Arylindenopyridines and related therapeutic and prophylactic methods

Abstract

This invention provides novel arylindenopyridines of the formula: 1

Description

FIELD OF THE INVENTION

[0002] 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

[0003] Adenosine A2a Receptors

[0004] 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).

[0005] 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).

[0006] 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).

[0007] 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).

[0008] Phosphodiesterase Inhibitors

[0009] 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.

[0010] 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.

[0011] 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.

[0012] 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.

[0013] 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): 2

SUMMARY OF THE INVENTION

[0014] This invention provides a compound having the structure of Formula I 3

[0015] or a pharmaceutically acceptable salt thereof, wherein

[0016] (a) R1 is selected from the group consisting of:

[0017] (i) —COR5, wherein R5 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;

[0018] 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 R2 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;

[0019] (ii) COOR6, wherein R6 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;

[0020] 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;

[0021] (iii) cyano;

[0022] (iv) a lactone or lactam formed with R4;

[0023] (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;

[0024] 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,

[0025] or R7 and R8 taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group;

[0026] (vi) a carboxylic ester or carboxylic acid bioisostere including optionally substituted heteroaryl groups

[0027] (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;

[0028] (c) R3 is from one to four groups independently selected from the group consisting of:

[0029] (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;

[0030] (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;

[0031] (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,

[0032] 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;

[0033] (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;

[0034] 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

[0035] (e) X is selected from S and O;

[0036] with the proviso that when R4 is isopropyl, then R3 is not halogen.

[0037] 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.

[0038] This invention also provides a pharmaceutical composition comprising the instant compound and a pharmaceutically acceptable carrier.

[0039] 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.

[0040] 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

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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 4

[0045] 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.

[0046] Preferred substituents for R3 include:

[0047] (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;

[0048] (ii) —NR10R11 wherein R10 and 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;

[0049] (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.

[0050] Particularly, R3 is selected from the group consisting of 5

[0051] alkyl(CO)NH—, NH2, and NO2—

[0052] Preferred embodiments for R4 include hydrogen, C1-3 straight or branched chain alkyl, particularly methyl, amine and amino.

[0053] 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.

[0054] 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: 6

[0055] alkyl(CO)NH—, and R4 is selected from hydrogen, C1-3 straight or branched chain alkyl, particularly methyl, and amino.

[0056] In a preferred embodiment, the compound is selected from the group of compounds shown in Table 1 hereinafter.

[0057] More preferably, the compound is selected from the following compounds: 7

5H-indeno[1,2-b]pyridine-3-carboxylic Acid, 2-amino-4-(1,3-benzodioxol-5-yl)-5-oxo-, Ethyl Ester

[0058] 8

5H-indeno[1,2-b]pyridine-3-carboxylic Acid, 4-(6-bromo-1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, Ethyl Ester

[0059] 9

5H-indeno[1,2-b]pyridine-3-carboxylic Acid, 7-amino-4-(1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, Ethyl Ester

[0060] 10

5H-indeno[1,2-b]pyridine-3-carboxylic Acid, 4-(6-bromo-1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, Methyl Ester

[0061] 11

5H-indeno[1,2-b]pyridine-3-carboxylic Acid, 4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, Methyl Ester

[0062] 12

5H-indeno[1,2-b]pyridine-3-carboxylic Acid, 8-(acetylamino)-4-(1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, Ethyl Ester

[0063] 13

5H-indeno[1,2-b]pyridine-3-carboxylic Acid, 2-methyl-4-(3-methylphenyl)-5-oxo-, Methyl Ester

[0064] 14

5H-indeno[1,2-b]pyridine-3-carboxylic Acid, 7-amino-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, Methyl Ester

[0065] 15

5H-indeno[1,2-b]pyridine-3-carboxylic Acid, 7-amino-2-methyl-4-(4-methyl-1-naphthalenyl)-5-oxo-, Methyl Ester

[0066] 16

5H-indeno[1,2-b]pyridine-3-carboxylic Acid, 4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-8-nitro-5-oxo-, Methyl Ester

[0067] 17

5H-indeno[1,2-b]pyridine-3-carboxylic Acid, 7,8-dichloro-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, Methyl Ester

[0068] 18

5H-indeno[1,2-b]pyridine-3-carboxylic Acid, 7-bromo-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, Methyl Ester

[0069] 19

5H-indeno[1,2-b]pyridine-3-carboxylic Acid, 8-bromo-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, Methyl Ester

[0070] 20

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

[0071] 21

5H-indeno[1,2-b]pyridine-3-carboxylic Acid, 8-[(3-carboxy-1-oxopropyl)amino]-2-methyl4-(4-methyl-1-naphthalenyl)-5-oxo-, Methyl Ester

[0072] 22

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

[0073] 23

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

[0074] 24

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

[0075] 25

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

[0076] 26

5H-indeno[1,2-b]pyridine-3-carboxylic Acid, 4-(3,5-dimethylphenyl)-2-methyl-8-[(4-morpholinylacetyl)amino]-5-oxo-, Methyl Ester

[0077] 27

5H-indeno[1,2-b]pyridine-3-carboxylic Acid, 4-(3,5-dimethylphenyl)-2-methyl-5-oxo-8-[(1-piperazinylacetyl)amino]-, Methyl Ester

[0078] 28

5H-indeno[1,2-b]pyridine-3-carboxylic Acid, 4-phenyl-2-amino-5-oxo-, Ethyl Ester

[0079] 29

5H-indeno[1,2-b]pyridine-3-carboxylic Acid, 4-(4-methylphenyl)-2-methyl-5-oxo-, Methyl Ester

[0080] 30

5H-indeno[1,2-b]pyridine-3-carboxylic Acid, 4-(3-bromophenyl)-2-methyl-5-oxo-, Methyl Ester

[0081] 31

5H-indeno[1,2-b]pyridine-3-carboxylic Acid, 4-(3-bromophenylamino)-2-methyl-5-oxo-, Methyl Ester

[0082] 32

5H-indeno[1,2-b]pyridine-3-carboxylic Acid, 4-phenyl-2-amino-5-oxo-, Methyl Ester

[0083] 33

5H-indeno[1,2-b]pyridine-3-carboxylic Acid, 4-(2-furyl)-2-amino-5-oxo-, Methyl Ester

[0084] 34

5H-indeno[1,2-b]pyridine-3-carboxylic Acid, 4-(3-furyl)-2-amino-5-oxo-, Methyl Ester

[0085] 35

5H-indeno[1,2-b]pyridine-3-carboxylic Acid, 4-(2-furyl)-2-amino-5-oxo-, Ethyl Ester

[0086] 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.

[0087] This invention also provides a pharmaceutical composition comprising the instant compound and a pharmaceutically acceptable carrier.

[0088] 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 Ringers 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.

[0089] 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.

[0090] 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.

[0091] In one preferred embodiment, the disorder is rheumatoid arthritis.

[0092] In another preferred embodiment, the disorder is Parkinson's disease.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] Definitions and Nomenclature

[0100] 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.

[0101] 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;

[0102] “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.

[0103] “Alkoxy” shall mean —O-alkyl and unless otherwise stated, it will have 1-8 carbon atoms.

[0104] The term “bioisostere” is defined as “groups or molecules which have chemical and physical properties producing broadly similar to logical properties.” (Burger's Medicinal Chemistry and Drug Discovery, M. E. Wolff, ed. Fifth Edition, Vol. 1, 1995, Pg. 785).

[0105] “Halogen” shall mean fluorine, chlorine, bromine or iodine; “PH” or “Ph” shall mean phenyl; “Ac” shall mean acyl; “Bn” shall mean benzyl.

[0106] 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.

[0107] “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.

[0108] 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.

[0109] The terms “heterocycle,” “heterocyclic,” and “heterocyclo” 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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

[0117] I. General Synthetic Schemes

[0118] 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. 36

[0119] 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.

[0120] 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.

[0121] 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). 37

[0122] 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. 38

[0123] 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. 39

[0124] 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. 40

[0125] 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. 41

[0126] 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). 42

[0127] 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. 43

[0128] 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. 44

[0129] 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). 45

[0130] 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. 46

[0131] II. Specific Compound Syntheses

[0132] 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.

[0133] 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)

[0134] 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)

[0135] 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; R4=Me)

[0136] 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)

[0137] 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)

[0138] 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)

[0139] 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)

[0140] 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)

[0141] 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)

[0142] 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)

[0143] 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-methoxyphenyl) and 1,3-indandione)

[0144] 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)

[0145] 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)

[0146] 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)

[0147] 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)

[0148] 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=0; n=2; R4=Me)

[0149] 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)

[0150] 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)

[0151] 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)

[0152] 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)

[0153] 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

[0154] 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)

[0155] 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)

[0156] 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).

[0157] Following the general synthetic procedures outlined above and in Examples 1-21, the compounds of Table 1 below were prepared.

TABLE 1
	Ia
47
								MS
No.	R1	R2	R3a	R3b	R3c	R3d	R4	(M + 1)
1	CN	48C7H5O2	H	H	H	H	Me	341
2	CO2Et	49C7H5O2	H	H	H	H	Me	388
3	CO2t-Bu	50C7H5O2	H	H	H	H	Me	416
4	CO2t-Bu	51C8H9O2	H	H	H	H	Me	432
5	CO2Et	52C6H4NO2	H	H	H	H	Me	389
6	CO2H	53C7H5O2	H	H	H	H	Me	360
7	CO2Et	54C14H13O2	H	H	H	H	Me	480
8	CO2Et	55C8H8BrO2	H	H	H	H	Me	482
9	CO2Et	56C11H9O2	H	H	H	H	Me	424
10	CO2H	57C8H9O2	H	H	H	H	Me	376
11	CO2Et	Ph	H	H	H	H	Me	344
12	CO2Et	58C7H7O2	H	H	H	H	Me	374
13	CO2Et	59C9H11O2	H	H	H	H	Me	434
14	CO2Et	60C6H4BrO2	H	H	H	H	Me	454
15	CO2Bn	61C7H5O2	H	H	H	H	Me	450
16	62C11H14NO2	63C7H5O2	H	H	H	H	Me	507
17	CO2Me	64C8H9O2	H	H	H	H	Me	390
18	CO2Me	65C7H5O2	H	H	H	H	Me	374
19	CO2Et	66C8H9O2	H	H	H	H	Me	404
20	CO2Et	67C8H9O2	H	H	H	H	Me	404
21	CO2Et	68C7H6BrO	H	H	H	H	Me	454
22	CO2Et	69C7H5O2	H	H	H	H	NH2	411 (M +23)
23	CO2Et	70C7H5O2	H	H	H	H	Me	388
25	CO2Et	71C8H9O2	H	H	H	H	NH2	405
26	CO2Et	72C6H4NO2	H	H	H	H	NH2	390
27	CO2Et	Ph	H	H	H	H	NH2	345
28	CO2Et	73C9H11O	H	H	H	H	Me	402
29	CO2Et	74C8H8BrO2	H	H	H	H	Me	483
30	CO2Me	Ph	H	H	H	H	Me	330
31	CO2Et	75C8H7O2	H	H	H	H	Me	402
32	CO2Et	76C7H5O2	H	NO2	H	H	Me	433
33	77C4H4NO2	78C7H5O2	H	H	H	H	Me	413
34	CO2Et	79C7H4NO2	H	H	H	H	Me	433
35	CO2Et	80C7H5O2	H	H	NO2	H	Me	433
36	CO2Me	81C7H4F3	H	H	H	H	Me	398
37	CO2Et	82C7H5O2	H	H	NH2	H	Me	403
38	CONH2	83C7H5O2	H	H	H	H	Me	359
39	CO2Et	84C8H9	H	H	H	H	Me	372
40	CO2Et	85C7H5O2	H	NH2	H	H	Me	403
41	CO2Et	86C4H3O	H	H	H	H	Me	334
42	CO2Et	2-Thienyl	H	H	H	H	Me	350
43	CO2Me	87C8H9	H	H	H	H	Me	358
44	CO2Me	88C7H5O2	H	H	H	H	Me	388
45	CO2Me	89C7H4NO2	H	H	H	H	Me	419
46	CO2Me	90C9H11O	H	H	H	H	Me	388
47	CO2Me	4-Pyridyl	H	H	H	H	Me	331
48	CO2Me	91C7H5O2	H	H	H	H	Me	374
49	CO2Me	92C7H4BrO2	H	H	H	H	Me	454
50	CO2Me	93C7H6BrO	H	H	H	H	Me	439
51	CO2Me	94C8H9	H	H	H	H	Me	358
52	CO2Et	95C8H9	H	H	H	H	Me	372
53	CO2Me	96C11H9	H	H	H	H	Me	410
54	CO2Me	97C6H4NO2	H	H	H	H	Me	375
55	CO2Et	98C7H5O2	H	NHAc	H	H	Me	445
56	CO2Et	99C7H5O2	H	H	NHAc	H	Me	445
57	CO2Et	100C7H7	H	H	H	H	Me	358
58	CO2Et	101C7H7	H	H	H	H	Me	358
59	CO2Et	102C7H7	H	H	H	H	Me	358
60	CO2Et	103C7H5F3	H	NO2	H	H	Me	457
61	CO2Et	104C7H4F3	H	H	NO2	H	Me	457
62	CO2Me	105C7H7	H	H	H	H	Me	344
63	CO2Et	106C7H4F3	H	NH2	H	H	Me	427
64	CO2Et	107C7H4F3	H	H	NH2	H	Me	427
65	CO2Me	108C8H2F6	H	H	H	H	Me	466
66	CO2Me	109C7H7	H	H	H	H	Me	344
67	CO2Me	110C7H7	H	H	H	H	Me	344
68	CO2Me	111C7H4F3	H	NO2	H	H	Me	443
69	CO2Me	112C7H4F3	H	H	NO2	H	Me	443
70	CO2Et	113C8H9	H	H	H	H	i-Pr	400
71	CO2Me	114C7H4F3	H	NH2	H	H	Me	413
72	CO2Me	115C6H3Cl2	H	H	H	H	Me	399
73	CO2Me	116C8H9	H	H	H	H	Et	372
74	CO2Me	117C7H4F3	H	H	H	H	Me	398
75	CO2Me	118C11H9	H	H	H	H	Me	394
76	CO2Me	119C9H11	H	H	H	H	Me	372
77	CO2Me	120C8H9	H	NO2	H	H	Me	403
78	CO2Me	121C8H9	H	H	NO2	H	Me	403
79	CO2Me	122C8H9	H	H	H	H	Me	394
80	CO2Me	123C7H4F3	H	NHAc	H	H	Me	455
81	CO2Me	124C6H3Br2	H	H	H	H	Me	488
82	CO2Me	125C8H9	H	NH2	H	H	Me	373
83	CO2Me	126C8H9	H	H	NH2	H	Me	373
84	CO2Me	127C7H6F	H	H	H	H	Me	362
85	CO2Me	128C6H4Br	H	H	H	H	Me	431 (M +23)
86	CO2Me	129C10H7	H	H	H	H	Me	380 (M +23)
87	CO2Me	130C11H9	H	NO2	H	H	Me	439
88	CO2Me	131C11H9	H	H	NO2	H	Me	439
89	CO2Me	132C14H9	H	H	H	H	Me	430
90	CO2Me	133C11H9	H	NH2	H	H	Me	409
91	CO2Me	134C11H9	H	H	NH2	H	Me	409
92	135C4H4NO2	136C8H9	H	H	H	H	Me	397
93	CN	137C8H9	H	H	H	H	Me	325
94	CO2Me	138C8H9	H	H	H	H	NH2	359
95	CO2Me	139C11H9	H	H	H	H	NH2	395
96	CO2H	140C8H9	H	H	H	H	Me	344
97	141C4H4NO2	142C11H9	H	H	H	H	Me	433
98	CN	143C11H9	H	H	H	H	Me	361
99	144C2H2O2	145C7H4F3	H	H	H	H	C2H2O2	358
100	146C2H2O2	147C8H10N	H	H	H	H	C2H2O2	357
101	148C2H2O2	Ph	H	H	H	H	C2H2O2	314
102	149C2H2O2	p-C6H4NO2	H	H	H	H	C2H2O2	361
103	150C2H2O2	151C10H7	H	H	H	H	C2H2O2	364
104	152C2H2O2	153C8H9	H	H	H	H	C2H2O2	342
105	CO2H	154C11H9	H	H	H	H	Me	380
106	CONH2	155C8H9	H	H	H	H	Me	343
107	CONHMe	156C8H9	H	H	H	H	Me	357
108	CONMe2	157C8H9	H	H	H	H	Me	371
109	158C2H2O2	159C11H9	H	H	H	H	C2H2O2	378
110	160C2H2O2	161C7H7	H	H	H	H	C2H2O2	328
111	162C2H2O2	163C9H11	H	H	H	H	C2H2O2	356
112	164C2H2O2	165C7H7	H	H	H	H	C2H2O2	328
113	CO2Me	166C6H4NO2	H	H	H	H	Me	375
114	167C2H2O2	168C7H7	H	H	H	H	C2H2O2	328
115	CO2Me	169C8H10N	H	H	H	H	Me	373
116	CONH3	170C11H9	H	H	H	H	Me	379
117	171C2H2O2	172C9H6N	H	H	H	H	C2H2O2	365
118	CO2Me	173C6H4NO2	H	H	H	H	Me	375
119	CONHMe	174C11H9	H	H	H	H	Me	393
120	CONMe2	175C11H9	H	H	H	H	Me	407
121	CO2Me	176C9H6N	H	H	H	H	Me	381
122	CO2Me	177C11H9	H	Cl	Cl	H	Me	463
123	CO2Me	178C8H9	H	Cl	Cl	H	Me	427
124	CO2Me	179C9H6N	H	H	H	H	Me	381
125	CO2Et	180C11H9	H	H	H	H	Me	408
126	CO2Me	181C6H3Br2	H	Cl	Cl	H	Me	555
127	CO2Me	182C8H9	Cl	H	H	Cl	Me	427
128	CO2Me	2-NO2-4,5-	H	H	H	H	Me	421
		OCH2O—
		C6H2
129	CO2Me	183C6H3Br2	Cl	H	H	Cl	Me	558
130	CO2Me	184C6H6N	H	H	H	H	Me	345
131	CO2Et	185C11H9	H	Cl	Cl	H	Me	477
132	CO2Me	186C6H4Br2N	H	H	H	H	Me	503
133	Ac	187C6H3Br2	H	H	H	H	Me	472
134	Ac	188C8H9	H	H	H	H	Me	342
135	CO2Me	189C5H4N	H	H	H	H	Me	331
136	190C4H4NO2	191C6H3Br2	H	H	H	H	Me	527
137	192C4H4NO2	193C8H9	H	H	H	H	Me	397
138	CO2Me	194C6H5O2	H	H	H	H	Me	362
139	CO2H	195C6H3Br2	H	H	H	H	Me	474
140	CO2H	196C8H9	H	H	H	H	Me	344
141	CO2Me	197C6H5O	H	H	H	H	Me	346
142	CO2Me	198C10H7	H	H	H	H	Me	380
143	CO2Me	199C16H25O	H	H	H	H	Me	486
144	CO2Me	200C13H11O	H	H	H	H	Me	436
145	CO2Me	201C7H5Br2O	H	H	H	H	Me	518
146	202C4H4NO2	203C7H5Br2O	H	H	H	H	Me	557
147	204C4H4NO2	205C8H9	H	Cl	Cl	H	Me	466
148	CO2Et	—NHPh	H	H	H	H	Me	359
149	CO2Me	206C7H7O	H	H	H	H	Me	360
150	CO2Me	207C6H3Br2O	H	H	H	H	Me	504
151	208C4H4NO2	209C9H6N	H	H	H	H	Me	420
152	C3H5O3	210C6H3Br2	H	H	H	H	Me	534
153	211C4H4NO2	212C6H5O	H	H	H	H	Me	385
154	213C2H4NO2	214C8H9	H	H	H	H	Me	373
155	215C4H4NO2	216C6H3Br2	H	H	NO2	H	Me	574
156	CO2Me	217C11H9	H	Br	H	H	Me	473
157	CO2Me	218C11H9	H	H	Br	H	Me	473
158	219	220C9H6N	H	Cl	Cl	H	Me	489
159	221C4H4NO2	222C6H3Br2O	H	H	NO2	H	Me	590
160	223C3H5O2	224C9H6N	H	H	H	H	Me	411
161	CO2Me	225C8H9	H	Br	H	H	Me	436
162	CO2Me	226C8H9	H	H	Br	H	Me	438
163	CO2Me	227C8H9	H	Br	Br	H	Me	516
164	228C4H4NO2	229C6H3Br2	H	Cl	Cl	H	Me	597
165	230C3H5O2	231C9H6N	H	Cl	Cl	H	Me	480
166	CO2Me	232C11H9	H	Br	Br	H	Me	552
167	CO2Et	233C8H9	H	Br	Br	H	Me	530
168	CO2Me	234C6H3Br2O	F	H	H	F	Me	540
169	CO2Me	235C6H3Br2O	H	H	NO2	H	Me	551
170	CO2Me	236C6H3Br2O	H	Cl	Cl	H	Me	573
171	237C4H4NO2	238C8H9	H	H	NO2	H	Me	444
172	239C4H4NO2	240C8H9	H	NO2	H	H	Me	444
173	CO2Me	241C8H9	F	H	H	F	Me	394
174	242C4H4NO2	243C8H9	F	H	H	F	Me	433
175	CO2Me	244C8H9O2	H	Br	Br	H	Me	548
176	CO2Me	245C7H4N	H	H	H	H	Me	355
177	CO2Me	246C8H9O	H	NO2	H	H	Me	421
178	CO2Me	247C8H9O	H	H	NO2	H	Me	453 (M +23)
179	CO2Me	248C8H9O	H	Cl	Cl	H	Me	443
180	CN	249C8H9O	H	H	H	H	Me	341
181	CO2Me	250C6H3I2O	H	H	H	H	Me	598
182	CO2Me	251C6H3F2	H	Cl	Cl	H	Me	435
183	CO2Et	252C8H10N	H	H	H	H	Me	387
184	CO2Et	253C7H8N	H	H	H	H	Me	373
185	CO2Me	254C7H2I2O	H	H	H	H	Me	612
186	CO2Et	255C9H2N2	H	H	H	H	Me	410
187	CO2Me	256C7H2I2O	H	H	NO2	H	Me	345
188	CO2Me	257C6H3F2	H	Cl	Cl	H	Me	668
189	CO2H	258C6H3F2	H	H	NO2	H	Me	413
190	CO2H	259C6H2Br2	H	Cl	Cl	H	Me	544
191	CN	260C6H3I2O	H	H	H	H	Me	565
192	CO2Me	261C6H3Br2O	H	Br	H	H	Me	606 (M +23)
193	CO2Me	262C6H3Br2O	H	H	Br	H	Me	584
194	CO2Et	263C7H8N	H	H	H	H	Me	373
195	CO2Et	264C6H3Cl2N	H	H	H	H	Me	427
196	CO2Et	265C6H3Br2O	H	Cl	Cl	H	Me	587
197	CO2Et	266C6H5BrN	H	H	H	H	Me	437
198	CO2Et	267C7H8NO	H	H	H	H	Me	389
199	CO2Et	268C6H3I2O	H	H	H	H	Me	612
200	CO2Et	269C6H3F2	H	Cl	Cl	H	Me	449
201	CO2Me	270C9H6N	H	Cl	Cl	H	Me	450
202	CO2Me	271C7H5F2O	H	Cl	Cl	H	Me	465
203	CO2Me	272C7H5F2O	H	H	H	H	Me	396
204	CO2Me	273C8H9	274C4H6NO3	H	H	Me	473
205	CO2Me	275C6H6N	H	H	H	H	Me	345
206	CO2Me	276C7H8N	H	H	H	H	Me	359
207	CO2Me	277C6H4NO2	H	Cl	Cl	H	Me	444
208	CO2Me	278C7H4N	H	H	H	H	Me	355
209	CO2H	279C10H7	H	H	H	H	Me	366
210	CO2Me	280C6H4NO2	H	Cl	Cl	H	Me	444
211	CO2Me	281C7H6F	H	Cl	Cl	H	Me	430
212	CO2Me	282C7H3F4	H	H	H	H	Me	416
213	CO2Me	283C7H6F	H	Cl	Cl	H	Me	430
214	CO2Me	284C7H4Cl2N	H	H	H	H	Me	413
215	CO2Me	285C8H9	H	OMe	OMe	H	Me	418
216	CO2Me	286C11H9	H	Me	OMe	H	Me	454
217	CO2Me	287	H	H	H	H	Me	362
218	CO2Me	288	H	289	H	H	Me	445
219	CO2Me	290	H	H	H	H	Me	359
220	CO2Me	NHPh	H	H	H	H	Me	345
221	CO2Me	291	H	H	H	H	Me	423
222	CO2Me	2-Pyridyl	H	H	H	H	Me	353 (M +23)
223	CO2Me	292	H	OMe	OMe	H	Me	459
224	CO2Me	293	H	Cl	Cl	H	Me	485
225	CO2Me	294	H	H	H	H	Me	345
226	CO2Me	295	H	H	NO2	H	Me	420
227	CO2Me	296	H	H	NO2	H	Me	420
228	CO2Me	297	H	H	H	H	Me	359
229	CO2Me	298	H	H	H	H	Me	396
230	CO2Me	299	H	OH	OH	H	Me	426
231	CO2Me	300	H	H	F	H	Me	376
232	CO2Me	301	H	H	NO2	H	Me	461
233	CO2Me	302	H	Cl	Cl	H	Me	468
234	CO2Me	303	H	H	H	H	Me	373
235	CO2Me	304	H	H	H	H	Me	375
236	CO2Me	305	H	NO2	H	H	Me	443
237	CO2Me	306	H	H	NO2	H	Me	443
238	CO2Me	307	H	H	H	H	Me	398
239	CO2Me	308	H	Cl	Cl	H	Me	491
240	CO2Me	309	H	310	H	H	Me	509
241	CO2Me	311	H	H	312	H	Me	473
242	CO2Me	313	H	H	314	H	Me	509
243	CO2Me	315	H	H	H	H	Me	310
244	CO2Me	316	H	317	H	H	Me	524
245	CO2Me	318	H	H	319	H	Me	488
246	CO2Me	320	H	H	H	H	Me	308
247	CO2Me	i-Pr	H	H	H	H	Me	296
248	CO2Me	321	H	H	H	H	Me	336
249	CO2Me	Me	H	H	H	H	Me	268
250	Co2Me	322	H	H	323	H	Me	474
251	CO2Me	324	H	H	325	H	Me	487
252	CO2Me	N-	H	H	H	H	Me	339
		Morpholino
253	CO2Me	326	H	H	H	H	Me	337
254	Cd 11H9	H	327C4H7N2O3	H	H	Me	524
245	CO2Me	328C8H9	H	H	329C4H7N2O3	H	Me	488
246	CO2Me	330C4H7	H	H	H	H	Me	308
247	CO2Me	i-Pr	H	H	H	H	Me	296
248	CO2Me	331Cyclohexyl	H	H	H	H	Me	336
249	CO2Me	Me	H	H	H	H	Me	268
250	Co2Me	332C8H9	H	H	333C4H9N2O2	H	Me	474
251	CO2Me	334C8H9	H	H	335C5H8NO3	H	Me	487
252	CO2Me	N- Morpholino	H	H	H	H	Me	339
253	CO2Me	336C5H10N	H	H	H	H	Me	337
254	CO2Me	337C8H9	H	H	338C5H11N2O2	H	Me	488
255	CO2Me	339C8H9	H	340C4H9N2O2	H	H	Me	474
256	CO2Me	341C8H9	H	342C4H7N2O	H	H	Me	456
257	CO2Me	343C8H9	H	344C2H4NO2	H	H	Me	431
258	CO2Me	345C8H9	H	346C6H11N2O2	H	H	Me	500
259	CO2Me	347C8H9	H	348C6H12N3O	H	H	Me	499
260	CO2Me	349C8H9	H	350C5H6N3O	H	H	Me	481
261	CO2Me	351C8H9	H	H	352C6H11N2O2	H	Me	500
262	CO2Me	353C8H9	H	H	354C6H12N3O	H	Me	499
263	CO2Me	355C8H9	H	H	356C2H4NO2	H	Me	431
264	CO2Me	357C7H5NO2	H	H	H	H	NH2	397 (M +23)
265	CO2Me	Ph	H	H	H	H	NH2	353 (M +23)
266	CO2Me	358C8H9O2	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	Br	H	NH2	413
275	CO2Et	359C7H4BrO2	H	H	H	H	Me	467
276	CO2Me	360C8H9	H	H	361C5H6N3O	H	Me	481
277	CO2Me	362C8H9	H	H	3634H7N2O	H	Me	456
278	CO2Me	364C8H9	H	365C4H6NO3	H	H	Me	473
279	CO2Me	366C8H9	H	367	H	H	Me	513
280	CO2Me	368C8H9	H	369	H	H	Me	516
281	CO2Me	370C8H9	H	371	H	H	Me	501
282	CO2Me	372C8H9	H	373	H	H	Me	566
283	CO2Me	374C8H9	H	375	H	H	Me	488
284	CO2Me	376C8H9	H	H	377	H	Me	541

[0158] III. Biological Assays and Activity

[0159] Ligand Binding Assay for Adenosine A2a Receptor

[0160] Ligand binding assay of adenosine A2a receptor was performed using plasma membrane of HEK293 cells containing human A2a adenosine receptor (PerkinElmer, RB-HA2a) and radioligand [3H]CGS21680 (PerkinElmer, NET 1021). 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 mL assay 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)

[0161] Adenosine A2a Receptor Functional Assay

[0162] 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)

[0163] Assay of Phosphodiesterase Activity

[0164] 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.

[0165] 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.

[0166] 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.

[0167] 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 1 $$ % ⁢   ⁢ Inhibition ⁢   ⁢ listed ⁢   ⁢ in ⁢   ⁢ Table ⁢   ⁢ 1 = ( 1 - Sample ⁢   ⁢ CPM ⁢ - ⁢ NSB ) ) TB ⁢ - ⁢ NSB × 100

[0168] 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
	Ia
378
								MS	IC50 (μM)/% inh. @ μM
No.	R1	R2	R3a	R3b	R3c	R3d	R4	(M + 1)	PDE7A	PDE4	PDE5
6	CO2H	379	H	H	H	H	Me	360	45% @20	49% @5
51	CO2Me	380	H	H	H	H	Me	358	0.055	0.353	2.7
56	CO2Et	381	H	H	NHAc	H	Me	445	0.074	0.333	2.5
70	CO2Et	382	H	H	H	H	i-Pr	400	2.11
73	CO2Me	383	H	H	H	H	Et	372	1.54		0.998
82	CO2Me	384	H	NH2	H	H	Me	373	0.021	0.204	1.11, 0.864
90	CO2Me	385	H	NH2	H	H	Me	409	0.005	0.237, 0.172	2.33
98	CN	386	H	H	H	H	Me	361	1.13
119	CONHMe	387	H	H	H	H	Me	393	0.658		41% @20
133	Ac	388	H	H	H	H	Me	472	1.54
134	Ac	389	H	H	H	H	Me	342	1.14
169	CO2Me	390	H	H	NO2	H	Me	551	0.0053		0.184
170	CO2Me	391	H	Cl	Cl	H	Me	573	0.0087		0.557
190	CO2H	392	H	Cl	Cl	H	Me	544	5.9
191	CN	393	H	H	H	H	Me	565	0.593
197	CO2Et	394	H	H	H	H	Me	437	0.728	69% @5	0.362
219	CO2Me	395	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	396	H	H	397	H	Me	473	0.0035	0.954	0.183
242	CO2Me	398	H	H	399	H	Me	509	0.0038	0.782	0.141
243	CO2Me	400	H	H	H	H	Me	310	2.6
245	CO2Me	401	H	H	402	H	Me	488	0.0053	0.875	0.185
248	CO2Me	403	H	H	H	H	Me	336	0.783	0.171	0.649
250	CO2Me	404	H	H	405	H	Me	474	0.0074	0.684	2.4
251	CO2Me	406	H	H	407	H	Me	487	0.0054	0.754	0.26
253	CO2Me	408	H	H	H	H	Me	337	0.905	0.85	0.303
254	CO2Me	409	H	H	410	H	Me	488	0.0067	0.664	0.765
261	CO2Me	411	H	H	412	H	Me	500	0.0063	0.477	0.63
262	CO2Me	413	H	H	414	H	Me	499	0.008	0.702	3.7

[0169]

TABLE 3
	Ia
415
									Ki (nM)
										A2a
								MS	A2a	antagonist	A1
No.	R1	R2	R3a	R3b	R3c	R3d	R4	(M + 1)	binding	function	binding
14	CO2Et	416	H	H	H	H	Me	454	451
22	CO2Et	417	H	H	H	H	NH2	411 (M + 23)	70	253
18	CO2Me	418	H	H	H	H	Me	374	159	>1000	584
27	CO2Et	Ph	H	H	H	H	NH2	345	42	36	554
23	CO2Et	419	H	H	H	H	Me	388	251
275	CO2Et	420	H	H	H	H	Me	467	263
41	CO2Et	421	H	H	H	H	Me	334	271
57	CO2Et	422	H	H	H	H	Me	358	400
67	CO2Me	423	H	H	H	H	Me	344	39	128	1853
66	CO2Me	424	H	H	H	H	Me	344	46	151	1591
85	CO2Me	425	H	H	H	H	Me	431 (M + 23)	35	>1000	5570
82	CO2Me	426	H	NH2	H	H	Me	373	294
95	CO2Me	427	H	H	H	H	NH2	395	286
135	CO2Me	428	H	H	H	H	Me	331	123
130	CO2Me	429	H	H	H	H	Me	345	222
141	CO2Me	430	H	H	H	H	Me	346	172
183	CO2Et	431	H	H	H	H	Me	387	191
208	CO2Me	432	H	H	H	H	Me	355	171
197	CO2Et	433	H	H	H	H	Me	437	148
217	CO2Me	434	H	H	H	H	Me	362	119
221	CO2Me	435	H	H	H	H	Me	423	76	258	2180
222	CO2Me	2-Pyridyl	H	H	H	H	Me	353	237
								(M + 23)
198	CO2Et	436	H	H	H	H	Me	389	185
199	CO2Et	437	H	H	H	H	Me	612	301
279	CO2Me	438	H	439	H	H	Me	513	179
261	CO2Me	440	H	H	441	H	Me	500	472
280	CO2Me	442	H	443	H	H	Me	516	237
276	CO2Me	444	H	H	445	H	Me	481	304
258	CO2Me	446	H	447	H	H	Me	500	211
281	CO2Me	448	H	449	H	H	Me	501	201
262	CO2Me	450	H	H	451	H	Me	499	332
184	CO2Et	452	H	H	H	H	Me	373	140
195	CO2Et	453	H	H	H	H	Me	427	171
260	CO2Me	454	H	455	H	H	Me	481	163
263	CO2Me	456	H	H	457	H	Me	431	480
245	CO2Me	458	H	H	459	H	Me	488	276
264	CO2Me	460	H	H	H	H	NH2	397 (M + 23)	342
265	CO2Me	Ph	H	H	H	H	NH2	353	50
								(M + 23)
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	NH2	Me	335	303
271	CO2Me	2-Furyl	NHOH	H	H	H	Me	351	276
272	CO2Et	2-Furyl	H	H	H	H	NH2	335	>5
273	CO2Et	2-Furyl	H	Br	H	H	NH2	413	279
274	CO2Et	2-Furyl	H	H	Br	H	NH2	413	143

Claims

1. A compound having the structure

2. The compound of claim 1, wherein R1 is COOR6, wherein R6 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl.

3. The compound of claim 2, wherein R6 is selected from H, or C1-8 straight or branched chain alkyl which may be optionally substituted with a substituent selected from CN and hydroxy.

4. The compound of claim 1, wherein R2 is selected from optionally substituted aryl and optionally substituted heteroaryl.

5. The compound of claim 4 wherein the aryl or heteroaryl groups are substituted with, one to five members selected from the group consisting of halogen, alkyl, alkoxy, alkoxyphenyl, halo, triflouromethyl, trifluoro or difluoromethoxy, amino, alkylamino, hydroxy, cyano, and nitro.

6. The compound of claim 4 wherein, R2 is optionally substituted furan, phenyl, napthyl or

7. The compound of claim 1 wherein R3 is selected from: (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 R10 and 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, R30R31 N (CH2)p-, R30R31 NCO(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.

8. The compound of claim 7, wherein R3 is selected from the group consisting of:

9. The compound of claim 1 wherein R4 is selected from hydrogen, and C1-3 straight or branched chain alkyl.

10. The compound of claim 1, wherein R4 is selected from the group consisting of methyl, amine and amino.

11. The compound of claim 1 wherein R1 is COOR6 and R2 is selected from the group consisting of substituted phenyl, and substituted naphthyl.

12. The compound of claim 1 wherein R1 is COOR6 where R6 is alkyl, R2 is substituted phenyl or naphthyl, and R3 is selected from the group consisting of H, nitro, amino, NHAc, halo, hydroxy, alkoxy, or a moiety of the formulae:

13. A compound having the structure:

14. The compound of claim 13, wherein R1 is COOR6 wherein R6 is alkyl, R2 is NR6R7, and R3 is selected from the group consisting of

15. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester.

16. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-(acetylamino)-4-(1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester.

17. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-amino-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester.

18. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-amino-2-methyl-4-(4-methyl-1-naphthalenyl)-5-oxo-, methyl ester.

19. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-8-nitro-5-oxo-, methyl ester.

20. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7,8-dichloro-4-(3,5-dibromo4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester.

21. The compound of claim 1, which is 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.

22. The compound of claim 1, which is 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.

23. The compound of claim 1, which is 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.

24. The compound of claim 1, which is 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.

25. The compound of claim 1, which is 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.

26. The compound of claim 1, which is 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.

27. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-2-methyl-8-[(4-morpholinylacetyl)amino]-5-oxo-, methyl ester.

28. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-2-methyl-5-oxo-8-[(1-piperazinylacetyl)amino]-, methyl ester.

29. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 2-amino-4-(1,3-benzodioxol-5-yl)-5-oxo-, ethyl ester.

30. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(6-bromo-1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester.

31. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-amino-4-(1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester.

32. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(6-bromo-1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, methyl ester.

33. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 2-methyl-4-(3-methylphenyl)-5-oxo-, methyl ester.

34. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-bromo-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester.

35. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-bromo-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester.

36. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-phenyl-2-amino-5-oxo-, ethyl ester.

37. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(4-methylphenyl)-2-methyl-5-oxo-, methyl ester.

38. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3-bromophenyl)-2-methyl-5-oxo-, methyl ester.

39. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3-bromophenylamino)-2-methyl-5-oxo-, methyl ester.

40. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-phenyl-2-amino-5-oxo-, methyl ester.

41. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(2-furyl)-2-amino-5-oxo-, methyl ester.

42. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3-furyl)-2-amino-5-oxo-, methyl ester.

43. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(2-furyl)-2-amino-5-oxo-, ethyl ester.

44. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

45. A pharmaceutical composition comprising the compound of claim 13 and a pharmaceutically acceptable carrier.

46. 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 the compound of claim 1 or 13.

47. A method of preventing a disorder ameliorated 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 or 13 either preceding or subsequent to an event anticipated to cause a disorder ameliorated by reducing PDE activity in appropriate cells in the subject.

48. The method of claim 46 comprising administering to the subject a therapeutically or prophylactically effective dose of the pharmaceutical composition of claim 44 or 45.

49. The method of claim 47 comprising administering to the subject a therapeutically or prophylactically effective dose of the pharmaceutical composition of claim 44 or 45.

50. A method of inhibiting PDE activity in a subject, which comprises contacting one or more T-cells with a therapeutically effective dose of the compound of claim 1 or 13.

51 The method of claim 46, wherein the disorder is selected from the group consisting of transplant-related disorders, inflammatory-related disorders, AIDS-related disorders, vascular diseases, and erectile dysfunction.

52. The method of claim 47, wherein the disorder is selected from the group consisting of transplant-related disorders, inflammatory-related disorders, AIDS-related disorders, vascular diseases, and erectile dysfunction.

53. The method of claim 50, wherein the disorder is selected from the group consisting of transplant-related disorders, inflammatory-related disorders, AIDS-related disorders, vascular diseases, and erectile dysfunction.

54. The method of claim 46, 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.

55. A method of artificially modifying an animal, comprising administering to the animal's T-cells a compound of claim 1 or 13.

56. The method of claim 55 wherein the animal is a mammal.

57. The method of claim 56 wherein the animal is selected from the group consisting of mouse, rat, rabbit, and guinea pig.

58. 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.

59. 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 the compound of claim 1 or 13.

60. 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 the compound of claim 1 or 13 either preceding or subsequent to an event anticipated to cause a disorder ameliorated by antagonizing Adenosine A2a receptors in appropriate cells in the subject.

61. The method of claim 59 comprising administering to the subject a therapeutically or prophylactically effective dose of the pharmaceutical composition of claim 44 or 45.

62. The method of claim 60 comprising administering to the subject a therapeutically or prophylactically effective dose of the pharmaceutical composition of claim 44 or 45.

63. The method of claim 59, wherein the disorder is a neurodegenerative disorder or a movement disorder.

64. The method of claim 63, 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.

65. The method of claim 60, wherein the disorder is a neurodegenerative disorder or a movement disorder.

66. The method of claim 65, 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.