Arylindenopyridines and related therapeutic and prophylactic methods

Abstract

This invention provides novel arylindenopyridines of the formula: ##STR1## 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

[0001] 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

[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

Adenosine A2a Receptors

[0003] 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).

[0004] 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).

[0005] 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).

[0006] 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

[0007] 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.

[0008] 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.

[0009] 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.

[0010] Few potent inhibitors of PDE7 have been reported. Most inhibitors of other phosphodiesterases have IC.sub.50's for PDE7 in the 100 .mu.M 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 IC.sub.50's of 8 and 13 .mu.M. However, these compounds were only 2-3 times selective for PDE7 over PDE4 and PDE3.

[0011] 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): ##STR2##

SUMMARY OF THE INVENTION

[0012] This invention provides a compound having the structure of Formula I ##STR3##

[0013] or a pharmaceutically acceptable salt thereof, wherein [0014] (a) R.sub.1 is selected from the group consisting of: [0015] (i) --COR.sub.5, wherein R.sub.5 is selected from H, optionally substituted C.sub.1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl; [0016] wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C.sub.1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR.sub.20R.sub.21 wherein R.sub.20 and R.sub.21 are independently selected from the group consisting of hydrogen, C.sub.1-8 straight or branched chain alkyl, C.sub.3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR.sub.20R.sub.21 taken together form a heterocycle or heteroaryl; [0017] (ii) COOR.sub.6, wherein R.sub.6 is selected from H, optionally substituted C.sub.1-8 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 C.sub.1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR.sub.20R.sub.21 wherein R.sub.20 and R.sub.21 are independently selected from the group consisting of hydrogen, C.sub.1-8 straight or branched chain alkyl, C.sub.3-.sub.7 cycloalkyl, benzyl, aryl, or heteroaryl or NR.sub.20R.sub.21 taken together form a heterocycle or heteroaryl; [0019] (iii) cyano; [0020] (iv) a lactone or lactam formed with R.sub.4; [0021] (v) --CONR.sub.7R.sub.8 wherein R.sub.7 and R.sub.8 are independently selected from H, C.sub.1-8 straight or branched chain alkyl, C.sub.3-7 cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl; [0022] 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, [0023] or R.sub.7 and R.sub.8 taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group; [0024] (vi) a carboxylic ester or carboxylic acid bioisostere including optionally substituted heteroaryl groups [0025] (b) R.sub.2 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl and optionally substituted C.sub.3-7 cycloalkyl; [0026] (c) R.sub.3 is from one to four groups independently selected from the group consisting of: [0027] (i) hydrogen, halo, C.sub.1-8 straight or branched chain alkyl, arylalkyl, C.sub.3-7 cycloalkyl, C.sub.1-8 alkoxy, cyano, C.sub.1-4 carboalkoxy, trifluoromethyl, C.sub.1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C.sub.1-8 carboxylate, aryl, heteroaryl, and heterocyclyl; [0028] (ii) --NR.sub.10R.sub.11 wherein R.sub.10 and R.sub.11 are independently selected from H, C.sub.1-8 straight or branched chain alkyl, arylalkyl, C.sub.3-7 cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R.sub.10 and R.sub.11 taken together with the nitrogen form a heteroaryl or heterocyclyl group; [0029] (iii) --NR.sub.12COR.sub.13 wherein R.sub.12 is selected from hydrogen or alkyl and R.sub.13 is selected from hydrogen, alkyl, substituted alkyl, C.sub.1-3alkoxyl, carboxyalkyl, R.sub.30R.sub.31N (CH.sub.2).sub.p--, R.sub.30R.sub.31NCO(CH.sub.2).sub.p--, aryl, arylalkyl, heteroaryl and heterocyclyl or R.sub.12 and R.sub.13 taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R.sub.30 and R.sub.31 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; [0030] (d) R.sub.4 is selected from the group consisting of (i) hydrogen, (ii) C.sub.1-3 straight or branched chain alkyl, (iii) benzyl and (iv) --NR.sub.13R.sub.14, wherein R.sub.13 and R.sub.14 are independently selected from hydrogen and C.sub.1-6 alkyl; [0031] wherein the C.sub.1-3alkyl and benzyl groups are optionally substituted with one or more groups selected from C.sub.3-7 cycloalkyl, C.sub.1-8 alkoxy, cyano, C.sub.1-4 carboalkoxy, trifluoromethyl, C.sub.1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C.sub.1-8 carboxylate, amino, NR.sub.13R.sub.14, aryl and heteroaryl; and [0032] (e) X is selected from S and O;

[0033] with the proviso that when R.sub.4 is isopropyl, then R.sub.3 is not halogen.

[0034] In an alternative embodiment, the invention is directed to compounds of Formula I wherein R.sub.1, R.sub.3 and R.sub.4 are as described above and R.sub.2 is --NR.sub.15R.sub.16 wherein R.sub.15 and R.sub.16 are independently selected from hydrogen, optionally substituted C.sub.1-8 straight or branched chain alkyl, arylalkyl, C.sub.3-7 cycloalkyl, aryl, heteroaryl, and heterocyclyl or R.sub.15 and R.sub.16 taken together with the nitrogen form a heteroaryl or heterocyclyl group; with the proviso that when R.sub.2 is NHR.sub.16, R.sub.1 is not --COOR.sub.6 where R.sub.6 is ethyl.

[0035] This invention also provides a pharmaceutical composition comprising the instant compound and a pharmaceutically acceptable carrier.

[0036] 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.

[0037] 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

[0038] 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.

[0039] 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.

[0040] Preferred embodiments for R.sub.1 are COOR.sub.6, wherein R.sub.6 is selected from H, optionally substituted C.sub.1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl. Preferably R.sub.6 is H, or C.sub.1-8 straight or branched chain alkyl which may be optionally substituted with a substituent selected from CN and hydroxy.

[0041] Preferred embodiments for R.sub.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. Preferably, R.sub.2 is optionally substituted furan, phenyl or napthyl or R.sub.2 is ##STR4## 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, R.sub.2 is --NR.sub.15R.sub.16.

[0042] Preferred substituents for R.sub.3 include: [0043] (i) hydrogen, halo, C.sub.1-8 straight or branched chain alkyl, C.sub.1-8 alkoxy, cyano, C.sub.1-4 carboalkoxy, trifluoromethyl, C.sub.1-8 alkylsulfonyl, halogen, nitro, and hydroxy; [0044] (ii) --NR.sub.10R.sub.11 wherein R.sub.10and R.sub.11 are independently selected from H, C.sub.1-8 straight or branched chain alkyl, arylC.sub.1-8alkyl, C.sub.3-7 cycloalkyl, carboxyC.sub.1-8alkyl, aryl, heteroaryl, and heterocyclyl or R.sub.10 and R.sub.11 taken together with the nitrogen form a heteroaryl or heterocyclyl group; [0045] (iii) --NR.sub.12COR.sub.13 wherein R.sub.12 is selected from hydrogen or alkyl and R.sub.13 is selected from hydrogen, alkyl, substituted alkyl, C.sub.1-3alkoxyl, carboxyC.sub.1-8alkyl, aryl, arylalkyl, R.sub.30R.sub.31N (CH.sub.2).sub.p--, R.sub.30R.sub.31NCO(CH.sub.2).sub.p--, heteroaryl and heterocyclyl or R.sub.12 and R.sub.13 taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein , R.sub.30 and R.sub.31 are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6.

[0046] Particularly, R.sub.3 is selected from the group consisting of ##STR5##

[0047] Preferred embodiments for R.sub.4 include hydrogen, C.sub.1-3 straight or branched chain alkyl, particularly methyl, amine and amino.

[0048] In a further embodiment of the instant compound, R.sub.1 is COOR.sub.6 and R.sub.2 is selected from the group consisting of substituted phenyl, and substituted naphthyl or R.sub.2 is NR.sub.15R.sub.16.

[0049] More particularly, R.sub.1 is COOR.sub.6 where R.sub.6 is alkyl, R.sub.2 is substituted phenyl or naphthyl or R.sub.2 is NR.sub.15R.sub.16, and R.sub.3 is selected from the group consisting of H, nitro, amino, NHAc, halo, hydroxy, alkoxy, or a moiety of the formulae: ##STR6## , alkyl(CO)NH--, and R.sub.4 is selected from hydrogen, C.sub.1-3 straight or branched chain alkyl, particularly methyl, and amino.

[0050] In a preferred embodiment, the compound is selected from the group of compounds shown in Table 1 hereinafter.

[0051] More preferably, the compound is selected from the following compounds: ##STR7##

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 2-amino-4-(1,3-benzodioxol-5-yl)-5-oxo-, ethyl ester

[0052] ##STR8##

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(6-bromo-1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester

[0053] ##STR9##

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-amino-4-(1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester

[0054] ##STR10##

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

[0055] ##STR11##

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester

[0056] ##STR12##

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-(acetylamino)-4-(1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester

[0057] ##STR13##

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 2-methyl-4-(3-methylphenyl)-5-oxo-, methyl ester

[0058] ##STR14##

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

[0059] ##STR15##

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

[0060] ##STR16##

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

[0061] ##STR17##

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

[0062] ##STR18##

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

[0063] ##STR19##

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

[0064] ##STR20##

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

[0065] ##STR21##

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-[(3-carboxy-1-oxopropyl)amino]-2-methyl-4-(4-methyl-1-naphthalenyl)-5-o- xo-, methyl ester

[0066] ##STR22##

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-8-[[4-(hydroxyamino)-1,4-dioxobutyl]amino]-2-methy- l-5-oxo-, methyl ester

[0067] ##STR23##

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

[0068] ##STR24##

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

[0069] ##STR25##

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-8-[[[(2-hydroxyethyl)methylamino]acetyl]amino]-2-m- ethyl-5-oxo-, methyl ester

[0070] ##STR26##

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

[0071] ##STR27##

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

[0072] ##STR28##

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-phenyl-2-amino-5-oxo-, ethyl ester

[0073] ##STR29##

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(4-methylphenyl)-2-methyl-5-oxo-, methyl ester

[0074] ##STR30##

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3-bromophenyl)-2-methyl-5-oxo-, methyl ester

[0075] ##STR31##

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3-bromophenylamino)-2-methyl-5-oxo-, methyl ester

[0076] ##STR32##

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-phenyl-2-amino-5-oxo-, methyl ester

[0077] ##STR33##

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(2-furyl)-2-amino-5-oxo-, methyl ester

[0078] ##STR34##

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3-furyl)-2-amino-5-oxo-, methyl ester

[0079] ##STR35##

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(2-furyl)-2-amino-5-oxo-, ethyl ester

[0080] 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.

[0081] This invention also provides a pharmaceutical composition comprising the instant compound and a pharmaceutically acceptable carrier.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] In one preferred embodiment, the disorder is rheumatoid arthritis.

[0086] In another preferred embodiment, the disorder is Parkinson's disease.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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 .mu.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. 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.

[0092] 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

[0093] 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.

[0094] 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.

[0095] "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.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-alkoxyl, C.sub.1-C.sub.8-alkylthio, C.sub.1-C.sub.8-alkyl-amino, di(C.sub.1-C.sub.8-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C.sub.1-C.sub.8-alkyl-CO--O--, C.sub.1-C.sub.8-alkyl-CO--NH--, carboxamide, hydroxamic acid, sulfonamide, sulfonyl, thiol, aryl, aryl(c.sub.1-c.sub.8)alkyl, heterocyclyl, and heteroaryl.

[0096] "Alkoxy" shall mean --O-alkyl and unless otherwise stated, it will have 1-8 carbon atoms.

[0097] 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).

[0098] "Halogen" shall mean fluorine, chlorine, bromine or iodine; "PH" or "Ph" shall mean phenyl; "Ac" shall mean acyl; "Bn" shall mean benzyl.

[0099] 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.

[0100] "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.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-alkoxyl, C.sub.1-C.sub.8-alkylthio, C.sub.1-C.sub.8-alkyl-amino, di(C.sub.1-C.sub.8-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C.sub.1-C.sub.8-alkyl-CO--O--, C.sub.1-C.sub.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.

[0101] 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, C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-alkoxyl, C.sub.1-C.sub.8-alkylthio, C.sub.1-C.sub.8-alkyl-amino, di(C.sub.1-C.sub.8-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C.sub.1-C.sub.8-alkyl-CO--O--, C.sub.1-C.sub.8-alkyl-CO--NH--, or carboxamide. Heteroaryl may be substituted with a mono-oxo to give for example a 4-oxo-1H-quinoline.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] Designated numbers of carbon atoms (e.g., C.sub.1-8) 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.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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

[0110] 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. ##STR36##

[0111] Procedures described in Scheme 1, wherein R.sub.3a, R.sub.3b, R.sub.3c, and R.sub.3d are independently any R.sub.3 group, and R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are as described above, can be used to prepare compounds of the invention wherein X is O.

[0112] 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 (R.sub.3) leads to a mixture of regioisomers, the products can be separated by column chromatography.

[0113] In some cases, especially where R.sub.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). Where R.sub.2 is an alkyl group it is also necessary to perform the oxidation with DDQ or MnO.sub.2 instead of chromium (VI) oxide (Vanden Eynde, J. J.; Delfosse, F.; Mayence, A.; Van Haverbeke, Y. Tetrahedron 1995, 51, 6511). ##STR37##

[0114] 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. ##STR38##

[0115] The procedure for making compounds where R.sub.4 is NH.sub.2 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 R.sub.5 or R.sub.6 as described above. ##STR39##

[0116] 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. ##STR40##

[0117] 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. ##STR41##

[0118] 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 .beta.-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). ##STR42##

[0119] 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. ##STR43##

[0120] 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 R.sub.6 is a hydroxyethyl group, the compounds can be further converted to piperazinones 17. ##STR44##

[0121] 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). ##STR45##

[0122] 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.sub.5 or R.sub.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. ##STR46## II. Specific Compound Syntheses

[0123] 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.

[0124] 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

(R.sub.1=COOMe; R.sub.2=3,5-dimethylphenyl; R.sub.3b,c=Cl; R.sub.3a,b=H; R.sub.4=Me)

[0125] 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.sup.++23), 428 (M.sup.++1).

EXAMPLE 2

Alternate Hantzsch Conditions to Form Dihydropyridine 4

(R.sub.1=CO.sub.2Me; R.sub.2=2,4-dimethylphenyl; R.sub.3=H; R.sub.4=Et)

[0126] 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.sup.++23), 374 (M.sup.++1).

EXAMPLE 3

Oxidation of Dihydropyridine 4 to Pyridine 1

(R.sub.1=COOMe; R.sub.2=3,5-dimethylphenyl; R.sub.3b,c=Cl; R.sub.3a,d=H; R.sub.4=Me)

[0127] 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.sup.++23), 426 (M.sup.++1).

EXAMPLE 4

Oxidation of Dihydropyridine 4 to Pyridine 1

(R.sub.1=COOMe; R.sub.2=(4-methyl)-1-naphthyl; R.sub.3b,c=H, NO.sub.2/NO.sub.2, H; R=Me)

[0128] 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 (R.sub.3b=NO.sub.2; R.sub.3c=H) and 0.765 g (21%) of its regioisomer (R.sub.3b=H: R.sub.3c=NO.sub.2). MS m/z 461 (M.sup.++23), 439 (M.sup.++1).

EXAMPLE 5

Alternate Three Component Hantzsch Reaction to Form Dihydropyridine 4

(R.sub.1=CO.sub.2Me; R.sub.2=cyclohexyl; R.sub.3=H; R.sub.4=Me)

[0129] 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.degree. 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.sup.--1).

EXAMPLE 6

DDQ Oxidation of Dihydropyridine 4

(R.sub.1=CO.sub.2Me; R.sub.2=cyclohexyl; R.sub.3=H; R.sub.4=Me)

[0130] 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.sup.++23), 336 (M.sup.++1).

EXAMPLE 7

MnO.sub.2 Oxidation of Dihydropyridine 4

(R.sub.1=CO.sub.2Me; R.sub.2=4-(dimethylamino)phenyl; R.sub.3=H; R.sub.4=Me)

[0131] 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.sup.++23), 373 (M.sup.++1).

EXAMPLE 8

Cleavage of Carboxylic Ester 5

(R.sub.2=2,4-dimethylphenyl; R.sub.3=H; R.sub.4=Me)

[0132] 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.times.100 mL). The aqueous layer was cooled to 0.degree. 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.sup.++23), 343 (M.sup.++1).

EXAMPLE 9

Preparation of Amide 7

(R.sub.2=2,4-dimethylphenyl; R.sub.3=H; R.sub.4=Me; R.sub.5=H; R.sub.6=Me)

[0133] 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 CCl.sub.4 and concentrated to remove the residual thionyl chloride. The residue was then dissolved in THF (3.5 mL) and added to a 0.degree. 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.sup.++1).

EXAMPLE 10

Preparation of Pyridine 1

(R.sub.1=CO.sub.2Et; R.sub.2=4-nitrophenyl; R.sub.3=H; R.sub.4=NH.sub.2)

[0134] 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.sup.++23), 390 (M.sup.++1).

EXAMPLE 11

Hantzsch Condensation of Benzylidene 8

(R.sub.2=3-methylphenyl) and 1,3-indandione)

[0135] 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.sup.++1).

EXAMPLE 12

Reduction to Prepare Amine 11

(R.sub.1=CO.sub.2Me; R.sub.2=4-methylnaphthyl; R.sub.4=Me)

[0136] 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.sup.++23), 409 (M.sup.++1).

EXAMPLE 13

Acetylation of Amine 11

(R.sub.1=CO.sub.2Et; R.sub.2=3,4-methylenedioxyphenyl; R.sub.4=Me)

[0137] 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.times.35 mL). The combined organics were washed with brine, dried over MgSO.sub.4, 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.sup.++23), 445 (M.sup.++1).

EXAMPLE 14

Preparation of Carboxylic Acid 13

(R.sub.1=CO.sub.2Me; R.sub.2=3,5-dimethylphenyl; R.sub.4=Me; Y=O; n=2).

[0138] 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.sup.++1).

EXAMPLE 15

Preparation of Carboxylic Acid 13

(R.sub.1=CO.sub.2Me; R.sub.2=3,5-dimethylphenyl; R.sub.4=Me; Y=H.sub.2; n=1)

[0139] To a refluxing solution of amine 11 (0.078 g, 0.210 mmol) in 5 mL of acetonitrile was added .beta.-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.times.25 mL). The combined organics were dried over MgSO.sub.4, 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.sup.++23), 445 (M.sup.++1).

EXAMPLE 16

Preparation of Hydroxamic Acid 14

(R.sub.1=CO.sub.2Me; R.sub.2=(4-methyl)-1-naphthyl; Y=O; n=2; R.sub.4=Me)

[0140] To a 0.degree. 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.degree. 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.sup.++1).

EXAMPLE 17

Preparation of Amide 15

(R.sub.1=CO.sub.2Me; R.sub.2=3,5-dimethylphenyl; R.sub.4=Me)

[0141] 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.degree. 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.sup.++23), 431 (M.sup.++1).

EXAMPLE 18

Preparation of Amide 16

(R.sub.1=CO.sub.2Me; R.sub.2=3,5-dimethylphenyl; R.sub.4=Me; NR.sub.6R.sub.7=morpholino)

[0142] To a 0.degree. C. mixture of amine 11 (0.123 g, 0.331 mmol) in 2 mL of 20% aqueous NaHCO.sub.3 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.degree. C. overnight. The reaction was diluted with water and cooled to room temperature. After extraction with ethyl acetate (3.times.25 mL), the combined organics were washed with brine, dried over MgSO.sub.4 and concentrated to yield 0.130 g (79%) of a yellow solid. MS m/z 522 (M.sup.++23), 500 (M.sup.++1).

EXAMPLE 19

Preparation of piperazinone 17

(R.sub.1=CO.sub.2Me; R.sub.2=3,5-dimethylphenyl; R.sub.4=Me; R.sub.7=H)

[0143] To a 0.degree. C. solution of amide 16 (R.sub.6=CH.sub.2CH.sub.2OH) (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.degree. C. overnight. 4.2 M ethanolic HCl was added dropwise. The mixture was cooled to 0.degree. 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 CH.sub.2Cl.sub.2 yielded 0.011 (12%) of a white solid. MS m/z 478 (M.sup.++23), 456 (M.sup.++1).

EXAMPLE 20

Preparation of 4-Aminoindenopyridine 19

(R.sub.1=CO.sub.2Me; R.sub.4=Me; R.sub.6=Me; R.sub.7=phenyl)

[0144] 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.sup.++1).

EXAMPLE 21

Preparation of 4-Aminoindenopyridine 19

(R.sub.1=CO.sub.2Me; R.sub.4=Me; R.sub.6=H; R.sub.7=cyclopentyl) by Palladium Catalyzed Coupling

[0145] 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.times.35 mL). The combined organics were washed with brine, dried over Na.sub.2SO.sub.4, 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.degree. 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.sup.++23), 337 (M.sup.++1).

EXAMPLE 22

Preparation of Dihydropyridine 21 (R.sub.1=CO.sub.2Me; R.sub.2=2-furyl; R.sub.3=H; R.sub.4=NH.sub.2)

[0146] 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.sup.++23).

EXAMPLE 23

DDQ Oxidation/Deprotection of Dihydropyridine 22

(R.sub.1=CO.sub.2Me; R.sub.2=3-furyl; R.sub.3=H; R.sub.4=NH.sub.2)

[0147] 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.sup.++23), 321 (M.sup.++1).

[0148] Following the general synthetic procedures outlined above and in Examples 1-21, the compounds of Table 1 below were prepared. TABLE-US-00001 TABLE 1 ##STR47## No. R.sub.1 R.sub.2 R.sub.3a R.sub.3b R.sub.3c R.sub.3d R.sub.4 MS (M + 1) 1 CN ##STR48## C.sub.7H.sub.5O.sub.2 H H H H Me 341 2 CO.sub.2Et ##STR49## C.sub.7H.sub.5O.sub.2 H H H H Me 388 3 CO.sub.2t-Bu ##STR50## C.sub.7H.sub.5O.sub.2 H H H H Me 416 4 CO.sub.2t-Bu ##STR51## C.sub.8H.sub.9O.sub.2 H H H H Me 432 5 CO.sub.2Et ##STR52## C.sub.6H.sub.4NO.sub.2 H H H Me 389 6 CO.sub.2H ##STR53## C.sub.7H.sub.5O.sub.2 H H H H Me 360 7 CO.sub.2Et ##STR54## C.sub.14H.sub.13O.sub.2 H H H H Me 480 8 CO.sub.2Et ##STR55## C.sub.8H.sub.8BrO.sub.2 H H H H Me 482 9 CO.sub.2Et ##STR56## C.sub.11H.sub.9O H H H H Me 424 10 CO.sub.2H ##STR57## C.sub.8H.sub.9 H H H H Me 376 11 CO.sub.2Et Ph H H H H Me 344 12 CO.sub.2Et ##STR58## C.sub.7H.sub.7O H H H H Me 374 13 CO.sub.2Et ##STR59## C.sub.9H.sub.11O.sub.3 H H H H Me 434 14 CO.sub.2Et ##STR60## C.sub.6H.sub.4BrO.sub.2 H H H H Me 454 15 CO.sub.2Bn ##STR61## C.sub.7H.sub.5O.sub.2 H H H H Me 450 16 ##STR62## C.sub.11H.sub.14NO.sub.2 ##STR63## C.sub.7H.sub.5O.sub.2 H H H H Me 507 17 CO.sub.2Me ##STR64## C.sub.8H.sub.9O.sub.2 H H H H Me 390 18 CO.sub.2Me ##STR65## C.sub.7H.sub.5O.sub.2 H H H H Me 374 19 CO.sub.2Et ##STR66## C.sub.8H.sub.9O.sub.2 H H H H Me 404 20 CO.sub.2Et ##STR67## C.sub.8H.sub.9O.sub.2 H H H H Me 404 21 CO.sub.2Et ##STR68## C.sub.7H.sub.6BrO H H H H Me 454 22 CO.sub.2Et ##STR69## C.sub.7H.sub.5O.sub.2 H H H H NH.sub.2 411 (M + 23) 23 CO.sub.2Et ##STR70## C.sub.7H.sub.5O.sub.2 H H H H Me 388 25 CO.sub.2Et ##STR71## C.sub.8H.sub.9O.sub.2 H H H H NH.sub.2 405 26 CO.sub.2Et ##STR72## C.sub.6H.sub.4NO.sub.2 H H H H NH.sub.2 390 27 CO.sub.2Et Ph H H H H NH.sub.2 345 28 CO.sub.2Et ##STR73## C.sub.9H.sub.11O H H H H Me 402 29 CO.sub.2Et ##STR74## C.sub.8H.sub.8BrO.sub.2 H H H H Me 483 30 CO.sub.2Me Ph H H H H Me 330 31 CO.sub.2Et ##STR75## C.sub.8H.sub.7O.sub.2 H H H H Me 402 32 CO.sub.2Et ##STR76## C.sub.7H.sub.5O.sub.2 H NO.sub.2 H H Me 433 33 ##STR77## C.sub.4H.sub.4NO.sub.2 ##STR78## C.sub.7H.sub.5O.sub.2 H H H H Me 413 34 CO.sub.2Et ##STR79## C.sub.7H.sub.4NO.sub.4 H H H H Me 433 35 CO.sub.2Et ##STR80## C.sub.7H.sub.5O.sub.2 H H NO.sub.2 H Me 433 36 CO.sub.2Me ##STR81## C.sub.7H.sub.4F.sub.3 H H H H Me 398 37 CO.sub.2Et ##STR82## C.sub.7H.sub.5O.sub.2 H H NH.sub.2 H Me 403 38 CONH.sub.2 ##STR83## C.sub.7H.sub.5O.sub.2 H H H H Me 359 39 CO.sub.2Et ##STR84## C.sub.8H.sub.9 H H H H Me 372 40 CO.sub.2Et ##STR85## C.sub.7H.sub.5O.sub.2 H NH2 H H Me 403 41 CO.sub.2Et ##STR86## C.sub.4H.sub.3O H H H H Me 334 42 CO.sub.2Et 2-Thienyl H H H H Me 350 43 CO.sub.2Me ##STR87## C.sub.8H.sub.9 H H H H Me 358 44 CO.sub.2Me ##STR88## C.sub.8H.sub.7O.sub.2 H H H H Me 388 45 CO.sub.2Me ##STR89## C.sub.7H.sub.4NO.sub.4 H H H H Me 419 46 CO.sub.2Me ##STR90## C.sub.9H.sub.11O H H H H Me 388 47 CO.sub.2Me 4-Pyridyl H H H H Me 331 48 CO.sub.2Me ##STR91## C.sub.7H.sub.5O.sub.2 H H H H Me 374 49 CO.sub.2Me ##STR92## C.sub.7H.sub.4BrO.sub.2 H H H H Me 454 50 CO.sub.2Me ##STR93## C.sub.7H.sub.6BrO H H H H Me 439 51 CO.sub.2Me ##STR94## C.sub.8H.sub.9 H H H H Me 358 52 CO.sub.2Et ##STR95## C.sub.8H.sub.9 H H H H Me 372 53 CO.sub.2Me ##STR96## C.sub.11H.sub.9O H H H H Me 410 54 CO.sub.2Me ##STR97## C.sub.6H.sub.4NO.sub.2 H H H H Me 375 55 CO.sub.2Et ##STR98## C.sub.7H.sub.5O.sub.2 H NHAc H H Me 445 56 CO.sub.2Et ##STR99## C.sub.7H.sub.5O.sub.2 H H NHAc H Me 445 57 CO.sub.2Et ##STR100## C.sub.7H.sub.7 H H H H Me 358 58 CO.sub.2Et ##STR101## C.sub.7H.sub.7 H H H H Me 358 59 CO.sub.2Et ##STR102## C.sub.7H.sub.7 H H H H Me 358 60 CO.sub.2Et ##STR103## C.sub.7H.sub.4F.sub.3 H NO.sub.2 H H Me 457 61 CO.sub.2Et ##STR104## C.sub.7H.sub.4F.sub.3 H H NO.sub.2 H Me 457 62 CO.sub.2Me ##STR105## C.sub.7H.sub.7 H H H H Me 344 63 CO.sub.2Et ##STR106## C.sub.7H.sub.4F.sub.3 H NH.sub.2 H H Me 427 64 CO.sub.2Et ##STR107## C.sub.7H.sub.4F.sub.3 H H NH.sub.2 H Me 427 65 CO.sub.2Me ##STR108## C.sub.8H.sub.3F.sub.6 H H H H Me 466 66 CO.sub.2Me ##STR109## C.sub.7H.sub.7 H H H H Me 344 67 CO.sub.2Me ##STR110## C.sub.7H.sub.7 H H H H Me 344 68 CO.sub.2Me ##STR111## C.sub.7HF.sub.3 H NO.sub.2 H H Me 443 69 CO.sub.2Me ##STR112## C.sub.7H.sub.4F.sub.3 H H NO.sub.2 H Me 443 70 CO.sub.2Et ##STR113## C.sub.8H.sub.9 H H H H i-Pr 400 71 CO.sub.2Me ##STR114## C.sub.7H.sub.4F.sub.3 H NH.sub.2 H H Me 413 72 CO.sub.2Me ##STR115## C.sub.6H.sub.3Cl.sub.2 H H H H Me 399 73 CO.sub.2Me ##STR116## C.sub.8H.sub.9 H H H H Et 372 74 CO.sub.2Me ##STR117## C.sub.7H.sub.4F.sub.3 H H H H Me 398 75 CO.sub.2Me ##STR118## C.sub.11H.sub.9 H H H H Me 394 76 CO.sub.2Me ##STR119## C.sub.9H.sub.11 H H H H Me 372 77 CO.sub.2Me ##STR120## C.sub.8H.sub.9 H NO.sub.2 H H Me 403 78 CO.sub.2Me ##STR121## C.sub.8H.sub.9 H H NO.sub.2 H Me 403 79 CO.sub.2Me ##STR122## C.sub.11H.sub.9 H H H H Me 394 80 CO.sub.2Me ##STR123## C.sub.7H.sub.4F.sub.3 H NHAc H H Me 455 81 CO.sub.2Me ##STR124## C.sub.6H.sub.3Br.sub.2 H H H H Me 488 82 CO.sub.2Me ##STR125## C.sub.8H.sub.9 H NH.sub.2 H H Me 373 83 CO.sub.2Me ##STR126## C.sub.8H.sub.9 H H NH.sub.2 H Me 373 84 CO.sub.2Me ##STR127## C.sub.7H.sub.6F H H H H Me 362 85 CO.sub.2Me ##STR128## C.sub.6H.sub.4Br H H H H Me 431 (M + 23) 86 CO.sub.2Me ##STR129## C.sub.10H.sub.7 H H H H Me 380 (M +23) 87 CO.sub.2Me ##STR130## C.sub.11H.sub.9 H NO.sub.2 H H Me 439 88 CO.sub.2Me ##STR131## C.sub.11H.sub.9 H H NO.sub.2 H Me 439 89 CO.sub.2Me ##STR132## C.sub.14H.sub.9 H H H H Me 430 90 CO.sub.2Me ##STR133## C.sub.11H.sub.9 H NH.sub.2 H H Me 409 91 CO.sub.2Me ##STR134## C.sub.11H.sub.9 H H NH.sub.2 H Me 409 92 ##STR135## C.sub.4H.sub.4NO.sub.2 ##STR136## C.sub.8H.sub.9 H H H H Me 397 93 CN ##STR137## C.sub.8H.sub.9 H H H H Me 325 94 CO.sub.2Me ##STR138## C.sub.8H.sub.9 H H H H NH.sub.2 359 95 CO.sub.2Me ##STR139## C.sub.11H.sub.9 H H H H NH.sub.2 395 96 CO.sub.2H ##STR140## C.sub.8H.sub.9 H H H H Me 344 97 ##STR141## C.sub.4H.sub.4NO.sub.2 ##STR142## C.sub.11H.sub.9 H H H H Me 433 98 CN ##STR143## C.sub.11H.sub.9 H H H H Me 361 99 ##STR144## C.sub.2H.sub.2 O.sub.2 ##STR145## C.sub.7H.sub.5O.sub.2 H H H H C.sub.2H.sub.2O.sub.2 358 100 ##STR146## C.sub.2H.sub.2O.sub.2 ##STR147## C.sub.8H.sub.10N H H H H C.sub.2H.sub.2O.sub.2 357 101 ##STR148## C.sub.2H.sub.2O.sub.2 Ph H H H H C.sub.2H.sub.2O.sub.2 314 102 ##STR149## C.sub.2H.sub.2O.sub.2 p-C.sub.6H.sub.4NO.sub.2 H H H H C.sub.2H.sub.2O.sub.2 361 103 ##STR150## C.sub.2H.sub.2O.sub.2 ##STR151## C.sub.8H.sub.9 H H H H C.sub.2H.sub.2O.sub.2 364 104 ##STR152## C.sub.2H.sub.2 ##STR153## C.sub.8H.sub.9 H H H H C.sub.2H.sub.2O.sub.2 342 105 CO.sub.2H ##STR154## C.sub.11H.sub.9 H H H H Me 380 106 CONH.sub.2 ##STR155## C.sub.8H.sub.9 H H H H Me 343 107 CONHMe ##STR156## C.sub.8H.sub.9 H H H H Me 357 108 CONMe.sub.2 ##STR157## C.sub.8H.sub.9 H H H H Me 371 109 ##STR158## C.sub.2H.sub.2O.sub.2 ##STR159## C.sub.11H.sub.9 H H H H C.sub.2H.sub.2O.sub.2 378 110 ##STR160## C.sub.2H.sub.2O.sub.2 ##STR161## C.sub.7H.sub.7 H H H H C.sub.2H.sub.2O.sub.2 328 111 ##STR162## C.sub.2H.sub.2O.sub.2 ##STR163## C.sub.9H.sub.11 H H H H C.sub.2H.sub.2O.sub.2 356 112 ##STR164## C.sub.2H.sub.2O.sub.2 ##STR165## C.sub.7H.sub.7 H H H H C.sub.2H.sub.2O.sub.2 328 113 CO.sub.2Me ##STR166## C.sub.6H.sub.4NO.sub.2 H H H H Me 375

114 ##STR167## C.sub.2H.sub.2O.sub.2 ##STR168## C.sub.7H.sub.7 H H H H C.sub.2H.sub.2O.sub.2 328 115 CO.sub.2Me ##STR169## C.sub.8H.sub.10N H H H H Me 373 116 CONH.sub.2 ##STR170## C.sub.11H.sub.9 H H H H Me 379 117 ##STR171## C.sub.2H.sub.2O.sub.2 ##STR172## C.sub.9H.sub.6N H H H H C.sub.2H.sub.2O.sub.2 365 118 CO.sub.2Me ##STR173## C.sub.6H.sub.4NO.sub.2 H H H H Me 375 119 CONHMe ##STR174## C.sub.11H.sub.9 H H H H Me 393 120 CONMe.sub.2 ##STR175## C.sub.131H.sub.9 H H H H Me 407 121 CO.sub.2Me ##STR176## C.sub.9H.sub.N H H H H Me 381 122 CO.sub.2Me ##STR177## C.sub.11H.sub.9 H Cl Cl H Me 463 123 CO.sub.2Me ##STR178## C.sub.8H.sub.9 H Cl Cl H Me 427 124 CO.sub.2Me ##STR179## C.sub.9H.sub.6N H H H H Me 381 125 CO.sub.2Et ##STR180## C.sub.11H.sub.9 H H H H Me 408 126 CO.sub.2Me ##STR181## C.sub.6H.sub.3Br.sub.2 H Cl Cl H Me 555 127 CO.sub.2Me ##STR182## C.sub.8H.sub.9 Cl H H Cl Me 427 128 CO.sub.2Me 2-NO.sub.2-4,5- OCH.sub.2O--C.sub.6H.sub.2 H H H H Me 421 129 CO.sub.2Me ##STR183## C.sub.6H.sub.3Br.sub.2 Cl H H Cl Me 558 130 CO.sub.2Me ##STR184## C.sub.6H.sub.6N H H H H Me 345 131 CO.sub.2Et ##STR185## C.sub.11H.sub.9 H Cl Cl H Me 477 132 CO.sub.2Me ##STR186## C.sub.6H.sub.4Br.sub.2N H H H H Me 503 133 Ac ##STR187## C.sub.6H.sub.3Br.sub.2 H H H H Me 472 134 Ac ##STR188## C.sub.8H.sub.9 H H H H Me 342 135 CO.sub.2Me ##STR189## C.sub.5H.sub.4N H H H H Me 331 136 ##STR190## C.sub.4H.sub.4NO.sub.2 ##STR191## C.sub.6H.sub.3Br.sub.2 H H H H Me 527 137 ##STR192## C.sub.4H.sub.4NO.sub.2 ##STR193## C.sub.8H.sub.9 H H H H Me 397 138 CO.sub.2Me ##STR194## C.sub.6H.sub.5O.sub.2 H H H H Me 362 139 CO.sub.2H ##STR195## C.sub.6H.sub.3Br.sub.2 H H H H Me 474 140 CO.sub.2H ##STR196## C.sub.8H.sub.9 H H H H Me 344 141 CO.sub.2Me ##STR197## C.sub.6H.sub.5O H H H H Me 346 142 CO.sub.2Me ##STR198## C.sub.10 H.sub.2 H H H H Me 380 143 CO.sub.2Me ##STR199## C.sub.16H.sub.25O H H H H Me 486 144 CO.sub.2Me ##STR200## C.sub.13H.sub.11O H H H H Me 436 145 CO.sub.2Me ##STR201## C.sub.7H.sub.5Br.sub.2O H H H H Me 518 146 ##STR202## C.sub.4H.sub.4NO.sub.2 ##STR203## C.sub.7H.sub.5Br.sub.2O H H H H Me 557 147 ##STR204## C.sub.4H.sub.4NO.sub.2 ##STR205## C.sub.8H.sub.9 H Cl Cl H Me 466 148 CO.sub.2Et --NHPh H H H H Me 359 149 CO.sub.2Me ##STR206## C.sub.7H.sub.7O H H H H Me 360 150 CO.sub.2Me ##STR207## C.sub.6H.sub.3Br.sub.2O H H H H Me 504 151 ##STR208## C.sub.4H.sub.4NO.sub.2 ##STR209## C.sub.9H.sub.6N H H H H Me 420 152 C.sub.3H.sub.5O.sub.3 ##STR210## C.sub.6H.sub.3Br.sub.2O H H H H Me 534 153 ##STR211## C.sub.4H.sub.4NO.sub.2 ##STR212## C.sub.6H.sub.5 O H H H H Me 385 154 ##STR213## C.sub.2H.sub.4NO.sub.2 ##STR214## C.sub.8H.sub.9 H H H H Me 373 155 ##STR215## C.sub.4H.sub.4NO.sub.2 ##STR216## C.sub.6H.sub.3Br.sub.2 H H NO.sub.2 H Me 574 156 CO.sub.2Me ##STR217## C.sub.11H.sub.9 H Br H H Me 473 157 CO.sub.2Me ##STR218## C.sub.11H.sub.9 H H Br H Me 473 158 ##STR219## C.sub.4H.sub.4NO.sub.2 ##STR220## C.sub.9H.sub.6N H Cl Cl H Me 489 159 ##STR221## C.sub.4H.sub.4NO.sub.2 ##STR222## C.sub.6H.sub.3Br.sub.2O H H NO.sub.2 H Me 590 160 ##STR223## C.sub.3H.sub.5O.sub.3 ##STR224## C.sub.9H.sub.6N H H H H Me 411 161 CO.sub.2Me ##STR225## C.sub.8H.sub.9 H Br H H Me 436 162 CO.sub.2Me ##STR226## C.sub.8H.sub.9 H H Br H Me 438 163 CO.sub.2Me ##STR227## C.sub.8H.sub.9 H Br Br H Me 516 164 ##STR228## C.sub.4H.sub.4NO.sub.2 ##STR229## C.sub.6H.sub.32Br.sub.2 H Cl Cl H Me 597 165 ##STR230## C.sub.3H.sub.5O.sub.3 ##STR231## C.sub.9H.sub.6N H Cl Cl H Me 480 166 CO.sub.2Me ##STR232## C.sub.11H.sub.9 H Br Br H Me 552 167 CO.sub.2Et ##STR233## C.sub.8H.sub.9 H Br Br H Me 530 168 CO.sub.2Me ##STR234## C.sub.6H.sub.3Br.sub.2O F H H F Me 540 169 CO.sub.2Me ##STR235## C.sub.6H.sub.3Br.sub.2O H H NO.sub.2 H Me 551 170 CO.sub.2Me ##STR236## C.sub.6H.sub.3Br.sub.2O H Cl Cl H Me 573 171 ##STR237## C.sub.4H.sub.4NO.sub.2 ##STR238## C.sub.8H.sub.9 H H NO.sub.2 H Me 444 172 ##STR239## C.sub.4H.sub.4NO.sub.2 ##STR240## C.sub.8H.sub.9 H NO.sub.2 H H Me 444 173 CO.sub.2Me ##STR241## C.sub.8H.sub.9 F H H F Me 394 174 ##STR242## C.sub.4H.sub.4NO.sub.2 ##STR243## C.sub.8H.sub.9 F H H F Me 433 175 CO.sub.2Me ##STR244## C.sub.8H.sub.9O.sub.2 H Br Br H Me 548 176 CO.sub.2Me ##STR245## C.sub.7H.sub.4N H H H H Me 355 177 CO.sub.2Me ##STR246## C.sub.8H.sub.9O H NO.sub.2 H H Me 421 178 CO.sub.2Me ##STR247## C.sub.8H.sub.9O H H NO.sub.2 H Me 453 179 CO.sub.2Me ##STR248## C.sub.8H.sub.9O H Cl Cl H Me 443 180 CN ##STR249## C.sub.8H.sub.9O H H H H Me 341 181 CO.sub.2Me ##STR250## C.sub.6H.sub.3I.sub.2O H H H H Me 598 182 CO.sub.2Me ##STR251## C.sub.6H.sub.3F.sub.2 H Cl Cl H Me 435 183 CO.sub.2Et ##STR252## C.sub.8H.sub.10N H H H H Me 387 184 CO.sub.2Et ##STR253## C.sub.7H.sub.8N H H H H Me 373 185 CO.sub.2Me ##STR254## C.sub.7H.sub.5I.sub.2O H H H H Me 612 186 CO.sub.2Et ##STR255## C.sub.9H.sub.7N.sub.2 H H H H Me 410 187 CO.sub.2Me ##STR256## C.sub.6H.sub.3I.sub.2O H H NO.sub.2 H Me 345 188 CO.sub.2Me ##STR257## C.sub.6H.sub.3I.sub.2O H Cl Cl H Me 668 189 CO.sub.2Me ##STR258## C.sub.6H.sub.3F.sub.2 H H NO.sub.2 H Me 413 190 CO.sub.2H ##STR259## C.sub.6H.sub.3Br.sub.2 H Cl Cl H Me 544 191 CN ##STR260## C.sub.6H.sub.3I.sub.2O H H H H Me 565 192 CO.sub.2Me ##STR261## C.sub.6H.sub.3Br.sub.2O H Br H H Me 606 (M + 23) 193 CO.sub.2Me ##STR262## C.sub.6H.sub.3Br.sub.2O H H Br H Me 584 194 CO.sub.2Et ##STR263## C.sub.7H.sub.8N H H H H Me 373 195 CO.sub.2Et ##STR264## C.sub.6H.sub.4Cl.sub.2N H H H H Me 427 196 CO.sub.2Et ##STR265## C.sub.6H.sub.3Br.sub.2O H Cl Cl H Me 587 197 CO.sub.2Et ##STR266## C.sub.6H.sub.5BrN H H H H Me 437 198 CO.sub.2Et ##STR267## C.sub.7H.sub.8NO H H H H Me 389 199 CO.sub.2Et ##STR268## C.sub.6H.sub.3I.sub.2O H H H H Me 612 200 CO.sub.2Et ##STR269## C.sub.6H.sub.3F.sub.2 H Cl Cl H Me 449 201 CO.sub.2Me ##STR270## C.sub.9H.sub.6N H Cl Cl H Me 450 202 CO.sub.2Me ##STR271## C.sub.7H.sub.5F.sub.2O H Cl Cl H Me 465 203 CO.sub.2Me ##STR272## C.sub.7H.sub.5F.sub.2O H H H H Me 396 204 CO.sub.2Me ##STR273## C.sub.8H.sub.9 H ##STR274## C.sub.4H.sub.6NO.sub.3 H H Me 473 205 CO.sub.2Me ##STR275## C.sub.6H.sub.6N H H H H Me 345 206 CO.sub.2Me ##STR276## C.sub.7H.sub.8N H H H H Me 359 207 CO.sub.2Me ##STR277## C.sub.6H.sub.4NO.sub.2 H Cl Cl H Me 444 208 CO.sub.2Me ##STR278## C.sub.7H.sub.4N H H H Me 355 209 CO.sub.2H ##STR279## C.sub.10H.sub.7 H H H H Me 366 210 CO.sub.2Me ##STR280## C.sub.6H.sub.4NO.sub.2 H Cl Cl H Me 444 211 CO.sub.2Me ##STR281## C.sub.7H.sub.6F H Cl Cl H Me 430 212 CO.sub.2Me ##STR282## C.sub.7H.sub.3F.sub.4 H H H H Me 416 213 CO.sub.2Me ##STR283## C.sub.7H.sub.6F H Cl Cl H Me 430 214 CO.sub.2Me ##STR284## C.sub.6H.sub.4Cl.sub.2N H H H H Me 413 215 CO.sub.2Me ##STR285## C.sub.8H.sub.9 H OMe OMe H Me 418 216 CO.sub.2Me ##STR286## C.sub.11H.sub.9 H OMe OMe H Me 454 217 CO.sub.2Me ##STR287## C.sub.7H.sub.6F H H H H Me 362 218 CO.sub.2Me ##STR288## C.sub.8H.sub.9 H ##STR289## C.sub.3H.sub.6NO.sub.2 H H Me 445 219 CO.sub.2Me ##STR290## H H H H Me 359 220 CO.sub.2Me --NHPh H H H H Me 345 221 CO.sub.2Me ##STR291## C.sub.6H.sub.5BrN H H H H Me 423 222 CO.sub.2Me 2-Pyridyl H H H H Me 353 223 CO.sub.2Me ##STR292## C.sub.6H.sub.3Cl.sub.2 H OMe OMe H Me 459 224 CO.sub.2Me ##STR293## C.sub.7H.sub.3F.sub.4 H Cl Cl H Me 485 225 CO.sub.2Me ##STR294## C.sub.6H.sub.6N H H H H Me 345 226 CO.sub.2Me ##STR295## C.sub.6H.sub.4NO.sub.2 H H NO.sub.2 H Me 420 227 CO.sub.2Me ##STR296## C.sub.6N.sub.4NO.sub.2 H H NO.sub.2 H Me 420

228 CO.sub.2Me ##STR297## C.sub.7H.sub.8N H H H H Me 359 229 CO.sub.2Me ##STR298## C.sub.9H.sub.7N.sub.2 H H H H Me 396 230 CO.sub.2Me ##STR299## C.sub.121H.sub.9 H OH OH H Me 426 231 CO.sub.2Me ##STR300## C.sub.8H.sub.9 H H F H Me 376 232 CO.sub.2Me ##STR301## C.sub.7H.sub.3F.sub.4 H H NO.sub.2 H Me 461 233 CO.sub.2Me ##STR302## C.sub.10H.sub.6F H Cl Cl H Me 468 234 CO.sub.2Me ##STR303## C.sub.8H.sub.10N H H H H Me 373 235 CO.sub.2Me ##STR304## C.sub.7H.sub.8NO H H H H Me 375 236 CO.sub.2Me ##STR305## C.sub.10H.sub.6F H NO.sub.2 H H Me 443 237 CO.sub.2Me ##STR306## C.sub.10H.sub.6F H H NO.sub.2 H Me 443 238 CO.sub.2Me ##STR307## C.sub.10 H.sub.6F H H H H Me 398 239 CO.sub.2Me ##STR308## C.sub.12H.sub.12N H Cl Cl H Me 491 240 CO.sub.2Me ##STR309## C.sub.11H.sub.9 H ##STR310## C.sub.4H.sub.6NO.sub.3 H H Me 509 241 CO.sub.2Me ##STR311## C.sub.8H.sub.9 H H ##STR312## C.sub.4H.sub.6NO.sub.3 H Me 473 242 CO.sub.2Me ##STR313## C.sub.11H.sub.9 H H ##STR314## C.sub.4H.sub.6NO.sub.3 H Me 509 243 CO.sub.2Me ##STR315## C.sub.4H.sub.9 H H H H Me 310 244 CO.sub.2Me ##STR316## C.sub.11H.sub.9 H ##STR317## C.sub.4H.sub.7N.sub.2O.sub.3 H H Me 524 245 CO.sub.2Me ##STR318## C.sub.8H.sub.9 H H ##STR319## C.sub.4H.sub.7N.sub.2O.sub.3 H Me 488 246 CO.sub.2Me ##STR320## C.sub.4H.sub.7 H H H H Me 308 247 CO.sub.2Me i-Pr H H H H Me 296 248 CO.sub.2Me ##STR321## Cyclohexyl H H H H Me 336 249 CO.sub.2Me Me H H H H Me 268 250 CO.sub.2Me ##STR322## C.sub.8H.sub.9 H H ##STR323## C.sub.4H.sub.9N.sub.2O.sub.2 H Me 474 251 CO.sub.2Me ##STR324## C.sub.7H.sub.9 H H ##STR325## C.sub.5H.sub.8NO.sub.3 H Me 487 252 CO.sub.2Me N-Mopholino H H H H Me 339 253 CO.sub.2Me ##STR326## C.sub.5H.sub.10 N H H H H Me 337 254 CO.sub.2Me ##STR327## C.sub.8H.sub.9 H H ##STR328## C.sub.5H.sub.11N.sub.2O.sub.2 H Me 488 255 CO.sub.2Me ##STR329## C.sub.8H.sub.9 H ##STR330## C.sub.4H.sub.9N.sub.2O.sub.2 H H Me 474 256 CO.sub.2Me ##STR331## C.sub.8H.sub.9 H ##STR332## C.sub.4H.sub.7N.sub.2O H H Me 456 257 CO.sub.2Me ##STR333## C.sub.8H.sub.9 H ##STR334## C.sub.2H.sub.4NO.sub.2 H H Me 431 258 CO.sub.2Me ##STR335## C.sub.8H.sub.9 H ##STR336## C.sub.6H.sub.11N.sub.2O.sub.2 H H Me 500 259 CO.sub.2Me ##STR337## C.sub.8H.sub.9 H ##STR338## C.sub.6H.sub.12N.sub.3O H H Me 499 260 CO.sub.2Me ##STR339## C.sub.8H.sub.9 H ##STR340## C.sub.5H.sub.6N.sub.3O H H Me 481 261 CO.sub.2Me ##STR341## C.sub.8H.sub.9 H H ##STR342## C.sub.6H.sub.11N.sub.2O.sub.2 H Me 500 262 CO.sub.2Me ##STR343## C.sub.8H.sub.9 H H ##STR344## C.sub.6H.sub.12N.sub.3O H Me 499 263 CO.sub.2Me ##STR345## C.sub.8H.sub.9 H H ##STR346## C.sub.2H.sub.4NO.sub.2 H Me 431 264 CO.sub.2Me ##STR347## C.sub.7H.sub.5O.sub.2 H H H H NH.sub.2 397 (M + 23) 265 CO.sub.2Me Ph H H H H NH.sub.2 353 (M + 23) 266 CO.sub.2Me ##STR348## C.sub.8H.sub.9O.sub.2 H H H H NH.sub.2 413 (M + 23) 267 CO.sub.2Me 2-Furyl H H H H NH.sub.2 321 268 CO.sub.2Me 3-Furyl H H H H NH.sub.2 321 269 CO.sub.2Me 2-Furyl H H H H Me 320 270 CO.sub.2Me 2-Furyl H H H NH.sub.2 Me 335 271 CO.sub.2Me 2-Furyl NHOH H H H Me 351 272 CO.sub.2Et 2-Furyl H H H H NH.sub.2 335 273 CO.sub.2Et 2-Furyl H Br H H NH.sub.2 413 274 CO.sub.2Et 2-Furyl H H Br H NH.sub.2 413 275 CO.sub.2Et ##STR349## C.sub.7H.sub.4Br.sub.O.sub.2 H H H H Me 467 276 CO.sub.2Me ##STR350## C.sub.8H.sub.9 H H ##STR351## C.sub.5H.sub.6N.sub.3O H Me 481 277 CO.sub.2Me ##STR352## C.sub.8H.sub.9 H H ##STR353## C.sub.4H.sub.7N.sub.2O H Me 456 278 CO.sub.2Me ##STR354## C.sub.8H.sub.9 H ##STR355## C.sub.4H.sub.6NO.sub.3 H H Me 473 279 CO2Me ##STR356## C.sub.8H.sub.9 H ##STR357## H H Me 513 280 CO.sub.2Me ##STR358## C.sub.8H.sub.9 H ##STR359## H H Me 516 281 CO.sub.2Me ##STR360## C.sub.8H.sub.9 H ##STR361## H H Me 501 282 CO.sub.2Me ##STR362## C.sub.8H.sub.9 H ##STR363## H H Me 566 283 CO.sub.2Me ##STR364## C.sub.8H.sub.9 H ##STR365## H H Me 488 284 CO.sub.2Me ##STR366## C.sub.8H.sub.9 H H ##STR367## H Me 541

III. Biological Assays and Activity Ligand Binding Assay for Adenosine A2a Receptor

[0149] 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 [.sup.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 MgCl.sub.2, 1 mM EDTA) containing [.sup.3H] CGS21680, 50 mL diluted compound (4.times.) 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 [.sup.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

[0150] 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.sub.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. Cells were then incubated at 37 C, 5% CO.sub.2 for 5 hrs before stopping experiments by washing cells with PBS twice. 50 mL 1.times. lysis buffer (Promega, 5.times. stock solution, needs to be diluted to 1.times. 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.times. 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

[0151] 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.

[0152] 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.

[0153] Specifically, enzyme was diluted in PDE buffer (50 mM pH 7.4 Tris, 8.3 mM MgCl.sub.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- .sup.3H-cAMP or 8-.sup.3H-cGMP, purchased from Amersham Pharmacia) was diluted in PDE (4, 5, 7A) buffer to 1 nCi per .mu.l (or 1 .mu.Ci/ml). For each test well, 48 .mu.l of enzyme was mixed with 47 .mu.l substrate and 5 .mu.l test compound (or DMSO) in a white Packard plate, followed by shaking to mix and incubation for 15 minutes at room temperature. A 50 .mu.l 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 .sup.3H glass program with color quench correction. Output was in color quench-corrected dpm.

[0154] Test compounds were diluted in 100% DMSO to a concentration 20.times. 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)).times.100

[0155] The IC.sub.50 values were calculated using the Deltagraph 4-parameter curve-fitting program. The IC.sub.50 and % Inhibition data on PDE 4, 5, and 7A are listed for the indicated compounds in Table 2 below. TABLE-US-00002 TABLE 2 ##STR368## MS IC.sub.50 (.mu.M)/% inh. @ .mu.M No. R.sub.1 R.sub.2 R.sub.3a R.sub.3b R.sub.3c R.sub.3d R.sub.4 (M + 1) PDE7A PDE4 PDE5 6 CO.sub.2H ##STR369## C.sub.7H.sub.5O.sub.2 H H H H Me 360 45% @20 49% @ 5 51 CO.sub.2Me ##STR370## C.sub.8H.sub.9 H H H H Me 358 0.055 0.353 2.7 56 CO.sub.2Et ##STR371## C.sub.7H.sub.5O.sub.2 H H NHAc H Me 445 0.074 0.333 2.5 70 CO.sub.2Et ##STR372## C.sub.8H.sub.9 H H H H i-Pr 400 2.11 73 CO.sub.2Me ##STR373## C.sub.9H.sub.9 H H H H Et 372 1.54 0.998 82 CO.sub.2Me ##STR374## C.sub.8H.sub.9 H NH.sub.2 H H Me 373 0.021 0.204 1.11, 0.864 90 CO.sub.2Me ##STR375## C.sub.11H.sub.9 H NH.sub.2 H H Me 409 0.005 0.237, 0.172 2.33 98 CN ##STR376## C.sub.11H.sub.9 H H H H Me 361 1.13 119 CONHMe ##STR377## C.sub.11H.sub.9 H H H H Me 393 0.658 41% @20 133 Ac ##STR378## C.sub.6H.sub.3Br.sub.2 H H H H Me 472 1.54 134 Ac ##STR379## C.sub.8H.sub.9 H H H H Me 342 1.14 169 CO.sub.2Me ##STR380## C.sub.6H.sub.3Br.sub.2O H H NO.sub.2 H Me 551 0.0053 0.184 170 CO.sub.2Me ##STR381## C.sub.6H.sub.3Br.sub.2O H Cl Cl H Me 573 0.0087 0.557 190 CO.sub.2H ##STR382## C.sub.6H.sub.3Br.sub.2 H Cl Cl H Me 544 5.9 191 CN ##STR383## C.sub.6H.sub.3I.sub.2O H H H H Me 565 0.593 197 CO.sub.2Et ##STR384## C.sub.6H.sub.5BrN H H H H Me 437 0.728 69% @ 5 0.362 219 CO.sub.2Me ##STR385## C.sub.7H.sub.8N H H H H Me 359 0.964 61% @ 5 1.1 220 CO.sub.2Me --NHPh H H H H Me 345 0.084 1.8 0.637 241 CO.sub.2Me ##STR386## C.sub.8H.sub.9 H H ##STR387## C.sub.4H.sub.6NO.sub.3 H Me 473 0.0035 0.954 0.183 242 CO.sub.2Me ##STR388## C.sub.11H.sub.9 H H ##STR389## C.sub.4H.sub.6NO.sub.3 H Me 509 0.0038 0.782 0.141 243 CO.sub.2Me ##STR390## C.sub.4H.sub.9 H H H H Me 310 2.6 245 CO.sub.2Me ##STR391## C.sub.8H.sub.9 H H ##STR392## C.sub.4H.sub.7N.sub.2O.sub.3 H Me 488 0.0053 0.875 0.185 248 CO.sub.2Me ##STR393## Cyclohexyl H H H H Me 336 0.783 0.171 0.649 250 CO.sub.2Me ##STR394## C.sub.8H.sub.9 H H ##STR395## C.sub.4H.sub.9N.sub.2O.sub.2 H Me 474 0.0074 0.684 2.4 251 CO.sub.2Me ##STR396## C.sub.8H.sub.9 H H ##STR397## C.sub.5H.sub.8NO.sub.3 H Me 487 0.0054 0.754 0.26 253 CO.sub.2Me ##STR398## C.sub.5H.sub.10N H H H H Me 337 0.905 0.85 0.303 254 CO.sub.2Me ##STR399## C.sub.8H.sub.9 H H ##STR400## C.sub.5H.sub.11N.sub.2O.sub.2 H Me 488 0.0067 0.664 0.765 261 CO.sub.2Me ##STR401## C.sub.8H.sub.9 H H ##STR402## C.sub.6H.sub.11N.sub.2O.sub.2 H Me 500 0.0063 0.477 0.63 262 CO.sub.2Me ##STR403## C.sub.8H.sub.9 H H ##STR404## C.sub.6H.sub.12N.sub.3O H Me 499 0.008 0.702 3.7

[0156] TABLE-US-00003 TABLE 3 ##STR405## Ki (nM) A2a A2a an- A1 MS bind- tagonist bind- No. R.sub.1 R.sub.2 R.sub.3a R.sub.3b R.sub.3c R.sub.3d R.sub.4 (M + 1) ing function ing 14 CO.sub.2Et ##STR406## C.sub.6H.sub.4BrO.sub.2 H H H H Me 454 451 22 CO.sub.2Et ##STR407## C.sub.7H.sub.5O.sub.2 H H H H NH.sub.2 411 (M +23) 70 253 18 CO.sub.2Me ##STR408## C.sub.7H.sub.5O.sub.2 H H H H Me 374 159 >1000 584 27 CO.sub.2Et Ph H H H H NH.sub.2 345 42 36 554 23 CO.sub.2Et ##STR409## C.sub.7H.sub.5O.sub.2 H H H H Me 388 251 275 CO.sub.2Et ##STR410## C.sub.7H.sub.4BrO.sub.2 H H H H Me 467 263 41 CO.sub.2Et ##STR411## C.sub.4H.sub.3O H H H H Me 334 271 57 CO.sub.2Et ##STR412## C.sub.7H.sub.7 H H H H Me 358 400 67 CO.sub.2Me ##STR413## C.sub.7H.sub.7 H H H H Me 344 39 128 1853 66 CO.sub.2Me ##STR414## C.sub.7H.sub.7 H H H H Me 344 46 151 1591 85 CO.sub.2Me ##STR415## C.sub.6H.sub.4Br H H H H Me 431 (M +23) 35 >1000 5570 82 CO.sub.2Me ##STR416## C.sub.8H.sub.9 H NH.sub.2 H H Me 373 294 95 CO.sub.2Me ##STR417## C.sub.11H.sub.9 H H H H NH.sub.2 395 286 135 CO.sub.2Me ##STR418## C.sub.5H.sub.4N H H H H Me 331 123 130 CO.sub.2Me ##STR419## C.sub.6H.sub.6N H H H H Me 345 222 141 CO.sub.2Me ##STR420## C.sub.6H.sub.5O H H H H Me 346 172 183 CO.sub.2Et ##STR421## C.sub.8H.sub.10N H H H H Me 387 191 208 CO.sub.2Me ##STR422## C.sub.7H.sub.4N H H H H Me 355 171 197 CO.sub.2Et ##STR423## C.sub.6H.sub.5BrN H H H H Me 437 148 217 CO.sub.2Me ##STR424## C.sub.7H.sub.6F H H H H Me 362 119 221 CO.sub.2Me ##STR425## C.sub.6H.sub.5BrN H H H H Me 423 76 258 2180 222 CO.sub.2Me 2-Pyridyl H H H H Me 353 (M +23) 237 198 CO.sub.2Et ##STR426## C.sub.7H.sub.8NO H H H H Me 389 185 199 CO.sub.2Et ##STR427## C.sub.6H.sub.3I.sub.2O H H H H Me 612 301 279 CO.sub.2Me ##STR428## C.sub.8H.sub.9 H ##STR429## H H Me 513 179 261 CO.sub.2Me ##STR430## C.sub.8H.sub.9 H H ##STR431## C.sub.6H.sub.11N.sub.2O.sub.2 H Me 500 472 280 CO.sub.2Me ##STR432## C.sub.8H.sub.9 H ##STR433## H H Me 516 237 276 CO.sub.2Me ##STR434## C.sub.8H.sub.9 H H ##STR435## C.sub.5H.sub.6N.sub.3O H Me 481 304 258 CO.sub.2Me ##STR436## C.sub.8H.sub.9 H ##STR437## C.sub.6H.sub.11N.sub.2O.sub.2 H H Me 500 211 281 CO.sub.2Me ##STR438## C.sub.8H.sub.9 H ##STR439## H H Me 501 201 262 CO.sub.2Me ##STR440## C.sub.8H.sub.9 H H ##STR441## C.sub.6H.sub.12N.sub.3O H Me 499 332 184 CO.sub.2Et ##STR442## C.sub.7H.sub.8N H H H H Me 373 140 195 CO.sub.2Et ##STR443## C.sub.6H.sub.4Cl.sub.2N H H H H Me 427 171 260 CO.sub.2Me ##STR444## C.sub.8H.sub.9 H ##STR445## C.sub.5H.sub.6N.sub.3O H H Me 481 163 263 CO.sub.2Me ##STR446## C.sub.8H.sub.9 H H ##STR447## C.sub.2H.sub.4NO.sub.2 H Me 431 480 245 CO.sub.2Me ##STR448## C.sub.8H.sub.9 H H ##STR449## C.sub.4H.sub.7N.sub.2O.sub.3 H Me 488 276 264 CO.sub.2Me ##STR450## C.sub.7H.sub.5O.sub.2 H H H H NH.sub.2 397 (M +23) 342 265 CO.sub.2Me Ph H H H H NH.sub.2 353 (M +23) 50 267 CO.sub.2Me 2-Furyl H H H H NH.sub.2 321 <15 268 CO.sub.2Me 3-Furyl H H H H NH.sub.2 321 21 269 CO.sub.2Me 2-Furyl H H H H Me 320 192 270 CO.sub.2Me 2-Furyl H H H NH Me 335 303 271 CO.sub.2Me 2-Furyl NH OH H H H Me 351 276 272 CO.sub.2Et H H H H NH.sub.2 335 <5 273 CO.sub.2Et H Br H H NH.sub.2 413 279 274 CO.sub.2Et H H Br H NH.sub.2 413 143

Claims

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 ##STR451## wherein (a) R.sub.1 is selected from the group consisting of: (i) --COR.sub.5, wherein R.sub.5 is selected from H, optionally substituted C.sub.1-8 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 C.sub.1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR.sub.20R.sub.21 wherein R.sub.20 and R.sub.21 are independently selected from the group consisting of hydrogen, C.sub.1-8 straight or branched chain alkyl, C.sub.3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR.sub.20R.sub.21 taken together form a heterocycle or heteroaryl; (ii) COOR.sub.6, wherein R.sub.6 is selected from H, optionally substituted C.sub.1-8 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 C.sub.1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR.sub.20R.sub.21 wherein R.sub.20 and R.sub.21, are independently selected from the group consisting of hydrogen, C.sub.1-8 straight or branched chain alkyl, C.sub.3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR.sub.20R.sub.21 taken together form a heterocycle or heteroaryl; (iii) cyano; (iv) a lactone or lactam formed with R.sub.4; (v) --CONR.sub.7R.sub.8 wherein R.sub.7 and R.sub.8 are independently selected from H, C.sub.1-8 straight or branched chain alkyl, C.sub.3-7 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 R.sub.7 and R.sub.8 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) R.sub.2 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl and optionally substituted C.sub.3-7 cycloalkyl; (c) R.sub.3 is from one to four groups independently selected from the group consisting of: (i) hydrogen, halo, C.sub.1-8 straight or branched chain alkyl, arylalkyl, C.sub.3-7 cycloalkyl, C.sub.1-8 alkoxy, cyano, C.sub.1-4 carboalkoxy, trifluoromethyl, C.sub.1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C.sub.1-8 carboxylate, aryl, heteroaryl, and heterocyclyl; (ii) --NR.sub.10R.sub.11 wherein R.sub.10 and R.sub.11 are independently selected from H, C.sub.1-8 straight or branched chain alkyl, arylalkyl, C.sub.3-7 cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R.sub.10 and R.sub.11 taken together with the nitrogen form a heteroaryl or heterocyclyl group; (iii) --NR.sub.12COR.sub.13 wherein R.sub.12 is selected from hydrogen or alkyl and R.sub.1-3 is selected from hydrogen, alkyl, substituted alkyl, C.sub.13alkoxyl, carboxyalkyl, R.sub.30R.sub.31N (CH.sub.2).sub.p--, R.sub.30R.sub.31NCO(CH.sub.2).sub.p--, aryl, arylalkyl, heteroaryl and heterocyclyl or R.sub.12 and R.sub.13 taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R.sub.30 and R.sub.31 are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6, (d) R.sub.4 is selected from the group consisting of (i) hydrogen, (ii) C.sub.1-3 straight or branched chain alkyl, (iii) benzyl and (iv) --NR.sub.13R.sub.14, wherein R.sub.13 and R.sub.14 are independently selected from hydrogen and C.sub.1-6 alkyl; wherein the C.sub.1-3alkyl and benzyl groups are optionally substituted with one or more groups selected from C.sub.3-7 cycloalkyl, C.sub.1-8 alkoxy, cyano, C.sub.1-4 carboalkoxy, trifluoromethyl, C.sub.1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C.sub.1-8 carboxylate, amino, NR.sub.13R.sub.14, aryl and heteroaryl; and (e) X is selected from S and O; with the proviso that when R.sub.4 is isopropyl, then R.sub.3 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: ##STR452## wherein (a) R.sub.1 is selected from the group consisting of: (i) --COR.sub.5, wherein R.sub.5 is selected from H, optionally substituted C.sub.1-8 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 C.sub.1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR.sub.20R.sub.21 wherein R.sub.20 and R.sub.21 are independently selected from the group consisting of hydrogen, C.sub.1-8 straight or branched chain alkyl, C.sub.3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR.sub.20R.sub.21 taken together form a heterocycle or heteroaryl; (ii) COOR.sub.6, wherein R.sub.6 is selected from H, optionally substituted C.sub.1-8 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 C.sub.1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR.sub.20R.sub.21 wherein R.sub.20 and R.sub.21 are independently selected from the group consisting of hydrogen, C.sub.1-8 straight or branched chain alkyl, C.sub.3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR.sub.20R.sub.21 taken together form a heterocycle or heteroaryl; (i) cyano; (ii) a lactone or lactam formed with R.sub.4; (iii) --CONR.sub.7R.sub.8 wherein R.sub.7 and R.sub.8 are independently selected from H, C.sub.1-8 straight or branched chain alkyl, C.sub.3-7 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 R.sub.7 and R.sub.8 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) R.sub.2 is --NR.sub.15R.sub.16 wherein R.sub.15 and R.sub.16 are independently selected from hydrogen, optionally substituted C.sub.1-8 straight or branched chain alkyl, arylalkyl, C.sub.3-7 cycloalkyl, aryl, heteroaryl, and heterocyclyl or R.sub.15 and R.sub.16 taken together with the nitrogen form a heteroaryl or heterocyclyl group; with the proviso that when R.sub.2 is NHR.sub.16, R.sub.1 is not --COOR.sub.6 where R.sub.6 is ethyl; (c) R.sub.3 is from one to four groups independently selected from the group consisting of: (i) hydrogen, halo, C.sub.1-8 straight or branched chain alkyl, arylalkyl, C.sub.3-7 cycloalkyl, C.sub.1-8 alkoxy, cyano, C.sub.1-4 carboalkoxy, trifluoromethyl, C.sub.1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C.sub.1-8 carboxylate, aryl, heteroaryl, and heterocyclyl; (ii) --NR.sub.10R.sub.11 wherein R.sub.10and R.sub.11 are independently selected from H, C.sub.1-8 straight or branched chain alkyl, arylalkyl, C.sub.3-7 cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R.sub.10 and R.sub.11 taken together with the nitrogen form a heteroaryl or heterocyclyl group; (iii) --NR.sub.12COR.sub.13 wherein R.sub.12 is selected from hydrogen or alkyl and R.sub.13 is selected from hydrogen, alkyl, substituted alkyl, C.sub.1-3alkoxyl, carboxyalkyl, R.sub.30R.sub.31N (CH.sub.2).sub.p--, R.sub.30R.sub.31NCO(CH.sub.2).sub.p--, aryl, arylalkyl, heteroaryl and heterocyclyl or R.sub.12 and R.sub.13 taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R.sub.30 and R.sub.31, 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) R.sub.4 is selected from the group consisting of (i) hydrogen, (ii) C.sub.1-3 straight or branched chain alkyl, (iii) benzyl and (iv) --NR.sub.13R.sub.14, wherein R.sub.13 and R.sub.14 are independently selected from hydrogen and C.sub.1-6 alkyl; wherein the C.sub.1-3alkyl and benzyl groups are optionally substituted with one or more groups selected from C.sub.3-7 cycloalkyl, C.sub.1-8 alkoxy, cyano, C.sub.1-4 carboalkoxy, trifluoromethyl, C.sub.1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C.sub.1-8 carboxylate, amino, NR.sub.13R.sub.14, 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 R.sub.4 is C.sub.1-8 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.