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US20060154949A1 - Arylindenopyridines and related therapeutic and prophylactic methods - Google Patents

Arylindenopyridines and related therapeutic and prophylactic methods Download PDF

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Publication number
US20060154949A1
US20060154949A1 US11/042,281 US4228105A US2006154949A1 US 20060154949 A1 US20060154949 A1 US 20060154949A1 US 4228105 A US4228105 A US 4228105A US 2006154949 A1 US2006154949 A1 US 2006154949A1
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heteroaryl
alkyl
aryl
group
heterocyclyl
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US11/042,281
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Geoffrey Heintzelman
Kristin Averill
John Dodd
Keith Demarest
Yuting Tang
Paul Jackson
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Priority claimed from US10/123,389 external-priority patent/US6958328B2/en
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Priority to US11/042,281 priority Critical patent/US20060154949A1/en
Priority to US11/148,114 priority patent/US20050239782A1/en
Publication of US20060154949A1 publication Critical patent/US20060154949A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • This invention relates to novel arylindenopyridines and their therapeutic and prophylactic uses.
  • Disorders treated and/or prevented using these compounds include neurodegenerative and movement disorders ameliorated by antagonizing Adenosine A2a receptors and inflammatory and AIDS-related disorders ameliorated by inhibiting phosphodiesterace activity.
  • Adenosine is a purine nucleotide produced by all metabolically active cells within the body. Adenosine exerts its effects via four subtypes of cell-surface receptors (A1, A2a, A2b and A3), which belong to the G protein coupled receptor superfamily (Stiles, G. L. Journal of Biological Chemistry, 1992, 267, 6451). A1 and A3 couple to inhibitory G protein, while A2a and A2b couple to stimulatory G protein. A2a receptors are mainly found in the brain, both in neurons and glial cells (highest level in the striatum and nucleus accumbens, moderate to high level in olfactory tubercle, hypothalamus, and hippocampus etc. regions) (Rosin, D. L.; Robeva, A.; Woodard, R. L.; Guyenet, P. G.; Linden, J. Journal of Comparative Neurology, 1998, 401, 163).
  • A2a receptors are found in platelets, neutrophils, vascular smooth muscle and endothelium (Gessi, S.; Varani, K.; Merighi, S.; Ongini, E.; Borea, P. A. British Journal of Pharmacology, 2000, 129, 2).
  • the striatum is the main brain region for the regulation of motor activity, particularly through its innervation from dopaminergic neurons originating in the substantia nigra.
  • the striatum is the major target of the dopaminergic neuron degeneration in patients with Parkinson's Disease (PD).
  • A2a receptors are co-localized with dopamine D2 receptors, suggesting an important site of for the integration of adenosine and dopamine signaling in the brain (Fink, J. S.; Weaver, D. R.; Rivkees, S. A.; Peterfreund, R. A.; Pollack, A. E.; Adler, E. M.; Reppert, S. M. Brain Research Molecular Brain Research, 1992, 14, 186).
  • A2a knockout mice with genetic blockade of A2a function have been found to be less sensitive to motor impairment and neurochemical changes when they were exposed to neurotoxin MPTP (Chen, J.
  • adenosine A2a receptor blockers may provide a new class of antiparkinsonian agents (Impagnatiello, F.; Bastia, E.; Ongini, E.; Monopoli, A. Emerging Therapeutic Targets, 2000, 4, 635).
  • PDE phosphodiesterases
  • These diseases include conditions such as hypersensitivity, allergy, arthritis, asthma, bee sting, animal bite, bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, premature labor, a urinary tract disorder, inflammatory bowel disease, stroke, erectile dysfunction, HIV/AIDS, cardiovascular disease, gastrointestinal motility disorder, and psoriasis.
  • PDE1 family are activated by calcium-calmodulin; its members include PDE1A and PDE1B, which preferentially hydrolyze cGMP, and PDE1C which exhibits a high affinity for both cAMP and cGMP.
  • PDE2 family is characterized as being specifically stimulated by cGMP.
  • PDE2A is specifically inhibited by erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA).
  • Enzymes in the PDE3 family e.g. PDE3A, PDE3B
  • PDE4 e.g.
  • PDE4A, PDE4B, PDE4C, PDE4D is a cAMP specific PDE present in T-cells, which is involved in inflammatory responses.
  • a PDE3 and/or PDE4 inhibitor would be predicted to have utility in the following disorders: autoimmune disorders (e.g. arthritis), inflammatory bowel disease, bronchial disorders (e.g. asthma), HIV/AIDS, and psoriasis.
  • a PDE5 (e.g. PDE5A) inhibitor would be useful for the treatment of the following disorders: cardiovascular disease and erectile dysfunction.
  • the photoreceptor PDE6 e.g. PDE6A, PDE6B, PDE6C
  • PDE8 family exhibits high affinity for hydrolysis of both cAMP and cGMP but relatively low sensitivity to enzyme inhibitors specific for other PDE families.
  • Phosphodiesterase 7 is a cyclic nucleotide phosphodiesterase that is specific for cyclic adenosine monophosphate (cAMP). PDE7 catalyzes the conversion of cAMP to adenosine monophosphate (AMP) by hydrolyzing the 3′-phosphodiester bond of cAMP. By regulating this conversion, PDE7 allows for non-uniform intracellular distribution of cAMP and thus controls the activation of distinct kinase signalling pathways. PDE7A is primarily expressed in T-cells, and it has been shown that induction of PDE7A is required for T-cell activation (Li, L.; Yee, C.; Beavo, J.
  • PDE7A activation is necessary for T-cell activation, small molecule inhibitors of PDE7 would be useful as immunosuppressants.
  • An inhibitor of PDE7A would be predicted to have immunosuppressive effects with utility in therapeutic areas such as organ transplantation, autoimmune disorders (e.g. arthritis), HIV/AIDS, inflammatory bowel disease, asthma, allergies and psoriasis.
  • This invention provides a compound having the structure of Formula I
  • the invention is directed to compounds of Formula I wherein R 1 , R 3 and R 4 are as described above and R 2 is —NR 15 R 16 wherein R 15 and R 16 are independently selected from hydrogen, optionally substituted C 1-8 straight or branched chain alkyl, arylalkyl, C 3-7 cycloalkyl, aryl, heteroaryl, and heterocyclyl or R 15 and R 16 taken together with the nitrogen form a heteroaryl or heterocyclyl group; with the proviso that when R 2 is NHR 16 , R 1 is not —COOR 6 where R 6 is ethyl.
  • This invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the instant compound and a pharmaceutically acceptable carrier.
  • This invention further provides a method of treating a subject having a condition ameliorated by antagonizing Adenosine A2a receptors or by reducing PDE activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition.
  • This invention further provides a method of preventing a disorder ameliorated by antagonizing Adenosine A2a receptors or by reducing PDE activity in appropriate cells in a subject, comprising administering to the subject a prophylactically effective dose of the compound of claim 1 either preceding or subsequent to an event anticipated to cause a disorder ameliorated by antagonizing Adenosine A2a receptors or reducing PDE activity in appropriate cells in the subject.
  • Compounds of Formula 1 are potent small molecule antagonists of the Adenosine A2a receptors that have demonstrated potency for the antagonism of Adenosine A2a, A1, and A3 receptors.
  • Compounds of Formula I are also potent small molecule phosphodiesterase inhibitors that have demonstrated potency for inhibition of PDE7, PDE5, and PDE4. Some of the compounds of this invention are potent small molecule PDE7 inhibitors which have also demonstrated good selectivity against PDE5 and PDE4.
  • R 1 are COOR 6 , wherein R 6 is selected from H, optionally substituted C 1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl.
  • R 6 is H, or C 1-8 straight or branched chain alkyl which may be optionally substituted with a substituent selected from CN and hydroxy.
  • R 2 are optionally substituted heterocycle, optionally substituted aryl and optionally substituted heteroaryl.
  • Preferred substituents are from one to three members selected from the group consisting of halogen, alkyl, alkoxy, alkoxyphenyl, halo, triflouromethyl, trifluoro or difluoromethoxy, amino, alkylamino, hydroxy, cyano, and nitro.
  • R 2 is optionally substituted furan, phenyl or napthyl or R 2 is optionally substituted with from one to three members selected from the group consisting of halogen, alkyl, hydroxy, cyano, and nitro.
  • R 2 is —NR 15 R 16 .
  • Preferred substituents for R 3 include:
  • R 3 is selected from the group consisting of
  • R 4 include hydrogen, C 1-3 straight or branched chain alkyl, particularly methyl, amine and amino.
  • R 1 is COOR 6 and R 2 is selected from the group consisting of substituted phenyl, and substituted naphthyl or R 2 is NR 15 R 16 .
  • R 1 is COOR 6 where R 6 is alkyl, R 2 is substituted phenyl or naphthyl or R 2 is NR 15 R 16 , and R 3 is selected from the group consisting of H, nitro, amino, NHAc, halo, hydroxy, alkoxy, or a moiety of the formulae: , alkyl(CO)NH—, and R 4 is selected from hydrogen, C 1-3 straight or branched chain alkyl, particularly methyl, and amino.
  • the compound is selected from the group of compounds shown in Table 1 hereinafter.
  • the compound is selected from the following compounds:
  • the instant compounds can be isolated and used as free bases. They can also be isolated and used as pharmaceutically acceptable salts.
  • salts include hydrobromic, hydroiodic, hydrochloric, perchloric, sulfuric, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroethanesulfonic, benzenesulfonic, oxalic, palmoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic and saccharic.
  • This invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the instant compound and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M and preferably 0.05 M phosphate buffer or 0.8% saline.
  • Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, ethanol, alcoholic/aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media.
  • Oral carriers can be elixirs, syrups, capsules, tablets and the like.
  • the typical solid carrier is an inert substance such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like.
  • Parenteral carriers include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils.
  • Intravenous carriers include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose and the like. Preservatives and other additives can also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like. All carriers can be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art.
  • This invention further provides a method of treating a subject having a condition ameliorated by antagonizing Adenosine A2a receptors or by reducing PDE activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition.
  • the disorder is a neurodegenerative or movement disorder.
  • the disorder is an inflammatory disorder.
  • the disorder is an AIDS-related disorder.
  • disorders treatable by the instant pharmaceutical composition include, without limitation, Parkinson's Disease, Huntington's Disease, Multiple System Atrophy, Corticobasal Degeneration, Alzheimer's Disease, Senile Dementia, organ transplantation, autoimmune disorders (e.g. arthritis), immune challenge such as a bee sting, inflammatory bowel disease, bronchial disorders (e.g. asthma), HIV/AIDS, cardiovascular disorder, erectile dysfunction, allergies, and psoriasis.
  • the disorder is rheumatoid arthritis.
  • the disorder is Parkinson's disease.
  • the term “subject” includes, without limitation, any animal or artificially modified animal having a disorder ameliorated by reducing PDE activity in appropriate cells.
  • the subject is a human.
  • the subject is a human.
  • appropriate cells include, by way of example, cells which display PDE activity.
  • appropriate cells include, without limitation, T-lymphocytes, muscle cells, neuro cells, adipose tissue cells, monocytes, macrophages, fibroblasts.
  • Administering the instant pharmaceutical composition can be effected or performed using any of the various methods known to those skilled in the art.
  • the instant compounds can be administered, for example, intravenously, intramuscularly, orally and subcutaneously.
  • the instant pharmaceutical composition is administered orally.
  • administration can comprise giving the subject a plurality of dosages over a suitable period of time. Such administration regimens can be determined according to routine methods.
  • a “therapeutically effective dose” of a pharmaceutical composition is an amount sufficient to stop, reverse or reduce the progression of a disorder.
  • a “prophylactically effective dose” of a pharmaceutical composition is an amount sufficient to prevent a disorder, i.e., eliminate, ameliorate and/or delay the disorder's onset. Methods are known in the art for determining therapeutically and prophylactically effective doses for the instant pharmaceutical composition.
  • the effective dose for administering the pharmaceutical composition to a human for example, can be determined mathematically from the results of animal studies.
  • the therapeutically and/or prophylactically effective dose is a dose sufficient to deliver from about 0.001 mg/kg of body weight to about 200 mg/kg of body weight of the instant pharmaceutical composition. In another embodiment, the therapeutically and/or prophylactically effective dose is a dose sufficient to deliver from about 0.05 mg/kg of body weight to about 50 mg/kg of body weight. More specifically, in one embodiment, oral doses range from about 0.05 mg/kg to about 100 mg/kg daily. In another embodiment, oral doses range from about 0.05 mg/kg to about 50 mg/kg daily, and in a further embodiment, from about 0.05 mg/kg to about 20 mg/kg daily.
  • infusion doses range from about 1.0 ⁇ g/kg/min to about 10 mg/kg/min of inhibitor, admixed with a pharmaceutical carrier over a period ranging from about several minutes to about several days.
  • the instant compound can be combined with a pharmaceutical carrier at a drug/carrier ratio of from about 0.001 to about 0.1.
  • This invention still further provides a method of preventing an inflammatory response in a subject, comprising administering to the subject a prophylactically effective amount of the instant pharmaceutical composition either preceding or subsequent to an event anticipated to cause the inflammatory response in the subject.
  • the event is an insect sting or an animal bite.
  • Alkyl shall mean straight, cyclic and branched-chain alkyl. Unless otherwise stated, the alkyl group will contain 1-20 carbon atoms. Unless otherwise stated, the alkyl group may be optionally substituted with one or more groups such as halogen, OH, CN, mercapto, nitro, amino, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxyl, C 1 -C 8 -alkylthio, C 1 -C 8 -alkyl-amino, di(C 1 -C 8 -alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C 1 -C 8 -alkyl-CO—O—, C 1 -C 8 -alkyl-CO—NH—, carboxamide, hydroxamic acid, sulfonamide, sulfonyl,
  • Alkoxy shall mean —O-alkyl and unless otherwise stated, it will have 1-8 carbon atoms.
  • bioisostere is defined as “groups or molecules which have chemical and physical properties producing broadly similar biological properties.” (Burger's Medicinal Chemistry and Drug Discovery, M. E. Wolff, ed. Fifth Edition, Vol. 1, 1995, Pg. 785).
  • Halogen shall mean fluorine, chlorine, bromine or iodine; “PH” or “Ph” shall mean phenyl; “Ac” shall mean acyl; “Bn” shall mean benzyl.
  • acyl as used herein, whether used alone or as part of a substituent group, means an organic radical having 2 to 6 carbon atoms (branched or straight chain) derived from an organic acid by removal of the hydroxyl group.
  • Ac as used herein, whether used alone or as part of a substituent group, means acetyl.
  • Aryl or “Ar,” whether used alone or as part of a substituent group, is a carbocyclic aromatic radical including, but not limited to, phenyl, 1- or 2-naphthyl and the like.
  • the carbocyclic aromatic radical may be substituted by independent replacement of 1 to 5 of the hydrogen atoms thereon with halogen, OH, CN, mercapto, nitro, amino, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxyl, C 1 -C 8 -alkylthio, C 1 -C 8 -alkyl-amino, di(C 1 -C 8 -alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C 1 -C 8 -alkyl-CO—O—, C 1 -C 8 -alkyl-CO—NH—, or carboxamide.
  • Illustrative aryl radicals include, for example, phenyl, naphthyl, biphenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl, carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl, acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl and the like.
  • “Ph” or “PH” denotes phenyl.
  • heteroaryl refers to a cyclic, fully unsaturated radical having from five to ten ring atoms of which one ring atom is selected from S, O, and N; 0-2 ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon.
  • the radical may be joined to the rest of the molecule via any of the ring atoms.
  • heteroaryl groups include, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrroyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazolyl, triazinyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, indolyl, isothiazolyl, 2-oxazepinyl, azepinyl, N-oxo-pyridyl, 1-dioxothienyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl-N-oxide, benzimidazolyl, benzopyranyl, benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofura
  • the heteroaryl group may be substituted by independent replacement of 1 to 5 of the hydrogen atoms thereon with halogen, OH, CN, mercapto, nitro, amino, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxyl, C 1 -C 8 -alkylthio, C 1 -C 8 -alkyl-amino, di(C 1 -C 8 -alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C 1 -C 8 -alkyl-CO—O—, C 1 -C 8 -alkyl-CO—NH—, or carboxamide.
  • Heteroaryl may be substituted with a mono-oxo to give for example a 4-oxo-1H-quinoline.
  • heterocycle refers to an optionally substituted, fully or partially saturated cyclic group which is, for example, a 4- to 7-membered monocyclic, 7- to 11 -membered bicyclic, or 10- to 15-membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom containing ring.
  • Each ring of the heterocyclic group containing a heteroatom may have 1, 2, or 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized.
  • the nitrogen atoms may optionally be quaternized.
  • the heterocyclic group may be attached at any heteroatom or carbon atom.
  • Exemplary monocyclic heterocyclic groups include pyrrolidinyl; oxetanyl; pyrazolinyl; imidazolinyl; imidazolidinyl; oxazolyl; oxazolidinyl; isoxazolinyl; thiazolidinyl; isothiazolidinyl; tetrahydrofuryl; piperidinyl; piperazinyl; 2-oxopiperazinyl; 2-oxopiperidinyl; 2-oxopyrrolidinyl; 4-piperidonyl; tetrahydropyranyl; tetrahydrothiopyranyl; tetrahydrothiopyranyl sulfone; morpholinyl; thiomorpholinyl; thiomorpholinyl sulfoxide; thiomorpholinyl sulfone; 1,3-dioxolane; dioxanyl; thietanyl; thi
  • bicyclic heterocyclic groups include quinuclidinyl; tetrahydroisoquinolinyl; dihydroisoindolyl; dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl); dihydrobenzofuryl; dihydrobenzothienyl; dihydrobenzothiopyranyl; dihydrobenzothiopyranyl sulfone; dihydrobenzopyranyl; indolinyl; isochromanyl; isoindolinyl; piperonyl; tetrahydroquinolinyl; and the like.
  • Substituted aryl, substituted heteroaryl, and substituted heterocycle may also be substituted with a second substituted-aryl, a second substituted-heteroaryl, or a second substituted-heterocycle to give, for example, a 4-pyrazol-1-yl-phenyl or 4-pyridin-2-yl-phenyl.
  • Designated numbers of carbon atoms shall refer independently to the number of carbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
  • the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more stereogenic centers, they may additionally exist as diastereomers. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
  • Some of the compounds of the present invention may have trans and cis isomers.
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared as a single stereoisomer or in racemic form as a mixture of some possible stereoisomers.
  • the non-racemic forms may be obtained by either synthesis or resolution.
  • the compounds may, for example, be resolved into their components enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation.
  • the compounds may also be resolved by covalent linkage to a chiral auxiliary, followed by chromatographic separation and/or crystallographic separation, and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using chiral chromatography.
  • Representative compounds of the present invention can be synthesized in accordance with the general synthetic methods described below and illustrated in the following general schemes.
  • the products of some schemes can be used as intermediates to produce more than one of the instant compounds.
  • the choice of intermediates to be used to produce subsequent compounds of the present invention is a matter of discretion that is well within the capabilities of those skilled in the art.
  • Benzylidenes 2 may be obtained by known methods (Bullington, J. L; Cameron, J. C.; Davis, J. E.; Dodd, J. H.; Harris, C. A.; Henry, J. R.; Pellegrino-Gensey, J. L.; Rupert, K. C.; Siekierka, J. J. Bioorg. Med. Chem. Lett. 1998, 8, 2489; Petrow, V.; Saper, J.; Sturgeon, B. J. Chem. Soc. 1949, 2134).
  • Hantzsch reaction of the benzylidene compounds with enamines 3 can be performed in refluxing acetic acid (Petrow et al., supra).
  • R 2 is an alkyl group
  • another modification of the Hantzsch may be performed which uses three components (Bocker, R. H.; Buengerich, P. J. Med. Chem. 1986, 29, 1596).
  • R 2 is an alkyl group it is also necessary to perform the oxidation with DDQ or MnO 2 instead of chromium (VI) oxide (Vanden Eynde, J. J.; Delfosse, F.; Mayence, A.; Van Haverbeke, Y. Tetrahedron 1995, 51, 6511).
  • the cyanoethyl esters 5 are prepared as described above.
  • the esters are converted to the carboxylic acids by treatment with sodium hydroxide in acetone and water (Ogawa, T.; Matsumoto, K.; Yokoo, C.; Hatayama, K.; Kitamura, K. J. Chem. Soc., Perkin Trans. 1 1993, 525).
  • the corresponding amides can then be obtained from the acids using standard means.
  • the dihydropyridine lactones 9 can be synthesized from benzylidenes 8 (Zimmer, H.; Hillstrom, W. W.; Schmidt, J. C.; Seemuth, P. D.; Vogeli, R. J. Org. Chem. 1978, 43, 1541) and 1,3-indanedione, as shown in Scheme 5, and the corresponding pyridine is then obtained by oxidation with manganese dioxide.
  • the amines 11 are obtained from the corresponding nitro compounds 10 by reduction with tin (II) chloride (Scheme 6). Reaction of the amines with acetyl chloride provide the amides 12.
  • an alkyl chain with a carboxylic acid at the terminal end can also be added to the amines 11.
  • succinic anhydride Omuaru, V. O. T.; Indian J. Chem., Sect B. 1998, 37, 81
  • ⁇ -propiolactone B.
  • These carboxylic acids are then converted to the hydroxamic acids 14 by treatment with ethyl chloroformate and hydroxylamine (Reddy, A. S.; Kumar, M. S.; Reddy, G. R. Tetrahedron Lett. 2000, 41, 6285).
  • the amines 11 can also be treated with glycolic acid to afford alcohols 15 (Jursic, B. S.; Zdravkovski, Z. Synthetic Comm. 1993, 23, 2761) as shown in Scheme 8.
  • the aminoindenopyridines 11 may also be treated with chloroacetylchloride followed by amines to provide the more elaborate amines 16 (Weissman, S. A.; Lewis, S.; Askin, D.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1998, 39, 7459). Where R 6 is a hydroxyethyl group, the compounds can be further converted to piperazinones 17.
  • the 4-aminoindenopyridines 19 can be synthesized from the 4-chloroindenopyridines 18 using a known procedure (Gorlitzer, K.; Herbig, S.; Walter, R. D. Pharmazie 1997, 504) or via palladium catalyzed coupling (Scheme 10).
  • Cyanoesters 20 can be prepared by known methods (Lee, J.; Gauthier, D.; Rivero, R. A. J. Org. Chem. 1999, 64, 3060). Reaction of 20 with enaminone 21 (Iida, H.; Yuasa, Y.; Kibayashi, C. J. Org. Chem. 1979, 44, 1074) in refluxing 1-propanol and triethylamine gave dihydropyridine 22, wherein R is R 5 or R 6 as described above, (Youssif, S.; El-Bahaie, S.; Nabih, E. J. Chem. Res. ( S ) 1999, 112 and Bhuyan, P.; Borush, R. C.; Sandhu, J. S. J. Org. Chem. 1990, 55, 568), which can then be oxidized and subsequently deprotected to give pyridine 23. II. Specific Compound Syntheses
  • Ligand binding assay of adenosine A2a receptor was performed using plasma membrane of HEK293 cells containing human A2a adenosine receptor (Perkin Elmer, RB-HA2a) and radioligand [ 3 H]CGS21680 (PerkinElmer, NET1021). Assay was set up in 96-well polypropylene plate in total volume of 200 mL by sequentially adding 20 mL 1:20 diluted membrane, 130 mLassay buffer (50 mM Tris.HCl, pH7.4 10 mM MgCl 2 , 1 mM EDTA) containing [ 3 H] CGS21680, 50 mL diluted compound (4 ⁇ ) or vehicle control in assay buffer.
  • mLassay buffer 50 mM Tris.HCl, pH7.4 10 mM MgCl 2 , 1 mM EDTA
  • Nonspecific binding was determined by 80 mM NECA. Reaction was carried out at room temperature for 2 hours beofre filtering through 96-well GF/C filter plate pre-soaked in 50 mM Tris.HCl, pH7.4 containing 0.3% polyethylenimine. Plates were then washed 5 times with cold 50 mM Tris.HCl, pH7.4., dried and sealed at the bottom. Microscintillation fluid 30 ml was added to each well and the top sealed. Plates were counted on Packard Topcount for [ 3 H]. Data was analyzed in Microsoft Excel and GraphPad Prism programs. (Varani, K.; Gessi, S.; Dalpiaz, A.; Borea, P. A. British Journal of Pharmacology, 1996, 117, 1693)
  • CHO-K1 cells overexpressing human adenosine A2a receptors and containing cAMP-inducible beta-galactosidase reporter gene were seeded at 40-50K/well into 96-well tissue culture plates and cultured for two days. On assay day, cells were washed once with 200 mL assay medium (F-12 nutrient mixture/0.1% BSA). For agonist assay, adenosine A2a receptor agonist NECA was subsequently added and cell incubated at 37 C, 5% CO 2 for 5 hrs before stopping reaction. In the case of antagonist assay, cells were incubated with antagonists for 5 minutes at R.T. followed by additon of 50 nM NECA.
  • the assay of phosphodiesterase activity follows the homogeneous SPA (scintillation proximity assay) format under the principle that linear nucleotides preferentially bind yttrium silicate beads in the presence of zinc sulfate.
  • SPA sintillation proximity assay
  • the enzyme converts radioactively tagged cyclic nucleotides (reaction substrate) to linear nucleotides (reaction product) which are selectively captured via ion chelation on a scintillant-containing bead.
  • Radiolabeled product bound to the bead surface results in energy transfer to the bead scintillant and generation of a quantifiable signal. Unbound radiolabel fails to achieve close proximity to the scintillant and therefore does not generate any signal.
  • enzyme was diluted in PDE buffer (50 mM pH 7.4 Tris, 8.3 mM MgCl 2 , 1.7 mM EGTA) with 0.1% ovalbumin such that the final signal:noise (enzyme:no enzyme) ratio is 5-10.
  • Substrate (2,8- 3 H-cAMP or 8- 3 H-cGMP, purchased from Amersham Pharmacia) was diluted in PDE (4, 5, 7A) buffer to 1 nCi per ⁇ l (or 1 ⁇ Ci/ml).
  • the IC 50 values were calculated using the Deltagraph 4-parameter curve-fitting program.
  • the IC 50 and % Inhibition data on PDE 4, 5, and 7A are listed for the indicated compounds in Table 2 below. TABLE 2 MS IC 50 ( ⁇ M)/% inh. @ ⁇ M No.

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Abstract

This invention provides novel arylindenopyridines of the formula:
Figure US20060154949A1-20060713-C00001
 and pharmaceutical compositions comprising same, useful for treating disorders ameliorated by antagonizing Adensine A2a receptors or reducing PDE activity in appropriate cells. This invention also provides therapeutic and prophylactic methods using the instant pharmaceutical compositions.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application is a divisional of co-pending application Ser. No. 10/259,139, filed on Sep. 9, 2002, which is a continuation-in-part of co-pending application Ser. No.10/123,389, filed on Apr. 16, 2002, which claims the benefit of provisional application Ser. No. 60/284,465 filed on Apr. 18, 2001, which are incorporated herein by reference.
    • FIELD OF THE INVENTION
  • This invention relates to novel arylindenopyridines and their therapeutic and prophylactic uses. Disorders treated and/or prevented using these compounds include neurodegenerative and movement disorders ameliorated by antagonizing Adenosine A2a receptors and inflammatory and AIDS-related disorders ameliorated by inhibiting phosphodiesterace activity.
    • BACKGROUND OF THE INVENTION
  • Adenosine A2a Receptors
  • Adenosine is a purine nucleotide produced by all metabolically active cells within the body. Adenosine exerts its effects via four subtypes of cell-surface receptors (A1, A2a, A2b and A3), which belong to the G protein coupled receptor superfamily (Stiles, G. L. Journal of Biological Chemistry, 1992, 267, 6451). A1 and A3 couple to inhibitory G protein, while A2a and A2b couple to stimulatory G protein. A2a receptors are mainly found in the brain, both in neurons and glial cells (highest level in the striatum and nucleus accumbens, moderate to high level in olfactory tubercle, hypothalamus, and hippocampus etc. regions) (Rosin, D. L.; Robeva, A.; Woodard, R. L.; Guyenet, P. G.; Linden, J. Journal of Comparative Neurology, 1998, 401, 163).
  • In peripheral tissues, A2a receptors are found in platelets, neutrophils, vascular smooth muscle and endothelium (Gessi, S.; Varani, K.; Merighi, S.; Ongini, E.; Borea, P. A. British Journal of Pharmacology, 2000, 129, 2). The striatum is the main brain region for the regulation of motor activity, particularly through its innervation from dopaminergic neurons originating in the substantia nigra. The striatum is the major target of the dopaminergic neuron degeneration in patients with Parkinson's Disease (PD). Within the striatum, A2a receptors are co-localized with dopamine D2 receptors, suggesting an important site of for the integration of adenosine and dopamine signaling in the brain (Fink, J. S.; Weaver, D. R.; Rivkees, S. A.; Peterfreund, R. A.; Pollack, A. E.; Adler, E. M.; Reppert, S. M. Brain Research Molecular Brain Research, 1992, 14, 186).
  • Neurochemical studies have shown that activation of A2a receptors reduces the binding affinity of D2 agonist to their receptors. This D2R and A2aR receptor-receptor interaction has been demonstrated in striatal membrane preparations of rats (Ferre, S.; von Euler, G.; Johansson, B.; Fredholm, B. B.; Fuxe, K. Proceedings of the National Academy of Sciences of the United States of America, 1991, 88, 7238) as well as in fibroblast cell lines after transfected with A2aR and D2R cDNAs (Salim, H.; Ferre, S.; Dalal, A.; Peterfreund, R. A.; Fuxe, K.; Vincent, J. D.; Lledo, P. M. Journal of Neurochemistry, 2000, 74, 432). In vivo, pharmacological blockade of A2a receptors using A2a antagonist leads to beneficial effects in dopaminergic neurotoxin MPTP(1-methyl-4-pheny-1,2,3,6-tetrahydropyridine)-induced PD in various species, including mice, rats, and monkeys (Ikeda, K.; Kurokawa, M.; Aoyama, S.; Kuwana, Y. Journal of Neurochemistry, 2002, 80, 262). Furthermore, A2a knockout mice with genetic blockade of A2a function have been found to be less sensitive to motor impairment and neurochemical changes when they were exposed to neurotoxin MPTP (Chen, J. F.; Xu, K.; Petzer, J. P.; Staal, R.; Xu, Y. H.; Beilstein, M.; Sonsalla, P. K.; Castagnoli, K.; Castagnoli, N., Jr.; Schwarzschild, M. A. Journal of Neuroscience, 2001, 21, RC143).
  • In humans, the adenosine receptor antagonist theophylline has been found to produce beneficial effects in PD patients (Mally, J.; Stone, T. W. Journal of the Neurological Sciences, 1995, 132, 129). Consistently, recent epidemiological study has shown that high caffeine consumption makes people less likely to develop PD (Ascherio, A.; Zhang, S. M.; Hernan, M. A.; Kawachi, I.; Colditz, G. A.; Speizer, F. E.; Willett, W. C. Annals of Neurology, 2001, 50, 56). In summary, adenosine A2a receptor blockers may provide a new class of antiparkinsonian agents (Impagnatiello, F.; Bastia, E.; Ongini, E.; Monopoli, A. Emerging Therapeutic Targets, 2000, 4, 635).
  • Phosphodiesterase Inhibitors
  • There are eleven known families of phosphodiesterases (PDE) widely distributed in many cell types and tissues. In their nomenclature, the number indicating the family is followed by a capital letter that indicates a distinct gene. A PDE inhibitor increases the concentration of cAMP in tissue cells, and hence, is useful in the prophylaxis or treatment of various diseases caused by the decrease in cAMP level which is induced by the abnormal metabolism of cAMP. These diseases include conditions such as hypersensitivity, allergy, arthritis, asthma, bee sting, animal bite, bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, premature labor, a urinary tract disorder, inflammatory bowel disease, stroke, erectile dysfunction, HIV/AIDS, cardiovascular disease, gastrointestinal motility disorder, and psoriasis.
  • Among known phosphodiesterases today, PDE1 family are activated by calcium-calmodulin; its members include PDE1A and PDE1B, which preferentially hydrolyze cGMP, and PDE1C which exhibits a high affinity for both cAMP and cGMP. PDE2 family is characterized as being specifically stimulated by cGMP. PDE2A is specifically inhibited by erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA). Enzymes in the PDE3 family (e.g. PDE3A, PDE3B) are specifically inhibited by cGMP. PDE4 (e.g. PDE4A, PDE4B, PDE4C, PDE4D) is a cAMP specific PDE present in T-cells, which is involved in inflammatory responses. A PDE3 and/or PDE4 inhibitor would be predicted to have utility in the following disorders: autoimmune disorders (e.g. arthritis), inflammatory bowel disease, bronchial disorders (e.g. asthma), HIV/AIDS, and psoriasis. A PDE5 (e.g. PDE5A) inhibitor would be useful for the treatment of the following disorders: cardiovascular disease and erectile dysfunction. The photoreceptor PDE6 (e.g. PDE6A, PDE6B, PDE6C) enzymes specifically hydrolyze cGMP. PDE8 family exhibits high affinity for hydrolysis of both cAMP and cGMP but relatively low sensitivity to enzyme inhibitors specific for other PDE families.
  • Phosphodiesterase 7 (PDE7A, PDE7B) is a cyclic nucleotide phosphodiesterase that is specific for cyclic adenosine monophosphate (cAMP). PDE7 catalyzes the conversion of cAMP to adenosine monophosphate (AMP) by hydrolyzing the 3′-phosphodiester bond of cAMP. By regulating this conversion, PDE7 allows for non-uniform intracellular distribution of cAMP and thus controls the activation of distinct kinase signalling pathways. PDE7A is primarily expressed in T-cells, and it has been shown that induction of PDE7A is required for T-cell activation (Li, L.; Yee, C.; Beavo, J. A. Science 1999, 283, 848). Since PDE7A activation is necessary for T-cell activation, small molecule inhibitors of PDE7 would be useful as immunosuppressants. An inhibitor of PDE7A would be predicted to have immunosuppressive effects with utility in therapeutic areas such as organ transplantation, autoimmune disorders (e.g. arthritis), HIV/AIDS, inflammatory bowel disease, asthma, allergies and psoriasis.
  • Few potent inhibitors of PDE7 have been reported. Most inhibitors of other phosphodiesterases have IC50's for PDE7 in the 100 μM range. Recently, Martinez, et al. (J. Med. Chem. 2000, 43, 683) reported a series of PDE7 inhibitors, among which the two best compounds have PDE7 IC50's of 8 and 13 μM. However, these compounds were only 2-3 times selective for PDE7 over PDE4 and PDE3.
  • Finally, the following compounds have been disclosed, and some of them are reported to show antimicrobial activity against strains such as Plasmodium falciparum, Candida albicans and Staphylococcus aureus (Gorlitzer, K.; Herbig, S.; Walter, R. D. Pharmazie 1997, 504):
    Figure US20060154949A1-20060713-C00002
    • SUMMARY OF THE INVENTION
  • This invention provides a compound having the structure of Formula I
    Figure US20060154949A1-20060713-C00003
  • or a pharmaceutically acceptable salt thereof, wherein
      • (a) R1 is selected from the group consisting of:
        • (i) —COR5, wherein R5 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;
        •  wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR20R21 taken together form a heterocycle or heteroaryl;
        • (ii) COOR6, wherein R6 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;
        •  wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR20R21 taken together form a heterocycle or heteroaryl;
        • (iii) cyano;
        • (iv) a lactone or lactam formed with R4;
        • (v) —CONR7R8 wherein R7 and R8 are independently selected from H, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl;
          • wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl groups may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl,
        •  or R7 and R8 taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group;
        • (vi) a carboxylic ester or carboxylic acid bioisostere including optionally substituted heteroaryl groups
      • (b) R2 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl and optionally substituted C3-7 cycloalkyl;
      • (c) R3 is from one to four groups independently selected from the group consisting of:
        • (i) hydrogen, halo, C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C1-8 carboxylate, aryl, heteroaryl, and heterocyclyl;
        • (ii) —NR10R11 wherein R10 and R11 are independently selected from H, C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R10 and R11 taken together with the nitrogen form a heteroaryl or heterocyclyl group;
        • (iii) —NR12COR13 wherein R12 is selected from hydrogen or alkyl and R13 is selected from hydrogen, alkyl, substituted alkyl, C1-3alkoxyl, carboxyalkyl, R30R31N (CH2)p—, R30R31NCO(CH2)p—, aryl, arylalkyl, heteroaryl and heterocyclyl or R12 and R13 taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R30 and R31 are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6, wherein the alkyl group may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl;
      • (d) R4 is selected from the group consisting of (i) hydrogen, (ii) C1-3 straight or branched chain alkyl, (iii) benzyl and (iv) —NR13R14, wherein R13 and R14 are independently selected from hydrogen and C1-6 alkyl;
      •  wherein the C1-3alkyl and benzyl groups are optionally substituted with one or more groups selected from C3-7 cycloalkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C1-8 carboxylate, amino, NR13R14, aryl and heteroaryl; and
      • (e) X is selected from S and O;
  • with the proviso that when R4 is isopropyl, then R3 is not halogen.
  • In an alternative embodiment, the invention is directed to compounds of Formula I wherein R1, R3 and R4 are as described above and R2 is —NR15R16 wherein R15 and R16 are independently selected from hydrogen, optionally substituted C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, aryl, heteroaryl, and heterocyclyl or R15 and R16 taken together with the nitrogen form a heteroaryl or heterocyclyl group; with the proviso that when R2 is NHR16, R1 is not —COOR6 where R6 is ethyl.
  • This invention also provides a pharmaceutical composition comprising the instant compound and a pharmaceutically acceptable carrier.
  • This invention further provides a method of treating a subject having a condition ameliorated by antagonizing Adenosine A2a receptors or by reducing PDE activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition.
  • This invention further provides a method of preventing a disorder ameliorated by antagonizing Adenosine A2a receptors or by reducing PDE activity in appropriate cells in a subject, comprising administering to the subject a prophylactically effective dose of the compound of claim 1 either preceding or subsequent to an event anticipated to cause a disorder ameliorated by antagonizing Adenosine A2a receptors or reducing PDE activity in appropriate cells in the subject.
    • DETAILED DESCRIPTION OF THE INVENTION
  • Compounds of Formula 1 are potent small molecule antagonists of the Adenosine A2a receptors that have demonstrated potency for the antagonism of Adenosine A2a, A1, and A3 receptors.
  • Compounds of Formula I are also potent small molecule phosphodiesterase inhibitors that have demonstrated potency for inhibition of PDE7, PDE5, and PDE4. Some of the compounds of this invention are potent small molecule PDE7 inhibitors which have also demonstrated good selectivity against PDE5 and PDE4.
  • Preferred embodiments for R1 are COOR6, wherein R6 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl. Preferably R6 is H, or C1-8 straight or branched chain alkyl which may be optionally substituted with a substituent selected from CN and hydroxy.
  • Preferred embodiments for R2 are optionally substituted heterocycle, optionally substituted aryl and optionally substituted heteroaryl. Preferred substituents are from one to three members selected from the group consisting of halogen, alkyl, alkoxy, alkoxyphenyl, halo, triflouromethyl, trifluoro or difluoromethoxy, amino, alkylamino, hydroxy, cyano, and nitro. Preferably, R2 is optionally substituted furan, phenyl or napthyl or R2 is
    Figure US20060154949A1-20060713-C00004
    optionally substituted with from one to three members selected from the group consisting of halogen, alkyl, hydroxy, cyano, and nitro. In another embodiment of the instant compound, R2 is —NR15R16.
  • Preferred substituents for R3 include:
        • (i) hydrogen, halo, C1-8 straight or branched chain alkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, and hydroxy;
        • (ii) —NR10R11 wherein R10and R11 are independently selected from H, C1-8 straight or branched chain alkyl, arylC1-8alkyl, C3-7 cycloalkyl, carboxyC1-8alkyl, aryl, heteroaryl, and heterocyclyl or R10 and R11 taken together with the nitrogen form a heteroaryl or heterocyclyl group;
        • (iii) —NR12COR13 wherein R12 is selected from hydrogen or alkyl and R13 is selected from hydrogen, alkyl, substituted alkyl, C1-3alkoxyl, carboxyC1-8alkyl, aryl, arylalkyl, R30R31N (CH2)p—, R30R31NCO(CH2)p—, heteroaryl and heterocyclyl or R12 and R13 taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein , R30 and R31 are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6.
  • Particularly, R3 is selected from the group consisting of
    Figure US20060154949A1-20060713-C00005
  • Preferred embodiments for R4 include hydrogen, C1-3 straight or branched chain alkyl, particularly methyl, amine and amino.
  • In a further embodiment of the instant compound, R1 is COOR6 and R2 is selected from the group consisting of substituted phenyl, and substituted naphthyl or R2 is NR15R16.
  • More particularly, R1 is COOR6 where R6 is alkyl, R2 is substituted phenyl or naphthyl or R2 is NR15R16, and R3 is selected from the group consisting of H, nitro, amino, NHAc, halo, hydroxy, alkoxy, or a moiety of the formulae:
    Figure US20060154949A1-20060713-C00006
    , alkyl(CO)NH—, and R4 is selected from hydrogen, C1-3 straight or branched chain alkyl, particularly methyl, and amino.
  • In a preferred embodiment, the compound is selected from the group of compounds shown in Table 1 hereinafter.
  • More preferably, the compound is selected from the following compounds:
    Figure US20060154949A1-20060713-C00007
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 2-amino-4-(1,3-benzodioxol-5-yl)-5-oxo-, ethyl ester
  • Figure US20060154949A1-20060713-C00008
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(6-bromo-1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester
  • Figure US20060154949A1-20060713-C00009
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-amino-4-(1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester
  • Figure US20060154949A1-20060713-C00010
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(6-bromo-1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, methyl ester
  • Figure US20060154949A1-20060713-C00011
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester
  • Figure US20060154949A1-20060713-C00012
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-(acetylamino)-4-(1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester
  • Figure US20060154949A1-20060713-C00013
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 2-methyl-4-(3-methylphenyl)-5-oxo-, methyl ester
  • Figure US20060154949A1-20060713-C00014
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-amino-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester
  • Figure US20060154949A1-20060713-C00015
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-amino-2-methyl-4-(4-methyl-1-naphthalenyl)-5-oxo-, methyl ester
  • Figure US20060154949A1-20060713-C00016
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-8-nitro-5-oxo-, methyl ester
  • Figure US20060154949A1-20060713-C00017
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7,8-dichloro-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester
  • Figure US20060154949A1-20060713-C00018
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-bromo-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester
  • Figure US20060154949A1-20060713-C00019
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-bromo-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester
  • Figure US20060154949A1-20060713-C00020
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-[(3-carboxy-1-oxopropyl)amino]-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester
  • Figure US20060154949A1-20060713-C00021
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-[(3-carboxy-1-oxopropyl)amino]-2-methyl-4-(4-methyl-1-naphthalenyl)-5-oxo-, methyl ester
  • Figure US20060154949A1-20060713-C00022
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-8-[[4-(hydroxyamino)-1,4-dioxobutyl]amino]-2-methyl-5-oxo-, methyl ester
  • Figure US20060154949A1-20060713-C00023
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-8-[[[(2-hydroxyethyl)amino]acetyl]amino]-2-methyl-5-oxo-, methyl ester
  • Figure US20060154949A1-20060713-C00024
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-[(4-carboxy-1-oxobutyl)amino]-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester
  • Figure US20060154949A1-20060713-C00025
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-8-[[[(2-hydroxyethyl)methylamino]acetyl]amino]-2-methyl-5-oxo-, methyl ester
  • Figure US20060154949A1-20060713-C00026
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-2-methyl-8-[(4-morpholinylacetyl)amino]-5-oxo-, methyl ester
  • Figure US20060154949A1-20060713-C00027
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-2-methyl-5-oxo-8-[(1-piperazinylacetyl)amino]-, methyl ester
  • Figure US20060154949A1-20060713-C00028
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-phenyl-2-amino-5-oxo-, ethyl ester
  • Figure US20060154949A1-20060713-C00029
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(4-methylphenyl)-2-methyl-5-oxo-, methyl ester
  • Figure US20060154949A1-20060713-C00030
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3-bromophenyl)-2-methyl-5-oxo-, methyl ester
  • Figure US20060154949A1-20060713-C00031
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3-bromophenylamino)-2-methyl-5-oxo-, methyl ester
  • Figure US20060154949A1-20060713-C00032
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-phenyl-2-amino-5-oxo-, methyl ester
  • Figure US20060154949A1-20060713-C00033
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(2-furyl)-2-amino-5-oxo-, methyl ester
  • Figure US20060154949A1-20060713-C00034
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3-furyl)-2-amino-5-oxo-, methyl ester
  • Figure US20060154949A1-20060713-C00035
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(2-furyl)-2-amino-5-oxo-, ethyl ester
  • The instant compounds can be isolated and used as free bases. They can also be isolated and used as pharmaceutically acceptable salts. Examples of such salts include hydrobromic, hydroiodic, hydrochloric, perchloric, sulfuric, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroethanesulfonic, benzenesulfonic, oxalic, palmoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic and saccharic.
  • This invention also provides a pharmaceutical composition comprising the instant compound and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M and preferably 0.05 M phosphate buffer or 0.8% saline. Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, ethanol, alcoholic/aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media. Oral carriers can be elixirs, syrups, capsules, tablets and the like. The typical solid carrier is an inert substance such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like. Parenteral carriers include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils. Intravenous carriers include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose and the like. Preservatives and other additives can also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like. All carriers can be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art.
  • This invention further provides a method of treating a subject having a condition ameliorated by antagonizing Adenosine A2a receptors or by reducing PDE activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition.
  • In one embodiment, the disorder is a neurodegenerative or movement disorder. In another embodiment, the disorder is an inflammatory disorder. In still another embodiment, the disorder is an AIDS-related disorder. Examples of disorders treatable by the instant pharmaceutical composition include, without limitation, Parkinson's Disease, Huntington's Disease, Multiple System Atrophy, Corticobasal Degeneration, Alzheimer's Disease, Senile Dementia, organ transplantation, autoimmune disorders (e.g. arthritis), immune challenge such as a bee sting, inflammatory bowel disease, bronchial disorders (e.g. asthma), HIV/AIDS, cardiovascular disorder, erectile dysfunction, allergies, and psoriasis.
  • In one preferred embodiment, the disorder is rheumatoid arthritis.
  • In another preferred embodiment, the disorder is Parkinson's disease.
  • As used herein, the term “subject” includes, without limitation, any animal or artificially modified animal having a disorder ameliorated by reducing PDE activity in appropriate cells. In a preferred embodiment, the subject is a human. In a more preferred embodiment, the subject is a human.
  • As used herein, “appropriate cells” include, by way of example, cells which display PDE activity. Specific examples of appropriate cells include, without limitation, T-lymphocytes, muscle cells, neuro cells, adipose tissue cells, monocytes, macrophages, fibroblasts.
  • Administering the instant pharmaceutical composition can be effected or performed using any of the various methods known to those skilled in the art. The instant compounds can be administered, for example, intravenously, intramuscularly, orally and subcutaneously. In the preferred embodiment, the instant pharmaceutical composition is administered orally. Additionally, administration can comprise giving the subject a plurality of dosages over a suitable period of time. Such administration regimens can be determined according to routine methods.
  • As used herein, a “therapeutically effective dose” of a pharmaceutical composition is an amount sufficient to stop, reverse or reduce the progression of a disorder. A “prophylactically effective dose” of a pharmaceutical composition is an amount sufficient to prevent a disorder, i.e., eliminate, ameliorate and/or delay the disorder's onset. Methods are known in the art for determining therapeutically and prophylactically effective doses for the instant pharmaceutical composition. The effective dose for administering the pharmaceutical composition to a human, for example, can be determined mathematically from the results of animal studies.
  • In one embodiment, the therapeutically and/or prophylactically effective dose is a dose sufficient to deliver from about 0.001 mg/kg of body weight to about 200 mg/kg of body weight of the instant pharmaceutical composition. In another embodiment, the therapeutically and/or prophylactically effective dose is a dose sufficient to deliver from about 0.05 mg/kg of body weight to about 50 mg/kg of body weight. More specifically, in one embodiment, oral doses range from about 0.05 mg/kg to about 100 mg/kg daily. In another embodiment, oral doses range from about 0.05 mg/kg to about 50 mg/kg daily, and in a further embodiment, from about 0.05 mg/kg to about 20 mg/kg daily. In yet another embodiment, infusion doses range from about 1.0 μg/kg/min to about 10 mg/kg/min of inhibitor, admixed with a pharmaceutical carrier over a period ranging from about several minutes to about several days. In a further embodiment, for topical administration, the instant compound can be combined with a pharmaceutical carrier at a drug/carrier ratio of from about 0.001 to about 0.1.
  • This invention still further provides a method of preventing an inflammatory response in a subject, comprising administering to the subject a prophylactically effective amount of the instant pharmaceutical composition either preceding or subsequent to an event anticipated to cause the inflammatory response in the subject. In the preferred embodiment, the event is an insect sting or an animal bite.
  • Definitions and Nomenclature
  • Unless otherwise noted, under standard nomenclature used throughout this disclosure the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment.
  • As used herein, the following chemical terms shall have the meanings as set forth in the following paragraphs: “independently”, when in reference to chemical substituents, shall mean that when more than one substituent exists, the substituents may be the same or different.
  • “Alkyl” shall mean straight, cyclic and branched-chain alkyl. Unless otherwise stated, the alkyl group will contain 1-20 carbon atoms. Unless otherwise stated, the alkyl group may be optionally substituted with one or more groups such as halogen, OH, CN, mercapto, nitro, amino, C1-C8-alkyl, C1-C8-alkoxyl, C1-C8-alkylthio, C1-C8-alkyl-amino, di(C1-C8-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C1-C8-alkyl-CO—O—, C1-C8-alkyl-CO—NH—, carboxamide, hydroxamic acid, sulfonamide, sulfonyl, thiol, aryl, aryl(c1-c8)alkyl, heterocyclyl, and heteroaryl.
  • “Alkoxy” shall mean —O-alkyl and unless otherwise stated, it will have 1-8 carbon atoms.
  • The term “bioisostere” is defined as “groups or molecules which have chemical and physical properties producing broadly similar biological properties.” (Burger's Medicinal Chemistry and Drug Discovery, M. E. Wolff, ed. Fifth Edition, Vol. 1, 1995, Pg. 785).
  • “Halogen” shall mean fluorine, chlorine, bromine or iodine; “PH” or “Ph” shall mean phenyl; “Ac” shall mean acyl; “Bn” shall mean benzyl.
  • The term “acyl” as used herein, whether used alone or as part of a substituent group, means an organic radical having 2 to 6 carbon atoms (branched or straight chain) derived from an organic acid by removal of the hydroxyl group. The term “Ac” as used herein, whether used alone or as part of a substituent group, means acetyl.
  • “Aryl” or “Ar,” whether used alone or as part of a substituent group, is a carbocyclic aromatic radical including, but not limited to, phenyl, 1- or 2-naphthyl and the like. The carbocyclic aromatic radical may be substituted by independent replacement of 1 to 5 of the hydrogen atoms thereon with halogen, OH, CN, mercapto, nitro, amino, C1-C8-alkyl, C1-C8-alkoxyl, C1-C8-alkylthio, C1-C8-alkyl-amino, di(C1-C8-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C1-C8-alkyl-CO—O—, C1-C8-alkyl-CO—NH—, or carboxamide. Illustrative aryl radicals include, for example, phenyl, naphthyl, biphenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl, carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl, acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl and the like. “Ph” or “PH” denotes phenyl.
  • Whether used alone or as part of a substituent group, “heteroaryl” refers to a cyclic, fully unsaturated radical having from five to ten ring atoms of which one ring atom is selected from S, O, and N; 0-2 ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon. The radical may be joined to the rest of the molecule via any of the ring atoms. Exemplary heteroaryl groups include, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrroyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazolyl, triazinyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, indolyl, isothiazolyl, 2-oxazepinyl, azepinyl, N-oxo-pyridyl, 1-dioxothienyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl-N-oxide, benzimidazolyl, benzopyranyl, benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, indazolyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, or furo[2,3-b]pyridinyl), imidazopyridinyl (such as imidazo[4,5-b]pyridinyl or imidazo[4,5-c]pyridinyl), naphthyridinyl, phthalazinyl, purinyl, pyridopyridyl, quinazolinyl, thienofuryl, thienopyridyl, thienothienyl, and furyl. The heteroaryl group may be substituted by independent replacement of 1 to 5 of the hydrogen atoms thereon with halogen, OH, CN, mercapto, nitro, amino, C1-C8-alkyl, C1-C8-alkoxyl, C1-C8-alkylthio, C1-C8-alkyl-amino, di(C1-C8-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C1-C8-alkyl-CO—O—, C1-C8-alkyl-CO—NH—, or carboxamide. Heteroaryl may be substituted with a mono-oxo to give for example a 4-oxo-1H-quinoline.
  • The terms “heterocycle,” “heterocyclic,” and “heterocycle” refer to an optionally substituted, fully or partially saturated cyclic group which is, for example, a 4- to 7-membered monocyclic, 7- to 11 -membered bicyclic, or 10- to 15-membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, or 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized. The nitrogen atoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom.
  • Exemplary monocyclic heterocyclic groups include pyrrolidinyl; oxetanyl; pyrazolinyl; imidazolinyl; imidazolidinyl; oxazolyl; oxazolidinyl; isoxazolinyl; thiazolidinyl; isothiazolidinyl; tetrahydrofuryl; piperidinyl; piperazinyl; 2-oxopiperazinyl; 2-oxopiperidinyl; 2-oxopyrrolidinyl; 4-piperidonyl; tetrahydropyranyl; tetrahydrothiopyranyl; tetrahydrothiopyranyl sulfone; morpholinyl; thiomorpholinyl; thiomorpholinyl sulfoxide; thiomorpholinyl sulfone; 1,3-dioxolane; dioxanyl; thietanyl; thiiranyl; and the like. Exemplary bicyclic heterocyclic groups include quinuclidinyl; tetrahydroisoquinolinyl; dihydroisoindolyl; dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl); dihydrobenzofuryl; dihydrobenzothienyl; dihydrobenzothiopyranyl; dihydrobenzothiopyranyl sulfone; dihydrobenzopyranyl; indolinyl; isochromanyl; isoindolinyl; piperonyl; tetrahydroquinolinyl; and the like.
  • Substituted aryl, substituted heteroaryl, and substituted heterocycle may also be substituted with a second substituted-aryl, a second substituted-heteroaryl, or a second substituted-heterocycle to give, for example, a 4-pyrazol-1-yl-phenyl or 4-pyridin-2-yl-phenyl.
  • Designated numbers of carbon atoms (e.g., C1-8) shall refer independently to the number of carbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
  • Unless specified otherwise, it is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.
  • Where the compounds according to this invention have at least one stereogenic center, they may accordingly exist as enantiomers. Where the compounds possess two or more stereogenic centers, they may additionally exist as diastereomers. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
  • Some of the compounds of the present invention may have trans and cis isomers. In addition, where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared as a single stereoisomer or in racemic form as a mixture of some possible stereoisomers. The non-racemic forms may be obtained by either synthesis or resolution. The compounds may, for example, be resolved into their components enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation. The compounds may also be resolved by covalent linkage to a chiral auxiliary, followed by chromatographic separation and/or crystallographic separation, and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using chiral chromatography.
  • This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that these are only illustrative of the invention as described more fully in the claims which follow thereafter. Additionally, throughout this application, various publications are cited. The disclosure of these publications is hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains.
  • Experimental Details
  • I. General Synthetic Schemes
  • Representative compounds of the present invention can be synthesized in accordance with the general synthetic methods described below and illustrated in the following general schemes. The products of some schemes can be used as intermediates to produce more than one of the instant compounds. The choice of intermediates to be used to produce subsequent compounds of the present invention is a matter of discretion that is well within the capabilities of those skilled in the art.
    Figure US20060154949A1-20060713-C00036
  • Procedures described in Scheme 1, wherein R3a, R3b, R3c, and R3d are independently any R3 group, and R1, R2, R3, and R4 are as described above, can be used to prepare compounds of the invention wherein X is O.
  • Benzylidenes 2 may be obtained by known methods (Bullington, J. L; Cameron, J. C.; Davis, J. E.; Dodd, J. H.; Harris, C. A.; Henry, J. R.; Pellegrino-Gensey, J. L.; Rupert, K. C.; Siekierka, J. J. Bioorg. Med. Chem. Lett. 1998, 8, 2489; Petrow, V.; Saper, J.; Sturgeon, B. J. Chem. Soc. 1949, 2134). Hantzsch reaction of the benzylidene compounds with enamines 3 can be performed in refluxing acetic acid (Petrow et al., supra). When the desired enamines are not available, alternate Hantzsch conditions may be utilized which involve adding ammonium acetate to the reaction. The resulting dihydropyridines 4 are oxidized with chromium trioxide to obtain the desired pyridines 1 (Petrow et al., supra). In cases where the substitution pattern on the fused aromatic ring (R3) leads to a mixture of regioisomers, the products can be separated by column chromatography.
  • In some cases, especially where R2 is an alkyl group, another modification of the Hantzsch may be performed which uses three components (Bocker, R. H.; Buengerich, P. J. Med. Chem. 1986, 29, 1596). Where R2 is an alkyl group it is also necessary to perform the oxidation with DDQ or MnO2 instead of chromium (VI) oxide (Vanden Eynde, J. J.; Delfosse, F.; Mayence, A.; Van Haverbeke, Y. Tetrahedron 1995, 51, 6511).
    Figure US20060154949A1-20060713-C00037
  • In order to obtain the corresponding carboxylic acids and amides, the cyanoethyl esters 5 are prepared as described above. The esters are converted to the carboxylic acids by treatment with sodium hydroxide in acetone and water (Ogawa, T.; Matsumoto, K.; Yokoo, C.; Hatayama, K.; Kitamura, K. J. Chem. Soc., Perkin Trans. 1 1993, 525). The corresponding amides can then be obtained from the acids using standard means.
    Figure US20060154949A1-20060713-C00038
  • The procedure for making compounds where R4 is NH2 may be slightly modified. These compounds are prepared in one step from the benzylidenes 2 and alkyl amidinoacetate (Kobayashi, T.; Inoue, T.; Kita, Z.; Yoshiya, H.; Nishino, S.; Oizumi, K.; Kimura, T. Chem. Pharm. Bull. 1995, 43, 788) as depicted in Scheme 4 wherein R is R5 or R6 as described above.
    Figure US20060154949A1-20060713-C00039
  • The dihydropyridine lactones 9 can be synthesized from benzylidenes 8 (Zimmer, H.; Hillstrom, W. W.; Schmidt, J. C.; Seemuth, P. D.; Vogeli, R. J. Org. Chem. 1978, 43, 1541) and 1,3-indanedione, as shown in Scheme 5, and the corresponding pyridine is then obtained by oxidation with manganese dioxide.
    Figure US20060154949A1-20060713-C00040
  • Representative schemes to modify substituents on the fused aromatic ring are shown below. The amines 11 are obtained from the corresponding nitro compounds 10 by reduction with tin (II) chloride (Scheme 6). Reaction of the amines with acetyl chloride provide the amides 12.
    Figure US20060154949A1-20060713-C00041
  • In accordance with Scheme 7 wherein Y is O, and n is an integer from 1-3, an alkyl chain with a carboxylic acid at the terminal end can also be added to the amines 11. For example, reaction with either succinic anhydride (Omuaru, V. O. T.; Indian J. Chem., Sect B. 1998, 37, 814) or β-propiolactone (Bradley, G.; Clark, J.; Kernick, W. J. Chem. Soc., Perkin Trans. 1 1972, 2019) can provide the corresponding carboxylic acids 13. These carboxylic acids are then converted to the hydroxamic acids 14 by treatment with ethyl chloroformate and hydroxylamine (Reddy, A. S.; Kumar, M. S.; Reddy, G. R. Tetrahedron Lett. 2000, 41, 6285).
    Figure US20060154949A1-20060713-C00042
  • The amines 11 can also be treated with glycolic acid to afford alcohols 15 (Jursic, B. S.; Zdravkovski, Z. Synthetic Comm. 1993, 23, 2761) as shown in Scheme 8.
    Figure US20060154949A1-20060713-C00043
  • As shown in Scheme 9, the aminoindenopyridines 11 may also be treated with chloroacetylchloride followed by amines to provide the more elaborate amines 16 (Weissman, S. A.; Lewis, S.; Askin, D.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1998, 39, 7459). Where R6 is a hydroxyethyl group, the compounds can be further converted to piperazinones 17.
    Figure US20060154949A1-20060713-C00044
  • The 4-aminoindenopyridines 19 can be synthesized from the 4-chloroindenopyridines 18 using a known procedure (Gorlitzer, K.; Herbig, S.; Walter, R. D. Pharmazie 1997, 504) or via palladium catalyzed coupling (Scheme 10).
    Figure US20060154949A1-20060713-C00045
  • Cyanoesters 20 can be prepared by known methods (Lee, J.; Gauthier, D.; Rivero, R. A. J. Org. Chem. 1999, 64, 3060). Reaction of 20 with enaminone 21 (Iida, H.; Yuasa, Y.; Kibayashi, C. J. Org. Chem. 1979, 44, 1074) in refluxing 1-propanol and triethylamine gave dihydropyridine 22, wherein R is R5 or R6 as described above, (Youssif, S.; El-Bahaie, S.; Nabih, E. J. Chem. Res. (S) 1999, 112 and Bhuyan, P.; Borush, R. C.; Sandhu, J. S. J. Org. Chem. 1990, 55, 568), which can then be oxidized and subsequently deprotected to give pyridine 23.
    Figure US20060154949A1-20060713-C00046
    II. Specific Compound Syntheses
  • Specific compounds which are representative of this invention can be prepared as per the following examples. No attempt has been made to optimize the yields obtained in these reactions. Based on the following, however, one skilled in the art would know how to increase yields through routine variations in reaction times, temperatures, solvents and/or reagents.
  • The products of certain syntheses can be used as intermediates to produce more than one of the instant compounds. In those cases, the choice of intermediates to be used to produce compounds of the present invention is a matter of discretion that is well within the capabilities of those skilled in the art.
    • EXAMPLE 1 Hantzsch Condensation to Form Dihydropyridine 4 (R1=COOMe; R2=3,5-dimethylphenyl; R3b,c=Cl; R3a,b=H; R4=Me)
  • To a refluxing solution of benzylidene 2 (0.500 g, 1.5 mmol) in acetic acid (10 mL) was added methyl-3-aminocrotonate (0.695 g, 6.0 mmol). The reaction was heated to reflux for 20 minutes, then water was added until a precipitate started to form. The reaction was cooled to room temperature. The mixture was filtered and washed with water to obtain 0.354 g (55%) of a red solid. MS m/z 450 (M++23), 428 (M++1).
    • EXAMPLE 2 Alternate Hantzsch Conditions to Form Dihydropyridine 4 (R1=CO2Me; R2=2,4-dimethylphenyl; R3=H; R4=Et)
  • To a refluxing solution of benzylidene 2 (1.00 g, 3.82 mmol) in acetic acid (12 Ml) was added methyl propionylacetate (1.98 g, 15.2 mmol) and ammonium acetate (1.17 g, 15.2 mmol). The reaction was heated for 20 min and then cooled to room temperature. No product precipitated from the solution, so the reaction was heated to reflux and then water was added until a solid began to precipitate. After cooling to room temperature, the mixture was filtered and the red solid washed with water to yield 1.29 g (90%) of product. MS m/z 396 (M++23), 374 (M++1).
    • EXAMPLE 3 Oxidation of Dihydropyridine 4 to Pyridine 1 (R1=COOMe; R2=3,5-dimethylphenyl; R3b,c=Cl; R3a,d =H; R 4=Me)
  • To a refluxing solution of dihydropyridine 4 (0.250 g, 0.58 mmol) in acetic acid (10 mL) was added a solution of chromium (VI) oxide (0.584 g, 0.58 mmol) in 1 mL water. After 30 minutes at reflux, the reaction was diluted with water until a precipitate started to form. The mixture was cooled to room temperature and allowed to stand overnight. The mixture was filtered and washed with water to give 0.199 g (81%) of a yellow solid. MS m/z 448 (M++23), 426 (M++1).
    • EXAMPLE 4 Oxidation of Dihydropyridine 4 to Pyridine 1 (R1=COOMe; R2=(4-methyl)-1-naphthyl; R3b,c=H, NO2/NO2, H; R=Me)
  • To a refluxing suspension of regioisomeric dihydropyridines 4 (3.59 g, 8.16 mmol) in acetic acid (40 mL) was added a solution of chromium (VI) oxide (0.816 g, 8.16 mmol) in 3 mL water. After 20 minutes at reflux, the reaction was diluted with water until a precipitate started to form. The mixture was cooled to room temperature and allowed to stand overnight. The mixture was filtered and washed with water to yield the mixture of regioisomers as a yellow solid. The products were purified by column chromatography eluting with hexanes:ethyl acetate to yield 1.303 g (37%) of pyridine 1 (R3b=NO2; R3c=H) and 0.765 g (21%) of its regioisomer (R3b=H: R3c=NO2). MS m/z 461 (M++23), 439 (M++1).
    • EXAMPLE 5 Alternate Three Component Hantzsch Reaction to Form Dihydropyridine 4 (R1=CO2Me; R2=cyclohexyl; R3=H; R4=Me)
  • Cyclohexane carboxaldehyde (2.0 g, 17.8 mmol), 1,3-indandione (2.6 g, 17.8 mmol), methylacetoacetate (2.0 g, 17.8 mmol), and ammonium hydroxide (1 mL) were refluxed in 8 mL of methanol for 1.5 hours. The temperature was lowered to approximately 50° C. and the reaction was stirred overnight. The reaction was cooled to room temperature, filtered and the solid washed with water. The residue was then dissolved in hot ethanol and filtered while hot. The filtrate was concentrated to yield 4.1 g (68%) of the product which was used without purification. MS m/z 336 (M−−1).
    • EXAMPLE 6 DDQ Oxidation of Dihydropyridine 4 (R1=CO2Me; R2=cyclohexyl; R3=H; R4=Me)
  • To a solution of dihydropyridine 4 (2.50 g, 7.40 mmol) in 15 mL of dichloromethane was added 2,3-dichloro-3,6-dicyano-1,4-benzoquinone (1.70 g, 7.40 mmol). The reaction was stirred at room temperature for four hours. The mixture was filtered and the residue was washed with dichloromethane. After the filtrate was concentrated, the residue was purified by column chromatography eluting with ethyl acetate: hexanes to yield 0.565 g (23%) of a yellow solid. MS m/z 358 (M++23), 336 (M++1).
    • EXAMPLE 7 MnO2 Oxidation of Dihydropyridine 4 (R1=CO2Me; R2=4-(dimethylamino)phenyl; R3=H; R4=Me)
  • To a solution of dihydropyridine 4 (0.50 g, 1.3 mmol) in 10 mL of dichloromethane was added manganese dioxide (2.5 g, 28.7 mmol). The reaction was stirred at room temperature overnight before filtering and washing with dichloromethane. The filtrate was concentrated to yield 0.43 g (88%) of orange solid 1. MS m/z 395 (M++23), 373 (M++1).
    • EXAMPLE 8 Cleavage of Carboxylic Ester 5 (R2=2,4-dimethylphenyl; R3=H; R4=Me)
  • To a suspension of ester 5 (2.75 g, 6.94 mmol) in acetone (50 mL) was added aqueous 1 M NaOH (100 mL). After stirring at room temperature for 24 hours, the reaction mixture was diluted with 100 mL of water and washed with dichloromethane (2×100 mL). The aqueous layer was cooled to 0° C. and acidified with concentrated HCl. The mixture was filtered and washed with water to yield 1.84 g (77%) yellow solid 6. MS m/z 366 (M++23), 343 (M++1).
    • EXAMPLE 9 Preparation of Amide 7 (R2=2,4-dimethylphenyl; R3=H; R4=Me; R5=H; R6=Me)
  • A solution of carboxylic acid 6 (0.337 g, 0.98 mmol) in thionyl chloride (10 mL) was heated at reflux for 1 hour. The solution was cooled and concentrated in vacuo. The residue was diluted with CCl4 and concentrated to remove the residual thionyl chloride. The residue was then dissolved in THF (3.5 mL) and added to a 0° C. solution of methylamine (1.47 mL of 2.0 M solution in THF, 2.94 mmol) in 6.5 mL THF. The reaction was warmed to room temperature and stirred overnight. The mixture was poured into water, filtered, washed with water and dried to yield 0.263 g (75%) of tan solid. MS m/z 357 (M++1).
    • EXAMPLE 10 Preparation of Pyridine 1 (R1=CO2Et; R2=4-nitrophenyl; R3=H; R4=NH2)
  • To a refluxing solution of benzylidene 2 (1.05 g, 3.76 mmol) in 10 mL of acetic acid was added ethyl amidinoacetate acetic acid salt (0.720 g, 3.76 mmol). The resulting solution was heated at reflux overnight. After cooling to room temperature, the resulting precipitate was removed by filtration and washed with water. This impure residue was heated in a minimal amount of ethanol and then filtered to yield 0.527 g (35%) of a yellow solid. MS m/z 412 (M++23), 390 (M++1).
    • EXAMPLE 11 Hantzsch Condensation of Benzylidene 8 (R2=3-methylphenyl) and 1,3-indandione)
  • The benzylidene 8 (2.00 g, 9.2 mmol), 1,3-indandione (1.34 g, 0.2 mmmol) and ammonium acetate (2.83 g, 36.7 mmol) were added to 30 mL of ethanol and heated to reflux overnight. The reaction mixture was cooled to room temperature and diluted with ethanol. A yellow precipitate was collected by filtration, washed with ethanol, and dried under vacuum to yield 1.98 g (63%) of the dihydropyridine 9. MS m/z 346 (M++1).
    • EXAMPLE 12 Reduction to Prepare Amine 11 (R1=CO2Me; R2=4-methylnaphthyl; R4=Me)
  • To a refluxing suspension of pyridine 10 (0.862 g, 1.97 mmol) in 35 mL of ethanol was added a solution of tin (II) chloride dihydrate (1.33 g, 5.90 mmol) in 6 mL of 1:1 ethanol: concentrated HCl. The resulting solution was heated at reflux overnight. Water was added until a precipitate started to form and the reaction was cooled to room temperature. The mixture was then filtered and washed with water. After drying, the residue was purified by column chromatography eluting with hexanes: ethyl acetate to yield 0.551 g (69%) of an orange solid. MS m/z 431 (M++23), 409 (M++1).
    • EXAMPLE 13 Acetylation of Amine 11 (R1=CO2Et; R2=3,4-methylenedioxyphenyl; R4=Me)
  • To a solution of amine 11 (0.070 g, 0.174 mmol) in 15 mL of dichloromethane was added triethylamine (0.026 g, 0.261 mmol) and acetyl chloride (0.015 g, 0.192 mmol). After stirring overnight at room temperature, the reaction mixture was diluted with water and then extracted with dichloromethane (3×35 mL). The combined organics were washed with brine, dried over MgSO4, and concentrated. The residue was purified by silica gel chromatography eluting with hexanes: ethyl acetate to yield 0.054 g (70%) of amide 12. MS m/z 467 (M++23), 445 (M++1).
    • EXAMPLE 14 Preparation of Carboxylic Acid 13 (R1=CO2Me; R2=3,5-dimethylphenyl; R4=Me; Y=O; n=2).
  • To a suspension of amine 11 (0.079 g, 0.212 mmol) in 5 mL of benzene was added succinic anhydride (0.021 g, 0.212 mmol). After heating at reflux for 24 hours, the reaction mixture was filtered and washed with benzene. The residue was dried under high vacuum and then washed with ether to remove the excess succinic anhydride. This yielded 0.063 g (63%) of carboxylic acid 13. MS m/z 473 (M++1).
    • EXAMPLE 15 Preparation of Carboxylic Acid 13 (R1=CO2Me; R2=3,5-dimethylphenyl; R4=Me; Y=H2; n=1)
  • To a refluxing solution of amine 11 (0.078 g, 0.210 mmol) in 5 mL of acetonitrile was added β-propiolactone (0.015 g, 0.210 mmol). The reaction was heated to reflux for 72 hours before cooling to room temperature. The reaction mixture was concentrated. The residue was mixed with 10% aqueous sodium hydroxide and washed sequentially with ether and ethyl acetate. The aqueous layer was acidified with concentrated HCl and extracted with dichloromethane (2×25 mL). The combined organics were dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography eluting with 5% MeOH in dichloromethane to yield 0.020 g (21%) of an orange solid. MS m/z 467 (M++23), 445 (M++1).
    • EXAMPLE 16 Preparation of Hydroxamic Acid 14 (R1=CO2Me; R2=(4-methyl)-1-naphthyl; Y=O; n=2; R4=Me)
  • To a 0° C. suspension of carboxylic acid 13 (0.054 g, 0.106 mmol) in 10 mL of diethyl ether was added triethylamine (0.014 g, 0.138 mmol) and then ethyl chloroformate (0.014 g, 0.127 mmol). The mixture was stirred at 0° C. for 30 minutes and them warmed to room temperature. A solution of hydroxylamine (0.159 mmol) in methanol was added and the reaction was stirred overnight at room temperature. The mixture was filtered and the residue was washed with ether and dried under vacuum to yield 0.030 g (54%) of a yellow solid. MS m/z 524 (M++1).
    • EXAMPLE 17 Preparation of Amide 15 (R1=CO2Me; R2=3,5-dimethylphenyl; R4=Me)
  • A mixture of amine 11 (0.201 g, 0.54 mmol) and glycolic acid (0.049 g, 0.65 mmol) was heated at 120-160° C. for 30 minutes. During heating, more glycolic acid was added to ensure that excess reagent was present. Once the starting material was consumed, the reaction was cooled to room temperature, and diluted with dichloromethane. The resulting mixture was extracted with 20% NaOH, followed by 10% HCl, and finally water. The combined organics were concentrated and triturated with ether. Purification by column chromatography eluting with ethyl acetate: hexanes yielded 0.012 g (5%) of a yellow solid. MS m/z 453 (M++23), 431 (M++1).
    • EXAMPLE 18 Preparation of Amide 16 (R1=CO2Me; R2=3,5-dimethylphenyl; R4=Me; NR6R7=morpholino)
  • To a 0° C. mixture of amine 11 (0.123 g, 0.331 mmol) in 2 mL of 20% aqueous NaHCO3 and 3 mL of ethyl acetate was added chloroacetyl chloride (0.047 g, 0.413 mmol). The reaction was warmed to room temperature and stirred for 45 minutes. The mixture was poured into a separatory funnel and the aqueous layer was removed. The organic layer containing the crude chloroamide was used without purification. To the ethyl acetate solution was added morpholine (0.086 g, 0.992 mmol) and the reaction was heated to approx. 65° C. overnight. The reaction was diluted with water and cooled to room temperature. After extraction with ethyl acetate (3×25 mL), the combined organics were washed with brine, dried over MgSO4 and concentrated to yield 0.130 g (79%) of a yellow solid. MS m/z 522 (M++23), 500 (M++1).
    • EXAMPLE 19 Preparation of piperazinone 17 (R1=CO2Me; R2=3,5-dimethylphenyl; R4=Me; R7=H)
  • To a 0° C. solution of amide 16 (R6=CH2CH2OH) (0.093 g, 0.20 mmol), tri n-butylphosphine (0.055 g, 0.27 mmol) in 0.35 mL ethyl acetate was slowly added di-tert-butyl azodicarboxylate (0.062 g, 0.27 mmol) in 0.20 mL ethyl acetate. The reaction was allowed to stand for 15 minutes and then heated to 40° C. overnight. 4.2 M ethanolic HCl was added dropwise. The mixture was cooled to 0° C. and allowed to stand for 2 hours. The mixture was filtered and washed with cold ethyl acetate. Purification by column chromatography with 1-5% MeOH in CH2Cl2 yielded 0.011 (12%) of a white solid. MS m/z 478 (M++23), 456 (M++1).
    • EXAMPLE 20 Preparation of 4-Aminoindenopyridine 19 (R1=CO2Me; R4=Me; R6=Me; R7=phenyl)
  • To a solution of 4-chloroindenopyridine 18 (0.069 g, 0.240 mmol) in 10 mL of 2-ethoxyethanol was added N-methylaniline (0.026 g, 0.240 mmol). The reaction was heated at reflux for 96 hours. After cooling to room temperature, the solution was concentrated. The residue was purified by column chromatography eluting with hexanes: ethyl acetate to yield 0.029 g (34%) of an orange solid. MS m/z 359 (M++1).
    • EXAMPLE 21 Preparation of 4-Aminoindenopyridine 19 (R1=CO2Me; R4=Me; R6=H; R7=cyclopentyl) by Palladium Catalyzed Coupling
  • A mixture of 4-chloroindenopyridine 18 (0.100 g, 0.347 mmol), cyclopentylamine (0.035 g, 0.416 mmol), palladium (II) acetate (0.004 g, 0.0017 mmol), 2-(di-t-butylphosphino)biphenyl (0.010 g, 0.0035 mmol), and cesium carbonate (0.124 g, 0.382 mmol) in 10 mL of dioxane was heated at reflux overnight. The reaction was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3×35 mL). The combined organics were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography eluting with ethyl acetate: hexanes. The purified oil was dissolved in ether and cooled to 0° C. To this solution was slowly added 1.0 M HCl in ether. The resulting precipitate was isolated by filtration, washed with ether, and dried under vacuum to yield 0.032 g (25%) of a yellow solid. MS m/z 359 (M++23), 337 (M++1).
    • EXAMPLE 22 Preparation of Dihydropyridine 21 (R1=CO2Me; R2=2-furyl; R3=H; R4=NH2)
  • Unsaturated cyanoester 20 (0.20 g, 1.10 mmol), enamine 21 (0.20 g, 0.75 mmol) and 5 drops of triethylamine were refluxed in 1-propanol (4 mL). After 3 hours, the reaction was concentrated to half the volume and cooled. The resulting precipitate was filtered and washed with 1-propanol. The precipitate was a mixture of products and therefore was combined with the filtrate and concentrated. Purification by column chromatography, eluting with ethyl acetate: hexane yielded 0.11 g (34%) of the red product 22. MS m/z 465 (M++23).
    • EXAMPLE 23 DDQ Oxidation/Deprotection of Dihydropyridine 22 (R1=CO2Me; R2=3-furyl; R3=H; R4=NH2)
  • To a solution of dihydropyridine 22(0.05 g, 0.11 mmol) in chlorobenzene (4 mL) was added 2,3-dichloro-3,6-dicyano-1,4-benzoquinone (0.05 g, 0.22 mmol). The reaction was refluxed overnight before cooling to room temperature and diluting with diethyl ether. The reaction mixture was filtered through celite and concentrated in vacuo. Purification by column chromatography, eluting with ethyl acetate:hexane yielded 0.018 g (52%) of yellow product 23. MS m/z 343 (M++23), 321 (M++1).
  • Following the general synthetic procedures outlined above and in Examples 1-21, the compounds of Table 1 below were prepared.
    TABLE 1
    Figure US20060154949A1-20060713-C00047
    No. R1 R2 R3a R3b R3c R3d R4 MS (M + 1)
    1 CN
    Figure US20060154949A1-20060713-C00048
     C7H5O2     		H H H H Me 341
    2 CO2Et
    Figure US20060154949A1-20060713-C00049
     C7H5O2     		H H H H Me 388
    3 CO2t-Bu
    Figure US20060154949A1-20060713-C00050
     C7H5O2     		H H H H Me 416
    4 CO2t-Bu
    Figure US20060154949A1-20060713-C00051
     C8H9O2     		H H H H Me 432
    5 CO2Et
    Figure US20060154949A1-20060713-C00052
     C6H4NO2     		H H H Me 389
    6 CO2H
    Figure US20060154949A1-20060713-C00053
     C7H5O2     		H H H H Me 360
    7 CO2Et
    Figure US20060154949A1-20060713-C00054
     C14H13O2     		H H H H Me 480
    8 CO2Et
    Figure US20060154949A1-20060713-C00055
     C8H8BrO2     		H H H H Me 482
    9 CO2Et
    Figure US20060154949A1-20060713-C00056
     C11H9O    		 H H H H Me 424
    10 CO2H
    Figure US20060154949A1-20060713-C00057
     C8H9     		H H H H Me 376
    11 CO2Et Ph H H H H Me 344
    12 CO2Et
    Figure US20060154949A1-20060713-C00058
     C7H7O    		 H H H H Me 374
    13 CO2Et
    Figure US20060154949A1-20060713-C00059
     C9H11O3     		H H H H Me 434
    14 CO2Et
    Figure US20060154949A1-20060713-C00060
     C6H4BrO2     		H H H H Me 454
    15 CO2Bn
    Figure US20060154949A1-20060713-C00061
     C7H5O2     		H H H H Me 450
    16
    Figure US20060154949A1-20060713-C00062
     C11H14NO2
    Figure US20060154949A1-20060713-C00063
     C7H5O2     		H H H H Me 507
    17 CO2Me
    Figure US20060154949A1-20060713-C00064
     C8H9O2     		H H H H Me 390
    18 CO2Me
    Figure US20060154949A1-20060713-C00065
     C7H5O2     		H H H H Me 374
    19 CO2Et
    Figure US20060154949A1-20060713-C00066
     C8H9O2     		H H H H Me 404
    20 CO2Et
    Figure US20060154949A1-20060713-C00067
     C8H9O2     		H H H H Me 404
    21 CO2Et
    Figure US20060154949A1-20060713-C00068
     C7H6BrO    		 H H H H Me 454
    22 CO2Et
    Figure US20060154949A1-20060713-C00069
     C7H5O2     		H H H H NH2 411 (M + 23)
    23 CO2Et
    Figure US20060154949A1-20060713-C00070
     C7H5O2     		H H H H Me 388
    25 CO2Et
    Figure US20060154949A1-20060713-C00071
     C8H9O2     		H H H H NH2 405
    26 CO2Et
    Figure US20060154949A1-20060713-C00072
     C6H4NO2     		H H H H NH2 390
    27 CO2Et Ph H H H H NH2 345
    28 CO2Et
    Figure US20060154949A1-20060713-C00073
     C9H11O    		 H H H H Me 402
    29 CO2Et
    Figure US20060154949A1-20060713-C00074
     C8H8BrO2     		H H H H Me 483
    30 CO2Me Ph H H H H Me 330
    31 CO2Et
    Figure US20060154949A1-20060713-C00075
     C8H7O2     		H H H H Me 402
    32 CO2Et
    Figure US20060154949A1-20060713-C00076
     C7H5O2     		H NO2 H H Me 433
    33
    Figure US20060154949A1-20060713-C00077
     C4H4NO2
    Figure US20060154949A1-20060713-C00078
     C7H5O2     		H H H H Me 413
    34 CO2Et
    Figure US20060154949A1-20060713-C00079
     C7H4NO4     		H H H H Me 433
    35 CO2Et
    Figure US20060154949A1-20060713-C00080
     C7H5O2     		H H NO2 H Me 433
    36 CO2Me
    Figure US20060154949A1-20060713-C00081
     C7H4F3     		H H H H Me 398
    37 CO2Et
    Figure US20060154949A1-20060713-C00082
     C7H5O2     		H H NH2 H Me 403
    38 CONH2
    Figure US20060154949A1-20060713-C00083
     C7H5O2     		H H H H Me 359
    39 CO2Et
    Figure US20060154949A1-20060713-C00084
     C8H9     		H H H H Me 372
    40 CO2Et
    Figure US20060154949A1-20060713-C00085
     C7H5O2     		H NH2 H H Me 403
    41 CO2Et
    Figure US20060154949A1-20060713-C00086
     C4H3O    		 H H H H Me 334
    42 CO2Et 2-Thienyl H H H H Me 350
    43 CO2Me
    Figure US20060154949A1-20060713-C00087
     C8H9     		H H H H Me 358
    44 CO2Me
    Figure US20060154949A1-20060713-C00088
     C8H7O2     		H H H H Me 388
    45 CO2Me
    Figure US20060154949A1-20060713-C00089
     C7H4NO4     		H H H H Me 419
    46 CO2Me
    Figure US20060154949A1-20060713-C00090
     C9H11O    		 H H H H Me 388
    47 CO2Me 4-Pyridyl H H H H Me 331
    48 CO2Me
    Figure US20060154949A1-20060713-C00091
     C7H5O2     		H H H H Me 374
    49 CO2Me
    Figure US20060154949A1-20060713-C00092
     C7H4BrO2     		H H H H Me 454
    50 CO2Me
    Figure US20060154949A1-20060713-C00093
     C7H6BrO    		 H H H H Me 439
    51 CO2Me
    Figure US20060154949A1-20060713-C00094
     C8H9     		H H H H Me 358
    52 CO2Et
    Figure US20060154949A1-20060713-C00095
     C8H9     		H H H H Me 372
    53 CO2Me
    Figure US20060154949A1-20060713-C00096
     C11H9O    		 H H H H Me 410
    54 CO2Me
    Figure US20060154949A1-20060713-C00097
     C6H4NO2     		H H H H Me 375
    55 CO2Et
    Figure US20060154949A1-20060713-C00098
     C7H5O2     		H NHAc H H Me 445
    56 CO2Et
    Figure US20060154949A1-20060713-C00099
     C7H5O2     		H H NHAc H Me 445
    57 CO2Et
    Figure US20060154949A1-20060713-C00100
     C7H7     		H H H H Me 358
    58 CO2Et
    Figure US20060154949A1-20060713-C00101
     C7H7     		H H H H Me 358
    59 CO2Et
    Figure US20060154949A1-20060713-C00102
     C7H7     		H H H H Me 358
    60 CO2Et
    Figure US20060154949A1-20060713-C00103
     C7H4F3     		H NO2 H H Me 457
    61 CO2Et
    Figure US20060154949A1-20060713-C00104
     C7H4F3     		H H NO2 H Me 457
    62 CO2Me
    Figure US20060154949A1-20060713-C00105
     C7H7     		H H H H Me 344
    63 CO2Et
    Figure US20060154949A1-20060713-C00106
     C7H4F3     		H NH2 H H Me 427
    64 CO2Et
    Figure US20060154949A1-20060713-C00107
     C7H4F3     		H H NH2 H Me 427
    65 CO2Me
    Figure US20060154949A1-20060713-C00108
     C8H3F6     		H H H H Me 466
    66 CO2Me
    Figure US20060154949A1-20060713-C00109
     C7H7     		H H H H Me 344
    67 CO2Me
    Figure US20060154949A1-20060713-C00110
     C7H7     		H H H H Me 344
    68 CO2Me
    Figure US20060154949A1-20060713-C00111
     C7HF3     		H NO2 H H Me 443
    69 CO2Me
    Figure US20060154949A1-20060713-C00112
     C7H4F3     		H H NO2 H Me 443
    70 CO2Et
    Figure US20060154949A1-20060713-C00113
     C8H9     		H H H H i-Pr 400
    71 CO2Me
    Figure US20060154949A1-20060713-C00114
     C7H4F3     		H NH2 H H Me 413
    72 CO2Me
    Figure US20060154949A1-20060713-C00115
     C6H3Cl2     		H H H H Me 399
    73 CO2Me
    Figure US20060154949A1-20060713-C00116
     C8H9     		H H H H Et 372
    74 CO2Me
    Figure US20060154949A1-20060713-C00117
     C7H4F3     		H H H H Me 398
    75 CO2Me
    Figure US20060154949A1-20060713-C00118
     C11H9     		H H H H Me 394
    76 CO2Me
    Figure US20060154949A1-20060713-C00119
     C9H11     		H H H H Me 372
    77 CO2Me
    Figure US20060154949A1-20060713-C00120
     C8H9     		H NO2 H H Me 403
    78 CO2Me
    Figure US20060154949A1-20060713-C00121
     C8H9     		H H NO2 H Me 403
    79 CO2Me
    Figure US20060154949A1-20060713-C00122
     C11H9     		H H H H Me 394
    80 CO2Me
    Figure US20060154949A1-20060713-C00123
     C7H4F3     		H NHAc H H Me 455
    81 CO2Me
    Figure US20060154949A1-20060713-C00124
     C6H3Br2     		H H H H Me 488
    82 CO2Me
    Figure US20060154949A1-20060713-C00125
     C8H9     		H NH2 H H Me 373
    83 CO2Me
    Figure US20060154949A1-20060713-C00126
     C8H9     		H H NH2 H Me 373
    84 CO2Me
    Figure US20060154949A1-20060713-C00127
     C7H6F    		 H H H H Me 362
    85 CO2Me
    Figure US20060154949A1-20060713-C00128
     C6H4Br    		 H H H H Me 431 (M + 23)
    86 CO2Me
    Figure US20060154949A1-20060713-C00129
     C10H7     		H H H H Me 380 (M +23)
    87 CO2Me
    Figure US20060154949A1-20060713-C00130
     C11H9     		H NO2 H H Me 439
    88 CO2Me
    Figure US20060154949A1-20060713-C00131
     C11H9     		H H NO2 H Me 439
    89 CO2Me
    Figure US20060154949A1-20060713-C00132
     C14H9     		H H H H Me 430
    90 CO2Me
    Figure US20060154949A1-20060713-C00133
     C11H9     		H NH2 H H Me 409
    91 CO2Me
    Figure US20060154949A1-20060713-C00134
     C11H9     		H H NH2 H Me 409
    92
    Figure US20060154949A1-20060713-C00135
     C4H4NO2
    Figure US20060154949A1-20060713-C00136
     C8H9     		H H H H Me 397
    93 CN
    Figure US20060154949A1-20060713-C00137
     C8H9     		H H H H Me 325
    94 CO2Me
    Figure US20060154949A1-20060713-C00138
     C8H9     		H H H H NH2 359
    95 CO2Me
    Figure US20060154949A1-20060713-C00139
     C11H9     		H H H H NH2 395
    96 CO2H
    Figure US20060154949A1-20060713-C00140
     C8H9     		H H H H Me 344
    97
    Figure US20060154949A1-20060713-C00141
     C4H4NO2
    Figure US20060154949A1-20060713-C00142
     C11H9     		H H H H Me 433
    98 CN
    Figure US20060154949A1-20060713-C00143
     C11H9     		H H H H Me 361
    99
    Figure US20060154949A1-20060713-C00144
     C2H2 O 2
    Figure US20060154949A1-20060713-C00145
     C7H5O2     		H H H H C2H2O2 358
    100
    Figure US20060154949A1-20060713-C00146
     C2H2O2
    Figure US20060154949A1-20060713-C00147
     C8H10N    		 H H H H C2H2O2 357
    101
    Figure US20060154949A1-20060713-C00148
     C2H2O2     		Ph H H H H C2H2O2 314
    102
    Figure US20060154949A1-20060713-C00149
     C2H2O2     		p-C6H4NO2 H H H H C2H2O2 361
    103
    Figure US20060154949A1-20060713-C00150
     C2H2O2
    Figure US20060154949A1-20060713-C00151
     C8H9     		H H H H C2H2O2 364
    104
    Figure US20060154949A1-20060713-C00152
     C2H2
    Figure US20060154949A1-20060713-C00153
     C8H9     		H H H H C2H2O2 342
    105 CO2H
    Figure US20060154949A1-20060713-C00154
     C11H9     		H H H H Me 380
    106 CONH2
    Figure US20060154949A1-20060713-C00155
     C8H9     		H H H H Me 343
    107 CONHMe
    Figure US20060154949A1-20060713-C00156
     C8H9     		H H H H Me 357
    108 CONMe2
    Figure US20060154949A1-20060713-C00157
     C8H9     		H H H H Me 371
    109
    Figure US20060154949A1-20060713-C00158
     C2H2O2
    Figure US20060154949A1-20060713-C00159
     C11H9     		H H H H C2H2O2 378
    110
    Figure US20060154949A1-20060713-C00160
     C2H2O2
    Figure US20060154949A1-20060713-C00161
     C7H7     		H H H H C2H2O2 328
    111
    Figure US20060154949A1-20060713-C00162
     C2H2O2
    Figure US20060154949A1-20060713-C00163
     C9H11     		H H H H C2H2O2 356
    112
    Figure US20060154949A1-20060713-C00164
     C2H2O2
    Figure US20060154949A1-20060713-C00165
     C7H7     		H H H H C2H2O2 328
    113 CO2Me
    Figure US20060154949A1-20060713-C00166
     C6H4NO2     		H H H H Me 375
    114
    Figure US20060154949A1-20060713-C00167
     C2H2O2
    Figure US20060154949A1-20060713-C00168
     C7H7     		H H H H C2H2O2 328
    115 CO2Me
    Figure US20060154949A1-20060713-C00169
     C8H10N    		 H H H H Me 373
    116 CONH2
    Figure US20060154949A1-20060713-C00170
     C11H9     		H H H H Me 379
    117
    Figure US20060154949A1-20060713-C00171
     C2H2O2
    Figure US20060154949A1-20060713-C00172
     C9H6N    		 H H H H C2H2O2 365
    118 CO2Me
    Figure US20060154949A1-20060713-C00173
     C6H4NO2     		H H H H Me 375
    119 CONHMe
    Figure US20060154949A1-20060713-C00174
     C11H9     		H H H H Me 393
    120 CONMe2
    Figure US20060154949A1-20060713-C00175
     C131H9     		H H H H Me 407
    121 CO2Me
    Figure US20060154949A1-20060713-C00176
     C9HN     		H H H H Me 381
    122 CO2Me
    Figure US20060154949A1-20060713-C00177
     C11H9     		H Cl Cl H Me 463
    123 CO2Me
    Figure US20060154949A1-20060713-C00178
     C8H9     		H Cl Cl H Me 427
    124 CO2Me
    Figure US20060154949A1-20060713-C00179
     C9H6N    		 H H H H Me 381
    125 CO2Et
    Figure US20060154949A1-20060713-C00180
     C11H9     		H H H H Me 408
    126 CO2Me
    Figure US20060154949A1-20060713-C00181
     C6H3Br2     		H Cl Cl H Me 555
    127 CO2Me
    Figure US20060154949A1-20060713-C00182
     C8H9     		Cl H H Cl Me 427
    128 CO2Me 2-NO2-4,5- OCH2O—C6H2 H H H H Me 421
    129 CO2Me
    Figure US20060154949A1-20060713-C00183
     C6H3Br2     		Cl H H Cl Me 558
    130 CO2Me
    Figure US20060154949A1-20060713-C00184
     C6H6N    		 H H H H Me 345
    131 CO2Et
    Figure US20060154949A1-20060713-C00185
     C11H9     		H Cl Cl H Me 477
    132 CO2Me
    Figure US20060154949A1-20060713-C00186
     C6H4Br2N    		 H H H H Me 503
    133 Ac
    Figure US20060154949A1-20060713-C00187
     C6H3Br2     		H H H H Me 472
    134 Ac
    Figure US20060154949A1-20060713-C00188
     C8H9     		H H H H Me 342
    135 CO2Me
    Figure US20060154949A1-20060713-C00189
     C5H4N    		 H H H H Me 331
    136
    Figure US20060154949A1-20060713-C00190
     C4H4NO2
    Figure US20060154949A1-20060713-C00191
     C6H3Br2     		H H H H Me 527
    137
    Figure US20060154949A1-20060713-C00192
     C4H4NO2
    Figure US20060154949A1-20060713-C00193
     C8H9     		H H H H Me 397
    138 CO2Me
    Figure US20060154949A1-20060713-C00194
     C6H5O2     		H H H H Me 362
    139 CO2H
    Figure US20060154949A1-20060713-C00195
     C6H3Br2     		H H H H Me 474
    140 CO2H
    Figure US20060154949A1-20060713-C00196
     C8H9     		H H H H Me 344
    141 CO2Me
    Figure US20060154949A1-20060713-C00197
     C6H5O    		 H H H H Me 346
    142 CO2Me
    Figure US20060154949A1-20060713-C00198
     C10 H2     		H H H H Me 380
    143 CO2Me
    Figure US20060154949A1-20060713-C00199
     C16H25O    		 H H H H Me 486
    144 CO2Me
    Figure US20060154949A1-20060713-C00200
     C13H11O    		 H H H H Me 436
    145 CO2Me
    Figure US20060154949A1-20060713-C00201
     C7H5Br2O    		 H H H H Me 518
    146
    Figure US20060154949A1-20060713-C00202
     C4H4NO2
    Figure US20060154949A1-20060713-C00203
     C7H5Br2O    		 H H H H Me 557
    147
    Figure US20060154949A1-20060713-C00204
     C4H4NO2
    Figure US20060154949A1-20060713-C00205
     C8H9     		H Cl Cl H Me 466
    148 CO2Et —NHPh H H H H Me 359
    149 CO2Me
    Figure US20060154949A1-20060713-C00206
     C7H7O    		 H H H H Me 360
    150 CO2Me
    Figure US20060154949A1-20060713-C00207
     C6H3Br2O    		 H H H H Me 504
    151
    Figure US20060154949A1-20060713-C00208
     C4H4NO2
    Figure US20060154949A1-20060713-C00209
     C9H6N    		 H H H H Me 420
    152 C3H5O3
    Figure US20060154949A1-20060713-C00210
     C6H3Br2O    		 H H H H Me 534
    153
    Figure US20060154949A1-20060713-C00211
     C4H4NO2
    Figure US20060154949A1-20060713-C00212
     C6H5 O     		H H H H Me 385
    154
    Figure US20060154949A1-20060713-C00213
     C2H4NO2
    Figure US20060154949A1-20060713-C00214
     C8H9     		H H H H Me 373
    155
    Figure US20060154949A1-20060713-C00215
     C4H4NO2
    Figure US20060154949A1-20060713-C00216
     C6H3Br2     		H H NO2 H Me 574
    156 CO2Me
    Figure US20060154949A1-20060713-C00217
     C11H9     		H Br H H Me 473
    157 CO2Me
    Figure US20060154949A1-20060713-C00218
     C11H9     		H H Br H Me 473
    158
    Figure US20060154949A1-20060713-C00219
     C4H4NO2
    Figure US20060154949A1-20060713-C00220
     C9H6N    		 H Cl Cl H Me 489
    159
    Figure US20060154949A1-20060713-C00221
     C4H4NO2
    Figure US20060154949A1-20060713-C00222
     C6H3Br2O    		 H H NO2 H Me 590
    160
    Figure US20060154949A1-20060713-C00223
     C3H5O3
    Figure US20060154949A1-20060713-C00224
     C9H6N    		 H H H H Me 411
    161 CO2Me
    Figure US20060154949A1-20060713-C00225
     C8H9     		H Br H H Me 436
    162 CO2Me
    Figure US20060154949A1-20060713-C00226
     C8H9     		H H Br H Me 438
    163 CO2Me
    Figure US20060154949A1-20060713-C00227
     C8H9     		H Br Br H Me 516
    164
    Figure US20060154949A1-20060713-C00228
     C4H4NO2
    Figure US20060154949A1-20060713-C00229
     C6H32Br2     		H Cl Cl H Me 597
    165
    Figure US20060154949A1-20060713-C00230
     C3H5O3
    Figure US20060154949A1-20060713-C00231
     C9H6N    		 H Cl Cl H Me 480
    166 CO2Me
    Figure US20060154949A1-20060713-C00232
     C11H9     		H Br Br H Me 552
    167 CO2Et
    Figure US20060154949A1-20060713-C00233
     C8H9     		H Br Br H Me 530
    168 CO2Me
    Figure US20060154949A1-20060713-C00234
     C6H3Br2O    		 F H H F Me 540
    169 CO2Me
    Figure US20060154949A1-20060713-C00235
     C6H3Br2O    		 H H NO2 H Me 551
    170 CO2Me
    Figure US20060154949A1-20060713-C00236
     C6H3Br2O    		 H Cl Cl H Me 573
    171
    Figure US20060154949A1-20060713-C00237
     C4H4NO2
    Figure US20060154949A1-20060713-C00238
     C8H9     		H H NO2 H Me 444
    172
    Figure US20060154949A1-20060713-C00239
     C4H4NO2
    Figure US20060154949A1-20060713-C00240
     C8H9     		H NO2 H H Me 444
    173 CO2Me
    Figure US20060154949A1-20060713-C00241
     C8H9     		F H H F Me 394
    174
    Figure US20060154949A1-20060713-C00242
     C4H4NO2
    Figure US20060154949A1-20060713-C00243
     C8H9     		F H H F Me 433
    175 CO2Me
    Figure US20060154949A1-20060713-C00244
     C8H9O2     		H Br Br H Me 548
    176 CO2Me
    Figure US20060154949A1-20060713-C00245
     C7H4N    		 H H H H Me 355
    177 CO2Me
    Figure US20060154949A1-20060713-C00246
     C8H9O    		 H NO2 H H Me 421
    178 CO2Me
    Figure US20060154949A1-20060713-C00247
     C8H9O    		 H H NO2 H Me 453
    179 CO2Me
    Figure US20060154949A1-20060713-C00248
     C8H9O    		 H Cl Cl H Me 443
    180 CN
    Figure US20060154949A1-20060713-C00249
     C8H9O    		 H H H H Me 341
    181 CO2Me
    Figure US20060154949A1-20060713-C00250
     C6H3I2O    		 H H H H Me 598
    182 CO2Me
    Figure US20060154949A1-20060713-C00251
     C6H3F2     		H Cl Cl H Me 435
    183 CO2Et
    Figure US20060154949A1-20060713-C00252
     C8H10N    		 H H H H Me 387
    184 CO2Et
    Figure US20060154949A1-20060713-C00253
     C7H8N    		 H H H H Me 373
    185 CO2Me
    Figure US20060154949A1-20060713-C00254
     C7H5I2O    		 H H H H Me 612
    186 CO2Et
    Figure US20060154949A1-20060713-C00255
     C9H7N2     		H H H H Me 410
    187 CO2Me
    Figure US20060154949A1-20060713-C00256
     C6H3I2O    		 H H NO2 H Me 345
    188 CO2Me
    Figure US20060154949A1-20060713-C00257
     C6H3I2O    		 H Cl Cl H Me 668
    189 CO2Me
    Figure US20060154949A1-20060713-C00258
     C6H3F2     		H H NO2 H Me 413
    190 CO2H
    Figure US20060154949A1-20060713-C00259
     C6H3Br2     		H Cl Cl H Me 544
    191 CN
    Figure US20060154949A1-20060713-C00260
     C6H3I2O    		 H H H H Me 565
    192 CO2Me
    Figure US20060154949A1-20060713-C00261
     C6H3Br2O    		 H Br H H Me 606 (M + 23)
    193 CO2Me
    Figure US20060154949A1-20060713-C00262
     C6H3Br2O    		 H H Br H Me 584
    194 CO2Et
    Figure US20060154949A1-20060713-C00263
     C7H8N    		 H H H H Me 373
    195 CO2Et
    Figure US20060154949A1-20060713-C00264
     C6H4Cl2N    		 H H H H Me 427
    196 CO2Et
    Figure US20060154949A1-20060713-C00265
     C6H3Br2O    		 H Cl Cl H Me 587
    197 CO2Et
    Figure US20060154949A1-20060713-C00266
     C6H5BrN    		 H H H H Me 437
    198 CO2Et
    Figure US20060154949A1-20060713-C00267
     C7H8NO    		 H H H H Me 389
    199 CO2Et
    Figure US20060154949A1-20060713-C00268
     C6H3I2O    		 H H H H Me 612
    200 CO2Et
    Figure US20060154949A1-20060713-C00269
     C6H3F2     		H Cl Cl H Me 449
    201 CO2Me
    Figure US20060154949A1-20060713-C00270
     C9H6N    		 H Cl Cl H Me 450
    202 CO2Me
    Figure US20060154949A1-20060713-C00271
     C7H5F2O    		 H Cl Cl H Me 465
    203 CO2Me
    Figure US20060154949A1-20060713-C00272
     C7H5F2O    		 H H H H Me 396
    204 CO2Me
    Figure US20060154949A1-20060713-C00273
     C8H9     		H
    Figure US20060154949A1-20060713-C00274
     C4H6NO3     		H H Me 473
    205 CO2Me
    Figure US20060154949A1-20060713-C00275
     C6H6N    		 H H H H Me 345
    206 CO2Me
    Figure US20060154949A1-20060713-C00276
     C7H8N    		 H H H H Me 359
    207 CO2Me
    Figure US20060154949A1-20060713-C00277
     C6H4NO2     		H Cl Cl H Me 444
    208 CO2Me
    Figure US20060154949A1-20060713-C00278
     C7H4N    		 H H H Me 355
    209 CO2H
    Figure US20060154949A1-20060713-C00279
     C10H7     		H H H H Me 366
    210 CO2Me
    Figure US20060154949A1-20060713-C00280
     C6H4NO2     		H Cl Cl H Me 444
    211 CO2Me
    Figure US20060154949A1-20060713-C00281
     C7H6F    		 H Cl Cl H Me 430
    212 CO2Me
    Figure US20060154949A1-20060713-C00282
     C7H3F4     		H H H H Me 416
    213 CO2Me
    Figure US20060154949A1-20060713-C00283
     C7H6F    		 H Cl Cl H Me 430
    214 CO2Me
    Figure US20060154949A1-20060713-C00284
     C6H4Cl2N    		 H H H H Me 413
    215 CO2Me
    Figure US20060154949A1-20060713-C00285
     C8H9     		H OMe OMe H Me 418
    216 CO2Me
    Figure US20060154949A1-20060713-C00286
     C11H9     		H OMe OMe H Me 454
    217 CO2Me
    Figure US20060154949A1-20060713-C00287
     C7H6F    		 H H H H Me 362
    218 CO2Me
    Figure US20060154949A1-20060713-C00288
     C8H9     		H
    Figure US20060154949A1-20060713-C00289
     C3H6NO2     		H H Me 445
    219 CO2Me
    Figure US20060154949A1-20060713-C00290
         		H H H H Me 359
    220 CO2Me —NHPh H H H H Me 345
    221 CO2Me
    Figure US20060154949A1-20060713-C00291
     C6H5BrN    		 H H H H Me 423
    222 CO2Me 2-Pyridyl H H H H Me 353
    223 CO2Me
    Figure US20060154949A1-20060713-C00292
     C6H3Cl2     		H OMe OMe H Me 459
    224 CO2Me
    Figure US20060154949A1-20060713-C00293
     C7H3F4     		H Cl Cl H Me 485
    225 CO2Me
    Figure US20060154949A1-20060713-C00294
     C6H6N    		 H H H H Me 345
    226 CO2Me
    Figure US20060154949A1-20060713-C00295
     C6H4NO2     		H H NO2 H Me 420
    227 CO2Me
    Figure US20060154949A1-20060713-C00296
     C6N4NO2     		H H NO2 H Me 420
    228 CO2Me
    Figure US20060154949A1-20060713-C00297
     C7H8N    		 H H H H Me 359
    229 CO2Me
    Figure US20060154949A1-20060713-C00298
     C9H7N2     		H H H H Me 396
    230 CO2Me
    Figure US20060154949A1-20060713-C00299
     C121H9     		H OH OH H Me 426
    231 CO2Me
    Figure US20060154949A1-20060713-C00300
     C8H9     		H H F H Me 376
    232 CO2Me
    Figure US20060154949A1-20060713-C00301
     C7H3F4     		H H NO2 H Me 461
    233 CO2Me
    Figure US20060154949A1-20060713-C00302
     C10H6F    		 H Cl Cl H Me 468
    234 CO2Me
    Figure US20060154949A1-20060713-C00303
     C8H10N    		 H H H H Me 373
    235 CO2Me
    Figure US20060154949A1-20060713-C00304
     C7H8NO    		 H H H H Me 375
    236 CO2Me
    Figure US20060154949A1-20060713-C00305
     C10H6F    		 H NO2 H H Me 443
    237 CO2Me
    Figure US20060154949A1-20060713-C00306
     C10H6F    		 H H NO2 H Me 443
    238 CO2Me
    Figure US20060154949A1-20060713-C00307
     C10 H6F    		 H H H H Me 398
    239 CO2Me
    Figure US20060154949A1-20060713-C00308
     C12H12N    		 H Cl Cl H Me 491
    240 CO2Me
    Figure US20060154949A1-20060713-C00309
     C11H9     		H
    Figure US20060154949A1-20060713-C00310
     C4H6NO3     		H H Me 509
    241 CO2Me
    Figure US20060154949A1-20060713-C00311
     C8H9     		H H
    Figure US20060154949A1-20060713-C00312
     C4H6NO3     		H Me 473
    242 CO2Me
    Figure US20060154949A1-20060713-C00313
     C11H9     		H H
    Figure US20060154949A1-20060713-C00314
     C4H6NO3     		H Me 509
    243 CO2Me
    Figure US20060154949A1-20060713-C00315
     C4H9     		H H H H Me 310
    244 CO2Me
    Figure US20060154949A1-20060713-C00316
     C11H9     		H
    Figure US20060154949A1-20060713-C00317
     C4H7N2O3     		H H Me 524
    245 CO2Me
    Figure US20060154949A1-20060713-C00318
     C8H9     		H H
    Figure US20060154949A1-20060713-C00319
     C4H7N2O3     		H Me 488
    246 CO2Me
    Figure US20060154949A1-20060713-C00320
     C4H7     		H H H H Me 308
    247 CO2Me i-Pr H H H H Me 296
    248 CO2Me
    Figure US20060154949A1-20060713-C00321
     Cyclohexyl    		 H H H H Me 336
    249 CO2Me Me H H H H Me 268
    250 CO2Me
    Figure US20060154949A1-20060713-C00322
     C8H9     		H H
    Figure US20060154949A1-20060713-C00323
     C4H9N2O2     		H Me 474
    251 CO2Me
    Figure US20060154949A1-20060713-C00324
     C7H9     		H H
    Figure US20060154949A1-20060713-C00325
     C5H8NO3     		H Me 487
    252 CO2Me N-Mopholino H H H H Me 339
    253 CO2Me
    Figure US20060154949A1-20060713-C00326
     C5H10 N     		H H H H Me 337
    254 CO2Me
    Figure US20060154949A1-20060713-C00327
     C8H9     		H H
    Figure US20060154949A1-20060713-C00328
     C5H11N2O2     		H Me 488
    255 CO2Me
    Figure US20060154949A1-20060713-C00329
     C8H9     		H
    Figure US20060154949A1-20060713-C00330
     C4H9N2O2     		H H Me 474
    256 CO2Me
    Figure US20060154949A1-20060713-C00331
     C8H9     		H
    Figure US20060154949A1-20060713-C00332
     C4H7N2O    		 H H Me 456
    257 CO2Me
    Figure US20060154949A1-20060713-C00333
     C8H9     		H
    Figure US20060154949A1-20060713-C00334
     C2H4NO2     		H H Me 431
    258 CO2Me
    Figure US20060154949A1-20060713-C00335
     C8H9     		H
    Figure US20060154949A1-20060713-C00336
     C6H11N2O2     		H H Me 500
    259 CO2Me
    Figure US20060154949A1-20060713-C00337
     C8H9     		H
    Figure US20060154949A1-20060713-C00338
     C6H12N3O    		 H H Me 499
    260 CO2Me
    Figure US20060154949A1-20060713-C00339
     C8H9     		H
    Figure US20060154949A1-20060713-C00340
     C5H6N3O    		 H H Me 481
    261 CO2Me
    Figure US20060154949A1-20060713-C00341
     C8H9     		H H
    Figure US20060154949A1-20060713-C00342
     C6H11N2O2     		H Me 500
    262 CO2Me
    Figure US20060154949A1-20060713-C00343
     C8H9     		H H
    Figure US20060154949A1-20060713-C00344
     C6H12N3O    		 H Me 499
    263 CO2Me
    Figure US20060154949A1-20060713-C00345
     C8H9     		H H
    Figure US20060154949A1-20060713-C00346
     C2H4NO2     		H Me 431
    264 CO2Me
    Figure US20060154949A1-20060713-C00347
     C7H5O2     		H H H H NH2 397 (M + 23)
    265 CO2Me Ph H H H H NH2 353 (M + 23)
    266 CO2Me
    Figure US20060154949A1-20060713-C00348
     C8H9O2     		H H H H NH2 413 (M + 23)
    267 CO2Me 2-Furyl H H H H NH2 321
    268 CO2Me 3-Furyl H H H H NH2 321
    269 CO2Me 2-Furyl H H H H Me 320
    270 CO2Me 2-Furyl H H H NH2 Me 335
    271 CO2Me 2-Furyl NHOH H H H Me 351
    272 CO2Et 2-Furyl H H H H NH2 335
    273 CO2Et 2-Furyl H Br H H NH2 413
    274 CO2Et 2-Furyl H H Br H NH2 413
    275 CO2Et
    Figure US20060154949A1-20060713-C00349
     C7H4BrO 2     		H H H H Me 467
    276 CO2Me
    Figure US20060154949A1-20060713-C00350
     C8H9     		H H
    Figure US20060154949A1-20060713-C00351
     C5H6N3O    		 H Me 481
    277 CO2Me
    Figure US20060154949A1-20060713-C00352
     C8H9     		H H
    Figure US20060154949A1-20060713-C00353
     C4H7N2O    		 H Me 456
    278 CO2Me
    Figure US20060154949A1-20060713-C00354
     C8H9     		H
    Figure US20060154949A1-20060713-C00355
     C4H6NO3     		H H Me 473
    279 CO2Me
    Figure US20060154949A1-20060713-C00356
     C8H9     		H
    Figure US20060154949A1-20060713-C00357
         		H H Me 513
    280 CO2Me
    Figure US20060154949A1-20060713-C00358
     C8H9     		H
    Figure US20060154949A1-20060713-C00359
         		H H Me 516
    281 CO2Me
    Figure US20060154949A1-20060713-C00360
     C8H9     		H
    Figure US20060154949A1-20060713-C00361
         		H H Me 501
    282 CO2Me
    Figure US20060154949A1-20060713-C00362
     C8H9     		H
    Figure US20060154949A1-20060713-C00363
         		H H Me 566
    283 CO2Me
    Figure US20060154949A1-20060713-C00364
     C8H9     		H
    Figure US20060154949A1-20060713-C00365
         		H H Me 488
    284 CO2Me
    Figure US20060154949A1-20060713-C00366
     C8H9     		H H
    Figure US20060154949A1-20060713-C00367
         		H Me 541

    III. Biological Assays and Activity
    Ligand Binding Assay for Adenosine A2a Receptor
  • Ligand binding assay of adenosine A2a receptor was performed using plasma membrane of HEK293 cells containing human A2a adenosine receptor (Perkin Elmer, RB-HA2a) and radioligand [3H]CGS21680 (PerkinElmer, NET1021). Assay was set up in 96-well polypropylene plate in total volume of 200 mL by sequentially adding 20 mL 1:20 diluted membrane, 130 mLassay buffer (50 mM Tris.HCl, pH7.4 10 mM MgCl2, 1 mM EDTA) containing [3H] CGS21680, 50 mL diluted compound (4×) or vehicle control in assay buffer. Nonspecific binding was determined by 80 mM NECA. Reaction was carried out at room temperature for 2 hours beofre filtering through 96-well GF/C filter plate pre-soaked in 50 mM Tris.HCl, pH7.4 containing 0.3% polyethylenimine. Plates were then washed 5 times with cold 50 mM Tris.HCl, pH7.4., dried and sealed at the bottom. Microscintillation fluid 30 ml was added to each well and the top sealed. Plates were counted on Packard Topcount for [3H]. Data was analyzed in Microsoft Excel and GraphPad Prism programs. (Varani, K.; Gessi, S.; Dalpiaz, A.; Borea, P. A. British Journal of Pharmacology, 1996, 117, 1693)
  • Adenosine A2a Receptor Functional Assay
  • CHO-K1 cells overexpressing human adenosine A2a receptors and containing cAMP-inducible beta-galactosidase reporter gene were seeded at 40-50K/well into 96-well tissue culture plates and cultured for two days. On assay day, cells were washed once with 200 mL assay medium (F-12 nutrient mixture/0.1% BSA). For agonist assay, adenosine A2a receptor agonist NECA was subsequently added and cell incubated at 37 C, 5% CO2 for 5 hrs before stopping reaction. In the case of antagonist assay, cells were incubated with antagonists for 5 minutes at R.T. followed by additon of 50 nM NECA. Cells were then incubated at 37 C, 5% CO2 for 5 hrs before stopping experiments by washing cells with PBS twice. 50 mL 1× lysis buffer (Promega, 5× stock solution, needs to be diluted to 1× before use) was added to each well and plates frozen at −20 C. For b-galactosidase enzyme colormetric assay, plates were thawed out at room temperature and 50 mL 2× assay buffer (Promega) added to each well. Color was allowed to develop at 37 C for 1 hr. or until reasonable signal appeared. Reaction was then stopped with 150 mL 1 M sodium carbonate. Plates were counted at 405 nm on Vmax Machine (Molecular Devices). Data was analyzed in Microsoft Excel and GraphPad Prism programs. (Chen, W. B.; Shields, T. S.; Cone, R. D. Analytical Biochemistry, 1995, 226, 349; Stiles, G. Journal of Biological Chemistry, 1992, 267, 6451)
  • Assay of Phosphodiesterase Activity
  • The assay of phosphodiesterase activity follows the homogeneous SPA (scintillation proximity assay) format under the principle that linear nucleotides preferentially bind yttrium silicate beads in the presence of zinc sulfate.
  • In this assay, the enzyme converts radioactively tagged cyclic nucleotides (reaction substrate) to linear nucleotides (reaction product) which are selectively captured via ion chelation on a scintillant-containing bead. Radiolabeled product bound to the bead surface results in energy transfer to the bead scintillant and generation of a quantifiable signal. Unbound radiolabel fails to achieve close proximity to the scintillant and therefore does not generate any signal.
  • Specifically, enzyme was diluted in PDE buffer (50 mM pH 7.4 Tris, 8.3 mM MgCl2, 1.7 mM EGTA) with 0.1% ovalbumin such that the final signal:noise (enzyme:no enzyme) ratio is 5-10. Substrate (2,8- 3H-cAMP or 8-3H-cGMP, purchased from Amersham Pharmacia) was diluted in PDE (4, 5, 7A) buffer to 1 nCi per μl (or 1 μCi/ml). For each test well, 48 μl of enzyme was mixed with 47 μl substrate and 5 μl test compound (or DMSO) in a white Packard plate, followed by shaking to mix and incubation for 15 minutes at room temperature. A 50 μl aliquot of evenly suspended yttrium silicate SPA beads in zinc sulfate was added to each well to terminate the reaction and capture the product. The plate was sealed using Topseal-S (Packard) sheets, and the beads were allowed to settle by gravity for 15-20 minutes prior to counting on a Packard TopCount scintillation counter using a 3H glass program with color quench correction. Output was in color quench-corrected dpm.
  • Test compounds were diluted in 100% DMSO to a concentration 20× final assay concentration. DMSO vehicle alone was added to uninhibited control wells. Inhibition (%) was calculated as follows:
    Nonspecific binding (NSB)=the mean of CPM of the substrate+buffer+DMSO wells
    Total Binding (TB)=the mean of the enzyme+substrate+DMSO wells
    % Inhibition listed in Table 1=(1−(Sample CPM−NSB))×100
  • The IC50 values were calculated using the Deltagraph 4-parameter curve-fitting program. The IC50 and % Inhibition data on PDE 4, 5, and 7A are listed for the indicated compounds in Table 2 below.
    TABLE 2
    Figure US20060154949A1-20060713-C00368
    MS IC50 (μM)/% inh. @ μM
    No. R1 R2 R3a R3b R3c R3d R4 (M + 1) PDE7A PDE4 PDE5
    6 CO2H
    Figure US20060154949A1-20060713-C00369
     C7H5O2     		H H H H Me 360 45% @20 49% @ 5
    51 CO2Me
    Figure US20060154949A1-20060713-C00370
     C8H9     		H H H H Me 358 0.055 0.353 2.7
    56 CO2Et
    Figure US20060154949A1-20060713-C00371
     C7H5O2     		H H NHAc H Me 445 0.074 0.333 2.5
    70 CO2Et
    Figure US20060154949A1-20060713-C00372
     C8H9     		H H H H i-Pr 400 2.11
    73 CO2Me
    Figure US20060154949A1-20060713-C00373
     C9H9     		H H H H Et 372 1.54 0.998
    82 CO2Me
    Figure US20060154949A1-20060713-C00374
     C8H9     		H NH2 H H Me 373 0.021 0.204 1.11, 0.864
    90 CO2Me
    Figure US20060154949A1-20060713-C00375
     C11H9     		H NH2 H H Me 409 0.005 0.237, 0.172 2.33
    98 CN
    Figure US20060154949A1-20060713-C00376
     C11H9     		H H H H Me 361 1.13
    119 CONHMe
    Figure US20060154949A1-20060713-C00377
     C11H9     		H H H H Me 393 0.658 41% @20
    133 Ac
    Figure US20060154949A1-20060713-C00378
     C6H3Br2     		H H H H Me 472 1.54
    134 Ac
    Figure US20060154949A1-20060713-C00379
     C8H9     		H H H H Me 342 1.14
    169 CO2Me
    Figure US20060154949A1-20060713-C00380
     C6H3Br2O    		 H H NO2 H Me 551 0.0053 0.184
    170 CO2Me
    Figure US20060154949A1-20060713-C00381
     C6H3Br2O    		 H Cl Cl H Me 573 0.0087 0.557
    190 CO2H
    Figure US20060154949A1-20060713-C00382
     C6H3Br2     		H Cl Cl H Me 544 5.9
    191 CN
    Figure US20060154949A1-20060713-C00383
     C6H3I2O    		 H H H H Me 565 0.593
    197 CO2Et
    Figure US20060154949A1-20060713-C00384
     C6H5BrN    		 H H H H Me 437 0.728 69% @ 5 0.362
    219 CO2Me
    Figure US20060154949A1-20060713-C00385
     C7H8N    		 H H H H Me 359 0.964 61% @ 5 1.1
    220 CO2Me —NHPh H H H H Me 345 0.084 1.8 0.637
    241 CO2Me
    Figure US20060154949A1-20060713-C00386
     C8H9     		H H
    Figure US20060154949A1-20060713-C00387
     C4H6NO3     		H Me 473 0.0035 0.954 0.183
    242 CO2Me
    Figure US20060154949A1-20060713-C00388
     C11H9     		H H
    Figure US20060154949A1-20060713-C00389
     C4H6NO3     		H Me 509 0.0038 0.782 0.141
    243 CO2Me
    Figure US20060154949A1-20060713-C00390
     C4H9     		H H H H Me 310 2.6
    245 CO2Me
    Figure US20060154949A1-20060713-C00391
     C8H9     		H H
    Figure US20060154949A1-20060713-C00392
     C4H7N2O3     		H Me 488 0.0053 0.875 0.185
    248 CO2Me
    Figure US20060154949A1-20060713-C00393
     Cyclohexyl    		 H H H H Me 336 0.783 0.171 0.649
    250 CO2Me
    Figure US20060154949A1-20060713-C00394
     C8H9     		H H
    Figure US20060154949A1-20060713-C00395
     C4H9N2O2     		H Me 474 0.0074 0.684 2.4
    251 CO2Me
    Figure US20060154949A1-20060713-C00396
     C8H9     		H H
    Figure US20060154949A1-20060713-C00397
     C5H8NO3     		H Me 487 0.0054 0.754 0.26
    253 CO2Me
    Figure US20060154949A1-20060713-C00398
     C5H10N    		 H H H H Me 337 0.905 0.85 0.303
    254 CO2Me
    Figure US20060154949A1-20060713-C00399
     C8H9     		H H
    Figure US20060154949A1-20060713-C00400
     C5H11N2O2     		H Me 488 0.0067 0.664 0.765
    261 CO2Me
    Figure US20060154949A1-20060713-C00401
     C8H9     		H H
    Figure US20060154949A1-20060713-C00402
     C6H11N2O2     		H Me 500 0.0063 0.477 0.63
    262 CO2Me
    Figure US20060154949A1-20060713-C00403
     C8H9     		H H
    Figure US20060154949A1-20060713-C00404
     C6H12N3O    		 H Me 499 0.008 0.702 3.7
  • TABLE 3
    Figure US20060154949A1-20060713-C00405
    Ki (nM)
    A2a
    A2a an- A1
    MS bind- tagonist bind-
    No. R1 R2 R3a R3b R3c R3d R4 (M + 1) ing function ing
    14 CO2Et
    Figure US20060154949A1-20060713-C00406
     C6H4BrO2     		H H H H Me 454 451
    22 CO2Et
    Figure US20060154949A1-20060713-C00407
     C7H5O2     		H H H H NH2 411 (M +23) 70 253
    18 CO2Me
    Figure US20060154949A1-20060713-C00408
     C7H5O2     		H H H H Me 374 159 >1000 584
    27 CO2Et Ph H H H H NH2 345 42 36 554
    23 CO2Et
    Figure US20060154949A1-20060713-C00409
     C7H5O2     		H H H H Me 388 251
    275 CO2Et
    Figure US20060154949A1-20060713-C00410
     C7H4BrO2     		H H H H Me 467 263
    41 CO2Et
    Figure US20060154949A1-20060713-C00411
     C4H3O    		 H H H H Me 334 271
    57 CO2Et
    Figure US20060154949A1-20060713-C00412
     C7H7     		H H H H Me 358 400
    67 CO2Me
    Figure US20060154949A1-20060713-C00413
     C7H7     		H H H H Me 344 39 128 1853
    66 CO2Me
    Figure US20060154949A1-20060713-C00414
     C7H7     		H H H H Me 344 46 151 1591
    85 CO2Me
    Figure US20060154949A1-20060713-C00415
     C6H4Br    		 H H H H Me 431 (M +23) 35 >1000 5570
    82 CO2Me
    Figure US20060154949A1-20060713-C00416
     C8H9     		H NH2 H H Me 373 294
    95 CO2Me
    Figure US20060154949A1-20060713-C00417
     C11H9     		H H H H NH2 395 286
    135 CO2Me
    Figure US20060154949A1-20060713-C00418
     C5H4N    		 H H H H Me 331 123
    130 CO2Me
    Figure US20060154949A1-20060713-C00419
     C6H6N    		 H H H H Me 345 222
    141 CO2Me
    Figure US20060154949A1-20060713-C00420
     C6H5O    		 H H H H Me 346 172
    183 CO2Et
    Figure US20060154949A1-20060713-C00421
     C8H10N    		 H H H H Me 387 191
    208 CO2Me
    Figure US20060154949A1-20060713-C00422
     C7H4N    		 H H H H Me 355 171
    197 CO2Et
    Figure US20060154949A1-20060713-C00423
     C6H5BrN    		 H H H H Me 437 148
    217 CO2Me
    Figure US20060154949A1-20060713-C00424
     C7H6F    		 H H H H Me 362 119
    221 CO2Me
    Figure US20060154949A1-20060713-C00425
     C6H5BrN    		 H H H H Me 423 76 258 2180
    222 CO2Me 2-Pyridyl H H H H Me 353 (M +23) 237
    198 CO2Et
    Figure US20060154949A1-20060713-C00426
     C7H8NO    		 H H H H Me 389 185
    199 CO2Et
    Figure US20060154949A1-20060713-C00427
     C6H3I2O    		 H H H H Me 612 301
    279 CO2Me
    Figure US20060154949A1-20060713-C00428
     C8H9     		H
    Figure US20060154949A1-20060713-C00429
         		H H Me 513 179
    261 CO2Me
    Figure US20060154949A1-20060713-C00430
     C8H9     		H H
    Figure US20060154949A1-20060713-C00431
     C6H11N2O2     		H Me 500 472
    280 CO2Me
    Figure US20060154949A1-20060713-C00432
     C8H9     		H
    Figure US20060154949A1-20060713-C00433
         		H H Me 516 237
    276 CO2Me
    Figure US20060154949A1-20060713-C00434
     C8H9     		H H
    Figure US20060154949A1-20060713-C00435
     C5H6N3O    		 H Me 481 304
    258 CO2Me
    Figure US20060154949A1-20060713-C00436
     C8H9     		H
    Figure US20060154949A1-20060713-C00437
     C6H11N2O2     		H H Me 500 211
    281 CO2Me
    Figure US20060154949A1-20060713-C00438
     C8H9     		H
    Figure US20060154949A1-20060713-C00439
         		H H Me 501 201
    262 CO2Me
    Figure US20060154949A1-20060713-C00440
     C8H9     		H H
    Figure US20060154949A1-20060713-C00441
     C6H12N3O    		 H Me 499 332
    184 CO2Et
    Figure US20060154949A1-20060713-C00442
     C7H8N    		 H H H H Me 373 140
    195 CO2Et
    Figure US20060154949A1-20060713-C00443
     C6H4Cl2N    		 H H H H Me 427 171
    260 CO2Me
    Figure US20060154949A1-20060713-C00444
     C8H9     		H
    Figure US20060154949A1-20060713-C00445
     C5H6N3O    		 H H Me 481 163
    263 CO2Me
    Figure US20060154949A1-20060713-C00446
     C8H9     		H H
    Figure US20060154949A1-20060713-C00447
     C2H4NO2     		H Me 431 480
    245 CO2Me
    Figure US20060154949A1-20060713-C00448
     C8H9     		H H
    Figure US20060154949A1-20060713-C00449
     C4H7N2O3     		H Me 488 276
    264 CO2Me
    Figure US20060154949A1-20060713-C00450
     C7H5O2     		H H H H NH2 397 (M +23) 342
    265 CO2Me Ph H H H H NH2 353 (M +23) 50
    267 CO2Me 2-Furyl H H H H NH2 321 <15
    268 CO2Me 3-Furyl H H H H NH2 321 21
    269 CO2Me 2-Furyl H H H H Me 320 192
    270 CO2Me 2-Furyl H H H NH Me 335 303
    271 CO2Me 2-Furyl NH OH H H H Me 351 276
    272 CO2Et H H H H NH2 335 <5
    273 CO2Et H Br H H NH2 413 279
    274 CO2Et H H Br H NH2 413 143

Claims (22)

1. A method of treating a subject having a disorder ameliorated by reducing PDE activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of a compound having the structure
Figure US20060154949A1-20060713-C00451
wherein
(a) R1 is selected from the group consisting of:
(i) —COR5, wherein R5 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;
wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR20R21 taken together form a heterocycle or heteroaryl;
(ii) COOR6, wherein R6 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;
 wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R20 and R21, are independently selected from the group consisting of hydrogen, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR20R21 taken together form a heterocycle or heteroaryl;
(iii) cyano;
(iv) a lactone or lactam formed with R4;
(v) —CONR7R8 wherein R7 and R8 are independently selected from H, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl;
wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl groups may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl,
 or R7 and R8 taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group;
(vi) a carboxylic ester or carboxylic acid bioisostere including optionally substituted heteroaryl groups
(b) R2 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl and optionally substituted C3-7 cycloalkyl;
(c) R3 is from one to four groups independently selected from the group consisting of:
(i) hydrogen, halo, C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C1-8 carboxylate, aryl, heteroaryl, and heterocyclyl;
(ii) —NR10R11 wherein R10 and R11 are independently selected from H, C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R10 and R11 taken together with the nitrogen form a heteroaryl or heterocyclyl group;
(iii) —NR12COR13 wherein R12 is selected from hydrogen or alkyl and R1-3 is selected from hydrogen, alkyl, substituted alkyl, C13alkoxyl, carboxyalkyl, R30R31N (CH2)p—, R30R31NCO(CH2)p—, aryl, arylalkyl, heteroaryl and heterocyclyl or R12 and R13 taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R30 and R31 are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6,
(d) R4 is selected from the group consisting of (i) hydrogen, (ii) C1-3 straight or branched chain alkyl, (iii) benzyl and (iv) —NR13R14, wherein R13 and R14 are independently selected from hydrogen and C1-6 alkyl;
 wherein the C1-3alkyl and benzyl groups are optionally substituted with one or more groups selected from C3-7 cycloalkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C1-8 carboxylate, amino, NR13R14, aryl and heteroaryl; and
(e) X is selected from S and O;
with the proviso that when R4 is isopropyl, then R3 is not halogen, and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.
2. A method of treating a subject having a disorder ameliorated by reducing PDE activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of a compound having the structure:
Figure US20060154949A1-20060713-C00452
wherein
(a) R1 is selected from the group consisting of:
(i) —COR5, wherein R5 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;
wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR20R21 taken together form a heterocycle or heteroaryl;
(ii) COOR6, wherein R6 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;
wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR20R21 taken together form a heterocycle or heteroaryl;
(i) cyano;
(ii) a lactone or lactam formed with R4;
(iii) —CONR7R8 wherein R7 and R8 are independently selected from H, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl;
wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl groups may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl,
 or R7 and R8 taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group;
(vi) a carboxylic ester or carboxylic acid bioisostere including optionally substituted heteroaryl groups
(b) R2 is —NR15R16 wherein R15 and R16 are independently selected from hydrogen, optionally substituted C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, aryl, heteroaryl, and heterocyclyl or R15 and R16 taken together with the nitrogen form a heteroaryl or heterocyclyl group; with the proviso that when R2 is NHR16, R1 is not —COOR6 where R6 is ethyl;
(c) R3 is from one to four groups independently selected from the group consisting of:
(i) hydrogen, halo, C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C1-8 carboxylate, aryl, heteroaryl, and heterocyclyl;
(ii) —NR10R11 wherein R10and R11 are independently selected from H, C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R10 and R11 taken together with the nitrogen form a heteroaryl or heterocyclyl group;
(iii) —NR12COR13 wherein R12 is selected from hydrogen or alkyl and R13 is selected from hydrogen, alkyl, substituted alkyl, C1-3alkoxyl, carboxyalkyl, R30R31N (CH2)p—, R30R31NCO(CH2)p—, aryl, arylalkyl, heteroaryl and heterocyclyl or R12 and R13 taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R30 and R31, are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6, wherein the alkyl group may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl;
(d) R4 is selected from the group consisting of (i) hydrogen, (ii) C1-3 straight or branched chain alkyl, (iii) benzyl and (iv) —NR13R14, wherein R13 and R14 are independently selected from hydrogen and C1-6 alkyl;
 wherein the C1-3alkyl and benzyl groups are optionally substituted with one or more groups selected from C3-7 cycloalkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C1-8 carboxylate, amino, NR13R14, aryl and heteroaryl; and
(e) X is selected from S and O;
and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.
3. A method of preventing a disorder ameliorated by reducing PDE activity in appropriate cells in a subject, comprising administering to the subject, in need of such treatment, a prophylactically effective dose of a compound as defined in claim 1 or claim 2 either preceding or subsequent to an event anticipated to cause a disorder ameliorated by reducing PDE activity in appropriate cells in the subject.
4. The method of claim 3 comprising administering to the subject a therapeutically or prophylactically effective dose of a pharmaceutical composition comprising a compound as defined in claim 1 or claim 2 and a pharmaceutically acceptable carrier.
5. The method of claim 3 comprising administering to the subject a therapeutically or prophylactically effective dose of the pharmaceutical composition comprising a compound as defined in claim 1 or claim 2 and a pharmaceutically acceptable carrier.
6. A method of inhibiting PDE activity in a subject, which comprises contacting one or more T-cells with a therapeutically effective dose of a compound as defined in claim 1 or claim 2.
7. The method of claim 1 or claim 2, wherein the disorder is selected from the group consisting of transplant-related disorders, inflammatory-related disorders, AIDS-related disorders, vascular diseases, and erectile dysfunction.
8. The method of claim 3, wherein the disorder is selected from the group consisting of transplant-related disorders, inflammatory-related disorders, AIDS-related disorders, vascular diseases, and erectile dysfunction.
9. The method of claim 6, wherein the disorder is selected from the group consisting of transplant-related disorders, inflammatory-related disorders, AIDS-related disorders, vascular diseases, and erectile dysfunction.
10. The method of claim 1 or claim 2, wherein the disorder is selected from the group consisting of hypersensitivity, allergy, arthritis, asthma, bee sting, animal bite, bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, premature labor, a urinary tract disorder, inflammatory bowel disease, stroke, erectile dysfunction, HIV/AIDS, cardiovascular disease, gastrointestinal motility disorder, and psoriasis.
11. A method of artificially modifying an animal, comprising administering to the animal's T-cells a compound as defined in claim 1 or claim 2.
12. The method of claim 11 wherein the animal is a mammal.
13. The method of claim 12 wherein the animal is selected from the group consisting of mouse, rat, rabbit, and guinea pig.
14. A method of treating a subject having a disorder ameliorated by reducing PDE activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of a compound having the structure of Formula I wherein R4 is C1-8 straight or branched chain alkyl and X is O.
15. A method of treating a subject having a disorder ameliorated by antagonizing Adenosine A2a receptors in appropriate cells in the subject, which comprises administering to the subject a therapeutically effective dose of a compound as defined in claim 1 or claim 2.
16. A method of preventing a disorder ameliorated by antagonizing Adenosine A2a receptors in appropriate cells in the subject, comprising administering to the subject a prophylactically effective dose of a compound as defined in claim 1 or claim 2, either preceding or subsequent to an event anticipated to cause a disorder ameliorated by antagonizing Adenosine A2a receptors in appropriate cells in the subject.
17. The method of claim 15 comprising administering to the subject a therapeutically or prophylactically effective dose of a pharmaceutical composition comprising the compound as defined in claim 1 or claim 2 and a pharmaceutically acceptable carrier.
18. The method of claim 16 comprising administering to the subject a therapeutically or prophylactically effective dose of the pharmaceutical composition comprising a compound as defined in claim 1 or claim 2 and a pharmaceutically acceptable carrier.
19. The method of claim 15 or claim 17, wherein the disorder is a neurodegenerative disorder or a movement disorder.
20. The method of claim 19, wherein the disorder is selected from the group consisting of Parkinson's Disease, Huntington's Disease, Multiple System Atrophy, Corticobasal Degeneration, Alzheimer's Disease, and Senile Dementia.
21. The method of claim 16, wherein the disorder is a neurodegenerative disorder or a movement disorder.
22. The method of claim 21, wherein the disorder is selected from the group consisting of Parkinson's Disease, Huntington's Disease, Multiple System Atrophy, Corticobasal Degeneration, Alzheimer's Disease, and Senile Dementia.
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