HK1118286B - Dipyrazoles as central nervous system agents - Google Patents

Description

Dipyrazoles as central nervous system active agents

Technical Field

The present invention relates to novel dipyrazoles, compositions and methods for the treatment and/or prevention of neuropsychiatric disorders arising primarily from dysfunction of the glutamate receptors AMPA and NMDA.

Background

Glutamate is the most abundant excitatory neurotransmitter in the mammalian Central Nervous System (CNS), which regulates fast and slow neurotransmission processes; this transmission process determines normal neurophysiological processes such as acquisition and processing of memory, and synaptic plasticity. Anatomical and pharmacological findings strongly suggest that there is a deregulation of glutamate neurotransmission in the pathophysiology of several neuropsychiatric disorders; such neuropsychiatric disorders include schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, attention deficit hyperactivity disorder, AIDS-related dementia, neuralgia, depression, mild cognitive impairment, learning and memory disorders, and other diseases (Lehohla et al, Metab Brian Dis, 2004; Coyle, et al, Ann. NY Acad. Sci., 2003; Coyle, et al, Curr. drug Targets CNS Neurol. D., 2002; Krystal, et al, ArchGen Psychiatry, 2002; Dingledine et al, Pharmacol. Rev., 1999; and Ozawa, et al, prog. Neurobiol., 1998).

Glutamate neurotransmission is mediated by three ionotropic glutamate receptors. These receptors are cation-specific ion channels that regulate the rapid synaptic neurotransmission process. Based on the unique pharmacological, electrophysiological and biochemical properties of these ionotropic glutamate receptors, they are divided into three classes: alpha-amino-3-hydroxy-5-methyliso-ylOxazole-4-propionic acid (AMPA) receptor, Kainic Acid (KA) receptor, and N-methyl-D-aspartic acid (NMDA) receptor (Nakanishi, Science, 1992). In addition, each of these ionotropic glutamate receptors consists of multiple heteropolypeptide subunits, conferring heterogeneity on the receptor in different tissues (Ozawa, et al, Prog Neurobiol, 1998).However, each ionotropic glutamate receptor contains certain important subunits essential for functionality and is considered to be the most crucial factor in regulating function.

The regulation of ionotropic glutamate receptors is achieved in part by phosphorylation of specific tyrosine, threonine and serine residues by several kinases, or conversely, by dephosphorylation of these residues by specific phosphatases (Carvalho, et al, neurochem. Res., 2000 and Swope, et al, Adv Second Messenger phosphoprotein Res.1999). The phosphorylation state of the receptor subunit plays a key role in receptor activity. For example, NMDA receptors are regulated by several kinases and phosphatases acting on their NR1 subunit. Protein kinase c (pkc) and cAMP-dependent Protein Kinase (PKA) have been shown to phosphorylate serine residues 896 and 897, respectively, on the NR1 subunit (Tingley, et al, j.biol.chem., 1997 and Snyder, et al, Neuropharmacology, 2003). Similarly, AMPA receptors are regulated by several kinases and phosphatases acting on their GluR1 subunit; PKA phosphorylates serine residue 845 (Roche, et al, Neuron 16: 1179-1188, 1999; Wang, et al, Science 253: 1132-1135, 1991). Protein phosphatase I (PP1) dephosphorylates these serine residues, resulting in a molecular switch in receptor activity.

Acanthophilic protein (also known as neurobin II) is a scaffold protein that is enriched in dendritic spines of CNS neurons; the dendritic spines are the major sites of glutamatergic synapses in the brain (Allen, et al, Proc. Natl. Acad. Sci. USA, 1997; Hsieh-Wilson, et al, Biochemistry, 1999). Acanthophilic protein was originally identified based on its ability to bind to F-actin and protein phosphatase I (PP 1). The interaction between echinophilic proteins and PP1 is particularly important for the function of ionotropic glutamate receptors, because echinophilic proteins modulate the ability of PP1 to dephosphorylate ionotropic glutamate receptors by localization, thereby acting as a modulator of glutamatergic synaptic neurotransmission processes. This function was confirmed using voltage whole-cell recordings of kainic acid-induced AMPA current decay in individual acutely isolated frontal lobe cortical neurons (Yan et al, Nature Neurosci, 1999). In these experiments, the agonist-induced current decay by kainic acid was inhibited by a peptide corresponding to the PP1 binding domain of acanthophilic protein, but not by the same peptide containing point mutations, indicating that when acanthophilic protein no longer interacts with PP1, the AMPA receptors (in this case) no longer dephosphorylate and function less, and therefore, they remained more active.

In order to find small molecule compounds that mimic the above described echinophilic peptide action, a novel method of analyzing the protein interaction between PP1 and echinophilic proteins was used to find inhibitors of the binding process. These compounds were then evaluated in a whole-cell voltage clamp assay to assess their ability to inhibit agonist-induced AMPA current decay, as well as modulation of NMDA-stimulated current.

Thus, the compounds found herein should be useful in the treatment of several neuropsychiatric disorders that have been found to be associated with abnormalities in the glutamate neurotransmission process.

Summary of The Invention

The present invention is a compound of formula I or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein:

R₁is selected from: aryl, benzyl, C_3-8Cycloalkyl radical, C_1-10Alkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl, heteroaryl, arylcarbonyl, aryl C_1-6Alkyl radical C_3-8Cycloalkyl carbonyl group, C_1-10Alkylcarbonyl, heteroarylcarbonyl and

and

wherein X is hydrogen, benzyl, aryl C_2-6Alkyl radical, C_3-8Cycloalkyl radical, C_1-10Alkyl, or C_3-8Cycloalkyl radical C_1-6An alkyl group;

wherein said aryl, benzyl or heteroaryl may be optionally substituted with one or several substituents independently from each other selected from the group consisting of: c_1-6Alkyl radical, C_1-6Perfluoroalkyl, halo, hydroxy, C wherein n is 1-4, x is 0-8, y is 1-9 and x + y is 2n +1_nH_xF_y-6Alkoxy radical, C₁-C₆Alkoxy, nitro or aryl;

R₂is selected from: c_1-6Alkyl radical, C_3-8Cycloalkyl and aryl, wherein said aryl is optionally substituted with one or several substituents independently from each other selected from the group consisting of: c_1-6Alkyl radical, C_1-6Perfluoroalkyl, halo, hydroxy, C wherein n is 1-4, x is 0-8, y is 1-9 and x + y is 2n +1_nH_xF_y-6Alkoxy radical, C₁-C₆Alkoxy, nitro, aryl, or alkoxy;

R₃is selected from: aryl radical, C_3-8Cycloalkyl radical, C_1-6Alkyl and heteroaryl groups; wherein said aryl or heteroaryl is optionally substituted with one or several substituents independently from each other selected from the group consisting of: c_1-6Alkyl radical, C_1-6Perfluoroalkyl, halo, hydroxy, C wherein n is 1-4, x is 0-8, y is 1-9 and x + y is 2n +1_nH_xF_y-6Alkoxy radical, C₁-C₆Alkoxy, nitro, aryl, or alkoxy;

R₄is selected from: H. aryl, aryl C_2-6Alkyl, benzyl, hydroxy C_2-6Alkyl radical C_1-6Perfluoroalkyl group, C_3-8Cycloalkyl and C_1-6An alkyl group; wherein said aryl or benzyl group may be optionally substituted with one or several substituents independently from each other selected from the group consisting of: c_1-6Alkyl radical, C_1-6Perfluoroalkyl, halo, hydroxy, C wherein n is 1-4, x is 0-8, y is 1-9 and x + y is 2n +1_nH_xF_y-6Alkoxy radical, C₁-C₆Alkoxy, nitro, aryl, or alkoxy;

R₅is H, C_1-6Alkyl, or C_3-8A cycloalkyl group; and the following conditions must be satisfied:

(a) when R is₁And R₄Is phenyl or 4-chlorophenyl and R₅When is hydrogen, R₂And R₃Cannot be simultaneously methyl;

(b) when R is₁Is phenyl or 4-chlorophenyl and R₄And R₅When is hydrogen, R₂And R₃And not both methyl groups.

The invention also relates to certain pharmaceutical compositions of formula (I).

In another aspect of the present invention, there is disclosed a method of treating neuropsychiatric disorders susceptible to modulation of AMPA and NMDA receptors, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I:

wherein:

R₁is selected from: aryl, benzyl, C_3-8Cycloalkyl radical, C_1-10Alkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl, heteroaryl, arylcarbonyl, aryl C_1-6Alkyl radical C_3-8Cycloalkyl carbonyl group, C_1-10Alkyl carbonyl, heteroAryl carbonyl and

and

wherein X is hydrogen, benzyl, aryl C_2-6Alkyl radical, C_3-8Cycloalkyl radical, C_1-10Alkyl, or C_3-8Cycloalkyl radical C_1-6An alkyl group;

wherein said aryl, benzyl or heteroaryl may be optionally substituted with one or several substituents independently from each other selected from the group consisting of: c_1-6Alkyl radical, C_1-6Perfluoroalkyl, halo, hydroxy, C wherein n is 1-4, x is 0-8, y is 1-9 and x + y is 2n +1_nH_xF_y-6Alkoxy radical, C₁-C₆Alkoxy, nitro or aryl;

R₂selected from: c_1-6Alkyl radical, C_3-8Cycloalkyl and aryl groups; wherein said aryl is optionally substituted with one or several substituents independently from each other selected from the group consisting of: c_1-6Alkyl radical, C_1-6Perfluoroalkyl, halo, hydroxy, C wherein n is 1-4, x is 0-8, y is 1-9 and x + y is 2n +1_nH_xF_y-6Alkoxy radical, C₁-C₆Alkoxy, nitro, aryl, or alkoxy;

R₃selected from: aryl radical, C_3-8Cycloalkyl radical, C_1-6Alkyl and heteroaryl groups; wherein said aryl or heteroaryl is optionally substituted with one or several substituents independently from each other selected from the group consisting of: c_1-6Alkyl radical, C_1-6Perfluoroalkyl, halo, hydroxy, C wherein n is 1-4, x is 0-8, y is 1-9 and x + y is 2n +1_nH_xF_y-6Alkoxy radical, C₁-C₆Alkoxy, nitro, aryl, or alkoxy;

R₄selected from: H. aryl, aryl C_2-6Alkyl, benzyl, hydroxy C_2-6Alkyl radical C_1-6Perfluoroalkyl group, C_3-8Cycloalkyl and C_1-6An alkyl group; wherein said aryl or benzyl is optionally substituted with one or several substituents independently from each other selected from the group consisting of: c_1-6Alkyl radical, C_1-6Perfluoroalkyl, halo, hydroxy, C wherein n is 1-4, x is 0-8, y is 1-9 and x + y is 2n +1_nH_xF_y-6Alkoxy radical, C₁-C₆Alkoxy, nitro, aryl, or alkoxy;

R₅is H, C_1-6Alkyl, or C_3-8A cycloalkyl group.

Detailed Description

The terms used herein have the following meanings:

the term "C" as used herein_1-6Alkyl ", whether used alone or in combination with other terms, means a straight or branched chain alkyl (or alkylene, as the case may be) including methyl and ethyl, straight or branched propyl, butyl, pentyl and hexyl. Particularly important alkyl groups are methyl, ethyl, n-propyl, isopropyl and tert-butyl. Derived expressions such as "C_1-6Alkoxy group "," C_1-6Alkoxy radical C_1-6Alkyl group and hydroxyl group C_1-6Alkyl group "," C_1-6Alkylcarbonyl group and C_1-6Alkoxycarbonyl radical C_1-6Alkyl group "," C_1-6Alkoxycarbonyl group and amino group C_1-6Alkyl group "," C_1-6Alkylcarbamoyl C_1-6Alkyl group "," C_1-6Dialkyl carbamoyl radical C_1-6Alkyl "," mono-or di-C_1-6Alkylamino radical C_1-6Alkyl group and amino group C_1-6Alkylcarbonyl group and diphenyl C_1-6Alkyl group "," phenyl group C_1-6Alkyl group "," phenylcarbonyl group C_1-6Alkyl radicals "and" phenoxy radicals C_1-6Alkyl ", should also be construed accordingly.

Terms used herein“C_2-6Alkenyl "includes ethenyl and straight or branched propenyl, butenyl, pentenyl and hexenyl. Similarly, "C_2-6The term "alkynyl" includes ethynyl and propynyl, as well as straight or branched butynyl, pentynyl and hexynyl.

The term "C" as used herein_1-6Perfluoroalkyl "means that all hydrogen atoms in the alkyl group have been replaced by fluorine atoms. Illustrative examples include trifluoromethyl and pentafluoroethyl, straight or branched heptafluoropropyl, nonafluorobutyl, undecafluoropentyl and tridecafluorohexyl. Derived expression "C_1-6Perfluoroalkoxy "should also be construed accordingly.

The term "C" as used herein_3-8Cycloalkyl "means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The term "C" as used herein_3-8Cycloalkyl radical C_1-6Alkyl "means C as defined herein_3-8Cycloalkyl is further defined as having C_1-6An alkyl group is attached. Typical examples include cyclopropylmethyl, 1-cyclobutylethyl, 2-cyclopentylpropyl, cyclohexylmethyl, 2-cycloheptylethyl, 2-cyclooctylbutyl and the like.

The term "halogen" or "halo" as used herein means fluorine, chlorine, bromine and iodine.

The term "carbamoyl" as used herein means a- -NC (O) - -group attached at two positions to two separate additional groups, respectively.

The term "aryl" as used herein represents carbocyclic aromatic ring systems such as phenyl, biphenyl, naphthyl, anthryl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylene and the like. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic aromatic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1, 2, 3, 4-tetrahydronaphthyl, 1, 4 dihydronaphthyl, and the like.

The term "hetero" as used hereinAryl "represents a heterocyclic aromatic ring system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, such as furyl, phenylthio, pyrrolyl,Azolyl, thiazolyl, imidazolyl, isoimidazolylAzolyl, isothiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1, 2, 3-triazinyl, 1, 2, 4-triazinyl, 1, 3, 5-triazinyl, 1, 2, 3-Oxadiazolyl, 1, 2, 4-Oxadiazolyl, 1, 2, 5-Oxadiazolyl, 1, 3, 4-Oxadiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1, 3, 4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl (thioindenyl), indazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolylAzolyl, benzisoylAzolyl, purinyl, quinazolinyl, quinolyl, isoquinolyl, quinoxalyl, naphthyridinyl, pteridinyl, carbazolyl, azanylRadical diazaMesityl, acridinyl and the like. Heteroaryl is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 2, 3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indolinyl, methyl, ethyl, propyl, isopropyl,oxazolidinyl group,Azolinyl, oxazazepineAnd the like.

The term "heterocyclyl" as used herein, represents a saturated 3-to 8-membered ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur. Representative examples are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, tetrahydrofuranyl and the like.

The term "tautomer" or "tautomerism" as used herein refers to the coexistence of two (or more) compounds that differ only in the position and electron distribution of one (or more) mobile atom, such as keto-enol tautomerism or tautomerism.

The term "treatment" as used herein, whether in verb or noun, means any form of treatment, including but not limited to temporary or permanent alleviation of symptoms, elimination of the cause of symptoms, or prevention or alleviation of the appearance of symptoms and the development of the disease, disorder or condition in question.

By "therapeutically effective amount" is meant an amount of a compound that is effective for the treatment of a particular disorder or condition.

The term "patient" as used herein means a warm-blooded animal, such as rat, mouse, dog, cat, guinea pig, and primates, such as humans.

The term "pharmaceutically acceptable carrier" as used herein means a non-toxic solvent, dispersant, excipient, adjuvant, or other material with which the compounds of the present invention are combined to form a pharmaceutical composition, i.e., a dosage form suitable for administration to a patient. An example of such a carrier is a pharmaceutically acceptable oil, typically for parenteral administration.

The term "pharmaceutically acceptable salt" as used herein denotes salts of the compounds of the present invention which are useful in pharmaceutical formulations. However, certain other salts may also be useful in the preparation of the compounds of the present invention and their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of the invention include acid addition salts which may be formed, for example, by mixing a solution of a compound of the invention with a pharmaceutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, hydroxymaleic acid, malic acid, ascorbic acid, succinic acid, glutaric acid, acetic acid, salicylic acid, cinnamic acid, 2-phenoxybenzoic acid, hydroxybenzoic acid, phenylacetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, gluconic acid, lactic acid, pyruvic acid, malonic acid, carbonic acid or phosphoric acid. Metal salts of acids such as sodium hydrogen phosphate and potassium hydrogen sulfate may also be formed. The salts formed in this way may be present as the mono-or di-acid salts and may also be present in hydrated or substantially anhydrous form. Furthermore, when the compounds of the present invention themselves contain an acidic moiety, pharmaceutically acceptable salts can include alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and salts with suitable organic ligands, such as quaternary ammonium salts.

The expression "stereoisomers" is a general term for all isomers of various molecules that differ only in the orientation of their atoms in space. Generally, it includes the mirror image isomers (enantiomers) that tend to form due to the presence of at least one asymmetric center. When the compounds of the present invention have two or more asymmetric centers, they may exist in the form of diastereoisomers, and in addition, some molecules may exist in the form of geometric isomers (cis/trans). It is to be understood that all such isomers and mixtures thereof in any proportion are within the scope of the present invention.

In the following examples and preparations, the terms used herein shall have the following meanings: "kg" means kilogram, "g" means gram, "mg" means milligram, "μ g" means microgram, "pg" means picogram, "mol" means mole, "mmol" means micromole, "nmole" means nanomole, "L" means liter, "mL" or "mL" means milliliter, "μ L" means microliter, "° c" means celsius, "Rf" means retention factor, "mp" or "m.p." means melting point, "dec" means decomposition, "bp" or "b.p." means boiling point, "mmHg" means pressure in millimeters of mercury, "cm" means centimeter, "nm" means nanometer, [ alpha ] ",]²⁰ _D"means the specific optical rotation measured by sodium Spectroscopy D-line at 20 ℃ in a1 dm cell," c "means the concentration in g/mL," THF "means tetrahydrofuran," DMF "means dimethylformamide," NMP "means 1-methyl-2-pyrrolidone," MP-carbonate "means resin-bound macroporous polystyrene anion exchange resin, corresponding to tetraalkylammonium carbonate," brine "means saturated aqueous sodium chloride solution," M "means moles," mM "means millimoles," μ M "means micromoles," nM "means nanomoles," TLC "means thin layer chromatography," HPLC "means high performance liquid chromatography," HRMS "means high resolution Mass Spectrometry," CIMS "means ionization chemical Mass Spectrometry," t "means micromoles_R"means retention time," lb "means pounds," gal "means gallons," l.o.d. "means loss on drying," μ Ci "means microcui," i.p. "means intraperitoneal," i.v. "means intravenous.

In one aspect of the present invention, there is disclosed a novel compound having the general formula shown in formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof:

wherein:

R₁is selected from: aryl, benzyl, C_3-8Cycloalkyl radical, C_1-10Alkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl, heteroaryl, arylcarbonyl, aryl C_1-6Alkyl radical C_3-8Cycloalkyl carbonyl group, C_1-10Alkylcarbonyl, heteroarylcarbonyl and

and

wherein X is hydrogen, benzyl, aryl C_2-6Alkyl radical, C_3-8Cycloalkyl radical, C_1-10Alkyl, or C_3-8Cycloalkyl radical C_1-6An alkyl group;

wherein said aryl, benzyl or heteroaryl is optionally substituted by one or several substituents independently of each other selected from the group consisting of: c_1-6Alkyl radical, C_1-6Perfluoroalkyl, halo, hydroxy, C wherein n is 1-4, x is 0-8, y is 1-9 and x + y is 2n +1_nH_xF_y-6Alkoxy radical, C₁-C₆Alkoxy, nitro or aryl;

R₂selected from: c_1-6Alkyl radical, C_3-8Cycloalkyl and aryl, wherein said aryl is optionally substituted with one or several substituents independently from each other selected from the group consisting of: c_1-6Alkyl radical, C_1-6Perfluoroalkyl, halo, hydroxy, C wherein n is 1-4, x is 0-8, y is 1-9 and x + y is 2n +1_nH_xF_y-6Alkoxy radical, C₁-C₆Alkoxy, nitro, aryl, or alkoxy;

_R3 is selected from: aryl radical, C_3-8Cycloalkyl radical, C_1-6Alkyl and heteroaryl, wherein said aryl or heteroaryl may optionally be substituted independently of one another by one or several substituents selected from the group consisting ofAnd (3) substitution: c_1-6Alkyl radical, C_1-6Perfluoroalkyl, halo, hydroxy, C wherein n is 1-4, x is 0-8, y is 1-9 and x + y is 2n +1_nH_xF_y-6Alkoxy radical, C₁-C₆Alkoxy, nitro, aryl, or alkoxy;

R₄selected from: H. aryl, aryl C_2-6Alkyl, benzyl, hydroxy C_2-6Alkyl radical C_1-6Perfluoroalkyl group, C_3-8Cycloalkyl and C_1-6Alkyl, wherein said aryl or benzyl may be optionally substituted with one or several substituents independently from each other selected from the group consisting of: c_1-6Alkyl radical, C_1-6Perfluoroalkyl, halo, hydroxy, C wherein n is 1-4, x is 0-8, y is 1-9 and x + y is 2n +1_nH_xF_y-6Alkoxy radical, C₁-C₆Alkoxy, nitro, aryl or alkoxy; r₅Is H, C_1-6Alkyl or C_3-8A cycloalkyl group; and the following conditions must be satisfied:

(a) when R is₁And R₄Is phenyl or 4-chlorophenyl and R₅When is hydrogen, R₂And R₃Cannot be simultaneously methyl;

(b) when R is₁Is phenyl or 4-chlorophenyl and R₄And R₅When is hydrogen, R₂And R₃And not both methyl groups.

In a further embodiment of the compounds of the formula I according to the invention, R₁Selected from: aryl, benzyl, C_3-8Cycloalkyl radical, C_1-10Alkyl, aryl C_1-6Alkyl and

wherein X is benzyl, R₂And R₃Is C_1-6Alkyl radical, R₅Is hydrogen or C_1-6An alkyl group.

In the inventionIn another embodiment of the compounds of formula I, R₁Is aryl, R₂And R₃Is C_1-6Alkyl radical, R₄Is hydrogen, R₅Is hydrogen or C_1-6An alkyl group.

Examples of representative compounds of this embodiment of the compounds of formula I are selected from: 2 '- (2-fluorophenyl) -5, 5' -dimethyl-2H, 2 'H- [3, 4' ] bipyrazolyl-3 '-ol, 2' - (4-isopropylphenyl) -5, 5 '-dimethyl-2H, 2' H- [3, 4 '] bipyrazolyl-3' -ol, 2 '- (4-fluorophenyl) -5, 5' -dimethyl-2H, 2 'H- [3, 4' ] bipyrazolyl-3 '-ol, 5' -dimethyl-2 '- (4-trifluoromethylphenyl) -2H, 2' H- [3, 4 '] bipyrazolyl-3' -ol, 5 '-dimethyl-2' - (4-methoxyphenyl) -2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol, 2 ' - (3-fluorophenyl) -5, 5 ' -dimethyl-2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol, 2 ' - (2-methylphenyl) -5, 5 ' -dimethyl-2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol, 55 ' -dimethyl-2 ' - (4-trifluoromethoxyphenyl) -2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol, 5 ' -dimethyl-2 ' - (4-methylphenyl) -2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol, 5, 5 ' -dimethyl-2 ' - (3-methylphenyl) -2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol, 5 ' -dimethyl-2 ' - (2-ethylphenyl) -2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol, 5 ' -dimethyl-2 ' - (3, 4-dichloro-phenyl) -2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol, 5 ' -dimethyl-2 ' - (3-chlorophenyl) -2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol, 2 ' - (4-tert-butylphenyl) -5, 5 '-dimethyl-2H, 2' H- [3, 4 '] bipyrazolyl-3' -ol, 5 '-dimethyl-2' - (3-trifluoromethylphenyl) -2H, 2 'H- [3, 4' ] bipyrazolyl-3 '-ol, and 5' -methoxy-5, 3 '-dimethyl-1' -phenyl-2H, 1 'H- [3, 4' ] bipyrazolyl.

In a further embodiment of the compounds of the formula I according to the invention, R₁Is aryl, R₂And R₃Is C_1-6Alkyl radical, R₄Is aryl C_2-6Alkyl or benzyl and R₅Is hydrogen or C_1-6An alkyl group.

Representative examples of compounds in this embodiment of the compounds of formula I are selected from: 5, 5 ' -dimethyl-2-phenylethyl-2 ' -phenyl-2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol, 2-benzyl-5, 5 ' -dimethyl-2 ' -phenyl-2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol, 2-benzyl-5 ' -methoxy-5, 3 ' -dimethyl-1 ' -phenyl-2H, 1 ' H- [3, 4 ' ] bipyrazolyl, and 2- (3-hydroxy-benzyl) -5, 5 ' -dimethyl-2 ' -phenyl-2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol.

In another embodiment of the compounds of formula I of the present invention, R₁Is aryl, R₂And R₃Is C_1-6Alkyl radical, R₄Is a hydroxy group C_2-6Alkyl radical C_1-6Perfluoroalkyl group, C_3-8Cycloalkyl or C_1-6Alkyl, and R₅Is hydrogen.

Examples of compounds of this embodiment of the compounds of formula I are selected from: 5, 5 ' -dimethyl-2 ' -phenyl-2- (2, 2, 2-trifluoro-ethyl) -2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol, 2-cyclohexyl-5, 5 ' -dimethyl-2 ' -phenyl-2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol, 2- (2-hydroxy-ethyl) -5, 5 ' -dimethyl-2 ' -phenyl-2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol, and 2, 5, 5 ' -trimethyl-2 ' -phenyl-2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol.

In another embodiment of the compounds of formula I of the present invention, R₁Is aryl, R₂And R₃Is C_1-6Alkyl radical, R₄Is aryl, and R₅Is hydrogen.

Representative examples of compounds of this embodiment of the compounds of formula I are selected from: 2- (4-methoxyphenyl) -5, 5 '-dimethyl-2' -phenyl-2H, 2 'H- [3, 4' ] bipyrazolyl-3 '-ol and 2- (4-fluorophenyl) -5, 5' -dimethyl-2 '-phenyl-2H, 2' H- [3, 4 '] bipyrazolyl-3' -ol.

In yet another embodiment of the compounds of formula I of the present invention, R₁Is aryl C_2-6Alkyl or benzyl, R₂And R₃Is C_1-6Alkyl, and R₄And R₅Is hydrogen.

Representative examples of compounds of this embodiment of the compounds of formula I are selected from: 5, 5 ' -dimethyl-2 ' -phenethyl-2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol, 2 ' - (3-hydroxy-benzyl) -5, 5 ' -dimethyl-2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol and 2 ' -benzyl-5, 5 ' -dimethyl-2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol.

In a further embodiment of the compounds of formula I according to the invention,

R₁is that

Wherein X is benzyl, R₂And R₃Is C_1-6Alkyl, and R₄And R₅Is hydrogen.

An example of a compound of this embodiment of the compound of formula I is 2 ' - (1-benzylpiperidin-4-yl) -5, 5 ' -dimethyl-2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol.

In another embodiment of the compounds of formula I of the present invention, R₁Is C_3-8Cycloalkyl radical, R₂And R₃Is C_1-6Alkyl, and R₄And R₅Is hydrogen.

An example of a compound of this embodiment of the compounds of formula I is 2 '-cyclohexyl-5, 5' -dimethyl-2H, 2 'H- [3, 4] bipyrazol-3' -ol.

In another embodiment of the present invention, a compound is disclosed which is named 5, 1 ', 5 ' -trimethyl-2 ' -phenyl-1 ', 2 ' -dihydro-2H- [3, 4 ' ] bipyrazolyl-3 ' -one.

In another embodiment of the present invention, a pharmaceutical composition is disclosed comprising an effective amount of a compound of formula I and a pharmaceutically acceptable carrier.

In yet another embodiment of the present invention, a method of treating neuropsychiatric disorders susceptible to modulation of AMPA and NMDA receptors is disclosed which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I, or a stereoisomer or pharmaceutically acceptable salt thereof,

wherein:

R₁is selected from: aryl, benzyl, C_3-8Cycloalkyl radical, C_1-10Alkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl, heteroaryl, arylcarbonyl, aryl C_1-6Alkyl radical C_3-8Cycloalkyl carbonyl group, C_1-10Alkylcarbonyl, heteroarylcarbonyl, and

and

wherein X is hydrogen, benzyl, aryl C_2-6Alkyl radical, C_3-8Cycloalkyl radical, C_1-10Alkyl, or C_3-8Cycloalkyl radical C_1-6An alkyl group;

wherein said aryl, benzyl or heteroaryl may be optionally substituted with one or several substituents independently from each other selected from the group consisting of: c_1-6Alkyl radical, C_1-6Perfluoroalkyl, halo, hydroxy, C wherein n is 1-4, x is 0-8, y is 1-9 and x + y is 2n +1_nH_xF_y-6Alkoxy radical, C₁-C₆Alkoxy, nitro or aryl;

R₂selected from: c_1-6Alkyl radical, C_3-8Cycloalkyl and aryl, wherein said aryl may be optionally substituted with one or several substituents independently from each other selected from the group consisting of: c_1-6Alkyl radical, C_1-6Perfluoroalkyl, halo, hydroxy, wherein n is 1-4, x is 0-8, y is 1-9 and x + yC equal to 2n +1_nH_xF_y-6Alkoxy radical, C₁-C₆Alkoxy, nitro, aryl or alkoxy;

R₃selected from: aryl radical, C_3-8Cycloalkyl radical, C_1-6Alkyl and heteroaryl, wherein said aryl or heteroaryl may be optionally substituted with one or several substituents independently from each other selected from the group consisting of: c_1-6Alkyl radical, C_1-6Perfluoroalkyl, halo, hydroxy, C wherein n is 1-4, x is 0-8, y is 1-9 and x + y is 2n +1_nH_xF_y-6Alkoxy radical, C₁-C₆Alkoxy, nitro, aryl or alkoxy;

R₄is selected from: H. aryl, aryl C_2-6Alkyl, benzyl, hydroxy C_2-6Alkyl radical C_1-6Perfluoroalkyl group, C_3-8Cycloalkyl and C_1-6Alkyl, wherein said aryl or benzyl may be optionally substituted with one or several substituents independently from each other selected from the group consisting of: c_1-6Alkyl radical, C_1-6Perfluoroalkyl, halo, hydroxy, C wherein n is 1-4, x is 0-8, y is 1-9 and x + y is 2n +1_nH_xF_y-6Alkoxy radical, C₁-C₆Alkoxy, nitro, aryl or alkoxy; and is

R₅Is H, C_1-6Alkyl or C_3-8A cycloalkyl group.

In another embodiment of the method of the invention, the neuropsychiatric disorder is selected from the group consisting of: depression, epilepsy, schizophrenia, alzheimer's disease, learning and memory disorders, and mild cognitive impairment.

In a further embodiment of the method of the invention, the disorder is schizophrenia.

In yet another embodiment of the method of the present invention, the disorder is depression.

In yet another embodiment of the method of the invention, the disorder is a learning or memory disorder.

The compounds of the present invention may be prepared by synthetic routes as shown in the following schemes or by other methods apparent to those skilled in the art. Unless otherwise indicated, the R substituents are the same as the R substituents in formula (I). In the following synthetic schemes, reactive functional groups of the compounds of the invention may be protected, if necessary, with suitable protecting groups. The protecting group may be removed at a later stage of the synthesis process. For methods of protecting reactive functional Groups and subsequently removing them see t.w.greene and p.g.m.wuts, Protective Groups in Organic Synthesis, Wiley and Sons, 1991.

Scheme A

Scheme A shows formula I and wherein R₄And R₅Synthesis of compounds that are hydrogen. In step A1, a pyrone substituted at the 6-position1A commercially available compound or one that can be readily synthesized by methods well known in the art (Lokot, et al, Tetrahedron, 55, 4783-2Acyl chloride reacts to obtain 3-acylated derivative3. Suitable strong organic acids which can be used for this reaction are, for example, trihaloacetic acids such as trifluoroacetic acid or a trifluoroalkyl sulfonic acid. This reaction is usually carried out in the range from 50 ℃ to the reflux temperature of the acid.

In step A2, the compound3With a hydrazine4React to form a compound5Hydrazone (c). This reaction is usually carried out in an inert organic solvent such as an alcohol; if a hydrazine salt is used as a reactant, it can optionally also be carried out in the presence of a suitable base. Suitable alcohols include methanol, ethanol, isopropanol or ethylene glycol, and suitable bases include basic carbonates such as sodium, potassium or cesium carbonate, or resin-supported carbonates such as MP-carbonate. The reaction temperature canSo as to be in the range from room temperature to the reflux temperature of the organic solvent.

As shown in step A3, by reacting in the presence of a suitable organic acid such as acetic acid, propionic acid or trifluoroacetic acid5Intramolecular cyclization is achieved, the compound5The hydrazone can be converted to a pyrazolyl dione 6. This reaction is usually carried out at a relatively high temperature ranging from 50 ℃ to the reflux temperature of the organic acid.

In step A4, the diketone6With hydrazine7Reaction of (a) to form the desired bipyrazole8. This reaction is typically carried out in an inert organic solvent such as an alcohol at or near the reflux temperature of the solvent.

Scheme B

Scheme B demonstrates a method that can be used to synthesize compounds of formula I (wherein R is₅Is C_1-6Alkyl radical, C_3-8Cycloalkyl groups). In step B1, a bipyrazole8The unsubstituted ring nitrogen atom is protected by an alkoxycarbonyl group to form a compound which is a positional isomer9And10a mixture of (a). This reaction is accomplished by employing methods well known in the art, such as treating the compound with t-butyl carbazate8Can produce a compound9. See kashima, et al, Tetrahedron, 54, 14679, 1998.

In step B2, the isomer9And10the mixture is mixed with an alkylating/cycloalkylating agent11Reacting wherein Lg is a leaving group such as halo, alkylsulfonate or arylsulfonate to form an O-alkylated compound12-and13and N-alkylated compounds14And15a mixture of (a). The reaction can be carried out in an aprotic polar solvent such as DMF, DMSO or acetonitrile in the presence of a suitable base. Suitable bases include alkaline carbonic acidSalts and bicarbonates, for example potassium and sodium carbonates and bicarbonates. The reaction temperature may range from room temperature to the reflux temperature of the organic solvent. The reaction mass was treated and chromatographed on silica gel to obtain two different mixtures. A mixture of the O-alkylated compound12And13another mixture consisting of the N-alkylated compound14And15and (4) forming.

The O-alkylated target compound16Can be made regioisomeric via N-alkoxycarbonyl as shown in step B312And13obtained by cracking. Such cleavage can be accomplished by methods well known in the art, for example, by treating the compound with an acid or base12And13。

similarly, step B4 uses the same conditions as step B3 to provide the N-alkylated compound17。

Biological examples

The following protocol was used to determine the biological properties of the compounds of the invention. The following examples are presented to further illustrate the invention. However, they should not be construed as limiting the invention in any way.

Echinophilic protein/protein phosphatase-I interaction analysis

Materials:

10 XTS (Tris buffered saline) stock was obtained from Bio-Rad. The echinophilus protein (6XHis) and GST-PP1 protein were cloned, expressed and purified by the protein production process inside the company. The Eu-anti-GST antibody, DELFIA assay buffer and DELFIA enhancer were obtained from Wallac (Perkin Elmer). High binding 384 well plates were produced by Greiner.

Method for ELISA time-resolved fluorescence 384-well assay:

plates were coated with 50ul of the acanthrin/TBS solution (50ug/ml) or 50ul of TBS buffer (0 control) and incubated overnight at 4 ℃. Test compounds were prepared and diluted on 96-well polypropylene plates using a Labsystems Wellpro liquid handler. After washing the plates 3 times with an Elx-405(Biotek) plate washer and TBS, the compounds were transferred from the 96-well plates to 384-well plates using a Multimek (Beckman) liquid processor. GST-PP1, 50ul (2.5ug/ml) was then added to the plates. The plates were incubated at room temperature for 3 to 6 hours. The plate was washed 3 times as described above, 50ul Eu-anti-GST antibody (. about.50 ng/ml) was added using a Multidrop Multi-well liquid charger (Titertek), and incubated at room temperature for 30 minutes. The plate was washed 3 times as described above, 100ul of enhancing solution was added using a Multidrop multi-well liquid charger, and incubated at room temperature for 1 hour. The plate was read using europium setting mode on a faryte (tecan) fluorescence plate reader. The ability of these compounds to inhibit the interaction between echinocandin (6XHis) and GST-PP1 was assessed by measuring the decrease in the fluorescence signal.

Voltage whole-cell recordings of AMPA and NMDA currents in frontal lobe cortical neurons:

acute neuron isolation method:

frontal Cortex (PFC) neurons in young adult rats (3 to 5 weeks postnatal) were acutely isolated using methods similar to those previously reported (Feng, et al, J Neurosci, 2001; Chen, et al, Proc Natl Acad Sci USA, 2004). Slicing brain in NaHCO₃After incubation in buffered saline, the PFCs were dissected and placed at room temperature in an oxygenated cabinet containing papain (Sigma, 0.8mg/ml) in HEPES-buffered Hank's Balanced salt solution (HBSS, Sigma). After 40 minutes of enzymatic digestion, the tissue was kept at low Ca⁺²Ion HEPES buffered saline was rinsed 3 times and mechanically separated using a series of graduated, fired edge papettes pipettes. The cell suspension was then spread on a 35mm Lux Petri dish and placed on a Nikon (Nikon) inverted microscope stage.

Whole cell recordings of AMPA and NMDA:

whole cell recordings of Whole cell ion channel currents standard voltage clamp techniques were used (Yan et al, Nat Neuroscience, 1999; Wang et al, J Neurosci, 2003; Tyszkiewicz et al, J physiol., 2004). The internal solution (inside the patch pipette) consisted of the following solutions (in nM): 180N-methyl-d-glucamine (NMG), 40 HEPES, 4 MgCl₂0.1 BAPTA, 12 creatine phosphate, 3 Na₂ATP、0.5 Na₂GTP and 0.1 leupeptin, pH 7.2-7.3, 265-270 mosm/L. The external solution consisted of the following solutions (in mM): 127 NaCl, 20 CsCl, 10HEPES, 1 CaCl₂、5 BaCl₂12 glucose, 0.001 TTX, 0.02 glycine, pH 7.3-7.4, 300-305 mOsm/L. Recorded data were obtained by an Axon Instruments 200B patch clamp amplifier controlled and monitored by an IBM computer; the software was pCLAMP (v.8) and the data acquisition system was DigiData 1320 series (Axon instruments). The electrode resistance in the water bath is typically 2-4 M.OMEGA.. After the seal is broken to reach the whole-cell recording condition, the series resistance (4-10 M.OMEGA.) is compensated (70-90%) and monitored periodically. The cell membrane potential was maintained at a level of-60 mV.

KA (200. mu.M) or NMDA (100. mu.M, dissolved in Mg-free solution)²⁺Ionic solution) initiates a partially desensitized inward current. KA or NMDA was injected every 30 seconds for 2 seconds to minimize desensitization-induced current amplitude drop. The medication is applied through a "drain" system that is gravity fed. The liquid-filled capillary bundle (internal diameter of about 150 μm) is located several hundred microns from the cell under study. Solution changes were accomplished by SF-77B rapid solution stimulus input devices (Warner Instruments). Data were collected using pclpap software and analyzed using AXOGRAPH, KALEIDOGRAPH and STATVIEW.

The compounds described herein inhibit KA-induced AMPA current decay by either stabilizing agonist-evoked current or increasing current. Likewise, the compounds described herein also increase NMDA-evoked currents. The lowest effective dose (MED) was found by determining the lowest concentration of inhibitor effective in each functional assay.

The results of these analyses are shown in tables I and II.

TABLE I

Inhibition of KA-induced AMPA current decay

Example numbering	Minimum effective concentration (μ M)
		4	0.1*
5	0.1*
		15	1.0
18	1.0
		25	1.0

^*The lowest concentration tested (MED) may be below 100 nM.

TABLE II

NMDA-induced current increase

Example numbering	Minimum effective concentration (μ M)	Average percent increase in NMDA Current (10. mu.M)
			8	1	303% (n ═ 3 neurons)
18	5	55% (n is 4 neurons)

Porsolt forced swimming test

The effect measured in this model is related to the antidepressant effectiveness of the drug. Examples of such models are: rats administered an effective antidepressant compound will attempt to escape the water tank more aggressively than rats administered the carrier solvent alone.

The animals used in this study were non-juvenile male Sprague Dawley rats weighing 225-350 g. The test apparatus consisted of six transparent PLEXIGLAS 40cm high and 19cm wideAnd (4) forming a round cylinder. The water depth in the cylinder is 18cm, and the water temperature is 25 ℃. Each rat was placed in a water jar for 15 minutes of practice. The rats are administered a carrier solvent (0.5% methylcellulose) or compound in a sub-chronic or acute mannerAfter 24 hours, the rats were returned to the water tank and the test was conducted for 5 minutes. These test procedures were videotaped for later scoring.

Sub-chronic administration includes three administrations of the drug over 24 hours from exercise to trial. The application time was 24 hours, 5 hours and 1 hour before the test, respectively. Acute administration was only one time of drug administration, 1 hour prior to the trial. Scoring is performed using a time-sampling computer program. Every five seconds, animals were scored for one of three behaviors: standing still, moderate swimming or climbing. The sample score is then converted to a percentage of the trial process.

The following examples of the compounds used herein further illustrate the invention. These examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention in any way.

Object identification test

The object recognition test is a memory test. It measures the ability of mice (and rats) to discriminate between known and unknown objects and is therefore suitable for use in determining the effect of the compounds of the invention on improving memory.

This assay can generally be performed as described in the literature (Blokland et al NeuroReport 1998, 9, 4205-4208; Ennaceur, A., Delaour, J., Behav. brain Res.1988, 31, 47-59; Ennaceur, A., Meliani, K., Psychopharmacology 1992, 109, 321-330; Prickaerts, et al Eur. J. Pharmacol.1997, 337, 125-136).

In the first stage, a mouse is faced with two identical objects in an observation area that is originally large without any object. The mouse will carefully examine both objects, sniffing them again. Mice were scored for the time spent on each object. In the second phase, after 24 hours, the mice were again placed in the observation area for testing. At this point, one of the known objects is replaced with another new unknown object. When a mouse recognizes a known object, it will examine the unknown object particularly carefully. However, after 24 hours, the mouse will usually forget which object it had been examined in the first stage, and will therefore examine both objects equally closely. If a substance having learning and memory improving effects is administered to the mouse, the mouse can recognize the object that had been seen in the first stage 24 hours ago. It will examine the new unknown object more closely than the known one. This memory capacity is expressed as a discrimination index. If the identification index is zero, it means that the mouse examines the old and new objects for the same time; that is, it does not recognize the old object, but does the same reaction on both objects, as if both were unknown new objects. If the discrimination index is greater than zero, it means that the mouse has a longer time to examine a new object than an old object; i.e. the mouse recognized the old object.

MK-801 induced psychosis model:

the uncompetitive NMDA receptor antagonist MK-801 induces stereotypical behavior and hyperactivity in rodents through interaction with NMDA receptor-associated ion channels (Contreras et al, Synapse 2: 240-243, 1988). Phencyclidine also interferes with NMDA receptors, producing psychotic symptoms in humans similar in many respects to schizophrenia. These findings suggest that defects in glutamate delivery may be a pathological factor in schizophrenia (Javitt & Zukin, am. J. Psychiator., 48: 1301-1308, 1991). Neuroleptic agents haloperidol, clozapine and raclopride reverse MK-801 induced changes in rat behavior (Carlsson et al, biol. Psychiator.46: 1388-. Thus, the activity and stereotypical behavior elicited by MK-801 in rats may represent a suitable animal model for testing the potential effectiveness of antipsychotics.

Experimental methods

Before the test, male Wistar rats weighing 250-300 g/cage were housed in the same cage and placed in an environment of 21 + -2 ℃ room temperature and 12 hours light/12 hours dark cycle (light on 7:00 early) for at least 5 days. All animals were provided with commercially available food and drinking water, and were allowed to take ad libitum.

On the day of the experiment, rats were administered either a control drug vehicle, a control drug haloperidol or clozapine, a test compound vehicle or a test compound. After administration, the rats were returned to their cages for 15 minutes. Animals treated with haloperidol, clozapine, test compound and vehicle received an intraperitoneal injection of 0.3mg/kg MK-801. The remaining rats treated with placebo received a second injection of vehicle. The standard injection volume was 2.0 ml/kg. After 10 minutes in the home cage, the rats were transferred to a test chamber (Plexiglas, 29X 12cm) 5 minutes before the start of the fitness evaluation, and the test chamber was cleaned with 70% ethanol before each evaluation was started. The stereotypical behavior (defined as touching the wall with the nose) and the activity (defined as a 180 degree large turn) were evaluated over several 5 minute periods.

Enhanced analysis of pentaerythrityl

Male CD-1 mice (20-30 g) were used. On the day of the experiment, animals were taken to the laboratory and randomized into groups. 10 mice per group were injected intraperitoneally with test compound (i.p., 10ml/kg) 60 minutes prior to stimulation with pentaerythrite (55mg/kg subcutaneously) as a primary screen. After administering pentaerythrine, the animals were placed in clear plastic cylinders (12X 5 inches), respectively, and observed for clonic seizures. Clonic seizures type epilepsy is defined as single seizures of clonic seizures for a period of at least 3 seconds. When these clonic seizures occur, mice treated with pentaerythrine are considered "enhanced".

If 50% of the animals show an enhancing effect during the primary screening process, it is necessary to determine a dosage range. For the vehicle control group, test compounds were tested using 3 or more doses during 60 minutes of pretreatment. Determining ED using linear regression₅₀The value is obtained.

Over-limit electric shock test

Male CD-1 mice (18-30 g) were used. Preparing the medicine by using distilled water; if the drug is insoluble, a surfactant is added. Control animals received vehicle. The medicine is injected into the abdominal cavity by the conventional method. The route of administration may vary (oral, subcutaneous). The dose volume was 10 ml/kg.

A constant current stimulator similar to the devices described in Woodbury and Davenport (arch. int. pharmacodyn.92: 97-107, 1952) produces a 60Hz shock through the corneal electrodes, which varies in current and duration. In 95% of the control mice, a 0.3 second 25mA shock (50V) was sufficient to produce extensor tone.

The compound is considered to provide protection if the mice do not exhibit extensor tone. Protection is expressed as a normalized percentage inhibition relative to the vector control. Time response experiments were performed using 6 animals per group. Animals were tested 30, 60 and 120 minutes after dosing. Further tests were performed in more time intervals if the previous test was specifically addressed. When peak activity was determined, dose response data was measured using 10 animals per group over this time interval. Calculating ED by computerized probability analysis₅₀And 95% confidence intervals.

Synthetic examples

SUMMARY

Commercially available reagents and solvents were used as purchased.¹H NMR nuclear magnetic resonance spectra were recorded on a Varian MeresuryPlus-300 (300MHz) or a Varian Unity Inova (400MHz) spectrometer as indicated. Proton chemical shift values are expressed in δ ppm with tetramethylsilane as internal standard (0.0 ppm). MS (LC-MS) data were obtained using a Micromass LCT time-of-flight mass spectrometer with an electrospray ionization device, with data acquisition times from m/z 100 to 1000 of 5 minutes. LC (LC-MS) was performed with Hypersil C18 column (4.6X 50mm, 3.5, mobile phase of 0.1% TFA in H₂O solution (a) and 0.1% TFA in ACN (B) with a gradient from 5% to 100% B in 3 minutes, then held at 100% B for 2 minutes. Alternatively, a Platform LC-MS with an electrically-charged nebulization source could be used, with the HP1100 LC system operating with ESI source dispensed at 2.0ml/min and 200. mu.L/min, and with an online HP1100 DAD detection and SEDEX ELS detection. Using a Luna C18(2) column (30X 4.6mm 3. mu. with a gradient from 5% to 95% B in 4.5 min, mobile phase 0.1% formic acid in H₂O solution and 0.1% formic acid in ACN (B). HPLC purification was performed on a Varian ProStar system using a reverse phase C18 column using ACN/H containing 0.1% trifluoroacetic acid₂And (4) performing linear gradient on the O.

Example 1

3-acetyl-4-hydroxy-6-methyl pyran-2-one

4-hydroxy-6-methyl-pyran-2-one (12.6g, 100mmol) was dissolved in trifluoroacetic acid (50ml) and 7.8g (100 mmol) of acetyl chloride was added dropwise. The mixture was heated at reflux for 5 hours. The reaction mixture was evaporated under reduced pressure. 50ml of water were added, extracted with ethyl acetate (50 ml. times. 3) and the organic layers were combined. Washed with brine and dried (sodium sulfate). Chromatography on silica gel eluting with chloroform gave 5.8g (34.5mmol) of 3-acetyl-4-hydroxy-6-methylpyran-2-one.

LCMS (M + H): m/z 169, retention time 3.24 min.

Example 2

3- {1- [ (2-fluorophenyl) group) -hydrazono group]-ethyl } -4-hydroxy-6-methyl-pyran-2-one

To a solution of 2-fluorophenylhydrazine hydrochloride (0.16g, 1.0mmol) in methanol (8ml) was added MP-carbonate (1.0g, 3.3 equivalents). The mixture was shaken at room temperature for 1 hour. The resin was filtered and washed with methanol. To the filtrate was added (2-fluorophenyl) -hydrazine (0.134g, 0.80 mmol). The reaction mixture was shaken at room temperature for 2 hours, and then the solvent was evaporated under reduced pressure. The solid was recrystallized from a minimum amount of methanol to give 0.185g (0.67mmol) of 3- {1- [ (2-fluorophenyl) -hydrazono ] -ethyl } -4-hydroxy-6-methyl-pyran-2-one.

LCMS (M + H): m/z 277, retention time 2.74 min.

Example 3

1- [1- (2-fluorophenyl) -3-methyl-5-oxo-4, 5-dihydro-1H-pyrazol-4-yl]-butane-1, 3-dione

A solution of 3- {1- [ (2-fluorophenyl) -hydrazono ] -ethyl } -4-hydroxy-6-methyl-pyran-2-one (0.045g, 0.163mmol) in acetic acid (0.3ml) was heated at reflux for 1 hour. Heptane (3ml) was added and the mixture was evaporated to dryness to give 1- [1- (2-fluorophenyl) -3-methyl-5-oxo-4, 5-dihydro-1H-pyrazol-4-yl ] -butane-1, 3-dione (0.045g, 0.163 mmol). This material was used in the next step without further purification.

LCMS (M + H): m/z 277, retention time 2.05 min.

Example 4

2 ' - (2-fluorophenyl) -5, 5 ' -dimethyl-2H, 2 'H-[3，4’]Bipyrazole-3' -alcohols

To 1- [1- (2-fluorophenyl) -3-methyl-5-oxo-4, 5-dihydro-1H-pyrazol-4-yl ] -butane-1, 3-dione (0.045g, 0.163mmol) was added a solution of hydrazine hydrate (0.016g, 0.32mmol) in ethanol (1.6 ml). The reaction mixture was heated at reflux for 1.5 h, then the ethanol was evaporated. The residue was washed with dichloromethane to give 2 ' - (2-fluorophenyl) -5, 5 ' -dimethyl-2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol (0.028g, 0.102 mmol).

LCMS (M + H): m/z 273, retention time 2.16 min.

Example 5

2 '- (4-chloro-phenyl) -5, 5' -dimethyl-2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 3-acetyl-4-hydroxy-6-methyl pyran-2-one and 4-chlorophenylhydrazine hydrochloride following the procedures shown in examples 2, 3 and 4.

LCMS (M + H): m/z 289, retention time 2.72 min.

Example 6

2 '- (4-isopropylphenyl) -5, 5' -dimethyl-2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 3-acetyl-4-hydroxy-6-methyl-pyran-2-one and 4-isopropylphenylhydrazine hydrochloride according to the methods shown in examples 2, 3 and 4.

LCMS (M + H): m/z 297, retention time 2.85 min.

Example 7

2 '- (4-fluorophenyl) -5, 5' -dimethyl-2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 3-acetyl-4-hydroxy-6-methyl pyran-2-one and 4-fluorophenylhydrazine hydrochloride following the procedures shown in examples 2, 3 and 4.

LCMS (M + H): m/z 273, retention time 2.00 min.

Example 8

5, 5 '-dimethyl-2' - (4-trifluoromethylphenyl) -2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 3-acetyl-4-hydroxy-6-methyl pyran-2-one and 4-trifluoromethylphenylhydrazine according to the methods shown in examples 2, 3 and 4.

LCMS (M + H): m/z 323, retention time 2.88 min.

Example 9

2 ' -cyclohexyl-5, 5 ' -dimethyl-2H, 2 ' H- [3, 4]Bipyrazole-3' -ol

The title compound was prepared from 3-acetyl-4-hydroxy-6-methyl pyran-2-one and cyclohexylhydrazine hydrochloride following the procedure outlined in examples 2, 3 and 4.

LCMS (M + H): m/z 261, retention time 1.80 min.

Example 10

5, 5 '-dimethyl-2' - (4-methoxyphenyl) -2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 3-acetyl-4-hydroxy-6-methyl pyran-2-one and 4-methoxyphenylhydrazine hydrochloride following the procedures shown in examples 2, 3 and 4.

LCMS (M + H): m/z 285, retention time 1.96 min.

Example 11

2 '- (3-fluorophenyl) -5, 5' -dimethyl-2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 3-acetyl-4-hydroxy-6-methyl pyran-2-one and 3-fluorophenylhydrazine hydrochloride following the procedures shown in examples 2, 3 and 4.

LCMS (M + H): m/z 273, retention time 2.45 min.

Example 12

2 '- (2-methylphenyl) -5, 5' -dimethyl-2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 3-acetyl-4-hydroxy-6-methyl pyran-2-one and 2-methylphenyl hydrazine hydrochloride following the procedures shown in examples 2, 3 and 4.

LCMS (M + H): m/z 269, retention time 1.70 min.

Example 13

55 '-dimethyl-2' - (4-trifluoromethoxyphenyl) -2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 3-acetyl-4-hydroxy-6-methyl pyran-2-one and 4-trifluoromethoxyphenylhydrazine hydrochloride following the procedures shown in examples 2, 3 and 4.

LCMS (M + H): m/z 339, retention time 3.02 min.

Example 14

5, 5 '-dimethyl-2' - (4-methylphenyl) -2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 3-acetyl-4-hydroxy-6-methyl pyran-2-one and 4-methylphenyl hydrazine hydrochloride following the procedures shown in examples 2, 3 and 4.

LCMS (M + H): m/z 269, retention time 2.44 min.

Example 15

5, 5 '-dimethyl-2' - (3-methylphenyl) -2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 3-acetyl-4-hydroxy-6-methyl pyran-2-one and 3-methylphenyl hydrazine hydrochloride following the procedures shown in examples 2, 3 and 4.

LCMS (M + H): m/z 269, retention time 2.46 min.

Example 16

5, 5 '-dimethyl-2' - (2-ethylphenyl) -2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 3-acetyl-4-hydroxy-6-methyl pyran-2-one and 2-ethylphenylhydrazine hydrochloride following the procedures shown in examples 2, 3 and 4.

LCMS (M + H): m/z 283, retention time 2.32 min.

Example 17

5, 5 '-dimethyl-2' - (3, 4-dichloro-phenyl) -2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 3-acetyl-4-hydroxy-6-methyl pyran-2-one and 3, 4-dichlorophenyl hydrazine hydrochloride according to the procedures shown in examples 2, 3 and 4.

LCMS (M + H): m/z 323, retention time 3.04 min.

Example 18

5, 5 '-dimethyl-2' - (3-chlorophenyl) -2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 3-acetyl-4-hydroxy-6-methyl pyran-2-one and 3-chlorophenylhydrazine hydrochloride following the procedures shown in examples 2, 3 and 4.

LCMS (M + H): m/z 289, retention time 2.28 min.

Example 19

2 '- (4-tert-butylphenyl) -5, 5' -dimethyl-2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 3-acetyl-4-hydroxy-6-methyl pyran-2-one and 4-tert-butylphenyl hydrazine hydrochloride according to the methods shown in examples 2, 3 and 4.

LCMS (M + H): m/z 311, retention time 2.62 min.

Example 20

5, 5 '-dimethyl-2' -phenethyl-2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 3-acetyl-4-hydroxy-6-methyl pyran-2-one and phenethylhydrazine sulfate by the method shown in examples 2, 3 and 4.

LCMS (M + H): m/z 283, retention time 2.07 min.

Example 21

5, 5 '-dimethyl-2' - (3-trifluoromethylphenyl) -2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 3-acetyl-4-hydroxy-6-methyl pyran-2-one and 3-trifluoromethylphenylhydrazine hydrochloride following the procedures shown in examples 2, 3 and 4.

LCMS (M + H): m/z 323, retention time 2.62 min.

Example 22

2 '- (1-benzylpiperidin-4-yl) -5, 5' -dimethyl-2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 3-acetyl-4-hydroxy-6-methyl pyran-2-one and 1-benzyl piperidin-4-yl hydrazine dihydrochloride according to the methods shown in examples 2, 3 and 4.

LCMS (M + H): m/z 352, retention time 1.52 min.

Example 23

2 '- (3-hydroxy-benzyl) -5, 5' -dimethyl-2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 3-acetyl-4-hydroxy-6-methyl pyran-2-one and 3-hydrazinomethylphenol dihydrochloride according to the procedure shown in examples 2, 3 and 4.

LCMS (M + H): m/z 285, retention time 1.57 min.

Example 24

2 '-benzyl-5, 5' -dimethyl-2H, 2 'H- [3, 4']Pyrazolyl-3' -ols

The title compound was prepared from 3-acetyl-4-hydroxy-6-methyl pyran-2-one and benzylhydrazine dihydrochloride according to the procedure shown in examples 2, 3 and 4.

LCMS (M + H): m/z 269, retention time 1.95 min.

Example 25

5, 5 '-dimethyl-2' -phenyl-2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 3-acetyl-4-hydroxy-6-methyl-pyran-2-one and phenylhydrazine according to the procedure described in examples 2, 3 and 4.

LCMS (M + H): m/z 255, retention time 1.77 min.

Example 26

5 ' -methoxy-5, 3 ' -dimethyl-1 ' -phenyl-2H, 1 ' H- [3, 4 ']Bipyrazoles

(A)5 '-hydroxy-5, 3' -dimethyl-1 '-phenyl-1' H- [3, 4 ″)]Bipyrazole-2-carboxylic acid tert-butyl ester

(B) 5 '-hydroxy-5, 3' -dimethyl-1 '-phenyl-1' H- [3, 4 ″)]Bipyrazole-1-carboxylic acid tert-butyl ester

To a solution of 5, 5 ' -dimethyl-2 ' -phenyl-2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol (0.118g, 0.457mmol) (example 25) in ethanol (4ml) was added tert-butyl carbazate (0.120g, 0.914 mmol). Heat at reflux for 1.5 hours, then evaporate the ethanol. Chromatography on silica gel eluting with 50% ethyl acetate/heptane gave 0.101g of a mixture of regioisomers A and B. The mixture was used in the next step.

LCMS (M + H): m/z 355, and the retention time is 1.97min and 3.24min respectively.

(C)5 ' -methoxy-5, 3 ' -dimethyl-1 ' -phenyl-1 ' H- [3, 4 ' ] bipyrazolyl-2-carboxylic acid tert-butyl ester

(D)5 ' -methoxy-5, 3 ' -dimethyl-1 ' -phenyl-1 ' H- [3, 4 ' ] bipyrazolyl-1-carboxylic acid tert-butyl ester

(E)5, 1 ', 5 ' -trimethyl-3 ' -oxo-2 ' -phenyl-2 ', 3 ' -dihydro-1 ' H- [3, 4 ″)]Bipyrazole-2-carboxylic acid tert-butyl ester Esters

(F)5, 1 ', 5 ' -trimethyl-3 ' -oxo-2 ' -phenyl-2 ', 3 ' -dihydro-1 ' H- [3, 4 ″)]Bipyrazole-1-carboxylic acid tert-butyl ester Esters

To a solution of a mixture of compounds (A) and (B) (0.100g, 0.282mmol) in DMF (5ml) was added NaHCO₃(0.071g, 0.845mmol) and methyl iodide (0.40g, 2.82 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (25ml), washed with water (30ml x5) and dried (sodium sulfate). Chromatography on silica gel eluting with 50% ethyl acetate/heptane afforded 0.013g of O-methylated product ((C) and (D), LCMS (M + H): M/z 369, retention time 3.30min) and 0.012g of N-methylated product ((E) and (F), LCMS (M + H): M/z 369, retention time 2.63 min). The O-methylated product was used in the next step.

5 ' -methoxy-5, 3 ' -dimethyl-1 ' -phenyl-2H, 1 ' H- [3, 4 ']Bipyrazoles

To a solution of the O-methylated product, a mixture of the compounds (C) and (D) (0.013g, 0.035mmol) in methylene chloride (1ml) was added trifluoroacetic acid (1 ml). The mixture was stirred at room temperature for 1 hour, then the mixture was evaporated to dryness. The residue was diluted with dichloromethane and washed with water, aqueous sodium bicarbonate solution and then water. The organic layer was dried (sodium sulfate) and concentrated to give 0.006g (0.022mmol) of the title compound.

LCMS (M + H): m/z 269, retention time 2.83 min.

Example 27

5, 1 ', 5' -trimethyl-2 '-phenyl-1', 2 '-dihydro-2H- [3, 4']Bipyrazole-3' -ones

To a solution of the mixture of N-methyl isomers (E) and (F) of example 26 (0.012g, 0.035mmol) in dichloromethane (1ml) was added trifluoroacetic acid (1 ml). The mixture was stirred at room temperature for 1 hour, and then the mixture was evaporated to dryness. The residue was diluted with dichloromethane and washed with water, aqueous sodium bicarbonate solution and then water. The organic layer was dried (sodium sulfate) and concentrated to give 0.009g (0.035mmol) of the title compound.

LCMS (M + H): m/z 269, retention time 2.06 min.

Example 28

2- (4-methoxyphenyl) -5, 5 ' -dimethyl-2 ' -phenyl-2H, 2, H- [3, 4 ']Bipyrazole-3' -alcohols

To a solution of (4-methoxyphenyl) -hydrazine hydrochloride (0.083g, 0.48mmol) in ethanol (5ml) was added sodium bicarbonate (0.067g, 0.80mmol) and the mixture was stirred for 10 min. 1- [ 1-phenyl-3-methyl-5-oxo-4, 5-dihydro-1H-pyrazol-4-yl ] -butane-1, 3-dione (0.103g, 0.40mmol) was added. The mixture was heated at reflux for 1.5 h and then evaporated to dryness. Chromatography on silica gel eluting with 50 to 100% ethyl acetate/heptane afforded 0.071g of the title compound.

LCMS (M + H): m/z 361, retention time 2.43 min.

Example 29

5, 5 '-dimethyl-2-phenylethyl-2' -phenyl-2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 1- [ 1-phenyl-3-methyl-5-oxo-4, 5-dihydro-1H-pyrazol-4-yl ] -butane-1, 3-dione and phenethylhydrazine sulfate according to the procedure shown in example 28.

LCMS (M + H): m/z 359, retention time 2.55 min.

Example 30

2- (4-fluorophenyl) -5, 5 '-dimethyl-2' -phenyl-2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 1- [ 1-phenyl-3-methyl-5-oxo-4, 5-dihydro-1H-pyrazol-4-yl ] -butane-1, 3-dione and 4-fluorophenylhydrazine hydrochloride according to the procedure shown in example 28.

LCMS (M + H): m/z 349, retention time 2.48 min.

Example 31

5, 5 '-dimethyl-2' -phenyl-2- (2, 2, 2-trifluoro-ethyl) -2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 1- [ 1-phenyl-3-methyl-5-oxo-4, 5-dihydro-1H-pyrazol-4-yl ] -butane-1, 3-dione and 2, 2, 2-trifluoro-ethylhydrazine (70% in water) according to the procedure described in example 28.

LCMS (M + H): m/z 337, retention time 2.35 min.

Example 32

2-cyclohexyl-5, 5 '-dimethyl-2' -phenyl-2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 1- [ 1-phenyl-3-methyl-5-oxo-4, 5-dihydro-1H-pyrazol-4-yl ] -butane-1, 3-dione and cyclohexylhydrazine hydrochloride according to the procedure described in example 28.

LCMS (M + H): m/z 337, retention time 2.50 min.

Example 33

2- (3-hydroxy-benzyl) -5, 5 '-dimethyl-2' -phenyl-2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 1- [ 1-phenyl-3-methyl-5-oxo-4, 5-dihydro-1H-pyrazol-4-yl ] -butane-1, 3-dione and 3-hydroxybenzylhydrazine dihydrochloride according to the procedure shown in example 28.

LCMS (M + H): m/z 361, retention time 2.18 min.

Example 34

2- (2-hydroxy-ethyl) -5, 5 '-dimethyl-2' -phenyl-2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 1- [ 1-phenyl-3-methyl-5-oxo-4, 5-dihydro-1H-pyrazol-4-yl ] -butane-1, 3-dione and 2-hydroxy-ethylhydrazine according to the procedure shown in example 28.

LCMS (M + H): m/z 299, retention time 1.83 min.

Example 35

5, 5 '-dimethyl-2, 2' -diphenyl-2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 1- [ 1-phenyl-3-methyl-5-oxo-4, 5-dihydro-1H-pyrazol-4-yl ] -butane-1, 3-dione and phenylhydrazine according to the method shown in example 28.

LCMS (M + H): m/z 331, retention time 2.42 min.

Example 36

2-benzyl-5, 5 '-dimethyl-2' -phenyl-2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 1- [ 1-phenyl-3-methyl-5-oxo-4, 5-dihydro-1H-pyrazol-4-yl ] -butane-1, 3-dione and benzylhydrazine hydrochloride according to the procedure shown in example 28.

LCMS (M + H): m/z 345, retention time 2.69 min.

Example 37

2, 5, 5 '-trimethyl-2' -phenyl-2H, 2 'H- [3, 4']Bipyrazole-3' -alcohols

The title compound was prepared from 1- [ 1-phenyl-3-methyl-5-oxo-4, 5-dihydro-1H-pyrazol-4-yl ] -butane-1, 3-dione and methylhydrazine according to the procedure described in example 28.

LCMS (M + H): m/z 269, retention time 2.10 min.

Example 38

2-benzyl-5, 1 ', 5' -trimethyl-2 '-phenyl-1', 2 '-dihydro-2H- [3, 4']Bipyrazole-3' -ones

To a solution of 2-benzyl-5, 5 ' -dimethyl-2 ' -phenyl-2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol (example 36, 0.200g, 0.58mmol) in DMF was added cesium carbonate (0.944g, 2.90mmol) followed by iodomethane (0.823g, 5.8 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water (25mlx5) and dried (sodium sulfate). Chromatography on silica gel eluting with 50-100% ethyl acetate/heptane yielded 0.045g of the title compound.

LCMS (M + H): m/z 359, retention time 2.84 min.

This reaction also produces an O-methyl compound. See example 39 below.

Example 39

2-benzyl-5 '-methoxy-5, 3' -dimethyl-1 '-phenyl-2H, 1' H- [3, 4 ″)]Bipyrazoles

The title compound was isolated by chromatography as described in example 38 to yield 0.033g of the O-methylated isomer.

LCMS (M + H): m/z 359, retention time 3.51 min.

While the invention has been illustrated by the foregoing examples, it is not to be construed as being limited thereby; but rather should be understood to cover the generic scope of the above disclosure. Various modifications and embodiments can be made without departing from the spirit and scope of the invention.

Claims (14)

1. A compound of formula I:

wherein:

R₁selected from: a phenyl group,

wherein said phenyl group may be optionally substituted with one or several substituents independently from each other selected from the group consisting of: c_1-6Alkyl radical, C_1-6PerfluoroalkanesRadical, halogen radical, hydroxyl radical, C₁-C₆Alkoxy, nitro;

R₂selected from: c_1-6An alkyl group;

R₃selected from: c_1-6An alkyl group;

R₄selected from: h and C_2-6An alkyl group;

R₅is H, C_1-6An alkyl group; and is

The following conditions must be satisfied:

when R is₁Is phenyl or 4-chlorophenyl and R₄And R₅When is hydrogen, R₂And R₃And not both methyl groups.

2. A compound according to claim 1, wherein

R₁Selected from: a phenyl group;

R₂and R₃Is C_1-6An alkyl group; and is

R₅Is hydrogen or C_1-6An alkyl group.

3. A compound according to claim 1, wherein

R₁Is phenyl;

R₂and R₃Is C_1-6An alkyl group;

R₄is hydrogen; and is

R₅Is hydrogen or C_1-6An alkyl group.

4. A compound according to claim 1, wherein

R₁Is phenyl;

R₂and R₃Is C_1-6An alkyl group;

R₄is C_2-6An alkyl group; and is

R₅Is hydrogen.

5. The compound according to claim 4 which is 2, 5, 5 ' -trimethyl-2 ' -phenyl-2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol.

6. The compound 5, 5 ' -dimethyl-2 ' -phenyl-2- (2, 2, 2-trifluoro-ethyl) -2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol.

7. A compound selected from:

2 ' - (2-fluorophenyl) -5, 5 ' -dimethyl-2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol,

2 ' - (4-isopropylphenyl) -5, 5 ' -dimethyl-2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol,

2 ' - (4-fluorophenyl) -5, 5 ' -dimethyl-2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol,

5, 5 ' -dimethyl-2 ' - (4-trifluoromethylphenyl) -2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol,

5, 5 ' -dimethyl-2 ' - (4-methoxyphenyl) -2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol,

2 ' - (3-fluorophenyl) -5, 5 ' -dimethyl-2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol,

2 ' - (2-methylphenyl) -5, 5 ' -dimethyl-2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol,

5, 5 ' -dimethyl-2 ' - (4-trifluoromethoxyphenyl) -2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol,

5, 5 ' -dimethyl-2 ' - (4-methylphenyl) -2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol,

5, 5 ' -dimethyl-2 ' - (3-methylphenyl) -2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol,

5, 5 ' -dimethyl-2 ' - (2-ethylphenyl) -2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol,

5, 5 ' -dimethyl-2 ' - (3, 4-dichloro-phenyl) -2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol,

5, 5 ' -dimethyl-2 ' - (3-chlorophenyl) -2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol,

2 ' - (4-tert-butylphenyl) -5, 5 ' -dimethyl-2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol,

5, 5 ' -dimethyl-2 ' - (3-trifluoromethylphenyl) -2H, 2 ' H- [3, 4 ' ] bipyrazolyl-3 ' -ol, and

5 ' -methoxy-5, 3 ' -dimethyl-1 ' -phenyl-2H, 1 ' H- [3, 4 ' ] bipyrazole.

8. The compound is named 5, 1 ', 5 ' -trimethyl-2 ' -phenyl-1 ', 2 ' -dihydro-2H- [3, 4 ' ] bipyrazolyl-3 ' -one.

9. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1-7 and a pharmaceutically acceptable carrier.

10. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of neuropsychiatric disorders susceptible to modulation of AMPA and NMDA receptors.

11. The use according to claim 10, wherein the neuropsychiatric disorder is selected from the group consisting of: depression, epilepsy, schizophrenia, alzheimer's disease, learning and memory disorders, and mild cognitive impairment.

12. The use according to claim 11, wherein the disorder is schizophrenia.

13. The use according to claim 11, wherein the disorder is depression.

14. The use according to claim 11, wherein the disorder is a learning and memory disorder.