Title of Invention | "A PDE4 INHIBITOR PYRAZOLE COMPOUND ACCORDING TO FORMULAS II, III, V, OR VI" |
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Abstract | A PDE4 inhibitor pyrazole compound according to Formulas II, III, V, or VI: wherein X isCHorN; L is a single bond; C1-C6 straight chain or branched alkylene, wherein a CH2 group is optionally replaced by O, NH, NR1, or S, which is unsubstituted or substituted one or more times by oxo, halogen, hydroxy, cyano or combinations thereof; (CH2)nCONH; (CH2)nCON(C1-6-alkyl); (CH2)nNHCO; (CH2)nCONHS02; (CH2)nS02NH; (CH2)nS02; or (CH2)nC02; n is 0 to 3; R1 is alkyl having 1 to 4 carbon atoms, which is unsubstituted or substituted one or more times by halogen; R3 is H. |
Full Text | This application claims the benefit of U.S. Provisional Application Serial No. 60/463,725, filed April 18, 2003, the entire disclosure of which is hereby incorporated. This application is related to copending applications Serial No. 10/270,724, filed October 16, 2002 (.which claims the benefit of Serial No. 60/329,314, filed October 16, 2001), the entire disclosures of which are hereby incorporated. FIELD OF THE INVENTION ' Thepresent invention relates generally to the field of phosphodiesterase 4 (PDE4) enzyme inhibition. More specifically, this invention relates to selective PDE4 inhibition by novel compounds, e.g., aryl and heteroaryl substituted pyrazole compounds, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof. BACKGROUND OF THE INVENTION The cyclic nucleotide specific phosphodiesterases (PDEs) represent a family of enzymes that catalyze the hydrolysis of various cyclic nucleoside monophosphates (including cAMP and cGMP). These cyclic nucleotides act as second messengers within cells, and as messengers, carry impulses from cell surface receptors having bound various hormones and neurotransmitters. PDEs act to regulate the level of cyclic nucleotides within cells and maintain cyclic nucleotide homeostasis by degrading such cyclic mononucleotides resulting in termination of their messenger role. PDE enzymes can be grouped into eleven families according to their specificity" toward hydrolysis of cAMP or cGMP, their sensitivity to regulation by calcium, calmodulin or cGMP, and their selective inhibition by various compounds. For example, PDE1 is stimulated by Ca2+/calmodulin. PDE2 is cGMP-dependent, and is found in the heart and adrenals. PDE3 is cGMP-inhibited, and inhibition of this enzyme creates positive inotropic activity. PDE4 is cAMP specific, and its inhibition causes airway relaxation, anti-inflammatory and antidepressant activity. PDE5 appears to be important in regulating cGMP content in vascular, smooth muscle, and therefore PDE5 inhibitors may have cardiovascular activity. Since the PDEs possess distinct biochemical properties, it is likely that they are subject to a variety of different forms of regulation. PDE4 is distinguished by various kinetic properties including low Michaelis constant for cAMP and sensitivity to certain drugs. The PDE4 enzyme family consists of four genes, which produce 4 isoforms of the PDE4 enzyme designated PDE4A, PDE4B, PDE4C, and PDE4D [Wang et al. , Expression, Purification, and Characterization of Human cAMP-Specific Phosphodiesterase (PDE4) Subtypes A, B, C, and D, Biochem. Biophys. Res. Comm., 234,320-324 (1997)]. In addition, various splice variants of each PDE4 isoform have been identified. PDE4 isoenzymes are localized in the cytosol of cells and are unassociated with any known membranous structures. PDE4 isoenzymes specifically inactivate cAMP by catalyzing its hydrolysis to adenosine 5'-monophosphate (AMP). Regulation of cAMP activity is important in many biological processes, including inflammation and memory. Inhibitors of PDE4 isoenzymes such as rolipram, piclamilast, CDP-840 and ariflo are powerful anti-inflammatory agents and therefore may be useful in treating diseases where inflammation is problematic such as asthma or arthritis. Further, rolipram improves the cognitive performance of rats and mice in learning paradigms. rolipram piclamilast In addition to such compounds as rolipram, xanthine derivatives such as pentoxifylline, denbufylline, and theophylline inhibit PDE4 and have received attention of late for their cognition enhancing effects. cAMP and cGMP are second messengers that mediate cellular responses to many different hormones and neurotransmitters. Thus, therapeutically significant effects may result from PDE inhibition and the resulting increase in intracellular cAMP or cGMP in key cells, such as those located in the nervous system and elsewhere in the body. 'Rolipram, previously in development as an antidepressant, selectively inhibits the PDE4 enzyme and has become a standard agent in the classification of PDE enzyme subtypes. Early work in the PDE4 field focused on depression and inflammation, and has subsequently been extended to include indications such as dementia. [see"The PDE IV Family Of Calcium-Phosphodiesterases Enzymes, "John A. Lowe, III, et al., Drugs of the Future 1992,17 (9): 799-807 for a general review]. Further clinical developments of rolipram and other first-generation PDE4 inhibitors were terminated due to the side effect profile of these compounds. The primary side effect in primates is emesis, while the primary side effects in rodents are testicular degranulation, weakening of vascular smooth muscle, psychotrophic effects, increased gastric acid secretion, and stomach erosion. In humans, the primary side effect is nausea and emesis. Thus, there is a continuing need to develop selective PDE4 inhibitors with improved side effect profiles (e. g. , are relatively non-emetic) while retaining therapeutic utility. SUMMARY OF THE INVENTION The present invention relates to novel compounds that inhibit, preferably selectively, PDE4 enzymes, and especially have improved side effect profiles, e. g., are relatively non-emetic (e. g. , as compared to the previously discussed prior art compounds). In particular, the present invention relates to aryl and heteroaryl substituted pyrazole compounds. The compounds of this invention at the same time facilitate entry into cells, especially cells of the nervous system. Still further, the present invention provides methods for synthesizing compounds with such activity and selectivity, as well as methods of and corresponding pharmaceutical compositions for treating a patient, e. g., mammals, including humans, in need of PDE inhibition. Treatment is preferably for a disease state that involves elevated intracellular PDE4 levels or decreased cAMP levels, e. g. , involving neurological syndromes, especially those states associated with depression and/or memory impairment, most especially major depression and/or long term memory impairment. In particular, such depression and/or memory impairment is due at least in part to catabolism of intracellular cAMP levels by PDE4 enzymes or where such an impaired condition can be improved by increasing cAMP levels. In a preferred aspect, the compounds of the inventions improve such diseases by inhibiting PDE4 enzymes at doses that do not induce emesis or other side effects. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to selective PDE4 inhibition by novel compounds, e. g. , aryl and heteroaryl substituted pyrazole compounds, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof. The present invention includes compounds selected from Formulas I, II, III, IV, V, VI, VII or VIII: wherein X is CH or N ; L is a single bond; Cl-C6 straight chain or branched alkylene, wherein a CH2 group is optionally replaced by O, NH, NR1, or S, which is unsubstituted or substituted one or more times by oxo, halogen (preferably F), hydroxy, cyano or combinations thereof; (CH2)nCONH ; (CH2)nCON(C1-6-alkyl) ; (CH2)nNHCO ; (CH2)nCONHSO2 ; (CH2) nSO21NH ; (CH2)nSO2 ; or (CH2) nCO2 (e. g., a bond, CH2CONH, SO2, CH2CO2, CH2CO) n is 0 to 3 ; Rl is alkyl having 1 to 4 carbon atoms, which is unsubstituted or substituted one or more times by halogen (e. g., CH3, CHF2) ; R is H, alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo or combinations thereof wherein optionally one or more-CH2CH2-groups are replaced in each case by-CH=CH-or- C=C-groups (e. g., CH3, CHF2), cycloalkyl having 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl having 1 to 4 carbon atoms or combinations thereof (e. g. , cyclopentyl), a heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom (e. g. , 3-thienyl, 2-thienyl, 3-tetrahydrofuranyl), which is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e. g. , trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof (e. g., tetrahydrofuranyl), aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e. g., acetamido), and acyloxy (e. g. , acetoxy), or combinations thereof, arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted, preferably in the aryl portion, one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e. g., acetamido), and acyloxy (e. g. , acetoxy), or combinations thereof (e. g. , benzyl, difluorobenzyl), a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, (e. g. , cyclohexenyl, cyclohexadienyl, indanyl, and tetrahydronaphthenyl), which is unsubstituted or substituted one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, arylalkenyl having 8 to 16 carbon atoms, wherein the alkenyl portion has up to 5. carbon atoms, which is unsubstituted or substituted, preferably in the aryl portion, one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e. g., acetamido), and acyloxy (e. g. , acetoxy), or combinations thereof, a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e. g. , trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof, or cycloalkylalkyl having 4 to 16 carbon atoms (e. g. , cyclopentylethyl and cyclopropylmethyl), which is unsubstituted or substituted one or more times by halogen, oxo, alkyl or combinations thereof; R3 is H, alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more-CH2CH2-groups are replaced in each case by- CH=CH-or-C-C-groups (e. g., C2H5, CH (CH3) 2, n-propyl, n-butyl, t.- butyl), cycloalkyl having 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl, or combinations thereof (e. g. , cyclopentyl, cyclohexyl), aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl, halogenated alkoxy (e. g., OCF3), nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, arylsulphinyl, arylsulphonyl, phenyl, halogenated phenyl, phenoxy, acyloxy (e. g. , acetoxy), acylamido (e. g., acetamido), imidazolyl, pyridinyl, morpholinyl, piperadinyl, piperazinyl, tetrazolyl, alkylsulphonimide (e. g., CH3SO2-NHCO-), arylsulphonimide (e. g., C6H5S02-NHCO-) or combinations thereof (e. g. , phenyl, bromophenyl, cyanophenyl, nitrophenyl, fluorophenyl, difluorophenyl, trifluoromethoxyphenyl, methylphenyl, dimethylphenyl, methoxyphenyl), heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl (e. g., trifluoromethyl), halogenated alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, arylsulphinyl, arylsulphonyl, phenyl, halogenated phenyl, phenoxy, acyloxy, tetrazolyl, alkylsulphonimide, arylsulphonimide, aryl, oxo, acylamido (e. g. , acetamido), or combinations thereof (e. g. , pyridyl, methylpyridyl, benzothiaolyl), arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted, preferably in the aryl portion, one or more times by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl (e. g. CF3), halogenated alkoxy (e. g. OCF3), nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, arylsulphinyl, arylsulphonyl, phenyl, halogenated phenyl, phenoxy, acyloxy (e. g., acetoxy), acylamido (e. g. , acetamido), tetrazolyl, alkylsulphonimide, arylsulphonimide, or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof (e. g. , benzyl, methylbenzyl, t. -butylbenzyl, methoxybenzyl, dimethoxybenzyl, fluorobenzyl, difluorobenzyl, trifluoromethylbenzyl, trifluoromethoxybenzyl, chlorobenzyl, aminobenzyl, nitrobenzyl, methoxycarbonylbenzyl, methylsulfonylbenzyl, phenethyl, phenpropyl), a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl (e. g., trifluoromethyl), halogenated alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy,. carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, arylsulphinyl, arylsulphonyl, phenyl, halogenated phenyl, phenoxy, acyloxy, tetrazolyl, alkylsulphonimide, arylsulphonimide, aryl, oxo, or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof (e. g., pyridylmethyl), cycloalkylalkyl having 4 to 16 carbon atoms (e. g. , cyclopentylethyl and cyclopropylmethyl), which is unsubstituted or substituted one or more times by halogen, oxo, alkyl or combinations thereof, or alkoxyalkyl having 3 to 8 carbon atoms; R4 is alkyl having 1 to 6 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more-CH2CH2-groups are replaced in each case by- CH=CH-or-C=-C-groups (e. g., CH3) ; R'is H, alkyl having 1 to 6 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more-CH2CH2-groups are replaced in each case by- CH=CH-or-C=-C-groups (e. g., CH3, C2Hs) ; R6 is H, alkyl having 1 to 6 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more-CH2CH2-groups are replaced in each case by- CH=CH-or-C=C-groups, cycloalkyl having 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl,, or combinations thereof (e. g. , cyclopentyl), cycloalkylalkyl having 4 to 16 carbon atoms (e. g., cyclopentylethyl and cyclopropylmethyl), which is unsubstituted or substituted one or more times by halogen, oxo, alkyl or combinations thereof, aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e. g., acetamido), and acyloxy (e. g. , acetoxy), or combinations thereof, arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted, preferably in the aryl portion, one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e. g. , acetamido), and acyloxy (e. g. , acetoxy), or combinations thereof, a heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom (e. g. , 3-thienyl, 2-thienyl, 3-tetrahydrofuranyl), which is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, alkoxycarbonyl, cyano, halogenated alkyl (e. g. , trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof, or a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e. g.,. trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof ; R is H, halogen, or alkyl having 1 to 6 carbon atoms wherein optionally one or more-CH2CH2-groups are replaced in each case by-CH=CH-or -C-C-groups and wherein the alkyl is unsubstituted or substituted one or more times by halogen; R8 is H, halogen, alkyl having 1 to 6 carbon atoms wherein optionally one or more-CH2CH2-groups are replaced in each case by-CH=CH-or-C=C- groups and wherein the alkyl is unsubstituted or substituted one or more times by halogen or hydroxyl (e. g. , CH3, C2Hs, CF3, hydroxymethyl, 2- (2- hydroxy) propyl, hydroxymethyl), carboxy, alkoxycarbonyl having 2 to 6 carbon atoms (e. g., ethoxycarbonyl),-CO-alkyl having 2 to 6 carbon atoms (e. g., CH3CO), or phenyl ; and R9 is halogen (e. g. , F); and pharmaceutically acceptable salts thereof. In accordance with the method aspect of the invention, there is provided a method of treating a patient (e. g., a mammal such as a human) suffering from a disease state (e. g., memory impairment) involving decreased cAMP levels and/or increased intracellular PDE4 levels, comprising administering to the patient a compound selected from Formulas I, II, III, IV, V, VI, VII or VIII : wherein X is CH or N ; L is a single bond; C1-C6 straight chain or branched alkylene,. wherein a CH2 group is optionally replaced by O, NH, NR1, or S, which is unsubstituted or substituted one or more times by oxo, halogen (preferably F), hydroxy, cyano or combinations thereof; (CH2)nCONH ; (CH2) nCON (CI 6-alkyl) ; (CH2) nNHCO ; (CH2) nCONHS02 ; (CH2) nSO2NH ; (CH2) nSO2 ; or (CH2) nCO2 (e. g., a bond, CH2CONH, SO2, CH2CO2, CH2CO) n is 0 to 3 ; R1 is alkyl having 1 to 4 carbon atoms, which is unsubstituted or substituted one or more times by halogen (e. g., CH3 CHF2) ; R is H, alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo or combinations thereof wherein optionally one or more-CH2CH2-groups are replaced in each case by-CH=CH-or- C=C-groups (e. g., CH3, CHF2), cycloalkyl having 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl having 1 to 4 carbon atoms or combinations thereof (e. g. , cyclopentyl), a heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom (e. g. , 3-thienyl, 2-thienyl, 3-tetrahydrofuranyl), which is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e. g., trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof (e. g., tetrahydrofuranyl), aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e. g., acetamido), and acyloxy (e. g. , acetoxy), or combinations thereof, arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted, preferably in the aryl portion, one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e. g. , acetamido), and acyloxy (e. g. , acetoxy), or combinations thereof (e. g. , benzyl, difluorobenzyl), a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, (e. g. , cyclohexenyl, cyclohexadienyl, indanyl, and tetrahydronaphthenyl), which is unsubstituted or substituted one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, arylalkenyl having 8 to 16 carbon atoms, wherein the alkenyl portion has up to 5 carbon atoms, which is unsubstituted or substituted, preferably in the aryl portion, one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e. g., acetamido), and acyloxy (e. g. , acetoxy), or combinations thereof, a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy,, cyano, halogenated allcyl (e. g. , trifluoromethyl), nitro, oxo, amino, allcylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof, or cycloallcylalkyl having 4 to 16 carbon atoms (e. g. , cyclopentylethyl and cyclopropylmethyl), which is unsubstituted or substituted one or more times by halogen, oxo, alkyl or combinations thereof; R3 is H, alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more-CH2CH2-groups are replaced in each case by- CH=CH-or-C=-C-groups (e. g., C2Hs, CH (CH3) 2, n-propyl, n-butyl, t.- butyl), cycloalkyl having 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl, or combinations thereof (e. g. , cyclopentyl, cyclohexyl), aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl, halogenated alkoxy (e. g., OCF3), nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, arylsulphinyl, arylsulphonyl, phenyl, halogenated phenyl, phenoxy, acyloxy (e. g. , acetoxy), acylamido (e. g., acetamido), imidazolyl, pyridinyl, morpholinyl, piperadinyl, piperazinyl, tetrazolyl, alkylsulphonimide (e. g., CH3SO2-NHCO-), arylsulphonimide (e. g., C6H5SO2-NHCO-) or combinations thereof (e. g. , phenyl, bromophenyl, cyanophenyl, nitrophenyl, fluorophenyl, difluorophenyl, trifluoromethoxyphenyl, methylphenyl,'dimethylphenyl, methoxyphenyl), heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl (e. g. , trifluoromethyl), halogenated alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, arylsulphinyl, arylsulphonyl, phenyl, halogenated phenyl, phenoxy, acyloxy, tetrazolyl, alkylsulphonimide, arylsulphonimide, aryl, oxo, acylamido (e. g. , acetamido), or combinations thereof (e. g. , pyridyl, methylpyridyl, benzothiaolyl), arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted, preferably in the aryl portion, one or more times by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl (e. g. CF3), halogenated alkoxy (e. g. OCF3), nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, arylsulphinyl, arylsulphonyl, phenyl, halogenated phenyl, phenoxy, acyloxy (e. g., acetoxy), acylamido (e. g., acetamido), tetrazolyl, alkylsulphonimide, arylsulphonimide, or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof (e. g. , benzyl, methylbenzyl, t. -butylbenzyl, methoxybenzyl, dimethoxybenzyl, fluorobenzyl, difluorobenzyl, trifluoromethylbenzyl, trifluoromethoxybenzyl, chlorobenzyl, aminobenzyl, nitrobenzyl, methoxycarbonylbenzyl, methylsulfonylbenzyl, phenethyl, phenpropyl), a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl (e. g. , trifluoromethyl), halogenated alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, arylsulphinyl, arylsulphonyl, phenyl, halogenated phenyl, phenoxy, acyloxy, tetrazolyl, alkylsulphonimide, arylsulphonimide, aryl, oxo, or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof (e. g., pyridylmethyl), cycloalkylalkyl having 4 to 16 carbon atoms (e. g. , cyclopentylethyl and cyclopropylmethyl), which is unsubstituted or substituted one or more times by halogen, oxo, alkyl or combinations thereof, or alkoxyalkyl having 3 to 8 carbon atoms; R4 is alkyl having 1 to 6 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more-CH2CH2-groups are replaced in each case by- CH=CH-or-C-=C-groups (e. g., CH3) ; R5 is H, alkyl having 1 to 6 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more-CH2CH2-groups are replaced in each case by- CH=CH-or-C--C-groups (e. g. , CH3, C2H5) ; R6 is H, alkyl having 1 to 6 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more-CH2CH2-groups are replaced in each case by- CH=CH-or-C=C-groups, cycloalkyl having 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl, or combinations thereof (e. g., cyclopentyl),. cycloalkylalkyl having 4 to 16 carbon atoms (e. g. , cyclopentylethyl and cyclopropylmethyl), which is unsubstituted or substituted one or more times by halogen, oxo, alkyl or combinations thereof, aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e. g., acetamido), and acyloxy (e. g. , acetoxy), or combinations thereof, arylalkyl having 7 to, 16 carbon atoms, which is unsubstituted or substituted, preferably in the aryl portion, one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e. g., acetamido), and acyloxy (e. g. , acetoxy), or combinations thereof, a heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom (e. g. , 3-thienyl, 2-thienyl ; 3-tetrahydrofuranyl), which is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, alkoxycarbonyl ; cyano, halogenated alkyl (e. g. , trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof, or a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e. g. , trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof ; R is H, halogen, or alkyl having 1 to 6 carbon atoms wherein optionally one or more-CH2CH2-groups are replaced in each case by-CH=CH-or -C-C-groups and wherein the alkyl is unsubstituted or substituted one or more times by halogen; R8 is H, halogen, alkyl having 1 to 6 carbon atoms wherein optionally one or more-CH2CH2-groups are replaced in each case by-CH=CH-or-C=C- groups and wherein the alkyl is unsubstituted or substituted one or more times by halogen or hydroxyl (e. g., CH3, C2Hs, CF3, hydroxymethyl, 2- (2- hydroxy) propyl, hydroxymethyl), carboxy, alkoxycarbonyl having 2 to 6 carbon atoms (e. g., ethoxycarbonyl),-CO-alkyl having 2 to 6 carbon atoms (e. g., CH3CO), or phenyl ; and R9 is halogen (e. g. , F); and pharmaceutically acceptable salts thereof. According to a further compound aspect, the present invention includes compounds selected from Formulas I, II, III, VI, V, or VI: wherein X is CH or N ; Y is CH or N ; L is a single bond; CI-C6 straight chain or branched alkylene, wherein a CH2 group is optionally replaced by O, NH, NR1, or S, which is unsubstituted or substituted one or more times by oxo, halogen (preferably F), hydroxy, cyano or combinations thereof; (CH2) nCONH ; (CH2)nNHCO ; (CH2) nCONHS02 ; (CH2)nSO2NH ; (CH2)nSWO2 ; or (CH2) nCO2 ; n is 0 to 3 ; R1 is alkyl having 1 to 4 carbon atoms, which is unsubstituted or substituted one or more times by halogen; R is H, alkyl having 2 to 8 carbon atoms wherein optionally one or more -CH2CH2-groups are replaced in each case by-CH=CH-or-C=C- groups, alkyl having 1 to 8 carbon atoms, which is substituted one or more times by halogen, oxo or combinations thereof wherein optionally one or more -CH2CH2-groups are replaced in each case by-CH=CH-or-C=C- groups, cycloalkyl having 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl having 1 to 4 carbon atoms or combinations thereof, a heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom (e. g. , 3-thienyl, 2-thienyl, 3-tetrahydrofuranyl), which is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e. g. , trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof, aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e. g., acetamido), and acyloxy (e. g. , acetoxy), or combinations thereof, arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted, preferably in the aryl portion, one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e. g., acetamido), and acyloxy (e. g. , acetoxy), or combinations thereof, a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, (e. g., cyclohexenyl, cyclohexadienyl, indanyl, and tetrahydronaphthenyl), which is unsubstituted or substituted one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, arylalkenyl having 8 to 16 carbon atoms, wherein the alkenyl portion has up to 5 carbon atoms, which is unsubstituted or substituted, preferably in the aryl portion, one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano,. acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e. g., acetamido), and acyloxy (e. g., acetoxy), or combinations thereof, a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more, times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e. g., trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof, or cycloalkylalkyl having 4 to 16 carbon atoms (e. g. , cyclopentylethyl and cyclopropylmethyl), which is unsubstituted or substituted one or more times by halogen, oxo, alkyl or combinations thereof; R3 is H, alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more-CH2CH2-groups are replaced in each case by- CH=CH-or-C-C-groups, cycloalkyl having 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl, or combinations thereof, aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, and acyloxy (e. g. , acetoxy), or combinations thereof, heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e. g. , trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof (e. g., pyridyl, methylpyridyl, azaindolyl), arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted, preferably in the aryl portion, one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e. g., acetamido), and acyloxy (e. g. , acetoxy), or combinations thereof, a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e. g. , trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof, cycloalkylalkyl having 4 to 16 carbon atoms (e. g. , cyclopentylethyl and cyclopropylmethyl), which is unsubstituted or substituted one or more times by halogen, oxo, alkyl or combinations thereof, or alkoxyalkyl having 3 to 8 carbon atoms; R is alkyl having 1 to 6 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more-CH2CH2-groups are replaced in each case by- CH=CH-or-C--C-groups ; R"is H, alkyl having 1 to 6 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more-CH2CH2-groups are replaced in each case by- CH=CH-or-C-C-groups ; R6 is H, alkyl having 1 to 6 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more-CH2CH2-groups are replaced in each case by- CH=CH-or-C=C-groups, cycloalkyl having 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl, or combinations thereof, cycloalkylalkyl. having 4 to 16 carbon atoms (e. g., cyclopentylethyl and cyclopropylmethyl), which is unsubstituted or substituted one or more times by halogen, oxo, alkyl or combinations thereof, aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e. g., acetamido), and acyloxy (e. g. , acetoxy), or combinations thereof, arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted, preferably in the aryl portion, one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e. g., acetamido), and acyloxy (e. g. , acetoxy), or combinations thereof, a heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom (e. g. , 3-thienyl, 2-thienyl, 3-tetrahydrofuranyl), which is unsubstituted or substituted one-or more times by halogen, aryl, alkyl, alkoxy, alkoxycarbonyl, cyano, halogenated alkyl (e. g. , trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof, or a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e. g. , trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof ; R7 is H, halogen, or alkyl having 1 to 6 carbon atoms wherein optionally one or more-CH2CH2-groups are replaced in each case by-CH=CH-or -C-C-groups and wherein the alkyl is unsubstituted or substituted one or more times by halogen; R8 is H, halogen, or alkyl having 1 to 6 carbon atoms wherein optionally one or more-CH2CH2-groups are replaced in each case by-CH=CH-or - C=C-groups and wherein the alkyl is unsubstituted or substituted one or more times by halogen; and pharmaceutically acceptable salts thereof. According to a further method aspect of the invention, there is provided a method of treating a patient (e. g. , a mammal such as a human) suffering from a disease state (e. g., . memory impairment) involving decreased cAMP levels and/or increased intracellular PDE4 levels, comprising administering to the patient a compound selected from Formulas I, II, III, IV, V, or VI: wherein X is CH or N ; Y is CH or N ; L is a single bond; Cl-C6 straight chain or branched alkylene, wherein a CH2 group is optionally replaced by O, NH, NR1, or S, which is unsubstituted or substituted one or more times by oxo, halogen (preferably F), hydroxy, cyano or combinations thereof; (CH2)nCONH ; (CH2)nNHCO ; (CH2)nCONHSO2 ; (CH2) SO2NH ; (CH2)nSO2 ; or (CH2) nCO2 ; n is 0 to 3 ; R1 is alkyl having 1 to 4 carbon atoms, which is unsubstituted or substituted one or more times by halogen; R2 is H, alkyl having 2 to 8 carbon atoms wherein optionally one or more -CH2CH2-groups are replaced in each case by-CH=CH-or-C=C- groups, alkyl having 1 to 8 carbon atoms, which is substituted one or more times by halogen, oxo or combinations thereof wherein optionally one or more -CH2CH2-groups are replaced in each case by-CH=CH-or-C-C- groups, cycloalkyl having 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl having 1 to 4 carbon atoms or combinations thereof, a heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom (e. g., 3-thienyl, 2-thienyl, 3-tetrahydrofuranyl), which is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e. g. , trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof, aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e. g., acetamido), and acyloxy (e. g. , acetoxy), or combinations thereof, arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted, preferably in the aryl portion, one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e. g., acetamido), and acyloxy (e. g. , acetoxy), or combinations thereof, a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, (e. g. , cyclohexenyl, cyclohexadienyl, indanyl, and tetrahydronaphthenyl), which is unsubstituted or substituted one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, arylalkenyl having 8 to 16 carbon atoms, wherein the alkenyl portion has up to 5 carbon atoms, which is unsubstituted or substituted, preferably in the aryl portion, one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e. g., acetamido), and acyloxy (e. g., acetoxy), or combinations thereof, a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e. g. , trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof, or cycloalkylalkyl having 4 to 16 carbon atoms (e. g., cyclopentylethyl and cyclopropylmethyl), which is unsubstituted or substituted one or more times by halogen, oxo, alkyl or combinations thereof ; R3 is H, alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more-CH2CH2-groups are replaced in each case by- CH=CH-or-C-C-groups, cycloalkyl having 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl, or combinations thereof, aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted, preferably in the aryl portion, one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, and acyloxy (e. g., acetoxy), or combinations thereof, heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e. g., trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof, arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted, preferably in the aryl portion, one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e. g. , acetamido), and acyloxy (e. g. , acetoxy), or combinations thereof, a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e. g., trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof, cycloalkylalkyl having 4 to 16 carbon atoms (e. g., cyclopentylethyl and cyclopropylmethyl), which is unsubstituted or substituted one or more times by halogen, oxo, alkyl or combinations thereof, or alkoxyalkyl having 3 to 8 carbon atoms; R4 is alkyl having 1 to 6 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more-CH2CH2-groups are replaced in each case by- CH=CH-or-C=C-groups ; Rus vis H, alkyl having 1 to 6 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more-CH2CH2-groups are replaced in each case by- CH=CH-or-C=C-groups ; R6 is H, alkyl having 1 to 6 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more-CH2CH2-groups are replaced in each case by- CH=CH-or-C-C-groups, cycloalkyl having 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl, or combinations thereof, cycloalkylalkyl having 4 to 16 carbon atoms (e. g., cyclopentylethyl and cyclopropylmethyl), which is unsubstituted or substituted one or more times by halogen, oxo, alkyl or combinations thereof, aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e. g., acetamido), and acyloxy (e. g. , acetoxy), or combinations thereof, arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or / substituted, preferably in the aryl portion, one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e. g. , acetamido), and acyloxy (e. g. , acetoxy), or combinations thereof, a heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N,. O or S atom (e. g. , 3-thienyl, 2-thienyl, 3-tetrahydrofuranyl), which is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, alkoxycarbonyl, cyano, halogenated alkyl (e. g., trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof, or a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e. g. , trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof ; R7 is H, halogen, or alkyl having 1 to 6 carbon atoms wherein optionally one or more-CH2CH2-groups are replaced in each case by-CH=CH-or- C-C-groups and wherein the alkyl is unsubstituted or substituted one or more times by halogen; R8 is H, halogen, or alkyl having 1 to 6 carbon atoms wherein optionally one or more-CH2CH2-groups are replaced in each case by-CH=CH-or- C-C-groups and wherein the alkyl is unsubstituted or substituted one or more times by halogen; and pharmaceutically acceptable salts thereof. The compounds of the present invention are effective in inhibiting, or modulating the activity of PDE4 in animals, e. g. , mammals, especially humans. These compounds exhibit neurological activity, especially where such activity affects cognition, including long term memory. These compounds will also be effective in treating diseases where decreased cAMP levels are involved. This includes, but is not limited to, inflammatory diseases. These compounds may also function as antidepressants, or be useful in treating cognitive and negative symptoms of schizophrenia. Assays for determining PDE4 inhibiting activity, selectivity of PDE4 inhibiting activity, and selectivity of inhibiting PDE4 isoenzymes are known within the art. See, e. g., US 6,136, 821, the disclosure of which is incorporated herein by reference. Halogen herein refers to F, Cl, Br, and I. Preferred halogens are F and Cl. Alkyl means a straight-chain or branched-chain aliphatic hydrocarbon radical. Suitable alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. Other examples of suitable alkyl groups include 1-, 2-or 3-methylbutyl, 1,1-, 1, 2- or 2, 2-dimethylpropylS l-ethylpropyl, 1-, 2-, 3-or 4-methylpentyl, 1,1-, 1, 2-, 1,3-, 2,2-, 2, 3- or 3,3-dimethylbutyl, 1-or 2-ethylbutyl, ethylmethylpropyl, trimethylpropyl, methylhexyl, dimethylpentyl, ethylpentyl, ethylmethylbutyl, dimethylbutyl, and the like. These alkyl radicals can optionally have one or more-CH2CH2-groups replaced in each case by-CH=CH-or-C=C-groups. Suitable alkenyl or alkynyl groups are 1- propenyl, 2-propenyl, 1-propynyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-butynyl, 1, 3- butadienyl, and 3-methyl-2-butenyl. In the arylalkyl groups, heterocyclic-alkyl groups, cycloalkyl-alkyl groups and alkoxyalkyl groups,"alkyl"refers to a divalent alkylene group having in general up to about 13 carbon atoms. In the case of the arylalkyl group, the"alkyl"portion has preferably 2 to 10 carbon atoms. In the heterocyclic-alkyl groups, the"alkyl"portion preferably has 1 to 12 carbon atoms. In the alkoxyalkyl groups, the"alkyl"portion preferably has 2 to 7 carbon atoms. In the cycloalkylalkyl groups, the"alkyl"portion preferably has 1 to 13 carbon atoms. In the cases where alkyl is a substituent (e. g., alkyl substituents on aryl and heterocyclic groups) or is part of a substituent (e. g. , in the alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkylsulphinyl, and alkylsulphonyl substituents for aryl), the alkyl portion preferably has 1 to 12 carbon atoms, especially 1 to 8 carbon atoms, in particular 1 to 4 carbon atoms. Alkoxy means alkyl-O-groups in which the alkyl portion has 1 to 8 carbon atoms, and which can be substituted, for example, by halogens. Suitable alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, sec-butoxy, pentoxy, hexoxy, heptoxy, octoxy, and trifuoromethoxy. Preferred alkoxy groups are methoxy and ethoxy. Similarly, alkoxycarbonyl means an alkyl-O-CO-group in which the alkyl portion has 1 to 8 carbon atoms. Alkenyl refers to straight-chain or branched-chain aliphatic radicals containing 2 to 12 carbon atoms in which one or more-CH2-CH2-structures is replaced by-CH=CH-. Suitable alkenyl groups are ethenyl, 1-propenyl, 2-methylethenyl, 1-butene, 2-butene, 1- pentenyl, and 2-pentenyl. In the arylalkenyl groups, alkenyl refers to an alkyenylene group having preferably 2 to 5 carbon atoms. Cycloalkyl means a monocyclic, bicyclic or tricyclic saturated hydrocarbon radical having 3 to 8 carbon atoms, preferably 4 to 6 carbon atoms, more preferably 5 carbon atoms. Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and norbornyl. Other suitable cycloalkyl groups include, spiropentyl, bicyclo [2.1. 0] pentyl, bicyclo [3.1. 0] hexyl, spiro [2.4] heptyl, spiro [2.5] octyl, bicyclo [5.1. 0] octyl, spiro [2.6] nonyl, bicyclo [2.2. 0] hexyl, spiro [3.3] heptyl, and bicyclo [4.2. 0] octyl. The cycloalkyl group can be substituted by halogens, oxo and/or alkyl. Halogens and/or alkyl groups are preferred substituents. Cycloalkylalkyl refers to a cycloalkyl-alkyl-radical in which the cycloalkyl and alkyl portions are in accordance with the previous descriptions. Suitable examples include cyclopentylethyl and cyclopropylmethyl. Aryl, as a group or substituent per se or as part of a group or substituent, refers to an aromatic carbocyclic radical containing 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms, especially 6 to 10 carbon atoms. Suitable aryl groups include phenyl, naphthyl and biphenyl. Substituted aryl groups include the above-described aryl groups which are substituted one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, and acyloxy (e. g. , acetoxy). Arylalkyl refers to an aryl-alkyl-radical in which the aryl and alkyl portions are in accordance with the previous descriptions. Suitable examples include 1-phenethyl, 2- phenethyl, phenpropyl, phenbutyl, phenpentyl, and naphthylenemethyl. Arylalkenyl refers to an aryl-alkenyl-radical in which the aryl and alkenyl portions are in accordance with the previous descriptions of aryl and alkenyl. Suitable examples include 3-aryl-2-propenyl.- Heterocyclic groups refer to saturated, partially saturated and fully unsaturated heterocyclic groups having one or two rings and a total number of 5 to 10 ring atoms wherein at least one of the ring atoms is an N, O or S atom. Preferably, the heterocyclic group contains 1 to. 3, especially 1 or 2, hetero-ring atoms selected from N, 0 and S. Suitable saturated and partially saturated heterocyclic groups include, but are not limited to tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolinyl and the like. Suitable heteroaryl groups include but are not limited to furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, naphthyridinyl, azaindolyl (e. g. , 7- azaindolyl), 1,2, 3,4,-tetrahydroisoquinolyl, and the like. Preferred heterocyclic and heteroaryl groups include terahydrofuranyl, tetrahydropyranyl, 2-thienyl, 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolinyl, 7-azaindolyl, and 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolinyl. Substituted heterocyclic groups refer to the heterocyclic groups described above which are substituted in one or more places by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e. g. , trifluoromethyl), nitro, oxo, amino, alkylamino, and dialkylamino. Heterocyclic-alkyl refers to a heterocyclic-alkyl-group wherein the heterocyclic and alkyl portions are in accordance with the previous discussions. Suitable examples are. pyridylmethyl, thienylmethyl, pyrimidinylmethyl, pyrazinylmethyl, isoquinolinylmethyl, pyridylethyl and thienylethyl. Partially unsaturated carbocyclic structures are non-aromatic monocyclic or bicyclic structures containing 5 to 14 carbon atoms, preferably 6 to 10 carbon atoms, wherein the ring structure (s) contains at least one C=C bond. Suitable examples are cyclopentenyl, cyclohexenyl, tetrahydronaphthenyl and indan-2-yl. Acyl refers to alkanoyl radicals having 1 to 13 carbon atoms in which the alkyl portion can be substituted by halogen, hydroxy, carboxy, alkyl, aryl and/or alkoxy; or aroyl radicals having 7 to 15 carbon atoms in which the aryl portion can be substituted by halogen, alkyl, alkoxy, nitro, carboxy and/or hydroxy. Suitable acyl groups include formyl, acetyl, propionyl, butanoyl and benzoyl. Substituted radicals preferably have 1 to 3 substituents, especially 1 or 2 substituents. Rl is preferably alkyl having 1 to 2 carbon atoms, which is unsubstituted or substituted, and more preferably 1 carbon atom. For Rl, the substituted alkyl groups are preferably substituted one or more times by halogen, especially F and Cl. More preferably, Rl is CH3 or CF2H. R is preferably alkyl having 1 to 4 carbon atoms. For R2, the substituted alkyl groups are preferably substituted one or more times by halogen, especially F and Cl. Preferably, R2 is alkyl having 1 to 4 carbons which is unsubstituted or substituted with one or more F atoms. R2 can also be preferably cycloalkylalkyl group, wherein the"alkyl"portion preferably has 1 to 2 carbon atoms. R is also preferably a cycloalkyl, which has 4 to 7 atoms. R is also preferably a saturated heterocyclic group with 5 to 7 atoms and containing 1 or 2 hetero-ring atoms selected from O and S. More preferably, R2 is a saturated heterocyclic group with 5 ring atoms containing 1 hetero-ring atom selected from O and S. R is also preferably a benzyl group. In particular, R2 is preferably alkyl, halogenated alkyl, cycloalkyl which is substituted or unsubstituted, cycloalkylalkyl which is substituted or unsubstituted, tetrahydrofuranyl, or arylalkyl which is substituted or unsubstituted. More preferably, R2. is CH3, C2Hs, isopropyl, CF2H, cyclobutyl, cyclopentyl, cyclopropylmethyl, or 3- tetrahydrofuranyl. R3 can also be preferably an aromatic carbocyclic radical preferably containing 6 to 14 carbon atoms. More preferably, R3 has 6 carbon atoms and is phenyl. R3 is preferably phenyl substituted with one or more halogen (preferably fluorine), cyano, nitro, amino, alkyl (preferably methyl), alkoxy (preferably methoxy) or carboxy (e. g., phenyl, bromophenyl, nitrophenyl, fluorophenyl, methoxyphenyl, carboxyphenyl, trifluoromethoxyphenyl, dimethylphenyl). More preferably, R3 is 4-carboxyphenyl, 2,3-difluorophenyl, 4-methylphenyl, 4- tert.-butylphenyl, 4-methoxyphenyl, 3, 4-difluorophenyl, or 4-fluorophenyl. R can also preferably be a cycloalkyl group, and more preferably cyclohexyl or cyclopentyl. R3 can also preferably be an alkyl group, more preferably ethyl, CH (CH3) 2, n-propyl, n-butyl, or t-butyl. R3 is also preferably a heterocyclic group, more preferably thiazolyl, pyridyl or benzothiazolyl, which in each case is substituted or unsubstituted. In accordance with a further preference, R3 is arylalkyl such as benzyl or phenethyl, which in each case is substituted or unsubstituted. In particular, R3 is an arylalkyl selected from benzyl, methylbenzyl, t.-butylbenzyl, methoxybenzyl, dimethoxybenzyl, carboxybenzyl, fluorobenzyl, difluorobenzyl, trifluoromethylbenzyl, trifluoromethoxybenzyl, chlorobenzyl, nitrobenzyl, methoxycarbonylbenzyl, and phenethyl. R4 is preferably alkyl having 1 to 3 carbon atoms, and more preferably R4 is CH3. R4 is preferably a substituted alkyl group having 1 to 3 carbon atoms and is preferably substituted one or more times by halogen, especially F and Cl. R5 is preferably alkyl having 1 to 3 carbon atoms. More preferably, R5 is CH3 or CH2CH3. R6 preferably is cycloalkyl having 4 to 7 carbon atoms, and more preferably 5 carbon atoms and is cyclopentyl. R7 and R8 are each preferably H. R8 can also preferably be alkyl, fluorinated alkyl, hydroxylalkyl, carboxy, alkoxycarbonyl having 2 to 6 carbon atoms (e. g., ethoxycarbonyl),-CO-alkyl having : 2 to 6 carbon atoms (e. g., CH3CO), or phenyl. For example, R8 can be H, CH3, C2H5, CF3, hydroxymethyl, 2- (2-hydroxy) propyl), carboxy, ethoxycarbonyl, CH3CO, or phenyl. X is preferably CH. L is preferably a bond, CH2, CH2CH2, CH2CO, CH2CO2, or CH2CONH. The subscript n is preferably 0 or 1. In addition, preferred PDE4 inhibitors in accordance with the invention are compounds described by subformulas Ia-Im, IIa-IIh, IIIa-IIIg, IVa-IVm, Va-Vh, VIa- VIg, and VIIa-VIId, which correspond to Formulas I, II, III, IV, V, VI, or VII but exhibit the following preferred groups: Ia or IVa R1 is CH3 or CF2H. Ib or IVb Rl is CH3 or CFZH ; and R2 is alkyl, cycloalkyl, cycloalkylalkyl, a heterocyclic group, or arylalkyl, which in each case is substituted or unsubstituted. Ic or IVc Rl is CH3 or CF2H ; and R2 is CF2H, cyclopropylmethyl, cyclopentyl, 3- tetrahydrofuranyl (preferably 3- (3R)- tetrahydrofuranyl), or benzyl. Id or IVd Rl is CH3 or CF2H ; and R2 is CF2H, cyclopropylmethyl, cyclopentyl, or 3- tetrahydrofuranyl (preferably 3- (3R)- tetrahydrofuranyl). Ie or IVe Rl is CH3 or CF2H; and R3 is aryl, heterocyclic, alkyl, or cycloalkyl. If or IVf Rl is CH3 or CF2H ; R3 is aryl, heterocyclic, alkyl, or cycloalkyl ; L is a bond, CH2, CH2CH2, or CH2CO. Ig or IVg Rl is CH3 or CF2H ; and R3 is H, isopropoxy, 2-(6-methyl-pyridyl), 2-cyanophenyl, 2,3- difluorophenyl, 2-methylphenyl, 4-nitrophenyl, 4-aminophenyl, phenyl, pyridyl (e. g. , 4-pyridyl), cyclohexyl, cyclopentyl, ethyl, t- butyl, tetrahydroisoquinolyl, 7-azaindolyl, or 4- methylsulfonylphenyl. Ih or IVh Ru ils CH3 or CF2H ; R2 is H, isopropoxy, CF2H, cyclopropylmethyl, cyclopentyl, 3- tetrahydrofuranyl (preferably 3- (3R)-tetrahydrofuranyl), 2,3- difluorobenzyl, or benzyl; and R3 is 2- (6-methyl-pyridyl), 2-cyanophenyl, 2, 3-difluorophenyl, 2- methylphenyl, 4-nitrophenyl, 4-aminophenyl, phenyl, pyridyl (e. g., 4-pyridyl), cyclohexyl, cyclopentyl, ethyl, t-butyl, tetrahydroisoquinolyl, 7-azaindolyl, or 4-methylsulfonylphenyl. Ii or IVi Rl is CH3 or CF2H ; R2 is CF2H, cyclopropylmethyl, cyclopentyl, 3-tetrahydrofuranyl (preferably 3- (3R)-tetrahydrofuranyl), 2, 3-difluorobenzyl, or benzyl; R3 is H, isopropoxy, 2- (6-methyl-pyridyl), 2-cyanophenyl, 2, 3- difluorophenyl, 2-methylphenyl, 4-nitrophenyl, 4-aminophenyl, phenyl, pyridyl (e. g., 4-pyridyl), cyclohexyl, cyclopentyl, ethyl, t- butyl, tetrahydroisoquinolyl, 7-azaindolyl, or 4- methylsulfonylphenyl ; X is CH; and L is CH2, CH2CH2, CH2CH2CH2, CHZCO, CH2CO2, SO2, CH2CONH, C02 or CH2S02. Ij or IVj' Rl is CH3 or CF2H ; R3 is phenyl, benzyl, phenethyl, cyclohexyl, 2-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4- bromophenyl, 4-methylbenzyl, 4-t-butylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 3,5-dimethoxybenzyl, 3-fluorobenzyl, 2,6- difluorobenzyl, 4-fluorobenzyl, 3,4-difluorobenzyl, or 4- carboxybenzyl; and L is a bond, CH2, CH2CH2, or CH2CONH. Ik or IVk, Rl is CH3 or CF2H; R2 is H, isopropoxy, CF2H, cyclopropylmethyl, cyclopentyl, 3- tetrahydrofuranyl (preferably 3- (3R)-tetrahydrofuranyl), 2,3- difluorobenzyl, or benzyl; R3 is phenyl, benzyl, phenethyl, cyclohexyl, 2-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4- bromophenyl, 4-methylbenzyl, 4-t-butylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 3,5-dimethoxybenzyl, 3-fluorobenzyl, 2,6- difluorobenzyl, 4-fluorobenzyl, 3, 4-difluorobenzyl, or 4- carboxybenzyl; and L is a bond, CH2, CH2CH2, or CH2CONH. Im or Nm Rl is CH3 or CFZH ; R2 is CF2H, cyclopropylmethyl, cyclopentyl, 3-tetrahydrofuranyl (preferably 3- (3R)-tetrahydrofuranyl), 2,3-difluorobenzyl, or benzyl ; R3 is phenyl, benzyl, phenethyl, cyclohexyl, 2-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4- bromophenyl, 4-methylbenzyl, 4-t-butylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 3, 5-dimethoxybenzyl, 3-fluorobenzyl, 2,6- difluorobenzyl, 4-fluorobenzyl, 3,4-difluorobenzyl, or 4- carboxybenzyl; L is a bond, CH2, CH2CH2, or CHzCONH ; and X is CH. IIa or Va R1 is CH3 or CF2H. IIb or Vb R1 is CH3 or CF2H ; and R3 is aryl, heterocyclic, alkyl, or cycloalkyl. IIc or Vc R1 is CH3 or CF2H ; and R3 is 2-(6-methyl-pyridyl), 2-cyanophenyl, 2, 3-difluorophenyl, 2- methylphenyl, 4-nitrophenyl, 4-aminophenyl, phenyl, pyridyl (e. g., 4-pyridyl), cyclohexyl, cyclopentyl, ethyl, t-butyl, tetrahydroisoquinolyl, 7-azaindolyl, or 4-methylsulfonylphenyl. IIb or Vd Rl is CH3 or CFzH ; and R4 is CH3 IIe or Ve R'is CH3 or CFZH ; R3 is 2- (6-methyl-pyridyl), 2-cyanophenyl, 2, 3-difluorophenyl, 2- methylphenyl, 4-nitrophenyl, 4-aminophenyl, phenyl, pyridyl (e. g., 4-pyridyl), cyclohexyl, cyclopentyl, ethyl, t-butyl, tetrahydroisoquinolyl, 7-azaindolyl, or 4-methylsulfonylphenyl ; and R4 is CH3 IIf or Vf Rl is CH3 or CF2H ; R3 is 2- (6-methyl-pyridyl), 2-cyanophenyl, 2, 3-difluorophenyl, 2- methylphenyl, 4-nitrophenyl, 4-aminophenyl, phenyl, pyridyl (e. g., 4-pyridyl), cyclohexyl, cyclopentyl, ethyl, t-butyl,- tetrahydroisoquinolyl, 7-azaindolyl, or 4-methylsulfonylphenyl ; R4 is CH3 ; and L is CH2, CH2CH2, CH2CH2CH2, CH2CO, CH2CO2, SO2, or CH2CONH. IIg or Vg Rl is CH3 or CF2H ; R3 is phenyl, benzyl, phenethyl, cyclohexyl, 2-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4- bromophenyl, 4-methylbenzyl, 4-t-butylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 3,5-dimethoxybenzyl, 3-fluorobenzyl, 2,6- difluorobenzyl, 4-fluorobenzyl, 3,4-difluorobenzyl, or 4- carboxybenzyl; and L is a bond, CH2, CH2CH2, or CH2CONH. IIh or Vh Rl is CH3 or CF2H; R3 is phenyl, benzyl, phenethyl, cyclohexyl, 2-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4- bromophenyl, 4-methylbenzyl, 4-t-butylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 3,5-dimethoxybenzyl, 3-fluorobenzyl, 2,6- difluorobenzyl, 4-fluorobenzyl, 3, 4-difluorobenzyl, or 4- carboxybenzyl; L is a bond, GHz, CH2CH2, or CH2CONH; and R4 is CH3 IIIa or VIa R3 is aryl, heterocyclic, alkyl, or cycloalkyl. IIIb or VIb R5 is alkyl having 1 to 3 carbon atoms. IIIc or Vie R6 is cycloalkyl having 4 to 7 carbon atoms. Hid or VId R3 is aryl, heterocyclic, alkyl, or cycloalkyl ; R5 is CH2CH3 ; and R6 is cyclopentyl. IIIe or VIe R3 is aryl, heterocyclic, alkyl, or cycloalkyl ; R5 is CH2CH3 ; R6 is cyclopentyl ; X is CH; and L is a bond, CH2, CH2CH2, CH2CH2CH2, CH2CO, CH2CO2, SO2, or CH2CONH. IIIf or VIf R3 is 4-methoxyphenyl or 2-pyridylmethyl; R is CH2CH3 ; R6 is cyclopentyl; X is CH; and L is a bond, CH2, CH2CH2, CH2CH2CH2, CH2CO, CH2CO2, SO2, or CH2CONH. IIIg or VIg R3 is 4-methoxyphenyl or 2-pyridylmethyl ; R5 is CH2CH3 ; R6 is cyclopentyl; X is CH; and L is a bond or CH2. VIIa or Villa Rl is CH3 ; R2 is F ; and R3 is substituted or unsubstituted aryl or arylalkyl. VIIb or VIIIb R1 is CH3 ; X is CH; R is F; R3 is substituted or unsubstituted phenyl or benzyl; L is a bond; and R7 and R8 are each H VIIc or VIIIc Rl is CH3 ; R2 is F; R3 is phenyl, benzyl, phenethyl, cyclohexyl, 2-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4- bromophenyl, 4-methylbenzyl, 4-t-butylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 3,5-dimethoxybenzyl, 3-fluorobenzyl, 2,6- difluorobenzyl, 4-fluorobenzyl, 3, 4-difluorobenzyl, or 4- carboxybenzyl; and L is a bond, CH2, CH2CH2, or CH2CONH. VIId or VIIId R1 is CH3 ; X is CH; R is F ; R3 is phenyl, benzyl, phenethyl, cyclohexyl, 2-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4- bromophenyl, 4-methylbenzyl, 4-t-butylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 3,5-dimethoxybenzyl, 3-fluorobenzyl, 2,6- difluorobenzyl, 4-fluorobenzyl, 3, 4-difluorobenzyl, or 4- carboxybenzyl; L is a bond, CH2, CH2CH2, or CH2CONH ; and R7 and R8 are each H. According to preferred compounds of the invention, 5-aryl-1-substituted pyrazoles and 5-heteroaryl-1-substituted pyrazoles (e. g. Formulas IV, V, and VI) are generally preferred over 3-aryl-1-substituted pyrazoles and 3-heteroaryl-1-substituted pyrazoles (e. g. Formulas I, II, and III). According to a further preferred compound aspect of the invention, the compounds of Formulas I, II, III, IV, V, VI, VII and VIII are selected from: 3- (3-Cyclopentyloxy-4-methoxyphenyl) pyrazole [which can also be called 3- (3- Cyclopentyloxy-4-methoxyphenyl)-lH-pyrazole] ; 3- (3-Cyclopentyloxy-4-methoxyphenyl)-1- (2-methylbenzyl) pyrazole [which can also be called 3- (3-Cyclopentyloxy-4-methoxyphenyl)-1- (2-methylbenzyl)-lH-pyrazole] ; 3- (3-Cyclopentyloxy-4-methoxyphenyl)-1- (2, 3-difluorobenzyl) pyrazole [which can also be called 3- (3-Cyclopentyloxy-4-methoxyphenyl)-l- (2, 3-difluorobenzyl)-lH-pyrazole], 3-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(4-nitrobenzyl)pyrazole [which can also be called 3- (3-Cyclopentyloxy-4-methoxyphenyl)-1- (4-nitrobenzyl)-lH-pyrazole] ; 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (2-methylbenzyl) pyrazole [which can also be called 3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (2-methylbenzyl)- 1H-pyrazole] ; 1- (2, 3-Difluorobenzyl)-3- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole [which can also be called 1- (2, 3-Difluorobenzyl)-3- [4-methoxy-3- (3R)- tetrahydrofuranyloxyphenyl]-IH-pyrazole] ; 1- (4-Aminobenzyl)-3- (3-cyclopentyloxy-4-methoxyphenyl) pyrazole [which can also be called 1-(4-Aminobenzyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-lH-pyrazole] ; 3-(4-Methoxy-3-(3R)-tetrahydrofuryloxyphenyl) pyrazole [which can also be called 3- [4- Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole] ; 3-(4-Methoxy-3-(3R)-tetrahydrofuryloxyphenyl)-1-(4-nitrobenzyl) pyrazole [which can also be called 3- [4-Methoxy-3- (3R)-tetrahydrofaranyloxyphenyl]-I- (4-nitrobenzyl)-IH- pyrazole] ; 1- (4-Aminobenzyl)-3- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole [which can also be called 1- (4-Aminobenzyl)-3- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]- IH-pyrazole] ; 3-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-1-(N-(2- methylphenyl) aminocarbonylmethyl) pyrazole [which can also be called 2-{3-[4- Difluoromethoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1-yl}-N- (2,- methylphenyl) acetamide] ; 3- [3, 4-Bis (difluoromethoxy) phenyl] pyrazole [which can also be called 3- [3, 4- Bis (difluoromethoxy) phenyl]-lH-pyrazole] ; 3-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl) pyrazole [which. can also be called 3-[4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole] ; 3-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-1-(N-(2, 3- difluorophenyl) aminocarbonylmethyl) pyrazole [which can also be called 2- {3- [4- Difluoromethoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1-yl}-N- (2, 3- difluorophenyl) acetamide] ; 3- [3,4-Bis (difluoromethoxy) phenyl]-1- (N- (2, 3-difluorophenyl) aminocarbonyl- methyl) pyrazole [which can also be called 2- {3- [3, 4-Bis (difluoromethoxy)-phenyl]- pyrazol-1-yl}-N- (2, 3-difluorophenyl) acetamide]; 3-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-1-(N-(2-(6- methylpyridyl)) aminocarbonylmethyl) pyrazole [which can also be called 2- {3- [4- Difluoromethoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1-yl}-N- [2- (6- methylpyridyl)] acetamide]; 1- (N- (2-Cyanophenyl) aminocarbonylmethyl)-3- (4-difluoromethoxy-3- (3R)- tetrahydrofuryloxyphenyl) pyrazole [which can also be called 1-N- (2-cyanopohenyl) -2-{3- [4-difluoromethoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1-yl} acetamide] ; 3- (4-Difluoromethoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (4-nitrobenzyl) pyrazole [which can also be called 3- [4-Difluoromethoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-l- (4-nitrobenzyl)-1 H-pyrazole] ; 3- (4-Difluoromethoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (2-methylbenzyl) pyrazole [which can also be called 3-[4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1- (2-methylbenzyl)-IH-pyrazole] ; 1-(2, 3-Difluorobenzyl)-3-(4-difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl) pyrazole [which can also be called 1- (2, 3-Difluorobenzyl)-3- [4-difluoromethoxy-3- (3R)- tetrahydrofuranyloxyphenyl]-lH-pyrazole] ; 3- (2-Acetyl-7-methoxybenzofuran-4-yl) pyrazole [which can also be called 3- (2-Acetyl-7- methoxybenzoiuran-4-yl)-lH-pyrazole], 1- (4-Aminobenzyl)-3- (4-difluoromethoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole [which can also be called 1- (4-Aminobenzyl)-3- [4-difluoromethoxy-3- (3R)- tetrahydrofuranyloxyphenyl]-1H-pyrazole] ; 1- (2, 3-Difluorobenzyl)-3- (4-methoxy-3- (3S)-tetrahydrofuryloxyphenyl) pyrazole [which can also be called 1- (2, 3-Difluorobenzyl)-3- [4-methoxy-3- (3S)- tetrahydrofuranyloxyphenyl]-lH-pyrazole] ; 1-Cyclohexylmethyl-3- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole [which can also be called 1-Cyclohexylmethyl-3- [4-methoxy-3- (3R)- tetrahydrofuranyloxyphenyl]-lH-pyrazole] ; 3-(4-Methoxy-3-(3R)-tetrahydrofuryloxyphenyl)-1-(3-phenpropyl) pyrazole [which can also be called 3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (3-phenpropyl)-1H- pyrazole]; 3-(4-Methoxy-3-(3R)-tetrahydrofuryloxyphenyl)-1-(4-pyridylmethyl) pyrazole [which can also be called 3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-l- (4-pyridylmethyl)- 1H-pyrazole] ; 1-Ethylsulfonyl-3- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole [which can also be called 1-Ethylsulfonyl-3-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H- pyrazole]; 3-(4-Methoxy-3-(3R)-tetrahydrofuryloxyphenyl)-1-(1-propyl) pyrazole [which can also be called 3-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(1-propyl)-1H-pyrazole] ; 1-Benzylsulfonyl-3-(4-methoxy-3-(3R)-tetrahydrofuryloxyphenyl) pyrazole [which can also be called 1-Benzylsulfonyl-3- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH- pyrazole] ; 3-(4-Methnoxy-3-(3R)-tetrahydrofuryloxyphenyl)-1-(2-pyridylmethyl) pyrazole [which can also be called 3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (2-pyridylmethyl)- 1H-pyrazole]; 3- [ (1-Cyclopentyl-3-ethylindazol)-6-yl] pyrazole [which can also be called 3- [ (1- Cyclopentyl-3-ethylindazol)-6-yl]-1H-pyrazole] ; 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole-1-ylacetic acid [which can also be called 2-{3-[4-Methoxy-3-(3R)--tetrahydrofuranyloxyphenyl]-1H-pyrazol-1-yl}acetic acid] ; 3- (3-Benzyloxy-4-methoxyphenyl) pyrazole [which can also be called 3- (3-Benzyloxy-4- methoxyphenyl)-lH-pyrazole], 3-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)pyrazole-1-ylacetic acid [which can also be called 2- {3- [4-Difluoromethoxy-3- (3R)- tetrahydrofuranyloxyphenyl] pyrazole-1-yl} acetic acid] 1-Cyclohexylmethyl-5- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole [which can also be called 1-Cyclohexylmethyl-5-[4-methoxy-3-(3R)- tetrahydrofuranyloxyphenyl]-lH-pyrazole] ; 3- (3-Benzyloxy-4-methoxyphenyl)-1- (2, 3-difluorobenzyl) pyrazole [which can also be called 3-(3-Benzyloxy-4-methoxyphenyl)-1-(2, 3-difluorobenzyl)-lH-pyrazole] ; 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- [N- (1, 2,3, 4- tetrahydroisoquinolyl) carbonylmethyl] pyrazole [which can also be called 3- [4-Methoxy- 3- (3R)-tetrahydrofuranyloxyphenyl]-1- [N- (1, 2,3, 4- tetrahydroisoquinolyl) carbonylmethyl]-lH-pyrazole] ; 1-[N-(7-Azaindolyl)carbonylmethyl]-3-(4-methoxy-3-(3R)- <. tetrahydrofuryloxyphenyl pyrazole can also be called azaindolyl carbonylmethyl methoxyphenyl phenyl-1-ethanone tert-butyl carboxylate h-pyrazole isopropyl acetate h- ethyl yl acetic acid pyrazol-1-yl n- trifluoromethyl-pyrazol-1-yl acetamide> 1- (4-tert-Butylbenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (4-trifluoromethylbenzyl)-1H- pyrazole; 1- (3, 4-Difluorobenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-IH-pyrazole ; 1- (2-Fluorobenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-, lH-pyrazole ; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (3-nitrobenzyl)-lH-pyrazole ; 5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(4-methoxycarbonylbenzyl)-1H- pyrazole; 1-Benzyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-lH-pyrazole ; 5- [4-Methoxy-3- (3R)-tetrahydrofiranyloxyphenyl]-3-methyl-1-phenyl-1 H-pyrazole ; 1- (3-Fluorobenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 1- (3, 5-Dimethoxybenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1H- pyrazole; 1-Cyclohexyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-lH-pyrazole ; 1- (3-Fluorobenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-trifluoromethyl- IH-pyrazole ; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1-phenyl-lH-pyrazole ; 1-Cyclohexyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole ; Ethyl l-Benzyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole-3- carboxylate; 1-Benzyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole ; 1- (3-Methoxybenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-IH-pyrazole ; 1- (4-Fluorobenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 1-(2-Methoxybenzyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1H- pyrazole; 1- (l-Butyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-lH-pyrazole ; 1- (2-Fluorophenyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1H- pyrazole; 1- (4-Chlorophenyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-lH- pyrazole; [5- (4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl)-lH-pyrazol-l-yl] acetic acid; N-Cyclopropyl-2-{5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-pyrazol-12- yl} acetamide; N-Isopropyl-2-{5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1- yl} acetamide ; 3-Ethyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]- 1-(2-methoxybenzyl)-1H- pyrazole; 1-Cyclohexyl-3-ethyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1 H-pyrazole ; 1-Benzyl-3-ethyl-5- [4-methoxy-3- (3R)-tetrahydrofi. ranyloxyphenyl]-lH-pyrazole ; Ethyl 3-ethyl- [5- (4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl)-1 H-pyrazol-1- yl] acetate; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]- 1- (4-methoxyphenyl)-. 1H-pyrazole ; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (2-phenylethyl)-lH-pyrazole ; 1-Benzyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole-3-carboxylic acid; 1- (2, 3-Dimethylphenyl)-3-ethyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH- pyrazole; 1- (4-Fluorophenyl)-5- [4-methnxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 1- (3, 4-Dimethylphenyl)-3-ethyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH- pyrazole; 3-Ethyl-5- [4-methoxy-3- (3 R)-tetrahydrofuranyloxyphenyl]-1- (2-metllylphenyl)-1 H- pyrazole; 1-(2-Benzothiazolyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1H- pyrazole; 1- (3, 4-Dimethylphenyl)-5- [4-methoxy-3- 3R)-tetrahydrofuranyloxyphenyl]-3-methyl- 1H-pyrazole ; 2- 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1-yl}-N- phenylacetamide; N, N-Diethyl-2-{5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1- yl} acetamide ; 1-(2, 3-Dimethylphenyl)-5- [4-methoxy-3-(3R)-tetrahydroiranyloxyphenyl]-3-methyl- 1H-pyreazole ; 1- {1-Benzyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazol-3- yl} ethanone ; 2-{ 1-B enzyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazol-3- yl} ethanone; 11-Benzyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazol-3- yl3methanone ; 1-(4-Bromophenyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1- (3-nitrophenyl)-1H- pyrazole; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1- (2-methylphenyl)-1 H- pyrazole; 1-(3,4-Difluorobenzyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole ; 5- (3-Fluoro-4-methoxyphenyl) 1- (4-methoxycarbonylbenzyl)-1 H-pyrazole ; 1- (2, 6-Difluorobenzyl)-5- [4-methoxy-3- (3R)-tetraliydrofuranyloxyphenyl]-lH-pyrazole ; 5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(4-trifluoromethoxyphenyl)-1H- pyrazole; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (2-pyridyl)-lH-pyrazole ; 1- (2-Benzothiazolyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 1- (4-Fluorobenzyl)-5- (3-fluoro-4-methoxyphenyl)-lH-pyrazole ; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1- (2-phenylethyl)-lH- pyrazole; 5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1-(4- trifluoromethoxyphenyl)-1H-pyrazole ; 5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1-(2-quinoxalinyl)-1H- pyrazole; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- [4- (4-morpholinyl) phenyl]-lH- pyrazole ; 5- (3-Fluoro-4-methoxyphenyl)-1- (4-methoxyphenyl)-1 H-pyrazole ; 1-Benzyl-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole; 1-(2-Methoxyphenyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole; 1- [2- (6-Fluoropyridyl)]-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 1- (4-Carboxybenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; Ethyl 2- {5- [4-methoxy-3- (3R)-tetrahydroiuranyloxyphenyl] pyrazol-l-yl} acetate; 1- (2-Hydroxyethyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 1-(2-Methoxyethyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole ; 1- (2-Cyclopropylmethoxyethyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1H- pyrazole; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (4-methoxyphenyl)-3-methyl-1H- pyrazole; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (2-methoxycarbonyl-3-thienyl)-3- methyl-lH-pyrazole ; 1- [2- (6-Fluoropyridyl)]-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1 H- pyrazole; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-l- (2-pyridyl)-lH-pyrazole ; 1- [2- (6-Chloropyridyl)]-5- [4-methoxy-3- (3R)-teirahydrofuranyloxyphenyl]-3-methyl- 1H-pyrazole ; 1- (4-Carboxyphenyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole ; 1- (4-Carboxybenzyl)-5- (3-fluoro-4-methoxyphenyl)-1 H-pyrazole ; 5-(3,4-Dimethoxyphenyl)-1-(4-fluorobenzyl)-1H-pyrazole; 5- (3, 4-Dimethoxyphenyl)-1- (4-methoxyphenyl)-1 H-pyrazole ; and physiologically acceptable salts thereof, wherein in each case the compound can be in the form of a mixture of enantiomers such as the racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer. According to a further compound aspect of the invention, the compounds of formulas I, II, III, IV, V, and VI are selected from : 3- (3-Cyclopentyloxy-4-methoxyphenyl) pyrazole 3-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2-methylbenzyl) pyrazole 3- (3-Cyclopentyloxy-4-methoxyphenyl)-1- (2, 3-difluorobenzyl) pyrazole 3- (3-Cyclopentyloxy-4-methoxyphenyl)-1- (4-nitrobenzyl) pyrazole 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (2-methylbenzyl) pyrazole 1- (2, 3-Difluorobenzyl)-3- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole 1- (4-Aminobenzyl)-3- (3-cyclopentyloxy-4-methoxyphenyl) pyrazole 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (4-nitrobenzyl) pyrazole 1- (4-Aminobenzyl)-3- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole 3-($Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-1-(N-(2- methylphenyl) aminocarbonylmethyl) pyrazole 3- [3, 4-Bis (difluoromethoxy) phenyl] pyrazole 3- (4-Difluoromethoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole 3- (4-Difluoromethoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (N- (2, 3- difluorophenyl) aminocarbonylmethyl) pyrazole 3- [3, 4-Bis (difluoromethoxy) phenyl]-1-(N-(2, 3- difluorophenyl) aminocarbonylmethyl) pyrazole 3-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-1-(N-(2-(6- methylpyridyl)) aminocarbonylmethyl) pyrazole 1-(N-(2-cyanophenyl) aminocarbonylmethyl)-3-(4-difluoromethoxy-3-(3R)- tetrahydrofuryloxyphenyl) pyrazole 3-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-1-(4-nitrobenzyl) pyrazole 3-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-1-(2-methylbenzyl) pyrazole 1- (2, 3-Difluorobenzyl)-3- (4-difluoromethoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole 3- (2-Acetyl-7-methoxybenzofuran-4-yl) pyrazole 1-(4-Aminobenzyl)-3-(4-difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl) pyrazole, 1-(2,3-Difluorobenzyl)-3-(4-methoxy-3-(3S)-tetrahydrofuryloxyphenyl) pyrazole, l-CyclohcxyImethyl-3- (4-methoxy-3- (3R)-tetrahydroiuryloxyphenyl) pyrazole, 3-(4-Methoxy-3-(3R)-tetrahydrofuryloxyphenyl)-1-(3-phenpropyl) pyrazole, 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (4-pyridylmethyl) pyrazole, 1-Ethylsulfonyl-3- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole, 3-(4-Methoxy-3-(3R)-tetrahydrofuryloxyphenyl)-1-(1-propyl) pyrazole, 1-Benzylsulfonyl-3- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole, 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (2-pyridylmethyl) pyrazole, 3- [(l-Cyclopentyl-3-ethylindazole)-6-yl] pyrazole, 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole-1-ylacetic acid, 3- (3-Benzyloxy-4-methoxyphenyl) pyrazole, 3- (4-Difluoromethoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole-1-ylacetic acid, 1-Cyclohexylmethyl-5-(4-methoxy-3-(3R)-tetrahydrofuryloxyphenyl) pyrazole, 3- (3-Benzyloxy-4-methoxyphenyl)-1- (2, 3-difluorobenzyl) pyrazole, 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- [N- (1, 2,3, 4- tetrahydroisoquinolyl) carbonylmethyl] pyrazole, 1- [N- (7-Azaindolyl) carbonylmethyl]-3- (4-methoxy-3- (3R)- tetrahydrofuryloxyphenyl) pyrazole, 3-(2-Acetyl-7-methoxybenzofuran-4-yl)-1-(2,3-difluorobenzyl) pyrazole, 3- (2-Acetyl-7-methoxybenzofuran-4-yl)-1- (4-methylsulfonylbenzyl) pyrazole, 1- (2, 3-Difluorobenzyl)-3- [3- (2, 3-difluorobenzyloxy) -4-methoxyphenyl] pyrazole, 3- [3- (2, 3-Difluorobenzyloxy)-4-methoxyphenyl] pyrazole, 1- (2, 3-Difluorobenzyl)-3- (3-hydroxy-4-methoxyphenyl) pyrazole, 3-(2-Acetyl-7-methoxybenzofiirån-4-yl)-1-(2-methylbenzyl) pyrazole, 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (2-phenethyl) pyrazole, 1- (Acetophenone-2-yl)-3- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole, 1-Benzyl-3- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole, 1-Cyclopentyl-3- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole, 3- [ (l-Cyclopentyl-3-ethylindazole)-6-yl]-1- (2, 3-difluorophenyl) pyrazole, 3- [ (1-Cyclopentyl-3-ethylindazole)-6-yl])-1- (2-methylbenzyl) pyrazole, 3- [ (1-Cyclopentyl-3-ethylindazole)-6-yl])-1- (4-methylsulfonylbenzyl) pyrazole, 3-[(1-Cyclopentyl-3-ethylindazole)-6-yl])-1-(2-pyridylmethyl) pyrazole, 3-(4-Methoxy-3-(3R)-tetrahydrofuryloxyphenyl)-1-pyrazole, 1-Cyclohexylmethyl-5- (4-methoxy-3- (3 S)-tetrahydrofuryloxyphenyl) pyrazole, 1-Cyclohexylmethyl-3- (4-methoxy-3- (3 S)-tetrahydrofuryloxyphenyl) pyrazole, 3-(3,4-Dimethoxyphenyl)-1-(tert-butyloxycarbonyl) pyrazole, 3-(4-Methoxy-3-(3R)-tetrahydrofuryloxyphenyl)-1-(methylsulfonylbenzyl)pyrazole, 1-Isopropyloxycarbonylmethyl-5-(4-methoxy-3-(3R)-tetrahydrofuranylphenyl) pyrazole, 1-(2, 3-Difluorobenzyl)-5-(4-methoxy-3-(3R)-tetrahydrofuranylphenyl) pyrazole, or physiologically acceptable salts thereof, wherein in each case the compound can be in the form of a mixture of enantiomers such as the racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer. According to further compound aspect of the invention, the compound of formulas I, II, III, IV, V, or VI is selected from : 3-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2, 3-åifluorobenzyl) pyrazole 1- (2, 3-Difluorobenzyl)-3- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole 1- (4-Aminobenzyl)-3- (3-cyclopentyloxy-4-methoxyphenyl) pyrazole 3-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-1-(N-(2, 3- difluorophenyl) aminocarbonylmethyl) pyrazole 3-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-1-(N-(2-(6- methylpyridyl)) aminocarbonylmethyl) pyrazole 1- (N- (2-cyanophenyl) aminocarbonylmethyl)-3- (4-difluoromethoxy-3- (3R)- tetrahydrofuryloxyphenyl) pyrazole 3- (4-Difluoromethoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (4-nitrobenzyl) pyrazole 1- (2, 3-Difluorobenzyl)-3- (4-difluoromethoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole 3-(2-Acetyl-7-methoxybenzofuran-4-yl) pyrazole, 3-[(1-Cyclopentyl-3-ethylindazole)-6-yl] pyrazole, 1-Cyclohexylmethyl-5-(4-methoxy-3-(3R)-tetrahydrofuryloxyphenyl) pyrazole, 3- (2-Aceyl-7-methoxybenzofuran-4-yl)-1- (4-methylsulfonylbenzyl) pyrazole, 3-[(1-Cyclopentyl-3-ethylindazole)-6-yl]-1-(2,3-difluorophenyl) pyrazole, 3-[(1-Cyclopentyl-3-ethylindazole)-6-yl])-1-(4-methylsulfonylbenzyl) pyrazole, 3- [ (1-Cyclopentyl-3-ethylindazole)-6-yl])-1- (2-pyridyhnethyl) pyrazole, 1-Isopropyloxycarbonylmethyl-5- (4-methoxy-3- (3R)-tetrahydrofuranylphenyl) pyrazole, 1- (2, 3-Difluorobenzyl)-5- (4-methoxy-3- (3R)-tetrahydrofuranylphenyl) pyrazole, or physiologically acceptable salts thereof, wherein in each case the compound can be in the form of a mixture of enantiomers such as the racemate, or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer. According to a further preferred method aspect of the invention, the compounds of Formulas I, II, III, IV, V, VI, VII and VIII are selected from: 3- (3-Cyclopentyloxy-4-methoxyphenyl) pyrazole [which can also be called 3- (3- Cyclopentyloxy-4-methoxyphenyl)-IH-pyrazole] ; 3- (3-Cyclopentyloxy-4-methoxyphenyl)-1- (2-methylbenzyl) pyrazole [which can also be called 3-(3-Cyclo'pentyloxy-4-methoxyphenyl)-1-(2-methylbenzyl)-lH-pyrazole] ; 3- (3-Cyclopentyloxy-4-methoxyphenyl)-l- (2, 3-difluorobenzyl) pyrazole [which can also be called 3-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2, 3-difluorobenzyl)-lH-pyrazole] ; 3- (3-Cyclopentyloxy-4-methoxyphenyl)-1- (4-nitrobenzyl) pyrazole [which can also be called 3-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(4-nitrobenzyl)-1H-pyrazole] ; 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (2-methylbenzyl) pyrazole [which can also be called 3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (2-methylbenzyl)- IH-pyrazole] ; 1- (2, 3-Difluorobenzyl)-3- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole [which can also be called 1- (2, 3-Difluorobenzyl)-3- [4-methoxy-3- (3R)- tetrahydrofuranyloxyphenyl]-1 H-pyrazole] ; 1- (4-Aminobenzyl)-3- (3-cyclopentyloxy-4-methoxyphenyl) pyrazole [which can also be called 1-(4-Aminobenzyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1H-pyrazole]; 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole [which can also be called 3- [4- Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole]; 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (4-nitrobenzyl) pyrazole [which can also be called 3-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(4-nitrobenzyl)-1H- pyrazole]; 1-(4-Aminobenzyl)-3-(A-methoxy-3-(3R)-tetrahydrofuTyloxyphenyl) pyrazole [which can also be called 1- (4-Aminobenzyl)-3- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]- IH-pyrazole] ; 3- (4-Difluoromethoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (N- (2- methylphenyl) aminocarbonylmethyl) pyrazole [which can also be called 2-f 3- [4- , Difluoromethoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1-yl}-N- (2,- methylphenyl) acetamide] ; 3- [3, 4-Bis (difluoromethoxy) phenyl] pyrazole [which can also be called 3- [3, 4- Bis (difluoromethoxy) phenyl]-1 H-pyrazole] ; 3- (4-Difluoromethoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole [which can also be called 3-[4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole] ; 3- (4-Difluoromethoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (N- (2, 3- difluorophenyl) aminocarbonylmethyl) pyrazole [which can also be called 2- {3- [4- Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1-yl}-N-(2, 3- difluorophenyl) acetamide]; 3- [3, 4-Bis (difluoromethoxy) phenyl]-1-(N-(2, 3-difluorophenyl) aminocarbonyl- methyl) pyrazole [which can also be called 2- {3- [3, 4-Bis (difluoromethoxy)-phenyl]- pyrazol-1-yl}-N-(2, 3-difluorophenyl) acetamide] ; 3- (4-Difluoromethoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (N- (2- (6- methylpyridyl)) aminocarbonylmethyl) pyrazole [which can also be called 2-13- [4- Difluoromethoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1-yl}-N- [2- (6- methylpyridyl) ] acetamide]; 1- (N- (2-Cyanophenyl) aminocarbonylmethyl)-3- (4-difluoromethoxy-3- (3R)- tetrahydrofuryloxyphenyl) pyrazole [which can also be called 1-N- (2-cyanophenyl)-2-{3- [4-difluoromethoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1-yl} acetamide]; 3-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-1-(4-nitrobenzyl) pyrazole [which can also be called 3-[4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1- (4-nitrobenzyl)-1H-pyrazole] ; 3-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-1-(2-methylbenzyl) pyrazole [which can also be called 3- [4-Difluoromethoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-l- (2-methylbenzyl)-IH-pyrazole] ; 1-(2,3-Difluorobenzyl)-3-(4-difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl) pyrazole [which can also be called 1- (2, 3-Difluorobenzyl)-3- [4-difluoromethoxy-3- (3R)- tetrahydrofuranyloxyphenyl]-1H-pyrazole] ; 3- (2-Acetyl-7-methoxybenzofuran-4-yl) pyrazole [which can also be called 3- (2-Acetyl-7- methoxybenzofuran-4-yl)-1H-pyrazole] ; 1- (4-Aminobenzyl)-3- (4-difluoromethoxy-3- (3R)-tetrahydrofLiryloxyphenyl) pyrazole [which can also be called 1- (4-Aminobenzyl)-3- [4-difluoromethoxy-3- (3R)- tetrahydrofuranyloxyphenyl]-1 H-pyrazole] ; 1- (2, 3-Difluorobenzyl)-3- (4-methoxy-3- (3S)-tetrahydrofuryloxyphenyl) pyrazole [which can also be called 1- (2, 3-Difluorobenzyl)-3- [4-methoxy-3- (3S)- tetrahydrofuranyloxyphenyl]-1H-pyrazole] ; 1-Cyclohexylmethyl-3- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole [which can also be called 1-Cyclohexylmethyl-3- [4-methoxy-3- (3R)- tetrahydrofuranyloxyphenyl]-1H-pyrazole] ; 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (3-phenpropyl) pyrazole [which can also be called 3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (3-phenpropyl)-1H- pyrazole]; 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (4-pyridylmethyl) pyrazole [which can also be called 3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (4-pyridylmethyl)- 1H-pyrazole]; 1-Ethylsulfonyl-3- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole [which can also be called 1-Ethylsulfonyl-3- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH- pyrazole]; 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (1-propyl) pyrazole [which can also be called 3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-l- (I-propyl)-lH-pyrazole] ; 1-Benzylsulfonyl-3- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole [which can also be called 1-Benzylsulfonyl-3-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H- pyrazole] ; 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (2-pyridylmethyl) pyrazole [which can also be called 3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (2-pyridylmethyl)- IH-pyrazole] ; 3- [ (1-Cyclopentyl-3-ethylindazol)-6-yl] pyrazole [which can also be called 3- [ (1- Cyclopentyl-3-ethylindazol)-6-yl]-lH-pyrazole] ; 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole-1-ylacetic acid [which can also be called 2-f 3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazol-1-yl} acetic acid] ; 3- (3-Benzyloxy-4-methoxyphenyl) pyrazole [which can also be called 3- (3-Benzyloxy-4- methoxyphenyl)-1 H-pyrazole] ; 3-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)pyrazole-1-ylacetic acid [which can also be called 2- {3- [4-Difluoromethoxy-3- (3R)- tetrahydrofuranyloxyphenyl] pyrazole-1-yl} acetic acid] 1-Cyclohexylmethyl-5- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole [which can also be called 1-Cyclohexylmethyl-5- [4-methoxy-3- (3R)- tetrahydrofuranyloxyphenyl]-1 H-pyrazole] ; 3- (3-Benzyloxy-4-methoxyphenyl)-1- (2, 3-difluorobenzyl) pyrazole [which can also be called 3-(3-Benzyloxy-4-methoxyphenyl)-1-(2, 3-difluorobenzyl)-lH-pyrazole] ; 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- [N- (1, 2,3, 4- tetrahydroisoquinolyl) carbonylmethyl] pyrazole [which can also be called 3- [4-Methoxy- 3-(3R)-tetrahydrofuranyloxyphenyl]-1-[N-(1, 2,3, 4- tetrahydroisoquinolyl) carbonylmethyl]-lH-pyrazole] ; 1- [N- (7-Azaindolyl) carbonylmethyl]-3- (4-methoxy-3- (3R)- tetrahydrofuryloxyphenyl) pyrazole [which can also be called 1- [N- (7- Azaindolyl) carbonylmethyl]-3- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1H- pyrazole]; 3-(2-Acetyl-7-methoxybenzofuran-4-yl)-1-(2,3-difluorobenzyl) pyrazole [which can also be called 3-(2-Acetyl-7-methoxybenzofuran-4-yl)-1-(2, 3-difluorobenzyl)-lH-pyrazole] ; 3- (2-Acetyl-7-methoxybenzofuran-4-yl)-1- (4-methylsulfonylbenzyl) pyrazole [which can also be called 3- (2-Acetyl-7-methoxybenzofuran-4-yl)-1- (4-methylsulfonylbenzyl)-lH- pyrazole] ; 1- (2, 3-Difluorobenzyl)-3- [3- (2, 3-difluorobenzyloxy)-4-methoxyphenyl] pyrazole [which can also be called 1- (2, 3-Difluorobenzyl)-3- [3- (2, 3-difluorobenzyloxy) -4- methoxyphenyl]-1H-pyrazole] ; 3- [3- (2, 3-Difluorobenzyloxy)-4-methoxyphenyl] pyrazole [which can also be called 3- [3- (2, 3-Difluorobenzyloxy)-4-methoxyphenyl]-1H-pyrazole] ; 1- (2, 3-Difluorobenzyl)-3- (3-hydroxy-4-methoxyphenyl) pyrazole [which can also be called 1-(2, 3-Difluorobenzyl)-3-(3-hydroxy-4-methoxyphenyl)-lH-pyrazole] ; 3-(2-Acetylo-7-methoxybenzofuran-4-yl)-1-(2-methylbenzyl) pyrazole [which can also be called 3-(2-Acetyl-7-methoxybenzofuran-4-yl)-1-(2-methylbenzyl)-lH-pyrazole] ; 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (2-phenethyl) pyrazole [which can also be called 3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (2-phenethyl)-1H- pyrazole] ; 1-(Acetophenone-2-yl)-3-(4-methoxy-3-(3R)-tetrahydrofuryloxyphenyl) pyrazolè [which can also be called 2-{3-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1-yl}-1- phenyl-1-ethanone] ; 1-Benzyl-3- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole [which can also be called 1-Benzyl-3- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole] ; 1-Cyclopentyl-3- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole [which can also be called 1-Cyclopentyl-3- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH- pyrazole]; 3- [ (l-Cyclopentyl-3-ethylindazol)-6-yl]-1- (2, 3-difluorobenzyl)-1 H-pyrazole ; 3- [(1-Cyclopentyl-3-ethylindazol)-6-yl]-1-(4-carboxyphenyl)-1H-pyrazole; 3-[(l-Cyclopentyl-3-ethylindazol)-6-yl]-1-(4-methoxyphenyl)-lH-pyrazole ; 3- [ (1-Cyclopentyl-3-ethylindazol)-6-yl])-1- (2-methylbenzyl) pyrazole [which can also be called 3-[(l-Cyclopentyl-3-ethylindazol)-6-yl])-1-(2-methylbenzyl)-lH-pyrazole] ; 3-[(1-Cyclopentyl-3-ethylindazol)-6-yl])-1-(4-methylsulfonylbenzyl) pyrazole [which can also be called 3-[(1-Cyclopentyl-3-ethylindazol)-6-yl])-1-(4-methylsulfonylbenzyl)-1H- pyrazole] ; 3-[(1-Cyclopentyl-3-ethylindazol)-6-yl])-1-(2-pyridylmethyl) pyrazole [which can also be called 3- [ (1-Cyclopentyl-3-ethylindazol)-6-yl])-1- (2-pyridylmethyl)-lH-pyrazole ; 5-[(1-Cyclopentyl-3-ethylindazol)-6-yl])-1-(2-pyridylmethyl)-lH-pyrazole ; 3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-l- [2- (6-methylpyridyl)-lH-pyrazole ; 1-Cyclohexylmethyl-5- (4-methoxy-3- (3S)-tetrahydrofuryloxyphenyl) pyrazole [which can also be called l-Cyclohexylmethyl-5- [4-methoxy-3- (3S)-tetrahydrofuranyloxyphenyl]- 1H-pyrazole]; 1-Cyclohexylmethyl-3- (4-methoxy-3- (3S)-tetrahydrofuryloxyphenyl) pyrazole [which can also be called 1-Cyclohexylmethyl-3- [4-methoxy-3- (3S)-tetrahydrofuranyloxyphenyl]- IH-pyrazole] ; 3- (3, 4-Dimethoxyphenyl)-1- (tert-butyloxycarbonyl) pyrazole [which can also be called tert-Butyl [3- (3, 4-Dimethoxyphenyl) -pyrazol-1-yl] carboxylate]; 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (methylsulfonylbenzyl) pyrazole [which can also be called 3- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (methylsulfonylbenzyl)-1 H-pyrazole] ; Isopropyl 2- 5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1-yl} acetate; 1- (2, 3-Difluorobenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyl-oxyphenyl]-lH- pyrazole ; 5- (3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-phenyl-lH-pyrazole ; 1-Benzyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-trifluoromethyl-1H- pyrazole; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (4-trifluoromethoxybenzyl)-lH- pyrazole; 5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-phenyl-3-trifluoromethyl-1 H- pyrazole; Ethyl [5- (4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl)-3-trifluoromethyl-lH-pyrazol- 1-yl] acetate; [5- (4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl)-3-trifluoromethyl-1H-pyrazol-1- yl] acetic acid; Isopropyl [5- (4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl)-3-trifluoromethyl-lH- pyrazol-1-yl] acetate; 1-(2, 3-Difluorobenzyl)-5-(3, 4-dimethoxyphenyl)-lH-pyrazole ; N- (3-Fluorophenyl)-2- {5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3- trifluoromethyl-pyrazol-1-yl} acetamide ; N- (5-Methylthiazol-2-yl)-2- {5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3- trifluoromethyl-pyrazol-1-yl} acetamide; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (4-methylbenzyl)-lH-pyrazole ; 1- (4-tert-Butylbenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (4-trifluoromethylbenzyl)-1H- pyrazole; 1- (3, 4-Difluorobenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-IH-pyrazole ; 1- (2-Fluorobenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (3-nitrobenzyl)-lH-pyrazole ; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (4-methoxycarbonylbenzyl)-1H- pyrazole; 1-Benzyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1H-pyrazole ; 5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1-phenyl-1H-pyrazole; 1-(3-Fluorobenzyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole; 1-(3,5-Dimethoxybenzyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H- pyrazole; 1-Cyclohexyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-lH-pyrazole ; 1- (3-Fluorobenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-trifluoromethyl- IH-pyrazole ; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1-phenyl-lH-pyrazole ; 1-Cyclohexyl-5- [4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole;l Ethyl 1-Benzyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole-3- carboxylate; 1-Benzyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 1- (3-Methoxybenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 1- (4-Fluorobenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 1- (2-Methoxybenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-lH- pyrazole; 1- (l-Butyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-lH-pyrazole ; 1-(2-Fluorophenyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1H- pyrazole ;- 1- (4-Chlorophenyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1 H- pyrazole; [5-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-1H-pyrazol-1-yl]acetic acid; N-Cyclopropyl-2- 5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1- yl} acetamide; N-Isopropyl-2-{5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1- yl} acetamide; 3-Ethyl-5-[4-methoxy-3-(3R)o-tetrahydrofuranyloxyphenyl]- 1-(2-methoxybenzyl)-1H- pyrazole ; 1-Cyclohexyl-3-ethyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1 H-pyrazole ; 1-Benzyl-3-ethyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; Ethyl 3-ethyl- [5- (4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl)-lH-pyrazol-1- yl] acetate; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]- 1- (4-methoxyphenyl)-lH-pyrazole ; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (2-phenylethyl)-lH-pyrazole ; 1-Benzyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole-3-carboxylic acid; l- (2, 3-Dimethylphenyl)-3-ethyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH- pyrazole; 1- (4-Fluorophenyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 1- (3, 4-Dimethylphenyl)-3-ethyl-S- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1H- pyrazole; 3-Ethyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (2-methylphenyl)-lH- pyrazole; l- (2-Benzothiazolyl)-5- [4-methoxy-3- (3R)-tetrahydroitiranyloxyphenyl]-3-methyl-lH- pyrazole; 1- (3, 4-Dimethylphenyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl- lH-pyrazole ; 2- {5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1-yl}-N- phenylacetamide; N, N-Diethyl-2- {5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1- yl} acetamide; 1-(2,3-Dimethylphenyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl- 1H-pyrazole ; 1-{ {l-Benzyl-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazol-3- yl} ethanone; 2- {1-Benzyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazol-3- yl} ethanone; {1-Benzyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazol-3- yl} methanone; 1- (4-Bromophenyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1- (3-nitrophenyl)-lH- pyrazole; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1- (2-methylphenyl)-lH- pyrazole ; 1-(3,4-Difluorobenzyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole; 5-(3-Fluoro-4-methoxyphenyl)1-(4-methoxycarbonylbenzyl)-1H-pyrazole ; 1- (2, 6-Difluorobenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (4-trifluoromethoxyphenyl)-1H- pyrazole; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- (2-pyridyl)-lH-pyrazole ; 1- (2-Benzothiazolyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 1-(4-Fluorobenzyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1- (2-phenylethyl)-1 H- pyrazole; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1- (4- trifluoromethoxyphenyl)-1 H-pyrazole ; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1- (2-quinoxalinyl)-lH- pyrazole ; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1- [4- (4-morpholinyl) phenyl]-1H- pyrazole; 5-(3-Fluoro-4-methoxyphenyl)-1-(4-methoxyphenyl)-1H-pyrazole ; 1-Benzyl-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole; 1- (2-Methoxyphenyl)-5- [4-methoxy-3- (3R)-tetrallydrofuranyloxyphenyl]-lH-pyrazole ; 1-[2-(6-Fluoropyridyl)]-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 1- (4-Carboxybenzyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1 H-pyrazole ; Ethyl 2- {5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl] pyrazol-1-yl} acetate; 1- (2-Hydroxyethyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 1- (2-Methoxyethyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 1- (2-Cyclopropylmethoxyethyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-1 H- pyrazole; 5- [4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(4-methoxyphenyl)-3-methyl-1H- pyrazole; 5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(2-methoxycarbonyl-3-thienyl)-3- methyl-lH-pyrazole ; l- [2- (6-Fluoropyridyl)]-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-lH- pyrazole; 5- [4-Methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1- (2-pyridyl)-lH-pyrazole ; 1- [2- (6-Chloropyridyl)]-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-3-methyl- lH-pyrazole ; 1- (4-Carboxyphenyl)-5- [4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl]-lH-pyrazole ; 1-(4-Carboxybenzyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole ; 5-(3,4-Dimethoxyphenyl)-1-(4-fluorobenzyl)-1H-pyrazole ; 5-(3,4-Dimethoxyphenyl)-1-(4-methoxyphenyl)-1 H-pyrazole; and physiologically acceptable salts thereof, wherein in each case the compound can be in the form of a mixture of enantiomers such as the racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer. According to a further method aspect of the invention, the compounds of formulas I, II, III, IV, V, and VI are selected from : 3- (3-Cyclopentyloxy-4-methoxyphenyl) pyrazole 3- (3-Cyclopentyloxy-4-methoxyphenyl)-l- (2-methylbenzyl) pyrazole 3-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2, 3-difluorobenzyl) pyrazole 3- (3-Cyclopentyl6xy-4-methoxyphenyl)-1- (4-nitrobenzyl) pyrazole 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (2-methylbenzyl) pyrazole 1- (2, 3-Difluorobenzyl)-3- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole 1- (4-Aminobenzyl)-3- (3-cyclopentyloxy-4-methoxyphenyl) pyrazole 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole 3-(4-Methoxy-3-(3R)-tetrahydrofuryloxyphenyl)-1-(4-nitrobenzyl) pyrazole 1- (4-Aminobenzyl)-3- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole 3- (4-Difluoromethoxy-3- (3R)-tetrahydrofuryloxyphenyl)-l- (N- (2- methylphenyl) aminocarbonylmethyl) pyrazole 3- [3, 4-Bis (difluoromethoxy) phenyl] pyrazole 3- (4-Difluoromethoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole 3-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-1-(N-(2, 3- difluorophenyl) aminocarbonylmethyl) pyrazole 3- [3, 4-Bis (difluoromethoxy)phenyl]-1-(N-(2, 3- difluorophenyl) aminocarbonylmethyl) pyrazole 3- (4-Difluoromethoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (N- (2- (6- methylpyridyl)) aminocarbonylmethyl) pyrazole 1-(N-(2-cyanophenyl) aminocarbonylmethyl)-3-(4-difluoromethoxy-3-(3R)- tetrahydrofuryloxyphenyl) pyrazole 3- (4-Difluoromethoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (4-nitrobenzyl) pyrazole 3- (4-Difluoromethoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (2-methylbenzyl) pyrazole 1- (2, 3-Difluorobenzyl)-3- (4-difluoromethoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole 3-(2-Acetyl-7-methoxybenzofuran-4-yl) pyrazole 1- (4-Aminobenzyl)-3- (4-difluoromethoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole, 1- (2, 3-Difluorobenzyl)-3- (4-methoxy-3- (3S)-tetrahydrofuryloxyphenyl) pyrazole, 1-Cyclohexylmethyl-3- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole, 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl)-l- (3-phenpropyl) pyrazole, 3-(4-Methoxy-3-(3R)-tetrahydrofuryloxyphenyl)-1-(4-pyridylmethyl)pyrazole, 1-Ethylsulfonyl-3-(4-methoxy-3-(3R)-tetrahydrofuryloxyphenyl) pyrazole, 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (1-propyl) pyrazole, 1-Benzylsulfonyl-3- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole, 3-(4-Methoxy-3-(3R)-tetrahydrofuryloxyphenyl)-1-(2-pyridylmethyl) pyrazole, 3- [ (1-Cyclopentyl-3-ethylindazole)-6-yl] pyrazole, 3-(4-Methoxy-3-(3R)-tetrahydrofuryloxyphenyl) pyrazole-1-ylacetic acid, 3- (3-Benzyloxy-4-methoxyphenyl) pyrazole, 3- (4-Difluoromethoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole-1-ylacetic acid, 1-Cyclohexylmethyl-5- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole, 3-(3-Benzyloxy-4-methoxyphenyl)-1-(2, 3-difluorobenzyl) pyrazole, 3-(4-Methoxy-3-(3R)-tetrahydrofuryloxyphenyl)-1-[N-(1, 2,3, 4- tetrahydroisoquinolyl) carbonylmethyl] pyrazole, 1-[N-(7-Azaindolyl) carbonylmethyl]-3-(4-methoxy-3-(3R)- tetrahydrofuryloxyphenyl) pyrazole, 3-(2-Acetyl-7-methoxybenzofuran-4-yl)-1-(2, 3-difluorobenzyl) pyrazole, 3- (2-Acetyl-7-methoxybenzofuran-4-yl)-1- (4-methylsulfonylbenzyl) pyrazole, 1- (2, 3-Difluorobenzyl)-3- [3- (2, 3-difluorobenzyloxy)-4-methoxyphenyl] pyrazole, 3- [3- (2, 3-Difluorobenzyloxy)-4-methoxyphenyl] pyrazole, 1- (2, 3-Difluorobenzyl)-3- (3-hydroxy-4-methoxyphenyl) pyrazole, 3- (2-Acetyl-7-methoxybenzofuran-4-yl)-1- (2-methylbenzyl) pyrazole, 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (2-phenethyl) pyrazole, 1- (Acetophenone-2-yl)-3- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole, 1-Benzyl-3- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole, 1-Cyclopentyl-3- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole, 3- [ (1-Cyclop entyl-3-ethylindazole)-6-yl]-1- (2, 3-difluorophenyl) pyrazole, 3- [ (l-Cyclopentyl-3-ethylindazole)-6-yl])-1- (2-methylbenzyl) pyrazole, 3- [ (1-Cyclopentyl-3-ethylindazole)-6-yl])-1- (4-methylsulfonylbenzyl) pyrazole, 3- [ (l-Cyclopentyl-3-ethylindazole)-6-yl])-1- (2-pyridylmethyl) pyrazole, 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1-pyrazole, 1-Cyclohexylmethyl-5- (4-methoxy-3- (3S)-tetrahydrofuryloxyphenyl) pyrazole, 1-Cyclohexylmethyl-3- (4-methoxy-3- (3 S)-tetrahydrofuryloxyphenyl) pyrazole, 3- (3, 4-Dimethoxyphenyl)-1- (tert-butyloxycarbonyl) pyrazole, 3- (4-Methoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (methylsulfonylbenzyl) pyrazole, 1-Isopropyloxycarbonylmethyl-5- (4-methoxy-3- (3R)-tetrahydrofuranylphenyl) pyrazole, 1- (2, 3-Difluorobenzyl)-5- (4-methoxy-3- (3R)-tetrahydrofuranylphenyl) pyrazole, and physiologically acceptable salts thereof, wherein in each case the compound can be in the form of a mixture of enantiomers such as the racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer. According to further method aspect of the invention, the compound of formulas I, II, III, IV, V, or VI is selected from: 3-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2, 3-difluorobenzyl) pyrazole 1- (2, 3-Difluorobenzyl)-3- (4-methoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole 1- (4-Aminobenzyl)-3- (3-cyclopentyloxy-4-methoxyphenyl) pyrazole 3- (4-Difluoromethoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (N- (2, 3- difluorophenyl) aminocarbonylmethyl) pyrazole 3- (4-Difluoromethoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (N- (2- (6- methylpyridyl) ) aminocarbonylmethyl) pyrazole 1-(N-(2-cyanophenyl) aminocarbonylmethyl)-3-(4-difluoromethoxy-3-(3R)- tetrahydrofuryloxyphenyl) pyrazole 3- (4-Difluoromethoxy-3- (3R)-tetrahydrofuryloxyphenyl)-1- (4-nitrobenzyl) pyrazole 1- (2, 3-Difluorobenzyl)-3- (4-difluoromethoxy-3- (3R)-tetrahydrofuryloxyphenyl) pyrazole 3-(2-Acetyl-7-methoxybenzofuran-4-yl) pyrazole, 3- [ (1-Cyclopentyl-3-ethylindazole)-6-yl] pyrazole, 1-Cyclohexylmethyl-5-(4-methoxy-3-(3R)-tetrahydrofuryloxyphenyl) pyrazole, 3- (2-Aceyl-7-methoxybenzofuran-4-yl)-1- (4-methylsulfonylbenzyl) pyrazole, 3- [ (1-Cyclopentyl-3-ethylindazole)-6-yl]-1- (2, 3-difluorophenyl) pyrazole, 3- [ (l-Cyclopentyl-3-ethylindazole)-6-yl])-1- (4-methylsulfonylbenzyl) pyrazole, 3- [ (1-Cyclopentyl-3-ethylindazole)-6-yl])-1- (2-pyridylmethyl) pyrazole, 1-Isopropyloxycarbonylmethyl-5-(4-methoxy-3-(3R)-tetrahydrofuranylphenyl) pyrazole, 1- (2, 3-Difluorobenzyl)-5- (4-methoxy-3- (3R)-tetrahydrofuranylphenyl) pyrazole, and physiologically acceptable salts thereof, wherein in each case the compound can be in the form of a mixture of enantiomers such as the racemate, or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer. Preferred aspects include pharmaceutical compositions comprising a compound of this invention and a pharmaceutically acceptable carrier and, optionally, another active agent as discussed below. A further preferred aspect includes a method of inhibiting a. PDE4 enzyme, especially an isoenzyme, e. g. , as determined by a conventional assay or one described herein, either in vitro or in vivo (in an animal, e. g. , in an animal model, or in a mammal or in a human); a method of treating a psychiatric or neurological syndrome, e. g., depression and loss of memory, especially major depression and long- term memory, cognitive impairment or decline, memory impairment, etc.; a method of treating a disease state modulated by PDE4 activity, in a mammal, e. g. , a human, e. g., those disease states mentioned herein. Methods of the invention include, but are not limited to, methods of enhancing cognition in a patient in whom such enhancement is desired, methods of treating a patient suffering from cognition impairment or decline, methods of treating a patient having a disease involving decreased cAMP levels, methods of inhibiting PDE4 enzyme activity in a patient, methods of treating a patient suffering from memory impairment due to neurodegenerative disease, methods of treating a patient suffering from depression, methods of treating a patient suffering from an allergic or inflammatory disease. All methods comprise administering to the patient an effective amount of a compound of the invention. Preferably, the patient is human. The compounds of the present invention may be prepared conventionally. Some of the known processes that can be used are described below. All starting materials are known or can be conventionally prepared from known starting materials. Preparation of starting materials: 1 A) R2Br, base R1 R 0XX 1 B) R20H, PPh3, DEAD 4 1 2 1 2 1 2 Z = CHO, COCH3, B (OR'0) or or halogen R'R' Ouzo i 1) Base . 1 2'I N 2) A 12 1 R O'Et0 RZ N-N H 3 4 5 Scheme. 1 The starting materials for Formulas I and IV are prepared as shown in Scheme 1. Thus, appropriately substituted benzaldehydes 3 (X = CH, N) are subjected to Horner- Wadsworth-Emmons conditions with phosphonate 2. The resulting olefin is not isolated, but heated to induce cyclization [Almirante, N.; Cerri, A. ; Fedrizzi, G.; Marazzi, G.; Santagostino, M. Tetrahedron Lett. 1998,39, 3287-3290] to provide the corresponding pyrazoles 5. Alternatively, 3-substituted pyrazoles can be made from beta-ketoaldehydes and hydrazine [Murray, W.; Wachter, M.; Barton, D.; Forenro-Kelly, Y. Synthesis, 1991,18] or from various palladium coupling using a pyrazole aptly substituted in the 3 position, for example with a bromine or a boron. [Cacchi, S.; Fabrizi, G.; Carnaio, A. Syn. Lett. 1997,959-961]. Substitution on the pyrazole nitrogen is accomplished by treatment of the pyrazole 5 with an appropriate base such as NaH, LDA or K2CO3 in a polar aprotic solvent. This is followed by the addition of electrophile R3-L-X', where X'is a suitable leaving group such as a halogen or sulfonate (Cl, Br, methanesulfonyl, etc. ). A mixture of substituted pyrazoles 6a and 6b are obtained with the major isomer being the 1.3- disubstituted pyrazoles (6a). These isomers can be separated by HPLC. R1 R I o1 1) Base + O 7C \ 2) R3LX'Q'X OZ X 2 N R N-N R3 r N 5 6a 6b 6b 5 6a 6b Scheme 2 Reaction of pyrazole 5 with alkyl bromoacetate (preferably t-butyl bromoacetate) gives pyrazole substituted acetate esters. These esters are saponified to acetic acid derivatives 6a and 6b (L = CH2CO, R3 = H) by treatment with either an acid, such as trifluoroacetic acid, or use of a base, such as sodium hydroxide. Treatment of the resultant acetic acid products with thionyl chloride or oxalyl chloride generates the corresponding acid chloride. Subsequent reaction with a nucleophile such as an amine (e. g. , aniline) gives the acetamide derivatives 6a and 6b (e. g. , L = CH2CONH, R3 = phenyl). Similarly, the acetic acid derivative (L=CH2C02, R3 = H) can be treated with HBTU or a suitable coupling reagent (i. e. , DCC, HOBT, etc) and an amine compound to give the desired acetamide analogues 6a and 6b. Alternatively, (Scheme 3) compounds of the type 6a where arylalkyl, alkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocyclic or heterocyclic-alkyl groups can be prepared by either Mitsunobu reaction between phenol 7b and an appropriate alcohol (R20H) or alkylation with a suitable electrophile, R2-X' (X'is a suitable leaving group such as a halogen or sulfonate (Cl, Br, methanesulfbnyl etc. ) ), and an appropriate base (i. e., K2CO3, NaH, NaOH). (RZ arylalkyl, alkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocyclic and heterocyclic-alkyl groups. ) 3-Aryloxy and 3-heteroaryloxy pyrazole derivatives of the type 6a (i. e. , where R2 is aryl or heteroaryl) are prepared by cross coupling reaction of phenol 7b with aryl boronic acids using a copper catalyst in the presence of an amine base. Suitable copper catalysts include copper diacetate, copper (II) chloride, etc. Generally, halogenated solvents are utilized, such as chloroform, dichloromethane, 1,2-dichloroethane, and the like. Commonly used bases include triethylamine, diisopropylethylamine, and pyrrolidine. Alternatively, 3-aryloxy and 3-heteroaryloxy pyrazole compounds can be synthesized in an analogous method as described previously for 3-phenyloxyrolipram, which utilizes an Ullman type coupling reaction starting with iodobenzene and 3- hydroxyrolipram [Schmiechen, R.; Horowski, R.; Palenschat, D.; Paschelke, G.; Wachtel, H.; Kehr, W., 4- (polyalkoxyphenyl)-2-pyrrolidones., US Patent 4,193, 926, filed Mar. 18, 1980]. The other regioisomer 6b may be formed in an analogous manner. Scheme 3 Compounds of Formulas II and V are synthesized in a similar manner starting from aldehyde 8. For these reactions, the ketone should be protected before pyrazole formation and can be deprotected afterwards. Suitable protecting groups include, but are not limited to, ketals and cyclic ketals. Compounds of Formulas III and VI are synthesized in a similar manner starting from aldehyde 9. [Marfat, A. , et al.,"Indazole Derivatives and Their Use as Inhibitors of Phosphodiesterase Type IV and the Production of Tumor Necrosis Factor TNF, U. S. Patent No. 6,262, 040. ] Synthesis of 1,5-pyrazoles A. Cross-Coupling reactions Alternatively, the 1,5-disubstiuted compounds of Formula IV through VII can be prepared from 1-hydroxypyrazole 10 (Scheme 4) (Eskildsen, J., Vedso, P, Begtrup, M., Synthesis, 2001,1053-1056. Eskildsen, J., Kristensen, J. , Vedso, P. , Begtrup, M., J. Org Chem, 2001, 66, 8654-8656. Paulson, A. S. , Eskildsen J. , Vedso, P. , Begtrup, M., J. Org. Chem., 2002, 67, 3904-3907). Thus, warming a solution of 1-hydroxypyrazole 10 with an electrophile such as a benzyl bromide or a-bromoacetate in CHC13 to 60 to 100 °C provides 2-substituted-pyrazol-1-oxides 11. Subsequent treatment with POC13 or POBr3 in a halogenated solvent such as CHC13 yields 5-halo-1-substituted pyrazoles 12. Such 5- halo-1-substituted pyrazoles can undergo cross-coupling type reaction with aryl boronic acids 2 (z = B (OH) 2) or can be metalated (e. g., halogen-magnesium exchange, transmetalation with ZnCl2) for a Negishi-type reaction with an aryl halide 2 (Z = halogen). Scheme 4 R3LX', CHCI,, 50 to 100 C \//POX'3, CHCI3 N-N\---, s N-N OH R L, 0 10 11 Suzukii or Negishi R10 Cross-coupling s N_N R, o w R2° X N-N R L R3L 20 12 Ro X z Alternatively, 1, 5-disubstituted pyrazoles 6b can be prepared from 2-aryldithianes 13 in a three step synthesis. Thus, dithiane intermediate 13 can be prepared by reaction of aldehyde 3 with propane dithiol and a Lewis acid catalyst such as BF3-Et2O in an aprotic solvent (Hatch, R. P. , Shringarpure, J. , Weinreb, S. M. , J. Org. Chem. , 1978,43, 4172- 4177). Subsequent reaction of the alkyl lithium produced dithiane anion with appropriately substituted epoxides provides 2,2-disubstituted dithianes 14. Oxidation of alcohol 14 to the protected-keto dithiane followed by treatment with an appropriately substituted hydrazine salt provides 1, 5-disubstitued pyrazoles 6b. Scheme 5 6) Dess Martin Ox R10 OH 7) R3LNHNH2 HX Toluene, heat i S R8 R O X /Re R O X J LN--N s L 14 6b Another method to prepare 1, 5-disubstituted pyrazoles of type 6b is through condensation reaction between 1,3-diketo derivative 16 and a substituted hydrazine (Reference: Nakamura, Toshio, et al., J Med Ch'em, 2003, 46, 5416; Penning, T. D. , et al, J. Med. Chem., 1997, 40, 1347-1365. ) The selectivity of this reaction for 1,5 versus 1,3- disubstituted pyrazoles varies pending the substitution at R8. Formation of the 1,5- disubstituted pyrazoles are favored when R8 is an electron withdrawing group such as carboxylate or trifluoromethyl, or a small group such as hydrogen. Starting 1,3-diketo derivatives 16 are prepared from acetophenone derivatives 15 by reaction with sodium hydride and an appropriately substituted ethyl acetate. Scheme 6 In a similar fashion, enamines of the type 17 undergo reaction with appropriately substituted hydrazines to provide target pyrazoles 6b. (Reference Yang, Ji, et al., J. Med. Chem. 2004, 47 (6), 1547) Scheme 7 Compounds of Formula VIII can also be prepared using the general procedure described above. One of ordinary skill in the art will recognize that some of the compounds of Formulas I, II, III, IV, V, VI, VII and VIII can exist in different geometrical isomeric forms. In addition, some of the compounds of the present invention possess one or more asymmetric atoms and are thus capable of existing in the form of optical isomers, as well as in the form of racemic or nonracemic mixtures thereof, and in the form of diastereomers and diastereomeric mixtures inter alia. For example, in the 3- tetrahydrofuranyl structure (R2), the carbon atom at the 3-ring position will be chiral. All of these compounds, including cis isomers, _ trans isomers, diastereomic mixtures, racemates, nonracemic mixtures of enantiomers, substantially pure, and pure enantiomers, are within the scope of the present invention. Substantially pure enantiomers contain no more than 5% w/w of the corresponding opposite enantiomer, preferably no more than 2%, most preferably no more than 1 %. The optical isomers can be obtained by resolution of the racemic mixtures- according to conventional processes, for example, by the formation of diastereomeric salts using an optically active acid or base. or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric,. dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e. g. , chiral HPLC columns), with or without conventional derivation, optimally chosen to maximize the separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Diacel, e. g. , Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivitization, are also useful. The optically active compounds of Formulas I-VIII can likewise be obtained by utilizing optically active starting materials in chiral syntheses processes under reaction conditions which do not cause racemization. In addition, one of ordinary skill in the art will recognize that the compounds can be used in different enriched isotopic forms, e. g. , enriched in the content of 2H, 3H,"C,- 13C and/or 14C. In one particular embodiment, the compounds are deuterated. Such deuterated forms can be made by the procedure described in U. S. Patent Nos. 5,846, 514 and 6,334, 997. As described in U. S. Patent Nos. 5,846, 514 and 6,334, 997, deuteration can improve the efficacy and increase the duration of action of drugs. Deuterium substituted compounds can be synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In : Curr. , Pharm. Des. , 2000; 6 (10) ] (2000), 110 pp. CAN 133: 68895 AN 2000: 473538 CAPLUS; Kabalka, George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates. Tetrahedron (1989), 45 (21), 6601-21, CODEN: TETRAB ISSN: 0040-4020. CAN 112: 20527 AN 1990: 20527 CAPLUS; and . Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem. (1981), 64 (1-2), 9-32. CODEN: JRACBN ISSN : 0022-4081, CAN 95 : 76229 AN 1981 : 476229 CAPLUS. The present invention also relates to useful forms of the compounds as disclosed herein, such as pharmaceutically acceptable salts or prodrugs of all the compounds of the present invention for which salts or prodrugs can be prepared. Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid. Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e. g. , sodium, potassium, calcium, magnesium, ammonium, and choline salts. Those skilled in the art will further recognize that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods. The following are further examples of acid salts that can be obtained by reaction with inorganic or organic acids: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, digluconates, cyclopentanepropionates, dodecylsulfates, ethanesulfonates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, fumarates, hydrobromides, hydroiodides, 2-hydroxy-ethanesulfonates, lactates, maleates, methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, palmoates, pectinates, persulfates, 3- phenylpropionates, picrates, pivalates, propionates, succinates, tartrates, thiocyanates, tosylates, mesylates and undecanoates. Preferably, the salts formed are pharmaceutically acceptable for administration to mammals. However, pharmaceutically unacceptable salts of the compounds are suitable as intermediates, for example, for isolating the compound as a salt and then converting the salt back to the free base compound by treatment with an alkaline reagent. The free base can then, if desired, be converted to a pharmaceutically acceptable acid addition salt. The compounds of the invention can be administered alone or as an active ingredient of a formulation. Thus, the present invention also includes pharmaceutical compositions of one or more compounds of Formulas I, II, III, IV, V, VI, VII or VIII containing, for example, one or more pharmaceutically acceptable carriers. Numerous standard references are available that describe procedures for preparing various formulations suitable for administering the compounds according to the invention. Examples of potential formulations and preparations are contained, for example, in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current edition, published by Marcel Dekker, Inc. , as well as Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current edition). In view of their high degree of selective PDE4 inhibition, the compounds of the present invention can be administered to anyone requiring PDE4 inhibition. Administration may be accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally and by infusion) by inhalation, rectally, vaginally, topically and by ocular administration. Various solid oral dosage forms can be used for administering compounds of the invention including such solid forms as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders. The compounds of the present invention can be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and excipients known in the art, including but not limited to suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like. Time release capsules, tablets and gels are also advantageous in administering the compounds of the present invention. Various liquid oral dosage forms can also be used for administering compounds of the inventions, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs. Such dosage forms can also contain suitable inert diluents known in the art such as water and suitable excipients known in the art such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspending the compounds of the invention. The compounds of the present invention may be injected, for example, intravenously, in the form of an isotonic sterile solution. Other preparations are also possible. Suppositories for rectal administration of the compounds of the present invention can be prepared by mixing the compound with a suitable excipient such as cocoa butter, salicylates and polyethylene glycols. Formulations for vaginal administration can be in the form of a pessary, tampon, cream, gel, paste, foam, or spray formula containing, in addition to the active ingredient, such suitable carriers as are known in the art. For topical administration, the pharmaceutical composition can be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye, ear or nose. Topical administration may also involve transdermal administration via means such as transdermal patches. Aerosol formulations suitable for administering via inhalation also can be made. For example, for treatment of disorders of the respiratory tract, the compounds according to the invention can be administered by inhalation in the form of a powder (e. g., micronized) or in the form of atomized solutions or suspensions. The aerosol formulation can be placed into a pressurized acceptable propellant. The compounds can be administered as the sole active agent or in combination with other pharmaceutical agents such as other agents used in the treatment of cognitive impairment and/or in the treatment of psychosis, e. g. , other PDE4 inhibitors, calcium channel blockers, chloinergic drugs, adenosine receptor modulators, ampakines NMDA- R modulators, mGluR modulators, and cholinesterase inhibitors (e. g. , donepezil, rivastigimine, and galanthamine). In such combinations, each active ingredient can be administered either in accordance with their usual dosage range or a dose below their usual dosage range. The present invention further includes methods of treatment that involve inhibition of PDE4 enzymes. Thus, the present invention includes methods of selective inhibition of PDE4 enzymes in animals, e. g. , mammals, especially humans, wherein such inhibition has a therapeutic effect, such as where such inhibition may relieve conditions involving neurological syndromes, such as the loss of memory, especially long-term memory. Such methods comprise administering to an animal in need thereof, especially a mammal, most especially a human, an inhibitory amount of a compound, alone or as part of a formulation, as. disclosed herein. The condition of memory impairment is manifested by impairment of the ability to learn new'information and/or the inability to recall previously learned information. Memory impairment is a primary symptom of dementia and can also be a symptom associated with such diseases as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease, HIV, cardiovascular disease, head trauma as well as age-related cognitive decline. Dementias are diseases that include memory loss and additional intellectual impairment separate from memory. The present invention includes methods for treating patients suffering from memory impairment in all forms of dementia. Dementias are classified according to their cause and include: neurodegenerative dementia (Alzheimer's, Parkinson's disease, Pick's disease), vascular (Infarcts, Hemorrhage, Cardiac Disorders), mixed vascular and Alzheimer's, bacterial meningitis, Creutzfeld- Jacob Disease, and multiple sclerosis), traumatic (subdural hematoma or traumatic brain injury), infectious (HIV), toxic (heavy metals, alcohol, medications), metabolic (Vitamin B12 or folate deficiency), CNS hypoxia, Cushing's disease, psychiatric (depression and schizophrenia) and hydrocephalus. The present invention also includes methods for treating memory loss separate from dementias, including mild cognitive impairment (MCI) and age-related cognitive. decline. The present invention includes methods of treatment for memory impairment as a result of disease including Huntington's disease and Down's syndrome. According to another aspect, the invention includes methods for treating memory loss from anesthetics, chemotherapy, radiation treatment, post-surgical trauma, post-traumatic stress disorder (PTSD), obesity, and diabetes. The compounds of the invention can also be used to treat schizophrenia, bipolar or manic depression, major depression, and drug addiction. PDE4 inhibitors can be used to raise cAMP levels and prevent neurons from undergoing apoptosis. PDE4 inhibitors are also known to be anti-inflammatory. The combination of preventing neuronal apoptosis and inhibiting inflammatory responses make these compounds useful to treat neurodegeneration resulting from any disease or injury, including stroke, Alzheimer's disease, multiple sclerosis, amyolaterosclerosis (ALS), and multiple systems atrophy (MSA), as well as spinal injury. PDE4 inhibitors have been shown to produce antidepressant effects in humans and antidepressant-like effects in animal models of depression. Clinical studies in humans suffering from major depression have demonstrated efficacy of the PDE4 inhibitor, rolipram, with comparable results in some of these studies to those of desipramine [Bobon D, Breulet M, Gerard-Vandenhove MA, Guito-Goffioul F, Plomteux G, Satre-Hernandez M, Schratzer M, Troisfontaines B, von Frenckell R, Wachtel H (1988) Is Phosphodiesterase Inhibition a New Mechanism of Antidepressant Action? Eur Arch Psychiatr Neurol Sci. 238: 2-6; Meya U, Wachtel H, Sastre-Hernandez M (1991) Inhibition of Phosphodiesterase as an Antidepressive Mechanism : Clinical Properties of Rolipram. In Ansseau M, von Frenckell, Franck G (eds) Biological Markers of Depression: State of the art. Elsevier Science Publishers B. V. , Pp. 209-213; Zhu J, Mix E, Winblad B (2001) The Antidepressant and Anti-inflammatory Effects of Rolipram in the Central Nervous System. CNS Drug Reviews 7: 387-398]. Rolipram was active in a number of biochemical and behavioral preclinical models of antidepressant activity [Wachtel H (1983) Potential Antidepressant Activity of Rolipram and other Selective Cyclic Adenosine 3', 5'-Monophosphate Phosphodiesterase Inhibitors. Neuropharmacology 22: 267-272; and Wachtel H. , Schneider HH (1986) Rolipram, a novel antidepressant drug, reverses the hypothermia and hypokinesia of monoamine-. depleted mice by an action beyond postsynaptic monoamine receptors. Neuropharmacology 25: 1119-1126]. More recently, studies with rolipram have demonstrated efficacy of this compound in the tail suspension and forced swimming models of antidepressant activity; these effects were eliminated in animals transgenically modified to lack the PDE4D subtype suggesting that the antidepressant effects of rolipram are mediated by its inhibition of the PDE4 enzyme, specifically the PDE4D subtype [Zhang H-T, Huang Y, Jin S-L, Frith SA, Suvarna N, Conti M, O'Donnell JM (2002) Antidepressant-like Profile and Reduced Sensitivity to Rolipram in Mice Deficient in the PDE4D Phosphodiesterase Enzyme. Neuropsychopharmacology 27: 587- 595]. Thus, in accordance with a preferred embodiment, the present invention includes methods of treating patients suffering from memory impairment due to, for example, mild cognitive impairment due to aging, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility, multiinfarct dementia and other neurological conditions, as well as HIV and cardiovascular diseases, comprising administering an effective amount of a compound according to Formulas I, II, III, IV, V, VI, VII or VIII or a pharmaceutically acceptable salt thereof. As mentioned, the compounds of. the invention also exhibit anti-inflammatory activity. As a result, the inventive compounds are useful in the treatment of a variety of allergic and inflammatory diseases, particularly disease states characterized by decreased cyclic AMP levels and/or elevated phosphodiesterase 4 levels. Thus, in accordance with a further embodiment of the invention, there is provided a method of treating allergic and inflammatory disease states, comprising administering an effective amunt of a compound according to Formulas I, II, III, IV, V, VI, VII or VIII or a pharmaceutically acceptable salt thereof. Such disease states include: asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, esoniophilic granuloma, psoriasis, inflammatory arthritis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock, adult respiratory distress syndrome, cystic fibrosis, emphysema, arterial restenosis, artherosclerosis, keratosis, rheumatoid spondylitis, osteoarthritis, pyresis, diabetes mellitus, pneumoconiosis, chronic obstructive airways disease, chronic obstructive pulmonary disease, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, prurits in the anogenital area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and wide-area pyodermias, endogenous and exogenous acne, acne rosacea, Beget's disease, anaphylactoid purpura nephritis, inflammatory bowel disease, leukemia, multiple sclerosis, gastrointestinal diseases, autoimmune diseases, osteoporosis, and the like. The compounds can also be used in a method of treating patients suffering from disease states characterized by decreased NMDA function, such as schizophrenia. The compounds may also be used for neuronal regeneration. The compounds can also be used to treat psychosis characterized by elevated levels of PDE4, for example, various forms of depression, such as manic depression, major depression, and depression associated with psychiatric and neurological disorders. The compounds may additionally be used for'neurogenesis.. The use of trisubstituted phenyl derivatives for treating asthma, chronic bronchitis, psoriasis, allergic rhinitis, and other inflammatory diseases, and for inhibiting tumor necrosis factor is known within the art. See, e. g. , WO 98/58901, JP 11-189577, JP 10-072415, WO 93/25517, WO 94/14742, US 5, 814, 651, and US 5,935, 978. These references describe 1,3, 4-trisubstituted phenyl compounds said to exhibit PDE4 inhibition activity. They also describe assays for determining PDE4 inhibition activity, and methods for synthesizing such compounds. The entire disclosures of these documents are hereby incorporated by reference. PDE4 inhibitors may be used to prevent or ameliorate osteoporosis, as an antibiotic, for treatment of cardiovascular disease by mobilizing cholesterol from atherosclerotic lesions, to treat rheumatoid arthritis (RA), for long-term inhibition of mesenchymal-cell proliferation after transplantation, for treatment of urinary obstruction secondary to benign prostatic hyperplasia, for suppression of chemotaxis and reduction of invasion of colon cancer cells, for treatment of B cell chronic lymphocytic leukemia (B- CLL), for inhibition of uterine contractions, to attenuate pulmonary vascular ischemia- reperfusion injury (IRI), for corneal hydration, for inhibition of IL-2R expression and thereby abolishing HIV-1 DNA nuclear import into memory T cells, for augmentation of glucose-induced insulin secretion, in both the prevention and treatment of colitis, and to inhibit mast cell degranulation. The invention is also suitable for use in the treatment of a class of disorders known astpolyglutamine-repeat diseases. These diseases share a common pathogenic mutation. The expansion of a CAG repeat, which encodes the amino acid glutamine, within the genome leads to production of a mutant protein having an expanded polyglutamine. region. For example, Huntington's disease has been linked to a mutation of the protein huntingtin. In individuals who do not have Huntington's disease, huntingtin has a polyglutamine region containing about 8 to 31 glutamine residues. For individuals who have Huntington's disease, huntingtin has a polyglutamine region with over 37 glutamine residues. Aside from Huntington's disease (HD), other known polyglutamine-repeat diseases and the associated proteins are: dentatorubral- pallidoluysian atrophy, DRPLA (atrophin-1) ; spinocerebellar ataxia type-1 (ataxin-1) ; spinocerebellar ataxia type-2 (ataxin-2); spinocerebellar ataxia type-3 also called Machado-Joseph disease, MJD (ataxin-3); spinocerebellar ataxia type-6 (alpha la-voltage dependent calcium channel); spinocerebellar ataxia type-7 (ataxin-7); and spinal and bulbar muscular atrophy, SBMA, also known as Kennedy disease (androgen receptor). Thus, in accordance with a further aspect of the invention, there is provided a method of treating a polyglutamine-repeat disease or CAG repeat expansion disease comprising administering to a patient, especially a human, a therapeutically effective amount of a compound according to Formulas I-VIII. In accordance with a further embodiment, there is provided a method of treating Huntington's disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), spinocerebellar ataxia type-1, spinocerebellar ataxia type-2, spinocerebellar ataxia type-3 (Machado-Joseph disease), spinocerebellar ataxia type-6, spinocerebellar ataxia type-7, or spinal and bulbar muscular atrophy, comprising administering to a patient, especially a human, a therapeutically effective amount of a compound according to Formulas I-VIII. The compounds of the present invention can be administered as the sole active agent or in combination with other pharmaceutical agents such as other agents used in the treatment of cognitive impairment and/or in the treatment of psychosis, e. g. , other PDE4 inhibitors, calcium channel blockers, chloinergic drugs, adenosine receptor modulators, amphakines NMDA-R modulators, mGluR modulators, and cholinesterase inhibitors (e. g. , donepezil, rivastigimine, and galanthamine). In such combinations, each active ingredient can be administered either in accordance with their usual dosage range or a dose below their usual dosage range. The dosages of the compounds of the present invention depend upon a variety of factors including the particular syndrome to be treated, the severity of the symptoms, the route of administration, the frequency of the dosage interval, the particular compound utilized, the efficacy, toxicology profile, pharmacokinetic profile of the compound, and the presence of any deleterious side-effects, among other considerations. The compounds of the invention are typically administered at dosage levels and in a mammal customary for PDE4 inhibitors such as those known compounds mentioned above. For example, the compounds can be administered, in single or multiple doses, by oral administration at a dosage level of generally 0.001-100 mg/kg/day, for example, 0.01-100 mg/kg/day, preferably 0.1-70 mg/kg/day, especially 0.5-10 mg/kg/day. Unit dosage forms can contain generally 0.01-1000 mg of active compound, for example, 0.1- 50 mg of active compound. For intravenous administration, the compounds can be administered, in single or multiple dosages, at a dosage level of, for example, 0. 001-50 mg/kg/day, preferably 0.001-10 mg/kg/day, especially 0.01-1 mg/kg/day. Unit dosage forms can contain, for example, 0.1-10 mg of active compound. In carrying out the procedures of the present invention, it is of course to be understood that reference to particular buffers, media, reagents, cells, culture conditions and the like are not intended to be limiting, but are to be read so as to include all related materials that one of ordinary skill in the art would recognize as being of interest or value in the particular context in which that discussion is presented. For example, it is often possible to substitute one buffer system or culture medium for another and still achieve similar, if not identical, results. Those of skill in the art will have sufficient knowledge of such systems and methodologies so as to be able, without undue experimentation, to make such substitutions as will optimally serve their purposes in using the methods and procedures disclosed herein. The present invention will now be further described by way of the following non- limiting examples. In applying the disclosure of these examples, it should be kept clearly in mind that other and different embodiments of the methods disclosed according to the present invention will no doubt suggest themselves to those of skill in the relevant art. In the foregoing and in the following examples, all. temperatures are set forth uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and percentages are by weight. The entire disclosures of all applications, patents and publications, cited above and below, including U. S. Provisional Application Serial No. 60/463,725, filed April 18, 2003, are hereby incorporated by reference in their entirety. EXAMPLES Example 1 Example 1A : Synthesis of 4-Methoxy-3- (3R)-tetrahydrofuryloxybenzaldehyde 3-Hydroxy-4-methoxybenzaldehyde (7.6 g; 50 mmol) was dissolved in THF (200 mL) followed by addition of (S)-3-hydroxytetrahydrofuran (6.0 mL; 75 mmol) and triphenylphosphine (19.7 g; 75 mmol). The resulting solution was cooled to 5 °C and diisopropyl azodicarboxylate (14. 8 mL; 75 mmol) was added dropwise over 10 minutes. The clear orange solution was stirred at ambient temperature for 16 hours. Thin layer chromatography analysis using a 1 : 1 mixtureaof hexane/ethyl acetate determined the reaction to be complete. The solvent was removed under reduced pressure and the residue was taken in ethyl acetate (60 mL) and extracted twice with 20% aqueous sodium bisulfite (150mL/extraction). The extracts were pooled and washed with ethyl acetate (75 mL). The aqueous layer was basified with solid sodium hydroxide (26 g) and then extracted with 3 x 150 mL of ethyl acetate (150 mL/extraction). The organic extracts were pooled, washed with 40 mL of brine, dried (Na2S04), and concentrated to afford 7.4 g (66%) of a pale yellow oil.'H NMR (CDC13 ; 300 MHz) 8 2. 2-2. 4 (m, 2H); 3.8-4. 1 (m, 7H); 5.0 (m, 1H); 7.0 (d, 1H) ; 7.4 (s, 1H) ; 7.5 (d, 1H) ; 9.9 (s, 1H). ES-MS [M+H] +=223. 2 The following compounds were prepared in a similar fashion with different starting materials: 1-Bromo-4-methoxy-3- (3R)-tetrahydrofuranyloxybenzene. 4-Methoxy-3-(3 S)-tetrahydrofuryloxybenzaldehyde. |
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4777-DELNP-2005-Abstract-(19-01-2010).pdf
4777-delnp-2005-Claims-(12-03-2010).pdf
4777-DELNP-2005-Claims-(19-01-2010).pdf
4777-DELNP-2005-Correspondence-Others (21-01-2010).pdf
4777-DELNP-2005-Correspondence-Others-(01-04-2010).pdf
4777-delnp-2005-Correspondence-Others-(12-03-2010).pdf
4777-DELNP-2005-Correspondence-Others-(19-01-2010).pdf
4777-delnp-2005-correspondence-others.pdf
4777-DELNP-2005-Description (Complete)-(19-01-2010).pdf
4777-DELNP-2005-Form-1-(19-01-2010).pdf
4777-DELNP-2005-Form-2-(19-01-2010).pdf
4777-DELNP-2005-Form-3-(01-04-2010).pdf
4777-DELNP-2005-Form-3-(19-01-2010).pdf
4777-DELNP-2005-GPA-(19-01-2010).pdf
Patent Number | 240645 | |||||||||||||||
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Indian Patent Application Number | 4777/DELNP/2005 | |||||||||||||||
PG Journal Number | 22/2010 | |||||||||||||||
Publication Date | 28-May-2010 | |||||||||||||||
Grant Date | 21-May-2010 | |||||||||||||||
Date of Filing | 19-Oct-2005 | |||||||||||||||
Name of Patentee | MEMORY PHARMACEUTICALS CORPORATION | |||||||||||||||
Applicant Address | 100 PHILIPS PARKWAY, MONTVALE, NEW JERSEY 07645, USA. | |||||||||||||||
Inventors:
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PCT International Classification Number | C07D 407/12 | |||||||||||||||
PCT International Application Number | PCT/US2004/011899 | |||||||||||||||
PCT International Filing date | 2004-04-16 | |||||||||||||||
PCT Conventions:
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