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  • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
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  • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
  • C07C217/88—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a ring other than a six-membered aromatic ring
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  • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
  • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
  • C07C217/92—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the nitrogen atom of at least one of the amino groups being further bound to a carbon atom of a six-membered aromatic ring
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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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  • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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Definitions

• the present 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., N-substituted aniline and diphenylamine analogs, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
• PDE4 phosphodiesterase 4
• the cyclic nucleotide specific phosphodiesterases 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.
• PDEs cyclic nucleotide specific phosphodiesterases
• 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.
• PDE 1 is stimulated by Ca 2+ /calmodulin.
• PDE 2 is cGMP-dependent, and is found in the heart and adrenals.
• PDE 3 is cGMP-dependent, and inhibition of this enzyme creates positive inotropic activity.
• PDE 4 is cAMP specific, and its inhibition causes airway relaxation, antiinflammatory and antidepressant activity.
• PDE 5 appears to be important in regulating cGMP content in vascular smooth muscle, and therefore PDE 5 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 ofthe PDE4 enzyme designated PDE4A, PDE4B, PDE4C, and PDE4D [See: 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)]
• PDE4A PDE4A
• PDE4B PDE4C
• PDE4D PDE4D
• 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 antiinflammatory 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 considerable 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 anti-depressant, 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 ofthe 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.
• the present invention relates to novel compounds, e.g., novel N-substituted aniline and diphenylamine compounds, that inhibit 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).
• the compounds selectively inhibit PDE4 enzymes.
• the compounds of this invention at the same time facilitate entry into cells, especially cells ofthe nervous system.
• 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, requiring PDE inhibition, especially PDE4 inhibition, for a disease state that involves elevated intracellular PDE 4 levels or decreased cAMP levels, e.g., involving neurological syndromes, especially those states associated with memory impairment, most especially long term memory impairment, as where such memory impairment is due in part to catabolism of intracellular cAMP levels by PDE 4 enzymes, or where such memory impairment may be improved by effectively inhibiting PDE4 enzyme activity.
• a patient e.g., mammals, including humans, requiring PDE inhibition, especially PDE4 inhibition, for a disease state that involves elevated intracellular PDE 4 levels or decreased cAMP levels, e.g., involving neurological syndromes, especially those states associated with memory impairment, most especially long term memory impairment, as where such memory impairment is due in part to catabolism of intracellular cAMP levels by PDE 4 enzymes
• the compounds of the invention improve such diseases by inhibiting PDE4 enzymes at doses which do not induce emesis.
• the present invention includes compounds of Formula I:
• R 1 is alkyl having 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen (e.g., CH 3 , CHF 2 , CF 3 , etc.);
• cycloalkylalkyl having 4 to 16, preferably 4 to 12 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, C . - 4 -alkyl, C ⁇ - 4 -alkoxy or combinations thereof (e.g., cyclopentylmethyl, cyclopropylmethyl, etc.),
• aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF 3; OCF 3 , alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, or combinations thereof (e.g., methylphenyl, methoxyphenyl, chlorophenyl, etc.),
• a partially unsaturated carbocyclic group having 5 to 14 carbon atoms which is unsubstituted or substituted one or more times by halogen, alkyl, alkoxy, hydroxy, nitro, cyano, oxo, or combinations thereof (e.g., cyclohexenyl, cyclohexadienyl, indanyl, tetrahydronaphthenyl, etc.),
• heterocychc group which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof (e.g., 3-thienyl, 3-tetrahydrofuranyl, 3-pyrrolyl, etc.), or
• a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion which is branched or unbranched has 1 to 5 carbon atoms, and which is unsubstituted or substituted in the carbocyclic portion one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, and the alkyl portion is optionally substituted by halogen, C ⁇ -alkoxy, cyano or combinations thereof (e.g., cyclohexenylmethyl, etc.),
• arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms
• arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF 3 O, nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl (e.g., benzyl, phenethyl, phenpropyl, methylbenzyl, methoxybenzyl, trfluoromethyl, benzyl, methylenedioxobenzyl, etc.), or
• heteroarylalkyl group wherein the heteroaryl portion may be partially or fully saturated and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, the heteroarylalkyl group is unsubstituted or substituted one or more times in the heteroaryl portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF 3 O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof (e.g., pyridylmethyl, pyridylpropyl, methylpyridylmethyl, chloropyridylmethyl, dichloropyridylmethyl, thienylmethyl, thiazolylmethyl, quinolinylmethyl
• aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF 3 , amino, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, 2(-heterocycle)tetrazole- 5-yl (eg., 2-(2-tetrahydropyranyl)tetrazole-5-yl), hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfmyl, alkylsulfonyl,
• R 5 -L- tert- butyldimethylsilyloxy
• R 5 -L- or combinations thereof (e.g., substituted or unsubstituted phenyl, naphthyl, and biphenyl, such as phenyl, methylphenyl,-chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.), or
• heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (eg.
• R 5 -L- tert- butyldimethylsilyloxy
• R 5 -L- or combinations thereof (e.g., pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl, etc.);
• alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is unsubstituted or substituted one or more times with halogen, C ⁇ - 4 -alkyl, C ⁇ - 4 -alkoxy, oxo, or combinations thereof (e.g., methyl, ethyl, propyl, etc.),
• a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion has 1 to 5 carbon atoms, which is unsubstituted or substituted, preferably in the carbocyclic portion, one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof (e.g., cyclohexenylmethyl, etc.), cycloalkyl having 3 to 10, preferably 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkoxy, alkyl having 1 to 4 carbon atoms, or combinations thereof (e.g., cyclopentyl),
• cycloalkylalkyl having 4 to 16, preferably 4 to 12 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, alkyl, alkoxy or combinations thereof (e.g., cyclopentylmethyl, cyclopropylmethyl, etc.),
• aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, (e.g., substituted or unsubstituted phenyl and naphthyl, methylphenyl, chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl,
• arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms
• arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF 3 O, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl (e.g., benzyl, phenethyl, phenpropyl, methylbenzyl, methoxybenzyl, trfluoromethyl, benzyl, methylenedioxobenzyl, etc.),
• a heterocychc group which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof (e.g., pyridyl, thi
• heterocycle-alkyl group wherein the heterocychc portion is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, and the alkyl portion which is branched or unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted or substituted one or more times in the heterocychc portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF 3 O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof (e.g., pyridylmethyl, pyridylpropyl, methylpridylmethyl, etc.);
• -CH 2 - groups are each optionally replaced by -O-, -S-, -NR 6 -, -SO 2 NH-, -NHSO 2 -, -CO-, -NR 6 CO-, -CONR 6 -, -NHCONH-, -OCONH, -NHCOO-, -SCONH-, -SCSNH-, or -NHCSNH- (e.g.,-O-, CH 2 -, -CO-, -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -CH 2 CH 2 CH 2 -NH- CO-, -CH 2 -CH 2 -O-, -SO 2 -NH-CH 2 CH 2 -O-, -O-CH 2 CH 2 -O-, -CH 2 -NH- CO-, -CO-
• R G is H
• R 3 and R 4 are other than H; and pharmaceutically acceptable salts thereof
• R , R , R , and R are as defined above.
• the compounds of this subgenus of formula I not only have PDE4 inhibitory activity, but also are useful as intermediates for preparing compounds of Formula I in which R 3 and R 4 are both other than H.
• preferred compounds of formula I are those ofthe sub formula IN
• R 1 , R 2 , and R 4 are as defined in Formula I and one of A, B and D is N and the others are C.
• B is N.
• R is preferably pyridyl or phenyl which in each case is substituted or unsubstituted.
• the present invention also includes compounds of Formula I':
• R 1 ' is methoxy, F, CI, CHF 2 or CF 3 ;
• alkyl having 1 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano, or combinations thereof,
• alkenyl having 2 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano or combinations thereof,
• alkynyl having 2 to 12 carbon atoms
• alkynyl having 2 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano or combinations thereof,
• cycloalkyl having 3 to 10 carbon atoms cycloalkyl having 3 to 10 carbon atoms substituted one or more times by halogen, oxo, alkyl, or combinations thereof,
• cycloalkylalkyl having 4 to 12 carbon atoms
• cycloalkylalkyl having 4 to 12 carbon atoms which is substituted one or more times by halogen, oxo, alkyl or combinations thereof,
• arylalkyl having 7 to 26 carbon atoms which is substituted one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, trifluoromethyl, or combinations thereof,
• heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, or
• substituted heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and which is substituted one or more times in the heteroaryl portion by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, amino, alkylamino, dialkylamino or combinations thereof and or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof;
• X is O or S;
• R 3 is aryl having 6 to 14 carbon atoms
• aryl having 6 to 14 carbon atoms which is substituted one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, heteroaryl which is unsubstituted or substituted by halogen, alkyl or alkoxy, or combinations thereof,
• heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, or
• substituted heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom which is substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof; '
• R .4 is alkyl having 1 to 12 carbon atoms
• alkyl having 1 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano, or combinations thereof,
• aryl having 6 to 14 carbon atoms and 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, alkylsulfinyl, alkylsulfonyl, phenoxy or combinations thereof, heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom,
• substituted heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and which is substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof,
• arylalkyl having 7 to 16 carbon atoms which is substituted one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, trifluoromethyl, or combinations thereof,
• heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, or
• substituted heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and which is substituted one or more times in the heteroaryl portion by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof; and
• the compounds ofthe 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.
• intermediate compounds which correspond to compounds of Formula I, wherein R 2 , R 3 , and R 4 are as previously defined for Formula I, but R 1 is H, tert-butyldimethylsilyl-, or a suitable phenolic protecting group.
• Suitable phenolic protecting groups are described, for example; in Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis, 3 rd Edition, John Wiley & Sons, 1999, pp. 246-293.
• radio-labeled compounds such as where R 1 is 3 H 3 C-, 14 CH 3 - or " CH 3 -, for example by removing the protecting group and reacting the resultant compound in which R 1 is H with suitable radio-labelled reagents.
• radio-labeled compounds are useful for determining compound tissue distribution in animals, in PET imaging studies, and for in vivo, ex vivo, and in vitro binding studies.
• intermediate compounds which correspond to compounds of Formula I, wherein R 1 , R 3 , and R 4 are as previously defined for Formula I, but R 2 is H, tert-butyldimethylsilyloxy-, or a suitable phenolic protecting group.
• Suitable phenolic protecting groups are described, for example, in Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis, 3 rd Edition, John Wiley & Sons, 1999, pp. 246- 293.
• Compounds in which R 2 is H are useful as intermediates, for example, as scaffolds for parallel or combinatorial chemistry applications. Further, these compounds are useful for the introduction of radio-labels such as H, C, or C.
• R and R are as previously described are useful intermediates for the production of compounds according to formula I where in R is other than H.
• Halogen herein refers to F, CI, Br, and I. Preferred halogens are F and CI.
• Alkyl as a group or substituent per se or as part of a group or substituent (e.g., alkylamino, trialkylsilyloxy, aminoalkyl, hydroxyalkyl), means a straight-chain or branched-chain aliphatic hydrocarbon radical having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, especially 1 to 4 carbon atoms.
• Suitable alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl.
• alkyl groups include 1-, 2- or 3- methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1 -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.
• Substituted alkyl groups are alkyl groups as described above which are substituted in one or more positions by halogens, oxo, hydroxyl, C ⁇ -4 -alkoxy and/or cyano.
• Halogens are preferred substituents, especially F and CI.
• Alkoxy means alkyl-O- groups and alkoxyalkoxy means alkyl-O-alkyl-O- groups in which the alkyl portions are in accordance with the previous discussion.
• Suitable alkoxy and alkoxyalkoxy groups include methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy methoxymethoxy ethoxymethoxy, propoxymethoxy, and methoxyethoxy.
• Preferred alkoxy groups are methoxy and ethoxy.
• alkoxycarbonyl means alkyl -O-CO- in which the alkyl portion is in accordance with the previous discussion. Examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and tert-butoxycarbonyl.
• Cycloalkyl means a monocyclic, bicyclic or tricyclic nonaromatic saturated hydrocarbon radical having 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, especially 3 to 6 carbon atoms.
• Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, 1-decalin, adamant-1-yl, and adamant-2-yl.
• Suitable cycloalkyl groups include spiropentyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, spiro[2.4]heptyl, s ⁇ iro[2.5]octyl, bicyclo[5.1.0]octyl, spiro[2.6]nonyl, bicyclo[2.2.0]hexyl, spiro[3.3]heptyl, bicyclo[4.2.0]octyl, and spiro[3.5]nonyl.
• Preferred cycloalklyl groups are cyclopropyl, cyclopentyl and cyclohexyl.
• the cycloalkyl group can be substituted, for example, substituted by halogens and/or alkyl groups.
• Cycloalkylalkyl refers to cycloalkyl-alkyl radicals in which the cycloalkyl and alkyl portions are in accordance with previous discussions. Suitable examples include cyclopropylmethyl and cyclopentylmethyl.
• 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, for example, halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, and phenoxy.
• Arylalkyl refers to an aryl-alkyl-radical in which the aryl and alkyl portions are in accordance with the previous descriptions. Suitable examples include benzyl, 1- phenethyl, 2-phenethyl, phenpropyl, phenbutyl, phenpentyl, and napthylmethyl.
• Heteroaryl refers to an aromatic heterocychc group having one or two rings and a total number of 5 to 10 ring atoms wherein at least one ofthe ring atoms is a heteroatom.
• the heteroaryl group contains 1 to 3, especially 1 or 2, hetero-ring atoms which are selected from N, O and S.
• Suitable heteroaryl groups include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, dithialyl, oxathialyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl, oxathiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazinyl, isoxazinyl, oxathiazinyl, oxadiazinyl, benzofuranyl, isobenzofuranyl, thionaphthenyl, isothionaphthenyl, indolyl, isoindolyl, indazoly
• Substituted heteroaryl refers to the heteroaryl groups described above which are substitued in one or more places by, for example, halogen, aryl, alkyl, alkoxy, carboxy, methylene, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, and dialkylamino.
• Heterocycles include heteroaryl groups as described above as well as non- aromatic cyclic groups containing at least one hetero-ring atom, preferably selected from N, S and O, for example, tetrahydrofuranyl, piperidinyl, and pyrrolidinyl.
• Heterocycle-alkyl refers to a heterocycle-alkyl-group wherein the heterocychc and alkyl portions are in accordance with the previous discussions. Suitable examples are pyridylmethyl, thienylmethyl, pyrimidinylmethyl, pyrazinylmethyl, and isoquinolinylmethyl.
• Suitable examples are cyclopentenyl, cyclohexenyl, cyclohexadienyl, tetrahydronaphthenyl and indan-2-yl.
• Suitable alkenyl groups are ethenyl, 1-propenyl, 2-methylethenyl, 1-butene, 2- butene, 1-pentenyl, and 2-pentenyl.
• Alkynyl refers to straight-chain or branched-chain aliphatic radicals containing 2 to 12 carbon atoms in which one or more -CH 2 -CH 2 - structures are each replaced by -C ⁇ C-.
• Suitable alkynyl groups are ethynyl, propynyl, 1-butynyl, and 2-butynyl.
• Acyl refers to alkanoyl radicals having 1 to 13 carbon atoms in which the alkyl portion can be substituted by halogen, alkyl, aryl and/or alkoxy, or aroyl radicals having 7 to 15 carbon atoms in which the aryl portion can be substituted by, for example, halogen, alkyl and/or alkoxy.
• Suitable acyl groups include formyl, acetyl, propionyl, butanoyl and benzoyl.
• Substituted radicals preferably have 1 to 3 substituents, especially 1 to 2 substituents.
• R 1 is an alkyl group having preferably 1 to 4 carbon atoms which is optionally substituted by halogen, preferably fluorine or chlorine.
• R 1 is preferably methyl or difluoromefhyl.
• R 2 is preferably cycloalkyl, particularly cyclopentyl.
• R 2 is also preferably aryl or arylalkyl, particularly substituted or unsubstituted phenyl or phenylalkyl, such as phenyl, methylphenyl, methoxyphenyl, chlorophenyl, phenethyl, phenpropyl, phenbutyl, phenylethenyl, phenoxyethyl, phenoxypropyl, phenoxybutyl, chlorophenylethyl, methoxyphenyl ethyl, chlorophenylethenyl, chlorophenoxyethyl, chlorophenypropyl, methoxyphenpropyl, methoxyphenbutyl, chlorophenbutyl, nitrophenbutyl, chlorophenylaminoethyl, and the like,
• R 2 is also preferably a partially unsaturated carbocyclic groups, which is unsubstituted or substituted, particularly cyclohexenyl, cyclohexadienyl, indan-2-yl.
• R 2 is also preferably an alkyl group having 1 to 8 carbon atoms, especially 1 to 4 carbon atoms, which is substituted or unsubstituted, e.g., methyl, difluoromethyl, trifluoromethyl, and methoxyethyl.
• R 2 is also preferably a heterocychc or heterocycle-alkyl group, particularly radicals in which the heterocychc group has 5 to 6 ring atoms and 1 to 2 hetero-ring atoms selected from N, O and S, e.g., tetrahydrofuranyl, pyrrolidinyl, pyrrolyl, pyridylmethyl, pyridylethyl, pyridylpropyl, piperazinylmethyl, piperazinylethyl, methylpiperazinylethyl and the like.
• the heterocychc group has 5 to 6 ring atoms and 1 to 2 hetero-ring atoms selected from N, O and S, e.g., tetrahydrofuranyl, pyrrolidinyl, pyrrolyl, pyridylmethyl, pyridylethyl, pyridylpropyl, piperazinylmethyl, piperazinylethy
• Preferred R include cyclopentyl, tetrahydrofuranyl, CHF 2 , methoxyethyl, cyclopropylmethyl, phenethyl, phenpropyl, phenylethenyl, phenoxyethyl, phenoxybutyl, phenylaminoethyl, indan-2-yl, pyridylethyl, and pyridylpropyl.
• R 3 is preferably hydrogen, alkyl having 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, or n-butyl), arylalkyl (e.g., substituted or unsubstitituted benzyl, phenethyl, and phenpropyl), or a heteroarylalkyl group (e.g., substituted or unsubstituted pyridylmethyl, furanylmethyl, thienylmethyl, pyrrolylmethyl, pyrimidinylmethyl, thiazolylmethyl, isoquinolinylmethyl and quinolmylmethyl).
• alkyl having 1 to 4 carbon atoms e.g., methyl, ethyl, n-propyl, or n-butyl
• arylalkyl e.g., substituted or unsubstitituted benzyl, phenethyl, and phenprop
• R 3 Preferred substituents for aryl and heteroaryl portions of R 3 are F, CI, CH 3 , C 2 H 5 , OCH 3 , and CN.
• R 4 is preferably aryl, or heteroaryl, especially phenyl, naphthyl, biphenyl, furanyl, pyrazinyl, pyrimidinyl, pyridyl, quinolinyl, and isoquinolinyl, which in each case is unsubstituted or is substituted one or more times.
• Preferred substituents are OH, F, CI, CF 3 , alkyl (such as methyl or ethyl), alkoxy (such as methoxy and ethoxy), CN, vinyl, CH 2 OH, CONHOH, CONH 2 , methylenedioxy, COOH, and combinations thereof.
• R 4 is aryl, especially, phenyl
• preferred substituents include R 5 - L-, e.g., R 5 -, R 5 -O-, R 5 -CO-, R 5 -NH-CO-, R 5 -SO 2 -NH-, R 5 -SO 2 -NH-alkylene-O-, NH 2 - alkyl-NH-CO-, R 5 -alkylene-NH-CO-, alkyl-CO-NH-alkyl- as well as methyl, ethyl, CI, F, CN, OCH 3 , CF 3 , amino, nitro, HOCH 2 and COOH.
• R 4 is aryl substituted by R 5 -SO -NH- it is preferably a substituted phenyl group and R 5 is preferably methyl, ethyl, propyl or phenyl.
• R 4 is aryl substituted by R 5 -SO 2 -NH-alkylene-O- it is preferably a substituted phenyl.
• R 5 is preferably methyl, ethyl, propyl or phenyl and alkylene is preferably -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
• R 4 When R 4 is aryl substituted by R s -L- it is preferably substituted phenyl.
• preferred R 5 groups include tetrazolyl, oxazinyl, piperazinyl, methylpiperazinyl, pyridyl, methylpyridyl, pyrrolinyl, methylpyrrolinyl, piperadinyl, or methylpiperadinyl, and L is preferably a single bond, -O-, -CO-, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 -O- , -CH 2 CH 2 -O-, -CH 2 CH 2 CH 2 -O-, -CH 2 -NH-CH 2 CH 2 -O-, -CO-NH- or -NH-CO-.
• PDE4 inhibitors in accordance with the invention are compounds described by sub formulas la-Hi which correspond to formula I but exhibit the following preferred groups:
• R 1 is methyl or CHF 2 ;
• R 2 is alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, heterocycle-alkyl, cycloalkylalkyl, aryl, or heterocychc, in each case substituted or unsubstituted;
• R 3 is H, alkyl, arylalkyl or heteroarylalkyl, in each case substituted or unsubstituted; and R 4 is aryl or heteroaryl, in each case substituted or unsubstituted. lb R 3 is heteroarylalkyl which is substituted or unsubstituted.
• Ic R 1 is methyl or CHF 2 ;
• R 2 is cyclopentyl, CHF 2 , cyclopropylmethyl, pyridylethyl (particularly 2-pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl).
• R l is methyl or CHF 2 ;
• R 2 is cyclopentyl;
• R 3 is heteroarylalkyl, in each case substituted or unsubstituted; and R 4 is substituted or unsubstituted aryl or heteroaryl.
• Ie R 1 is methyl
• R I 22 i iss cyclopentyl; and R 3 is heteroarylalkyl which is substituted or unsubstituted.
• R is cyclopentyl
• R 3 is heteroarylalkyl which is substituted or unsubstituted.
• R 4 is phenyl which is substituted or unsubstituted.
• R 1 is methyl; R is cyclopentyl;
• R 3 is pyridylmethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl, or pyrazinylmethyl, which in each case is substituted or unsustituted, or methyl, ethyl, or propyl;
• R 4 is phenyl or phenyl substituted with 1 to 3 substituents.
• Ih R 1 is methyl
• R 2 is cyclopentyl
• R 3 is pyridylmethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl, pyrazinylmethyl, which in each case is substituted or unsustituted, or methyl, ethyl, or propyl;
• R 4 is phenyl, naphthyl, biphenyl, pyridyl, pyrimidinyl, thiazolyl, pyrazinyl, quinolinyl, or isoquinolinyl, in each case substituted or unsubstituted.
• PDE4 inhibitors in accordance with the invention are compounds described by subformulas Ila-IId which correspond to formula II but exhibit the following preferred groups:
• R 1 is methyl or CHF 2 ;
• R 2 is cyclopentyl, CHF 2 , cyclopropylmethyl, pyridylethyl
• R 4 is phenyl, naphthyl, pyridyl, quinolinyl, or isoquinolinyl, which in each case is substituted or unsubstituted.
• R 1 is methyl or CHF 2 ;
• R 2 is cyclopentyl, CHF 2 , cyclopropylmethyl, pyridylethyl
• R 4 is phenyl which is unsubstituted or substituted by methyl, ethyl, methoxy, CI, F, CF 3 , vinyl, cyano, amino, carboxy, hydroxymethyl, or ethylsulfonamido, or is 3-pyridyl which is unsubstituted or substituted by carboxy or alkoxycarbonyl.
• R 1 is methyl
• R 2 is cyclopentyl
• R 4 is phenyl, naphthyl, pyridyl, quinolinyl, or isoquinolinyl, which in each case is substituted or unsubstituted.
• R 1 is methyl
• R 2 is cyclopentyl
• R 4 is phenyl which is unsubstituted or substituted by methyl, ethyl, methoxy, CI, F, CF 3 , vinyl, cyano, amino, carboxy, hydroxymethyl, or ethylsulfonamido, or is 3-pyridyl which is unsubstituted or substituted by carboxy or alkoxycarbonyl.
• prefe ⁇ ed PDE4 inhibitors in accordance with the invention are compounds described by subformulas Illa-IIId which correspond to formula III but exhibit the following prefe ⁇ ed groups:
• R 1 is methyl or CHF 2 ;
• R 2 is cyclopentyl, CHF 2 , cyclopropylmethyl, pyridylethyl
• R 3 is benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl, thienylmethyl, pyridylmethyl, quinolinymethyl, isoquinolinylmethyl, thiazolylmethyl, or pyrrolylmethyl, which in each case is substituted or unsubstituted.
• Illb R- is methyl or CHF 2 ;
• R 2 is cyclopentyl, CHF 2 , cyclopropylmethyl, pyridylethyl (particularly 2- pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl); and
• R 3 is pyrazinylmethyl, pyrimidinylmethyl or pyridylmethyl, which in each is unsubstituted or substituted.
• R 1 is methyl
• R 2 is cyclopentyl; and R 3 is benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl, thienylmethyl, pyrazinylmethyl, pyrimidinylmethyl, pyridylmethyl, quinolinymethyl, isoquinohnylmethyl, isoimidazolyl, thiazolylmethyl, or pyrrolylmethyl, which in each case is substituted or unsubstituted.
• Hid R 1 is methyl
• R 2 is cyclopentyl
• R 3 is pyrazinylmethyl or pyridylmethyl, which in each is unsubstituted or substituted.
• prefe ⁇ ed PDE4 inhibitors in accordance with the invention are compounds described by subformulas IVa-IVp which correspond to formula IV but exhibit the following preferred groups:
• IVb R 1 is methyl or CHF 2 .
• IVc R 1 is methyl or CHF 2 .
• R 2 is cyclopentyl, CHF 2 , cyclopropylmethyl, pyridylethyl (particularly 2- pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl).
• IVd R 1 is methyl or CHF 2
• B is N
• R 2 is cyclopentyl, CHF 2 , cyclopropylmethyl, pyridylethyl (particularly 2- pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl).
• IVe R 1 is methyl or CHF 2 .
• R 4 is 3-pyridyl or phenyl, which in each case is substituted or unsubstituted.
• IVf R 1 is methyl or CHF 2 , B is N, and
• R 4 is 3-pyridyl or phenyl, which in each case is substituted or unsubstituted.
• INg R 1 is methyl or CHF 2 ,
• R 2 is cyclopentyl, CHF 2 , cyclopropylmethyl, pyridylethyl (particularly 2- pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl), and
• R 4 is 3-pyridyl or phenyl, which in each case is substituted or unsubstituted.
• R 1 is methyl or CHF 2 , B is ⁇ , R 2 is cyclopentyl, CHF 2 , cyclopropylmethyl, pyridylethyl (particularly 2- pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl),
• R 4 is 3-pyridyl or phenyl, which in each case is substituted or unsubstituted.
• IVi R 1 is methyl or CHF 2 .
• R 4 is phenyl which is substituted in the 3- or 4- position.
• R 1 is methyl or CHF 2 , B is N, and R 4 is phenyl which is substituted in the 3- or 4- position.
• IVk R 1 is methyl or CHF 2 ,
• R 2 is cyclopentyl, CHF 2 , cyclopropylmethyl, pyridylethyl (particularly 2- pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl), and
• R 4 is phenyl which is substituted in the 3- or 4- position.
• IVI R 1 is methyl or CHF 2 ,
• R 2 is cyclopentyl, CHF 2 , cyclopropylmethyl, pyridylethyl (particularly 2- pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl), and
• R 4 is phenyl which is substituted in the 3- or 4- position.
• JNm R 1 is methyl or CHF 2 .
• R 4 is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3- ethylsulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl- phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamido- phenyl, 4-tetrazol-5-yl-phenyl, or 4-hydroxymethyl-phenyl.
• IVn R 1 is methyl or CHF 2 , B is ⁇ , and
• R 4 is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3- ethylsulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl- phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamido- phenyl, 4-tetrazol-5-yl-phenyl, or 4-hydroxymethyl-phenyl.
• IVo R 1 is methyl or CHF 2 ,
• R 2 is cyclopentyl, CHF 2 , cyclopropylmethyl, pyridylethyl (particularly 2- pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl), and R 4 is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3- ethylsulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl- phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamido- phenyl, 4-tetrazol-5-yl-phenyl, or 4-hydroxymethyl-phenyl.
• IVp R 1 is methyl or CHF 2 , B is N,
• R 2 is cyclopentyl, CHF 2 , cyclopropylmethyl, pyridylethyl (particularly 2- pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl), and
• R 4 is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3- ethylsulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl- phenyl, 3-nitro-phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4- ethylsulfonamido-phenyl, 4-tetrazol-5-yl-phenyl, or 4-hydroxymethyl- phenyl.
• 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 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 neurological syndrome, e.g., loss of memory, especially 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 mentioned herein.
• the compounds ofthe present invention may be prepared conventionally. Some ofthe processes which can be used are described below. All starting materials are known or can be conventionally prepared from known starting materials.
• Aniline intermediates 3 are produced in two steps; first, an addition reaction provides intermediate 2, followed by reduction ofthe nitro group.
• Intermediate nitro compounds 2 can be prepared by numerous published procedures, such as by Mitsunobu reactions or standard alkylation reactions.
• R2 is aryl or heteroaryl
• R2 is aryl or heteroaryl
• aryl or heteroaryl iodides under Ullman conditions oor by coupling aryl-, vinyl-, or heteroaryl- boronic acids with phenol 2 in the presence of a copper catalyst (e.g., Cu(OAc) 2 ) and base such as TEA.
• a copper catalyst e.g., Cu(OAc) 2
• base such as TEA.
• Mitsunobu reaction between aarn appropriately substituted nitrophenol and a primary or secondary alcohol using an azodicarboxylate (e.g., DEAD, DIAD), and a suitable phosphine (e.g., Ph 3 P, Bu 3 P) provides alkylated nitrophenols 2.
• Mitsunobu reactions are general performed in aprotic solvents such as dichloromethane or THF.
• alkylation can be achieved by the reaction between an appropriately substituted nitrophenol and an alkyl halide in the presence of a base (e.g., K 2 CO 3 or NaH) in a polar aprotic solvent (e.g., DMF or CH 3 CN).
• a base e.g., K 2 CO 3 or NaH
• a polar aprotic solvent e.g., DMF or CH 3 CN
• Nitrocatechols 2 are subsequently reduced to the co ⁇ esponding anilines 3 by methods standard in the art such as by hydrogenation using a suitable catalyst (e.g., Pd on carbon) in a polar protic solvent (e.g., MeOH or EtOH) under an atmosphere of hydrogen.
• a suitable catalyst e.g., Pd on carbon
• a polar protic solvent e.g., MeOH or EtOH
• nitrocatechols 3 can be reduced by using a hydride source (e.g., NaBH ) and a transition metal catalyst (e.g., NiCl 2 , Pd on carbon) or by using metals (e.g., Zn, Sn, Fe) in mineral acid solutions (e.g., HCI) to produce the corresponding anilines.
• polar protic solvents such as ethanol or methanol are used in these reactions.
• N-Arylalkylanilines 4 are synthesized by standard methods in the art such as by reductive amination reaction, alkylation reaction, or by reduction of corresponding amides.
• the reductive amination reaction of an aryl or arylalkyl aldehyde with appropriately substituted anilines in the presence of a borohydride reducing agent such as ⁇ aBH or NaBH 3 CN with an acid catalyst such as acetic acid or pTsOH provides desired N-arylalkylanilines.
• a borohydride reducing agent such as ⁇ aBH or NaBH 3 CN
• an acid catalyst such as acetic acid or pTsOH
• These reactions generally take place in polar protic solvents such as methanol, ethanol, isopropanol, n-propanol and the like.
• N-Arylalkylanilines 4 readily undergo N-arylation by methods standard to the art including Ullman coupling reaction, metal-catalyzed coupling, or aromatic nucleophilic substitution reaction.
• the metal catalyzed reaction between an N- benzylaniline and an aryl halide using a palladium catalyst, (e.g., Pd 2 dba 3 ), a bulky electron rich phosphine ligand (e.g., tributylphosphine), and suitable base (e.g., ⁇ aOtBu) provides N-Arylalkyldiphenylamines.
• Nickel and copper catalysts have been employed as well.
• Solvents useful in this reaction include non-polar aprotic solvents such as toluene, benzene, xylenes, tetrahydrofuran, and ether.
• non-polar aprotic solvents such as toluene, benzene, xylenes, tetrahydrofuran, and ether.
• Carboxylic ester intermediates 6 can be hydrolyzed under acidic or basic conditions to give the corresponding carboxylic acids 7.
• aqueous base e.g., NaOH, KOH
• an aqueous acid e.g., HCI, formic acid, TFA
• THP- protected tetrazoles 8 Coupling of protected tetrazole bromo or iodobenzenes (e.g., 5-(3-iodophenyl)-2- (2-tetrahydropyran)tetrazole) with N-substituted aniline derivatives 4 produce THP- protected tetrazoles 8.
• Hydrolysis of THP -protected tetrazoles 8 can be accomplished by using an aqueous acid, such as HCI in water and a miscible solvent such as THF or EtOH to provide tetrazoles 9.
• THP tetrazoles 8 can also be oxidatively cleaved using reagents such as CAN and DDQ in halognenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane and the like to yield tetrazoles 9.
• tetrazole analogs 9 can be prepared from the corresponding nitriles by treatment with azide ion (e.g., KN 3 , NaN 3 , etc.) and a proton source (e.g., NH 4 C1) in a polar aprotic solvent such as DMF. They also may be prepared by treatment with an azide ion and a Lewis acid (e.g., ZnBr 2 ) in water, using a water miscible co-solvent such as isopropanol if necessary.
• azide ion e.g., KN 3 , NaN 3 , etc.
• a proton source e.g., NH 4 C1
• a polar aprotic solvent such as DMF.
• a Lewis acid e.g., ZnBr 2
• Another method of preparation is by treatment of a nitrile with tin or silicon azides (e.g., Me 3 SiN 3 , Bu 3 SnN 3 ) in an aprotic organic solvent such as benzene, toluene, dichloromethane, dichloroethane, ether, THF, and the like.
• tin or silicon azides e.g., Me 3 SiN 3 , Bu 3 SnN 3
• an aprotic organic solvent such as benzene, toluene, dichloromethane, dichloroethane, ether, THF, and the like.
• Diphenylamines 10 can be prepared by coupling appropriately substituted anilines 3, such as 3-cyclopentyloxy-4-methoxyaniline, with arylboronic acids in the presence of a base such as triethylamine and a copper catalyst such as copper acetate (as described by Chan et al, Tetrahedron Lett, 39, 2933-2936 (1998)).
• a base such as triethylamine
• a copper catalyst such as copper acetate
• halogenated solvents such as dichloromethane, chloroform, dichloroethane, and the like as well as nonpolar aprotic solvents such as benzene, toluene, or xylene are utilized.
• Such diphenylamines can more preferably be synthesized by metal catalyzed amination reactions.
• a base e.g., K 3 PO , CsCO 3 , or NaOtBu
• a palladium or nickel catalyst for example Pd(dppf)C_ 2 , a ligand (e.g., dppf) and a base (e.g., NaOtBu)
• Solvents most commonly utilized in this type of reaction include non-polar aprotic solvents such as benzene, toluene, tetrahydrofuran, ether, and the like.
• Diphenylamines 10 can then be alkylated with various alkyl halides or arylalkyl halides such as, but not limited to iodomethane, ethylbromide, benzylchloride, 3- (chloromethyl)pyridine, 4-(ch_oromethyl)-2,6-dichloropyridine, and 4-(bromomethyl)- benzoic acid, or salts thereof, in the presence of a non-nucleophilic base such as sodium hydride, potassium hexamethyldisilazide or potassium diisopropylamide to provide N- substituted diphenylamines 5.
• Solvents useful in this reaction include aprotic solvents such as benzene, toluene, tetrahydrofuran, ether, DMF, and the like.
• Carboxylic acids 7 can be further manipulated to form carboxamides 11 using methods standard in the art.
• a carboxylic acid can be treated with a suitable primary or secondary amine, in the presence of a suitable coupling reagent such as BOP, pyBOP or DCC, and a base such as Et 3 N or DIEA to yield a carboxamide.
• a suitable coupling reagent such as BOP, pyBOP or DCC
• a base such as Et 3 N or DIEA
• Carboxylic esters 6 or acids 7 can be reduced using methods standard in the art to give the co ⁇ esponding carboxaldehyde or hydroxymethyl analogs.
• an appropriate reducing agent e.g., LAH, DIBAL, etc.
• an aprotic solvent such as ether or THF
• carboxamides e.g., structure 11
• nitriles can be reduced using methods standard in the art to provide the corresponding substituted amines or aminomethyl analogs.
• an aryl carboxamide 11 can be reduced with an appropriate reducing agent (e.g., LAH) in an aprotic solvent (e.g., benzene, toluene, ether, THF, etc.) to give the corresponding substituted aminomethyl analog.
• an aryl nitrile yields the corresponding primary aminomethyl analog.
• Nitrobenzene compounds 12 can be reduced to the corresponding anilines 13 by methods standard in the art such as hydrogenation using a suitable catalyst (e.g., Pd on carbon) in a polar protic solvent (e.g., EtOH, MeOH, etc.). Nitrobenzenes 12 can also be reduced using a hydride source (e.g., NaBH ) and a transition metal catalyst (e.g., NiCl 2 , Pd on carbon) in polar protic solvents such as EtOH, to produce the corresponding anilines 13. These anilines can then befurther substituted by methods standard in the art.
• a suitable catalyst e.g., Pd on carbon
• a polar protic solvent e.g., EtOH, MeOH, etc.
• Nitrobenzenes 12 can also be reduced using a hydride source (e.g., NaBH ) and a transition metal catalyst (e.g., NiCl 2 , Pd on carbon) in polar protic solvents such as Et
• anilines of the type 13 can be alkylated, acylated, or sulfonylated to give the corresponding N-alkyl amines, carboxamides (e.g., structure 15) or sulfonamides (e.g., structure 14) respectively.
• a sulfonamide can be prepared from an aniline and an appropriate sulfonyl halide or sulfonic anhydride (e.g., MeSO 2 Cl, EtS0 2 ⁇ , BnSO 2 Cl, PhSO 2 Cl, etc.) in the presence of a base (e.g., Et 3 ⁇ , pyridine, DIEA, etc.).
• Suitable solvents for this reaction include non-polar aprotic solvents such as dichloromethane, chloroform, ether, and the like.
• Trialkylsilylethers ofthe type 16 are prepared as described in Scheme 1.
• the tert-butyldimethylsilyl protected catechol intermediates 16 are readily deprotected by numerous literature methods (see Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis, 3 r Edition, John Wiley & Sons, 1999, pp. 273-276.) such as by using a fluoride ion source (e.g., BmNF) in an aprotic solvent such as ether or THF; or under acidic conditions (e.g., KF, 48% HBr, DMF).
• a fluoride ion source e.g., BmNF
• aprotic solvent such as ether or THF
• acidic conditions e.g., KF, 48% HBr, DMF
• the resultant phenol 17, which is a very useful synthetic intermediate, can then be alkylated by methods standard in the art and in a similar manner as described for the alkylation of nitrophenol 2 in Scheme 1.
• Method 1 for example, by the Mitsunobu reaction, by reaction with an alkyl halide in the presence of a base, or by Ullman type aryl coupling or by reaction with vinyl-, aryl- or heteroaryl- boronic acids in the precence of a copper catalyst.
• Haloalkoxy intermediates 18, prepared by alkylation ofthe corresponding phenol, can be alkylated by reactions with substituted amines, alcohols, or thiols in the presence of a base to provide analogs such as 19.
• an alkyl halide can be aminated with an appropriate primary or secondary amine and a base such as K 2 CO 3 , in a polar aprotic solvent such as THF, DMF, or CH 3 CN.
• the optical isomers can be obtained by resolution ofthe racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
• appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid.
• Mixtures of diastereoisomers 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 Formulae I and F can likewise be obtained by chiral syntheses utilizing optically active starting materials.
• the present invention also relates to useful forms ofthe compounds as disclosed herein, such as pharmaceutically acceptable salts and prodrugs of all the compounds of the present invention.
• 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, methane sulfonic acid, camphor sulfonic 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, mangnesium, ammonium, and choline salts.
• acid addition salts ofthe 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.
• alkali and alkaline earth metal salts are prepared by reacting the compounds ofthe invention with the appropriate base via a variety of known methods.
• 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
• the salts formed are pharmaceutically acceptable for administration to mammals.
• pharmaceutically unacceptable salts ofthe 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 ofthe invention can be administered alone or as an active ingredient of a formulation.
• the present invention also includes pharmaceutical compositions of compounds of Formulae I or F containing, for example, one or more pharmaceutically acceptable carriers.
• the compounds ofthe present invention can be administered to anyone requiring or desiring PDE4 inhibition, and/or enhancement of cognition. Administration may be accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intraveneously, intramuscularly, intrasternally and by infusion), by inhalation, rectally, vaginally, topically, locally, transdermally, and by ocular administration.
• 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 ofthe 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 ofthe present invention.
• liquid oral dosage forms can also be used for administering compounds of the invention, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs.
• 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 ofthe invention.
• the compounds ofthe 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 ofthe present invention can be prepared by mixing the compound with a suitable excipient such as cocoa butter, salicylates and polyethylene glycols.
• 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.
• 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.
• 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, amphakines NMDA- R modulators, mGluR modulators, and cholinesterase inhibitors (e.g., donepezil, rivastigimine, and glanthanamine).
• each active ingredient can be administered either in accordance with their usual dosage range or a dose below its usual dosage range.
• the present invention further includes methods of treatment that involve inhibition of PDE4 enzymes.
• 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 ofthe ability to leam 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, and 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 dementias (e.g., Alzheimer's, Parkinson's disease, Huntington's disease, Pick's disease), vascular (e.g., infarcts, hemorrhage, cardiac disorders), mixed vascular and Alzheimer's, bacterial meningitis, Creutzfeld-Jacob Disease, multiple sclerosis, traumatic (e.g., subdural hematoma or traumatic brain injury), infectious (e.g., HIV), genetic (down syndrome), toxic (e.g., heavy metals, alcohol, some medications), metabolic (e.g., vitamin B12 or folate deficiency), CNS hypoxia, Cushing's disease, psychiatric (e.g., depression and schizophrenia), and hydrocephalus.
• neurodegenerative dementias e.g., Alzheimer
• the present invention includes methods for dealing with memory loss separate from dementia, including mild cognitive impairment (MCI) and age-related cognitive decline.
• MCI mild cognitive impairment
• the present invention includes methods of treatment for memory impairment as a result of disease.
• the invention includes methods for dealing with memory loss resulting from the use of general anesthetics, chemotherapy, radiation treatment, post-surgical trauma, and therapeutic intervention.
• the compounds may be used to treat psychiatric conditions including schizophrenia, bipolar or manic depression, major depression, and drug addiction and morphine dependence. These compounds may enhance wakefulness.
• 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 anti-apoptotic and anti-inflammatory properties make these compounds useful to treat neurodegeneration resulting from any disease or injury, including stroke, spinal cord injury, neurogenesis, Alzheimer's disease, multiple sclerosis, amylolaterosclerosis (ALS), and multiple systems atrophy (MSA).
• the present invention includes methods of treating patients suffering from memory impairment due to, for example, 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 including acute neuronal diseases, as well as HIV and cardiovascular diseases, comprising administering an effective amount of a compound according to Formula (I) or (F) or pharmaceutically acceptable salts thereof.
• the compounds ofthe present invention can also be used in a method of treating patients suffering from disease states characterized by decreased NMDA function, such as schizophrenia.
• the compounds can also be used to treat psychosis characterized by elevated levels of PDE 4, for example, various forms of depression, such as manic depression, major depression, and depression associated with psychiatric and neurological disorders.
• the compounds of the invention also exhibit anti-inflammatory activity.
• 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.
• a method of treating allergic and inflammatory disease states comprising administering an effective amount of a compound according to Formulae (I) or (F) 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, 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,
• PDE4 inhibitors for, treating asthma, chronic bronchitis, psoriasis, allergic rhinitis, and other inflammatory diseases, and for inhibiting tumor necrosis factor are known within the art. See, e.g., WO 98/58901, JP11-18957, JP 10-072415, WO 93/25517, WO 94/14742, US 5,814,651, and US 5,935,9778. These references also describe assays for determining PDE4 inhibition activity, and methods for synthesizing such compounds. The entire disclosures of these documents are hereby inco ⁇ orated 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 hype ⁇ lasia, for suppression of chemotaxis and reduction of invasion of colon cancer cells, for treatment of B cell chronic ⁇ ymphocytic 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.
• RA rheumatoid arthritis
• RA rheumatoid arthritis
• 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 glanthanamine).
• each active ingredient can be administered either in accordance with their usual dosage range or a dose below their usual dosage range.
• the dosages ofthe compounds ofthe present invention depend upon a variety of factors including the particular syndrome to be treated, the severity ofthe symptoms, the route of administration, the frequency ofthe dosage interval, the particular compound utilized, the efficacy, toxicology profile, pharmacokinetic profile ofthe compound, and the presence of any deleterious side-effects, among other considerations.
• the compounds ofthe invention are typically administered at dosage levels and in a mammal customary for PDE4 inhibitors such as those known compounds mentioned above.
• the compounds can be administered, in single or multiple doses, by oral administration at a dosage level of, 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, for example, 0.1-50 mg of active compound.
• 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.
• 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 pu ⁇ oses in using the methods and procedures disclosed herein.
• the reaction mixture was diluted with EtOAc and washed twice with H 2 O and extracted with 3 x 15 mL of 3N HCI.
• the combined acid extracts were washed with 15 mL of EtOAc and then carefully neutralized with 6N ⁇ aOH to pH greater than 12.
• the basic solution was extracted with 2 x 15 mL of EtOAc and the combined organic fractions were subsequently washed with 15 mL of H 2 O and brine, dried (MgSO 4 ), and concentrated.
• the residue was purified by chromatography over silica gel (Biotage Flash 40M) eluting with 25%> EtOAc in hexanes.
• the material was further purified by crystallization from hexanes to give 550 mg of a white solid.
• the formic acid was removed in vacuo and the residue was loaded onto a column of silica gel (RediSep, 4.2 g).
• the product was eluted with a linear gradient from 40%) EtOAc in hexanes to 60%> EtOAc in hexanes over 15 min to yield 16 mg of product as a brown solid.
• Human PDE4 was obtained from baculovirus-infected Sf9 cells that expressed the recombinant enzyme.
• the cD ⁇ A encoding hPDE-4D6 was subcloned into a baculovirus vector.
• Insect cells (Sf9) were infected with the baculovirus and cells were cultured until protein was expressed.
• the baculovirus-infected cells were lysed and the lysate was used as source of hPDE-4D6 enzyme.
• the enzyme was partially purified using a DEAE ion exchange chromatography. This procedure can be repeated using cD ⁇ A encoding other PDE-4 enzymes.
• Type 4 phosphodiesterases convert cyclic adenosine monophosphate (cAMP) to 5'-adenosine monophosphate (5'-AMP).
• cAMP cyclic adenosine monophosphate
• 5'-AMP 5'-adenosine monophosphate
• ⁇ ucleotidase converts 5'-AMP to adenosine. Therefore the combined activity of PDE4 and nucleotidase converts cAMP to adenosine.
• Adenosine is readily separated from cAMP by neutral alumina columns.
• Phosphodiesterase inhibitors block the conversion of cAMP to adenosine in this assay; consequently, PDE4 inhibitors cause a decrease in adenosine.
• Cell lysates (40 ul) expressing hPDE-4D6 were combined with 50 ul of assay mix and 10 ul of inhibitors and incubated for 12 min at room temperature. Final concentrations of assay components were: 0. 4 ug enzyme, lOmM Tris-HCl (pH 7.5), lOmM MgCl 2 , 3 uM cAMP, 0.002 U 5'-nucleotidase, and 3 x IO 4 cpm of [3H]cAMP. The reaction was stopped by adding 100 ⁇ l of boiling 5mN HCI. An aliquot of 75 ⁇ l of reaction mixture was transfe ⁇ ed from each well to alumina columns (Multiplate; Millipore).
• adenosine was eluted into an OptiPlate by spinning at 2000 ⁇ m for 2 min; 150 ⁇ l per well of scintillation fluid was added to the OptiPlate. The plate was sealed, shaken for about 30 min, and cpm of [ 3 H] adenosine was determined using a Wallac Triflux®.
• test compounds are dissolved in 100% DMSO and diluted into the assay such that the final concentration of DMSO is 0.1%. DMSO does not affect enzyme activity at this concentration.
• pIC 0 values were determined by screening 6 to 12 concentrations of compound ranging from 0.1 nM to 10,000 nM and then plotting drug concentration versus 3 H-adenosine concentration.
• Nonlinear regression software (Assay Explorer®) was used to estimate pIC 50 values.
• the test was performed as previously described (Zhang, H.-T., Crissman, A.M., Dorairaj, N.R., Chandler, L.J., and O'Donnell, J.M., Neuropsychopharmacology, 2000, 23, 198-204.).
• the apparatus (Model E10-16SC, Coulbourn Instruments, Allentown, PA) consisted of a two-compartment chamber with an illuminated compartment connected to a darkened compartment by a guillotine door.
• the floor ofthe darkened compartment consisted of stainless steel rods through which an electric foot-shock could be delivered from a constant current source. All experimental groups were first habituated to the apparatus the day before the start ofthe experiment.
• the rat (Male Spraque-Dawley (Harlan) weighing 250 to 350 g) was placed in the illuminated compartment facing away from the closed guillotine door for 1 minute before the door was raised. The latency for entering the darkened compartment was recorded. After the rat entered the darkened compartment, the door was closed and a 0.5 mA electric shock was administered for 3 seconds. Twenty-four hours later, the rat was administered 0.1 mg/kg MK-801 or saline, 30 minutes prior to the injection of saline or test compound (dosed from 0.1 to 2.5 mg/kg, i.p.), which was 30 minutes before the retention test started. The rat was again placed in the illuminated compartment with the guillotine door open. The latency for entering the darkened compartment was recorded for up to 180 seconds, at which time the trial was terminated.
• mice Male Spraque-Dawley (Harlan) weighing 250 to 350 g were placed in the eight-arm radial maze (each arm was 60x10x12 cm high; the maze was elevated 70 cm above the floor) for acclimation for two days.
• Rats were then placed individually in the center ofthe maze for 5 minutes with food pellets placed close to the food wells, and then, the next day, in the wells at the end ofthe arms; 2 sessions a day were conducted. Next, four randomly selected arms were then baited with one pellet of food each. The rat was restricted to the center platform (26 cm in diameter) for 15 seconds and then allowed to move freely throughout the maze until it collected all pellets of food or 10 minutes passed, whichever came first.
• test duration i.e., the time spent in the collection of all the pellets in the maze. If the working memory error was zero and the average reference memory error was less than one in five successive trials, the rats began the drug tests. MK-801 or saline was injected 15 minutes prior to vehicle or test agent, which was given 45 minutes before the test. Experiments were performed in a lighted room, which contained several extra-maze visual cues.
• MK-801 0.1 mg/kg, i.p.
• MK-801 increased the frequencies of both working and reference memory e ⁇ ors (p ⁇ 0.01).

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