Substituted 5-oxo-5,6,7,8-tetrahydro-4H-1-benzopyrans and benzothiopyrans and the use thereof as potentiators of AMPA

Disclosed is a 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 I: or a pharmaceutically acceptable salt or prodrug thereof, wherein:Y is NH2, NHR, and NHCOR; Z is O and S; and R1, R2, R3, R4, and X are defined herein. These compounds can be used as cognitive enhancers, for the treatment of 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. Also disclosed are pharmaceutical compositions useful for treating disorders responsive to the positive modulation of AMPA receptors, and novel compounds of Formula I.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is in the field of medicinal chemistry. In particular, the invention relates to the use of substituted 5-oxo-5,6,7,8-tetrahydro-4H-1-benzopyrans as positive modulators of AMPA receptors, and for the treatment of neurodegenerative conditions, for the treatment of schizophrenia, and as cognitive enhancers.

2. Related Background Art

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 . 15:41 (1990).

There is much evidence suggesting that the interaction of glutamate with membrane receptors plays a key role on many critical neurological functions such as cognition, learning and memory. Cognitive deficits likely arising from hypoactivity of glutamate receptors are known to be associate with neurodegenerative disorders such as Alzheimer's disease. Hypoactivity of glutamate receptors also might be associated with schizophrenia. One therapeutic approach is the direct stimulation of glutamate receptors with agonists. However, this approach increases the risk of excitotoxicity and may lead to further neurodegeneration. Selective positive modulation of certain glutamate receptor subtypes would be a better approach. Therefore positive modulators of AMPA receptors are expected to be useful for the treatment or amelioration of a number of chronic neurologic disorders such as schizophrenia, Alzheimer's disease and malnutrition, as well as neural maldevelopment (Thomas, R. J., J. Am. Geriatr. Soc . 43:1279-1289 (1995)). It has been shown that the 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 . 91:777-778 (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 . 738:353-356 (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 . 58:1199-1204 (1992)). A recent clinical study showed that piracetam was effective in treating patients with myoclonus, especially that of cortical origin (Ikeda et al., Movement Disorders 11:691-700 (1996)). Thus, AMPA receptor positive modulators are expected to be useful in treating myoclonus.

SUMMARY OF THE INVENTION

The invention relates to the discovery that the compounds represented by Formula I are positive modulators of ax-amino-3-hydroxy-5-methyoisoxazole-4-propionic acid (AMPA) receptors. 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 I:

R 3 is hydrogen, or C 1-10 alkyl;

R 4 is substituted or unsubstituted aryl or heteroaryl, carbocycle or heterocycle;

wherein R, R x and R y are independently hydrogen, C 1-10 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.

These compounds can be used as cognitive enhancers, for the treatment of 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. 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 I 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 I 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. Thus, the present invention is also directed to novel substituted 5-oxo-5,6,7,8-tetrahydro-4H-1-benzopyrans of Formula I. Further, the present invention is directed to 3 H and 14 C radiolabeled compounds of Formula I and their use as radioligands for their binding site on the sodium channel.

DETAILED DESCRIPTION OF THE INVENTION

The substituted 5-oxo-5,6,7,8-tetrahydro-4H-1-benzopyrans and benzothiopyrans are represented by Formula I. Generally, preferred structures of the substituted 5-oxo-5,6,7,8-tetrahydro-4H-1-benzopyrans are those compounds where R 1 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-1-benzopyrans of and useful in the present invention are represented by Formulae II-VI. Thus, preferred embodiments are represented by Formula II:

or a pharmaceutically acceptable salt or prodrug thereof;

or a pharmaceutically acceptable salt or prodrug thereof;

or a pharmaceutically acceptable salt or prodrug thereof;

or a pharmaceutically acceptable salt or prodrug thereof;

or a pharmaceutically acceptable salt or prodrug thereof;

wherein R 1 , R 2 , R 3 and R 4 are as defined previously with respect to Formula I;

With respect to the formulae above:

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 .

Preferred values of R 1 and R 2 include hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, or C 1-6 thioalkyl, more preferable hydrogen or C 1-6 alkyl. Most preferably, R 1 and R 2 are both hydrogen or are both methyl.

A preferred subgenus of, and useful in, the present invention includes compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein:

R 1 and R 2 are independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 thioalkyl C 6-10 aryl, C 4-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl(C 1-6 )alkyl, C 6-10 aryl(C 2-6 )alkenyl, C 6-10 aryl(C 2-6 )alkynyl, or C 4-7 cycloalkyl(C 1-6 )alkyl; or R 1 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 1-6 alkyl;

R 4 is an optionally substituted C 6-10 aryl, heteroaryl, carbocycle or heterocycle;

wherein R, R x and R y are independently hydrogen, C 1-10 alkyl,

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:

2-amino-3-cyano-7,7-dimethyl-4-(2-naphthyl)-5-oxo-5,6,7,8-tetrahydro-4H-1-benzopyran; and

or a pharmaceutically acceptable salt or prodrug thereof.

Novel compounds of the present invention include compounds of Formula IV:

R 1 and R 2 are independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 thioalkyl C 6-10 aryl, C 4-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl(C 1-6 )alkyl, C 6-10 aryl(C 2-6 )alkenyl, C 6-10 aryl (C 2-6 )alkynyl, or C 4-7 cycloalkyl(C 1-6 )alkyl; or R 1 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 1-6 alkyl; and

Preferably, 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.

Novel compounds of the present invention include:

2-amino-3-cyano-7,7-dimethyl-4-(5-methoxy-3,4-methylenedioxyphenyl)-5-oxo-5,6,7,8-tetrahydro-4-H-1-benzopyran; and

and a pharmaceutically acceptable salt or prodrug thereof.

With respect to the present invention, the following definitions apply, unless otherwise explicitly provided for.

Useful cycloalkyl groups are C 3-8 cycloalkyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Useful halo or halogen groups include fluorine, chlorine, bromine and iodine.

Useful alkyl groups include straight-chained and branched C 1-10 alkyl groups, more preferably C 1-6 alkyl groups. Typical C 1-10 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 arylalkyl (or aralkyl) groups include any of the above-mentioned C 1-10 alkyl groups substituted by any of the above-mentioned C 6-14 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 6-14 aryl groups.

Useful arylalkynyl groups include any of the above-mentioned C 2-4 alkynyl groups substituted by any of the above-mentioned C 6-14 aryl groups. Useful values include phenylethynyl and phenylpropynyl.

Useful heteroarylalkyl groups include any of the above-mentioned C 1-10 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 C 1-10 alkyl groups substituted by any of the above-mentioned cycloalkyl groups.

Useful alkoxy groups include oxygen substituted by one of the C 1-10 alkyl groups mentioned above.

Useful alkylthio groups include sulfur substituted by one of the C 1-10 alkyl groups mentioned above.

The term 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 quaternized, 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 C 1-10 alkyl groups substituted by any of the above-mentioned heterocyclic groups.

Useful alkylamino and dialkylamino groups are NHR 20 and NR 20 and NR 20 R 21 , wherein R 20 and R 21 are C 1-10 alkyl groups.

Useful alkylaminocarbonyl groups are carbonyl groups substituted by NHR 20 and NR 20 R 21 , wherein R 20 and R 21 are C 1-10 alkyl groups as defined above.

Useful alkylthiol groups include any of the above-mentioned C 1-10 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.

Examples of prodrugs include esters or amides of Formula I 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, asparginate, glutamate and the like.

The invention disclosed herein is also meant to encompass prodrugs of the disclosed compounds. 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 I 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. Examples of 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 Cl, 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. When 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.

As used herein, the term 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).

The term chiral center refers to a carbon atom to which four different groups are attached.

The term 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.

The term racemic refers to a mixture of equal parts of enantiomers and which is optically inactive.

The term resolution refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule. The phrase 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 I and their use as radioligands for their binding site on the sodium channel. For example, 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 I and at increasing concentrations of a test compound in a competition assay.

Tritiated compounds of Formula I can be prepared by introducing tritium into the compound of Formula I by, for example, catalytic dehalogenation with tritium. This method includes reacting a suitably halogen-substituted precursor of a compound of Formula I with tritium gas in the presence of a suitable catalyst, for example Pd/C, in the presence or absence of a base. Other suitable methods for preparing tritiated compounds can be found in Filer, Isotopes in the Physical and Biomedical Sciences, Vol . 1 , Labeled Compounds ( Part A ), Chapter 6. 14 C-labeled compounds can be prepared by employing starting materials having a 14 C carbon.

Also included within the scope of the present invention are the non-toxic pharmaceutically acceptable salts of the compounds 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.

The pharmaceutical compositions of the invention may be administered to any animal that may experience the beneficial effects of the compounds of the invention. Foremost among such 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.

The 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. Thus, the present invention is directed to compounds that are positive modulators of AMPA receptors.

Compositions within the scope of this invention include all compositions 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. Typically, 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. For intramuscular injection, the dose is generally about one-half of the oral dose.

For the treatment of AIDS associated neuronal damage, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and Down's Syndrome, 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. Of course, it is understood that the exact treatment level will depend upon the case history of the animal, e.g., human being, that is treated. The precise treatment level can be determined by one of ordinary skill in the art without undue experimentation.

The unit oral dose may comprise from about 0.01 to about 50 mg, preferably about 0.1 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 0.1 to about 10, conveniently about 0.25 to 50 mg of the compound or its solvates.

In addition to administering the compound as a raw chemical, 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. Preferably, 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 0.25 to 75 percent of active compound(s), together with the excipient.

Also included within the scope of the present invention are the non-toxic pharmaceutically acceptable salts of the compounds 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.

The pharmaceutical compositions of the invention may be administered to any animal which may experience the beneficial effects of the compounds of the invention. Foremost among such animals are mammals, e.g., humans, although the invention is not intended to be so limited.

The pharmaceutical compositions of the present invention may be administered by any means that achieve their intended purpose. For example, administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, or buccal routes. Alternatively, or concurrently, 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. Thus, pharmaceutical preparations 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.

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. In addition, it is also possible to use 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. In addition, 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. Optionally, 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. Thus, 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 3 H, 11 C, 14 C or 18 F. Alternatively, a fluorescent group Y may be employed. Examples of such groups include 4-nitrobenzofurazan.

The following examples are illustrative, but not limiting, of the method and compositions of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in clinical therapy and which are obvious to those skilled in the art are within the spirit and scope of the invention.

A stirred solution of p-anisaldehyde (1.74 mL, 14.3 mmol) and malononitrile (0.90 mL, 14.28 mmol) in 75 mL of 95% EtOH at RT was treated with a few drops of piperidine and after about 5 min, a yellow precipitate was formed and the mixture was stirred for another 10 min after which 5,5-dimethylcyclohexan-1,3-dione (2.00 g, 14.3 mmol) was added as a solid in one portion. The stirred suspension became a solution after about 5 min. After about 2 h a white precipitate was formed and TLC analysis showed complete reaction. The precipitate was filtered and washed with cold 95% EtOH then dried under vacuum, resulting in 3.71 g (81%) of the title compound as a white solid, mp 197-200 C. 1 H NMR (DMSO-d 6 ): 7.04 (d, 2H), 6.96 (bs, 2H), 6.83 (d, 2H), 4.11 (s, 1H), 3.71 (s, 3H), 2.49 (m, 2H), 2.15 (m, 2H), 1.03 (s, 3H), 0.94 (s, 3H).

Total 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 (containing in mM: NaCl, 88; KCl, 1; CaCl 2 , 0.41; Ca(NO 3 ) 2 , 0.33; MgSO 4 , 0.82; NaHCO 3 , 2.4; HEPES 5; pH 7.4, with 0.1 mg/ml gentamycin sulphate) for 6 days prior to recording. Membrane current responses were recorded in frog Ringer solution containing (in mM): NaCl, 115; KCl, 2; CaCl 2 , 1.8; HEPES, 5; pH 7.4, or in a nominally Ca 2 -free Ringer solution containing (in mM): NaCl, 115; KCl, 2; BaCl 2 , 1.8; HEPES, 5; pH 7.4. Electrical recordings were made using a conventional two-electrode voltage clamp (Dagan TEV-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-1-benzopyrans elicited potentiation of AMPA responses as exemplified by compound of Example 4 (FIG. 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-1-benzopyrans required for 2-fold potentiation is shown in Table 1.

TABLE 1 Potentiation of AMPA Response by 5-Oxo-5,6,7,8-tetrahydro-4H-1-benzopyrans AMPA positive potentiation Example 2-fold M 1 7.0 2 4.0 3 12.0 4 4.0 5 35.0 6 18.0 7 12.0 8 12.0 9 12.0 10 14.0 11 6.0 12 60.0 13 60.0 14 12.0 15 18.0 16 20.0 17 27.0 18 1.6 Having now fully described this invention, it will be understood by those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations and other parameters without affecting the scope of the invention or any embodiment thereof. All patents and publications cited herein are fully incorporated by reference herein in their entirety.