skin can include water, buffered solutions, various alcohols, glycols such as glycerin, lipid materials such as fatty acids, mineral oils, phosphoglycerides, collagen, gelatin and silicone based materials.
  • the compounds of the present invention may be made into suppositories by mixing with a variety of bases, such as emulsifying bases or water-soluble bases.
  • bases such as emulsifying bases or water-soluble bases.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.
  • the dose administered to a mammal, particularly, a human, in accordance with the present invention should be sufficient to effect the desired response.
  • Such responses include reversal or prevention of the adverse effects of the disease for which treatment is desired or to elicit the desired benefit.
  • dosage will depend upon a variety of factors, including the age, condition, and body weight of the human, as well as the source, particular type of the disease, and extent of the disease in the human.
  • the size of the dose will also be determined by the route, timing and frequency of administration as well as the existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular compound and the desired physiological effect. It will be appreciated by one of skill in the art that various conditions or disease states may require prolonged treatment involving multiple administrations.
  • Suitable doses and dosage regimens can be determined by conventional range- finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.
  • the present inventive method typically will involve the administration of about 0. 1 to about 300 mg of one or more of the compounds described above per kg body weight of the animal or mammal. j 00581
  • the therapeutically effective amount of the compound or compounds administered can vary depending upon the desired effects and the factors noted above.
  • dosages will be between 0.01 mg/kg and 250 mg/kg of the subject’s body weight, and more typically between about 0.05 mg/kg and 100 mg/kg, such as from about 0.2 to about 80 mg/kg, from about 5 to about 40 mg/kg or from about 10 to about 30 mg/kg of the subject’s body weight.
  • unit dosage forms can be formulated based upon the suitable ranges recited above and the subject’s body weight.
  • the term “unit dosage form” as used herein refers to a physically discrete unit of therapeutic agent appropriate for the subject to be treated.
  • dosages are calculated based on body surface area and from about 1 mg/m 2 to about 200 mg/m 2 , such as from about 5 mg/m 2 to about 100 mg/m 2 will be administered to the subject per day.
  • administration of the therapeutically effective amount of the compound or compounds involves administering to the subject from about 5 mg/m 2 to about 50 mg/m 2 , such as from about 10 mg/m 2 to about 40 mg/m 2 per day. It is currently believed that a single dosage of the compound or compounds is suitable, however a therapeutically effective dosage can be supplied over an extended period of time or in multiple doses per day.
  • unit dosage forms also can be calculated using a subject’s body surface area based on the suitable ranges recited above and the desired dosing schedule.
  • the present invention provides a method of antagonizing a 5-HT2B serotonin receptor in an animal in need thereof comprising administering a compound, salt, or isomer or a pharmaceutical composition as described above.
  • the present invention further provides a method of treating fibrosis of the lung, skin, coronary and or liver fibrosis, pulmonary arterial hypertension, valvular heart disease, pain, or cancer in an animal in need thereof, comprising administering a compound, salt, or isomer or a pharmaceutical composition as described above.
  • the present invention discloses use of a compound of formula (I) or (II), salt, or optical isomer as described above, or a pharmaceutical composition thereof, for antagonizing a 5-HT2B serotonin receptor in an animal in need thereof, in particular, for treating fibrosis of the lung, skin, coronary and or liver fibrosis, pulmonary arterial hypertension, valvular heart disease, pain, or cancer in an animal in need thereof.
  • j 00631 The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.
  • This example illustrates a method of synthesis of certain compounds of the present invention, as illustrated in FIG. 1.
  • the protected 6-chloro nucleoside precursors 57 and 58 were synthesized by a Mitsunobu reaction from methanocarba sugar 56.
  • Amination of the nucleobase 6 position with either ammonia or various dicycloalkyl-methylamines in the presence of DIPEA in isopropanol provided 2-C1 and 2-1 intermediates 59 - 64.
  • Silyl deprotection at the 5'-position of the nucleoside precursor with TBAF gave the isopropylidene-protected intermediates 65 - 68.
  • the 5 '-hydroxymethyl group was modified with different functional groups to give chloro derivatives (72, 73, using thionyl chloride), fluoro derivative (75, using DAST) or mesylated compounds 69 - 71 (using mesyl chloride).
  • 5 '-Chi oro-5 '-deoxy nucleosides (72, 73) were further transformed to various thioalkyl derivatives by a SN2 reaction with the appropriate sodium alkylthioate in DMF.
  • DAST direct fluorination reaction by DAST, some unwanted impurities often contaminated the desired product.
  • TLC analysis was carried out on glass sheets precoated with silica gel F254 (0.2 mm) from Sigma- Aldrich. The purity of final nucleoside derivatives was checked using a Hewlett ⁇ Packard 1100 HPLC equipped with a Zorbax SB- Aq 5 ⁇ m analytical column (50 ⁇ 4.6 mm; Agilent Technologies Inc., Palo Alto, CA, USA).
  • Mobile phase linear gradient solvent system, 5 mM TBAP (tetrabutylammonium dihydrogen phosphate): CH3CN from 80:20 to 0:100 in 13 min; the flow rate was 0.5 mL/min. Peaks were detected by UV absorption with a diode array detector at 230, 254, and 280 nm.
  • Diisopropyl azodicarboxylate (DIAD) (0.22 mL, 1.16 mmol) was added to a solution of triphenylphosphine (306 mg, 1.16 mmol) and 3-deaza-2,6- dichloro-purine (220 mg, 1.16 mmol) in dry THF (5 mL) at 0 °C and stirred at room temperature for 10 min.
  • a solution of compound 56 (256 mg, 0.58 mmol) in THF (2 mL) was added to the reaction mixture and stirred overnight at room temperature.
  • Compound 94 (84%) was prepared from compound 93a following the same method as for compound 90 (see Fig.4; Reagents and Conditions: (i) R 1 NH 2 .HCl, DIPEA, 2-propanol, rt; (ii) 10% TFA, MeOH, 70 o C).
  • Compound 95 (86%) was prepared from compound 93b following the same method as for compound 90 (Reagents and Conditions: (i) TEMPO, BAIB, CH 3 CN-H 2 O, rt; (ii) Deoxo- Fluor, CH2Cl2, rt; (iii) Dowex50, MeOH-H2O).
  • Deoxo-Fluor (0.21 mL, 45% solution in THF, 0.32 mmol) was added to a solution of compound 97 (prepared as reported, 975 mg, 0.16 mmol) in dry CH 2 Cl 2 and stirred overnight at room temperature (Reagents and Conditions: (i) TEMPO, BAIB, CH3CN-H2O, rt; (ii) Deoxo-Fluor, CH 2 Cl 2 , rt; (iii) Dowex50, MeOH-H 2 O).
  • TEMPO 8 mg, 0.05 mmol
  • iodine 201 m, 1.68 mmol
  • CH 2 Cl 2 5 mL
  • ammonium hydroxide solution 5 mL
  • Saturated solution of Na2S2O3 10 mL was added into the reaction mixture to quench the reaction and aqueous layer was extracted with CH 2 Cl 2 (3 times), dried (Na 2 SO 4 ), filtered and evaporated under vacuum.
  • Figure 8 depicts a reaction scheme to synthesize certain 4′-modified (N)- methanocarba-adenosine derivatives in accordance with an aspect of the invention.
  • Reagents and Conditions (i) R 1 NH2, DIPEA, 2-propanol, rt-70 o C; (ii) TBAF, THF, rt; (iii) TEMPO, I2, CH2Cl2, NH4OH, rt-60 o C; (iv) (a) TEMPO, BAIB, CH3CN, rt; (b) Deoxofluoro or DAST, CH2Cl2, rt; (v) acetone cyanohydrin, Ph3P, DIAD, THF, rt; (vi) (a) MsCl, pyridine, rt; (b) KSCN, DMF, 80 o C; (vii) 2H-1,2,3-triazole, Ph3P, DIAD, THF,
  • Figure 9 depicts a reaction scheme to synthesize certain 4’-aryl derivatives in accordance with another aspect of the invention.
  • Reagents and Conditions (i) TEMPO, BAIB, CH 3 CN-H 2 O rt; (ii) DCC, N'-hydroxyacetimidamide, DMF, 90 o C; (iii) 10% TFA, MeOH, 70 o C.
  • EXAMPLE 2 This example illustrates the binding affinities of some of the compounds of the invention. The binding affinity at the three human (h) 5-HT 2 Rs and 2 - 3 subtypes of hARs was determined as reported in Tosh et al.2016. The compounds showed weak binding at the 5-HT 2A R.
  • N 6 -alkyl, cycloalkyl or dicycloalkylmethyl group was required for binding at 5- HT2Rs, as indicated by the inactivity of 6-NH2 derivatives 9 and 10, which nevertheless displayed AR affinity.
  • N 6 -dicycloalkylmethyl 4′-CH 2 OH analogues with the same (Cl) substitution at the C2 position, with increasing the cycloalkyl ring size from 3 to 5 carbons, there was a progression toward lower 5-HT 2B R affinity (Ki, nM): 4 (11) > 18 (136) > 24 (797).
  • the 5-HT2BR affinity varied according to asymmetric N 6 substitution: (R)-cyclobutyl-cyclopropyl) (42, Ki 77 nM) > ((R)- cyclopropyl-prop-2-yl) (37, Ki 163 nM) analogues (both being 2-Cl-4′-CH2OH analogues).
  • the 5-HT 2B R affinity improved significantly in both cases (43, 17 nM; 38, 82 nM, respectively).
  • the 5 HT2BR affinity improved 2 fold for dicyclobutyl analogue 19 (80 nM) compared to 18 but remained the same for the dicyclopropyl 11 (11.2 nM) analogue compared to 4.
  • the adenine 3-deaza substitution was well tolerated at the 5-HT 2B R with retention of moderate affinity in 25 compared to 24.
  • the 4′-CH2F analogue 12 displayed moderate 5- HT 2B R but not 5-HT 2C R affinity, while the corresponding 4′-CH 2 SCH 3 analogue 15 displayed greater 5-HT2BR (23 nM) and 5-HT2CR affinity.
  • 2-iodo substitution in 16 significantly reduced the 5-HT 2B R affinity (24-fold) compared to 15 without change at the 5- HT2CR.
  • Truncation of the 5′ group combined with 2-iodo substitution greatly reduced affinity in 13 (5-HT2BR Ki 1270 nM) and the corresponding 7-deaza analogue 14.
  • the 2- chloro equivalent of truncated derivative 13 (not shown) 9 displayed Ki values of 675 and 1860 nM at the 5-HT2BR and 5-HT2CR, respectively.5′-Phenyl-thio ethers in the N 6 - dicyclopentylmethyl series displayed moderate 5-HT2BR affinity, e.g., Ki of 256 nM with 3,4-dimethoxy substitution in 33. In the 5′-ester series, the rank order of 5-HT2BR affinity (Ki, nM) was 5 (dicyclopropyl, 15 nM) > 7 nM (dicyclobutyl, 136 nM) ⁇ 47 (dicyclopentyl, 239 nM).
  • the 5-HT2BR affinity of ribosides appeared only in a 5′-CONH2 derivative 52 compared to the inactive 4′-CH 2 OH analogue 51.
  • a 2-iodo-adenine nucleobase 54 displayed moderate 5-HT2BR affinity (313 nM).
  • affinity generally varied in the order hA 1A R > h A3 AR > hA 2A AR.
  • A2BAR affinity was not determined, because this receptor is consistently the weakest for this series of (N)-methanocarba adenosine derivatives.
  • Compounds 11, 15, 19, 38 and 43 (2-I) had nearly balanced A1AR and 5-HT2BR affinity, and 5-HT2CR affinity was somewhat lower.
  • Compound 43 was 3.7-, 186- and >500-fold fold selective in 5-HT 2B R binding compared to A1AR, A2AAR and A3AR.
  • ((S)-cyclobutyl-cyclopropyl)-2-iodo 4′-CH2OH analogue 44 had at least an order of magnitude 5-HT 2B R selectivity compared to other 5- HT2Rs and ARs.
  • the mouse (m) AR affinity can vary greatly compared to the hARs, especially at the A 3 AR.
  • Substitution of the 5′-hydroxyl with halo (Cl or F) increased A1AR affinity for N 6 - cyclopropylmethyl analogues (cf.12 and 4; 39 and 37).
  • A1AR affinity With larger cycloalkyl rings, the A1AR affinity either remained the same (27) or decreased (20, 21, 26, 35 and 36).
  • the 2-S- alkyl substitution (31) greatly decreased A 1 AR affinity.
  • a 5′-deoxy-5′-methylthio substitution decreased A1AR, but not A3AR affinity, by roughly 2 – 10-fold (10, 15, 16 and 28).
  • a 2-iodo group substantially decreased the AR affinity compared to 2-chloro.
  • the adenine 3-deaza substitution in 25 greatly reduced A1AR and A3AR affinity.
  • Compound 51 was selective for the A 1A R and lacked 5-HT 2B /CR affinity.
  • Radioligands used are: 5-HT2A, [ 3 H]ketanserin (HEKT); 5-HT2B, [3H]LSD (stable HEK); 5-HT 2C , [ 3 H]mesulergine (Flp-IN HEK); A1, [ 3 H]R-PIA (HEK); A 2A , [ 3 H]CGS21680 (HEK); A3, [ 125 I]I-AB-MECA (HEK), according to published procedures c . D. K. Tosh (2021), D. K. Tosh et al. (2019); and J. Besnard et al. (2012).
  • a percent refers to inhibition at 10 ⁇ M (or 1 ⁇ M, as noted).
  • the pKi value as a mean ⁇ SEM is given in parentheses.
  • the Ki value or percent inhibition at the A2AAR is given in parentheses (under A1AR data) as a mean ⁇ SEM.
  • d Ki at 5HT1D receptor is 1.99 ⁇ M.
  • e Data from Jacobson et al., 2005. Synthesis reported in Tosh et al., 2020. g Pottie, 2022. h n 1. NA, not applicable. ND, not determined.
  • EXAMPLE 3 This example illustrates some of the pharmacological properties of compounds in accordance with an aspect of the invention.
  • the KB values of all 3 compounds at the 5-HT2BR were in the range of 2 – 3 nM.
  • the ratio of 5-HT 2B R and 5-HT 2C R functional antagonist affinities ranged from 45 (48) to 113-fold (43).
  • Compound 43 was >500- and 32-fold fold selective in binding compared to 5-HT2AR and 5-HT2CR.
  • Table 2 sets forth antagonist affinity (KB) estimates for selected analogues using 5-HT stimulated 5-HT2 Gq-mediated calcium flux functional responses compared to binding assays 3 .
  • Fig- 2 depicts functional assays showing antagonism of compounds 43, 45 and 48 in Flp-In 293 T-Rex cell lines stably-expressing 5-HT2BR (A), 5-HT2cR (B) and 5-HT2AR (C) measuring Gq-mediated calcium flux activity.
  • Clozapine was used as a reference antagonist.
  • the absence of agonism in the nucleosides was shown in 5-HT2B BRET orthologous assays measuring Gq dissociation (D), [3-arrestinl (E) and [3-arrestin2 recruitment (F) assays.
  • Serotonin (5-HT) was used as agonist in all assays (at 10 nM in antagonist mode, A-C).
  • Compounds 9, 10 and 48 had no significant off- target interactions at 10 pM (>50% inhibition of radioligand bound).
  • the physicochemical parameters were calculated for compounds 11, 15, 36, 43, 45, 48 and 51 using the StarDrop software. None of the compounds are predicted to cross the BBB, but 15 and 36 are in the predicted human intestinal absorption (H1A) category.
  • Compound 43 had a LogS at pH 7.4 of 1 .144 (predicted aqueous solubility of 14 pg/mL), a LogD of 1.254 and TPSA of 1 16 A2.
  • the calculated ligand efficiency (LE) of 43 was 0.375.
  • the highest 5-HT2BR affinities were Ki 10 - 30 nM (N 6 -dicyclopropyl-methyl-2-iodo 11, 2-chloro-5'-deoxy-5'- methylthio 15 and N 6 -(R)-cyclobuty-cyclopropyl-methyl-2-iodo 43), followed by 44 and 45.
  • the enhancement of AR affinity of adenosine derivatives upon introducing an (N)-methanocarba modification often follows the order A3 > Ai » A2A. However, substantial AiAR selectivity compared to A3AR was still present in many of these compounds, suggestive of dual acting compounds: 5-HT2B antagonist and AiAR agonist.
  • 5-HT2BR-enhancing 2-iodo and 3-deaza substitutions also decreased AiAR affinity. Given its affinity (17 nM) and moderate 5-HT2BR selectivity (32-fold vs. 5-HT2cR, 4-fold vs. AIAR). 2-iodo derivative 43 could potentially be useful for therapy targeting fibrosis.
  • Compound 11 was a balanced mixed 5-HT2BR antagonist (Ki 11 nM) and AiAR agonist (Ki 13 nM).
  • Compound 54 is likely a mixed HT2BR/A3AR antagonist, considering that adenine derivatives lacking a ribose moiety generally bind to ARs as antagonists.
  • n 2-4, unless noted.
  • b Data from Tosh et al., 2023.
  • Radioligands (parental cells) used are: 5-HT2A, [ 3 H]ketanserin (HEKT); 5-HT 2 B, [ 3 H]LSD (stable HEK); 5- HT 2 c, [ 3 H]mesulergine (Flp-IN HEK); Al, [ 3 H]R-PIA (HEK); A 2A . [ 3 H]CGS21680 (HEK); A?, [ 125 I]I-AB-MECA (HEK), according to published procedures. Data from D. K.
  • the StarDrop software was used to predict properties of potent antagonists 27, 35, 37, 40, 66 and 67 (Table 5). All of the compounds were predicted to be peripherally selective, with BBB permeability (log([brain]: [blood])) of -0.73 to -1.14.
  • BBB permeability log([brain]: [blood])
  • the cLogD ranged from hydrophilic derivatives values 0.611 (66) and 0.829 (40) to more moderately hydrophobic, 2.03 (27).
  • the predicted aqueous solubility at pH 7.4 ranged from 7.7 (27) to 243 (66) pg/mL.
  • EXAMPLE 9 This examples illustrates off-target activity of compounds in accordance with an aspect of the invention.
  • the off-target activity was determined according to the published procedures: https://pdsp.unc.edu/pdspweb/content/UNC-CH%20Protocol%20Book.pdf. The results obtained are set forth in Table 8.
  • Ki values in ⁇ M, or % inhibition at 10 ⁇ M are given. Table 8. Off-target activity of the compounds in accordance with an aspect of the invention. Compound numbers and receptor interactions (other than 5-HT2B and 5-HT2C, Ki, ⁇ M) are as follows: 9a, none 9b, none 10a, none 10b, none 11, ⁇ 1 8.2, ⁇ 2 5.5 12, ⁇ 1 7.5, ⁇ 2 4.8 13, ⁇ 2 , ⁇ 2B 14, none 15, ⁇ 1 6.2, ⁇ 2 3.4, ⁇ 1 6.2 16, ⁇ 1 0.95, ⁇ 2 1.2 17, none 18, none 19, ⁇ 22.0, TSPO 2.1 20, ⁇ 3 1.7 21, none 22, none 23, ⁇ 1 5.0, ⁇ 2 2.1 24, ⁇ 1 4.0, ⁇ 2 2.3, DOR 3.9, KOR 0.11, MOR 3.5 25, ⁇ 1 3.1, ⁇ 2 2.5, D 5 5.1, DAT 2.8, ⁇ 3 4.7 26, ⁇ 1 1.9, ⁇ 2 1.2, DAT
  • EXAMPLE 10 This examples illustrates an advantageous property of a compound of formula (I) in accordance with an aspect of the invention.
  • the 4’-cyano derivative MRS8209 (compound 40) was tested in a mouse model of hypothermia, which is a known activity of AR agonists.
  • the mice had implanted sensors to monitor changes in core body temperature and locomotor activity. Agonists of any of the four AR subtypes were previously found to reduce core body temperature and locomotor activity upon i.p. administration in the mouse.
  • MRS8209 advantageously, failed to reduce core body temperature or locomotor activity at doses of 1 and 3 mg/kg, i.p.; see, Figure 10A and 10B, respectively.
  • EXAMPLE 11 This examples illustrates advantageous properties of compound 34 as set forth in Table 9. The predicted aqueous solubility at pH 7.4 ranged from 7.7 for compound 27) to 243 for compound 34 ⁇ g/mL. Table 9. Calculated properties of selected molecules, using the StarDrop (v.7.3.2) software.

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Abstract

Sont divulgués des composés de formules (I) et (II), un sel correspondant, ou un isomère optique correspondant, R1-R3, X et Y étant tels que définis dans la présente invention, qui sont des antagonistes sélectifs du récepteur sérotoninergique 5-HT2B, des compositions pharmaceutiques comprenant de tels composés, et des méthodes de traitement de diverses maladies et affections chez un animal comprenant la fibrose pulmonaire, cutanée, coronaire et hépatique, l'hypertension artérielle pulmonaire, la cardiopathie valvulaire, la douleur et le cancer par l'utilisation de ces composés.
PCT/US2024/038286 2023-07-17 2024-07-17 Antagonistes du récepteur sérotoninergique 5-ht 2b, leurs compositions pharmaceutiques et leurs procédés d'utilisation Pending WO2025019529A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006031505A1 (fr) * 2004-09-09 2006-03-23 Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Derives de purine comme agonistes du recepteur d'adenosine a3 et a1

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006031505A1 (fr) * 2004-09-09 2006-03-23 Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Derives de purine comme agonistes du recepteur d'adenosine a3 et a1

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
JEONG, L. S. ET AL.: "Structure-activity relationships of 2-chloro-N6-substituted-4`-thioadenosine-5'-uronamides as highly potent and selective agonists at the human A3 adenosine receptor", JOURNAL OF MEDICINAL CHEMISTRY, vol. 49, 2006, pages 273 - 281, XP055020040, DOI: 10.1021/jm050595e *
STORME JOLIEN, TOSH DILIP K., GAO ZHAN-GUO, JACOBSON KENNETH A., STOVE CHRISTOPHE P.: "Probing structure-activity relationship in β-arrestin2 recruitment of diversely substituted adenosine derivatives", BIOCHEMICAL PHARMACOLOGY, ELSEVIER, US, vol. 158, 1 December 2018 (2018-12-01), US , pages 103 - 113, XP093263012, ISSN: 0006-2952, DOI: 10.1016/j.bcp.2018.10.003 *
TCHILIBON S,ET AL: "(N)-Methanocarba 2,N6-disubstituted adenine nucleoside as highly potent and selective A3 adenosine receptor agonists", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 48, 23 September 2004 (2004-09-23), US , pages 1745 - 1758, XP002362942, ISSN: 0022-2623, DOI: 10.1021/jm049580r *
TOSH, D. K. ET AL.: "Structure-based scaffold repurposing for G protein-coupled receptors: transformation of adenosine derivatives into 5HT2B/5HT2C serotonin receptor antagonists", JOURNAL OF MEDICINAL CHEMISTRY, vol. 59, no. 24, 2016, pages 11006 - 11026, XP055475516, DOI: 10.1021/acs.jmedchem.6b01183 *

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