MXPA06003737A - Arylindenopyridines and arylindenopyridines and their use as adenosine a2a receptor antagonist - Google Patents

Abstract

This invention provides novel arylindenopyridines and arylindenopyrimidines of formula (I), (II) wherein R1, R2, R3, R4, and X are as defined above, and pharmaceutical compositions comprising same, useful for treating disorders ameliorated by antagonizing adenosine A2a receptors. This invention also provides therapeutic and prophylactic methods using the instant compounds and pharmaceutical compositions.

Description

AR1LINDENOPIR1DINAS AND ARILINDENOPIRIMINES AND ITS USE AS AN ANTAGONIST OF THE ADENOSINE A2A RECEIVER CROSS REFERENCE TO RELATED REQUESTS This application is a continuation in part of the co-pending application serial number 10 / 259,139, filed on September 27, 2002, which is a continuation in part of the co-pending application with serial number 10 / 123,389, filed on 16 April 2002, both incorporated herein by reference.

FIELD OF THE INVENTION This invention relates to arylindenopyridines and arylindenopyrimidines and their therapeutic and prophylactic uses. The treated and / or prevented disorders using these compounds include neurodegenerative and movement disorders alleviated by antagonizing adenosine A2a receptors.

BACKGROUND OF THE INVENTION Adenosine A2a Receptors Adenosine is a purine nucleotide produced by metabolically active cells within the body. Adenosine exerts its effects by four subtypes of cell surface receptors (A1, A2a, A2b and A3), which belong to the superfamily of G protein-coupled receptors (Stiles, G.L. Journal of Biological Chemistry, 1992, 267, 6451). A1 and A3 are coupled to inhibitory G protein, while A2a and A2b are coupled to stimulatory G protein. A2a receptors are found mainly in the brain, both in neurons and in glial cells (the highest level in the striatum and the nucleus accumbens, moderate to high level in the olfactory tubercle, hypothalamus and hippocampus regions, etc.) (Rosin, DL, Robeva, A., Woodard, RL, Guyenet, PG, Linden, J. Journal of Comparative Neurology, 1998, 401, 163). In peripheral tissues, A2a receptors are found in platelets, neutrophils, vascular smooth muscle and endothelium (Gessi, S .; Varani, K .; Erighi, S .; Ongini, E .; Borea, PA. 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 the dopaminergic neurons that originate in the substantia nigra. The striatum is the main target of the degeneration of dopaminergic neurons in patients with Parkinson's disease (PD). Within the striatum, A2a receptors are colocalized with dopamine D2 receptors, suggesting an important site for the integration of adenosine and dopamine signaling in the brain (Fink, JS; Weaver, DR; Rivkees, SA; Peterfreund; , RA; Pollack, AE; Adier, EM; Reppert, SM Brain Research Molecular Brain Research, 1992, 14, 186). Neurochemical studies have shown that the activation of A2a receptors have shown that activation of A2a receptors reduces the binding affinity of D2 agonists to their receptors. This receptor-receptor interaction of D2R and A2aR has been demonstrated in rat striatum membrane preparations (Ferré, S., von Euler, G., Johansson, B., Fredholm, BB, 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 being transfected with A2aR and D2R cDNA (Salim, H., Ferré, S .; Dalal, A. Peterfreund, RA, Fuxe, K., Vincent, JD, Lledo, PM Journal of Neurochemistry, 2000, 74, 432). In vivo, the pharmacological blockade of A2a receptors leads to beneficial effects in PD-induced dopaminergic neurotoxin MPTP (1-methyl-4-pheny-1, 2,3,6-tetrahydropyridine) in several species, including mice, rats and monkeys (Ikeda, K .; Kurokawa, M .; Aoyama, S .; Kuwana, Y. Journal of Neurochemistry, 2002, 80, 262). In addition, A2a knockout mice with A2a function genetic blocking have been found to be less sensitive to motor disturbance and neurochemical changes when exposed to the MPTP neurotoxin (Chen, JF; Xu, K .; Petzer, JP; Staal, R.; Xu, YH; Beilstein, M .; Sonsalla, P. K .; Castagnoli, K .; Castagnoli, N., Jr .; Schwarzschild, M.A. Journal of Neuroscience, 2001, 21, RC143). In humans, the adenosine receptor antagonist, theophylline, has been found to produce beneficial effects in patients with PD (Mally, J .; Stone, T. W. Journal of the Neurological Sciences, 1995, 132, 129).

Consistently, a 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 can provide a new class of antiparkinsonian agents (Impagnatiello, F., Bastía, E., Ongini, E .; Monopoli, A. Emerging Therapeutic Targets, 2000, 4, 635).

BRIEF DESCRIPTION OF THE INVENTION This invention provides a compound having the structure of formula I or II Formula I or a pharmaceutically acceptable salt thereof, wherein (a) Ri is selected from the group consisting of (i) -COR5, wherein R5 is selected from H, straight or branched chain Ci-β alkyl optionally substituted , optionally substituted aryl and optionally substituted arylalkyl; wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C 1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR R8 wherein R7 and R8 are independently selected of the group consisting of hydrogen, straight or branched chain C-8 alkyl, C3-7 cycloalkyl, benzyl, aryl or heteroaryl or NR R3 taken together form a heterocycle or heteroaryl; (ii) COOR5, wherein R5 is as defined above; (ii) cyano; (iii) -CONRgR-io wherein Rg and R- are independently selected from H, straight or branched chain Cis alkyl, C3-7 cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl; wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl groups can be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide , sulfonyl, hydroxy, thiol, amino, alkoxy or arylalkyl, or Rg and R-10 taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group; (v) optionally substituted straight or branched chain C? -8 alkyl; wherein the substituents on the alkyl group are selected from C? -8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, carboxyl, aryl, heterocyclyl, heteroaryl, sulfonyl, thiol, alkylthio, or NR7R8 wherein R7 and R8 are as defined above; (b) R2 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl and optionally substituted C3-7 cycloalkyl, C? -8 alkoxy, aryloxy, C? -8 alkylsulfonyl , aryisulfonyl, arylthio, C-β8 alkylthio, or -NR24R25 wherein R <2> and R <25> are independently selected from H, straight or branched chain C [beta] -8 alkyl, arylalkyl, C3-7 cycloalkyl, carboxyalkyl, aryl , heteroaryl and heterocyclyl or R24 and R25 taken together with the nitrogen form a heteroaryl or heterocyclyl group, (c) R3 is one to four groups independently selected from the group consisting of: hydrogen, halogen, C? -8 chain alkyl straight or branched, arylalkyl, C3-7 cycloalkyl, C1-8 alkoxy, cyano, C? - carboalkoxy, trifluoromethyl, C8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C? -8 carboxylate, aryl , heteroaryl and heter occylyl, -NRnR? 2l wherein Rn and R12 are independently selected from H, straight or branched chain C? -8 alkyl, arylalkyl, C3-7 cycloalkyl, carboxyalkyl, aryl, heteroaryl and heterocyclyl, or R ™ and Rn taken together with the nitrogen form a heteroaryl or heterocyclyl group, wherein R 3 is selected from hydrogen or alkyl and R-? is selected from hydrogen, alkyl, substituted alkyl, C? -3 alkoxy, carboxyalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, R? 5R-? 6 (CH2) P-, or R? 5Ri6NCO (CH2) p-, wherein R-? 5 and R-iß are independently selected from H, OH, alkyl and alkoxy, and p is an integer of 1-6, wherein the alkyl group can be substituted with carboxyl , alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl, or R13 and R-? taken together with the carbonyl form a heterocyclyl group containing carbonyl; (d) R is selected from the group consisting of hydrogen, straight or branched chain C 1-6 alkyl, benzyl wherein the alkyl and benzyl groups are optionally substituted with one or more groups selected from C 3 cycloalkyl. , C? -8 alkoxy, cyano, C? - carboalkoxy, trifluoromethyl, C? -8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C1-8 carboxylate, amino, NR-? 7R? 8, aryl and heteroaryl, -OR17, and -NR17R18, wherein R-? 7 and R-? 8 are independently selected from hydrogen, and optionally substituted C-? -6 alkyl or aryl; and (e) X is selected from C = S, C = 0; CH2, CHOH, CHORig; or CHNR20R2? where R19, R20, and R2? are selected from optionally substituted straight or branched chain C1-8 alkyl, wherein the substituents on the alkyl group are selected from C? -8 alkoxy, hydroxy, halogen, amino, cyano, or NR22R23 wherein R22 and R23 are independently selected from the group consisting of hydrogen, straight or branched chain C? -8 alkyl, C3-7 cycloalkyl, benzyl, aryl, heteroaryl, or NR22R23 taken together form heterocycle or heteroaryl; with the proviso that in a compound of formula II when Ri is a cyano, then R2 is not phenyl. This invention also provides a pharmaceutical composition comprising the present compound and a pharmaceutically acceptable carrier. This invention further provides a method for treating a subject having a relieved condition by antagonizing adenosine A2a receptors, which comprises administering to the subject a therapeutically effective dose of the present pharmaceutical composition. This invention further provides a method for preventing a disorder alleviated by antagonizing adenosine A2a receptors in a subject, which comprises administering to the subject a prophylactically effective dose of the compound of claim 1 either before or after an anticipated event to cause a relieved disorder. by antagonizing adenosine A2a receptors in the subject.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the formula I are potent small molecule antagonists of the adenosine A2a receptors that have shown potency for the antagonism of adenosine A2a, A1, and A3 receptors. Preferred embodiments for R1 are COOR5 wherein R5 is an optionally substituted straight or branched C1-8 alkyl. Preferably, the alkyl chain is substituted with a dialkylamino group. Preferred embodiments for R2 are optionally substituted heteroaryl and optionally substituted aryl. Preferably, R2 is an optionally substituted furan. Preferred substituents for R3 include hydrogen, halogen, hydroxy, amino, trifluoromethyl, alkoxy, hydroxyalkyl chains, and aminoalkyl chains. Preferred substituents for R 4 include NH 2 and alkylamino. In a preferred embodiment, the compound is selected from the group of compounds shown in Tables 1 and 2 below. Most preferably, the compound is selected from the following compounds: The compound of claim 1, formula I, wherein R4 is Not me. 2-amino-4-furan-2-yl-indene [1,2-d] pyrimidin-5-one 2-amino-4-phenyl-indene [1,2-d] pyrimidin-5-one 2-amino-4-thiophen-2-yl-indene [1,2-d] pyrimidin-5-one 2-amino-4- (5-methyl-furan-2-yl) -indeno [1,2-d] pyrimidin-5-one 2,6-diamino-4-furan-2-yl-indene [1, 2 -d] pyrimidin-5-one -amino-1-furan-2-yl-9-oxo-9H-indene [2,1-c] pyridin-4-carbonitrile, 3-amino-1-furan-2-yl-9-oxo-9H-indene [2,1-c] pyridine-4-carboxylic acid 2-dimethylaminoethyl ester, 3-amino-1-phenyl-9-oxo-9H-indene [2,1-c] pyridine-4-carboxylic acid 2-dimethylaminoethyl ester 3-Amino-1-furan-2-yl-9-oxo-9H-indene [2,1-c] pyridine-4-carboxylic acid (2-dimethylamino-1-methyl-ethyl) -amide. 3-Amino-1-furan-2-yl-9-oxo-9H-indene [2,1-c] pyridin-4-carboxylic acid (2-dimethylamino-ethyl) -methyl-amide 1-methyl-pyrrolidin-2-ylmethyl ester of 3-amino-1-furan-2-yl-9-oxo-9H-indene [2,1-c] pyridine-4-carboxylic acid The present 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, cyclohexansulfamic and saccharic. . This invention also provides a pharmaceutical composition comprising the present compound and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M and preferably pH buffer of 0.05 M phosphate or 0.8% saline. Said pharmaceutically acceptable vehicles 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 vehicles include water, ethanol, alcoholic / aqueous solutions, glycerol, emulsions or suspensions, including saline and pH regulated medium. Oral vehicles 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 vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer and fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose and the like. The preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like. All vehicles can be mixed as necessary with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art. This invention further provides a method for treating a subject having a relieved condition by antagonizing adenosine A2a receptors, which comprises administering to the subject a therapeutically effective dose of the present pharmaceutical composition. In one embodiment, the disorder is a neurodegenerative or movement disorder. Examples of disorders treatable by the present pharmaceutical composition include, without limitation, Parkinson's disease, Huntington's disease, multiple system atrophy, corticobasal degeneration, Alzheimer's disease, and senile dementia. In a preferred embodiment, the disorder is Parkinson. As used herein, the term "subject" includes, without limitation, any artificially modified animal or animal that has a disorder alleviated by antagonizing adenosine A2a receptors. In a preferred embodiment, the subject is a human. The administration of the present pharmaceutical composition can be carried out or carried out using any of several methods known to those skilled in the art. The present compounds can be administered, for example, intravenously, intramuscularly, orally and subcutaneously. In the preferred embodiment, the present pharmaceutical composition is administered orally. In addition, the administration may comprise giving the subject a plurality of doses for a suitable period. Said administration regimens can be determined according to routine methods. How it is used here, 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, ie, eliminate, alleviate and / or delay the onset of the disorder. Methods for determining therapeutic and prophylactically effective doses for the present pharmaceutical composition are known in the art. The effective dose for administering the pharmaceutical composition to a human, for example, can be determined mathematically from the results of animal studies. In one embodiment, the therapeutically and / or prophylactically effective dose is a sufficient dose to deliver from about 0.001 mg / kg of body weight to about 200 mg / kg of body weight of the present pharmaceutical composition. In another embodiment, the therapeutically and / or prophylactically effective dose is a sufficient dose to deliver from about 0.05 mg / kg body weight to about 50 mg / kg body weight. More specifically, in one embodiment, the oral dose ranges from about 0.05 mg / kg to about 100 mg / kg daily. In another embodiment, the oral dose ranges from about 0.05 mg / kg to about 50 mg / kg daily, and in an additional embodiment, from about 0.05 mg / kg to about 20 mg / kg daily. In yet another embodiment, the infusion doses may range from about 1.0 μg / kg / min to about 10 mg / kg / min of inhibitor, mixed with a pharmaceutical carrier for a period ranging from about a few minutes to about a few days. In a further embodiment, for topical administration, the present compound can be combined with a pharmaceutical carrier at a drug / vehicle ratio of about 0.001 to about 0.1.

Definitions and nomenclature Unless otherwise indicated, under standard nomenclature used throughout the description, the terminal portion of the designated side chain is described first, followed by functionality adjacent to the point of attachment. As used herein, the following chemical terms will have the meanings set forth in the following paragraphs: "independently", when referring to chemical substituents, will mean that no more than one substituent exists, the substituents may be the same or different;. "Alkyl" will mean straight chain, cyclic or branched alkyl.

Unless otherwise indicated, the alkyl group will contain 1-20 carbon atoms. Unless otherwise indicated, the alkyl group may be opcionalmeníe substituted with one or more groups such as halogen, OH, CN, mercapto, nitro, amino, alkyl CRC8 alkoxy CRC8, alkylthio C C8 alkyl Ci -Cs-amino, di (C 1 -C 8 alkyl) amino, (mono-, di-, tri-, and per-) halogeno-alkyl, formyl, carboxy, alkoxycarbonyl, C 1 -C 8 alkyl-CO-O - alkyl of CrC8-CO-NH-, carboxamide, hydroxamic acid, sulfonamide, sulfonyl, thiol, aryl, aryl-alkyl (CrC8), heterocyclyl, and heteroaryl. "Alkoxy" will mean -O-alkyl and unless otherwise indicated, will have 1-8 carbon atoms. The term "bioisosterer" is defined as "groups or molecules that have chemical and physical properties that produce broadly similar biological properties" (Burger's Medicinal Chemistry and Drug Discovery, ME Wolff, ed., Fifth edition, Vol. 1, 1995, page 785 ). "Halogen" shall mean fluorine, chlorine, bromine or iodine; "PH" or "Ph" shall mean phenyl; "Ac" will mean acyl; "Bn" will mean benzyl. The term "acyl", as used herein, whether used alone or as part of a substituent group, means an organic radical having 2 to 6 carbon atoms (straight or branched chain) supplied from an organic acid by removal of the hydroxyl group. The term "Ac", as used herein, whether used alone or as part of a substituent group, means acetyl. "Aryl" or "Ar," whether used alone or as part of a substituent group, is a carbocyclic aromatic radical including, but not limited to, phenyl, 1- or 2-naphthyl and the like. The carbocyclic aromatic radical may be substituted by independent replacement of 1 to 5 of the hydrogen atoms thereon with halogen, OH, CN, mercapto, nitro, amino, alkyl of C? C8, alkoxy C? C8 alkylthio of C -? - C8, Ci-Cs-amino alkyl, di (alkyl) of CrC8) amine, (mono-, di-, tri-, and per-) halogeno-alkyl, formyl, carboxy, alkoxycarbonyl , alkyl of CrC8-CO-O-, C8-alkyl-CO-NH-, or carboxamide. Illustrative aryl radicals include, for example, phenyl, naphthyl, biphenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl, carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl, acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl and the like. "Ph" or "PH" denotes phenyl. Whether used alone or as part of a substituent group, "heteroaryl" refers to a cyclic, fully unsaturated radical having 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 can be attached to the rest of the molecule through any ring atoms. heteroaryl groups include, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrroyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazolyl, triazinyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, indolyl, isothiazolyl, 2- oxazepinyl, azepinyl, N-oxo-pyridyl, 1-dioxothienyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl N-oxide, benzimidazolyl, benzopyranyl, Benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzotiopiraniio, 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, tienofuryl, 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, alkyl of C C8 alkoxy CRC8, alkylthio CRC8, alkyl CRC8 -amino, di (C? -C8 alkyl) amino, (mono-, di-, tri-, and per-) halogeno-alkyl, formyl, carboxy, alkoxycarbonyl, alkyl of CrC8-CO-0-, alkyl of C -? - C8-CO-NH-, or carboxamide. Heteroaryl can be substituted with a mono-oxo to give for example a 4-oxo-1 H-quinoline. The terms "heterocycle," "heterocyclic" and "heterocyclo" refer to an optionally substituted cyclic group, fully or partially saturated, for example, a monocyclic ring of 4 to 7 membered bicyclic 7 to 11 membered, or tricyclic of 10 to 15 members, having at least one heteroatom in at least one ring of carbon atoms. 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 be optionally oxidized. The nitrogen atoms may optionally be quaternized. The heterocyclic group can be attached to any heteroatom or carbon atom. Exemplary monocyclic heterocyclic groups include pyrrolidinyl; oxetanyl; pyrazolinyl; imidazolinyl; imidazolidinyl; oxazoliio; oxazolidinyl; isoxazolinyl; thiazolidinyl; isothiazolidinyl; tetrahydrofuryl; piperidinyl; piperazinyl; 2-oxopiperazinyl; 2-oxopiperidinyl; 2-oxopyrrolidinyl; 4-piperidonyl; tetrahydropyranyl; tetrahydrothiopyranyl; tetrahydrothiopyranylsulfone; morpholinyl; thiomorpholinyl; thiomorpholinyl sulfoxide; thiomorpholinyl sulfone; 1,3-dioxolane; dioxanil; thietanyl; tyranyl; and similar.

Illustrative nicicyclic heterocyclic groups include quinuclidinyl; tetrahydroisoquinolinyl; dihydroisoindolyl; dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl); dihydrobenzofuryl; dihydrobenzothienyl; dihydrobenzothiopyranyl; dihydrobenzothiopyranylsulfone; dihydrobenzopyranyl; indolinyl; isochromanyl; isoindolinyl; piperonyl; tetrahydroquinolinyl; and similar. Substituted aryl, substituted heteroaryl and substituted heterocycle can be substituted with a second substituted aryl, a second substituted heteroaryl, or a second substituted heterocycle to give, for example, a 4-pyrazol-1-phenyl or 4-pyridin-2 il-phenyl. Designated numbers of carbon atoms (e.g., C -? - 8) will independently refer to the number of carbon atoms in an alkyl or cycloalkyl portion or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root. Unless otherwise specified, it is intended that the definition of any substituent or variable in a particular place in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns in the compounds of this invention may be selected by one skilled 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 the methods set forth herein. Where the compounds according to this invention have at least one stereogenic center, they can therefore exist as enantiomers. Where the compounds possess two or more stereogenic centers, they may additionally exist as diastereomers. In addition, 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 (ie, hydrates) or common organic solvents, and said solvates are also intended to be encompassed within the scope of this invention. Some of the compounds of the present invention may have trans and cis isomers. Furthermore, where the processes for the preparation of the compounds according to the invention give rise to a mixture of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography. The compounds can be prepared as a single stereoisomer or in racemic form as a mixture of some possible stereoisomers. The non-racemic forms can be obtained either by synthesis or resolution. The compounds can, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation. The compounds can also be resolved by covalent binding to a chiral auxiliary, followed by chromatographic separation and / or crystallographic separation, and removal of the chiral auxiliary. Alternatively, the compounds can be resolved using chiral chromatography. This invention will be better understood by reference to the experimental details that 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 that follow. In addition, several publications are cited throughout this application. The description of these publications is therefore incorporated by reference in this application to more fully describe the most advanced technique to which this invention pertains.

Experimental details I. General Synthesis Schemes Representative Compounds of the Present Invention they can be synthesized in accordance with the general synthesis 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 present compounds. The choice of intermediates to be used to produce subsequent compounds of the present invention is a matter of discretion that is within the capabilities of those skilled in the art. The procedures described in schemes 1 to 7, wherein R3a, 3b, 3c, and R3d are independently any group R3, and R-i, R2, R3, and R4 are as described above, can be used to prepare the compounds of the invention. The substituted pyrimidines 1 can be prepared as shown in scheme 1. The indanone or indanedione 2 or the indene ester 3 can be condensed with an aldehyde to give the substituted benzylidenes 4 (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). This is then condensed with guanidine carbonate to form indenopyrimidine 1.

SCHEME 1 Alternatively, the pyrimidine compounds can be prepared as shown in scheme 2. Sulfone 6 can be prepared by oxidation of thiol ether 5 and the desired amines 7 can be obtained by treatment of the sulfone with aromatic amines.

SCHEME 2 The pyrimidines with substituents on the fused aromatic ring could also be synthesized by the following procedure (scheme 3). The synthesis begins with the alkylation of furan with allyl bromide to provide 2-allylfuran. The Diels-Alder reaction of 2-allylfuran with dimethylacetylene dicarboxylate followed by deoxygenation (Xing, YD; Huang, NZJ Org Chem, 1982, 47, 140) gave the phthalate ester 8. The phthalate ester 8 then passed through a condensation of Claisen with ethyl acetate to give styrylindanedione 9 after acid treatment (Buckle, DR; Morgan, NJ; Ross, JW; Smith, H .; Spicer, BAJ Med. Chem. 1973, 16, 1334). The indanedione 9 is then converted to dimethyl ketene dithioacetal using carbon disulfide in the presence of KF. The addition of Grignard reagents to dithioacetal 10 and the subsequent reaction with guanidine provides the pyrimidines 11 as a mixture of isomers.

SCHEME 3 R3a- R3d ~ CHCHCH3, H Dihydroxylation and oxidation give the aromatic aldehydes 13 which can be reductively aminated to provide amines 14. The other isomer can be treated in a similar manner.

SCHEME 4 3-dicyanovinylindan-1-one (15) was obtained (scheme 5) was obtained using the published procedure (Bello, K.A., Cheng, L., Griffiths, J.J. Chem. Soc, Perkin Trans. II 1987, 815). The reaction of 3-dicyanovinylindan-1-one with an aldehyde in the presence of ammonium hydroxide produced dihydropyridines 16 (El-Taweel, FMA, Sofan, MA, E.-Maati, TMA, Elagamey, AA Boil, Chim. , 140, 306). These compounds were then oxidized to the corresponding pyridines 17 using chromium trioxide in acetic acid under reflux.

SCHEME 5 The pyridine ketone 17 can be reduced to provide the benzylic alcohols 18. Alternatively, the nitriles can be hydroxylated with sodium hydroxide to give the carboxylic acids 19 (scheme 6).

SCHEME 6 The acids can then be converted to carboxylic esters 20 or amides 21 using a variety of methods. In general, the esters 20 are obtained by treatment with silver carbonate followed by an alkyl chloride or medium coupling with diethylphosphoryl cyanide (DEPC) and the appropriate alcohol (Okawa, T .; Toda, M .; Eguchi, S .; Kakehi, A. Synthesis 1998, 1467). The amides 21 are obtained by coupling the carboxylic acid with the appropriate amine in the presence of DEPC or 1- (3-dimethylaminopropyl) -3-eylcarbodiimide hydrochloride (EDCI). Esters can also be obtained by first reacting the carboxylic acids 19 with a dibromoalkane followed by displacement of the terminal bromide with an amine (scheme 7).

SCHEME 7 21 R-, = CONR'2 II. Syntheses of specific compounds Specific compounds which are representative of this invention can be prepared by means of the following examples. No attempt has been made to optimize the yields obtained in these reactions. Based on the following, however, an expert in the technique would know how to increase yields through variations of ruin in reaction times, emperations, solveníes and / or reactive. The products of certain syntheses can be used as intermediaries to produce more than one of the present compounds. In those cases, the choice of the intermediaries to be used to produce compounds of the present invention is a matter of discretion which is within the capabilities of those skilled in the art.

EXAMPLE 1 Synthesis of benzylidene 4 (R2 = 2-furyl, R = F, Rjh, R ^ .R ^ = H) A mixture of 3 (3.0 g, 11.69 mmol) and 2-furaldehyde (1.17 g, 12. 17 mmol) in 75 ml of ethanol and 3 ml of concentrated hydrogen chloride was allowed to stir at reflux for 16 hours. The reaction was then cooled to ambient temperature, and the resulting precipitate was filtered, washed with diethyl ether, and dried with air to give 1.27 g (45%) of yield.

EXAMPLE 2 Synthesis of indenopyrimidine 1 A mixture of 4 (0.5 g, 2.06 mmol), guanidine carbonate (0.93 g, 5.16 mmoles), and 20.6 ml of 0.5 M sodium meioxide in meianol was stirred at reflux for 16 hours. The reaction mixture was cooled to ambient temperature, and diluted with water. The resulting precipitate was collected, washed with water, diethyl ether, diethyl ether, and then dried. The crude material was then purified on silica gel to give 0.024 g (4%) of production. MS m / z 282.0 (M + H).

EXAMPLE 3 Synthesis of 2-Amino-4-methanesuifonyl-indeno1'2, 2-dlpyrimidin-5-one To a suspension of 5 (Augusíin, M .; Groíh, C; Krisien, H .; Peseke, K .; Wiechmann, CJ Prakí, Chem. 1979, 321, 205) (1.97 g, 8.10 mmol) in MeOH (150 ml. ) a solution of oxone (14.94 g, 24.3 mmol) in H20 (100 mL) was added. The mixture was stirred at room temperature overnight, then diluted with cold H20 (500 ml), made basic with K2CO3 and filtered. The product was washed with water and ether to give 0.88 g (40%) of sulfone 6.

MS m / z 297.9 (M + Na).

EXAMPLE 4 Synthesis of Aminopyrimidine 7 (Rg = NHPh, Rg = H) A mixture of sulfone 6 (0.20 g, 0.73 mmol) and aniline (0.20 g, 2.19 mmol) in N-methylpyrrolidinone (3.5 ml) was heated at 100 ° C for 90 minutes. After cooling to room temperature, the mixture was diluted with EtOAc (100 ml), washed with brine (2 x 75 ml) and water (2 x 75 ml), and dried over Na 2 SO 4. After filtering and concentrating under vacuum, the residue was purified by column chromatography eluting with 0-50% EtOAc in hexane to give 0.0883 g (42%) of product 7. MS m / z 289.0 (M + H).

EXAMPLE 5 Synthesis of phthalate ester 8 A solution in 1.37 M hexanes of n-BuLi (53.6 mL, 73.4 mmol) was added to a solution in cold THF (100 mL), -78 ° C, of furan (5.3 mL, 73.4 mmol) and the reaction was then heated at 0 ° C. After 1.25 hr at 0 ° C, net allyl bromide (7.9 ml, 91.8 mmol) was added in one portion.

After 1 hr at 0 ° C, saturated aqueous NH 4 Cl was added and the layers separated. The aqueous phase was exfoliated with EOAc and the combined organics were washed with water and brine, dried over Na2SO4, and concentrated to give 4.6 g (58%) of 2-allylfuran which was used without further purification. Crude allylfuran (4.6 g, 42.6 mmol) and dimethylacetylene dicarboxylate (5.2 ml, 42.6 mmol) were heated to 90 ° C in a sealed tube without solvation. After 6 hr at 90 ° C the material was cooled and purified by column chromatography eluting with 25% EfOAc in hexanes to give 5.8 g (54% o) of the oxabicycle as a yellow oil. MS m / z 251 (M + H). Terahydrofuran (60 ml) was added in goium to TiCl4 net (16.5 ml, 150.8 mmol) at 0 ° C. A 1.0 M THF solution of LiAIH4 (60.3 ml, 60.3 mmole) was added to go, changing the color of the suspension from yellow to dark green or black suspension. Trieylamine (2.9 ml, 20.9 mmol) was added and the mixture refluxed at 75-80 ° C. After 45 min, the solution was cooled to ambient temperature and a THF solution (23 ml) of the oxabicyclo (5.8 g, 23.2 mmol) was added to the dark solution. After 2.5 hr at room temperature, the solution was emptied into a 20% aqueous K2CO3 solution (200 ml) and the resulting suspension was filtered. The precipitate was washed several times with CH2Cl2 and the layers of the filtrate were separated. The aqueous phase was extracted with CH2Cl2 and the combined organics were washed with water and brine, dried over Na2SO4, concentrated, and purified by column chromatography eluting with 25% of EOAc in hexanes to give 3.5 g (64%). of the ester of phthalate 8 as a yellow oil. MS m / z 235 (M + H).

EXAMPLE 6 Synthesis of indanedione 9 A 60% dispersion of sodium hydride in mineral oil (641 mg, 16.0 mmol) was added to a solution in EfOAc (3.5 ml) of phthalaryl ester 8 (2.5 g, 10.7 mmol), and the resulting suspension was placed in Reflux. After 1 hr, the solution became viscous so an additional 7.5 ml of EtOAc were added. After 4 h at reflux, the suspension was cooled to room temperature and filtered to give a yellow solid. This solid was added in portions to a solution of HCl (25 ml of water and 5 ml of concentrated HCl) at 80 ° C. The suspension was heated for an additional 30 min at 80 ° C, cooled to room temperature, and filtered to give 1.2 g (60%) of the indanedione 9 as a yellow solid. MS m / z 187 (M + H).

EXAMPLE 7 Synthesis of dimethyl ketene dithioacetal 10 Solid potassium fluoride (7.5 g, 129.1 mmol) was added to a solution of indanedione 9 (1.2 g, 6.5 mmol) at 0 ° C and CS2 (0.47 mL, 7.8 mmol) in DMF (10 mL). The cold bath was removed and after 30 min. Iodomethane net (1.00 ml, 16.3 mmol) was added. After 5 hr at ambient temperature, the suspension was diluted with EfOAc and then washed with water and brine. The organic layer was dried over Na2SO4, concentrated, and purified by column chromatography eluting with 20% of EOAc in hexanes to give 1.4 g (75%) of the diioacetal of dimethylacecene 10 as a yellow solid. MS m / z 291 (M + H).

EXAMPLE 8 Synthesis of pyrimidine 11 A solution of PhMgCl 2.0 M in THF (13 mL, 25.7 mmol) was added to a diioacetic solution of dimethyloxycene 10 (5.7 g, 19.8 mmol) at -78 ° C in 200 mL of THF. After 3 hr at -78 ° C, saturated aqueous NH 4 Cl was added and the layers were separated. The aqueous layer was extracted with EOAc and the combined organic extracts were washed with water and brine, dried over Na2SO, concentrated and purified by column chromatography eluting with 20% EtOAc in hexanes to give 4.9 g (77%) of the Thioenol ether as a yellow solid. MS m / z 321 (M + H). Solid guanidine hydrochloride (1.5 g, 15.3 mmol) was added to a solution of the ioenol ether (4.9 g, 15.3 mmol) and K2CO3 (2.6 g, 19.1 mmol) in 30 mL of DMF and the solution was heated to 80 ° C. . After 6 hr at 80 ° C, the solution was diluted with EOAc and washed with water and brine. The organic layer was dried over Na2SO4, concentrated, and purified by column chromatography eluting with 40% EtOAc in hexanes to give 4.6 g (96%) of the pyrimidine regioisomers 11 as yellow solids. MS m / z 314 (M + H).

EXAMPLE 9 Synthesis of aldehyde 13 ÍR2 = Ph) Solid MeSO2NH2 (277 mg, 2.9 mmol) was added in a solution of t-BuOH: H20 (1: 1) (30 ml) of AD-mix-a (4.0 g). The yellow solution was added to a solution of EOAc (15 ml) of the pyrimidine (910 mg, 2.9 mmol). After 3 days, solid sodium sulfite (4.4 g, 34.9 mmol) was added. After being stirred for 1.5 hr, the heterogeneous solution was diluted with EOAc and the layers were separated. The aqueous phase was exfoliated with EOAc and the combined exiphases were washed with water and brine, dried over Na2SO4, concentrated, and purified by column chromatography eluting with 100% EOAc to give 710 mg (70%) of the indole diol. 12. MS m / z 348 (M + H). HIO4-2H20 solid (933 mg, 4.1 mmol) was added to a solution of diol 12 (710 mg, 2.1 mmol) at 0 ° C in THF. After 1.5 hr at 0 ° C, the solution was diluted with EfOAc and the organic phase was washed with saturated aqueous NaHCO3, water, and brine. The organic layer was dried over Na2SO4 and concentrated to give 603 mg (98%) of the aldehyde 13 as a yellow solid which was used without further purification. MS m / z 302 (M + H).

EXAMPLE 10 Synthesis of amine 14 by reductive amination (Rg, = N (-CH2CHzOCHgCH) Solid NaBH (OAc) 3 (53 mg, 0.25 mmol) was added to a solution of aldehyde 13 (50 mg, 0.17 mmol), morpholine (0.034 ml, 0.34 mmol), and AcOH (0.014 ml, 0.25 mmol) in 1 ml of THF. After 3 days, the solution was filtered and concentrated. The material was dissolved in CH 2 Cl 2 and washed with saturated aqueous NaHCO 3 and brine, dried over Na 2 SO, concentrated, and purified by column chromatography eluting with 0-10% MeOH in CH 2 Cl 2 to give 38 mg (60%) of amine 14 as a yellow solid. MS m / z 373 (M + H). The product was dissolved in a minimum amount of CH 2 Cl 2 and treated with 1.0 M HCl in ether to obtain hydrochloride salt.

EXAMPLE 11 Cyclization to form dihydropyridine 16 (Rg = 2-furyl, R3 = H) To a solution of 3-dicyanovinylindan-1-one (4.06 g, 20.9 mmol) in 200 ml of ethanol was added 2-furaldehyde (3.01 g, 31.4 mmol) and 25 ml of concentrated NH 4 OH. The solution was heated to reflux for 2 hr and allowed to cool to ambient temperature during the night. The mixture was concentrated under vacuum to remove efanol. The residue was filtered and washed with water. The purple solid obtained was dried to give 5.92 g (89%). MS m / z 290 (M ++ 1).

EXAMPLE 12 Oxidation of dihydropyridine 16 to pyridine 17 (Rg = 2-furyl, R = H, R¿ = NHg, Rg = CN, X = O) To a refluxing solution of dihydropyridine 16 (5.92 g, 20.4 mmol) in acetic acid (100 ml) was added a solution of chromium (VI) oxide (2.05 g, 20.4 mmol) in 12 ml of water. After 10 minutes at reflux, the reaction was diluted with water until a precipitate began to form. The mixture was cooled to room temperature and filtered. The residue was washed with water to give 4.64 g (79%) of a brown solid. MS m / z 288 (M ++ 1).

EXAMPLE 13 Reduction of Ketone 17 to Alcohol 18 (Rg = 2-furyl, Rg = H, R¿ = NH 2, Rg = CN, X = H, OH) To a solution of ketone 17 at 0 ° C (0.115 g, 0.40 mmol) in 12 mL of THF was added a solution of 1.0 M LiAIH4 in THF (0.40 mL, 0.40 mmol). The reaction was stirred at 0 ° C for 1. hr. The reaction was quenched by the addition of acetyl ether (1.5 ml), water (1.5 ml), 10% aqueous NaOH (1.5 ml), and aqueous safed NH4CI (3.0 ml). The mixture was extracted with ethyl ether (3 x 35 ml), washed with brine, and dried over sodium sulfate. The resin solution was concentrated to give 0.083 g (72%) of a yellow solid. EM miz 290 (M ++ 1).

EXAMPLE 14 Hydrolysis of nitrile 17 to carboxylic acid 19 (Rg-2-furyl, Rg = H, R¿ = NHg, Rs = COOH, X = O) To a mixture of nitrile 17 (0.695 g, 2.42 mmol) and ethanol (30 ml) was added 5 ml of 35% aqueous sodium hydroxide. The mixture was heated to reflux overnight. After cooling to ambient temperature, the solution was poured into water and acidified with 1N HCl. The resulting precipitate was isolated by filtration and washed with water to give 0.623 g (84%) of a brown solid. MS m / z 329 (M ++ 23).

EXAMPLE 15 Synthesis of carboxylic ester 20 with silver carbonate (R? = 2-furyl, Rg = H, R4 = NHg, Rg = COgCHsCH? NMe ?, X = O) A suspension of carboxylic acid 19 (5.0 g, 16.3 mmol), silver carbonate (5.8 g, 21.2 mmol), and teirabuphylammonium iodide (1.5 g, 4.1 mmol) in 80 mL of DMF was heated at 90 ° C. After 1 hr, the mixture was cooled to ambient temperature and 2- (dimethylamino) ethyl chloride hydrochloride (2.4 g, 16.3 mmol) was added and the mixture was heated to 100 ° C. After 7 hr, the reaction was filtered while hot, concentrated and purified by column chromatography eluting with 0-10% MeOH / CH2CI2 to give 0.160 g (3%) of a yellow solid. MS m / z 378 (M ++ 1). The product was dissolved in a minimum of dichloromethane and triturated with 1.0 M HCl in ether to obtain the hydrochloride salt.

EXAMPLE 16 Synthesis of carboxylic ester 20 with DEPC (Rg = 2-furyl, Rg = H, F = NH ?, Rg = COgCHgCH-CHgCHgCHg MeW-), X = O) To a mixture of carboxylic acid 19 (0.40 g, 1.3 mmol) and (S) -1-methyl-2-pyrrolidinomethanol (0.50 mL, 3.9 mmol) in DMF (30 mL) was added 0.20 mL (1.3 mmol) of cyanide. diethylphosphoryl and eryrylamine (0.20 ml, 1.3 mmol). The reaction was stirred at 0 ° C for one hour and then heated to about 70 ° C overnight. The reaction was then cooled to ambient temperature and diluted with ethyl ether. The organic mixture was washed with saturated aqueous NaHCO3, water, and brine. After drying with sodium sulfate, the solution was concentrated. The residue was purified by column chromatography eluting with 10-100% ethyl acetate in hexane and then preparative CCD eluting with 2% MeOH in dichloromethane to give 1.9 mg (0.4%) of a yellow solid. MS m / z 404 (M ++ 1).

EXAMPLE 17 Synthesis of carboxylic amide 21 with DEPC (R? = 2-furyl) Rg = H, R? = NHg, Rg = COgCHgCH (-CHgCHgCH £ (Me) N-), X = O) To a mixture of carboxylic acid 19 (0.25 g, 0.82 mmol) and NNN'-aryrylyyleylenediamine (0.14 mL, 1.08 mmol) in DMF (20 mL) was added 0.12 mL (0.82 mmol) of diethylphosphoryl cyanide and eryrylamine (0.11 mL). , 0.82 mmoles). The reaction was stirred at 0 ° C for one hour and then heated to about 60 ° C during the night. The reaction was then cooled to ambient temperature and diluted with ethyl ether. The organic mixture was washed with aqueous saturated NaHCO3., water, and brine. After drying with magnesium sulfate, the solution was concentrated. The residue was purified by column chromatography eluting with 0-10% meianol in dichloromethane and then preparative CCD eluting with 1% MeOH in dichloromethane to give 3.3 mg (10%) of a yellow solid. MS m / z 391 (M ++ 1). The product was dissolved in a minimum of diethyl ether and evaporated with 1.0 M HCl in ether to obtain the hydrochloride salt.

EXAMPLE 18 Synthesis of carboxylic amide 21 with EDCI (R, = 2-furyl, Rg = H, R¿ = NHg, Rfi = CON (-CH? CHgN eCHgCHg-), X = O) A mixture of carboxylic acid 19 (0.300 g, 0.979 mmole), N-methylpiperazine (0.295 g, 2.94 mmole), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.563 g, 2.94 mmole), 1-hydroxybenzoeryriazole hydrate (0.397 g, 2.94 mmol), triethylamine (0.298 g, 2.94 mmol) in DMF (8 mL) was stirred at room temperature overnight. The mixture was then diluted with water and extracted several times with acetyl ether. The -compound organic compounds were washed twice with brine and then dried over sodium sulfate. The solution was concentrated and then purified by column chromatography to give 0.092 g (2%) of solid. MS m / z 389 (M ++ l). Production was plotted with 1.0 M HCl in ether to obtain the hydrochloride salt.

EXAMPLE 19 Synthesis of carboxylic ester 20 via a dibromoalkane (R? = Ph, Rg = H, R? = NH2_, Rg = CQgCHg CHgCH? NMe ?, X = O) To a solution of carboxylic acid 19 (0.100 g, 0.32 mmol) in DMF (1.5 ml) was added 60% dispersion of NaH in mineral oil (0.013 g, 0.32 mmol). After 10 minutes at room temperature, 1,3-dibromopropane (0.035 ml, 0.35 mmol) was added and the solution was stirred at room temperature for 17 hr. After it was concentrated, the residue was purified by column chromatography eluting with 40% ethyl acetate in hexanes to give 0.014 g (9%) of a yellow solid. MS m / z 437 (M ++ 1). To a solution of the yellow solid (0.014 mg, 0.03 mmol) in a sealed tube was added a 40% aqueous solution of dimethylamine (0.5 ml, 3.0 mmol). The tube was heated to 75 ° C for 2 hr before concentrating. The residue was purified by column chromatography eluting with 0-10% methanol in dichloromethane to give 0.009 g (70%) of a yellow solid. MS m / z 402 (M ++ 1). The product was dissolved in a minimum amount of CH2Cl2 and treated with 1 N HCl in ether to obtain the hydrochloride salt. Following the general synthetic procedures delineated above and in Examples 1-19, the compounds of Table 1 below were prepared.

TABLE 1 II. Biological tests and activity Ligand binding test for adenosine A2a receptor Ligand binding test of adenosine A2a receptor was performed using plasma membrane of HEK293 cells containing human adenosine A2a receptor (PerkinElmer, RB-HA2a) and radioligand [3H] CGS21680 ( PerkinElmer, NET1021). The test was peparated in a 96-well polypropylene plate in a total volume of 200 μl sequentially adding 20 μl of 1: 20 diluted membrane, 130 μl of test pH buffer (50 mM Tris-HCl, pH 7.4, 10 mM MgCl 2, 1 mM EDTA) containing [3 H] CGS21680, 50 μl of diluted compound (4X) or vehicle control in test pH buffer. The non-specific binding was determined by 80 mM of ÑECA. The reaction was carried out at ambient temperature for 2 hours after being looked through a 96-well GF / C filter plate pre-soaked in 50 mM Tris-HCl, pH7.4, containing 0.3% polyethylenimine. The plates were then washed 5 times with 50 mM cold Tris-HCl, pH 7.4, dried and sealed at the bottom. Microsilicacylation fluid, 30 μl was added to each well and the top was sealed. Plates were concocted in Packard Topcount for [3H]. The data was analyzed in the Microsoft Excel and GraphPad Prism programs (Varani, K .; Gessi, S., Dalpiaz, A., Borea, P.A. British Journal of Pharmacology, 1996, 117, 1693).

Functional test of adenosine A2a receptor CHO-K1 cells overexpressing human adenosine A2a receptors and containing cAMP-inducible beta-galactosidase reporter gene were seeded at 40-50K / well in 96-well tissue culture plates and cultured two days. On the day of the test, the cells were washed once with 200 μl of test medium (nutrient mixture F-12 / 0.1% BSA). For agonist test, the adenosine A2a receptor agonist ÑECA was subsequently added and the cells were incubated at 37 ° C, 5% CO2 for 5 hr before stopping the reaction. In the case of antagonist test, the cells were incubated with antagonists for 5 min. At room temperature, followed by the addition of 50 nM of ÑECA. The cells were then incubated at 37 ° C, 5% CO2 for 5 hr before stopping the experiments by washing the cells twice with PBS. 50 μl 1X lysis pH regulator (Promega, 5X supply solution, need to be diluted 1X before use) was added to each well and the plates were frozen at -20 ° C. For colorimetric assay of β-galactosidase enzyme, the plates were thawed at ambient temperature and 50 μl 2X of test pH regulator (Promega) were added to each well. Color was allowed to develop at 37 ° C for 1 hour or until a reasonable signal appeared. The reaction was then quenched with 150 μl of 1M sodium carbonate. Plates were coned at 405 nm on a Vmax machine (Molecular Devices). Damages were analyzed in Microsoft Excel and GraphPad Prism programs. (Chen, W.B.; Shields, T.S .; Cone, R. D. Analyíical Biochemisíry, 1995, 226, 349; Síiles, G. Journal of Biological Chemisfry, 1992, 267, 6451).

Study of haloperidol-induced caylepsy in C57bl / 6 mice C57bl / 6 mature mice (9-12 weeks of age ACE) were housed two per cage in a room for rodents. The ambient temperature was maintained at 17.7-26.1 degrees and humidity at 30-70% and room light at a 12-hr light / 12-hr dark cycle. On the day of the study, the lines were transferred to the study room. The roots were injected with haloperidol (Sigma H1512, 1.0 mg / ml made in 0.3% iartaric acid, then diluted to 0.2 mg / ml with saline) subcutaneously or vehicle at 1.5 mg / kg, 7.5ml / kg. The roots were placed in their home cages with access to water and food. 30 minutes more farde, the rations were dosed orally with vehicle (0.3% Tween 80 in saline) or the compounds at 10 mg / kg, 10 ml / kg (compounds, 1 mg / ml, made in 0.3% of Tween 80 in saline, subjected to sonication to obtain a uniform suspension). The mice were then placed in their home cages with access to water and food. 1 hour after oral dose, the catalepsy test was performed. A vertical metal wire grid (1.0 cm squares) was used for the test. The roots were placed on the grid and given a few seconds to settle and their immobility time was recorded until the mice moved their hind legs. The rails were gently removed from the grid and replaced on the grid and their immotility time was again measured. The measurement was repeated several times. The average of measurements was used for data analysis. Compound 70 showed 87% inhibition and compound 3 showed 90% inhibition of haloperidol-induced calalepsy when dosed orally at 10 mg / kg.

TABLE 3

Claims (26)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound that has the structure of formula I or II

Formula I or a pharmaceutically acceptable salt thereof, wherein (a) Ri is selected from the group consisting of (i) -COR5, wherein R5 is selected from H, optionally substituted straight or branched chain C? -8 alkyl, aryl optionally substituted and arylalkyl optionally susíiuuido; wherein the members in the alkyl, aryl and arylalkyl group are selected from Cis alkoxy, phenylacetyloxy, hydroxy, halogen, p-fosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR7R8 wherein R and R8 are independently selected from the group consists of hydrogen, straight or branched chain C? -8 alkyl, C3- cycloalkyl, benzyl, aryl or heteroaryl or NR7R8 taken together form a heterocycle or heteroaryl; (ii) COOR5, wherein R5 is as defined above; (iv) cyano; (iii) -CONRgR-io wherein Rg and R10 are independently selected from H, straight or branched chain C? -8 alkyl, C3-7 cycloalkyl, frifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heeroaryl and heyerocyclyl; wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl, and heteroaryl group can be substituted with carboxyl, alkyl, aryl, substituted aryl, heteroaryl cyclic, heteroaryl cycloalkyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide , sulfonyl, hydroxy, thiol, amino, alkoxy or arylalkyl, or Rg and R-io taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group; (v) optionally straight or branched chain C?-8 alkyl optionally susíiuuido; wherein the susfifuyeníes in the alkyl group are selected from C? -8 alkoxy, phenylacetyloxy, hydroxy, halogen, p -osiloxy, mesyloxy, amino, cyano, carboalkoxy, carboxyl, aryl, heterocyclyl, heteroaryl, sulfonyl, thiol, alkylthio, or NR7R8 wherein R7 and R8 are as defined above; (b) R 2 is selected from the group consisting of optionally sushloid alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted C 3-7 cycloalkyl, C? -8 alkoxy, aryloxy, C? .8 alkylsulfonyl. , aryisulfonyl, aryllium, C? _8 alkyl, or -NR2 R25, wherein R24 and R25 are independently selected from H, straight or branched chain C1-8 alkyl, arylalkyl, C3- cycloalkyl, carboxyalkyl, aryl, heteroaryl and heterocyclyl or R2 and R25 taken together with the nitrogen form a heteroaryl or heterocyclyl group, (c) R3 is one to four groups independently selected from the group consisting of: hydrogen, halogen, straight chain C -? - 8 alkyl or branched, arylalkyl, C3.7 cycloalkyl, C?. 8 alkoxy, cyano, C- | carboalkoxy. , cyfluoromethyl, Cis alkylsulfonyl, halogen, Ni, hydroxy, trifluoromethoxy, C-- 8 carboxylic acid, aryl, heteroaryl and heterocyclyl, -NRnR? 2, wherein R n and Ri 2 are independently selected from H, C alquilo alkyl 8 straight or branched chain, arylalkyl, C3.7 cycloalkyl, carboxyalkyl, aryl, heteroaryl and heterocyclyl, or Rio v R11 taken together with the niologen form a heteroaryl or heyerocyclyl group, -NR13COR? 4, wherein R13 is selected from hydrogen or alkyl and R-14 is selected from hydrogen, alkyl, alkyl, alkoxy, carboxyalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, R 5R16N (CH2) P-, or R15R? 6NCO (CH2) p -, wherein R15 and R-? 6 are independently selected from H, OH, alkyl and alkoxy, and p is an integer from 1-6, wherein the alkyl group may be susfidified with carboxyl, alkyl, aryl, sushilid aryl, heterocyclyl , susiiluido heyerocyclyl, heyeroaryl, solid, acidic, acidic or hydroxamic, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl, or R13 and R4 taken together with the carbonyl form a heterocyclyl group containing carbonyl; (d) R4 is selected from the group consisting of hydrogen, straight or branched chain C---6 alkyl, benzyl, wherein the alkyl and benzyl groups are optionally substituted with one or more groups selected from C3-7 cycloalkyl. , C -? - 8 alkoxy, cyano, C -? - 4 carboalkoxy, trifluoromethyl, C? -8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C? -8 carboxylate, amino, NR17R? 8, aryl and heeroaryl, -OR-? 7, and -NR17R 8, wherein R17 and R-? 8 are independently selected from hydrogen, and C1-6alkyl optionally susiiuuid or aryl; and (e) X is selected from C = S, C = 0; CH2, CHOH, CHOR19; or CHNR20R2i where R-ig, R20, and R2? are selected from optionally substituted straight or branched chain C? -8 alkyl, wherein the substituents in the alkyl group are selected from C 1-8 alkoxy, hydroxy, halogen, amino, cyano, or NR22R23 wherein R22 and R23 are independently selected from the group consisting of hydrogen, straight or branched chain Ct.sub.8 alkyl, C3-7l benzyl cycloalkyl, aryl, heteroaryl, or NR22R23 taken together form a heterocycle or heteroaryl; with the proviso that in a compound of formula II when R-i is a cyano, then R2 is not phenyl. 2. The compound according to claim 1, formula I, further characterized in that R4 is amino. 3. The compound according to claim 1, formula

I, further characterized in that R2 is aryl or heteroaryl. 4. The compound according to claim 1, formula

II, further characterized in that R2 is aryl or heteroaryl.

5. The compound according to claim 4, further characterized in that R2 is furyl or substituted furyl.

6. The compound according to claim 4, further characterized in that R-i is COOR5, wherein R5 is selected from optionally substituted straight or branched chain C-8 alkyl.

7. The compound according to claim 1, further characterized in that it is 2-amino-4-furan-2-yl-indeno [1,2-d] pyrimidin-5-one.

8. The compound according to claim 1, further characterized in that it is 2-amino-4-phenyl-indeno [1,2-d] pyrimidin-5-one.

9. The compound according to claim 1, further characterized in that it is 2-amino-4-thiophen-2-yl-indene [1,2-d] pyrimidin-5-one.

10. The compound according to claim 1, further characterized in that it is 2-amino-4- (5-methyl-furan-2-yl) -indeno [1,2-d] pyrimidin-5-one.

11. The compound according to claim 1, further characterized in that it is 2,6-diamino-4-furan-2-yl-indene [1,2-d] pyrimidin-5-one.

12. The compound according to claim 1, further characterized in that it is 3-amino-1-furan-2-yl-9-oxo-9H-indeno [2,1-c] pyridine-4-carbonitrile.

13. The compound according to claim 1, further characterized in that it is 2-dimethylamino-ylyl ester of 3-amino-1-furan-2-yl-9-oxo-9H-indene [2,1-c] pyridine-4-carboxylic acid.

14. The compound according to claim 1, further characterized in that it is 2-dimethylamino-ylyl ester of 3-amino-1-phenyl-9-oxo-9-indo [2,1-c] pyridin. -4-carboxylic acid.

15. The compound according to claim 1, further characterized in that it is 3-amino-1-furan-2-yl-9-oxo-9 - / (2-dimethylamino-1-methylethyl) -amide. -indeno [2,1-c] pyridine-4-carboxylic acid.

16. The compound according to claim 1, further characterized in that it is (2-dimethylamino-ethyl) -methyl-amide of 3-amino-1-furan-2-yl-9-oxo-9H-indene [2,1-c] pyridine-4-carboxylic acid.

17. The compound according to claim 1, further characterized in that it is 1-methyl-pyrrolidin-2-ylmeiyl ester of 3-amino-1-furan-2-yl-9-oxo-9H-indene [ 2,1-c] pyridine-4-carboxylic acid.

18. A pharmaceutical composition comprising the compound defined in claim 1 and a pharmaceutically acceptable carrier.

19. The use of the compound defined in claim 1 for preparing a medicament for trapping a subject that has a relieved condition by aniagonizing adenosine A2a receptors in appropriate cells in the subject.

20. The use of the compound defined in claim 1 for preparing a medicament for preventing a disorder alleviated by antagonizing adenosine A2a receptors in appropriate cells in the subject, wherein said medicament is administrable either before or after an event. anticipated to cause a relieved disorder by antagonizing adenosine A2a receptors on appropriate cells in the subject.

21. The use claimed in claim 19, wherein the medicament comprises the pharmaceutical composition claimed in claim 18.

22. The use claimed in claim 20, wherein the medicament comprises the pharmaceutical composition. which is claimed in claim 18.

23. - The use claimed in claim 19, wherein the írasíorno is a neurodegenerative íraslorno or an írasíomo of movement.

24. The use claimed in 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. 25.- The use claimed in claim 20, wherein the disorder is a neurodegenerative disorder or a motion phenomenon. 26. The use claimed in claim 20, wherein the írasíorno is selected from the group consisting of Parkinson's disease, Hunf.ingf.on disease, multiple system aírophy, corticobasal degeneration, Alzheimer's disease, and dementia. senile.