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EP1353907A2 - Phosphodiesterase 4 inhibitors - Google Patents

Phosphodiesterase 4 inhibitors

Info

Publication number
EP1353907A2
EP1353907A2 EP02731078A EP02731078A EP1353907A2 EP 1353907 A2 EP1353907 A2 EP 1353907A2 EP 02731078 A EP02731078 A EP 02731078A EP 02731078 A EP02731078 A EP 02731078A EP 1353907 A2 EP1353907 A2 EP 1353907A2
Authority
EP
European Patent Office
Prior art keywords
pyridylmethyl
diphenylamine
methoxy
cyclopentyloxy
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02731078A
Other languages
German (de)
French (fr)
Inventor
Allen Hopper
Richard A. Schumacher
Ashok Tehim
Michael De Vivo
William Frederick Brubaker, Jr.
Ruiping Liu
Hans-Jürgen Ernst HESS
Axel Unterbeck
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Memory Pharmaceuticals Corp
Original Assignee
Memory Pharmaceuticals Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Memory Pharmaceuticals Corp filed Critical Memory Pharmaceuticals Corp
Publication of EP1353907A2 publication Critical patent/EP1353907A2/en
Withdrawn legal-status Critical Current

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    • C07D213/02—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
    • 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
    • C07D213/60—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 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
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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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
    • C07C217/84—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 an acyclic carbon atom
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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
    • C07C217/88—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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    • C07C217/78—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
    • 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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    • C07D213/00—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
    • C07D213/02—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
    • 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
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D333/04—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
    • C07D333/06—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07D333/04—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
    • 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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    • C07D401/02—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
    • 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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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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Abstract

PDE4 inhibition is achieved by novel compounds, e.g., N-substituted aniline and diphenylamine analogs. The compounds of the present invention are of Formula (I): wherein R?1, R2, R3 and R4¿ are as defined herein.

Description

PHOSPHODIESTERASE 4 INHIBITORS
This application claims benefit of U.S. Provisional application Serial No. 60/262,651, filed January 22, 2001, U.S. provisional application Serial No. 60/267,196, filed February 8, 2001, and U.S. Provisional application Serial No. 60/306,140, filed July 14, 2001.
FIELD OF THE INVENTION
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.
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, PDE 1 is stimulated by Ca2+/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)] 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 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.
SUMMARY OF THE INVENTION
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). Preferably, the compounds selectively inhibit PDE4 enzymes. The compounds of this invention at the same time facilitate entry into cells, especially cells ofthe 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, 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.
In a preferred aspect, 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:
wherein
R1 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., CH3, CHF2, CF3, etc.);
R is alkyl having 1 to 12, preferably 1 to 8 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano, Cι-4-alkoxy, oxo or combinations thereof, and wherein optionally one or more -CH2CH2- groups is replaced in each case by -CH=CH- or -C≡C- (e.g., CH3, CHF2, CF3, methoxyethyl, 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, alkyl having 1 to 4 carbon atoms, alkoxy 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, C.-4-alkyl, Cι-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, CF3; OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, or combinations thereof (e.g., methylphenyl, methoxyphenyl, chlorophenyl, etc.),
arylalkyl in which the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, which the arylalkyl radical is unsubstituted or is substituted in the aryl portion one or more times by halogen, CF3j OCF , alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, and wherein in the alkyl portion one or more -CH2CH2- groups are each optionally replaced by -CH=CH- or -C≡C-, and one or more -CH2- groups are each optionally-replaced by -O- or -NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof (e.g., phenylethyl, phenylpropyl, phenylbutyl, methoxyphenylethyl, methoxyphenylpropyl, chlorophenylethyl, chlorophenylpropyl, phenylethenyl, phenoxyethyl, phenoxybutyl, chlorophenoxyethyl, chlorophenylaminoethyl, 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.),
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, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof (e.g., 3-thienyl, 3-tetrahydrofuranyl, 3-pyrrolyl, etc.), or
a 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 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, OCF3, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, wherein in the alkyl portion one or more -CH2CH - groups are each optionally replaced by -CH=CH- or -C≡C-, and one or more -CH2- groups are each optionally replaced by -O- or -NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof (e.g., pyridylethyl, pydridylpropyl, methylpiperazinylethyl, etc.);
is H,
alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, cyano, Cι-4-alkoxy, 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 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, CF3O, 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, CF3O, 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, isoquinolinylmethyl, piperidinylmethyl, furanylmethyl, imidazolylmethyl, methylimidazolylmethyl, pyrrolylmethyl, etc.);
is H,
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, OCF3, 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, phenoxy, trialkylsilyloxy (eg. tert- butyldimethylsilyloxy), R5-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. tert- butyldimethylsilyloxy), R5-L-, or combinations thereof (e.g., pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl, etc.);
is H,
alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is unsubstituted or substituted one or more times with halogen, Cι-4-alkyl, Cι-4-alkoxy, oxo, or combinations thereof (e.g., methyl, ethyl, propyl, etc.),
alkylamino or dialkylamino wherein each alkyl portion has independently 1 to 8, preferably 1 to 4 carbon atoms (e.g., dimethylamino, 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, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, 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, CF3O, 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, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl, etc.), or
a 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, CF3O, 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.);
is a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms wherein one or more -CH2- groups are each optionally replaced by -O-, -S-, -NR6-, -SO2NH-, -NHSO2-, -CO-, -NR6CO-, -CONR6-, -NHCONH-, -OCONH, -NHCOO-, -SCONH-, -SCSNH-, or -NHCSNH- (e.g.,-O-, CH2-, -CO-, -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -CH2CH2CH2-NH- CO-, -CH2-CH2-O-, -SO2-NH-CH2CH2-O-, -O-CH2CH2-O-, -CH2-NH- CO-, -CO-NH-CH2-, -SO2- H-, -CH2-NH-SO2-, -CH2CH2CH2-SO2- NH-, etc.); and
RG is H,
alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, Cι-4-alkyl, Cι-4-alkoxy, oxo, or combinations thereof (e.g., methyl, ethyl, propyl, etc.);
wherein at least one of R3 and R4 is other than H; and pharmaceutically acceptable salts thereof
According to a further aspect of the invention there is provided a genus of novel compounds according to the formulas II and III:
wherein 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 R3 and R4 are both other than H.
In addition, preferred compounds of formula I are those ofthe sub formula IN
wherein R1, R2, and R4 are as defined in Formula I and one of A, B and D is N and the others are C. Preferably, B is N. Also, R is preferably pyridyl or phenyl which in each case is substituted or unsubstituted.
The present invention also includes compounds of Formula I':
wherein
R1 ' is methoxy, F, CI, CHF2 or CF3;
R-" 1S 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,
alkenyl having 2 to 12 carbon atoms,
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,
a partially unsaturated carbocyclic group having 5 to 14 carbon atoms,
a partially unsaturated carbocyclic group having 5 to 14 carbon atoms which is substituted one or more times by halogen, alkyl, alkyloxy, nitro, cyano, oxo, or combinations thereof,
arylalkyl having 7 to 26 carbon atoms
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;
R3 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; '
is -NH-, -NR4'-, -NHCH2-, -NR4'CH2-, or -CH2NR4'-; and
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,
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
pharmaceutically acceptable salts thereof.
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.
Assays for determining PDE inhibiting activity as well as selectivity of PDE 4 inhibiting activity and selectivity of inhibiting PDE 4 isoenzymes are known within the art. See, e.g., US 6,136,821, the disclosure of which is incorporated herein by reference.
According to a further aspect of the invention there are provided compounds useful as intermediates for the production of the PDE4 inhibitors described herein (e.g., PDE4 inhibitors of Formula I) and/or useful for the synthesis of radio-labeled analogs of the PDE4 inhibitors with in this application.
Thus, there are provided intermediate compounds which correspond to compounds of Formula I, wherein R2, R3, and R4 are as previously defined for Formula I, but R1 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, 3rd Edition, John Wiley & Sons, 1999, pp. 246-293. These intermediates are also useful for the synthesis of radio-labeled compounds, such as where R1 is 3H3C-, 14CH3- or " CH3-, for example by removing the protecting group and reacting the resultant compound in which R1 is H with suitable radio-labelled reagents. Such 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.
Also provided are intermediate compounds which correspond to compounds of Formula I, wherein R1, R3, and R4 are as previously defined for Formula I, but R2 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, 3rd Edition, John Wiley & Sons, 1999, pp. 246- 293. Compounds in which R2 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.
As previously described, compounds according to formula II, wherein R1, R2 and R4 are as previously described are useful intermediates for the production of compounds according to formula I where in R3 is other than H.
Also, as previously described, compounds according to formula III, wherein R1,
9 "
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. Other examples of suitable 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, Cι-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. Similarly, 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. Other suitable cycloalkyl groups include spiropentyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, spiro[2.4]heptyl, sρiro[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. Preferably, 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, indazolyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzisothiazolyl, purinyl, benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, naphthyridinyl, and benzoxazinyl, e.g., 2-thienyl, 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, and 1-, 3-, 4-, 5-, 6-, 7- or 8- isoquinolinyl.
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. 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, cyclohexadienyl, tetrahydronaphthenyl and indan-2-yl.
Alkenyl refers to straight-chain or branched-chain aliphatic radicals containing 2 to 12 carbon atoms in which one or more -CH2-CH2- structures are each replaced by - CH=CH-. 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 -CH2-CH2- 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.
In the compounds of Formula I, R1 is an alkyl group having preferably 1 to 4 carbon atoms which is optionally substituted by halogen, preferably fluorine or chlorine. In particular, R1 is preferably methyl or difluoromefhyl.
R2 is preferably cycloalkyl, particularly cyclopentyl. R2 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,
R2 is also preferably a partially unsaturated carbocyclic groups, which is unsubstituted or substituted, particularly cyclohexenyl, cyclohexadienyl, indan-2-yl.
R2 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.
R2 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.
Preferred R include cyclopentyl, tetrahydrofuranyl, CHF2, methoxyethyl, cyclopropylmethyl, phenethyl, phenpropyl, phenylethenyl, phenoxyethyl, phenoxybutyl, phenylaminoethyl, indan-2-yl, pyridylethyl, and pyridylpropyl.
R3 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). Preferred substituents for aryl and heteroaryl portions of R3 are F, CI, CH3, C2H5, OCH3, and CN. R4 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, CF3, alkyl (such as methyl or ethyl), alkoxy (such as methoxy and ethoxy), CN, vinyl, CH2OH, CONHOH, CONH2, methylenedioxy, COOH, and combinations thereof.
In addition, when R4 is aryl, especially, phenyl, preferred substituents include R5- L-, e.g., R5-, R5-O-, R5-CO-, R5-NH-CO-, R5-SO2-NH-, R5-SO2-NH-alkylene-O-, NH2- alkyl-NH-CO-, R5-alkylene-NH-CO-, alkyl-CO-NH-alkyl- as well as methyl, ethyl, CI, F, CN, OCH3, CF3, amino, nitro, HOCH2 and COOH.
When R4 is aryl substituted by R5-SO -NH- it is preferably a substituted phenyl group and R5 is preferably methyl, ethyl, propyl or phenyl.
When R4 is aryl substituted by R5-SO2-NH-alkylene-O- it is preferably a substituted phenyl. In such cases, R5 is preferably methyl, ethyl, propyl or phenyl and alkylene is preferably -CH2-, -CH2CH2- or -CH2CH2CH2-.
When R4 is aryl substituted by Rs-L- it is preferably substituted phenyl. In such cases, preferred R5 groups include tetrazolyl, oxazinyl, piperazinyl, methylpiperazinyl, pyridyl, methylpyridyl, pyrrolinyl, methylpyrrolinyl, piperadinyl, or methylpiperadinyl, and L is preferably a single bond, -O-, -CO-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2-O- , -CH2CH2-O-, -CH2CH2CH2-O-, -CH2-NH-CH2CH2-O-, -CO-NH- or -NH-CO-.
In addition, preferred 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:
la R1 is methyl or CHF2; R2 is alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, heterocycle-alkyl, cycloalkylalkyl, aryl, or heterocychc, in each case substituted or unsubstituted;
R3 is H, alkyl, arylalkyl or heteroarylalkyl, in each case substituted or unsubstituted; and R4 is aryl or heteroaryl, in each case substituted or unsubstituted. lb R3 is heteroarylalkyl which is substituted or unsubstituted.
Ic R1 is methyl or CHF2; and
R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (particularly 2-pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl).
Id Rl is methyl or CHF2; R2 is cyclopentyl;
R3 is heteroarylalkyl, in each case substituted or unsubstituted; and R4 is substituted or unsubstituted aryl or heteroaryl.
Ie R1 is methyl;
R I22 iiss cyclopentyl; and R3 is heteroarylalkyl which is substituted or unsubstituted.
If R , 11 : i.s methyl;
R is cyclopentyl;
R3 is heteroarylalkyl which is substituted or unsubstituted; and
R4 is phenyl which is substituted or unsubstituted.
Ig R1 is methyl; R is cyclopentyl;
R3 is pyridylmethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl, or pyrazinylmethyl, which in each case is substituted or unsustituted, or methyl, ethyl, or propyl; and
R4 is phenyl or phenyl substituted with 1 to 3 substituents.
Ih R1 is methyl;
R2 is cyclopentyl;
R3 is pyridylmethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl, pyrazinylmethyl, which in each case is substituted or unsustituted, or methyl, ethyl, or propyl; and
R4 is phenyl, naphthyl, biphenyl, pyridyl, pyrimidinyl, thiazolyl, pyrazinyl, quinolinyl, or isoquinolinyl, in each case substituted or unsubstituted.
In addition, preferred 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:
Ila R1 is methyl or CHF2;
R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl
(particularly 2-pyridylethyl), or tetrahydrofuranyl
(particularly (3R)-tetrahydrofuranyl); and
R4 is phenyl, naphthyl, pyridyl, quinolinyl, or isoquinolinyl, which in each case is substituted or unsubstituted. R1 is methyl or CHF2;
R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl
(particularly 2-pyridylethyl), or tetrahydrofuranyl
(particularly (3R)-tetrahydro_uranyl); and
R4 is phenyl which is unsubstituted or substituted by methyl, ethyl, methoxy, CI, F, CF3, vinyl, cyano, amino, carboxy, hydroxymethyl, or ethylsulfonamido, or is 3-pyridyl which is unsubstituted or substituted by carboxy or alkoxycarbonyl.
R1 is methyl;
R2 is cyclopentyl; and
R4 is phenyl, naphthyl, pyridyl, quinolinyl, or isoquinolinyl, which in each case is substituted or unsubstituted.
R1 is methyl;
R2 is cyclopentyl; and
R4 is phenyl which is unsubstituted or substituted by methyl, ethyl, methoxy, CI, F, CF3, vinyl, cyano, amino, carboxy, hydroxymethyl, or ethylsulfonamido, or is 3-pyridyl which is unsubstituted or substituted by carboxy or alkoxycarbonyl. In addition, prefeπed PDE4 inhibitors in accordance with the invention are compounds described by subformulas Illa-IIId which correspond to formula III but exhibit the following prefeπed groups:
Ilia R1 is methyl or CHF2;
R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl
(particularly 2-pyridylethyl), or tetrahydrofuranyl
(particularly (3R)-tetrahydrofuranyl); and
R3 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 CHF2;
R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (particularly 2- pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl); and
R3 is pyrazinylmethyl, pyrimidinylmethyl or pyridylmethyl, which in each is unsubstituted or substituted.
IIIc R1 is methyl;
R2 is cyclopentyl; and R3 is benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl, thienylmethyl, pyrazinylmethyl, pyrimidinylmethyl, pyridylmethyl, quinolinymethyl, isoquinohnylmethyl, isoimidazolyl, thiazolylmethyl, or pyrrolylmethyl, which in each case is substituted or unsubstituted.
Hid R1 is methyl;
R2 is cyclopentyl; and
R3 is pyrazinylmethyl or pyridylmethyl, which in each is unsubstituted or substituted.
In addition, prefeπed 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:
IVa R .1 . i-s methyl or CHF2.
IVb R1 is methyl or CHF2, and
B is N.
IVc R1 is methyl or CHF2, and
R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (particularly 2- pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl). IVd R1 is methyl or CHF2, B is N, and
R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (particularly 2- pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl).
IVe R1 is methyl or CHF2, and
R4 is 3-pyridyl or phenyl, which in each case is substituted or unsubstituted.
IVf R1 is methyl or CHF2, B is N, and
R4 is 3-pyridyl or phenyl, which in each case is substituted or unsubstituted.
INg R1 is methyl or CHF2,
R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (particularly 2- pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl), and
R4 is 3-pyridyl or phenyl, which in each case is substituted or unsubstituted.
IVh R1 is methyl or CHF2, B is Ν, R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (particularly 2- pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl),
and
R4 is 3-pyridyl or phenyl, which in each case is substituted or unsubstituted.
IVi R1 is methyl or CHF2, and
R4 is phenyl which is substituted in the 3- or 4- position.
IVj R1 is methyl or CHF2, B is N, and R4 is phenyl which is substituted in the 3- or 4- position.
IVk R1 is methyl or CHF2,
R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (particularly 2- pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl), and
R4 is phenyl which is substituted in the 3- or 4- position.
IVI R1 is methyl or CHF2,
B is N, R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (particularly 2- pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl), and
R4 is phenyl which is substituted in the 3- or 4- position.
JNm R1 is methyl or CHF2, and
R4 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 R1 is methyl or CHF2, B is Ν, and
R4 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 R1 is methyl or CHF2,
R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (particularly 2- pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl), and R4 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 R1 is methyl or CHF2, B is N,
R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (particularly 2- pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl), and
R4 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.
SCHEME 1
Starting nitrophenols ofthe type 1 are either commercially available (e.g., RI = CH3) or prepared by published procedures (e.g., RI = CHF2 or both RI and R2 = CHF2, see Mueller, Klaus-Helmut. Eur. Pat. Appl. (1994), 8 pp. CODEN: EPXXDW EP 626361 Al; Touma, Toshihiko; Asai, Tomoyuki. Jpn. Kokai Tokkyo Koho (1999), 6 pp. CODEN: JKXXAF JP 11071319 A2; Platonov, Andrew; Seavakov, Andrew; Maiyorova, Helen; Chistokletov, Victor. Int. Symp. Wood. Pulping Chem., 1995, 8th, 3, 295-299; Christensen, Siegfried Benjamin; Dabbs, Steven; Kaφinski, Joseph M. PCT Int. Appl. (1996), 12 pp. CODEN: PIXXD2 WO 9623754 Al 19960808). 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. Compounds where R2 is aryl or heteroaryl can be prepared by copper catalyzed reactions with 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. 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., Ph3P, Bu3P) provides alkylated nitrophenols 2. Mitsunobu reactions are general performed in aprotic solvents such as dichloromethane or THF. Alternatively, alkylation can be achieved by the reaction between an appropriately substituted nitrophenol and an alkyl halide in the presence of a base (e.g., K2CO3 or NaH) in a polar aprotic solvent (e.g., DMF or CH3CN).
Nitrocatechols 2 are subsequently reduced to the coπesponding 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. Alternatively, nitrocatechols 3 can be reduced by using a hydride source (e.g., NaBH ) and a transition metal catalyst (e.g., NiCl2, Pd on carbon) or by using metals (e.g., Zn, Sn, Fe) in mineral acid solutions (e.g., HCI) to produce the corresponding anilines. Generally 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. For example, the reductive amination reaction of an aryl or arylalkyl aldehyde with appropriately substituted anilines in the presence of a borohydride reducing agent such as ΝaBH or NaBH3CN with an acid catalyst such as acetic acid or pTsOH provides desired N-arylalkylanilines. 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. For example, the metal catalyzed reaction between an N- benzylaniline and an aryl halide using a palladium catalyst, (e.g., Pd2dba3), a bulky electron rich phosphine ligand (e.g., tributylphosphine), and suitable base (e.g., ΝaOtBu) 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. When synthesizing compounds of the type 5 wherein R4 is an alkoxycarbonylphenyl, it is advantageous that amine 4 is coupled with 1.1 equivalents of tert-butyl 3-iodobenzene and that 22 mol % of (tBu)3P, 5.5 mol % of Pd2(dba)3 and 1.3 equivalents of tBuONa are used.
SCHEME 2
Carboxylic ester intermediates 6 can be hydrolyzed under acidic or basic conditions to give the corresponding carboxylic acids 7. For example, an ethyl ester (R5 = Et) can be hydrolyzed using a mixture of aqueous base (e.g., NaOH, KOH) and a water miscible solvent (e.g., EtOH, THF). While t-Butyl esters (R5 = t-butyl) can be hydrolyzed using an aqueous acid (e.g., HCI, formic acid, TFA) in a water miscible organic solvent, if necessary. SCHEME 3
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. Further, 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.
Alternatively, tetrazole analogs 9 can be prepared from the corresponding nitriles by treatment with azide ion (e.g., KN3, NaN3, etc.) and a proton source (e.g., NH4C1) 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., ZnBr2) in water, using a water miscible co-solvent such as isopropanol if necessary. Another method of preparation is by treatment of a nitrile with tin or silicon azides (e.g., Me3SiN3, Bu3SnN3) in an aprotic organic solvent such as benzene, toluene, dichloromethane, dichloroethane, ether, THF, and the like.
SCHEME 4 10 5
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)). In general, 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 (e.g., 10) can more preferably be synthesized by metal catalyzed amination reactions. For example, reaction of an appropriately substituted aniline 3 with an arylhalide in the presence of a base (e.g., K3PO , CsCO3, or NaOtBu) and a palladium or nickel catalyst, for example Pd(dppf)C_2, a ligand (e.g., dppf) and a base (e.g., NaOtBu) (JACS. 1996, 118, 1211) or with Pd2dba3, a bulky electron rich phosphine such as P(tBu)3, and a base (e.g., NaOtBu) (J. Org. Chem. 1999, 64, 5575) provides the desired diphenylamines 10. 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. SCHEME 5
Carboxylic acids 7 can be further manipulated to form carboxamides 11 using methods standard in the art. For example, 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 Et3N or DIEA to yield a carboxamide. These reactions generally take place in non-polar aprotic solvents such as dichloromethane, chloroform, or dichloroethane.
Carboxylic esters 6 or acids 7 can be reduced using methods standard in the art to give the coπesponding carboxaldehyde or hydroxymethyl analogs. For example, an aryl ethyl ester (e.g., structure 6, R5 = ethyl) can be treated with an appropriate reducing agent (e.g., LAH, DIBAL, etc.)'in an aprotic solvent such as ether or THF, to produce the corresponding carboxaldehydes or hydroxymethyl analogs. Such aldehydes and alcohols can be further derivatised by methods standard in the art.
Similarly carboxamides (e.g., structure 11) and nitriles can be reduced using methods standard in the art to provide the corresponding substituted amines or aminomethyl analogs. For example, 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. Whereas reduction of an aryl nitrile yields the corresponding primary aminomethyl analog. SCHEME 6
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., NiCl2, 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. For example, 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. For example, a sulfonamide can be prepared from an aniline and an appropriate sulfonyl halide or sulfonic anhydride (e.g., MeSO2Cl, EtS02θ, BnSO2Cl, PhSO2Cl, etc.) in the presence of a base (e.g., Et3Ν, pyridine, DIEA, etc.). Suitable solvents for this reaction include non-polar aprotic solvents such as dichloromethane, chloroform, ether, and the like. SCHEME 7
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, 3r 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). 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. 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. For example, an alkyl halide can be aminated with an appropriate primary or secondary amine and a base such as K2CO3, in a polar aprotic solvent such as THF, DMF, or CH3CN.
Many of these synthetic procedures are described more fully in the examples below.
One of ordinary skill in the art will recognize that some ofthe compounds of Formulae (I) and (F) can exist in different geometrical isomeric forms. In addition, some ofthe compounds ofthe present invention possess one or more asymmetric carbon 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. All of these compounds, including cis isomers, trans isomers, diastereomic mixtures, racemates, nonracemic mixtures of enantiomers, and substantially pure and pure enantiomers, are within the scope of the present invention. Substantially pure enantiomers contain no more than 5% w/w ofthe corresponding opposite enantiomer, preferably no more than 2%, most preferably no more than 1%.
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. Examples of 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. Those skilled in the art will further recognize that 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. Alternatively, alkali and alkaline earth metal salts are prepared by reacting the compounds ofthe 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 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. Thus, the present invention also includes pharmaceutical compositions of compounds of Formulae I or F 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 (cunent edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) cunent 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 PDE4 inhibition, 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.
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 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.
Various 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. 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 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. 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, amphakines NMDA- R modulators, mGluR modulators, and cholinesterase inhibitors (e.g., donepezil, rivastigimine, and glanthanamine). In such combinations, 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. 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 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.
The present invention includes methods for dealing with memory loss separate from dementia, 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. In another application, 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).
Thus, in accordance with a prefeπed embodiment, 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.
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 ofthe invention, there is provided 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, seboπheic eczema, lichen simplex, sunburn, pruritis in the anogenital area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, systemic lupus erythematosus, follicular and wide-area pyodermias, endogenous and exogenous acne, acne rosacea, Beghet's disease, anaphylactoid puφura nephritis, inflammatory bowel disease, leukemia, multiple sclerosis, gastrointestinal diseases, autoimmune diseases and the like.
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 incoφorated 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 hypeφlasia, for suppression of chemotaxis and reduction of invasion of colon cancer cells, for treatment of B cell chronic ϊymphocytic 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 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). 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 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. For example, 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. 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 puφoses 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 uncoπected 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, are hereby incoφorated by reference.
EXAMPLE IA l-Cyclopentyloxy-2-methoxy-5-nitrobenzene
To a suspension of 2-methoxy-5 -nitrophenol (525g, 3.104 mol) and potassium carbonate (643.5g, 4.66 mol) in dimethyl formamide (1 L), under N2 protection, was added cyclopentyl bromide (499.2 mL, 4.66 mol). The suspension was heated to 100°C for 6h. Potassium carbonate (85.8g, 0.62 mol) and cyclopentyl bromide (50 mL, 0.46 mol) were added. The suspension was heated to 100°C for 4h. TLC indicated the reaction was complete (9:1 DCM:MeOH). The reaction mixture was cooled to room temperature and diluted with water (3L) and ether (3L). The layers were separated and the aqueous layer was re-extracted with ether (2L). The combined organic layers were washed with IN NaOH (2L), water (2L), and brine (2L). The organic layer was dried over sodium sulfate, filtered, and evaporated. The resulting solid was azeotroped with toluene (2 x 300 mL) to obtain 136.1% (99.6% yield) as a yellow solid.
The following compounds were prepared in a similar manner as described above:
a) 1 -Cyclopropylmethoxy-2-methoxy-5-nitrobenzene b) l-Cyclopentoxy-2-difluoromethoxy-5-nitrobenzene c) l-Cyclopropylmethoxy-2-difluoromethoxy-5 -nitrobenzene
EXAMPLE IB
2-Methoxy-5-nitro-l-((3R)-tetrahydrofuryloxy)benzene
To a mixture of 2-Methoxy-5-nitrophenol (1.69 g, 10 mmol), triphenylphosphine (5.24 g, 20 mmol) and 3-(R)-hydroxytetrahydrofuran (1.80 g, 20 mmol) in anhydrous tetrahydrofuran (40 mL) was added drop-wise, with stirring, dusopropylazodicarboxylate (4.0 mL, 20 mmol) and the mixture was allowed to stir at room temperature for 16 h. The mixture was diluted with ether (150 mL) and washed with 2N NaOH (3 x 50 mL) and brine (50 mL), (MgSO4) and concentrated in vacuo. The crude residue was purified by flash column chromatography over silica gel (Biotage Flash 40M) eluting with 20%> ethyl acetate in hexanes to give 1.05 g of product
The following compounds were prepared in a similar manner as described above:
a) 2-Methoxy-5-ni.ro- 1 -(3-tetrahydrofuryloxy)benzene b) 2-Methoxy-5-nitro- 1 -((3S)-tetrahydrofuryloxy)benzene c) 2-Difluoromethoxy-5 -nitro- 1 -(3-tetrahydrofuryloxy)benzene d) 2-Difluoromethoxy-5 -nitro- 1 -((3R)-tetrahydrofuryloxy)benzene e) 2-Difluoromethoxy-5 -nitro- 1 -((3S)-tetrahydrofuryloxy)benzene f) 2-Methoxy-5 -nitro- 1 -(3-phenpropyloxy)benzene g) 1 -(2-Indanyloxy)-4-methoxy-5-nitrobenzene
EXAMPLE IC l-(tert-Butyldimethy_si_y_)oxy-2-methoxy-5-nitrobenzene
To a mixture of 2-methoxy-5-nitrophenol (1.53 g, 9.0 mmol) and imidazole (1.08 g, 15.9 mmol) in anhydrous DMF (40 mL) was added, with stirring, tert- butyldimethylsilyl chloride (2.05 g, 13.6 mmol) and the mixture was allowed to stir at room temperature for 16 h. The solvent was removed in vacuo and the residue was dissolved in 40 mL of 50% ethyl acetate in hexanes and filtered through 10 g of silica gel. The silica gel was washed with an additional 200 mL of 50%> ethyl acetate in hexanes and the filtrates were combined and concentrated in vacuo to give 2.01 g of product as a tan crystalline solid. Η NMR (CDC13) δ 7.89 (dd, 1H, J = 9.0 Hz, 2.8 Hz), 7.69 (d, 1H, J = 2.8 Hz), 6.88 (d, 1H, J - 9.0), 3.90 (s, 3H), 1.00 (s, 9H), 0.18 (s, 6H).
EXAMPLE 2 3-Cyclopentyloxy-4-methoxyaniline
To a suspension of 10%> Pd on activated carbon (25g) in ethanol (4L), under N2 protection, was added l-cyclopentyloxy-2-methoxy-5-nitrobenzene (250g, 1.054 mol). The reaction mixture was degassed under vacuum three times. The reaction mixture was stirred vigorously while hydrogen gas was allowed to flow over the reaction mixture. After 4h the reaction was complete by TLC (5:1 hex:EA). The reaction mixture was filtered through a pad of celite and the celite was rinsed with additional ethanol. The solvent was removed in-vacuo to obtain 208.38g (95% yield) of 3-cyclopentyloxy-4- methoxyaniline as a red liquid. Η NMR (CDCI3) δ 6.85 (d. J - 8.4Hz, 1H), 6.29 (s, 1H), 6.19 (dd, J = 2.8, 8.4, 1H), 4.69 (p, J = 4.4 Hz, 1H), 3.75 (s, 3H), 3.44 (bs, 2H), 1.90-1.81 (m, 6H), 1.61-1.55 (m, 2H).
The following compounds were prepared in a similar manner as described above:
a) 3-Cyclopentyloxy-4-difluoromefhoxyaniline b) 3-Cyclopropylmethoxy-2-methoxyaniline c) 3-Cyclopropylmethoxy-4-difluoromethoxyaniline d) 4-Methoxy-3-((3R)-tetrahydrofuryloxy)aniline e) 4-Methoxy-3-(tetrahydrofuryloxy)aniline f) 4-Methoxy-3-((3S)-tetrahydrofuryloxy)aniline g) 4-Difluoromethoxy-3-(3-tetrahydrofuryloxy)aniline h) 4-Difluoromethoxy-3-((3R)-tetrahydrofuryloxy)aniline i) 4-Difluoromethoxy-3-((3S)-tetrahydrofuryloxy)aniline j) 3-(tert-Butyldimethylsilyl)oxy-4-methoxyaniline k) 4-Methoxy-3-(3-phenpropyloxy)aniline 1) 3-(2-Indanyloxy)-4-methoxyaniline
EXAMPLE 3 5 3-Cyclopentyl-4-methoxy-N-(3-pyridyImethy_)aniline
To a mixture of 3-pyridinecarboxaldehyde (106.55g, 0.995 mol) in methanol (5L) was added 3-cyclopentyloxy-4-methoxyaniline (208.38g, 1.005 mol) and p-toluenesulfonic acid monohydrate (200 mg). The reaction mixture was stirred for 4h. The flask was then cooled to 0°C and sodium borohydride (37.64g, 2.3 mol) was added portionwise over 4h.
0 The reaction mixture was allowed to warm to room temperature over 16h with stirring. TLC indicated the reaction was complete (1 :3 hex:EA). The solvent was evaporated until approximately 0.5L of slurry remained. The sluπy was diluted with water (IL) and extracted with ethyl acetate (2 x 2L). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, and concentrated to yield 300g (100% yield)
5 of the desired product as a brown viscous liquid. Η ΝMR (CDC13) δ 8.61-8.48 (m, 2H), 7.69-7.67 (m, 1H), 7.24-7.21 (m, 1H), 6.72 (d. J = 8.4 Hz, 1H), 6.23 (s, 1H), 6.13 (dd, J = 2.6, 8.6, 1H), 4.65 (bs, 1H), 4.27 (s, 2H), 4.0 (bs, 1H), 3.73 (s, 3H), 1.88-1.70 (m, 6H), 1.65-1.45 (m, 2H).
!0 The following compounds were prepared in a similar manner as described above:
a) 3-Cyclopentyloxy-4-methoxy-N-(3-thienylmethyl)aniline b) 3-Cyclopentyloxy-4-methoxy-N-(4-pyridylmethyl)aniline c) 3-Cyclopentyloxy-N-(2,6-dichloro-4-pyridylmethyl)- 4-methoxyaniline 15 d) 3-Cyclopentyloxy-4-methoxy-N-(2-quinolinylmethyl)aniline e) 3-Cyclopentyloxy-4-methoxy-N-(3-quinolinylmethyl)aniline f) 3-Cyclopentyloxy-4-methoxy-N-(4-quinolinylmethyl)aniline g) 3-Cyclopentyloxy-4-methoxy-N-(2-pyrazinylmethyl)aniline h) 4-Methoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)aniline 10 i) 4-Methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)aniline j) 4-Methoxy-N-(3-pyridylmethyl)-3-((3S)-tetrahydrofuryloxy)aniline k) 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3-pyridylmethyl)aniline
I) 3-Cyclopentyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)aniline m) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)aniline n) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)aniline o) 3,4-Bis(difluoromethoxy)-N-(3-pyridylmethyl)aniline p) 3-tert-Butyldimethylsilyloxy-4-methoxy-N-(3-pyridylmethyl)aniline q) 3-Cyclopentyloxy-4-methoxy-N-(2-pyridylmethyl)aniline r) 3-Cyclopentyloxy-4-methoxy-N-[ 1 -(2-phenethyl)]aniline s) N-Benzyl-3-cyclopentyloxy-4-methoxyaniline t) N-[(Cyclohex-l-en-l-yl)methyl]-3-cyclopentyloxy-4-methoxyaniline u) 3-Cyclopentyloxy-4-methoxy-N-(3,4,5-trimethoxybenzyl)aniline v) N-[(Cyclohex-3-en-l-yl)methyl]-3-cyclopentyloxy-4-methoxyaniline w) 3-Cyclopentyloxy-4-methoxy-N-(2,4,6-trimethylbenzyl)aniline x) 3-Cyclopentyloxy-4-methoxy-N-(2-methylbenzyl)aniline y) 3-Cyclopentyloxy-4-methoxy-N-(2-trifluoromethylbenzyl)aniline z) 3-Cylclopentyloxy-4-methoxy-N-((3,4-methylenedioxy)benzyl)aniline aa) 3-Cyclopentyloxy-N-(2-hydroxy-3-methoxylbenzyl)-4-methoxyaniline bb) 3-Cyclopentyloxy-N-(3-furylmethyl)-4-methoxyaniline cc) 3-Cyclopentyloxy-4-methoxy-N-(3 -methylbenzyl)aniline dd) 3-Cyclopentyloxy-4-methoxy-N-(2-methoxybenzyl)aniline ee) 3-Cyclopentyloxy-4-methoxy-N-(3-chlorobenzyl)aniline ff) 3-Cyclopentyloxy-4-methoxy-N-(3-methoxybenzyl)aniline gg) 3-Cyclopentyloxy-4-methoxy-N-(2-chlorobenzyl)aniline hh) 3-Cyclopentyloxy-4-methoxy-N-(3 -methylbenzyl)aniline ii) 4-Methoxy-3-(3-phenpropyloxy)-N-(4-pyridylmethyl)aniline jj) N-(2,6-Dichloro-4-pyridylmethyl)-3-(2-indanyloxy)-4-methoxyaniline kk) 4-Methoxy-3-(3-phenpropyloxy)-N-(2-pyridylmethyl)aniline
II) N-(2,6-Dichloro-4-pyridylmethyl)-4-methoxy-3-(3-phenpropyloxy)aniline mm) 4-Methoxy-3-(3-phenpropyloxy)-N-(3-pyridylmethyl)aniline nn) 3-Cyclopentyloxy-4-methoxy-N-(2-thienylmethyl)aniline oo) 3-(2-Indanyloxy)-4-methoxy-N-(3-thienylmethyl)aniline pp) 4-Methoxy-3-(3-phenpropyloxy)-N-(3-thienylmethyl)aniline qq) 3-(2-Indanyloxy)-4-methoxy-N-(2-pyridylmethyl)aniline rr) 3-(2-Indanyloxy)-4-methoxy-N-(3-pyridylmethyl)aniline ss) 3-(2-Indanyloxy)-4-methoxy-N-(4-pyridylmethyl)aniline tt) 3-Cyclopentyloxy-4-methoxy-N-(3-piperidinemethyl)aniline uu) 3-Cyclopentyloxy-4-methoxy-N-(3-(l-tert- butyloxycarbonyl)piperidinemethyl)aniline vv) 3-Cyclopentyloxy-4-methoxy-N-(6-methyl-2-pyridylmethyl)aniline ww) N-(2-Chloro-3-pyridylmethyl)-3-cyclopentyloxy-4-methoxyaniline xx)N-(2-Chloro-5-pyridylmethyl)-3-cyclopentyloxy-4-methoxyaniline yy) 3-Cyclopentyloxy-4-methoxy-N-(2-thiazolylmethyl)aniline
EXAMPLE 4 3-Cyclopentyloxy-4-methoxy-N-(3-pyridyl_nethy_)diphenylamine
To a 100 mL oven dried, argon flushed flask was added in the following order 0.59 g (6.10 mmol) of NaOtBu, 360 mg of Pd2dba3, 20 mL of toluene, 0.14 mL of P(tBu)3, and a 20 mL solution of 1.3 g (4.36 mmol) of Ν-(3-pyridylmethyl)-3-cyclopentyloxy-4- methoxyaniline in toluene. With stirring, 3.1 g (15' mmol) of iodobenzene was added dropwise and the mixture was stirred for 18 hours. The reaction mixture was diluted with EtOAc and washed twice with H2O 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 ΝaOH 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 H2O and brine, dried (MgSO4), 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. Η NMR (CDC13) δ 8.61 (s, 1H), 8.49 (d, 1H, J = 4.2 Hz), 7.67 (d, 1H, 7.9 Hz), 7.30-7.10 (m, 3H), 6.90-6.80 (m, 4H), 6.80-6.60 (m, 2H), 4.94 (s, 2H), 4.64 (p, 1H, J = 4.1 Hz),3.84 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H).
The following compounds were prepared in a similar manner as described above: a) 3-Cyclopentyloxy-4-methoxy-2'-methyl-N-(3-pyridylmethyl)diphenylamine b) 3-Cyclopentyloxy-4-methoxy-3'-methyl-N-(3-pyridylmethyl)diphenylamine c) 3-Cyclopentyloxy-4-methoxy-4'-methyl-N-(3-pyridylmethyl)diphenylamine d) 3-Cyclopentyloxy-4'-ethyl-4-methoxy-N-(3-pyridylmethyl)diphenylamine e) 3'-Chloro-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine f) 4'-Chloro-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine g) 3-Cyclopentyloxy-2',4-dimethoxy-N-(3-pyridylmethyl)diphenylamine h) 3-Cyclopentyloxy-3',4-dimethoxy-N-(3-pyridylmethyl)diphenylamine i) 3 -Cyclopentyloxy-4,4 ' -di methoxy-N-(3 -pyridylmethyl)diphenyl amine j) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3'-trifluoromethyldiphenylamine k) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-trifluoromethyldiphenylamine
1) 3-Cyclopentyloxy-3'-fluoro-4-methoxy-N-(3-pyridylmethyl)diphenylamine m) 3-Cyclopentyloxy-4'-fluoro-4-methoxy-N-(3-pyridylmethyl)diphenylamine n) 3-Cyclopentyloxy-4-methoxy-3'-phenyl-N-(3-pyridylmethyl)diphenylamine o) 3-Cyclopentyloxy-4-methoxy-4'-phenyl-N-(3-pyridylmethyl)diphenylamine p) 3'-Cyano-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine q) 4'-Cyano-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine r) Ethyl N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoate s) Ethyl N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoate t) 3-Cyclopentyloxy-4-methoxy-3'-nitro-N-(3-pyridylmethyl)diphenylamine u) 3-Cyclopentyloxy-4-methoxy-4'-nitro-N-(3-pyridylmethyl)diphenylamine v) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)- 1 -naphthylamine w) 3-Cyclopentyloxy-2 ' ,3 '-dimethyl-4-methoxy-N-(3-pyridylmethyl)diphenylamine x) 3-Cyclopentyloxy-2',4'-dimethyl-4-methoxy-N-(3-pyridylmethyl)diphenylamine y) 3-Cyclopentyloxy-2',5'-dimethyl-4-methoxy-N-(3-pyridylmethyl)diphenylamine z) 3-Cyclopentyloxy-3',4'-dimethyl-4-methoxy-N-(3-pyridylmethyl)diphenylamine aa) 3-Cyclopentyloxy-2',3'-dichloro-4-methoxy-N-(3-pyridylmethyl)diphenylamine bb) 3 -Cyclopentyloxy-3 ' ,4 ' -dichloro-4-me thoxy-N-(3 -pyridylmethyl)diphenylamine cc) 3-Cyclopentyloxy-3 ',5 '-dichloro-4-methoxy-N-(3-pyridylmethyl)diphenylamine dd) 3'-Chloro-3-cyclopentyloxy-4'-fluoro-4-methoxy-N-(3-pyridylmethyl)diphenylamine ee) 4'-Chloro-3-cyclopentyloxy-3'-fluoro-4-methoxy-N-(3-pyridylmethyl)diphenylamine ff) 4 ' -Chloro-3-cyclopentyloxy-4-methoxy-N-(3 -pyridylmethyl)-3 ' - trifluoromethyldiphenylamine gg) 3-Cyclopentyloxy-4-methoxy-N-(3-thienylmethyl)diphenylamine hh)N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-thienylmethyl)-l-naphthylamine ii) 3-Cyclopentyloxy-2',3'-dichloro-4-methoxy-N-(3-thienylmethyl)diphenylamine jj) 3-Cyclopentyloxy-4-methoxy-4'-methyl-N-(4-pyridylmethyl)diphenylamine kk) 3-Cyclopentyloxy-N-(2,6-dichloro-4-pyridylmethyl)-4-methoxy-3'- methyldiphenylamine 11) 2'-Chloro-3-cyclopentyloxy-N-(2,6-dichloro-4-pyridylmethyl)-4- methoxydiphenylamine mm) 3-Cyclopentyloxy-N-(2,6-dichloro-4-pyridylmethyl)-4-methoxydiphenylamine nn) 3-Cyclopentyloxy-4-methoxy-N-(6-methyl-2-pyridylmethyl)diphenylamine oo) 3-Cyclopentyloxy-4-methoxy-N-(3-quinolinylmethyl)diphenylamine pp) 3-Cyclopentyloxy-4-methoxy-N-(4-quinolinylmethyl)diphenylamine qq) 3-Cyclopentyloxy-4-methoxy-N-(2-pyrazinylmethyl)diphenylamine rr) 4-Methoxy-3'-methyl-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine ss) 4-Methoxy-4'-methyl-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine tt) 4,4'-Dimethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine uu) 3'-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine vv) 4-Methoxy-4' -(4-methylpiperazin- 1 -ylcarbonyl)-N-(3 -pyridylmethyl)-3 -(3 - tetrahydrofuryloxy)diphenylamine ww) 3 ' -Cyano-4-methoxy-N-(3 -pyridylmethyl)-3 -((3R)- tetrahydrofuryloxy)diphenylamine xx) 3'-Cyano-4-methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)diphenylamine yy) 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3-pyridylmethyl)diphenylamine zz) 3-Cyclopentyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)diphenylamine aaa) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine bbb) 3,4-Bis(difluoromethoxy)-N-(3-pyridylmethyl)diphenylamine ccc) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)- tetrahydrofuryloxy)diphenylamine ddd) 3'-Cyano-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)- tetrahydrofuryloxy)diphenylamine eee) 3'-Chloro-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)- tetrahydrofuryloxy)diphenylamine fff) Ethyl N-(3-cycloprop ylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoate ggg) 3-Cyclopentyloxy-4-methoxy-3'-(4-methylpiperazin-l-ylcarbonyl)-N-(3- pyridylmethyl)diphenylamine hhh) 3-Cyclopentyloxy-4-methoxy-4'-(4-methylpiperazin-l-ylcarbonyl)-N-(3- pyridylmethyl)diphenylamine iii) 3'-tert-Butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine jjj) 4'-tert-Butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine kkk) tert-Butyl N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoate 111) Ethyl N-(3-cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoate mmm) Ethyl N-(4-difluoromethoxy-3-(3-tetrahydrofuryloxy)phenyl)-N-(3- pyridylmethyl)-3-aminobenzoate nnn) Ethyl N-(3,4-Bis(difluoromethoxy)phenyl)-N-(3-pyridylmethyl)-3-aminobenzoate ooo) Ethyl N-(4-methoxy-3-((3R)-tetrahydrofuryloxy)phenyl)-N-(3-pyridylmethyl)- -3- aminobenzoate ppp) Ethyl N-(3-cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoate qqq) 3-Cyclopentyloxy-4-methoxy-4'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-N-
(3-pyridylmethyl)diphenylamine rrr) 3-Cyclopentyloxy-4-methoxy-3'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-N-(3- pyridylmethyl)diphenylamine sss) 4-Methoxy-4'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-N-(3-pyridylmethyl)-3-
((3R)-tetrahydrofuryloxy)diphenylamine ttt) 3-Cyclopropylmethoxy-4-methoxy-4'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-N-
(3-pyridylmethyl)diphenylamine uuu) 4-Difluoromethoxy-4'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-N-(3- pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)diphenylamine vvv) 3-Cyclopropylmethoxy-4-difluoromethoxy-4'-(2-(tetrahydropyran-2-yl)-2H- tetrazol-5-yl)-N-(3-pyridylmethyl)diphenylamine www) 3-Cyclopentyloxy-4-difluoromethoxy-4'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5- yl)-N-(3-pyridylmethyl)diphenylamine xxx) 3-Cyclopropylmethoxy-4-difluoromethoxy-3'-(2-(tetrahydropyran-2-yl)-2H- tetrazol-5-yl)-N-(3-pyridylmethyl)diphenylamine yyy) Bis-(3,4-difluoromethoxy)-3'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-N-(3- pyridylmethyl)diphenylamine zzz) 3 -tert-Butyldimethylsilyloxy-4-methoxy-N-(3 -pyridylmethyl)diphenylamine aaaa) 3-tert-Butyldimethylsilyloxy-3'-chloro-4-methoxy-N-(3- pyridylmethyl)diphenylamine bbbb) Ethyl N-(3-tert-butyldimethylsilyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoate cccc) 3-Cyclopentyloxy-2'-chloro-4-methoxy-N-(3-pyridylmethyl)diphenylamine dddd) 3-(2-indanyloxy)-4-methoxy-N-(3-pyridylmethyl)diphenylamine
EXAMPLE 5 N-(3-CycIopentyloxy-4-methoxyphenyl)-N-(3-pyridylmet__yl)-3-aminobenzoic acid
A solution of 6.5 g of ethyl N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3- pyridylmethyl)-3-aminobenzoate in 50 mL of EtOH was treated with 10 mL of 6Ν NaOH. The mixture was allowed to stand for 6 hours, concentrated, and diluted with 50 mL of H2O. The aqueous mixture was extracted with 2 x 50 mL of ether, acidified with AcOH to pH 3, and extracted with 2 x 50 mL of EtOAc. The combined EtOAc fractions were washed with 25 mL of H2O and 25 mL of brine, dried (MgSO4), and concentrated. The residue was purified by chromatography over SiO (35 g RediSep® column) using a linear gradient of EtOAc and hexanes as eluant (50%> EtOAc to 70% EtOAc over 20 minutes) to provide 4.8 g of a yellow solid product after drying in vacuo for 12 h at 60°C. Η NMR (CDCI3) δ 11.15 (bs, 1H), 8.70-8.55 (m, 2H), 7.77-6.71 (m, 9H), 4.99 (s, 2H), 4.65 (p, J = 3.8 Hz, 1H), 3.84 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H).
The following compounds were prepared in a similar manner as described above:
a) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid b) N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoic acid c) N-[4-Difluoromethoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid d) N-3,4-Bis(difluoromethoxy)phenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid e) N-[4-Methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid f) N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid g) N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoic acid h) N-(3-Cyclopentyloxy-4-methoxyphenyl)-3-aminobenzoic acid i) N-[3-(4-Chlorophenyl)prop-l-yloxy-4-methoxyphenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid j) N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid k) N-[3-(2-Indanyloxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid 1) N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid m) N-[4-Methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid n) N-[3-(2-Methoxyethoxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid o) N-[4-Methoxy-3-(2-(2-pyridyl)ethyl)oxyphenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid EXAMPLE 6 N-(3-Cyclopentyioxy-4-methoxyphenyI)-N-(3-pyridylmethyl)-2-aminobenzoic acid rert-Butyl N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-2- aminobenzoate (60 mg, 0.13 mmol) was taken up in 2 mL 98% formic acid and heated at 40 °C for 4 h. 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. Η ΝMR (CDC13) δ 8.47 (d, IH, J = 4.9), 8.43 (s, IH), 8.10 (d, IH, J = 7.8), 7.67 (d, IH, J = 7.8 Hz), 7.56 (m, IH), 7.40-7.20 (m, 3H), 6.75 (d, IH, J = 8.7), 6.57 (d, IH, J = 8.7), 6.47 (s, IH), 4.72 (s, 2H), 4.54 (p, IH, J = 4.3), 3.77 (s, 3H), 1.80-1.60 (m, 6H), 1.60-1.40 (m, 2H).
The following compounds were prepared in a similar manner as described above:
a) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid b) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-6-aminonicotinic acid
EXAMPLE 7
3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-4'-
(2H-tetrazol-5-yl)diphenylamine
3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3-pyridylmethyl)-4'-[2-(2- tetrahydropyranyl)-2H-tetrazol-5-yl]diphenylamine (1.5 g, 0.26 mmol) was dissolved in THF (5 mL) and 3 mL of IN HCI was added. After 6 h at room temperature, the mixture was neutralized to pH = 5 with saturated aqueous sodium bicarbonate and extracted with EtOAc (3 x 50 mL). The EtOAc extracts were combined, washed with brine (50 mL), dried (MgSO4), and concentrated in vacuo. The crude residue was loaded onto a RediSep column (10 g, silica gel) and the product was eluted using a linear gradient from 0% MeOH in EtOAc to 5% MeOH in EtOAc over 20 min to give 0.96 g of product as a white powder. 1H ΝMR (CD3OD) δ 8.55 (s, IH), 8.43 (d, IH, J = 4.9 Hz), 7.65 (d, IH, 8.0 Hz), 7.21 (dd, IH, J = 4.9 Hz, 8.0 Hz), 7.18 (d, IH, J = 8.9 Hz), 7.10-6.90 (m, 3H), 6.87 (dd, IH, J = 8.6 Hz, 2.5 Hz), 6.75 (t, IH, J = 75.5 Hz), 5.14 (s, 2H), 3.82 (d, 2H, J = 6.9 Hz), 1.23 (m, IH), 0.60 (m, 2H), 0.33 (m, 2H).
The following compounds were prepared in a similar manner as described above:
a) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5- yl)diphenylamine b) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3'-(2H-tetrazol-5- yl)diphenylamine c) 4-Methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4'-(2H-tetrazol-5- yl)diphenylamine d) 3-Cyclopropylmethyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5- yl)diphenylamine e) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4'-(2H-tetrazol- 5-yl)diphenylamine f) 3-Cyclopentyloxy-4-difluromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5- yl)diphenylamine g) 3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-3'-(2H-tetrazol-5- yl)diphenylamine h) Bis-3,4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl)diphenylamine
EXAMPLE 8 (Method A) 3-Cyclopentyloxy-4-methoxydiphenylamine
Method A. (Ref Chan, D.M.T.; Monaco, K.L.; Wang, R.P.; Winters, M.P., Tetrahedron Lett., 1998, 39, 2933-2936.). A slurry of 207 mg of 4-methoxy-3- cyclopentyloxyaniline, 280 mg of phenylboronic acid, 182 mg of Cu(OAc)2, 280 μL of Et3Ν and 4.0 mL of CH2C12 was stiπed for 20 h at room temp. The black mixture was filtered through silica eluting with CH2C12, concentrated, and purified by chromatoghraphy over SiO2 using EtOAc/Hexanes (15/85) as eluant to provide 75 mg of the desired product. 1H NMR (CDC13) δ 7.26-7.20 (m, 2H), 6.94-6.63 (m, 6H), 5.50 (s, IH), 4.71 (m, IH), 3.82 (s, 3H), 1.89-1.54 (m, 8H). The following compounds were prepared in a similar manner as described above:
a) 3-Cyclopentyloxy-3 ',4-dimethoxydiphenylamine b) 3 ' -Chloro-3 -eye lopentyloxy-4-methoxydiphenyl amine c) 3-Cyclopentyloxy-4-methoxy-3 'methyldiphenylamine d) 3-Cyclopentyloxy-4'-fluoro-4-methoxydiphenylamine e) 3 -Cyclopentyloxy-4-methoxy-4 ' -vinyldiphenylamine f) 3'-Cyano-3-cyclopentyloxy-4-methoxydiphenylamine g) 4' -Chloro-3 -cyclopentyloxy-4-methoxydiphenylamine h) 3-Cyclopentyloxy-4,4'-dimethoxydiphenylamine i) 3-Cyclopentyloxy-4-methoxy-2'-methyldiphenylamine j) 3-Cyclopentyloxy-4-methoxy-4'-methyldiphenylamine k) 2'-Chloro-3-cyclopentyloxy-4-methoxydiphenylamine
1) 3-Cyclopentyloxy-2',4-dimethoxydiphenylamine m) 3-Cyclopentyloxy-4-methoxy-3'-trifluoromethyldiphenylamine n) 3-Cyclopentyloxy-4-methoxy-4'-trifluoromethyldiphenylamine o) 3 -Cyclopentyloxy-2 ' ,5 ' -dimethyl-4-methόxydiphenylamine
EXAMPLE 8 (Method B) 3-Cyclopentyloxy-4-methoxydiphenylamine
Method B (Angerw Chem. Int. Ed., 1995, 34(11), 1348-1351.) A mixture of 207 mg of 3-cyclopentyloxy-4-methoxyaniline, 204 mg of iodobenzene, 115 mg of NaOtBu, 9 mg of Pd2(dba)3, 12 mg of P(ø-tol)3 and 7 mL of toluene was combined and warmed with stirring to 100 °C for 4h. The mixture was cooled to room temp, diluted with 25 mL of EtOAc and washed with 10 mL of H20, 10 mL of brine, dried (MgSO4) and concentrated. The residue was purified by chromatography over SiO2 using EtOAc/hexanes (5/95) as eluant to provide 84 mg ofthe desired product.
The following compounds were prepared in a similar manner as described above: a) 3-Cyclopentyloxy-4-methoxy-2',4'-dimethyldiphenylamine b) 3-Cyclopentyloxy-2',5'-dimethyl-4-methoxydiphenylamine c) 3-Cyclopentyloxy-2',3'-dimethyl-4-methoxydiphenylamine d) 3-Cyclopentyloxy-3 ',4'-dimethyl-4-methoxydiphenylamine e) 3-Cyclopentyloxy-3 ',4' -methyl enedioxydiphenylamine f) 4'-tert-Butyl-3-cyclopentyloxy-4-methoxydiphenylamine g) 3-Cyclopentyloxy-3 ',4'-dichloro-4-methoxydiphenylamine h) 3-Cyclopentyloxy-2',3'-dichloro-4-methoxydiphenylamine
EXAMPLE 8 (Method C) 3-Cyclopentyloxy-2',4,5'-trimethoxydiphenylamine
Method C. To a mixture of Pd(dppf)Cl2 (0.025 mmol, 5mol%), dppf (0.075 mmol, 3dppf/Pd) and NaOtBu (0.70 mmol, 1.4 equivalents) and 1.0 mL THF was added 1- bromo-2,5-dimethoxybenzene (0.55 mmol, 1.1 equivalents) followed by 1.0 mL of a 0.5M solution of 3-cyclopentyloxy-4-methoxyaniline in THF. The mixture was heated to 60 °C for 3 hours and diluted with ether and washed with H2O and brine, dried (MgSO ), and concentrated. The crude residue was purified by chromatography over silica gel (Biotage Flash 12) eluting with 15% EtOAc in hexanes.
The following compounds were prepared in a similar manner as described above:
a) N-(3-Cyclopentyloxy-4-methoxyphenyl)-3-pyridylamine b) 3-Cyclopentyloxy-2',4',4-trimethoxydiphenylamine c) N-(3-Cyclopentyloxy-4-methoxyphenyl)-2-pyridylamine d) N-(3-Cyclopentyloxy-4-methoxyphenyl)-8-quinolinylamine e) N-(_?-Cyclopentyloxy-4-methoxyphenyl)-2-naphthylamine f) N-(3-Cyclopentyloxy-4-methoxyphenyl)-l-naphthylamine g) 3-Cyclopentyloxy-4'-ethyl-4-methoxydiphenylamine h) 3-Cyclopentyloxy-2'-fluoro-4-methoxy-5'-methyldiphenylamine i) 3-Cyclopentyloxy-3 '-fluoro-4-methoxy-4'-methyldiphenylamine j) N-(3-Cyclopentyloxy-4-methoxyphenyl)-2-pyrimidinylamine k) 3-Cyclopentyloxy-3 ',5 '-dichloro-4-methoxydiphenylamine 1) 3 -Cyclopentyloxy-2 ' -ethyl-4-methoxydiphenylamine m) 4 ' -Chloro-3 -cyclopentyloxy-3 ' -fluoro-4-methoxydiphenylamine n) N-(3-Cyclopentyloxy-4-methoxyphenyl)-4-isoquinolinylamine o) N-(3-Cyclopentyloxy-4-methoxyphenyl)-2-pyrazinylamine p) N-(3-Cyclopentyloxy-4-methoxyphenyl)-5-pyrimidinylamine q) N-(3 -Cyclopentyl oxy-4-methoxyphenyl)-l-isoquinolinylamine r) N-(3-Cyclopentyloxy-4-methoxyphenyl)-3-quinolinylamine s) N-(3-Cyclopentyloxy-4-methoxyphenyl)-4-pyridylamine t) N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-3-pyridylamine u) N-(3-Cyclopropylmethyloxy-4-methoxyphenyl)-3-pyridylamine v) N-(3-Cyclopropylmethyloxy-4-difluoromethoxyphenyl)-3-pyridylamine w) N-(4-Methoxy-3-(3R)-tetrahydrofuryloxyphenyl)-3-pyridylamine x) N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-3-pyridylamine y) Ethyl N-(3-cyclopentyloxy-4-methoxyphenyl)-3-aminobenzoate z) 3-Cyclopentyloxy-4'-(N,N-dimethylamino)-4-methoxydiphenylamine aa) N-(3-Cyclopentyloxy-4-methoxyphenyl)-3-(6-methoxypyridyl)amine bb) Methyl N-(3 -eye lopentyloxy-4-methoxyphenyl)-2-aminonicotinate cc) tert-Butyl N-(3-cyclopentyloxy-4-methoxyphenyl)-6-aminonicotinate dd) 2 ' - Amino-3 -cyclopentyloxy-4-methoxydiphenylamine ee) 3 -Cyclopentyloxy-4-methoxy-3 ' -( 1 -phthalimido)diphenylamine ff) 3-Cyclopentyloxy-4-methoxy-3'-[2-(2-tetrahydropyranyl)-2H-tetrazol-5- yljdiphenylamine
EXAMPLE 9 (Method A) 3-Cyclopenty_oxy-4-methoxy- N-_nethyldiphenylamine
To a solution of 3-cyclopentyloxy-4-methoxydiphenylamine (70 mg, 0.25 mmol) in 3 mL of THF at 0 °C was added 0.55 mL of 0.5 M KΝ(TMS)2 in toluene. The solution was stiπed at 0 °C for 0.5 h and 2.0 equivalents of iodomethane was added and the reaction mixture was warmed to room temperature. Upon reaction completion as indicated by TLC, 10 mL of EtOAc was added and the mixture was washed with 3 mL of H2O, 3 mL of brine, dried (MgSO4) and concentrated. The crude residue was purified by column chromatography (Biotage flash 12) using 5% EtOAc in hexanes as eluant.
The following compounds were prepared in a similar manner as described above:
a) 3-Cyclopentyloxy-N-ethyl-4-methoxydiphenylamine b) 3-Cyclopentyloxy-4-methoxy-N-(l-propyl)diphenylamine c) 3-Cyclopentyloxy-4-methoxy-N-[ 1 -(3-phenpropyl)]diphenylamine d) N-Benzyl-3-cyclopentyloxy-4-methoxydiphenylamine e) 3-Cyclopentyloxy-4-methoxy-N-(4-pyridylmethyl)diphenylamine f) 3-Cyclopentyloxy-4-methoxy-N-(2-pyridylmethyl)diphenylamine g) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine h) 3-Cyclopentyloxy-4-methoxy-N-[3-(3-pyridyl)-l-propyl]diphenylamine i) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-ethyl-4-isoquinolinylamine j) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-benzyl-4-isoquinolinylamine k) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-methyl-4-isoquinolinylamine 1) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-propyl-4-isoquinolinylamine m) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(4-isoquinolinyl)-N-(4- pyridylmethyl)amine n) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(4-isoquinolinyl)-N-(3- pyridylmethyl)amine o) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-N-(5- pyrimidinyl)amine p) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(2-pyrazinyl)-N-(3-pyridylmethyl)amine q) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(2-pyridyl)-N-(3-pyridylmethyl)amine r) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl)amine s) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(4-pyridyl)-N-(3-pyridylmethyl)amine t) tert-Butyl N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-6- aminonicotinate u) N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridyl)-N-(3- pyridylmethyl)amine v) N-(4-Methoxy-3-(3R)-tetrahydrofuryloxyphenyl)-N-(3-pyridyl)-N-(3- pyridylmethyl)amine w) N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridy_)-N-(3- pyridylmethyl)amine x) N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3- pyridylmethyl)amine y) N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-N-(3-pyridyl)-N-(3- pyridylmethyl)amine z) N-(4-Chloro-3-pyridylmethyl)-N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(2- pyridyl)amine aa) N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(4-methyl-3-pyridylmethyl)-N-(2- pyridyl)amine bb) 3-Cyclopentyloxy-4-methoxy-N-(2-thiazolylmethyl)diphenylamine cc) N-(2-Chloro-3-pyridylmethyl)-3-cyclopentyloxy-4-methoxydiphenylamine dd)N-(6-Chloro-3-pyridylmethyl)-3-cyclopentyloxy-4-methoxydiphenylamine
EXAMPLE 9 (Method B)
N-4-C__loro-3-pyridylmethyl)-N-(3-cyclopenty_-4- methoxyphenyl)-N-(2-pyridyl)a ine
To a solution of (3-cyclopentyloxy-4-methoxyphenyl)-2-pyridylamine (30 mg, 0.10 mmol) and 4-chloropicolyl chloride hydrochloride (50 mg, 0.25 mmol) was dissolved in DMF (1 mL) and sodium hydride (50 mg of a 60% mineral oil dispersion, 1.3 mmol) was added in small portions. After stirring for lh at room temperature, the mixture was poured into 25 mL ice water. The mixture was extracted with EtOAc (2 x 15 mL) and the EtOAc extracts were combined, washed with brine (15 mL), dried (MgSO4), and concentrated in vacuo. The crude residue was loaded onto a RediSep column (4.2 g, silica gel) and the product was eluted with 15% EtOAc in hexanes to give 20 mg of product as a yellow crystalline solid. 1H ΝMR (CDC13) δ 8.61 (s, IH), 8.34 (d, IH, J = 5.3 Hz), 8.17 (d, IH, 5.0 Hz), 7.33 (m, IH), 7.25 (m, IH), 6.83 (d, IH, J = 8.5), 6.75 (d, IH, J = 8.5), 6.71 (s, IH), 6.62 (m, IH), 6.42 (d, IH, J = 8.6), 5.31 (s, 2H), 4.63 (p, IH, J = 4.12 Hz), 3.83 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H).
The following compounds were prepared in a similar manner as described above:
a) 3,4-Bis(difluoromethoxy)-N-(4-chloro-3-pyridylmethyl)-3'-(2-(tetrahydropyran-2- yl)-2H-tetrazol-5-yl)diphenylamine b) 3,4-Bis(difluoromethoxy)-N-(4-methyl-3-pyridylmethyl)-3'-(2-(tetrahydropyran-2- yl)-2H-tetrazol-5-yl)diphenylamine
EXAMPLE 10 3-Cyclopentyloxy-4-methoxyanilino-N-(3-pyridylmethyl)-N-3-(4-pyridy_)benzamide
To a solution of N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoic acid (20 mg, 0.05 mmol) and pyBOP (40 mg. 0.08 mmol) in CH2C12 (2 mL) at room temperature was added diisopropylethylamine (20 L, 0.11 mmol). After stirring for 15 min, 4-aminopyridine (15 mg, 0.15 mmol) was added and the mixture was allowed to stir 16 h. The mixture was diluted with EtOAc (25 mL) and washed with water (2 x 15 mL) and brine (15 mL), dried (MgSO4),'and concentrated in vacuo. The crude residue was loaded onto a RediSep column (4.2 g, silica gel) and the product was eluted with a linear gradient from 40% EtOAc in hexanes to 60% EtOAc in hexanes over 15 min to give 22 mg of product. Η ΝMR (CDC1 ) δ 8.70-8.40 (m, 3H), 8.24 (s, IH), 7.72 (d, IH, 9.0 Hz), 7.68-7.55 (m, 2H), 7.30-7.20 (m, IH), 6.88 (d, 2H, J = 8.5), 6.80- 6.65 (m, 3H), 4.98 (s, 2H), 4.66 (p, IH, J = 4.1 Hz), 3.86 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H).
The following compounds were prepared in a similar manner as described above:
a) 3-(3-Cyclopentyloxy-4-methoxyanilino)-N-(3-pyridylmethyl)-N-3-[3-(N,N- dimethylamino)prop- 1 -yl]benzamide b) 3-Cyclopentyloxy-4-methoxy-3'-(4-methylpiperazin-l-ylcarbonyl)-N-(3- pyridylmethyl)diphenylamine c) 3-Cyclopentyloxy-4-difluoromethoxy-4'-(4-methylpiperazin-l-ylcarbonyl)-N-(3- pyridylmethyl)diphenylamine d) 3-Cyclopentyloxy-4-methoxy-4'-(4-methylpiperazin-l-ylcarbonyl)-N-(3- pyridylmethyl)-3-(3-tetrahydrofuranyloxy)-diphenylamine
EXAMPLE 11
The following compounds were prepared in a similar fashion as described in Example 2: a) 4'-Amino-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine b) 3'-Amino-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine c) 3'-Amino-3-cyclopropylmethoxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine d) 3 '-Amino-4-methoxy-N-(3-pyridylmethyl)-3-[(3R)- tetrahydrofuryloxyjdiphenylamine
EXAMPLE 12
3-Cyclopentyloxy-4'-methanesulfonylamino-4-methoxy-N-
(3-pyridylmethy_)-diphenyIa_nine
To a solution of 4'-amino-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)- diphenylamine (47 mg, 0.12 mmol) in CH2C1 (2 mL) at room temperature was added pyridine (20 microliters, 0.24 mmol) followed by methanesulfonyl chloride (15 microliters, 0.18 mmol) and the mixture was allowed to stand at room temperature for 16 h. The mixture was diluted with ether (50 mL) and washed with water (25 mL) and brine (25 mL), dried (MgSO4), and concentrated. The crude residue was purified by flash column chromatography (4.2 g RediSep column, silica gel) eluting with a linear gradient from 45%o EtOAc in hexanes to 60% EtOAc in hexanes over 20 min to yield 41 mg of product. 1H ΝMR (CDC13) δ 8.51 (s, IH), 8.41 (d, IH, J = 4.8 Hz), 7.56 (d, IH, 7.9 Hz), 7.16 (m, IH), 6.98 (d, 2H, J = 9.0 Hz), 6.80-6.60 (m, 6H), 4.82 (s, 2H), 4.56 (p, IH, J = 4.0 Hz), 3.75 (s, 3H), 2.86 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H). The following compounds were prepared in a similar manner as described above:
a) 3-Cyclopentyloxy-3 '-ethanesulfonylamino-4-methoxy-N-(3- pyridylmethyl)diphenylamine b) 3-Cyclopentyloxy-4-methoxy-3'-(l-propanesulfonylamino)-N-(3- pyridylmethyl)diphenylamine c) 3 '-(1 -Butanesulfonylamino)-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine d) 3 '-Benzylsulfonylamino-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine e) 3'-Acetamido-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine f) 3 -Cyclopentyloxy-4 ' -ethanesulfonylamino-4-methoxy-N-(3 - pyridylmethyl)diphenylamine g) 3-Cyclopentyloxy-4-methoxy-4'-(l-propanesulfonylamino)-N-(3- pyridylmethyl)diphenylamine h) 3 -Cyclop ropylmethoxy-3 '-ethanesulfonylamino-4-methoxy-N-(3- pyridylmethyl)diphenylamine i) 4-Difluoromethoxy-3'-ethanesulfonylamino-N-(3-pyridylmethyl)-3-[(3R)- tetrahydrofuryloxyjdiphenylamine
EXAMPLE 13 3-Cyciopentyloxy-4-methoxy-3'-hydroxymethyl-N-(3-pyrid-ylmethyl)diphenylamine
To a solution of Ethyl N-(3-cyclopentyloxy-4-methoxyphenyl)-/V-(3- pyridylmethyl)-3-aminobenzoate (50 mg, 0.11 mmol) in THF (5 mL) at 0 °C was added drop-wise, with stirring, 2.5M diisobutylaluminum hydride in toluene (0.4 mL, 1.00 mmol). The mixture was stirred at 0 °C for 1 h and the excess diisobutylaluminum hydride was quenched by adding 5 drops of EtOAc to the mixture. The mixture was concentrated and the residue was partitioned between CH2C12 (50 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with CH2C12 (2 x 10 mL). The organic extracts were combined and washed with brine (50 mL), dried (MgSO4), and concentrated. The crude residue was purified by flash column chromatography (4.2 g RediSep column, silica gel) eluting with 300 mL 50%> EtOAc in hexanes then 100% EtOAc to give 15 mg of product. 1H NMR (CDC13) δ 8.51 (s, IH), 8.40 (br, IH), 7.58 (d, IH, 7.9 Hz), 7.25-7.05 (m, 3H), 6.80-6.60 (m, 5H), 4.85 (s, 2H), 4.56 (p, IH, J = 4.1 Hz), 4.50 (s, 2H), 3.76 (s, 3H), 1.86-1.70 (m, 7H), 1.65-1.45 (m, 2H).
The following compounds were prepared in a similar manner as described above:
a) 3-Cyclopentyloxy-4-methoxy-4'-hydroxymethyl-N-(3-pyridylmethyl)diphenylamine
EXAMPLE 14 3-Cyclopenty_oxy-4-methoxy-N-(3-pyridylι__ethy.)-4'-(2H-tetrazo_-5- yl)diphenylamine
To a solution of N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzonitrile (100 mg, 0.25 mmol) in DMF (3 mL) was added ΝaΝ3 (163 mg, 2.5 mmol) and NH4C1 (135 mg, 2.5 mmol) and the mixture was stirred at 120 °C for 6 h. The mixture was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (2 x 25 mL). The EtOAc extracts were combined, washed with water (25 mL) and brine (25 mL), dried (MgSO4), and concentrated in vacuo. The residue was loaded onto a RediSep column (4.2 g, silica gel) and eluted with a linear gradient from 50% to 75% EtOAc in hexanes to yield 12 mg of product. 1H NMR (CDC13) δ 12.50 (br, IH), 8.64 (s, IH), 8.54 (br, IH), 7.86 (d, 2H, J = 8.8 Hz), 7.75 (d, IH, 7.8 Hz), 7.36 (m, IH), 6.80-6.60 (m, 5H), 4.99 (s, 2H), 4.66 (p, IH, J = 4.1 Hz), 3.84 (s, 3H), 1.86-1.70 (m, 7H), 1.65-1.45 (m, 2H).
EXAMPLE 15
3-Cyclopentyloxy-4-methoxy-4'-(4-methyI-l-piperaziny_methy_)-
N-(3-pyridyImethyl)diphenyla_nine
To a solution of 3-cyclopentyloxy-4-methoxy-4'-(4-methylpiperazin-l- ylcarbonyl)dipheylamine (100 mg, 0.20 mmol) in THF (5 mL) was carefully added, with stirring, lithium aluminum hydride (50 mg, 1.3 mmol). The mixture was stiπed for 15 min and a few drops of EtOAc was carefully added to quench the excess hydride. Water (50 mL) and CH2C12 (50 mL) were added and the mixtures were filtered through Celite. The CH2C12 layer was separated, washed with brine (25 mL), dried (MgSO4), and concentrated in vacuo. The crude residue was purified on an ISCO RediSep column (4.2 g, silica) eluting with a gradient from 5% MeOH in EtOAc to 15% MeOH in EtOAc to yield 60 mg of product as a light yellow oil. 1H NMR (CDC1 ) δ 8.59 (s, IH), 8.47 (d, IH, J = 4.8 Hz), 7.65 (d, IH, 7.9 Hz), 7.21 (dd, IH, J = 4.8 Hz, 7.9 Hz), 7.11 (d, 2H, J = 8.6 Hz), 6.82-6.73 (m, 3H), 6.70-6.65 (m, 2H), 4.91 (s, 2H), 4.62 (p, IH, J = 4.12 Hz),' 3.82 (s, 3H), 3.41 (s, 2H), 2.75-2.20 (m, 8H), 2.27 (s, 3H), 1.86-1.70 ( , 6H), 1.65-1.45 (m, 2H).
The following compounds were prepared in a similar manner as described above:
a) 3-Cyclopentyloxy-4-methoxy-3'-(4-methyl-l-piperazinylmethyl)N-(3- pyridylmethyl)diphenylamine
EXAMPLE 16 3'-Aminomethyl-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethy_)diphenylamine
To a solution of N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzonitrile (50 mg, 0.12 mmol) in THF (5 mL) was carefully added, with stirring, lithium aluminum hydride (20 mg, 0.52 mmol). The mixture was stirred for 4 h and a few drops of water were carefully added to quench the excess hydride. Water (50 mL) and CH2C12 (50 mL) were added and the mixtures were filtered through Celite. The CH2C12 layer was separated, washed with brine (25 mL), dried (MgSO4), and concentrated in vacuo. The crude residue was purified on an ISCO RediSep column (4.2 g, silica) eluting with 10% MeOH in EtOAc to yield 20 mg of product. Η ΝMR (CDCI3) δ 8.60 (s, IH), 8.47 (br, IH), 7.65 (d, IH, 7.8 Hz), 7.26-7.10 (m, 2H), 6.90-6.65 (m, 6H), 4.94 (s, 2H), 4.63 (p, IH, J =,4.1 Hz), 3.83 (s, 3H), 3.75 (m, 2H), 2.29 (br, 2H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H). EXAMPLE 17 3-Hydroxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
To a solution of 3-(tert-butyldimethylsiloxy)-N-(3-pyridylmethyl)-4- methoxydiphenylamine (1.20 g, 2.85 mmol) in THF (40 mL) at 0 °C, was added 1.0M tetrabutylammonium fluoride in THF (10 mL, 10 mmol). The mixture was stirred at 0 °C for 30 min. Water (50 mL) was added and the mixture was extracted with ether (3 x 25 mL). The ether extracts were combined and washed with water (3 x 25 mL) and brine (25 mL), dried (MgSO4), and concentrated in vacuo. The residue was triturated with hexanes and collected by vacuum filtration to give 0.85 g of product. 1H ΝMR (CDCI3) δ 8.58 (s, IH), 8.46 (br, IH), 7.67 (d, IH, 7.8 Hz), 7.26-7.10 (m, 3H), 6.90-6.65 (m, 5H), 6.64 (dd, IH, J = 8.6 Hz, 2.6 Hz), 6.53 (br, IH), 4.92 (s, 2H), 3.86 (s, 3H).
The following compounds were prepared in a similar manner as described above:
a) 3'-Chloro-3-hydroxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine b) Ethyl N-(3-hydroxy-4-methoxyphenyl)-N-(3 -pyridylmethyl)-3-aminobenzoate
EXAMPLE 18 (Method B)
The following compounds were prepared in a similar manner as described in Example IB: a) 3-[3-(4-Chlorophenyl)prop-l-yloxy]-4-methoxy-N-(3-pyridylmethyl)diphenylamine b) 3-[2-(4-Chlorophenyl)ethoxy]-4-methoxy-N-(3-pyridylmethyl)diphenylamine c) 4-Methoxy-3-(4-phenoxybut-l-yl)oxy-N-(3-pyridylmethyl)diphenylamine d) 4-Methoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine e) 4-Methoxy-3-[3-(4-methoxyphenyl)prop-l -yl]oxy-N-(3- pyridylmethyl)diphenylamine f) 4-Methoxy-3-[3-(4-pyridyl)prop-l-yl]oxy-N-(3-pyridylmethyl)diphenylamine g) 4-Methoxy-3-[2-(4-methoxyphenyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine h) 4-Methoxy-3-(4-phenylbut-l-yl)oxy-N-(3-pyridylmethyl)diphenylamine i) 4-Methoxy-3-[4-(4-methoxyphenyl)but-l-yl]oxy-N-(3-pyridylmethyl)diphenylamine j) 4-Methoxy-3-[4-(4-nitrophenyl)but- 1 -yl]oxy-N-(3-pyridylmethyl)diphenylamine k) 4-Methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine
1) 4-Methoxy-3-[2-(4-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine m) 4-Methoxy-3-[3-(2-pyridyl)prop-l-yl]oxy-N-(3-pyridylmethyl)diphenylamine n) 4-Methoxy-3-(2-methoxyethoxy)-N-(3-ρyridylmethyl)diphenylamine o) 3-Cyclopropylmethoxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine p) 4-Methoxy-3-(l-methylpyrrolidin-3-yl)oxy-N-(3-pyridylmethyl)diphenylamine q) 4-Methoxy-3-(l-methylpiperidin-4-yl)oxy-N-(3-pyridylmethyl)diphenylamine r) 4-Methoxy-N-(3-pyridylmethyl)-3-[(3S)-tetrahydrofuryloxy]diphenylamine s) 4-Methoxy-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy]diphenylamine t) 3'-Chloro-4-methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine u) 3'-Chloro-4-methoxy-3-[2-(4-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine v) 3'-Chloro-4-methoxy-3-(2-methoxyethoxy)-N-(3-pyridylmethyl)diphenylamine w) 3 '-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-[(3R)- tetrahydrofuryloxyjdiphenylamine x) 3-Cyclohexyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine y) 3 -Cycloheptyloxy-4-methoxy-N-(3 -pyridylmethyl)diphenylamine z) 3-(2-Cyclopropylethoxy)-4-methoxy-N-(3-pyridylmethyl)diphenylamine aa) 3-Cyclopentylmethoxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine bb) Ethyl N-[3-(4-chlorophenyl)prop-l-yloxy-4-methoxyphenyl]-N-(3-pyridylmethyl)-3- aminobenzoate cc) Ethyl N-(3-cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoate dd) Ethyl N-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoate ee) Ethyl N-[3-(2-indanyloxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoate ff) Ethyl N-[4-methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3- aminobenzoate gg) Ethyl N-[4-methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3- aminobenzoate hh) Ethyl N-[3-(2-methoxyethoxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3- aminobenzoate ii) Ethyl N-[4-methoxy-3-(2-(2-pyridyl)ethyl)oxyphenyl]-N-(3-pyridylmethyl)-3- aminobenzoate
EXAMPLE 18 (Method C)
The following compounds were prepared in a similar manner as described in Example 8A by coupling a phenol with a boronic acid rather than coupling an aniline with a boronic acid: a) 4-Methoxy-3-(4-methoxyphenoxy)-N-(3-pyridylmethyl)diphenylamine b) 4-Methoxy-3-phenoxy-N-(3-pyridylmethyl)diphenylamine c) 4-Methoxy-3-(4-methylphenoxy)-N-(3-pyridylmethyl)diphenylamine d) 3-(4-Chlorophenoxy)-4-methoxy-N-(3-pyridylmethyl)diphenylamine e) 3-[2-(4-Chlorophenyl)ethenyloxy]-4-methoxy-N-(3-pyridylmethyl)diphenylamine
EXAMPLE 19
The following compounds were prepared in a similar manner as described in Example 17: a) 3-Cyclopentyloxy-3'-hydroxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine b) 3-Cyclopentyloxy-4'-hydroxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine c) 3-Cyclopropylmethoxy-4'-hydroxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
EXAMPLE 20 (Method A)
The following compounds were prepared in a similar manner as described in Example IA:
a) 3 '-(2-Bromoethoxy)-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine
EXAMPLE 20 (Method B)
The following compounds were prepared in a similar manner as described in Example IB: a) 3-Cyclopentyloxy-4'-(2-methoxyethoxy)-4-methoxy-N-(3- pyridylmethyl)diphenylamine b) 3-Cyclopentyloxy-4'-(3-methyl- 1 -butoxy)-4-methoxy-N-(3- pyridylmethyl)diphenylamine c) 3 -Cyclopentyloxy-4-methoxy-N-(3 -pyridylmethyl)-4' - [(3S)-tetrahydrofuranyloxy] - diphenylamine d) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-[(3R)-tetrahydrofuranyloxy]- diphenylamine e) 3 -Cyclopentyloxy-4 ' -cyclopropylmethoxy-4-methoxy-N-(3 - pyridylmethyl)diphenylamine f) 4 ' -Cyclohexylethoxy-3 -cyclopentyloxy-4-methoxy-N-(3 - pyridylmethyl)diphenylamine g) 4'-Cyclopentylethoxy-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine h) 3-Cyclopentyloxy-4-methoxy-4'-(l-methylpiperidin-4-yloxy)-N-(3- pyridylmethyl)diphenylamine i) 3-Cyclopentyloxy-4-methoxy-4'-(l-methylpyrrolidin-3-yloxy)-N-(3- pyridylmethyl)diphenylamine j) 3-Cyclopentyloxy-4-methoxy-4'-[2-(l-methylpyπolidin-2-yl)ethoxy]-N-(3- pyridylmethyl)diphenylamine k) 3-Cyclopentyloxy-4-methoxy-4'-[2-(l-pyrrolidinylethoxy)-N-(3- pyridylmethyl)diphenylamine 1) 3-Cyclopentyloxy-4-methoxy-4'-[2-(6-methylpyridyl)methoxy)-N-(3- pyridylmethyl)diphenylamine m) 3-Cyclopentyloxy-4-methoxy-4'-[3-(l-methylpiperidinyl)methoxy]-N-(3- pyridylmethyl)diphenylamine n) 3-Cyclopentyloxy-4-methoxy-4'-[2-(l-methylpiperidinyl)methoxy]-N-(3- pyridylmethyl)diphenylamine o) 3-Cyclopentyloxy-4-methoxy-4'-[2-(5-oxopyrrolidinyl)methoxy]-N-(3- pyridylmethyl)diphenylamine p) 4'-[l-(3-Bromopropyl)oxy]-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine q) 3-Cyclopentyloxy-4-methoxy-4'-[2-(N-phthalimido)ethoxy]-N-(3- pyridylmethyl)diphenylamine
EXAMPLE 21
3-Cyclopenty_oxy-4-methoxy-3'-[2-(l-piperidinyl)ethoxy]-N-(3- pyridylmethyl)diphenylamine
To a solution of 3'-(2-bromoethoxy)-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine (17 mg, 0.03 mmol) in acetonitrile (1 mL) was added potassium carbonate (25 mg, 0.18 mmol) and piperidine (5 μL, 0.05 mmol) and the mixture was stiπed at 60 °C for 4 h. The mixture was partitioned between water (50 mL) and EtOAc (50 mL). The layers were separated and the organic layer was washed with water (25 mL) and brine (25 mL), dried (MgSO4), and concentrated in vacuo. The residue was loaded on an ISCO RediSep column (4.2g, silica) and the column was eluted with a linear gradient from 5%> MeOH in EtOAc to 15%) MeOH in EtOAc to give 11 mg of product. Η ΝMR (CDC13) δ 8.59 (s, IH), 8.48 (d, IH, J = 4.7), 7.64 (d, IH, 8.2 Hz), 7.26-7.20 (m, IH), 7.06 (t, IH, J = 8.6 Hz), 6.81 (d, IH, J = 9.2 Hz), 6.75-6.68 (m, 2H), 6.45-6.35 (m, 3H), 4.91 (s, 2H), 4.64 (p, IH, J = 4.1 Hz), 4.00 (t, 2H, J = 6.2 Hz), 3.84 (s, 3H), 2.71 (t, 2H, J = 6.2 Hz), 2.47 (m, 4H), 1.90-1.70 (m, 6H), 1.86-1.70 (m, 6H), 1.65- 1.45 (m, 2H).
The following compounds were prepared in a similar manner as described above:
a) 3-Cyclopentyloxy-3 '-[2-(l -imidazolyl)ethoxy]-4-methoxy-N-(3- pyridylmethyl)diphenylamine b) 3-Cyclopentyloxy-4-methoxy-3'-[2-(l-methylpiperazin-4-yl)ethoxy]-N-(3- pyridylmethyl)diphenylamine c) 3 -Cyclopentyloxy-4-methoxy-4 ' - [3-(2-methylpiperazin-4-yl)propoxy]-N-(3 - pyridylmethyl)diphenylamine d) 3-Cyclopentyloxy-4-methoxy-4'-[3-(l-methylpiperazin-4-yl)propoxy]-N-(3- pyridylmethyl)diphenylamine e) 3-Cyclopentyloxy-4-methoxy-4'-[3-(2-moφholin-4-ylethylamino)propoxy]-N-(3- pyridylmethyl)diphenylamine f) 4-Methoxy-3-(2-phenoxyethoxy)-N-(3-pyridylmethyl)diphenylamine g) 3-[2-(4-Chlorophenoxy)ethoxy)-4-methoxy-N-(3-pyridylmethyl)diphenylamine h) 4-Methoxy-3-(2-pyrrolidin-l-yl)ethoxy-N-(3-pyridylmethyl)diphenylamine i) 4-Methoxy-3-(2-(4-methylpiperazin- 1 -yl)ethoxy)-N-(3-pyridylmethyl)diphenylamine j) 3-[2-(4-Chlorophenylamino)ethoxy]-4-methoxy-N-(3-pyridylmethyl)diphenylamine
EXAMPLE 22 4'-Aminoethoxy-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine
To a solution of N-(3-ρyridylmethyl)-3'-[2-(2-phthalimido)ethoxy]-3- cyclopentyloxy-4-methoxydiphenylamine (0.39 g, 0.69 mmol) in MeOH (5 mL) was added hydrazine hydrate (1.0 mL, 20 mmol). After 6 h at room temperature, EtOAc was added (50 mL) and the precipitate was filtered off. The filtrate was washed with water (25 mL) and brine (25 mL), dried (MgSO ), and concentrated in vacuo. The residue was loaded on an ISCO RediSep column (10 g, silica). The column was washed with 10% MeOH in EtOAc (200 mL) and the product was eluted with 50% MeOH in EtOAc to yield 0.21 g. 1H ΝMR (CDC13) δ 8.55 (s, IH), 8.42 (d, IH, J = 3.8 Hz), 7.62 (d, IH, 7.7 Hz), 7.20-7.10 (m, IH), 6.91 (d, 2H, J = 9.0 Hz), 6.78 (d, 2H, J = 9.0 Hz), 6.70 (d, IH, J = 8.6 Hz), 6.50-6.35 (m, 2H), 4.82 (s, 2H), 4.54 (p, IH, J = 4.1 Hz), 3.90 (t, 2H, J = 6.1 Hz), 3.74 (s, 3H), 3.01 (m, 2H), 1.86-1.70 (m, 8H), 1.65-1.45 (m, 2H).
EXAMPLE 23
The following compounds were prepared in a similar manner as described in Example 12: a) 3-Cyclopentyloxy-4'-(2-methanesulfonylamino)ethoxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine b) 3-Cyclopenty_oxy-4'-(2-ethanesulfonylam_no)ethoxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine c) 3-Cyclopentyloxy-4-methoxy-4'-[2-(2-propanesulfonylamino)ethoxy]-N-(3- pyridylmethyl)diphenylamine d) 3-Cyclopentyloxy-4-methoxy-4'-[2-(l-propanesulfonylamino)ethoxy]-N-(3- pyridylmethyl)diphenylamine e) 4'-[2-(l-Butanesulfonylamino)ethoxy]-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine
EXAMPLE 24
In Vitro Measurement of Type 4 Phosphodiesterase Inhibition Activity
Human PDE4 was obtained from baculovirus-infected Sf9 cells that expressed the recombinant enzyme. The cDΝA 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 cDΝA encoding other PDE-4 enzymes.
Assay:
Type 4 phosphodiesterases convert cyclic adenosine monophosphate (cAMP) to 5'-adenosine monophosphate (5'-AMP). Νucleotidase 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 MgCl2, 3 uM cAMP, 0.002 U 5'-nucleotidase, and 3 x IO4 cpm of [3H]cAMP. The reaction was stopped by adding 100 μl of boiling 5mN HCI. An aliquot of 75 μl of reaction mixture was transfeπed from each well to alumina columns (Multiplate; Millipore). Labeled adenosine was eluted into an OptiPlate by spinning at 2000 φm for 2 min; 150 μl per well of scintillation fluid was added to the OptiPlate. The plate was sealed, shaken for about 30 min, and cpm of [3H] adenosine was determined using a Wallac Triflux®.
All 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.
A decrease in adenosine concentration is indicative of inhibition of PDE activity.. 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 3H-adenosine concentration. Nonlinear regression software (Assay Explorer®) was used to estimate pIC50 values.
EXAMPLE 25 (Method A)
Passive Avoidance in Rats, an in vivo Test for Learning and Memory
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. During the training, 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.
All data were analyzed by analyses of variance (ANOVA); individual comparisons were made using Kewman-Keuls tests. Naive rats required less than 30 seconds, on average, to cross from the illuminated compartment to the darkened compartment. However, 24 hours after the electric shock exposure, most rats pretreated with vehicle did not re-enter the darkened compartment; the average latency was increased up to 175 seconds (p < 0.001). Pretreatment with MK-801 (0.1 mg/kg) markedly reduced this latency when compared to the vehicle (pO.OOl). This amnesic effect of MK-801 is reversed in a statistically significant manner by actual test compounds in a dose-dependent fashion (e.g., 3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl) diphenylamine, Effective dose range = 0.5 to 2.5 mg/kg, i.p.; and N-(3- cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid, effective dose range = 0.1 to 2.5 mg/kg, ip).
EXAMPLE 25 (Method B)
Radial arm maze task in Rats, an in vivo Test for Learning and Memory
The test was performed as previously described (Zhang, H.-T., Crissman, A.M., Dorairaj, Ν.R., Chandler, L.J., and O'Donnell, J.M., Neuropsychopharmacology, 2000, 23, 198-204.). Five days after initial housing, rats (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. Four parameters were recorded: 1) working memory errors, i.e., entries into baited arms that had already been visited during the same trial; 2) reference memory errors, i.e., entries into unbaked arms; 3) total arm entries; and 4) the test duration (seconds), 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.
All data were analyzed by analyses of variance (ANOVA); individual comparisons were made using Kewman-Keuls tests. Compared to control, MK-801 (0.1 mg/kg, i.p.) increased the frequencies of both working and reference memory eπors (p<0.01). This amnesic effect of MK-801 on working memory is reversed in a statistically significant manner by the administration of actual test compounds in a dose- dependent fashion (e.g., 3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine, Effective dose = 2.5 mg/kg, i.p.; pO.Ol)
The preceding examples can be repeated with similar success by substituting the genetically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
While the invention has been illustrated with respect to the production and of particular compounds, it is apparent that variations and modifications ofthe invention can be made without departing from the spirit or scope ofthe invention.

Claims

What Is Claimed is:
1. A compound of Formula I
wherein:
R1 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 ;
R2 is alkyl having 1 to 12 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano, Cι- -alkoxy, oxo or combinations thereof, and wherein optionally one or more -CH2CH2- groups is replaced in each case by -CH=CH- or -C≡C- ,
cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or combinations thereof,
cycloalkylalkyl having 4 to 16 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, Cι-4-alkyl, Cι-4-alkoxy 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, cyano, or combinations thereof ,
arylalkyl in which the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, which the arylalkyl radical is unsubstituted or is substituted in the aryl portion one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, and wherein in the alkyl portion one or more -CH2CH2- groups are each optionally replaced by -CH=CH- or -C≡C-, and one or more -CH2- groups are each optionally replaced by -O- or -NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof ,
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 , 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, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, or
a heterocyclicalkyl 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 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, OCF3, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, wherein in the alkyl portion one or more -CH2CH2- groups are each optionally replaced by -CH=CH- or -C≡C-, and one or more -CH - groups are each optionally replaced by -O- or -NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof;
is H,
alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, cyano, Cι- -alkoxy, or combinations thereof , 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, Cι-4-alkoxy, cyano or combinations thereof,
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, CF3O, nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl, 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, CF3O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof;
is H,
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, OCF3, amino, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, 2(-heterocycle)tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (eg. tert- butyldimethylsilyloxy), R5-L-, or combinations thereof, 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 hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy, or combinations thereof;
R ,53 is H,
alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times with halogen, Cι-4-alkyl, Cι-4-alkoxy, oxo, or combinations thereof ,
alkylamino or dialkylamino wherein each alkyl portion has independently 1 to 8 carbon atoms,
a partially unsaturated carbocycle-alkyl group wherein the 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, cycloalkyl having 3 to 10 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 ,
cycloalkylalkyl having 4 to 16 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,
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, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or combinations thereof,
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, CF3O, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl,
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, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof , or
a heterocyclicalkyl 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, CF3O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof;
L is a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms wherein one or more -CH2- groups are each optionally replaced by -O-, -S-, -NR6-, -SO2NH-, -NHSO2-, -CO-, -NR6CO-, -CONR6-, -NHCONH-, -OCONH, -NHCOO-, -SCONH-, -SCSNH-, or -NHCSNH-; and
R° is H, or
alkyl having 1 to 8 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, Ci- 4-alkyl, Cι-4-alkoxy, oxo, or combinations thereof;
wherein at least one of R3 and R4 is other than H; and pharmaceutically acceptable salts thereof.
2. A compound according to claim 1, wherein R4 is other than H.
3. A compound according to claim 1, wherein R1 is methyl or CHF2; R2 is alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, heterocycle- alkyl, cycloalkylalkyl, aryl, or heterocychc, in each case substituted or unsubstituted; R3 is H, alkyl, arylalkyl or heteroarylalkyl, in each case substituted or unsubstituted; and R4 is aryl or heteroaryl, in each case substituted or unsubstituted.
4. A compound according to claim 1, wherein R is heteroarylalkyl which is substituted or unsubstituted.
5. A compound according to claim 1, wherein R1 is methyl or CHF2, and R is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or (3R)- tetrahydrofuranyl.
6. A compound according to claim 1, wherein
1 7 1 •
R is methyl or CHF2; R is cyclopentyl; R is heteroarylalkyl, in each case substituted or unsubstituted; and R4 is substituted or unsubstituted aryl or heteroaryl.
7. A compound according to claim 1, wherein
R1 is methyl; R2 is cyclopentyl; R3 is arylalkyl or heteroarylalkyl, in each case substituted or unsubstituted; and R4 is substituted or unsubstituted aryl.
8. A compound according to claim 1 , wherein R is methyl; R is cyclopentyl; and
R3 is heteroarylalkyl which is substituted or unsubstituted.
9. A compound according to claim 1, wherein R is methyl; R2 is cyclopentyl; R3 is heteroarylalkyl which is substituted or unsubstituted; and R is phenyl which is substituted or unsubstituted.
• 1 •
10. A compound according to claim 1 , wherein R is methyl; R is cyclopentyl; R is pyridylmethyl, pyrimidinylmethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl, or pyrazinylmethyl, which in each case is substituted or unsustituted, or methyl, ethyl, or propyl; and R4 is phenyl or phenyl substituted with 1 to 3 substituents.
11. A compound according to claim 1 , wherein R is methyl; R is cyclopentyl; R is pyridylmethyl, pyrimidinylmethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl, pyrazinylmethyl, which in each case is substituted or unsustituted, or methyl, ethyl, or propyl; and R4 is phenyl, naphthyl, biphenyl, pyridyl, pyrimidinyl, thiazolyl, pyrazinyl, quinolinyl, or isoquinolinyl, in each case substituted or unsubstituted.
12. A compound according to claim 1, wherein R1 is methyl or CHF2; R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; R3 is H; and R4 is phenyl, naphthyl, pyridyl, quinolinyl, or isoquinolinyl, which in each case is substituted or unsubstituted.
1 9
13. A compound according to claim 1, R is methyl or CHF2; R is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; R3 is H; and R4 is phenyl which is unsubstituted or substituted by methyl, ethyl, methoxy, CI, F, CF3, vinyl, cyano, amino, carboxy, hydroxymethyl, or ethylsulfonamido, or is 3-pyridyl which is unsubstituted or substituted by carboxy or alkoxycarbonyl.
14. A compound according to claim 1, wherein R1 is methyl; R2 is cyclopentyl; R3 is H; and R4 is phenyl, naphthyl, pyridyl, quinolinyl, or isoquinolinyl, which in each case is substituted or unsubstituted.
15. A compound according to claim 1, wherein R1 is methyl; R2 is cyclopentyl; R3 is H; and R4 is phenyl which is unsubstituted or substituted by methyl, ethyl, methoxy, CI, F, CF3, vinyl, cyano, amino, carboxy, hydroxymethyl, or ethylsulfonamido, or is 3- pyridyl which is unsubstituted or substituted by carboxy or alkoxycarbonyl.
16. A compound according to claim 1, wherein R1 is methyl or CHF2; R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; R3 is benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl, thienylmethyl, pyridylmethyl, quinolinymethyl, isoquinohnylmethyl, thiazolylmethyl, or pyπolylmethyl, which in each case is substituted or unsubstituted; and R is H.
17. A compound according to claim 1, wherein R1 is methyl or CHF2; R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; R3 is pyrazinylmethyl, pyrimidinylmethyl, or pyridylmethyl, which in each is unsubstituted or substituted; and R4 is H.
18. A compound according to claim 1, wherein R1 is methyl; R2 is cyclopentyl; R3 is benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl, thienylmethyl, pyrazinylmethyl, pyrimidinylmethyl, pyridylmethyl, quinolmylmethyl, isoquinohnylmethyl, thiazolylmethyl, or pyrrolylmethyl, which in each case is substituted or unsubstituted; and R4 is H.
19. A compound according to claim 1, wherein R1 is methyl; R2 is cyclopentyl; R is pyrazinylmethyl or pyridylmethyl, which in each is unsubstituted or substituted; and R4 is H.
20. A compound according to claim 1 , wherein said compound is of formula
IV
wherein R and R are as defined, at least one of A, B, and D is N and the others are CH, and R4 is pyridyl or phenyl which is each case is substituted or unsubstituted, and pharmaceutically acceptable salts thereof.
21. A compound according to claim 20, wherein R1 is methyl or CHF2.
22. A compound according to claim 21, wherein B is N.
23 A compound according to claim 20, wherein R1 is methyl or CHF2, and R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl or tetrahydrofuranyl.
24. A compound according to claim 23, wherein B is N.
25. A compound according to claim 19, wherein R1 is methyl or CHF2, and R4 is 3-pyridyl or phenyl, which in each case is substituted or unsubstituted.
26. A compound according to claim 25, wherein B is N.
27. A compound according to claim 20, wherein R1 is methyl or CHF2, R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl or tetrahydrofuranyl, and R4 is 3- pyridyl or phenyl, which in each case is substituted or unsubstituted.
28. A compound according to claim 27, wherein B is N.
29. A compound according to claim 20, wherein R1 is methyl or CHF2, and R4 is phenyl which is substituted in the 3- or 4- position.
30. A compound according to claim 29, wherein B is N.
31. A compound according to claim 19, wherein R1 is methyl or CHF2, R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl, and R4 is phenyl which is substituted in the 3- or 4- position.
32. A compound according to claim 31 , wherein B is N.
33. A compound according to claim 20, wherein R1 is methyl or CHF2, and R4 is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-ethyl-sulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 3-nitro-phenyl, 4-pyridyl, 4-COOH- phenyl, 4-cyano-phenyl, 4-ethyl-sulfonamido-phenyl, 4-tetrazol-5-yl-phenyl, or 4- hydroxymethyl-phenyl.
34. A compound according to claim 33, wherein B is N.
35. A compound according to claim 20, wherein R1 is methyl or CHF2, R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl, and R4 is 3- pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-ethyl-sulfonamido-phenyl, 3- tetrazo 1-5 -yl -phenyl, 3-hydroxymethyl-phenyl, 3-nitro-phenyl, 4-pyridyl, 4-COOH- phenyl, 4-cyano-phenyl, 4-ethyl-sulfonamido-phenyl, 4-tetrazol-5-yl-phenyl, or 4- hydroxymethyl-phenyl.
36. A compound according to claim 35, wherein B is N.
37. A compound according to claim 1, wherein said compound is selected from: a) 3-Cyclopentyloxy-4'-ethyl-4-methoxy-N-(3-pyridylmethyl)diphenylamine b) 3-Cyclopentyloxy-3',4-dimethoxy-N-(3-pyridylmethyl)diphenylamine c) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3'-trifluoromethyldiphenylamine d) 3-Cyclopentyloxy-3'-fluoro-4-methoxy-N-(3-pyridylmethyl)diphenylamine e) 3-Cyclopentyloxy-4'-fluoro-4-methoxy-N-(3-pyridylmethyl)diphenylamine f) 3-Cyclopentyloxy-4-methoxy-3'-phenyl-N-(3-pyridylmethyl)diphenylamine g) 4'-Cyano-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine h) 3-Cyclopentyloxy-4-methoxy-3'-nitro-N-(3-pyridylmethyl)diphenylamine i) 4'-Chloro-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3 '- tri fluoromethyldiphenylamine j) 4-Methoxy-3'-methyl-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine k) 3-Cyclopentyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)diphenylamine 1) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-6-aminonicotinic acid m) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(2-pyrazinyl)-N-(3-pyridylmethyl)amine n) 3 '-Benzylsulfonylamino-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine o) 3-[3-(4-Chlorophenyl)prop-l-yloxy]-4-methoxy-N-(3-pyridylmethyl)diphenylamine p) 4-Methoxy-3-[3-(4-methoxyphenyl)prop-l-yl]oxy-N-(3- pyridylmethyl)diphenylamine q) 4-Methoxy-3-[3-(2-pyridyl)prop-l-yl]oxy-N-(3-pyridylmethyl)diphenylamine r) 3-Cyclopentyloxy-4'-(2-methoxyethoxy)-4-methoxy-N-(3- pyridylmethyl)diphenylamine s) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-[(3R)-tetrahydrofuranyloxy]- diphenylamine t) 3-Cyclopentyloxy-4-methoxy-4'-(l-methylpiperidin-4-yloxy)-N-(3- pyridylmethyl)diphenylamine u) 3-Cyclopentyloxy-4-methoxy-4'-(l-methylpy_τolidin-3-yloxy)-N-(3- pyridylmethyl)diphenylamine v) 3-Cyclopentyloxy-4-methoxy-4'-[2-(l -pyrrolidinylethoxy)-N-(3- pyridylmethyl)diphenylamine w) 3-Cyclopentyloxy-4-methoxy-4'-[2-(6-methylpyridyl)methoxy)-N-(3- pyridylmethyl)diphenylamine x) 3-Cyclopentyloxy-4-methoxy-4'-[2-(l-methylpiperidinyl)methoxy]-N-(3- pyridylmethyl)diphenylamine y) 3-Cyclopentyloxy-4-methoxy-3 '-[2-(l -piperidinyl)ethoxy]-N-(3- pyridylmethyl)diphenylamine z) 3-Cyclopentyloxy-3'-[2-(l-imidazolyl)ethoxy]-4-methoxy-N-(3- pyridylmethyl)diphenylamine aa) 3-Cyclopentyloxy-4-methoxy-4'-[3-(2-methylpiperazin-4-yl)propoxy]-N-(3- pyridylmethyl)diphenylamine bb) 3-Cyclopentyloxy-4-methoxy-4'-[3-(2-moφholin-4-ylethylamino)propoxy]-N-(3- pyridylmethyl)diphenylamine cc) 3-[2-(4-Chlorophenoxy)ethoxy)-4-methoxy-N-(3-pyridylmethyl)diphenylamine dd)3-[2-(4-Chlorophenylamino)ethoxy]-4-methoxy-N-(3-pyridylmethyl)diphenylamine ee) 3-Cyclopentyloxy-4'-(2-methanesulfonylamino)ethoxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine ff) 4'-[2-(l-Butanesulfonylamino)ethoxy]-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diρhenylamine gg) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine hh) 3-Cyclopentyloxy-4-methoxy-3'-methyl-N-(3-pyridylmethyl)diphenylamine ii) 3-Cyclopentyloxy-4-methoxy-4'-methyl-N-(3-pyridylmethyl)diphenylamine jj) 3-Cyclopentylpxy-4-methoxy-4'-nitro-N-(3-pyridylmethyl)diphenylamine kk) 3-Cyclopentyloxy-3',4'-dichloro-4-methoxy-N-(3-pyridylmethyl)diphenylamine
11) 3 ' -Chloro-3 -cyclopentyloxy-4 ' -fluoro-4-methoxy-N-(3 -pyridylmethyl)diphenylamine mm) 3-Cyclopentyloxy-N-(2,6-dichloro-4-pyridylmethyl)-4-methoxydiphenylamine nn) 4-Methoxy-4' -methyl-N-(3 -pyridylmethyl)-3 -(3 -tetrahydrofuryloxy)diphenylamine oo) 4,4'-Dimethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine pp) 3-Indanyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine qq)N-[4-Methoxy-3-(2-(2-pyridyl)ethyl)oxyphenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid π) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(4-isoquinolinyl)-N-(3- pyridylmethyl)amine ss) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-N-(5- pyrimidinyl)amine tt) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(2-pyridyl)-N-(3-pyridylmethyl)amine uu)N-(4-Methoxy-3-(3R)-tetrahydrofuryloxyphenyl)-N-(3-pyridyl)-N-(3- pyridylmethyl)amine w) 3-Cyclopentyloxy-4-methoxyanilino-N-(3-pyridylmethyl)-N-3-(4-pyridyl)benzamide w ) 3-Cyclopentyloxy-4-methoxy-3'-(4-methylpiperazin-l-ylcarbonyl)-N-(3- pyridylmethyl)diphenylamine xx)3-Cyclopentyloxy-4-difluoromethoxy-4'-(4-methylpiperazin-l-ylcarbonyl)-N-(3- pyridylmethyl)diphenylamine yy) 4-Methoxy-4'-(4-methylpiperazin-l-ylcarbonyl)-N-(3-pyridylmethyl)-(3-(3- tetrahydrofuryloxy)diphenylamine zz) 3'-(l-Butanesulfonylamino)-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine aaa) 3'-Acetamido-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine bbb) 4-Methoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine ccc) 4-Methoxy-3-[2-(4-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine ddd) 4-Methoxy-3-(2-methoxyethoxy)-N-(3-pyridylmethyl)diphenylamine eee) 3 -Cyclopropylmethoxy-4-methoxy-N-(3 -pyridylmethyl)diphenylamine fff) 4-Methoxy-N-(3-pyridylmethyl)-3-[(3S)-tetrahydrofuryloxy]diphenylamine ggg) 3'-Chloro-4-methoxy-3-[2-(4-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine hhh) 3-[2-(4-Chlorophenyl)ethenyloxy]-4-methoxy-N-(3-pyridylmethyl)diphenylamine iii) 3-Cyclopentyloxy-3'-hydroxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine jjj) 3-Cyclopentyloxy-4'-hydroxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine kkk) 4'-Cyclohexylethoxy-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine 111) 3-Cyclopentyloxy-4-methoxy-4'-[2-(l-methylpyπolidin-2-yl)ethoxy]-N-(3- pyridylmethyl)diphenylamine mmm) 3-Cyclopentyloxy-4-methoxy-4'-[3-(l-methylpiperidinyl)methoxy]-N-(3- pyridylmethyl)diphenylamine nnn) 3-Cyclopentyloxy-4-methoxy-4'-[3-(l-methylpiperazin-4-yl)propoxy]-N-(3- pyridylmethyl)diphenylamine ooo) 4-Methoxy-3-(2-phenoxyethoxy)-N-(3-pyridylmethyl)diphenylamine ppp) 3-Cyclopentyloxy-4-methoxy-4'-[2-(2-propanesulfonylamino)ethoxy]-N-(3- pyridylmethyl)diphenylamine qqq) 3'-Cyano-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine ιτr) 4 ' -Chloro-3 -eye lopentyloxy-3 ' -fluoro-4-me thoxy-N-(3 -pyridylmethyl)diphenylamine sss) 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3-pyridylmethyl)diphenylamine ttt) 3-Cyclopentyloxy-4-methoxy-4'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-N-(3- pyridylmethyl)diphenylamine uuu) 3-Cyclopentyloxy-4'-methanesulfonylamino-4-methoxy-N-(3-pyridylmethyl)- diphenylamine vw) 3-Cyclopentyloxy-4-methoxy-3 '-hydroxymethyl-N-(3- pyridylmethyl)diphenylamine www) 3 -Cyclopentyloxy-4-methoxy-4 ' -hydroxymethyl-N-(3- pyridylmethyl)diphenylamine xxx) 4-Methoxy-3-[3-(4-pyridyl)prop-l-yl]oxy-N-(3-pyridylmethyl)diphenylamine yyy) 3'-Chloro-4-methoxy-3-(2-methoxyethoxy)-N-(3-pyridylmethyl)diphenylamine zzz) 3 -Cyclopropylmethoxy-4 ' -hydroxy-4-methoxy-N-(3 - pyridylmethyl)diphenylamine aaaa) 3-Cyclopentyloxy-4'-(2-ethanesulfonylamino)ethoxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine bbbb) 3-Cyclopentyloxy-4-methoxy-4'-[2-(l-propanesulfonylamino)ethoxy]-N-(3- pyridylmethyl)diphenylamine cccc) 3'-Chloro-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine dddd) 3 '-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-(3- tetrahydrofuryloxy)diphenylamine eeee) 3'-Cyano-4-methoxy-N-(3-pyridylmethyl)-3-((3R)- tetrahydrofuryloxy)diphenylamine ffff) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine gggg) 3,4-Bis(difluoromethoxy)-N-(3-pyridylmethyl)diphenylamine hhhh) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)- tetrahydrofuryloxy)diphenylamine iiii)3'-Cyano-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)- tetrahydrofuryloxy)diphenylamine jjjj)3'-Chloro-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)- tetrahydrofuryloxy)diphenylamine kkkk) 4'-tert-Butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine llll)N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid mmmm) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4- aminobenzoic acid nnnn) N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoic acid oooo) N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid pppp) N-3,4-Bis(difluoromethoxy)phenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid qqqq) N-[4-methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid rrrr) N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4- aminobenzoic acid ssss) N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoic acid tttt)N-(3-Cyclopentyloxy-4-methoxyphenyl)-3-aminobenzoic acid uuuu) N-[3-(4-Chlorophenyl)prop- 1 -yloxy-4-methoxyphenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid ww) N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoic acid wwww) N-[3-(2-Indanyloxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid xxxx) N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid yyyy) N-[4-Methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid zzzz) N-[3-(2-Methoxyethoxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid aaaaa) 3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H- tetrazol-5-yl)diphenylamine bbbbb) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5- yl)diphenylamine ccccc) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3'-(2H-tetrazol-5- yl)diphenylamine ddddd) 4-Methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4'-(2H-tetrazol-5- yl)diphenylamine eeeee) 3-Cyclopropylniethyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5- yl)diphenylamine fffff) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4'-(2H- tetrazol-5-yl)diphenylamine ggggg) 3-Cyclopentyloxy-4-difluromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5- yl)diphenylamine l_l_l_hh) 3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-3'-(2H- tetrazol-5-yl)diphenylamine iiiii) Bis-3,4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5- yl)diphenylamine jjjjj) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl)amine _d__ ck)N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3- pyridylmethyl)amine 11111) N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3- pyridylmethyl)amine mmmmm) N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-N-(3-pyridyl)-
N-(3-pyridylmethyl)amine nnnnn) 3-Cyclopentyloxy-3 '-ethanesulfonylamino-4-methoxy-N-(3- pyridylmethyl)diphenylamine ooooo) 3-Cyclopentyloxy-4-methoxy-3 '-(1 -propanesulfonylamino)-N-(3- pyridylmethyl)diphenylamine ppppp) 3-Cyclopentyloxy-4'-ethanesulfonylamino-4-methoxy-N-(3- pyridylmethyl)diphenylamine qqqqq) 3-Cyclopentyloxy-4-methoxy-4'-(l-propanesulfonylamino)-N-(3- pyridylmethyl)diphenylamine rrrrr) 3-Cyclopropylmethoxy-3 '-ethanesulfonylamino-4-methoxy-N-(3- pyridylmethyl)diphenylamine sssss) 4-Difluoromethoxy-3'-ethanesulfonylamino-N-(3-pyridylmethyl)-3-[(3R)- tetrahydrofuryloxyjdiphenylamine ttttt) 4-Methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine uuuuu) 4-Methoxy-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy]diphenylamine wwv) 3'-Chloro-4-methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine wwwww) 3'-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-[(3R)- tetrahydrofuryloxyj iphenylamine xxxxx)3-Cyclopentyloxy-4-methoxy-4'-[2-(5-oxopyrrolidinyl)methoxy]-N-(3- pyridylmethyl)diphenylamine; and pharmaceutically acceptable salts thereof.
38. A compound according to claim 1, wherein said compound is selected from: a) 3-Cyclopentyloxy-4-methoxy-N-(3 -pyridylmethyl)diphenylamine b) 3-Cyclopentyloxy-4-methoxy-3'-methyl-N-(3-pyridylmethyl)diphenylamine c) 3-Cyclopentyloxy-4-methoxy-4'-methyl-N-(3-pyridylmethyl)diphenylamine d) 3-Cyclopentyloxy-4-methoxy-4'-nitro-N-(3-pyridylmethyl)diphenylamine e) 3-Cyclopentyloxy-3',4'-dichloro-4-methoxy-N-(3-pyridylmethyl)diphenylamine f) 3'-Chloro-3-cyclopentyloxy-4'-fluoro-4-methoxy-N-(3-pyridylmethyl)diphenylamine g) 3-Cyclopentyloxy-N-(2,6-dichloro-4-pyridylmethyl)-4-methoxydiphenylamine h) 4-Methoxy-4'-methyl-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine i) 4,4'-Dimethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine j) 3-Indanyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine k) N-[4-Methoxy-3-(2-(2-pyridyl)ethyl)oxyphenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid 1) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(4-isoquinolinyl)-N-(3- pyridylmethyl)amine m) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-N-(5- pyrimidinyl)amine n) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(2-pyridyl)-N-(3-pyridylmethyl)amine o) N-(4-Methoxy-3-(3R)-tetrahydrofuryloxyphenyl)-N-(3-pyridyl)-N-(3- pyridylmethyl)amine p) 3-Cyclopentyloxy-4-methoxyanilino-N-(3-pyridylmethyl)-N-3-(4-pyridyl)benzamide q) 3-Cyclopentyloxy-4-methoxy-3'-(4-methylpiperazin-l-ylcarbonyl)-N-(3- pyridylmethyl)diphenylamine r) 3-Cyclopentyloxy-4-difluoromethoxy-4'-(4-methylpiperazin-l-ylcarbonyl)-N-(3- pyridylmethyl)diphenylamine s) 4-Methoxy-4'-(4-methylpiperazin- 1 -ylcarbonyl)-N-(3-pyridylmethyl)-(3-(3- tetrahydrofuryloxy)diphenylamine t) 3 '-(1 -Butanesulfonylamino)-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine u) 3'-Acetamido-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine v) 4-Methoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine w) 4-Methoxy-3-[2-(4-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine x) 4-Methoxy-3-(2-methoxyethoxy)-N-(3-pyridylmethyl)diphenylamine y) 3-Cyclopropylmethoxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine z) 4-Methoxy-N-(3-pyridylmethyl)-3-[(3S)-tetrahydrofuryloxy]diphenylamine aa) 3'-Chloro-4-methoxy-3-[2-(4-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine bb) 3-[2-(4-Chlorophenyl)ethenyloxy]-4-methoxy-N-(3-pyridylmethyl)diphenylamine cc) 3-Cyclopentyloxy-3'-hydroxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine dd) 3-Cyclopentyloxy-4'-hydroxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine ee) 4'-Cyclohexylethoxy-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine ff) 3-Cyclopentyloxy-4-methoxy-4'-[2-(l-methylpyrrolidin-2-yl)ethoxy]-N-(3- pyridylmethyl)diphenylamine gg) 3-Cyclopentyloxy-4-methoxy-4'-[3-(l-methylpiperidinyl)methoxy]-N-(3- pyridylmethyl)diphenylamine hh) 3-Cyclopentyloxy-4-methoxy-4'-[3-(l-methylpiperazin-4-yl)propoxy]-N-(3- pyridylmethyl)diphenylamine ii) 4-Methoxy-3-(2-phenoxyethoxy)-N-(3-pyridylmethyl)diphenylamine jj) 3-Cyclopentyloxy-4-methoxy-4'-[2-(2-propanesulfonylamino)ethoxy]-N-(3- pyridylmethyl)diphenylamine kk) 3'-Cyano-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine 11) 4'-Chloro-3-cyclopentyloxy-3'-fluoro-4-methoxy-N-(3-pyridylmethyl)diphenylamine mm) 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3-pyridylmethyl)diphenylamine nn) 3-Cyclopentyloxy-4-methoxy-4'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-N-(3- pyridylmethyl)diphenylamine oo) 3-Cyclopentyloxy-4'-methanesulfonylamino-4-methoxy-N-(3-pyridylmethyl)- diphenylamine pp) 3-Cyclopentyloxy-4-methoxy-3'-hydroxymethyl-N-(3-pyridylmethyl)diphenylamine qq) 3-Cyclopentyloxy-4-methoxy-4'-hydroxymethyl-N-(3-pyridylmethyl)diphenylamine rr) 4-Methoxy-3-[3-(4-pyridyl)prop- 1 -yl]oxy-N-(3-pyridylmethyl)diphenylamine ss) 3'-Chloro-4-methoxy-3-(2-methoxyethoxy)-N-(3-pyridylmethyl)diphenylamine tt) 3 -Cyclopropylmethoxy-4 ' -hydroxy-4-methoxy-N-(3 -pyridylmethyl)diphenylamine uu) 3-Cyclopentyloxy-4'-(2-ethanesulfonylamino)ethoxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine vv) 3-Cyclopentyloxy-4-methoxy-4'-[2-(l-propanesulfonylamino)ethoxy]-N-(3- pyridylmethyl)diphenylamine ww) 3'-Chloro-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine xx) 3'-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine yy) 3'-Cyano-4-methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)diphenylamine zz) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine aaa) 3,4-Bis(difluoromethoxy)-N-(3-pyridylmethyl)diphenylamine bbb) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)- tetrahydrofuryloxy)diphenylamine ccc) 3 '-Cyano-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)- tetrahydrofuryloxy)diphenylamine ddd) 3'-Chloro-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)- tetrahydrofuryloxy)diphenylamine eee) 4'-tert-Butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine fff)N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid ggg) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid hhh) N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3-
' aminobenzoic acid iii) N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid jjj) N-3,4-Bis(difluoromethoxy)phenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid kkk) N-[4-methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid 111) N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid mmm) N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoic acid nnn) N-(3-Cyclopentyloxy-4-methoxyphenyl)-3-aminobenzoic acid ooo) N-[3-(4-Chlorophenyl)prop-l-yloxy-4-methoxyphenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid ppp) N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoic acid qqq) N-[3-(2-Indanyloxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid πτ) N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid sss) N-[4-Methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid ttt) N-[3-(2-Methoxyethoxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid uuu) 3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H- tetrazol-5-yl)diphenylamine vw) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5- yl)diphenylamine www) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3'-(2H-tetrazol-5- yl)diphenylamine xxx) 4-Methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4'-(2H-tetrazol-5- yl)diphenylamine yyy) 3-Cyclopropylmethyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5- yl)diphenylamine zzz) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4'-(2H- tetrazol-5-yl)diphenylamine aaaa) 3-Cyclopentyloxy-4-difluromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5- yl)diphenylamine bbbb) 3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-3'-(2H- tetrazol-5-yl)diphenylamine cccc) Bis-3,4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5- yl)diphenylamine dddd) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl)amine eeee) N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3- pyridylmethyl)amine ffff) N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3- pyridylmethyl)amine gggg) N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-N-(3-pyridyl)-N-(3- pyridylmethyl)amine hhhh) 3-Cyclopentyloxy-3 '-ethanesulfonylamino-4-methoxy-N-(3- pyridylmethyl)diphenylamine iiii)3-Cyclopentyloxy-4-methoxy-3'-(l-propanesulfonylamino)-N-(3- pyridylmethyl)diphenylamine jjjj)3-Cyclopentyloxy-4'-ethanesulfonylamino-4-methoxy-N-(3- pyridylmethyl)diphenylamine kkkk) 3-Cyclopentyloxy-4-methoxy-4'-(l-propanesulfonylamino)-N-(3- pyridylmethyl)diphenylamine llll)3-Cyclopropylmethoxy-3'-ethanesulfonylamino-4-methoxy-N-(3- pyridylmethyl)diphenylamine mmmm) 4-Difluoromethoxy-3'-ethanesulfonylamino-N-(3-pyridylmethyl)-3-[(3R)- tetrahydrofuryloxy] diphenylamine nnnn) 4-Methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine oooo) 4-Methoxy-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy]diphenylamine pppp) 3'-Chloro-4-methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine qqqq) 3'-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-[(3R)- tetrahydrofuryloxy] diphenylamine rrrr) 3-Cyclopentyloxy-4-methoxy-4'-[2-(5-oxopyrrolidinyl)methoxy]-N-(3- pyridylmethyl)diphenylamine; and pharmaceutically acceptable salts thereof.
39. A compound according to claim 1, wherein said compound is selected from: a) 3'-Cyano-3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine b) 4'-Chloro-3-cyclopentyloxy-3'-fluoro-4-methoxy-N-(3-pyridylmethyl)diphenylamine c) 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3-pyridylmethyl)diphenylamine d) 3-Cyclopentyloxy-4-methoxy-4'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-N-(3- pyridylmethyl)diphenylamine e) 3-Cyclopentyloxy-4'-methanesulfonylamino-4-methoxy-N-(3-pyridylmethyl)- diphenylamine f) 3-Cyclopentyloxy-4-methoxy-3'-hydroxymethyl-N-(3-pyridylmethyl)diphenylamine g) 3-Cyclopentyloxy-4-methoxy-4'-hydroxymethyl-N-(3-pyridylmethyl)diphenylamine h) 4-Methoxy-3-[3-(4-pyridyl)prop-l-yl]oxy-N-(3-pyridylmethyl)diphenylamine i) 3'-Chloro-4-methoxy-3-(2-methoxyethoxy)-N-(3-pyridylmethyl)diphenylamine j) 3-Cyclopropylmethoxy-4'-hydroxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine k) 3-Cyclopentyloxy-4'-(2-ethanesulfonylamino)ethoxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine 1) 3-Cyclopentyloxy-4-methoxy-4'-[2-(l-propanesulfonylamino)ethoxy]-N-(3- pyridylmethyl)diphenylamine m) 3 ' -Chloro-3 -cyclopentyloxy-4-methoxy-N-(3 -pyridylmethyl)diphenylamine n) 3'-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine o) 3'-Cyano-4-methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)diphenylamine p) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine q) 3,4-Bis(difluoromethoxy)-N-(3-pyridylmethyl)diphenylamine r) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)diphenylamine s) 3 '-Cyano-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)- tetrahydrofuryloxy)diphenylamine t) 3 '-Chloro-4-difluoromethoxy-N-(3-ρyridylmethyl)-3-((3R)- tetrahydrofuryloxy)diphenylamine u) 4'-tert-Butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine v) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid w) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid x) N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoic acid y) N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid z) N-3,4-Bis(difluoromethoxy)phenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid aa) N-[4-methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid bb)N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid cc) N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoic acid dd) N-(3-Cyclopentyloxy-4-methoxyphenyl)-3-aminobenzoic acid ee) N-[3-(4-Chlorophenyl)prop-l-yloxy-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-
' aminobenzoic acid ff) N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid gg)N-[3-(2-Indanyloxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid hh)N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid ii) N-[4-Methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid jj) N-[3-(2-Methoxyethoxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid kk) 3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5- yl)diphenylamine 11) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5- yl)diphenylamine mm) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3'-(2H-tetrazol-5- yl)diphenylamine nn) 4-Methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4'-(2H-tetrazol-5- yl)diphenylamine oo) 3-Cyclopropylmethyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5- yl)diphenylamine pp) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4'-(2H-tetrazol-
5 -yl)diphenylamine qq) 3-Cyclopentyloxy-4-difluromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5- yl)diphenylamine rr) 3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-3'-(2H-tetrazol-5- yl)diphenylamine ss) Bis-3,4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl)diphenylamine tt) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl)amine uu)N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3- pyridylmethyl)amine vv)N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3- pyridylmethyl)amine ww) N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-N-(3-pyridyl)-N-(3- pyridylmethyl)amine xx) 3-Cyclopentyloxy-3 '-ethanesulfonylamino-4-methoxy-N-(3- pyridylmethyl)diphenylamine yy) 3-Cyclopentyloxy-4-methoxy-3'-(l-propanesulfonylamino)-N-(3- pyridylmethyl)diphenylamine zz) 3-Cyclopentyloxy-4'-ethanesulfonylamino-4-methoxy-N-(3- pyridylmethyl)diphenylamine aaa) 3-Cyclopentyloxy-4-methoxy-4'-(l-propanesulfonylamino)-N-(3- pyridylmethyl)diphenylamine bbb) 3-Cyclopropylmethoxy-3'-ethanesulfonylamino-4-methoxy-N-(3- pyridylmethyl)diphenylamine ccc) 4-Difluoromethoxy-3'-ethanesulfonylamino-N-(3-pyridylmethyl)-3-[(3R)- tetrahydrofuryloxyjdiphenylamine ddd) 4-Methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine eee) 4-Methoxy-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy]diphenylamine ffϊ) 3 ' -Chloro-4-methoxy-3 -[2-(2-pyridyl)ethoxy] -N-(3 -pyridylmethyl)diphenylamine ggg) 3 '-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-[(3R)- tetrahydrofuryloxyjdiphenylamine hhh) 3-Cyclopentyloxy-4-methoxy-4'-[2-(5-oxopyrrolidinyl)methoxy]-N-(3- pyridylmethyl)diphenylamine; and pharmaceutically acceptable salts thereof.
40. A compound according to claim 1, wherein said compound is selected from: a) 3 '-Chloro-3 -eye lopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine b) 3'-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine c) 3'-Cyano-4-methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)diphenylamine d) 4-Difluoromethoxy-N-(3 -pyridylmethyl)-3 -(3 -tetrahydrofuryloxy)diphenylamine e) 3,4-Bis(difluoromethoxy)-N-(3-pyridylmethyl)diphenylamine f) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)diphenylamine g) 3 '-Cyano-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)- tetrahydrofuryloxy)diphenylamine h) 3 '-Chloro-4-difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)- tetrahydrofuryloxy)diphenylamine i) 4'-tert-Butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-N-(3- pyridylmethyl)diphenylamine j) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid k) N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid 1) N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoic acid m) N-[4-Methoxy-3-(3-tetrahydrofuryloxy)ρhenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid n) N-3,4-Bis(difluoromethoxy)phenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid
no o) N-[4-methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid p) N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid q) N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoic acid r) N-(3-Cyclopentyloxy-4-methoxyphenyl)-3-aminobenzoic acid s) N-[3-(4-Chlorophenyl)prop-l-yloxy-4-methoxyphenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid t) N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid u) N-[3-(2-Indanyloxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid v) N-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid w) N-[4-Methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-N-(3-pyridylmethyl)-3- aminobenzoic acid x) N-[3-(2-Methoxyethoxy)-4-methoxyphenyl]-N-(3-pyridylmethyl)-3-aminobenzoic acid y) 3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5- yl)diphenylamine z) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5- yl)diphenylamine aa) 3-Cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)-3'-(2H-tetrazol-5- yl)diphenylamine bb) 4-Methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4'-(2H-tetrazol-5- yl)diphenylamine cc) 3-Cyclopropylmethyloxy-4-methoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5- yl)diphenylamine dd) 4-Difluoromethoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuryloxy)-4'-(2H-tetrazol-
5-yl)diphenylamine ee) 3-Cyclopentyloxy-4-difluromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5- yl)diphenylamine ff) 3-Cyclopropylmethyloxy-4-difluoromethoxy-N-(3-pyridylmethyl)-3'-(2H-tetrazol-5- yl)diphenylamine gg) Bis-3,4-difluoromethoxy-N-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl)diphenylamine hh)N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl)amine ii) N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridy_)-N-(3- pyridylmethyl)amine jj) N-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-N-(3-pyridyl)-N-(3- pyridylmethyl)amine kk)N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuryloxyphenyl)-N-(3-pyridyl)-N-(3- pyridylmethyl)amine 11) 3-Cyclopentyloxy-3 '-ethanesulfonylamino-4-methoxy-N-(3- pyridylmethyl)diphenylamine mm) 3-Cyclopentyloxy-4-methoxy-3'-(l-propanesulfonylamino)-N-(3- pyridylmethyl)diphenylamine nn) 3 -Cyclopentyloxy-4 ' -ethanesulfonylamino-4-methoxy-N-(3 - pyridylmethyl)diphenylamine oo) 3-Cyclopentyloxy-4-methoxy-4'-(l-propanesulfonylamino)-N-(3- pyridylmethyl)diphenylamine pp) 3-Cyclopropylmethoxy-3'-ethanesulfonylamino-4-methoxy-N-(3- pyridylmethyl)diphenylamine qq) 4-Difluoromethoxy-3'-ethanesulfonylamino-N-(3-pyridylmethyl)-3-[(3R)- tetrahydrofuryloxyjdiphenylamine rr) 4-Methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine ss) 4-Methoxy-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuryloxy]diphenylamine tt) 3'-Chloro-4-methoxy-3-[2-(2-pyridyl)ethoxy]-N-(3-pyridylmethyl)diphenylamine uu) 3 '-Chloro-4-methoxy-N-(3-pyridylmethyl)-3-[(3R)- tetrahydrofuryloxy]diphenylamine vv) 3-Cyclopentyloxy-4-methoxy-4'-[2-(5-oxopyrrolidinyl)methoxy]-N-(3- pyridylmethyl)diphenylamine; and pharmaceutically acceptable salts thereof.
41. A compound according to formula F :
wherein
R1 ' is methoxy, F, CI, CHF2 or CF3;
R2' 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,
alkenyl having 2 to 12 carbon atoms,
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,
a partially unsaturated carbocyclic group having 5 to 14 carbon atoms,
a partially unsaturated carbocyclic group having 5 to 14 carbon atoms which is substituted one or more times by halogen, alkyl, alkyloxy, nitro, cyano, oxo, or combinations thereof,
arylalkyl having 7 to 26 carbon atoms
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;
R3 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;
is -NH-, -NR4'-, -NHCHr, -NR4 CH2-, or -CH2NR4'-; and
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,
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
pharmaceutically acceptable salts thereof.
42. A method for enhancing cognition in a patient in whom such enhancement is desired comprising administering to said patient an effective amount of a compound according to claim 1.
43. A method according to claim 42, wherein said compound is administered in an amount of 0.01-100 mg/kg of body weight/day.
44. A method according to claim 42, wherein said patient is a human.
45. A method of treating a patient suffering from cognition impairment or decline comprising administering to said patient an effective amount of a compound according to claim 1.
46. A method according to claim 45, wherein said patient is a human.
47. A method according to claim 46, wherein said patient is suffering from memory impairment.
48. A method according to claim 45, wherein said compound is administered in an amount of 0.01-100 mg/kg of body weight/day.
49. A method according to claim 47, wherein said patient is suffering from memory impairment due to 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, HIV or cardiovascular disease.
50. A method for treating a patient having a disease involving decreased cAMP levels comprising administering to said patient an effective amount of a compound according to claim 1.
51. A method of inhibiting PDE4 enzyme activity in a patient comprising administering to said patient an effective amount of a compound according to claim 1.
52. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
53. A composition according to claim 51, wherein said composition contains 0.1-50 mg of said compound.
54. A method of treating a patient suffering from memory impairment due to a neurodegenerative disease comprising administering to said patient an effective amount of a compound according to claim 1.
55. A method of treating a patient suffering from memory impairment due to an acute neurodegenerative disorder comprising administering to said patient an effective amount of a compound according to claim 1.
56. A method of treating a patient suffering from an allergic or inflammatory disease comprising administering to said patient an effective amount of a compound according to claim 1.
57. A compound ofthe Formula
wherein:
R1 is H, tert-butydimethylsilyl, 3H3C-, 14CH3-, nCH3- or a phenolic protective group;
R2 is alkyl having 1 to 12 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano, Cι-4-alkoxy, oxo or combinations thereof, and wherein optionally one or more -CH2CH2- groups is replaced in each case by -CH=CH- or -C≡C- ,
cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or combinations thereof,
cycloalkylalkyl having 4 to 16 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, Cι-4-alkyl, Cι-4-alkoxy 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, cyano, or combinations thereof ,
arylalkyl in which the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, which the arylalkyl radical is unsubstituted or is substituted in the aryl portion one or more times by halogen, CF3ι OCF3, alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, and wherein in the alkyl portion one or more -CH2CH2- groups are each optionally replaced by -CH=CH- or -C≡C-, and one or more -CH2- groups are each optionally replaced by -O- or -NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof ,
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 ,
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, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, or
a 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 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, OCF3, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, wherein in the alkyl portion one or more -CH2CH2- groups are each optionally replaced by -CH=CH- or -C≡C-, and one or more -CH2- groups are each optionally replaced by -O- or -NH- and or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof;
is H,
alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, cyano, Cι- -alkoxy, or combinations thereof ,
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, Cι- -alkoxy, cyano or combinations thereof,
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, CF3O, nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl, 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, CF3O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof;
R4 is H,
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, OCF3, amino, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, 2(-heterocycle)tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (eg. tert- butyldimethylsilyloxy), R5-L-, or combinations thereof, 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 hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy R5-L-, dialkylamino-L-, or combinations thereof;
R3 is H,
alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times with halogen, Cι-4-alkyl, Cj-4-alkoxy, oxo, or combinations thereof , alkylamino or dialkylamino wherein each alkyl portion has independently 1 to 8 carbon atoms,
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,
cycloalkyl having 3 to 10 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 ,
cycloalkylalkyl having 4 to 16 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,
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, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or combinations thereof,
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, CF3O, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl,
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, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof , or
a 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, CF3O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof;
L is a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms wherein one or more -CH2- groups are each optionally replaced by -O-, -S-, -NR6-, -SO2NH-, -NHSO2-, -CO-, -NR6CO-, -CONR6-, -NHCONH-, -OCONH, -NHCOO-, -SCONH-, -SCSNH-, or -NHCSNH-; and
R6 is H, or alkyl having 1 to 8 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, C\- 4-alkyl, Cι-4-alkoxy, oxo, or combinations thereof ;
wherein at least one of R3 and R4 is other than H; and pharmaceutically acceptable salts thereof.
58. A compound of the Formula
wherein:
R , ι 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 ;
R is H, tert-butyldimethylsilyloxy- or a phenolic protectibe group;
R3 is H,
alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, cyano, Cι-4-alkoxy, or combinations thereof ,
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, Cι-4-alkoxy, cyano or combinations thereof,
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, CF3O, nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl, 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, CF3O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof;
is H,
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, OCF3, amino, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, 2(-heterocycle)tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (eg. tert- butyldimethylsilyloxy), R5-L-, or combinations thereof, 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 hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy R5-L-, dialkylamino-L-, or combinations thereof;
is H,
alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times with halogen, Cι-4-alkyl, Cι-4-alkoxy, oxo, or combinations thereof ,
alkylamino or dialkylamino wherein each alkyl portion has independently 1 to 8 carbon atoms,
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,
cycloalkyl having 3 to 10 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 ,
cycloalkylalkyl having 4 to 16 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,
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, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or combinations thereof,
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, CF3O, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl,
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, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof , or
a 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, CF3O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof;
is a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms wherein one or more -CH2- groups are each optionally replaced by -O-, -S-, -NR6-, -SO2NH-, -NΗSO2-, -CO-, -NR6CO-, -CONR6-, -NHCONH-, -OCONH, -NHCOO-, -SCONH-, -SCSNH-, or -NHCSNH-; and
R 16° is H, or
alkyl having 1 to 8 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, Q- 4-alkyl, Cι-4-alkoxy, oxo, or combinations thereof ;
wherein at least one of R3 and R4 is other than H; and pharmaceutically acceptable salts thereof.
59. A compound sleeted from: a) 3-Cyclopentyl-4-methoxy-N-(3-pyridylmethyl)aniline; b) 3-tert-Butyldimethylsilyloxy-4-methoxy-N-(3-pyridylmethyl)aniline; c) 3-tert-Butyldimethylsilyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine; d) 3-tert-Butyldimethylsilyloxy-3 '-chloro-4-methoxy-N-(3- pyridylmethyl)diphenylamine e) Ethyl N-(3-tert-butyldimethylsilyloxy-4-methoxyphenyl)-N-(3- pyridylmethyl)-3-aminobenzoate; f) 3-Cyclopentyloxy-4-methoxydiphenylamine; g) 3-Hydroxy-4-methoxy-Ν-(3-pyridylmethyl)diphenylamine; h) 3'-Chloro-3-hydroxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine; i) Ethyl N-(3-hydroxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3- aminobenzoate; j) 3 '-(2-Bromoethoxy)-3-cyclopentyloxy-4-methoxy-Ν-(3- pyridylmethyl)diphenylamine; k) 4 ' - [ 1 -(3 -Bromopropyl)oxy] -3 -cyclopentyloxy-4-methoxy-N-(3 - pyridylmethyl)diphenylamine; and 1) 4-hydroxy-3-cyclopenthloxy-Ν-(3-pyridylmethyl)diphenlamine. ,
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