KR20060108652A - 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

Arylindenopyridines and arylindenopyridines and their use as adenosine A2a receptor antagonist}

[Reference to Related Application]

This application is partly pending application for pending application No. 10 / 259,139, filed September 27, 2002, and this application is partly pending application No. 10 / 123,389, filed April 16, 2002. All belong to the references in the present invention.

The present invention relates to novel arylenedenopyridine and allyldenopyrimidine and their therapeutic and prophylactic use. Diseases treated and / or prevented using these compounds include neurodegenerative diseases and movement disorders that are ameliorated by antagonizing adenosine A2a.

Adenosine A2a Receptor

Adenosine is a purine nucleotide produced by all metabolic active cells in the body. Adenosine exhibits its effect by four subtypes of cell-surface receptors (A1, A2a, A2b and A3), which belong to the receptor superfamily to which G proteins are coupled (Stiles, GL Journal of Biological Chemistry, 1992, 267, 6451). A1 and A3 are coupled to inhibitory G proteins, while A2a and A2b are coupled to stimulatory G proteins. A2a receptors are found primarily in the brain and in both neurons and glial cells (highest levels in the striatum and nucleus acumbens, moderate to high levels in regions such as the nodules, the hypothalamus, and the hippocampus) (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 .; Merighi, S .; Ongini, E .; Borea, PA British Journal of Pharmacology, 2000, 129 , 2). Stripes are a major brain region for the regulation of motor activity, in particular through neurostimulatory transmission from dopaminergic nerves derived from melanoma. Stripes are a major target of dopaminergic neurodegeneration in patients with Parkinson's disease (PD). Within the striped body, the A2a receptor is colocalized with the dopamine D2 receptor and has been proposed as an important site for the integration of adenosine and dopamine signaling in the brain (Fink, JS; Weaver, DR; Rivkees, SA; Peterfreund, RA). Pollack, AE; Adler, EM; Reppert, SM Brain Research Molecular Brain Research, 1992, 14, 186).

Neurochemical studies have shown that activation of A2a receptors reduces the binding affinity of D2 agonists to these receptors. This D2R and A2aR receptor-receptor interactions have been described in the rat striped membrane preparations (Ferre, 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) and else in fibroblast lines after transfection with A2aR and D2R cDNAs (Salim, H .; Ferre, S .; Dalal, A .; Peterfreund, RA; Fuxe, K Vincent, JD; Lledo, PM Journal of Neurochemistry, 2000, 74, 432). In vivo, pharmacological blockade of A2a receptors with A2a antagonists results in dopaminergic neurotoxin MPTA (1-methyl-4-phenyl-1,2,3,6-tetra) in various species, including rats, mice, and monkeys. Beneficial effects are induced in hydropyridine) -induced PD (Ikeda, K .; Kurokawa, M .; Aoyama, S .; Kuwana, Y. Journal of Neurochemistry, 2002, 80, 262). In addition, A2a knockout mice genetically blocked with A2a function have been known to be hardly sensitive to motor deficits and neurochemical changes when exposed to neurotoxin MPTP (Chen, JF; Xu, K .; Petzer, JP). ; Staal, R .; Xu, YH; Beilstein, M .; Sonsalla, PK; Castagnoli, K .; Castagnoli, N., Jr .; Schwarzschild, MA Journal of Neuroscience, 2001, 21, RC143).

In humans, the adenosine receptor antagonist theophylline has been known to show useful effects in PD patients (Mally, J .; Stone, T. W. Journal of the Neurological Sciences, 1995, 132, 129). Consistently, recent epidemiological studies have shown that caffeine consumption does not express PD in humans (Ascherio, A .; Zhang, SM; Hernan, MA; Kawachi, I .; Colditz, GA; Speizer, FE; Willett, WC Annals of Neurology, 2001, 50, 56). In summary, adenosine A2a receptor blockers can provide a new class of antiparkinsonian agents (Impagnatiello, F .; Bastia, E .; Ongini, E .; Monopoli, A. Emerging Therapeutic Targets, 2000, 4). , 635).

[Summary of invention]

Provided are compounds having the formula I or II structures of the present invention or pharmaceutically acceptable salts thereof:

Where

(a) R ₁ is

(i) -COR ₅ ;

(ii) COOR ₅ ;

(ii) cyano;

(iii) -CONR ₉ R ₁₀ ;

(v) an optionally substituted C _{1 -8} linear or branched alkyl

Is selected from the group consisting of;

(b) R ₂ is an optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, be a heterocycle, optionally substituted and optionally substituted C _{3 -7-cycloalkyl,} C _{1 -8} alkoxy, aryloxy, C _{1 -8} alkylsulfonyl, arylsulfonyl, arylthio, C _{1 -8} alkylthio, or is selected from the group consisting of -NR ₂₄ R _25;

(c) R ₃ is hydrogen, halo, C _{1 -8} linear or branched alkyl, arylalkyl, C _{3 -7-cycloalkyl,} C _{1 -8} alkoxy, cyano, C _{1 -4} carboalkoxy, trifluoromethyl , C _{1 -8} alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C _{1 -8-carboxylate,} aryl, heteroaryl, and _{heterocyclyl, -NR 11 R 12, -NR 13} COR 14 1 to 4 groups independently selected from the group consisting of;

(d) R ₄ is hydrogen, C _{1 -6} straight or branched chain alkyl, benzyl, -OR _17, and is selected from the group consisting of -NR ₁₇ R _18;

(e) X is C = S, C = O; CH ₂ , CHOH, CHOR ₁₉ ; Or CHNR ₂₀ R ₂₁ ;

Wherein, R ₅ is H, optionally substituted C _{1 -8} linear or branched alkyl, optionally substituted aryl, and optionally is selected from substituted aryl alkyl; Substituents on the alkyl, aryl and aryl alkyl groups are C _{1 -8} alkoxy, phenyl-acetyloxy, hydroxy, halogen, p- tosyloxy, mesyl-oxy, amino, cyano, carboalkoxy, or NR ₇ R ₈ is selected from , R ₇ and R ₈ are independently hydrogen, C _{1 -8} selected from straight or branched chain alkyl, C _{3 -7-cycloalkyl,} the group consisting of benzyl, aryl, or heteroaryl group or, NR ₇ R ₈ together are a heterocycle or To form a heteroaryl;

Wherein R ₉ and R ₁₀ are independently H, C _{1 -8} linear or branched alkyl, C _{3 -7-cycloalkyl,} trifluoromethyl, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heteroaryl Cycle days are selected; Alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl groups include carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, Heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, amino, alkoxy or arylalkyl may be substituted, or R ₉ and R ₁₀ are hetero with the nitrogen to which they are attached To form a cyclic or heteroaryl group;

Substituents on the alkyl group in the group (v) is a C _{1 -8} alkoxy, phenyl-acetyloxy, hydroxy, halogen, p- tosyloxy, mesyl-oxy, amino, cyano, carboalkoxy, carboxyl, aryl, heterocyclyl , Heteroaryl, sulfonyl, thiol, alkylthio, or NR ₇ R ₈ ;

Where R ₂₄ And R ₂₅ is independently H, C _{1 -8} linear or branched alkyl, arylalkyl, C _{3 -7-cycloalkyl,} carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R ₂₄ be selected from And R ₂₅ together with nitrogen form a heteroaryl or heterocyclyl group,

Where R ₁₁ And R ₁₂ is independently H, C _{1 -8} linear or branched alkyl, arylalkyl, C _{3 -7-cycloalkyl,} carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R ₂₄ be selected from And R ₂₅ together with nitrogen form a heteroaryl or heterocyclyl group,

Wherein R ₁₃ is selected from hydrogen or alkyl and R ₁₄ is hydrogen, alkyl, substituted alkyl, C _{1 -3} alkoxyl, carboxyalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, R ₁₅ R ₁₆ N (CH ₂ ) _p- , or R ₁₅ R ₁₆ NCO (CH ₂ ) _p- , R ₁₅ and R ₁₆ are independently selected from H, OH, alkyl, and alkoxy, p is an integer from 1-6, Wherein the alkyl group is carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or May be substituted by arylalkyl, or R ₁₃ and R ₁₄ together with carbonyl form a carbonyl containing heterocyclyl group;

Alkyl and benzyl groups from the group (d) is a C _{3 -7-cycloalkyl,} C _{1 -8} alkoxy, cyano, C _1-4 carboalkoxy, trifluoromethyl, C _{1 -8} alkylsulfonyl, halogen, nitro , hydroxy, trifluoromethoxy, C _{1 -8-carboxylate,} amino, NR ₁₇ R _18, aryl and heteroaryl, -OR _17, and -NR ₁₇ R ₁₈ is optionally substituted by one or more groups selected from;

Wherein R ₁₇ and R ₁₈ are independently selected from hydrogen, and optionally substituted C _{1 -6} alkyl or aryl;

Wherein R _19, R _20, and R ₂₁ is selected from optionally substituted C _{1 -8} linear or branched alkyl substituents on the alkyl groups are C _{1 -8} alkoxy, hydroxy, halogen, amino, cyano, or NR ₂₂ R ₂₃ is selected from, R ₂₂ and R ₂₃ are independently hydrogen, selected from C _{1 -8} linear or branched alkyl, C _{3 -7-cycloalkyl,} the group consisting of benzyl, aryl, or heteroaryl, NR ₂₂ R ₂₃ together To form a heterocycle or heteroaryl;

With the proviso that when R ₁ is cyano in the compound of formula II, R ₂ is not phenyl.

The invention also provides a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier.

The present invention further provides a method for treating a subject with improved symptoms by antagonizing adenosine A2a receptor, the method comprising administering to the subject a therapeutically charged dose of the pharmaceutical composition.

The invention further comprises antagonizing the adenosine A2a receptor in a subject, comprising administering a prophylactically effective dose of the compound of claim 1 before or after an event that is expected to antagonize the adenosine A2a receptor in the subject to ameliorate the disease. Provided are methods for preventing improved disease.

Detailed Description of the Invention

Compounds of formula (I) are potent small molecule antagonists of adenosine A2a receptors that exhibit potency against the antagonism of adenosine A2a, A1, and A3 receptors.

A preferred example for R ₁ is COOR ₅ in R ₅ is optionally substituted C _{1 -8} linear or branched alkyl. Preferably the alkyl chain is substituted with a dialkylamino group.

Preferred examples for R ₂ are optionally substituted heteroaryl and optionally substituted aryl. Preferably, R ₂ is optionally substituted furan.

Preferred examples for R ₃ include hydrogen, halo, 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 set forth in Tables 1 and 2 below.

More preferably, the compound is selected from the following compounds:

The compound of claim 1 wherein R ₄ is amino.

2-amino-4-furan-2-yl-indeno [1,2-d] pyrimidin-5-one

2-amino-4-phenyl-indeno [1,2-d] pyrimidin-5-one

2-amino-4-thiophen-2-yl-indeno [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-indeno [1,2-d] pyrimidin-5-one

9 H-indeno [2,1-c] pyridine-4-carbonitrile, 3-amino-1-furan-2-yl-9-oxo-

9 H -indeno [2,1-c] pyridine-4-carboxylic acid, 3-amino-1-furan-2-yl-9-oxo-, 2-dimethylamino-ethyl ester

9 H-indeno [2,1-c] pyridine-4-carboxylic acid, 3-amino-1-phenyl-9-oxo-, 2-dimethylamino-ethyl ester

9 H-indeno [2,1-c] pyridine-4-carboxylic acid, 3-amino-1-furan-2-yl-9-oxo-, (2-dimethylamino-1-methyl-ethyl) amides

9 H -indeno [2,1-c] pyridine-4-carboxylic acid, 3-amino-1-furan-2-yl-9-oxo-, (2-dimethylamino-ethyl) -methyl-amide

9 H -indeno [2,1-c] pyridine-4-carboxylic acid, 3-amino-1-furan-2-yl-9-oxo-, 1-methyl-pyrrolidin-2-ylmethyl ester

The compound can be isolated and used as the free base. They can also be isolated and used as pharmaceutically acceptable salts. Examples of such salts are hydrobromic, hydroiodic, hydrochloric, perchloric, sulfuric, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulphonic, hydroethane Phonics, benzenesulphonic, oxalic, palmoic, 2-naphthalenesulphonic, p-toluenesulphonic, cyclohexanesulfamic and saccharic.

The invention also provides a pharmaceutical composition comprising the 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, 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, alcohol / aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media. Oral carriers can be elixirs, syrups, capsules, tablets and the like. Typical solid carriers are inert materials 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 solution, and fixed oils. Intravenous carriers include fluid and nutritional supplements, electrolyte supplements such as those based on Ringer's dextrose and the like. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases, and the like. All carriers can be mixed with disintegrants, diluents, granules, lubricants, binders and the like if necessary using conventional techniques known in the art.

The present invention further provides a method of treating a subject with improved symptoms by antagonizing adenosine A2a receptor, the method comprising administering to the subject a therapeutically effective dose of the pharmaceutical composition.

In one type, the disease is a neurodegenerative disease or movement disorder. Examples of diseases treatable by the pharmaceutical composition include, but are not limited to, Parkinson's disease, chorea, multiple systemic degeneration, Corticobasal degeneration, Alzheimer's disease, and senile dementia.

In a preferred embodiment, the disease is Parkinson's disease.

As used herein, “subject” includes, but is not limited to, animals or artificially modified animals with diseases that are ameliorated by antagonizing adenosine A2a receptors. In a preferred embodiment, the subject is a human.

Administration of the pharmaceutical compositions can be carried out or carried out using a variety of methods known to those skilled in the art. The compounds can be administered, for example, intravenously, intramuscularly, orally and subcutaneously. In a preferred embodiment, the pharmaceutical composition is administered orally. In addition, administration can include supplying a plurality of dosages over a period of time appropriate for the subject. Such dosing regimen may be determined in a routine manner.

As used herein, a "therapeutically effective dose" of a pharmaceutical composition is an amount sufficient to stop, reverse or reduce the progression of the disease. A “prophylactically effective dose” of a pharmaceutical composition is an amount sufficient to prevent the disease, ie eliminate, ameliorate and / or delay the onset of the disease. Methods for determining therapeutic and prophylactically effective dosages for the present pharmaceutical compositions are known in the art. Effective dosages for administering pharmaceutical compositions to humans can be determined mathematically, for example, from animal studies.

In one type, the therapeutic and / or prophylactically effective dosage is a dosage sufficient to dispense the present pharmaceutical composition from about 0.001 mg / kg body weight to about 200 mg / kg body weight. In another type, the therapeutic and / or prophylactically effective dosage is a dosage sufficient to dispense from about 0.05 mg / kg body weight to about 50 mg / kg body weight. More specifically, in one type, the oral dosage is about 0.05 mg / kg to about 100 mg / kg per day. In another type, the oral dosage is from about 0.05 mg / kg to about 50 mg / kg per day, and in further embodiments, from about 0.05 mg / kg to about 20 mg / kg per day. In another embodiment, the infusion dose is about 1.0 μg / kg / min to about 10 mg / kg / min of inhibitor in admixture with the pharmaceutical carrier over a period of about a few minutes to about several days. In a further type, for topical administration, the compounds may be combined with the pharmaceutical carrier at a drug / carrier ratio of about 0.001 to about 0.1.

Definition and nomenclature

Unless otherwise indicated, under standard nomenclature used throughout this specification, the terminal portion of the designated side chain is first described, followed by adjacent functional groups by the point of attachment.

As used herein, the following chemical terms will have the meanings set forth in the following paragraphs: “Independently” with respect to a chemical substituent, when one or more substituents are present, the substituents may be the same or different;

"Alkyl" shall mean straight, cyclic and branched alkyl. Unless otherwise specified, alkyl groups will contain 1-20 carbon atoms. Unless otherwise specified, the alkyl group is an optionally halogen, OH, CN, mercapto, nitro, amino, C ₁ -C ₈ - alkyl, C ₁ -C ₈ - alkoxyl, C ₁ -C ₈ - alkylthio, C ₁ -C ₈ -alkyl-amino, di (C ₁ -C ₈ -alkyl) amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C ₁ -C ₈ -alkyl-CO-O-, C ₁ -C ₈ -alkyl-CO-NH-, carboxamide, hydroxamic acid, sulfonamide, sulfonyl, thiol, aryl, aryl (c ₁ -c ₈ ) It may be substituted by one or more groups such as alkyl, heterocyclyl, and heteroaryl.

 "Alkoxy" means -O-alkyl and, unless stated otherwise, will have 1-8 carbon atoms.

"Bioisostere" is defined as "a group or molecule with chemical and physical properties that exhibits broadly similar biological properties" (Burger's Medicinal Chemistry and Drug Discovery, ME Wolff, ed. Fifth Edition, Vol. 1, 1995, Pg. 785).

"Halogen" means fluorine, chlorine, bromine or iodine; "PH" or "Ph" means phenyl; "Ac" means acyl; "Bn" will mean benzyl.

As used herein, "acyl" means an organic radical having 2 to 6 carbon atoms (side chain or straight chain) derived from an organic acid, either alone or as part of a substituent group, or by removal of a hydroxyl group. As used herein, "Ac", used alone or as part of a substituent group, means acetyl.

"Aryl" or "Ar" is a carbocyclic aromatic radical, including but not limited to, phenyl, 1- or 2-naphthyl, etc., used alone or as part of a substituent group. Carbocyclic aromatic radical is a halogen, OH, CN, mercapto, nitro, amino, C ₁ -C ₈ - alkyl, C ₁ -C ₈ - alkoxyl, C ₁ -C ₈ - alkylthio, C ₁ -C ₈ -Alkyl-amino, di (C ₁ -C ₈ -alkyl) amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C ₁ -C _8- It may be substituted by independent substitution on 1 to 5 hydrogen atoms by alkyl-CO-O-, C ₁ -C ₈ -alkyl-CO-NH-, or carboxamide. Examples of aryl radicals are, for example, phenyl, naphthyl, biphenyl, fluorophenyl, difluorophenyl, benzyl, benzyloxyphenyl, carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxy Phenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl, acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl and the like. "Ph" or "PH" defines phenyl.

Used alone or as part of a substituent group, "heteroaryl" refers to a cyclic, fully unsaturated radical having 5 to 10 ring atoms, wherein one ring atom is selected from S, O, and N; 0-2 ring atoms are additional heteroatoms independently selected from S, O, and N; The remaining ring atoms are carbon. The radical may be bound to the rest of the molecule by ring atoms. Examples of heteroaryl groups include, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrroylyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazoleyl, triazolyl, Triazinyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, indolyl, isothiazolyl, 2-oxazinylyl, azepinyl, N-oxo-pyridyl, 1-dioxothienyl, Benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl-N-oxide, benzimidazolyl, benzopyranyl, benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazyl, benzothiopyranyl , Indazolyl, indolizinyl, benzofuryl, chromoyl, coumarinyl, cinnolineyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, furopyridinyl [3,2-b] pyridinyl, or furo [2,3-b] pyridinyl), imidazopyridinyl (such as imidazo [4,5-b] pyrid) Yl or imidazo [4,5-c] pyridinyl), naphthyridinyl, phthalazinyl, purinyl, pyridopyridyl, quinazolinyl, thienofuryl, thienopyridyl, thienothienyl, and Contains furyl. Heteroaryl group is a halogen, OH, CN, mercapto, nitro, amino, C ₁ -C ₈ - alkyl, C ₁ -C ₈ - alkoxyl, C ₁ -C ₈ - alkylthio, C ₁ -C ₈ - alkyl, -Amino, di (C ₁ -C ₈ -alkyl) amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C ₁ -C ₈ -alkyl- May be substituted by independent substitution on 1 to 5 hydrogen atoms by CO-O-, C ₁ -C ₈ -alkyl-CO-NH-, or carboxamide. Heteroaryl may be substituted by mono-oxo to provide, for example, 4-oxo-1H-quinoline.

"Heterocycle", "heterocyclic", and "heterocyclo" refer to optionally substituted, fully or partially saturated cyclic groups, for example 4- to 7-membered monocyclic, 7- to 11- A 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 heteroatom containing heterocyclic group may have one, two or three heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, wherein the nitrogen and sulfur heteroatoms may also be optionally oxidized. The nitrogen atom can be optionally quaternized. Heterocyclic groups may be bonded to heteroatoms or carbon atoms.

Examples of monocyclic heterocyclic groups include pyrrolidinyl; Oxetanyl; Pyrazolinyl; Imidazolinyl; Oxazolyl; Oxazolidinyl; Isoxazolinyl; Thiazolidinyl; Isothiazolidinyl; Tetrahydrofuryl; Piperidinyl; Piperazinyl; 2-oxopiperazinyl; 2-oxopiperidinyl; 2-oxopyrrolidinyl; 2-oxopyrrolidinyl; 4-piperidoneyl; Tetrahydropyranyl; Tetrahydrothiopyranyl; Tetrahydrothiopyranyl sulfone; Morpholinyl; Thiomorpholinyl; Thiomorpholinyl sulfoxide; Thiomorpholinyl sulfone; 1,3-dioxolane; Dioxanyl; Thiethanyl; Thiirayl; And the like. One example of a bicyclic heterocyclic group is quinuclidinyl; Tetrahydroisoquinolinyl; Dihydroisoindolyl; Dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl); Dihydrobenzofuryl; Dihydrobenzothienyl; Dihydrobenzothiopyranyl; Dihydrobenzothiopyranyl sulfone; Dihydrobenzopyranyl; Indolinyl; Isocromanyl; Isoindolinyl; Piperonyl; Tetrahydroquinolinyl; And the like.

Substituted aryl, substituted heteroaryl, and substituted heterocycle may also be substituted with a second substituted-aryl, a second substituted-heteroaryl, or a second substituted-heterocycle, for example, 4- Pyrazol-1-yl-phenyl or 4-pyridin-2-yl-phenyl may be provided.

The specified number of carbon atoms (e.g., C _{1 -8)} means a carbon atom in the alkyl or cycloalkyl portion independently or more means the alkyl portion of a larger substituent alkyl can be seen as its prefix part.

Unless otherwise specified, the definition of a substituent or variable at a particular position in a molecule is independent of the other definitions in that molecule. It is understood that the substituents and substitution patterns on the compounds of the present invention are selected by those skilled in the art and are chemically stable and can be readily synthesized by the methods presented in the present invention in addition to those known in the art.

If the compounds dl according to the invention have at least one stereogenic center, these compounds may therefore exist as enantiomers. If the compound has two or more stereogenic centers, these compounds may further exist as diastereomers. In addition, some of the crystalline forms for the compounds may exist as polymorphs and are included as such in the present invention. In addition, some compounds may form solvates with water (ie, hydrates) or common organic solvents, such solvates are also within the scope of the present invention.

Some compounds of the present invention may have trans and cis isomers. In addition, when producing mixtures of stereoisomers by the process for the preparation of compounds according to the invention, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form as single stereoisomers or as a mixture of some possible stereoisomers. Non-racemic forms can be obtained by synthesis or decomposition. The compounds can be decomposed into their component enantiomers, for example by the formation of diastereomeric pairs by standard techniques such as salt formation. The compounds may also be degraded by covalent bonding of chiral aids, followed by chromatographic separation and / or crystallographic separation, and by removal of chiral aids. Alternatively, compounds can be resolved using chiral chromatography.

While the present invention will be further understood with reference to the following experimental details, those skilled in the art will readily appreciate that they have been presented for purposes of illustration of the invention only as described more fully in the following claims. In addition, throughout this application, many publications are cited. The disclosures in these publications belong to the references of this application to more fully describe the state of the art to which this invention pertains.

Experiment Details

I. General Synthetic Schemes

Representative compounds of the present invention can be synthesized according to the general synthetic methods described below and shown in the following general scheme. The products of some schemes may be used as intermediates to prepare one or more of the compounds. Selecting intermediates used to prepare subsequent compounds of the present invention is a matter of discretion within the ability of those skilled in the art.

The procedures described in Schemes 1-7 can be used to prepare the compounds of the present invention, wherein R _3a , R _3b , R _3c , and R _3d are independently R ₃ groups, R ₁ , R ₂ , R ₃ , And R ₄ is as described above.

Substituted pyrimidine 1 can be prepared as shown in Scheme 1. Indanone or indandione 2 or indene ester 3 can be condensed with aldehydes to yield substituted benzylidene 4 (Bullington, JL; Cameron, JC; Davis, JE; Dodd, JH; Harris, CA; Henry, JR; Pellegrino-Gensey, JL; Rupert, KC; Siekierka, JJ Bioorg.Med. Chem. Lett. 1998, 8, 2489; Petrow, V .; Saper, J .; Sturgeon, BJ Chem. Soc. 1949, 2134). This is then condensed with guanidine carbonate to form indenopyrimidine 1.

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

In addition, pyrimidine having a substituent on the fused aromatic ring can be synthesized by the following procedure (Scheme 3). The synthesis begins with alkylation of allyl bromide with furan to give 2-allylfuran. Diels-Alder reaction of dimethylacetylene dicarboxylate with 2-allylfuran followed by deoxygenation (Xing, Y.D .; Huang, N.Z. J. Org. Chem. 1982, 47, 140) provided phthalate ester 8. The phthalate ester 8 was then condensed with ethyl acetate and Claisen to give styryl indandione 9 after acid workup (Buckle, DR; Morgan, NJ; Ross, JW; Smith, H .; Spicer, BAJ Med. Chem. 1973, 16, 1334). Indandione 9 was then converted to dimethylketene dithioacetal 10 using carbon disulfide in the presence of KF. Grignard reagent was added to dithioacetal 10 and subsequent reaction with guanidine provided pyrimidine 1 as a mixture of isomers.

Reductive amination with dihydroxylation and oxidation reactions provided aromatic aldehyde 13 which can provide amine 14. Other isomers can be processed in a similar manner.

3-dicyanovinylindan-1-one (15) was obtained using published procedures (Bello, K.A .; Cheng, L .; Griffiths, J. J. Chem. Soc., Perkin Trans. II 1987, 815). Reaction of aldehyde with 3-dicyanovinylindan-1-one in the presence of ammonium hydroxide produced dihydropyridin 16 (El-Taweel, FMA; Sofan, MA; E.-Maati, TMA; Elagamey, AA Boll. Chim. Farmac. 2001, 140, 306). These compounds were then oxidized to the corresponding pyridine 17 using chromium trioxide in reflux acetic acid.

Pyridine ketone 17 may be reduced to provide benzylic alcohol 18. Alternatively, the nitrile can be hydrolyzed with sodium hydroxide to give carboxylic acid 19 (Scheme 6).

Various methods can then be used to convert the acid to carboxylic ester 20 or amide 21. Generally, treatment with silver carbonate followed by alkyl chloride or coupling with diethylphosphoryl cyanide (DEPC) with a suitable alcohol yields ester 20 (Okawa, T .; Toda, M .; Eguchi, S. Kakehi, A. Synthesis 1998, 1467). The carboxylic acid is coupled with a suitable amine in the presence of DEPC or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCl) to afford amide 21. It is also possible to first react carboxylic acid 19 with dibromoalkane and then replace the terminal bromide with an amine to give ester 20 (Scheme 7).

II. Specific compound synthesis

Specific compounds which are representative compounds of the present invention can be prepared according to the following examples. No attempt was made to optimize the yields obtained in these reactions. However, based on the following examples, one skilled in the art knows how to increase the yield through routine changes in reaction time, temperature, solvent and / or reagents.

The product of any synthesis can be used as an intermediate to produce one or more compounds. In these cases, selecting the intermediate to be used to produce the compounds of the present invention is a matter of discretion within the skill of the person skilled in the art.

Example 1

Synthesis of Benzylidene 4

(R ₂ = 2-furyl, R _3a = F, R _3b , R _3c , R _3d = H)

A mixture of 75 mL of ethanol, 3 mL of concentrated hydrochloric acid compound 3 (3.0 g, 11.69 mmol) and 2-furaldehyde (1.17 g, 12.17 mmol) was stirred under reflux for 16 hours. The reaction was then cooled to room temperature and the resulting precipitate was filtered off, washed with ethanol, diethyl ether and air dried to yield 1.27 g (45%) of product.

Example 2

Synthesis of Indenopyrimidine 1

(R ₂ = 2-furyl, R _3a = F, R _3b , R _3c , R _3d = H)

A mixture of compound 4 (0.5 g, 2.06 mmol), guanidine carbonate (0.93 g, 5.16 mmol) in methanol, and 20.6 mL of 0.5 M sodium methoxide was stirred at reflux for 16 hours. The reaction mixture was cooled to rt and diluted with water. The resulting precipitate was collected, washed with water, ethanol, diethyl ether and dried. The crude material was then purified on silica gel to yield 0.024 g (4%) of product. MS m / z 282.0 (M + H).

Example 3

Synthesis of 2-amino-4-methanesulfonyl-indeno [1,2-d] pyrimidin-5-one

Compound 5 (Augustin, M .; Groth, C .; Kristen, H .; Peseke, K .; Wiechmann, CJ Prakt. Chem. M. Augustin et. Al. Journal fuer Praktische Chemie (Leipzig)) in MeOH (150 mL) (1979), 321 (2), 205-14) (1.97 g, 8.10 mmol) was added a solution of oxone (14.94 g, 24.3 mmol) in H ₂ O (100 mL). The mixture was stirred at rt overnight then diluted with cooled H ₂ O (500 mL), made basic with K ₂ CO ₃ 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

(R ₂ = NHPh, R ₃ = 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 to 100 ° C. for 90 minutes. After cooling to rt, the mixture was diluted with EtOAc (100 mL), washed with brine (2 × 75 mL) and water (2 × 75 mL) and dried over Na ₂ SO ₄ . After filtration and concentration in vacuo, the residue was purified by column chromatography eluting with 0-50% EtOAc in hexanes to afford 0.0883 g (42%) of product 7. MS m / z 289.0 (M + H).

Example 5

Synthesis of Phthalate Ester 8 A 1.37 M hexane solution of n-BuLi (53.6 mL, 73.4 mmol) was added to a cooled, −78 ° C., THF solution (100 mL) of furan (5.3 mL, 73.4 mmol) and the reaction was then 0. Heated to ° C. After 1.25 h at 0 ° C., partly pure allyl bromide (7.9 mL, 91.8 mmol) was added. After 1 hour at 0 ° C., saturated aqueous NH ₄ Cl was added and the layers were separated. The aqueous phase was extracted with EtOAc and the combined organics were washed with water and brine, dried over Na ₂ S0 ₄ and concentrated to give 4.6 g (58%) of 2-allylfuran and used without further purification.

Crude allyl furan (4.6 g, 42.6 mmol) and dimethylacetylene dicarboxylate (5.2 mL, 42.6 mmol) were heated to 90 ° C. in a solvent free sealed tube. After 6 hours at 90 ° C. the material was cooled and purified by column chromatography eluting with 25% EtOAc in hexanes to give 5.8 g (54%) of oxabicycle as a yellow oil. MS m / z 251 (M + H).

Tetrahydrofuran (60 mL) was added dropwise to pure TiCl ₄ (16.5 mL, 150.8 mmol) at 0 ° C. 1.0 M THF solution of LiAlH ₄ (60.3 mL, 60.3 mmol) was added dropwise to change the color of the suspension from yellow to dark green or black suspension. Triethylamine (2.9 mL, 20.9 mmol) was added and the mixture was refluxed at 75-80 ° C. After 45 minutes, the solution was cooled to room temperature and oxabicycle (5.8 g, 23.2 mmol) THF solution (23 mL) was added to the concentrated solution. After 2.5 h at rt, the solution was washed with 20% aq. Pour into K ₂ CO ₃ solution (200 mL) and filter the resulting suspension. The precipitate was washed several times with CH ₂ Cl ₂ and the filtration layer was separated. The aqueous phase is extracted with CH ₂ Cl ₂ and the combined organics are washed with water and brine, dried over Na ₂ SO ₄ , and concentrated, In hexane Purified by column chromatography eluted with 25% EtOAc. 3.5 g (64%) of phthalate ester 8 was obtained as a yellow oil. MS m / z 235 (M + H).

Example 6

Synthesis of Indandione 9

A 60% suspension of sodium hydride in sodium hydride in mineral oil (641 mg, 16.0 mmol) in 60% dispersion is added to an EtOAc solution (3.5 mL) of phthalate ester 8 (2.5 g, 10.7 mmol) and the resulting slurry is It was refluxed. After 1 hour the solution became viscous and therefore an additional 7.5 mL of EtOAc was added. After 4 hours at reflux, the suspension was cooled to room temperature and filtered to give a yellow solid. This solid was partially added to a solution of HCl (25 mL water and 5 mL concentrated HCl) at 80 ° C. The suspension was heated at 80 ° C. for another 30 minutes, cooled to room temperature and filtered to yield 1.2 g (60%) of indandione 9 as a yellow solid. MS m / z 187 (M + H).

Example 7

Synthesis of Dimethylketene Dithioacetal 10

Solid potassium fluoride (7.5 g, 129.1 mmol) was added to a 0 ° C. solution of indandione 9 (1.2 g, 6.5 mmol) and CS ₂ (0.47 mL, 7.8 mmol) in DMF (10 mL). Thirty minutes after the cooling bath was removed, pure iodomethane (1.00 mL, 16.3 mmol) was added. After 5 h at rt, the suspension was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na ₂ SO ₄ , concentrated and purified by column chromatography eluting with 20% EtOAc in hexanes to afford 1.4 g (75%) of dimethylketene dithioacetal 10 as a yellow solid. MS m / z 291 (M + H).

Example 8

Synthesis of Pyrimidine 11

(R ₂ = Ph, R _3a = CHCHCH ₃ , R _3d = H)

Of PhMgCl in THF (13 mL, 25.7 mmol) A 2.0 M solution was added to a -78 ° C solution of dimethylketene dithioacetal 10 (5.7 g, 19.8 mmol) in 200 mL of THF. After 3 hours at -78 ° C, saturated aqueous NH ₄ Cl was added and the layers were separated. The aqueous layer was extracted as EtOAc and the combined organic extracts were washed with water and brine, Na ₂ SO ₄ , dried over, concentrated and purified by column chromatography eluting with 20% EtOAc in hexanes to give 4.9 g (77%) of 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 thioenol ether (4.9 g, 15.3 mmol) and K ₂ CO ₃ (2.6 g, 19.1 mmol) in 30 mL of DMF and the solution was heated to 80 ° C. Heated. After 6 h at 80 ° C., the solution was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na ₂ SO ₄ , concentrated and purified by column chromatography eluted with 40% EtOAc in hexanes to give 4.6 g (96%) of pyrimidine regioisomer 11 as a yellow solid. MS m / z 314 (M + H).

Example 9

Synthesis of Aldehyde 13

(R ₂ = Ph)

Solid MeSO ₂ NH ₂ (277 mg, 2.9 mmol) was added to a t-BuOH: H ₂ O (1: 1) solution (30 mL) of AD-mix-α (4.0 g). The resulting yellow solution was added to an EtOAc solution (15 mL) of pyrimidine (910 mg, 2.9 mmol). After 3 days, solid sodium sulfite (4.4 g, 34.9 mmol) was added. After stirring for 1.5 hours, the mixture was diluted with heterogeneous solution EtOAc and the layers separated. The aqueous phase was extracted with EtOAc and the combined extracts were washed with water and brine, dried over Na ₂ SO ₄ , concentrated and purified by column chromatography eluted with 100% EtOAc to 710 mg (70%) of intermediate diol 12 Obtained. MS m / z 348 (M + H).

The solid _{HIO 4 -2H 2 O (933 mg} , 4.1 mmol) was added to the THF solution of 0 ℃ within the diol 12 (710 mg, 2.1 mmol) . After 1.5 h at 0 ° C., the solution was diluted with EtOAc and the organic phase was washed with saturated aqueous NaHCO ₃ , water, and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated to afford 603 mg (98%) of 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

(R _3a = N (-CH ₂ CH ₂ OCH ₂ CH _2- )

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. Was added. After 3 hours the solution was filtered and concentrated. The resulting material was dissolved in CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ and brine, dried over Na ₂ SO ₄ , concentrated and purified by column chromatography eluted 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 give the hydrochloride.

Example 11

Cycling to Form Dihydropyridine 16

(R ₂ = 2-furyl, R ₃ = 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 hours and cooled to room temperature overnight. The mixture was concentrated in vacuo to remove ethanol. The residue was filtered off and washed with water. The resulting purple solid was dried to give 5.92 g (89%). MS m / z 290 (M ⁺ +1).

Example 12

Oxidation of Dihydropyridine 16 to Pyridine 17

(R ₂ = 2-furyl, R ₃ = H, R ₄ = NH ₂ , R ₅ = CN, X = O)

To a reflux 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 rt and filtered. The residue was washed with water to yield 4.64 g (79%) of a brown solid. MS m / z 288 (M ⁺ +1).

Example 13

Reduction of ketone 17 with alcohol 18

(R ₂ = 2-furyl, R ₃ = H, R ₄ = NH ₂ , R ₅ = CN, X = H, OH)

To a 0 ° C. solution of ketone 17 (0.115 g, 0.401 mmol) in 12 mL of THF was added a 1.0 M LiAlH ₄ solution in THF (0.40 mL, 0.40 mmol). The reaction was stirred at 0 ° C for 1 h. The reaction was diluted with ethyl acetate (1.5 mL), water (1.5 mL), 10% aq. NaOH (1.5 mL), and saturated aq. NH ₄ Cl (3.0 mL) was added to cool. The mixture was extracted with ethyl acetate (3 x 35 mL), washed with brine and then dried over sodium sulfate. The remaining solution was concentrated to yield 0.083 g (72%) of a yellow solid. MS m / z 290 (M ⁺ +1).

Example 14

Hydrolysis of Nitrile 17 with Carboxylic Acid 19

(R ₂ = 2-furyl, R ₃ = H, R ₄ = NH ₂ , R ₅ = 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 solution. The resulting mixture was heated to reflux overnight. After cooling to room temperature, the solution was poured into water and acidified with 1 N HCl. The resulting precipitate was separated by filtration and washed with water to yield 0.623 g (84%) of a brown solid. MS m / z 329 (M ⁺ +23).

Example 15

Synthesis with Silver Carbonate of Carboxylic Ester 20

(R ₂ = 2-furyl, R ₃ = H, R ₄ = NH ₂ , R ₅ = CO ₂ CH ₂ CH ₂ NMe ₂ , X = O)

A suspension of carboxylic acid 19 (5.0 g, 16.3 mmol), silver carbonate (5.8 g, 21.2 mmol), and tetrabutylammonium iodide (1.5 g, 4.1 mmol) in 80 mL of DMF was heated to 90 ° C. After 1 h, the mixture was cooled to rt and 2- (dimethylamino) ethylchloride hydrochloride (2.4 g, 16.3 mmol) was added and the mixture was heated to 100 ° C. After 7 hours, the reaction was filtered while hot, concentrated and purified by column chromatography eluted with 0-10% MeOH / CH ₂ Cl ₂ to give 0.160 g (3%) of a yellow solid. MS m / z 378 (M ⁺ +1). The product was dissolved in a minimum amount of dichloromethane and treated with 1.0 M HCl in ether to give the hydrochloride.

Example 16

Synthesis with DEPC of Carboxylic Ester 20

(R ₂ = 2-furyl, R ₃ = H, R ₄ = NH ₂ , R ₅ = CO ₂ CH ₂ CH (-CH ₂ CH ₂ CH ₂ (Me) N-), X = O)

0.20 mL (1.3 mmol) of di in a mixture of 19 (0.40 g, 1.3 mmol) of carboxylic acid and ( S ) -1-methyl-2-pyrrolidinemethanol (0.50 mL, 3.9 mmol) in DMF (30 mL). Ethylphosphoryl cyanide and triethylamine (0.20 mL, 1.3 mmol) were added. The reaction was stirred at 0 ° C. for 1 hour and then heated to about 70 ° C. overnight. The reaction was cooled to rt and then diluted with ethyl acetate. The organic mixture was washed with saturated aqueous NaHCO ₃ , 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 by preparative TLC 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 with DEPC of Carboxylic Amide 21

(R ₂ = 2-furyl, R ₃ = H, R ₄ = NH ₂ , R ₅ = CO ₂ CH ₂ CH (-CH ₂ CH ₂ CH ₂ (Me) N-), X = O)

0.12 mL (0.82 mmol) of diethylphosphoryl cya to a mixture of carboxylic acid 19 (0.25 g, 0.82 mmol) and N, N, N'-trimethylethylenediamine (0.14 mL, 1.08 mmol) in DMF (20 mL) Nide and triethylamine (0.11 mL, 0.82 mmol) were added. The reaction was stirred at 0 ° C. for 1 hour and then heated to about 60 ° C. overnight. The reaction was cooled to rt and diluted with ethyl acetate. The organic mixture was washed with saturated aqueous NaHCO ₃ , water, and brine. After drying over magnesium sulfate, the solution was concentrated. The residue was purified by column chromatography eluting with 0-10% methanol in dichloromethane followed by preparative TLC 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 minimal diethyl ether and treated with 1.0 M HCl in ether to give the hydrochloride.

Example 18

Synthesis with EDCl of Carboxylamide 21

(R ₂ = 2-furyl, R ₃ = H, R ₄ = NH ₂ , R ₅ = CON (-CH ₂ CH ₂ NMeCH ₂ CH _2- ), X = O)

Carboxylic acid 19 (0.300 g, 0.979 mmol), N-methylpiperazine (0.295 g, 2.94 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in DMF (8 mL) ( 0.563 g, 2.94 mmol), a mixture of 1-hydroxybenzotriazole hydrate (0.397 g, 2.94 mmol) and triethylamine (0.298 g, 2.94 mmol) was stirred overnight at room temperature. The mixture was then diluted with water and extracted several times with ethyl acetate. The combined organics were washed twice with brine and dried over sodium sulfate. The solution was concentrated and then purified by column chromatography to yield 0.092 g (2%) of solids. MS m / z 389 (M ⁺ +1). The product was treated with 1.0 M HCl in ether to give hydrochloride.

Example 19

Synthesis of Carboxylic Acid Ester 20 by Dibromoalkanes

(R ₂ = Ph, R ₃ = H, R ₄ = NH ₂ , R ₅ = CO ₂ CH ₂ CH ₂ CH ₂ NMe ₂ , X = O)

To a solution of carboxylic acid 19 (0.100 g, 0.32 mmol) in DMF (1.5 mL) was added 60% NaH suspension in mineral oil (0.013 g, 0.32 mmol). After 10 min at rt, 1.3-dibromopropane (0.035 mL, 0.35 mmol) was added and the solution was stirred at rt for 17 h. After concentration, the residue was purified by column chromatography eluted with 40% ethyl acetate in hexanes to afford 0.014 g (9%) of a yellow solid. MS m / z 437 (M ⁺ +1).

To a solution of a yellow solid (0.014 mg, 0.03 mmol) in a sealed tube was added a 40% aqueous solution of diethylamine (0.5 mL, 3.0 mmol) in a sealed tube was added a 40% aqueous solution. The tube was heated to 75 ° C. for 2 hours before concentration. Purification by column chromatography eluting with 0-10% methanol in dichloromethane gave 0.009 g (70%) of a yellow solid. MS m / z 402 (M ⁺ +1). The product was dissolved in a minimum amount of CH ₂ Cl ₂ and treated with 1 N HCl in ether to give the hydrochloride.

Following the general synthesis procedure outlined above and Examples 1-19, the compounds of Table 1 were prepared.

III. Biological test and activity

Ligand Binding Test for Adenosine A2a Receptor

Ligand binding tests of adenosine A2a receptors were performed using plasma membranes of HEK293 cells containing human A2a adenosine receptors (PerkinElmer, RB-HA2a) and radioligand [ ³ H] CGS21680 (PerkinElmer, NET1021). 130 μl of test buffer (50 mM Tris.HCl, pH7.4 10 mM MgCl) containing 20 μl of a 1:20 dilution membrane, [ ³ H] CGS21680 in test buffer in a total volume of 200 μl 96-well polypropylene plates. ₂ , 1 mM EDTA). The test was started by adding 50 μl of diluted compound (4 ×) or vehicle regulator in series. Nonspecific binding was measured by 80 mM NECA. A 96-well GF / C filter plate presoaked in 50 mM Tris.HCl, pH7.4 containing 0.3% polyethyleneimine was allowed to react for 2 hours at room temperature before filtration. The plate was then washed five times with chilled 50 mM Tris.HCl, pH7.4, dried and the bottom sealed. 30 μl of microscintillation fluid was added to each well and the top was sealed. Plates were counted on Packard Topcount for [ ³ H]. Data was analyzed in the Microsoft Excel and GraphPad Prism programs (Varani, K .; Gessi, S .; Dalpiaz, A .; Borea, PA British Journal of Pharmacology, 1996, 117, 1693).

Adenosine A2a Receptor Function Test

CHO-K1 cells overexpressing the human adenosine A2a receptor and containing the cAMP-induced beta-galactosidase receptor gene were inoculated with 96-well tissue culture plates at 40-50K / well and incubated for 2 days. . On test days, cells were washed once with 200 μl test medium (F-12 nutrient mixture / 0.1% BSA). For agonist testing, adenosine A2a receptor agonist NECA was then added and cell cultured at 37 ° C., 5% CO ₂ for 5 hours before stopping the reaction. For antagonist tests, cells were incubated with antagonists for 5 minutes at room temperature followed by the addition of 50 nM NECA. Cells were then incubated for 5 hours at 37 ° C., 5% CO ₂ before stopping the experiment by washing the cells twice with PBS. 50 μl 1 × cell lysis buffer (Promega, 5X stock solution, required dilution to 1 × before use) was added to each well and the plate was frozen to −20 ° C. For β-galactosidase enzyme color test, plates were thawed at room temperature and 50 μl 2 × test buffer (Promega) was added to each well. Coloring was carried out at 37 ° C. for 1 hour or until a suitable signal appeared. The reaction was then stopped with 150 μl of 1M sodium carbonate. Plates were counted at 405 nm on a Vmax Machine (Molecular Devices). Data was analyzed by Microsoft Excel and GraphPad Prism programs (Chen, WB; Shields, TS; Cone, RD Analytical Biochemistry, 1995, 226, 349; Stiles, G. Journal of Biological Chemistry, 1992, 267, 6451).

Haloperidol-induced Catalepsy in C57b1 / 6 Rats

Two adult male C57bl / 6 rats (9-12 weeks old from ACE) were housed in cages of rodents. Room temperature was maintained at 64-79 degrees Celsius, humidity at 30-70% and room lighting was maintained at a 12 hour light / 12 hour dark cycle. Birds were injected subcutaneously at haloperidol (Sigma H1512, 1.0 mg / ml prepared in 0.3% tartaric acid, then diluted to 0.2 mg / ml with saline) or 1.5 mg / kg, 7.5 ml / kg with vehicle. After that, the mice were placed in their original cages with access to water and food. After 30 minutes, the rats were prepared in vehicle (0.3% Tween 80 in saline) or compound at 10 mg / kg, 10 ml / kg (compound, 1mg / ml, 0.3% Tween 80 in saline), sonicated to give a homogeneous suspension. Obtained orally). After that, the mice were placed in their original cages with access to water and food. After 1 hour of oral administration, the catalepsy test was performed. Vertical metal-wire grid (1.0 cm 2) was used for the test. The rats were placed on the grid, allowed to settle for a few seconds and the immobility time was recorded until the rats moved their hind paws. The juvenile was slowly removed from the grid and placed back on the grid to measure the dead time again. Three measurements were repeated. The average of three measurements was used for data analysis.

Compound 70 showed 87% inhibition and Compound 3 showed 90% inhibition against haloperidol-induced anorexia when administered orally at 10 mg / kg.

Table 5

No. Ki (nM) A2a bond A2a antagonist action A1 antagonist action One 44.64 233.7 52.98 2 2.032 6.868 5.32 3 0.26 0.0066 0.288 4 0.885 2.63 15.57 5 5.355 9.64 27.1 6 3.9 4.56 16.44 7 0.26 0.49 6.89 8 58.41 5.5 11.59 9 20.82 4.85 7.69 10 6.1 0.109 1.2 11 8.85 1.63 2.47 12 33.49 32.52 172.3 13 5.16 35.59 10.35 14 2.19 0.59 3.19 15 3.23 0.258 3.46 16 1.75 0.169 5.22 17 6.3 67.14 111.29 18 317.95 > 3000 188.99 19 110.73 20.88 21.64 20 0.05 0.126 0.91 21 0.376 0.053 3.51 22 14.16 0.055 2.75 23 13.58 0.55 1.47 24 30.32 > 3000 5.99 25 172.85 5.69 17.44 26 34.57 0.88 3.13 27 146.84 68.28 > 1000 28 48.9 3.53 5.86 29 20.95 1.42 4.27 30 31.55 10.15 4.05 31 140.68 15.22 17.5 32 3.55 0.634 9.89 33 0.175 0.34 0.021 34 560.13 35 3.49 0.265 7.09 36 4.37 0.052 2.52 37 2.86 0.143 3.07 38 2.34 0.956 9.44 39 4.92 0.926 2.31 40 2720.46 41 88.01 575.43 > 3000 42 118.2 782.18 > 10000 43 39.9 3.68 2.34 44 3.93 0.208 7.4 45 4.013 0.005 0.016 46 60.56 490.14 32.54 47 1076.76 48 470.84 > 1000 > 1000 49 51.12 40.13 119.03 50 80.15 11.31 94.24 51 36.81 3.26 32.92 52 94.41 18.33 107.17 53 64.15 14.25 40.82 54 40.79 3.19 19.56 55 32.82 5.84 19.86 56 25.72 6.81 25.76 57 34.02 15.93 39.29 58 30.65 11.65 60.99 59 40.79 7.94 34.11 60 34.29 61 29.83 62 58.39 63 0.59 0.0002 0.18 64 13.09 0.138 4.61 65 574.71 244.96 163.36 66 4.21 0.069 15.59 67 13.4 0.618 4.37 68 7.59 0.73 34.84 69 2261 90.16 > 1000 70 9.89 0.44 20.13 71 17.24 3.39 2.42 72 12.64 2.54 6.24 73 4.925 0.06 9.7 74 14.67 5.7 7.28 75 23.72 1.51 78.33 76 33.03 22.13 > 500 77 6.254 0.68 > 500 78 17.65 1.58 > 500 79 8.03 12.48 > 1000 80 69.08 15.86 55.99 81 228.7 29.03 33.63 82 20.24 1.36 29.58 83 200.06 74.87 117.05 84 173.98 24.71 27.42 85 507.72 86 244.07 > 1000 39.26 87 98.93 39.45 > 300 88 129.6 48.87 > 300 89 5.85 1.12 11.16 90 202.17 57.7 > 300 91 208.32 22.07 14.67 92 38.82 13.9 32.88 93 64.05 23.57 104.31 94 49.55 > 1000 35.99 95 338.13 > 1000 110.22 96 48.55 10.08 52.45

Claims (26)

Compounds having the structure of Formula I or II or pharmaceutically acceptable salts thereof:

Where (a) R ₁ is (i) -COR ₅ ; (ii) COOR ₅ ; (iv) cyano; (v) -CONR ₉ R ₁₀ ; (v) an optionally substituted C _{1 -8} linear or branched alkyl Is selected from the group consisting of; (b) R ₂ is an optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, be a heterocycle, optionally substituted and optionally substituted C _{3 -7-cycloalkyl,} C _{1 -8} alkoxy, aryloxy, C _{1 -8} alkylsulfonyl, arylsulfonyl, arylthio, C _{1 -8 alkylthio,} or is selected from the group consisting of -NR ₂₄ R _25; (c) R ₃ is hydrogen, halo, C _{1 -8} linear or branched alkyl, arylalkyl, C _{3 -7-cycloalkyl,} C _{1 -8} alkoxy, cyano, C _{1 -4} carboalkoxy, trifluoromethyl , C _{1 -8} alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C _{1 -8-carboxylate,} aryl, heteroaryl, and _{heterocyclyl, -NR 11 R 12, -NR 13} COR 14 1 to 4 groups independently selected from the group consisting of; (d) R ₄ is hydrogen, C _{1 -6} straight or branched chain alkyl, benzyl, -OR _17, and is selected from the group consisting of -NR ₁₇ R _18; (e) X is C = S, C = O; CH ₂ , CHOH, CHOR ₁₉ ; Or CHNR ₂₀ R ₂₁ ; Wherein, R ₅ is H, optionally substituted C _{1 -8} linear or branched alkyl, optionally substituted aryl, and optionally is selected from substituted aryl alkyl; Substituents on the alkyl, aryl and aryl alkyl groups are C _{1 -8} alkoxy, phenyl-acetyloxy, hydroxy, halogen, p- tosyloxy, mesyl-oxy, amino, cyano, carboalkoxy, or NR ₇ R ₈ is selected from , R ₇ and R ₈ are independently hydrogen, C _{1 -8} selected from straight or branched chain alkyl, C _{3 -7-cycloalkyl,} the group consisting of benzyl, aryl, or heteroaryl group or, NR ₇ R ₈ together are a heterocycle or To form a heteroaryl; Wherein R ₉ and R ₁₀ are independently H, C _{1 -8} linear or branched alkyl, C _{3 -7-cycloalkyl,} trifluoromethyl, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heteroaryl Cycle days are selected; Alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl groups include carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, Heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, amino, alkoxy or arylalkyl may be substituted, or R ₉ and R ₁₀ are hetero with the nitrogen to which they are attached To form a cyclic or heteroaryl group; Substituents on the alkyl group in the group (v) is a C _{1 -8} alkoxy, phenyl-acetyloxy, hydroxy, halogen, p- tosyloxy, mesyl-oxy, amino, cyano, carboalkoxy, carboxyl, aryl, heterocyclyl , Heteroaryl, sulfonyl, thiol, alkylthio, or NR ₇ R ₈ ; Where R ₂₄ And R ₂₅ is independently H, C _{1 -8} linear or branched alkyl, arylalkyl, C _{3 -7-cycloalkyl,} carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R ₂₄ be selected from And R ₂₅ together with nitrogen form a heteroaryl or heterocyclyl group, Where R ₁₁ And R ₁₂ is independently H, C _{1 -8} linear or branched alkyl, arylalkyl, C _{3 -7-cycloalkyl,} carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R ₂₄ be selected from And R ₂₅ together with nitrogen form a heteroaryl or heterocyclyl group, Wherein R ₁₃ is selected from hydrogen or alkyl and R ₁₄ is hydrogen, alkyl, substituted alkyl, C _{1 -3} alkoxyl, carboxyalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, R ₁₅ R ₁₆ N (CH ₂ ) _p- , or R ₁₅ R ₁₆ NCO (CH ₂ ) _p- , R ₁₅ and R ₁₆ are independently selected from H, OH, alkyl, and alkoxy, p is an integer from 1-6, Wherein the alkyl group is carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or May be substituted by arylalkyl, or R ₁₃ and R ₁₄ together with carbonyl form a carbonyl containing heterocyclyl group; Alkyl and benzyl groups from the group (d) is a C _{3 -7-cycloalkyl,} C _{1 -8} alkoxy, cyano, C _1-4 carboalkoxy, trifluoromethyl, C _{1 -8} alkylsulfonyl, halogen, nitro , hydroxy, trifluoromethoxy, C _{1 -8-carboxylate,} amino, NR ₁₇ R _18, aryl and heteroaryl, -OR _17, and -NR ₁₇ R ₁₈ is optionally substituted by one or more groups selected from; Wherein R ₁₇ and R ₁₈ are independently selected from hydrogen, and optionally substituted C _{1 -6} alkyl or aryl; Wherein R _19, R _20, and R ₂₁ is selected from optionally substituted C _{1 -8} linear or branched alkyl substituents on the alkyl groups are C _{1 -8} alkoxy, hydroxy, halogen, amino, cyano, or NR ₂₂ R ₂₃ is selected from, R ₂₂ and R ₂₃ are independently hydrogen, selected from C _{1 -8} linear or branched alkyl, C _{3 -7-cycloalkyl,} the group consisting of benzyl, aryl, or heteroaryl, NR ₂₂ R ₂₃ together To form a heterocycle or heteroaryl; With the proviso that when R ₁ is cyano in the compound of formula II, R ₂ is not phenyl. 2. Compounds according to claim 1, wherein in formula (I) R ₄ is amino. 2. Compounds according to claim 1, wherein in formula (I) R ₂ is aryl or heteroaryl. The compound of claim 1, wherein R ₂ in formula (II) is aryl or heteroaryl. The compound of claim 4, wherein R ₂ is furyl or substituted furyl. The method of claim 4, wherein R ₁ is COOR _5, where R ₅ is optionally substituted C _{1 -8} linear or branched alkyl. The compound of claim 1, which is 2-amino-4-furan-2-yl-indeno [1,2-d] pyrimidin-5-one. The compound of claim 1, which is 2-amino-4-phenyl-indeno [1,2-d] pyrimidin-5-one. The compound of claim 1, which is 2-amino-4-thiophen-2-yl-indeno [1,2-d] pyrimidin-5-one. The compound of claim 1, which is 2-amino-4- (5-methyl-furan-2-yl) -indeno [1,2-d] pyrimidin-5-one. The compound of claim 1, which is 2,6-diamino-4-furan-2-yl-indeno [1,2-d] pyrimidin-5-one. The compound of claim 1, which is 9 H -indeno [2,1-c] pyridine-4-carbonitrile, 3-amino-1-furan-2-yl-9-oxo-. The compound of claim 1, wherein 9 H -indeno [2,1-c] pyridine-4-carboxylic acid, 3-amino-1-furan-2-yl-9-oxo-, 2-dimethylamino-ethyl ester Phosphorus compounds. The compound of claim 1, which is 9 H -indeno [2,1-c] pyridine-4-carboxylic acid, 3-amino-1-phenyl-9-oxo-, 2-dimethylamino-ethyl ester. The compound of claim 1, wherein 9 H -indeno [2,1-c] pyridine-4-carboxylic acid, 3-amino-1-furan-2-yl-9-oxo-, (2-dimethylamino-1 -Methyl-ethyl) -amide. The compound of claim 1, wherein 9 H -indeno [2,1-c] pyridine-4-carboxylic acid, 3-amino-1-furan-2-yl-9-oxo-, (2-dimethylamino-ethyl ) -Methyl-amide. The compound of claim 1, wherein 9 H -indeno [2,1-c] pyridine-4-carboxylic acid, 3-amino-1-furan-2-yl-9-oxo-, 1-methyl-pyrrolidine 2-ylmethyl ester. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. A method of treating a subject having a disease that is ameliorated by antagonizing adenosine A2a receptors in suitable cells of the subject, comprising administering to the subject a therapeutically effective dose of the compound of claim 1. Antagonizing the adenosine A2a receptor in a suitable cell of the subject, comprising administering a prophylactically effective dose of the compound of claim 1 to the subject before or after an event in which the disease is expected to be ameliorated by antagonizing the adenosine A2a receptor in the subject's suitable cell. How to prevent and improve disease. The method of claim 19, comprising administering to the subject a therapeutic or prophylactically effective dosage of the pharmaceutical composition of claim 18. The method of claim 20, comprising administering to the subject a therapeutic or prophylactically effective dosage of the pharmaceutical composition of claim 18. The method of claim 19, wherein the disease is a neurodegenerative disease or a movement disorder. 20. The method of claim 19, wherein the disease is selected from the group consisting of Parkinson's disease, chorea, multiple systemic degeneration, Corticobasal degeneration, Alzheimer's disease, and senile dementia. The method of claim 20, wherein the disease is a neurodegenerative disease or a movement disorder. The method of claim 20, wherein the disease is selected from the group consisting of Parkinson's disease, chorea, multiple systemic degeneration, cortico-Basic degeneration, Alzheimer's disease, and senile dementia.