EP1189896A1 - 5-oxo-5,6,7,8-tetrahydro-4h-1-benzopyrannes et benzothiopyrannes substitues et utilisation de ces substances comme potentialisateurs de ampa - Google Patents

5-oxo-5,6,7,8-tetrahydro-4h-1-benzopyrannes et benzothiopyrannes substitues et utilisation de ces substances comme potentialisateurs de ampa

Info

Publication number
EP1189896A1
EP1189896A1 EP00938095A EP00938095A EP1189896A1 EP 1189896 A1 EP1189896 A1 EP 1189896A1 EP 00938095 A EP00938095 A EP 00938095A EP 00938095 A EP00938095 A EP 00938095A EP 1189896 A1 EP1189896 A1 EP 1189896A1
Authority
EP
European Patent Office
Prior art keywords
amino
cyano
oxo
tetrahydro
benzopyran
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00938095A
Other languages
German (de)
English (en)
Inventor
Christopher S. Konkoy
David B. Fick
Sui Xiong Cai
Nancy C. Lan
John F. W. Keana
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Euro Celtique SA
Original Assignee
Euro Celtique SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Euro Celtique SA filed Critical Euro Celtique SA
Publication of EP1189896A1 publication Critical patent/EP1189896A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/74—Benzo[b]pyrans, hydrogenated in the carbocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention is in the field of medicinal chemistry.
  • the invention relates to the use of substituted 5-oxo-5,6,7,8-tetrahydro-4H-l- benzopyrans as positive modulators of AMPA receptors, and for the treatment of neurodegenerative conditions, for the treatment of schizophrenia, and as cognitive enhancers.
  • Excitatory amino acid receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are termed "ionotropic.” This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonist N-methyl-aspartate (NMDA), ⁇ - amino-3-hydroxy-5-methyoisoxazole-4-propionic acid (AMPA), and kainic acid (KA).
  • the second general type is the G-protein or second messenger- linked "metabotropic" excitatory amino acid receptor. This second type, when activated by the agonists quisqualate, ibotenate, or trans- 1 -aminocyclopentane-
  • 1,3-dicarboxylic acid leads to enhanced phosphoinositide hydrolysis in the postsynaptic cell.
  • Both types of receptors appear not only to mediate normal synaptic connections during development, but also changes in the efficiency of synaptic transmission throughout life. See Schoepp, Bockaert, and Sladeczek, Trends Pharm. Sci. 11: 508 (1990); McDonald and Johnson, Brain Res. Rev. 75: 41 (1990).
  • AMPA receptor positive modulator BDP 1-(1,3- benzodioxol-5-ylcarbonyl)piperidine and its derivatives enhance memory in rat (Staubli et al., Proc. Natl. Acad. Sci. 91:111-118 (1994)).
  • the AMPA- positive modulator BDP-29 also has been shown to attenuate the amount of stereotypic rearings seen in rats after methamphetamine injection, suggesting that AMPA receptor modulators might be useful for the treatment of schizophrenia (Larson et al., Brain Res. 7JS.J53-356 (1996)). Furthermore, piracetam, a well-known nootropic agent, which is used to treat cognitive impairment in the elderly, was found to be a positive modulator of AMPA receptors (Copani et al., J. Neurochem. 55J 199-1204 (1992)).
  • AMPA receptor positive modulators are expected to be useful in treating myoclonus.
  • the invention relates to the discovery that the compounds represented by Formula / are positive modulators of ⁇ -amino-3-hydroxy-5- methyoisoxazole-4-propionic acid (AMPA) receptors.
  • AMPA ⁇ -amino-3-hydroxy-5- methyoisoxazole-4-propionic acid
  • a first aspect of the invention is directed to method for treating a disorder responsive to the positive modulation of AMPA receptors in animals suffering therefrom, comprising administering to an animal in need thereof a compound of Formula J:
  • Ri and R are independently hydrogen, C M O alkyl, haloalkyl, aryl, fused aryl, a carbocyclic group, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloalkylalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl or thioalkyl; or Ri and R are taken together to form a carbocycle or heterocycle;
  • R 3 is hydrogen, or C M O alkyl; 4 is substituted or unsubstituted aryl or heteroaryl, carbocycle or heterocycle;
  • X is hydrogen, NO 2 , CN, C M O alkyl, haloalkyl, aryl, heteroaryl, COR, CO 2 R and CONR x R y , wherein R, R x and R y are independently hydrogen, C M O alkyl, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl ⁇ hydroxyalkyl or aminoalkyl; or R x and R y are taken together to form a heterocycle; Y is NH 2 , NHR, and NHCOR; and Z is O and S.
  • a further aspect of the present invention is to provide a method for treating, preventing or ameliorating neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, AIDS associated dementia and Down's syndrome as well as for the treatment of schizophrenia and myoclonus by administering a compound of Formula / to a mammal in need of such treatment.
  • a further aspect of the present invention is to provide a pharmaceutical composition useful for treating disorders responsive to the positive modulation of AMPA receptors, comprising an effective amount of a compound of Formula / in a mixture with one or more pharmaceutically acceptable carriers or diluents.
  • a pharmaceutical composition useful for treating disorders responsive to the positive modulation of AMPA receptors comprising an effective amount of a compound of Formula / in a mixture with one or more pharmaceutically acceptable carriers or diluents.
  • a number of compounds useful in the present invention have not been heretofor reported.
  • the present invention is also directed to novel substituted 5-oxo-5,6,7,8-tetrahydro-4H-l-benzopyrans of Formula /.
  • the present invention is directed to 3 H and 14 C radiolabeled compounds of Formula / and their use as radioligands for their binding site on the sodium channel.
  • FIG. 1 depicts a graph showing the concentration-effect relationship for the potentiation of AMPA-evoked currents in Xenopus oocytes by the compound of Example 4.
  • Xenopus oocytes were injected with rat cortical poly (A+) RNA and membrane currents were measured by a standard, two- microelectrode voltage clamp method.
  • a solution of AMPA (10 ⁇ M) was superfused through the recording chamber in the absence (control) or presence of increasing concentrations of the compound of Example 4.
  • "I" is membrane current.
  • substituted 5-oxo-5,6,7,8-tetrahydro-4H-l-benzopyrans and benzothiopyrans are represented by Formula /.
  • preferred structures of the substituted 5-oxo-5,6,7,8-tetrahydro-4H-l-benzopyrans are those compounds where Ri and R 2 are each hydrogen or are each methyl, preferably methyl. More preferred compounds are those where R 3 is hydrogen and R 4 is optionally substitued aryl. Even more preferred are compounds above where
  • X is CN, Y is NH 2 and Z is O.
  • Preferred structures of the substituted 5-oxo- 5,6,7,8-tetrahydro-4H-l-benzopyrans of and useful in the present invention are represented by Formulae II-VI. Thus, preferred embodiments are represented by Formula II:
  • R ⁇ , R , R and R 4 are as defined previously with respect to Formula /;
  • R 5 -R are independently hydrogen, halo, haloalkyl, aryl, fused aryl, a carbocyclic group, a heterocyclic group, a heteroaryl group, C M O alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido or alkylthiol; or
  • R 5 and R ⁇ , or R 6 and R are taken together to form a carbocycle or heterocycle, including -OCH 2 O-, -OCF 2 O-, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -OCH 2 CH 2 O-,
  • Optional substituents on the aryl, aralkyl, aryloxy, arylthioxy, aroyl, heterocyclic, heterocycloxy, heteroaryl, heteroaryloxy, cycloalkyl, and cycloalkoxy groups listed above can include one or more of halo, haloalkyl, aryl, fused aryl, heterocyclic, heteroaryl, C O alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, amino, cyano, acylamino, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, and alkylthiol groups mentioned above.
  • Preferred optional substituents on optionally substituted groups include one or more groups independently selected from the group consisting of halo, halo(C ⁇ - 6 )alkyl, aryl, pyrimidine, cycloalkyl, C ⁇ -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl(C ⁇ - 6 )alkyl, aryl(C 2 - 6 )alkenyl, aryl(C 2-6 )alkynyl, cycloalkyl(C ⁇ _ )alkyl, hydroxy(C ⁇ - )alkyl, amino(C ⁇ -6 )alkyl, carboxy(C ⁇ - )alkyl, alkoxy(C ⁇ .
  • Preferred compounds of, and for use in, the present invention include compounds where Z is O; particularly when X is CN and Y is NH 2 .
  • Ri and R 2 include hydrogen, C 1-6 alkyl, C ⁇ -6 haloalkyl, C ⁇ -6 hydroxyalkyl, C ⁇ -6 aminoalkyl, or C ⁇ -6 thioalkyl, more preferable hydrogen or C ⁇ -6 alkyl. Most preferably, Ri and R 2 are both hydrogen or are both methyl.
  • R 4 are optionally substituted phenyl, naphthyl and pyridyl, more preferably optionally substituted phenyl.
  • Suitable values of R 4 are 4-methoxyphenyl, 2,4,6-trimethylphenyl, phenyl, 3,4- methylenedioxyphenyl, 4-methoxyphenyl, 4-chlorophenyl, 3-hydroxyphenyl,
  • a preferred subgenus of, and useful in, the present invention includes compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein:
  • Ri and R 2 are independently hydrogen, C ⁇ - 6 alkyl, C ⁇ -6 haloalkyl, C ⁇ -6 hydroxyalkyl, C ⁇ - 6 aminoalkyl, C ⁇ -6 thioalkyl C 6- ⁇ o aryl, C 4-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6- ⁇ 0 aryl(C ⁇ -6 )alkyl, C 6- ⁇ 0 aryl(C 2 - 6 )alkenyl, C 6- ⁇ 0 aryl(C 2 .
  • Ri and R 2 are taken together with the carbon atom to which they are attached to form a C 3-7 cycloalkyl or a 5 or 6 membered heterocycle having one or two of N, S, O or a combination thereof;
  • R 3 is hydrogen, or C ⁇ -6 alkyl
  • R 4 is an optionally substituted C 6- ⁇ o aryl, heteroaryl, carbocycle or heterocycle;
  • X is hydrogen, NO 2 , CN, C M O alkyl, haloalkyl, aryl, heteroaryl, COR, CO 2 R or CONR x R y , wherein R, R x and R y are independently hydrogen, C MO alkyl, haloalkyl, aryl, fused aryl, a carbocyclic group, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl or aminoalkyl; or R x and R y are taken together to form a heterocycle; Y is NH 2 , NHR, or NHCOR, where R is as defined above; and
  • Z is O or S.
  • Exemplary preferred compounds that may be employed in the compositions and methods of invention include, without limitation:
  • Novel compounds of the present invention include compounds of
  • Ri and R 2 are independently hydrogen, C ⁇ -6 alkyl, C ⁇ - 6 haloalkyl, C 1-6 hydroxyalkyl, C ⁇ -6 aminoalkyl, C !-6 thioalkyl C 6- ⁇ o aryl, C 4 .
  • Ri and R 2 are taken together with the carbon atom to which they are attached to form a C 3-7 cycloalkyl or a 5 or 6 membered heterocycle having one or two of N, S, O or a combination thereof;
  • R 3 is hydrogen, or C ⁇ - 6 alkyl; and
  • R5-R9 are independently hydrogen, halo, haloalkyl, aryl, fused aryl, a carbocyclic group, a heterocyclic group, a heteroaryl group, C M O alkyl, alkenyl, alky
  • R 5 and R 6 are taken together with the carbon atoms to which they are attached, or R 6 and R 7 are taken together with the carbon atoms to which they are attached form a carbocycle or heterocycle.
  • R 5 and R(, taken together are with the carbon atoms to which they are attached to form one of -OCH 2 O-, -OCF 2 O-, -(CH 2 ) 3 -, -(CH 2 ) 4 -
  • R 6 and R 7 taken together are with the carbon atoms to which they are attached to form one of -OCH 2 O-, -OCF 2 O-, -(CH 2 ) 3 -, -(CH 2 ) 4 -
  • Novel compounds of the present invention include: 2-amino-3-cyano-7J-dimethyl-4-(2,4,6-trimethylphenyl)-5-oxo-5, 6,7,8- tetrahydro-4-H- 1 -benzopyran;
  • Useful aryl groups are C 6 - ⁇ 4 aryl, especially C 6 - ⁇ o aryl.
  • Typical C 6 - ⁇ 4 aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups.
  • Useful cycloalkyl groups are C 3-8 cycloalkyl.
  • Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • heteroaryl refers to groups having 5 to 14 ring atoms; 6, 10 or 14 ⁇ electrons shared in a cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms (where examples of heteroaryl groups are: thienyl, benzo[b]thienyl, naphtho[2,3- bjthienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzoxazonyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazoly
  • Useful alkyl groups include straight-chained and branched C M O alkyl groups, more preferably C ⁇ -6 alkyl groups.
  • Typical C M O alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl and octyl groups.
  • Also contemplated is a trimethylene group substituted on two adjoining positions on the benzene ring of the compounds of the invention.
  • Useful alkenyl groups are C 2-6 alkenyl groups, preferably C 2-4 alkenyl.
  • Typical C 2-4 alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and -sec-butenyl.
  • Useful alkynyl groups are C 2 - 6 alkynyl groups, preferably C 2-4 alkynyl.
  • Typical C alkynyl groups include ethynyl, propynyl, butynyl, and 2-butynyl groups.
  • Useful arylalkyl (or aralkyl) groups include any of the above-mentioned C M O alkyl groups substituted by any of the above-mentioned
  • C 6 - ⁇ 4 aryl groups Useful values include benzyl, phenethyl and naphthylmethyl.
  • Useful arylalkenyl groups include any of the above-mentioned C 2-4 alkenyl groups substituted by any of the above-mentioned C 6- ⁇ 4 aryl groups.
  • Useful arylalkynyl groups include any of the above-mentioned C 2-4 alkynyl groups substituted by any of the above-mentioned C 6- ⁇ 4 aryl groups.
  • Useful values include phenylethynyl and phenylpropynyl.
  • Useful heteroarylalkyl groups include any of the above-mentioned C M O alkyl groups substituted by any of the above-mentioned heteroaryl groups.
  • Useful heteroarylalkenyl groups include any of the above-mentioned C 2-4 alkenyl groups substituted by any of the above-mentioned heteroaryl groups.
  • Useful heteroarylalkynyl groups include any of the above-mentioned C 2-4 alkynyl groups substituted by any of the above-mentioned heteroaryl groups.
  • Useful cycloalkylalkyl groups include any of the above-mentioned Cj. ⁇ o alkyl groups substituted by any of the above-mentioned cycloalkyl groups.
  • Useful haloalkyl groups include C MO alkyl groups substituted by one or more fluorine, chlorine, bromine or iodine atoms, e.g. fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1 J -difluoroethyl and trichloromethyl groups.
  • Useful hydroxyalkyl groups include C M O alkyl groups substituted by hydroxy, e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups.
  • Useful alkoxy groups include oxygen substituted by one of the C MO alkyl groups mentioned above.
  • Useful alkylthio groups include sulfur substituted by one of the C M O alkyl groups mentioned above.
  • Useful acylamino groups are any C ⁇ -6 acyl (alkanoyl) attached to an amino nitrogen, e.g. acetamido, propionamido, butanoylamido, pentanoylamido, hexanoylamido as well as aryl-substituted C 2-6 substituted acyl groups.
  • acyloxy groups are any C ⁇ -6 acyl (alkanoyl) attached to an oxy (- O-) group, e.g. acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy and the like.
  • heterocycle is used herein to mean saturated or partially unsaturated 3-7 membered monocyclic, or 7-10 membered bicyclic ring system, which consists of carbon atoms and from one to four heteroatoms independently selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, the nitrogen can be optionally quatemized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, and wherein the heterocyclic ring can be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
  • Examples include, but are not limited to, pyrrolidine, piperazine, morpholine, imidazoline, pyrazolidine, benzodiazepines and the like.
  • Useful heterocycloalkyl groups include any of the above-mentioned Ci. ⁇ o alkyl groups substituted by any of the above-mentioned heterocyclic groups.
  • Useful alkylamino and dialkylamino groups are — NHR o and —
  • Aminocarbonyl group is -C(O)NH 2 .
  • Useful alkylaminocarbonyl groups are carbonyl groups substituted by - NHR 2 o and -NR 20 R 2 ⁇ , wherein R 2 o and R ⁇ are C MO alkyl groups as defined above.
  • Useful alkylthiol groups include any of the above-mentioned C M O alkyl groups substituted by a -SH group.
  • a carbamoyloxy group is -O-C(O) -NH 2 .
  • a carboxy group is -COOH.
  • An azido group is — N 3 .
  • An ureido group is -NH-C(O)-NH 2 .
  • An amino group is -NH 2 .
  • An amide group is an organic radical having -NHC(O)- as a functional group.
  • Certain of the compounds of the present invention may exist as optical isomers and the invention includes both the racemic mixtures of such optical isomers as well as the individual entantiomers that may be separated according to methods that are well known to those of ordinary skill in the art.
  • Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalate.
  • prodrugs include esters or amides of Formula / with R 3 as hydroxyalkyl or aminoalkyl, by reacting such compounds with an anhydride such as succinic anhydride.
  • the invention disclosed herein is meant to encompass all pharmaceutically acceptable salts thereof of the disclosed compounds.
  • the pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt and the like; inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like; amino acid salts such as arginate, asparg
  • prodrugs are considered to be any covalently bonded carriers which release the active parent drug in vivo.
  • Examples of prodrugs include esters or amides of Formula / with R 1 -R 9 as hydroxyalkyl or aminoalkyl, and these may be prepared by reacting such compounds with anhydrides such as succinic anhydride.
  • the invention disclosed herein is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically are identified by preparing a radiolabelled compound of the invention, administering it parenterally in a detectable dose to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur and isolating its conversion products from the urine, blood or other biological samples.
  • the invention disclosed herein is also meant to encompass the disclosed compounds being isotopically-labelled by having one or more atoms replaced by an atom having a different atomic mass or mass number.
  • isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
  • Some of the compounds disclosed herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms.
  • the present invention is also meant to encompass racemic mixtures, resolved forms mixtures thereof, as well as the individual enantiomers that may be separated according to methods that are well know to those of ordinary skill in the art.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended to include both E and Z geometric isomers. All tautomers are intended to be encompassed by the present invention as well.
  • stereoisomers is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).
  • chiral center refers to a carbon atom to which four different groups are attached.
  • enantiomer or “enantiomeric” refers to a molecule that is nonsuperimposeable on its mirror image and hence optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction.
  • racemic refers to a mixture of equal parts of enantiomers and which is optically inactive.
  • resolution refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule.
  • enantiomeric excess refers to a mixture wherein one enantiomer is present is a greater concentration than its mirror image molecule.
  • the invention is also directed to 3 H and 14 C radiolabeled compounds of Formula / and their use as radioligands for their binding site on the sodium channel.
  • one use of the labeled compounds of the invention is the characterization of specific receptor binding.
  • Another use of the labeled compounds of the invention is an alternative to animal testing for the evaluation of structure-activity relationships.
  • the receptor assay is performed at a fixed concentration of a labeled compound of Formula / and at increasing concentrations of a test compound in a competition assay.
  • Tritiated compounds of Formula / can be prepared by introducing tritium into the compound of Formula / by, for example, catalytic dehalogenation with tritium.
  • This method includes reacting a suitably halogen- substituted precursor of a compound of Formula / with tritium gas in the presence of a suitable catalyst, for example Pd/C, in the presence or absence of a base.
  • a suitable catalyst for example Pd/C
  • Other suitable methods for preparing tritiated compounds can be found in Filer, Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled
  • 14 C-labeled compounds can be prepared by employing starting materials having a 14 C carbon.
  • non- toxic pharmaceutically acceptable salts of the compounds of the present invention are also included within the scope of the present invention.
  • Acid addition salts are formed by mixing a solution of the particular heteroaryl compound of the present invention with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, and the like.
  • Basic salts are formed by mixing a solution of the heteroaryl compound of the present invention with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate and the like.
  • compositions of the invention may be administered to any animal that may experience the beneficial effects of the compounds of the invention.
  • animals are mammals, e.g., humans, although the invention is not intended to be so limited.
  • the compounds of this invention may be prepared using methods well known to those skilled in the art, such as those described by Abdel-Latif et al. (J. Chem. Res. Miniprint, 5, 1220-1228 (1995)) or by the novel methods of this invention. Exemplary reactions are illustrated in Equations 1-4.
  • the starting materials employed in Equations 1 -4 are readily available or can be prepared by known methods.
  • novel compounds of the invention were assessed by electrophysiological assays in Xenopus oocytes expressing rat whole brain poly(A) + RNA (see Keana et al, J. Med. Chem. 38: 4367-4379 (1995)) or in cultured rat cortical neurons (see Woodward et al, Mol. Pharmacol. 47: 568- 581 (1995)) for AMPA receptor activity.
  • the compounds that potentiate currents across the oocyte membrane are expected to be useful as cognitive enhancers or for the treatment of schizophrenia, myoclonus or neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease.
  • the present invention is directed to compounds that are positive modulators of AMPA receptors.
  • compositions within the scope of this invention include all composi- tions wherein the compounds of the present invention are contained in an amount which is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is with the skill of the art.
  • the compounds may be administered to mammals, e.g. humans, orally at a dose of 0.0025 to 50 mg/kg, or an equivalent amount of the pharmaceutically acceptable salt thereof, per day of the body weight of the mammal being treated for psychosis disorders. Preferably, about 0.01 to about 10 mg/kg is orally administered to treat or prevent such disorders.
  • the dose is generally about one-half of the oral dose.
  • the pharmaceutical compositions of the invention may comprise the compounds of the present invention at a unit dose level of about 0.01 to about 50 mg/kg of body weight, or an equivalent amount of the pharmaceutically acceptable salt thereof, on a regimen of 1 -4 times per day.
  • a unit dose level of about 0.01 to about 50 mg/kg of body weight, or an equivalent amount of the pharmaceutically acceptable salt thereof, on a regimen of 1 -4 times per day.
  • the unit oral dose may comprise from about 0.01 to about 50 mg, preferably about 0J to about 10 mg of the compound.
  • the unit dose may be administered one or more times daily as one or more tablets each containing from about 0J to about 10, conveniently about 0J5 to 50 mg of the compound or its solvates.
  • the compounds of the invention may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the compounds into preparations which can be used pharmaceutically.
  • the preparations particularly those preparations which can be administered orally and which can be used for the preferred type of administration, such as tablets, dragees, and capsules, and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, contain from about 0.01 to 99 percent, preferably from about 0J5 to 75 percent of active compound(s), together with the excipient.
  • Non- toxic pharmaceutically acceptable salts of the compounds of the present invention are also included within the scope of the present invention.
  • Acid addition salts are formed by mixing a solution of the particular AMPA positive modulator of the present invention with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, dichloroacetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, and the like.
  • Basic salts are formed by mixing a solution of the particular AMPA positive modulator of the present invention with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate and the like.
  • compositions of the invention may be administered to any animal which may experience the beneficial effects of the compounds of the invention.
  • animals are mammals, e.g., humans, although the invention is not intended to be so limited.
  • compositions of the present invention may be administered by any means that achieve their intended purpose.
  • administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, or buccal routes.
  • administration may be by the oral route.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • the pharmaceutical preparations of the present invention are manufactured in a manner which is itself known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes.
  • compositions for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
  • fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose,
  • disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross- linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices.
  • concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropymethyl-cellulose phthalate, are used.
  • Dye stuffs or pigments jnay be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
  • Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.
  • the push- fit capsules can contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin.
  • stabilizers may be added.
  • Possible pharmaceutical preparations which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons.
  • gelatin rectal capsules which consist of a combination of the active compounds with a base.
  • Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
  • Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water- soluble salts and alkaline solutions.
  • suspensions of the active compounds as appropriate oily injection suspensions may be administered.
  • Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400).
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension include, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.
  • the suspension may also contain stabilizers. The characterization of non-competitive AMPA receptors modulators in vitro has been difficult because of the lack of selective drug ligands.
  • the AMPA ligands of the present invention may be used to characterize the AMPA receptors and their distribution.
  • Particularly preferred AMPA positive modulator of the present invention which may be used for this purpose are isotopically radiolabelled derivatives, e.g. where one or more of the atoms are replaced with * ⁇ H, ⁇ C, ⁇ C or °F.
  • a fluorescent group Y may be employed. Examples of such groups include 4-nitrobenzofurazan.
  • RNA was prepared from rat cerebral cortex by homogenization in urea/LiCl followed by phenol/chloroform extraction. Polyadenylated (poly
  • a + ) mRNA was isolated from total cellular RNA by oligo-dT cellulose chromatography.
  • Xenopus oocytes were prepared by the method of Woodward et al. (Mol. Pharmacol. 41, 89-103 (1992)). Oocytes were microinjected with approximately 50 ng of cortical poly(A) + RNA and stored in Barth's medium
  • HEPES 5; pH 7.4, or in a nominally Ca 2+ -free Ringer solution containing (in mM): NaCl, 115; KC1, 2; BaCl2, 1.8; HEPES, 5; pH 7.4.
  • Electrical recordings were made using a conventional two-electrode voltage clamp (Dagan TEN- 200).
  • the oocyte was placed in a 5 ml chamber lined with nylon mesh, impaled with two micro-electrodes and voltage-clamped at a holding potential of -70 mV.
  • a scaled up linear array system (Benveniste and Mayer, J. Physiol. 464, 131-163 (1993)) was used to superfuse the oocyte in Ringer solution and to apply drugs and wash solutions.
  • a control concentration (10 ⁇ M) of AMPA was applied to the oocyte to determine a baseline membrane current response.
  • the modulation of this response by AMPA potentiators was measured by applying increasing concentrations of the potentiator in Ringer solution for -30 s followed by coapplication of the potentiator with 10 ⁇ M AMPA.
  • the resulting membrane current responses were analyzed by sigmoidal curve fitting (Origin, Microcal Software , Inc.).
  • the 5-oxo-5,6,7,8-tetrahydro-4H-l-benzopyrans elicited potentiation of AMPA responses as exemplified by compound of Example 4 ( Figure 1).
  • the maximal potentiation of the AMPA response was 11 -fold at 100 ⁇ M, and was half-maximally effective at 16.6 ⁇ M.
  • a 2-fold potentiation of the AMPA response was elicited at 4 ⁇ M for Example 4.
  • the concentration of 5-oxo- 5,6,7,8-tetrahydro-4H-l-benzopyrans required for 2-fold potentiation is shown in Table 1. Table 1

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Méthode permettant de traiter une pathologie répondant à la modulation positive de récepteurs AMPA chez des animaux souffrant desdites pathologies. Ladite méthode consiste à administrer à un animal le nécessitant un composé de formule (I) ou un sel pharmaceutiquement acceptable ou un promédicament dudit composé. Dans la formule (I), Y représente NH2, NHR et NHCOR; Z représente O et S; et R1, R2, R3, R4 et X sont tels que définis dans le descriptif. Ces composés peuvent être utilisés en tant que substances favorisant les processus cognitifs, pour le traitement de maladies dégénératives dont la maladie d'Alzheimer, la sclérose latérale amyotrophique, la chorée de Huntington, la maladie de Parkinson, la démence associée au sida et le syndrome de Down, ainsi que pour le traitement de la schizophrénie et de la myoclonie. Des compositions pharmaceutiques utiles pour traiter des pathologies répondant à la modulation positive des récepteurs AMPA et des nouveaux composés de formule (I) sont également décrits.
EP00938095A 1999-06-04 2000-06-05 5-oxo-5,6,7,8-tetrahydro-4h-1-benzopyrannes et benzothiopyrannes substitues et utilisation de ces substances comme potentialisateurs de ampa Withdrawn EP1189896A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US13750199P 1999-06-04 1999-06-04
US137501P 1999-06-04
PCT/US2000/015307 WO2000075123A1 (fr) 1999-06-04 2000-06-05 5-oxo-5,6,7,8-tetrahydro-4h-1-benzopyrannes et benzothiopyrannes substitues et utilisation de ces substances comme potentialisateurs de ampa

Publications (1)

Publication Number Publication Date
EP1189896A1 true EP1189896A1 (fr) 2002-03-27

Family

ID=22477711

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00938095A Withdrawn EP1189896A1 (fr) 1999-06-04 2000-06-05 5-oxo-5,6,7,8-tetrahydro-4h-1-benzopyrannes et benzothiopyrannes substitues et utilisation de ces substances comme potentialisateurs de ampa

Country Status (4)

Country Link
EP (1) EP1189896A1 (fr)
JP (1) JP4761683B2 (fr)
AU (1) AU5318300A (fr)
WO (1) WO2000075123A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100526119B1 (ko) * 2002-04-10 2005-11-08 동부한농화학 주식회사 테트라졸을 포함하는 이차아민으로 치환된 벤조피란 유도체
WO2010066253A1 (fr) * 2008-12-12 2010-06-17 Bunch, Lennart Inhibiteurs sélectifs du sous-type 1 du transporteur d'acides aminés excitateurs (eaat1/glast)
CN102424675B (zh) * 2011-11-07 2014-04-16 镇江市高等专科学校 制备2-氨基-3-氰基苯并吡喃衍生物的方法
EP3311842A1 (fr) 2013-06-13 2018-04-25 VeroScience LLC Compositions et procédés de traitement des troubles métaboliques

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2156162T3 (es) * 1994-02-08 2001-06-16 Nps Pharma Inc Compuestos activos en un nuevo sitio sobre canales del calcio accionados por un receptor, utiles para el tratamiento de trastornos y enfermedades neurologicas.
DE4430639A1 (de) * 1994-08-29 1996-03-07 Bayer Ag Verwendung von 5-substituierten Pyridin- und Hexahydrochinolin-3-carbonsäurederivaten
WO1997043272A2 (fr) * 1996-05-14 1997-11-20 Glaxo Group Limited Benzofurans et benzopyrans utilises en tant qu'agents chronobiologiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0075123A1 *

Also Published As

Publication number Publication date
WO2000075123A1 (fr) 2000-12-14
JP4761683B2 (ja) 2011-08-31
AU5318300A (en) 2000-12-28
JP2003501422A (ja) 2003-01-14

Similar Documents

Publication Publication Date Title
US10273214B2 (en) Subunit selective NMDA receptor potentiators for the treatment of neurological conditions
JP4759649B2 (ja) 中枢及び末梢神経系障害を治療するための方法及び組成物、並びにそれらに有用な新規の化合物
US5650409A (en) Benzoyl piperidines/pyrrolidines for enhancing synaptic response
TWI714566B (zh) 軸手性異構體及其製備方法和製藥用途
RU2583787C2 (ru) Гетероциклические соединения бензодиоксола или бензодиоксепина в качестве ингибиторов фосфодиэстераз
US5519019A (en) N-acyl-2,3-benzoidazepine derivatives, pharmaceutical compositions containing them and process for preparing same
US5094782A (en) Synthesis of capsacin derivatives and their use as an analgesic drug and vessel dilation drug
US6680332B1 (en) Substituted 5-oxo-5,6,7,8-tetrahydro-4H-1-benzopyrans and benzothiopyrans and the use thereof as potentiators of AMPA
CA2828831C (fr) Composes et methodes de traitement de la douleur et d'autres troubles
US5639751A (en) N-acyl-2,3-benzodiazepine derivatives for treating acute and chronic neurodegenerative disorders
JPH11263761A (ja) 新規なナフタレン化合物、それらの製造方法、及びそれらを含む医薬組成物
EP1189896A1 (fr) 5-oxo-5,6,7,8-tetrahydro-4h-1-benzopyrannes et benzothiopyrannes substitues et utilisation de ces substances comme potentialisateurs de ampa
JP6430015B2 (ja) 新規クロモンオキシム誘導体、および代謝型グルタミン酸受容体のアロステリックモジュレーターとしてのそれの使用
SU1169538A3 (ru) Способ получени трициклических соединений
CA2690789C (fr) Derives de la 4-phenylpiperazine avec des lieurs fonctionnalises tels que les ligands selectifs du recepteur d<sb>3</sb> de la dopamine et procedes d'utilisation
CA3238026A1 (fr) Composes multicycliques
CN110372665A (zh) 一种阿哌沙班吡啶酮杂质的制备方法
EP2099815B1 (fr) Nouveaux amides agissant sur les récepteurs d'adénosine
US6703390B2 (en) Sulfur containing dihydrophthalazine antagonists of excitatory amino acid receptors
WO2010066253A1 (fr) Inhibiteurs sélectifs du sous-type 1 du transporteur d'acides aminés excitateurs (eaat1/glast)
WO1996025927A1 (fr) Inhibiteur des recepteurs de l'acide glutamique et ameliorant des fonctions cerebrales
JP2019515021A (ja) フッ素含有トリアゾロピリジン系化合物、その製造方法、医薬組成物及び用途
JP2002519350A (ja) ６−（４−アリールアルキルピペラジン−１−イル）ベンゾジオキサン及び６−（４−アリールアルキルピペラジン−１−イル）クロマン誘導体：ドーパミン受容体サブタイプ特異的リガンド
WO1986002644A1 (fr) Derives de 1,5-benzoxathiepines et leur procede de preparation

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20020104

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT

AX Request for extension of the european patent

Free format text: AL;LT;LV;MK;RO;SI

17Q First examination report despatched

Effective date: 20030624

RBV Designated contracting states (corrected)

Designated state(s): DE FR GB NL

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20050826