WO2010045017A1 - Amines and sulfoxides of thieno [2,3-d] pyrimidine and their use as adenosine a2a receptor antagonists - Google Patents

Amines and sulfoxides of thieno [2,3-d] pyrimidine and their use as adenosine a2a receptor antagonists Download PDF

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WO2010045017A1
WO2010045017A1 PCT/US2009/058746 US2009058746W WO2010045017A1 WO 2010045017 A1 WO2010045017 A1 WO 2010045017A1 US 2009058746 W US2009058746 W US 2009058746W WO 2010045017 A1 WO2010045017 A1 WO 2010045017A1
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alkyl
phenyl
disorder
group
optionally substituted
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Devraj Chakravarty
Brian Christopher Shook
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Janssen Pharmaceutica NV
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • This invention relates to a novel arylindenopyrimidine and its therapeutic and prophylactic uses.
  • Disorders treated and/or prevented include neurodegenerative and movement disorders ameliorated by antagonizing Adenosine A2a receptors.
  • Adenosine A2a Receptors Adenosine is a purine nucleotide produced by all metabolically active cells within the body. Adenosine exerts its effects via four subtypes of cell surface receptors (Al, A2a, A2b and A3), which belong to the G protein coupled receptor superfamily (Stiles, G.L. Journal of Biological Chemistry, 1992, 267, 6451). Al and A3 couple to inhibitory G protein, while A2a and A2b couple to stimulatory G protein.
  • A2a receptors are mainly found in the brain, both in neurons and glial cells (highest level in the striatum and nucleus accumbens, moderate to high level in olfactory tubercle, hypothalamus, and hippocampus etc. regions) (Rosin, D. L.; Robeva, A.; Woodard, R. L.; Guyenet, P. G.; Linden, J. Journal of Comparative Neurology, 1998, 401, 163).
  • A2a receptors are found in platelets, neutrophils, vascular smooth muscle and endothelium (Gessi, S.; Varani, K. ; Merighi, S. ; Ongini, E.; Bores, P. A. British Journal of Pharmacology, 2000, 129, T).
  • the striatum is the main brain region for the regulation of motor activity, particularly through its innervation from dopaminergic neurons originating in the substantial nigra.
  • the striatum is the major target of the dopaminergic PRD 3029 US and PCT
  • A2a receptors are co-localized with dopamine D2 receptors, suggesting an important site for the integration of adenosine and dopamine signaling in the brain (Fink, J. S.; Weaver, D. Ri; Rivkees, S. A.; Peterfreund, R. A.; Pollack, A. E.; Adler, E. M.; Reppert, S. M. Brain Research Molecular Brain Research, 1992,14,186).
  • A2a knockout mice with genetic blockade of A2a function have been found to be less sensitive to motor impairment and neurochemical changes when they were exposed to neurotoxin MPTP (Chen, J. F.; Xu, K.; I Petzer, J. P.; Steal, R.; Xu, Y. H.; Beilstein, M.; Sonsalla, P. K.; Castagnoli, K.; Castagnoli, N., Jr.; Schwarsschild, M. A. Journal of Neuroscience, 2001, 1 21, RCl 43).
  • adenosine A2a receptor blockers may provide a new class of antiparkinsonian agents (Impagnatiello, F.; Bastia, E.; Ongini, E.; Monopoli, A. Emerging Therapeutic Targets, 2000, 4, 635).
  • PRD 3029 US and PCT
  • Antagonists of the A 2A receptor are potentially useful therapies for the treatment of addiction.
  • Major drugs of abuse opiates, cocaine, ethanol, and the like
  • dopamine signaling in neurons particularly those found in the nucleus accumbens, which contain high levels of A 2A adenosine receptors.
  • An A 2A receptor antagonist could be used to treat attention deficit hyperactivity disorder (ADHD) since caffeine (a non selective adenosine antagonist) can be useful for treating ADHD, and there are many interactions between dopamine and adenosine neurons.
  • ADHD attention deficit hyperactivity disorder
  • caffeine a non selective adenosine antagonist
  • Antagonists of the A 2A receptor are potentially useful therapies for the treatment of depression.
  • a 2A antagonists are known to induce activity in various models of depression including the forced swim and tail suspension tests. The positive response is mediated by dopaminergic transmission and is caused by a prolongation of escape-directed behavior rather than by a motor stimulant effect.
  • Antagonists of the A 2A receptor are potentially useful therapies for the treatment of anxiety.
  • a 2 A antagonist have been shown to prevent emotional/anxious responses in vivo. Neurobiology of Disease (2007), 28(2) 197-205.
  • Compounds of Formula A are potent small molecule antagonists of the Adenosine A2a receptor.
  • PRD 3029 US and PCT are potent small molecule antagonists of the Adenosine A2a receptor.
  • R 1 is phenyl wherein said phenyl is optionally substituted with up to three substituents independently selected from the group consisting of F, Cl, Br, and OCH3, or a single substituent selected from the group consisting of: OH, OCH 2 CF 3 , OC ( i_ 4) alkyl, C ( i_ 4) alkyl,
  • R 1 is heteroaryl optionally substituted with one substituent selected from the group consisting of: -OH, OC ( i_ 4) alkyl, CF 3 , OCF 3 , Cl, Br, -CN,
  • R 2 is is an aromatic ring selected from the group consisting of phenyl and heteroaryl, wherein said aromatic ring is optionally substituted with -CN, F, Cl, Br, NO 2 , -CF 3 , OC ( i_ 4 )alkyl,
  • X is NH, NC ( i_ 4) alkyl, S, S(O), or S(O) 2 ;
  • the invention provides compounds of Formula A.
  • R 1 is phenyl wherein said phenyl is optionally substituted with up to three substituents independently selected from the group consisting of F, Cl, Br, and OCH 3 , or a single substituent selected from the group consisting of: OH, OCH 2 CF 3 , OC (1-4 )alkyl, C ⁇ alkyl, CHF 2 , OCF 3 , CF 3 , cyclopropyl and CN; or R 1 is heteroaryl optionally substituted with one PRD 3029 US and PCT
  • substituent selected from the group consisting of: -OH, OC ( i_ 4) alkyl, CF 3 , OCF 3 , Cl, Br, -CN,
  • R 2 is is an aromatic ring selected from the group consisting of phenyl and heteroaryl, wherein said aromatic ring is optionally substituted with -CN, F, Cl, Br, NO 2 , -CF 3 , OC ( i_ 4 )alkyl,
  • X is NH, NC ( i_ 4) alkyl, S, S(O), or S(O) 2 ; and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof.
  • R 1 is an aromatic ring selected from the group consisting of phenyl, furyl, oxazolyl, isoxazolyl, pyridyl, and thiazolyl, wherein said aromatic ring is optionally substituted with -
  • R is is an aromatic ring selected from the group consisting of phenyl, furyl, oxazolyl, isoxazolyl, pyridyl, and thiazolyl, wherein said aromatic ring is optionally substituted with -
  • X is NH, NC ( i_ 4) alkyl, S, S(O), or S(O) 2 ; and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof.
  • R 1 is an aromatic ring selected from the group consisting of phenyl, furyl, oxazolyl, isoxazolyl, pyridyl, and thiazolyl, wherein said aromatic ring is optionally substituted with -
  • R 2 is an aromatic ring selected from the group consisting of phenyl, furyl, oxazolyl, isoxazolyl, pyridyl, and thiazolyl, wherein said aromatic ring is optionally substituted with -
  • X is NH, NC ( i_ 4) alkyl, S, or S(O) 2 ; and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof.
  • R 1 is phenyl, wherein said phenyl is optionally substituted with -CN, -CF 3 , 0C ( i_ 4) alkyl,
  • R 2 is phenyl, or pyridyl, wherein said phenyl, or pyridyl is optionally substituted with -CN,
  • X is NH, NC(i- 4) alkyl, or S(O) 2 ; and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof.
  • R 1 is phenyl, wherein said phenyl is substituted with -CN;
  • R 2 is phenyl, or pyridyl, wherein said phenyl, or pyridyl is optionally substituted with OCH 3,
  • X is NH, NCH 3 , or S(O) 2 ; and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof.
  • the invention is directed to a compound selected from the group consisting of:
  • This invention further provides a method of treating a subject having a condition ameliorated by antagonizing Adenosine A2a receptors, which comprises administering to the subject a therapeutically effective dose of a compound of Formula A.
  • This invention further provides a method of preventing a disorder ameliorated by antagonizing Adenosine A2a receptors in a subject, comprising of administering to the subject a prophylactically effective dose of the compound of claim 1 either preceding or subsequent to an event anticipated to cause a disorder ameliorated by antagonizing Adenosine A2a receptors in the subject.
  • Compounds of Formula A can be isolated and used as free bases. They can also be isolated and used as pharmaceutically acceptable salts.
  • salts include hydrobromic, hydroiodic, hydrochloric, perchloric, sulfuric, maleic, fumaric, malic, tartaric, citric, adipic, benzoic, mandelic, methanesulfonic, hydroethanesulfonic, benzenesulfonic, oxalic, palmoic, 2 naphthalenesulfonic, p- toluenesulfonic, cyclohexanesulfamic and saccharic.
  • This invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula A and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M and preferably 0.05 M phosphate buyer or 0.8% saline.
  • Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, ethanol, alcoholic/aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media.
  • Oral carriers can be elixirs, syrups, capsules, tablets and the like.
  • the typical solid carrier is an inert substance such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like.
  • Parenteral carriers include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils.
  • Intravenous carriers include PRD 3029 US and PCT
  • electrolyte replenishes such as those based on Ringer's dextrose and the like.
  • Preservatives and other additives can also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like. All carriers can be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art.
  • This invention further provides a method of treating a subject having a condition ameliorated by antagonizing Adenosine A2a receptors, which comprises administering to the subject a therapeutically effective dose of a compound of Formula A.
  • the disorder is a neurodegenerative or movement disorder.
  • disorders treatable by the instant pharmaceutical composition include, without limitation, Parkinson's Disease, Huntington's Disease, Multiple System Atrophy, Corticobasal Degeneration, Alzheimer's Disease, and Senile Dementia.
  • the disorder is Parkinson's disease.
  • the term "subject” includes, without limitation, any animal or artificially modified animal having a disorder ameliorated by antagonizing adenosine A2a receptors.
  • the subject is a human.
  • Administering the instant pharmaceutical composition can be effected or performed using any of the various methods known to those skilled in the art.
  • Compounds of Formula A can be administered, for example, intravenously, intramuscularly, orally and subcutaneously.
  • the instant pharmaceutical composition is administered orally.
  • administration can comprise giving the subject a plurality of dosages over a suitable period of time. Such administration regimens can be determined according to routine methods.
  • a “therapeutically effective dose” of a pharmaceutical composition is an amount sufficient to stop, reverse or reduce the progression of a disorder.
  • effective dose of a pharmaceutical composition is an amount sufficient to prevent a disorder, i.e., eliminate, ameliorate and/or delay the disorder's onset. Methods are known in the art for determining therapeutically and prophylactically effective doses for the instant pharmaceutical composition.
  • the effective dose for administering the pharmaceutical composition to a human can be determined mathematically from the results of animal studies.
  • the therapeutically and/or prophylactically effective dose is a dose sufficient to deliver from about 0.001 mg/kg of body weight to about 200 mg/kg of body weight of a compound of Formula A. In another embodiment, the therapeutically and/or prophylactically effective dose is a dose sufficient to deliver from about 0.05 mg/kg of body weight to about 50 mg/kg of body weight. More specifically, in one embodiment, oral doses range from about 0.05 mg/kg to about 100 mg/kg daily. In another embodiment, oral doses range from about 0.05 mg/kg to about 50 mg/kg daily, and in a further embodiment, from about 0.05 mg/kg to about 20 mg/kg daily.
  • infusion doses range from about 1.0,ug/kg/min to about 10 mg/kg/min of inhibitor, admixed with a pharmaceutical carrier over a period ranging from about several minutes to about several days.
  • the instant compound can be combined with a pharmaceutical carrier at a drug/carrier ratio of from about 0.001 to about 0.1.
  • the invention also provides a method of treating addiction in a mammal, comprising administering a therapeutically effective dose of a compound of Formula A.
  • the invention also provides a method of treating ADHD in a mammal, comprising administering a therapeutically effective dose of a compound of Formula A.
  • the invention also provides a method of treating depression in a mammal, comprising administering a therapeutically effective dose of a compound of Formula A.
  • the invention also provides a method of treating anxiety in a mammal, comprising administering a therapeutically effective dose of a compound of Formula A.
  • PRD 3029 US and PCT
  • C a- * refers to an alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl radical or to the alkyl portion of a radical in which alkyl appears as the prefix root containing from a to b carbon atoms inclusive.
  • Ci_ 4 denotes a radical containing 1, 2, 3 or 4 carbon atoms.
  • alkyl refers to a saturated branched or straight chain monovalent hydrocarbon radical, wherein the radical is derived by the removal of one hydrogen atom from a single carbon atom. Unless specifically indicated (e.g. by the use of a limiting term such as "terminal carbon atom"), substituent variables may be placed on any carbon chain atom.
  • Typical alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl and the like. Examples include Ci-salkyl, Ci- ⁇ alkyl and Ci- 4 alkyl groups.
  • heteroaryl refers to a radical derived by the removal of one hydrogen atom from a ring carbon atom of a heteroaromatic ring system.
  • Typical heteroaryl radicals include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, indolyl, isoindolyl, benzo[ ⁇ ]furyl, benzo[ ⁇ ]thienyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthal
  • Scheme 1 illustrates the synthetic routes (Paths 1 and 2) leading to compounds of Formula A.
  • the aminopyrimidine II is then reacted with N-bromosuccinimide (NBS), which gives the bromothiophene III.
  • N-bromosuccinimide N-bromosuccinimide
  • DMAP 4-dimethylamino pyridine
  • Example 1 (4-Amino-6-phenylamino-thieno[2,3-d]pyrimidin-2-yl)-benzonitrile
  • Example 1 step a
  • Example 12 step a
  • Ligand binding assay of adenosine A2a receptor was performed using plasma membrane of HEK293 cells containing human A2a adenosine receptor (PerkinElmer, RB- HA2a) and radioligand [ 3 H]CGS21680 (PerkinElmer, NET1021). Assay was set up in 96- well polypropylene plate in total volume of 200 ⁇ L by sequentially adding 20 ⁇ Ll :20 diluted membrane, 130 ⁇ Lassay buffer (50 mM Tris ⁇ Cl, pH7.4 10 mM MgCl 2 , 1 mM EDTA) containing [ 3 H] CGS21680, 50 ⁇ L diluted compound (4X) or vehicle control in assay buffer.
  • Assay was set up in 96- well polypropylene plate in total volume of 200 ⁇ L by sequentially adding 20 ⁇ Ll :20 diluted membrane, 130 ⁇ Lassay buffer (50 mM Tris ⁇ Cl, pH7.4 10 mM M
  • Nonspecific binding was determined by 80 mM NECA. Reaction was carried out at room temperature for 2 hours before filtering through 96-well GF/C filter plate pre-soaked in 50 mM Tris ⁇ Cl, pH7.4 containing 0.3% polyethylenimine. Plates were then washed 5 times with cold 50 mM Tris ⁇ Cl, pH7.4, dried and sealed at the bottom. Microscintillation fluid 30 ⁇ L was added to each well and the top sealed. Plates were counted on Packard Topcount for [ 3 H]. Data was analyzed in Microsoft Excel and GraphPad Prism programs. (Varani, K.; Gessi, S.; Dalpiaz, A.; Borea, P.A. British Journal of Pharmacology, 1996, 117, 1693)
  • A2a Receptor Functional Assay A2AGAL2
  • cryopreserved CHO-Kl cells overexpressing the human adenosine A2a receptor and containing a cAMP inducible beta-galactosidase reporter gene were thawed, centrifuged, DMSO containing media removed, and then seeded with fresh culture media into clear 384-well tissue culture treated plates (BD #353961) at a concentration of 1OK cells/well. Prior to assay, these plates were cultured for two days at 37°C, 5% CO 2 , 90% Rh. On the day of the functional assay, culture media was removed and replaced with 45uL assay medium (Hams/F-12 Modified (Mediatech # 10-080CV) supplemented w/ 0.1% BSA).
  • Test compounds were diluted and 11 point curves created at a 100Ox concentration in 100% DMSO. Immediately after addition of assay media to the cell plates, 5OnL of the appropriate test compound antagonist or agonist control curves were added to cell plates using a Cartesian Hummingbird. Compound curves were allowed to incubate at room temperature on cell plates for approximately 15 minutes before addition of a 15nM NECA (Sigma E2387) agonist challenge (5uL volume). A control curve of NECA, a DMSO/Media control, and a single dose of Forskolin (Sigma F3917) were also included on PRD 3029 US and PCT
  • Adenosine Al Receptor Functional Assay (A1 GAL2)
  • cryopreserved CHO-Kl cells overexpressing the human adenosine Al receptor and containing a cAMP inducible beta-galactosidase reporter gene were thawed, centrifuged, DMSO containing media removed, and then seeded with fresh culture media into clear 384-well tissue culture treated plates (BD #353961) at a concentration of 1OK cells/well. Prior to assay, these plates were cultured for two days at 37°C, 5% CO 2 , 90% Rh. On the day of the functional assay, culture media was removed and replaced with 45uL assay medium (Hams/F-12 Modified (Mediatech # 10-080CV) supplemented w/ 0.1% BSA).
  • Test compounds were diluted and 11 point curves created at a 100Ox concentration in 100% DMSO. Immediately after addition of assay media to the cell plates, 5OnL of the appropriate test compound antagonist or agonist control curves were added to cell plates using a Cartesian Hummingbird. Compound curves were allowed to incubate at room temperature on cell plates for approximately 15 minutes before addition of a 4nM r-PIA (Sigma P4532)/luM Forskolin (Sigma F3917) agonist challenge (5uL volume). A control curve of r-PIA inluM Forskolin, a DMSO/Media control, and a single dose of Forskolin were also included on each plate.

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Abstract

This invention relates to a novel thieno[2,3-d]pyrimidine, (A), and its therapeutic and prophylactic uses, wherein R1 and R2 are definedin the specification. Disorders treated and/or prevented include Parkinson's Disease.

Description

PRD 3029 US and PCT
AMINES AND SULFOXIDES OF THIENO [2,3-d]PYRIMIDINE AND THEIR USE AS ADENOSINE A2a RECEPTOR ANTAGONISTS
CROSS-REFERENCE TO RELATED APPLICATIONS
The present application claims the benefits of the filing of U.S. Provisional Application No. 61/104,796 filed October 13, 2008. The complete disclosures of the aforementioned related patent applications are hereby incorporated herein by reference for all purposes.
FIELD OF THE INVENTION
This invention relates to a novel arylindenopyrimidine and its therapeutic and prophylactic uses. Disorders treated and/or prevented include neurodegenerative and movement disorders ameliorated by antagonizing Adenosine A2a receptors.
BACKGROUND OF THE INVENTION
Adenosine A2a Receptors Adenosine is a purine nucleotide produced by all metabolically active cells within the body. Adenosine exerts its effects via four subtypes of cell surface receptors (Al, A2a, A2b and A3), which belong to the G protein coupled receptor superfamily (Stiles, G.L. Journal of Biological Chemistry, 1992, 267, 6451). Al and A3 couple to inhibitory G protein, while A2a and A2b couple to stimulatory G protein. A2a receptors are mainly found in the brain, both in neurons and glial cells (highest level in the striatum and nucleus accumbens, moderate to high level in olfactory tubercle, hypothalamus, and hippocampus etc. regions) (Rosin, D. L.; Robeva, A.; Woodard, R. L.; Guyenet, P. G.; Linden, J. Journal of Comparative Neurology, 1998, 401, 163).
In peripheral tissues, A2a receptors are found in platelets, neutrophils, vascular smooth muscle and endothelium (Gessi, S.; Varani, K. ; Merighi, S. ; Ongini, E.; Bores, P. A. British Journal of Pharmacology, 2000, 129, T). The striatum is the main brain region for the regulation of motor activity, particularly through its innervation from dopaminergic neurons originating in the substantial nigra. The striatum is the major target of the dopaminergic PRD 3029 US and PCT
neuron degeneration in patients with Parkinson's Disease (PD). Within the striatum, A2a receptors are co-localized with dopamine D2 receptors, suggesting an important site for the integration of adenosine and dopamine signaling in the brain (Fink, J. S.; Weaver, D. Ri; Rivkees, S. A.; Peterfreund, R. A.; Pollack, A. E.; Adler, E. M.; Reppert, S. M. Brain Research Molecular Brain Research, 1992,14,186).
Neurochemical studies have shown that activation of A2a receptors reduces the binding affinity of D2 agonist to their receptors. This D2R and A2aR receptor-receptorinteraction has been demonstrated instriatal membrane preparations of rats (Ferre, S.; con Euler, G.; Johansson, B.; Fredholm, B. B.; Fuxe, K. Proceedings of the National Academy of Sciences I of the United States of America, 1991, 88, 7238) as well as in fibroblast cell lines after transfected with A2aR and D2R cDNAs (Salim, H. ; Ferre, S.; Dalai, A.; Peterfreund, R. A.; Fuxe, K.; Vincent, J. D.; Lledo, P. M. Journal of Neurochemistry, 2000, 74, 432). In vivo, pharmacological blockade of A2a receptors using A2a antagonist leads to beneficial effects in dopaminergic neurotoxin MPTP(I -methyl-4-pheny- 1,2,3, 6-tetrahydropyridine)-induced PC) in various species, including mice, rats, and monkeys (Ikeda, K.; Kurokawa, M.; Aoyana, S.; Kuwana, Y. Journal of Neurochemistry, 2002, 80, 262).
Furthermore, A2a knockout mice with genetic blockade of A2a function have been found to be less sensitive to motor impairment and neurochemical changes when they were exposed to neurotoxin MPTP (Chen, J. F.; Xu, K.; I Petzer, J. P.; Steal, R.; Xu, Y. H.; Beilstein, M.; Sonsalla, P. K.; Castagnoli, K.; Castagnoli, N., Jr.; Schwarsschild, M. A. Journal of Neuroscience, 2001, 1 21, RCl 43).
In humans, the adenosine receptor antagonist theophylline has been found to produce beneficial effects in PD patients (Mally, J.; Stone, T. W. Journal of the Neurological Sciences, 1995, 132, 129). Consistently, recent epidemiological study has shown that high caffeine consumption makes people less likely to develop PD (Ascherio, A.; Zhang, S. M.; Hernan, M. A.; Kawachi, L; Colditz, G. A.; Speizer, F. E.; Willett, W. C. Annals of Neurology, 2001, 50, 56). In summary, adenosine A2a receptor blockers may provide a new class of antiparkinsonian agents (Impagnatiello, F.; Bastia, E.; Ongini, E.; Monopoli, A. Emerging Therapeutic Targets, 2000, 4, 635). PRD 3029 US and PCT
Antagonists of the A2A receptor are potentially useful therapies for the treatment of addiction. Major drugs of abuse (opiates, cocaine, ethanol, and the like) either directly or indirectly modulate dopamine signaling in neurons particularly those found in the nucleus accumbens, which contain high levels of A2A adenosine receptors. Dependence has been shown to be augmented by the adenosine signaling pathway, and it has been shown that administration of an A2A receptor antagonist redues the craving for addictive substances ("The Critical Role of Adenosine A2A Receptors and Gi βγ Subunits in Alcoholism and Addiction: From Cell Biology to Behavior", by Ivan Diamond and Lina Yao, (The Cell Biology of Addiction, 2006, pp 291-316) and "Adaptations in Adenosine Signaling in Drug Dependence: Therapeutic Implications", by Stephen P. Hack and Macdonald J. Christie, Critical Review in Neurobiology, Vol. 15, 235-274 (2003)). See also Alcoholism: Clinical and Experimental Research (2007), 31(8), 1302-1307.
An A2A receptor antagonist could be used to treat attention deficit hyperactivity disorder (ADHD) since caffeine (a non selective adenosine antagonist) can be useful for treating ADHD, and there are many interactions between dopamine and adenosine neurons. Clinical Genetics (2000), 58(1), 31-40 and references therein.
Antagonists of the A2A receptor are potentially useful therapies for the treatment of depression. A2A antagonists are known to induce activity in various models of depression including the forced swim and tail suspension tests. The positive response is mediated by dopaminergic transmission and is caused by a prolongation of escape-directed behavior rather than by a motor stimulant effect. Neurology (2003), 61(suppl 6) S82-S87.
Antagonists of the A2A receptor are potentially useful therapies for the treatment of anxiety. A2A antagonist have been shown to prevent emotional/anxious responses in vivo. Neurobiology of Disease (2007), 28(2) 197-205.
SUMMARY OF THE INVENTION
Compounds of Formula A are potent small molecule antagonists of the Adenosine A2a receptor. PRD 3029 US and PCT
K2 SγNγR1 χ-ΛJγI
NH2 A
wherein:
R1 is phenyl wherein said phenyl is optionally substituted with up to three substituents independently selected from the group consisting of F, Cl, Br, and OCH3, or a single substituent selected from the group consisting of: OH, OCH2CF3, OC(i_4)alkyl, C(i_4)alkyl,
CHF2, OCF3, CF3, cyclopropyl and CN; or R1 is heteroaryl optionally substituted with one substituent selected from the group consisting of: -OH, OC(i_4)alkyl, CF3, OCF3, Cl, Br, -CN,
F, CHF2, cyclopropyl, and C(i_4)alkyl;
R2 is is an aromatic ring selected from the group consisting of phenyl and heteroaryl, wherein said aromatic ring is optionally substituted with -CN, F, Cl, Br, NO2, -CF3, OC(i_4)alkyl,
OCF3, C(i-4)alkyl, or cyclopropyl;
X is NH, NC(i_4)alkyl, S, S(O), or S(O)2;
and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
The invention provides compounds of Formula A.
xΛΛfI
NH2 .
wherein:
R1 is phenyl wherein said phenyl is optionally substituted with up to three substituents independently selected from the group consisting of F, Cl, Br, and OCH3, or a single substituent selected from the group consisting of: OH, OCH2CF3, OC(1-4)alkyl, C^alkyl, CHF2, OCF3, CF3, cyclopropyl and CN; or R1 is heteroaryl optionally substituted with one PRD 3029 US and PCT
substituent selected from the group consisting of: -OH, OC(i_4)alkyl, CF3, OCF3, Cl, Br, -CN,
F, CHF2, cyclopropyl, and C(i_4)alkyl;
R2 is is an aromatic ring selected from the group consisting of phenyl and heteroaryl, wherein said aromatic ring is optionally substituted with -CN, F, Cl, Br, NO2, -CF3, OC(i_4)alkyl,
OCF3, C(i_4)alkyl, or cyclopropyl;
X is NH, NC(i_4)alkyl, S, S(O), or S(O)2; and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof.
In another embodiment of the invention:
R1 is an aromatic ring selected from the group consisting of phenyl, furyl, oxazolyl, isoxazolyl, pyridyl, and thiazolyl, wherein said aromatic ring is optionally substituted with -
CN, F, Cl, Br, -CF3, OC(1-4)alkyl, OCF3, C(1-4)alkyl, or cyclopropyl;
R is is an aromatic ring selected from the group consisting of phenyl, furyl, oxazolyl, isoxazolyl, pyridyl, and thiazolyl, wherein said aromatic ring is optionally substituted with -
CN, F, Cl, Br, NO2, -CF3, OC(i_4)alkyl, OCF3, C(i_4)alkyl, or cyclopropyl;
X is NH, NC(i_4)alkyl, S, S(O), or S(O)2; and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof.
In another embodiment of the invention:
R1 is an aromatic ring selected from the group consisting of phenyl, furyl, oxazolyl, isoxazolyl, pyridyl, and thiazolyl, wherein said aromatic ring is optionally substituted with -
CN, F, -CF3, OC(i_4)alkyl, OCF3, C(i_4)alkyl, or cyclopropyl;
R2 is an aromatic ring selected from the group consisting of phenyl, furyl, oxazolyl, isoxazolyl, pyridyl, and thiazolyl, wherein said aromatic ring is optionally substituted with -
CN, F, Cl, -CF3, OC(i-4)alkyl, OCF3, C(i-4)alkyl, or cyclopropyl;
X is NH, NC(i_4)alkyl, S, or S(O)2; and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof.
In another embodiment of the invention:
R1 is phenyl, wherein said phenyl is optionally substituted with -CN, -CF3, 0C(i_4)alkyl,
OCF3, C(i_4)alkyl, or cyclopropyl; PRD 3029 US and PCT
R2 is phenyl, or pyridyl, wherein said phenyl, or pyridyl is optionally substituted with -CN,
F, Cl, -CF3, OC(i_4)alkyl, OCF3, C(i_4)alkyl, or cyclopropyl;
X is NH, NC(i-4)alkyl, or S(O)2; and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof.
In another embodiment of the invention:
R1 is phenyl, wherein said phenyl is substituted with -CN;
R2 is phenyl, or pyridyl, wherein said phenyl, or pyridyl is optionally substituted with OCH3,
Cl, or F;
X is NH, NCH3, or S(O)2; and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof.
In another embodiment of the invention, the invention is directed to a compound selected from the group consisting of:
Figure imgf000007_0001
PRD 3029 US and PCT
Figure imgf000008_0001
PRD 3029 US and PCT
Figure imgf000009_0001
and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof. PRD 3029 US and PCT
This invention further provides a method of treating a subject having a condition ameliorated by antagonizing Adenosine A2a receptors, which comprises administering to the subject a therapeutically effective dose of a compound of Formula A.
This invention further provides a method of preventing a disorder ameliorated by antagonizing Adenosine A2a receptors in a subject, comprising of administering to the subject a prophylactically effective dose of the compound of claim 1 either preceding or subsequent to an event anticipated to cause a disorder ameliorated by antagonizing Adenosine A2a receptors in the subject.
Compounds of Formula A 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, adipic, benzoic, mandelic, methanesulfonic, hydroethanesulfonic, benzenesulfonic, oxalic, palmoic, 2 naphthalenesulfonic, p- toluenesulfonic, cyclohexanesulfamic and saccharic.
This invention also provides a pharmaceutical composition comprising a compound of Formula A and a pharmaceutically acceptable carrier.
Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M and preferably 0.05 M phosphate buyer or 0.8% saline. Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, ethanol, alcoholic/aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media. Oral carriers can be elixirs, syrups, capsules, tablets and the like. The typical solid carrier is an inert substance such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like. Parenteral carriers include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils. Intravenous carriers include PRD 3029 US and PCT
fluid and nutrient replenishes, electrolyte replenishes such as those based on Ringer's dextrose and the like.
Preservatives and other additives can also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like. All carriers can be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art.
This invention further provides a method of treating a subject having a condition ameliorated by antagonizing Adenosine A2a receptors, which comprises administering to the subject a therapeutically effective dose of a compound of Formula A.
In one embodiment, the disorder is a neurodegenerative or movement disorder. Examples of disorders treatable by the instant pharmaceutical composition include, without limitation, Parkinson's Disease, Huntington's Disease, Multiple System Atrophy, Corticobasal Degeneration, Alzheimer's Disease, and Senile Dementia.
In one preferred embodiment, the disorder is Parkinson's disease.
As used herein, the term "subject" includes, without limitation, any animal or artificially modified animal having a disorder ameliorated by antagonizing adenosine A2a receptors. In a preferred embodiment, the subject is a human.
Administering the instant pharmaceutical composition can be effected or performed using any of the various methods known to those skilled in the art. Compounds of Formula A can be administered, for example, intravenously, intramuscularly, orally and subcutaneously. In the preferred embodiment, the instant pharmaceutical composition is administered orally. Additionally, administration can comprise giving the subject a plurality of dosages over a suitable period of time. Such administration regimens can be determined according to routine methods.
As used herein, a "therapeutically effective dose" of a pharmaceutical composition is an amount sufficient to stop, reverse or reduce the progression of a disorder. A "prophylactically PRD 3029 US and PCT
effective dose" of a pharmaceutical composition is an amount sufficient to prevent a disorder, i.e., eliminate, ameliorate and/or delay the disorder's onset. Methods are known in the art for determining therapeutically and prophylactically effective doses for the instant pharmaceutical composition. The effective dose for administering the pharmaceutical composition to a human, for example, can be determined mathematically from the results of animal studies.
In one embodiment, the therapeutically and/or prophylactically effective dose is a dose sufficient to deliver from about 0.001 mg/kg of body weight to about 200 mg/kg of body weight of a compound of Formula A. In another embodiment, the therapeutically and/or prophylactically effective dose is a dose sufficient to deliver from about 0.05 mg/kg of body weight to about 50 mg/kg of body weight. More specifically, in one embodiment, oral doses range from about 0.05 mg/kg to about 100 mg/kg daily. In another embodiment, oral doses range from about 0.05 mg/kg to about 50 mg/kg daily, and in a further embodiment, from about 0.05 mg/kg to about 20 mg/kg daily. In yet another embodiment, infusion doses range from about 1.0,ug/kg/min to about 10 mg/kg/min of inhibitor, admixed with a pharmaceutical carrier over a period ranging from about several minutes to about several days. In a further embodiment, for topical administration, the instant compound can be combined with a pharmaceutical carrier at a drug/carrier ratio of from about 0.001 to about 0.1.
The invention also provides a method of treating addiction in a mammal, comprising administering a therapeutically effective dose of a compound of Formula A.
The invention also provides a method of treating ADHD in a mammal, comprising administering a therapeutically effective dose of a compound of Formula A.
The invention also provides a method of treating depression in a mammal, comprising administering a therapeutically effective dose of a compound of Formula A.
The invention also provides a method of treating anxiety in a mammal, comprising administering a therapeutically effective dose of a compound of Formula A. PRD 3029 US and PCT
DEFINITIONS:
The term "Ca-*" (where a and b are integers referring to a designated number of carbon atoms) refers to an alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl radical or to the alkyl portion of a radical in which alkyl appears as the prefix root containing from a to b carbon atoms inclusive. For example, Ci_4 denotes a radical containing 1, 2, 3 or 4 carbon atoms.
The term "alkyl," whether used alone or as part of a substituent group, refers to a saturated branched or straight chain monovalent hydrocarbon radical, wherein the radical is derived by the removal of one hydrogen atom from a single carbon atom. Unless specifically indicated (e.g. by the use of a limiting term such as "terminal carbon atom"), substituent variables may be placed on any carbon chain atom. Typical alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl and the like. Examples include Ci-salkyl, Ci-βalkyl and Ci-4alkyl groups.
The term "heteroaryl" refers to a radical derived by the removal of one hydrogen atom from a ring carbon atom of a heteroaromatic ring system. Typical heteroaryl radicals include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, indolyl, isoindolyl, benzo[έ]furyl, benzo[έ]thienyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalzinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl and the like.
ABBREVIATIONS:
Herein and throughout this application, the following abbreviations may be used.
Cy cyclohexyl
DMF dimethylformamide
DMSO dimethylsulfoxide
Et ethyl
EtOAc ethyl acetate PRD 3029 US and PCT
KOtBu potassium tert-butoxide
Me methyl
NBS N-bromo succinimide
OAc acetate
Pd(dppf)Cl2 [l,l '-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) py pyridine
THF tetrahydrofuran
Xantphos 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene
EXAMPLES:
Compounds of formula A can be prepared by methods known to those who are skilled in the art. The following reaction schemes are only meant to represent examples of the invention and are in no way meant to be a limit of the invention.
PRD 3029 US and PCT
Procedure
Scheme 1
Figure imgf000015_0001
(BoC)2O, 2ATn 2 (BoC)2O, DMAP, THF DMAP, THF
Figure imgf000015_0002
1
IV
1. LDA, R2-X-X-R2 ' /1. R -X, Pd(OAc)2,
2. Oxone, THF, H2O Xantphos, Cs2CO3, dioxane
3. TFA, CH2CI2 2. TFA, CH2CI2
Figure imgf000015_0003
Scheme 1 illustrates the synthetic routes (Paths 1 and 2) leading to compounds of Formula A. Starting with 2-amino-3cyanothiophene I and following path 1 indicated by the arrows, condensation under basic conditions with arylnitriles affords the aminopyrimidine II. The aminopyrimidine II is then reacted with N-bromosuccinimide (NBS), which gives the bromothiophene III. Reacting the amino group in III with di-tert-butyldicarbonate [(Boc)2θ] in the presence of 4-dimethylamino pyridine (DMAP) gives the corresponding protected amine IV. Palladium catalyzed amination followed by trifluoroacetic acid (TFA) deprotection gives compounds of the formula A. Alternatively, following path 2, aminopyrimidine II can be reacted with (Boc)2θ in the presence of 4-dimethylamino pyridine (DMAP) gives the corresponding protected amine V. The thiophene V can be deprotonated with lithium diisopropylamide (LDA) and reacted with aryldisulfides to give an intermediate arylsulfide PRD 3029 US and PCT
that is then oxidized to the corresponding sulfone with Oxone and finally deprotected with TFA to give compounds of the formula A.
Example 1: (4-Amino-6-phenylamino-thieno[2,3-d]pyrimidin-2-yl)-benzonitrile Example 1: step a
3-(4-Amino-thieno[2,3-d]pyrimidin-2-yl)-benzonitrile
Figure imgf000016_0001
Solid potassium-tert-butoxide (1.1 g, 10.1 mmol) was added to a dioxane solution (20 mL) of 2-Amino-thiophene-3-carbonitrile (5.0 g, 40.3 mmol) and 1,3-dicyanobenzene (7.2 g, 56.5 mmol). The resulting slurry was stirred vigorously at 130 0C for 15 minutes. The dark slurry was cooled to room temperature, diluted with THF, and dry packed onto silica gel. The material was the purified via column chromatography to give 10.2 g of the title compound.
Example 1: step b
3-(4-Amino-6-bromo-thieno [2,3-d] pyrimidin-2-yl)-benzonitrile
Figure imgf000016_0002
Solid NBS (1.6 g, 8.7 mmol) was added to a DMF solution (20 mL) of 3-(4-Amino- thieno[2,3-d]pyrimidin-2-yl)-benzonitrile (2.0 g, 7.9 mmol). After 45 minutes water was added and the resulting precipitate was collected by filtration, washed with water, and dried in vacuo to give 2.4 g of the title compound.
Example 1: step c
[6-Bromo-2-(3-cyano-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-bis-carbamic acid tert-butyl ester PRD 3029 US and PCT
Figure imgf000017_0001
Solid DMAP (9 mg, 0.07 mmol) was added to a THF solution (4 mL) of 3-(4-Amino-6- bromo-thieno[2,3-d]pyrimidin-2-yl)-benzonitrile (240 mg, 0.73 mmol) and (Boc)2θ (396 mg, 1.81 mmol). After 16 h the mixture was diluted with EtOAc and then washed consecutively with water and brine, dried (Na2SO4), concentrated and purified via column chromatography to give 216 mg of the title compound.
Figure imgf000017_0002
A dioxane solution (1.5 mL) of [6-Bromo-2-(3-cyano-phenyl)-thieno[2,3-d]pyrimidin-4-yl]- bis-carbamic acid tert-butyl ester (100 mg, 0.19 mmol), aniline (25 μL, 0.28 mmol), Xantphos (11 mg, 0.02 mmol), Pd(OAc)2 (4 mg, 0.02 mmol), and Cs2CO3 (142 mg, 0.44 mmol) was heated to 100 0C. After 4 h the mixture was cooled to rt, diluted with EtOAc and washed with water and brine, dried (Na2SO4), concentrated and purified via column chromatography to give 56 mg of the amine coupled product. This material was then dissolved in CH2C12/TFA (2 mL/ 0.5 mL) and stirred at room temperature. After 2 h the solution was neutralized with saturated aqueous NaHCO3 and the aqueous layer was extracted with EtOAc, dry packed onto silica gel and then purified via column chromatography to give 33 mg of the title compound as the free base, which was dissolved in THF and added to 1 mL of 1 N HCl in ether, concentrated, and dried in vacuo to give the title compound as the di-HCl salt. 1H NMR (CHLOROFORM-d, 300MHz): δ = 8.75 (s, 1 H), 8.66 (d, J=7.9 Hz, 1 H), 7.70 (d, J=7.5 Hz, 1 H), 7.57 (t, J=7.9 Hz, 1 H), 7.29 - 7.39 (m, 3 H), 7.17 - 7.24 (m, 2 H), 7.04 - 7.15 (m, 1 H), 6.52 (s, 1 H), 6.39 ppm (s, 1 H) 3.17 - 3.80 ppm (m, 1 H); MS m/e 344 (M+H). PRD 3029 US and PCT
Example 2: 3- [4-Amino-6-(2-methoxy-phenylamino)-thieno [2,3-d] pyrimidin-2-yl] - benzonitrile
Figure imgf000018_0001
The title compound was prepared using 2-methoxy-phenylamine in place of aniline as described in Example 1. 1H NMR (CHLOROFORM-d, 300MHz): δ = 8.74 (s, 1 H), 8.65 (d, J=7.9 Hz, 1 H), 7.68 (d, J=7.5 Hz, 1 H), 7.54 (t, J=7.7 Hz, 1 H), 7.34 - 7.45 (m, 1 H), 6.87 - 7.01 (m, 3 H), 6.67 (s, 1 H), 6.61 (s, 1 H), 5.16 (br. s., 2 H), 3.93 ppm (s, 3 H); MS m/e 374 (M+H).
Example 3: 3-{4-Amino-6-[(2-methoxy-phenyl)-methyl-amino]-thieno [2,3-d] pyrimidin- 2-yl}-benzonitrile
Figure imgf000018_0002
The title compound was prepared using (2-methoxy-phenyl)-methyl-amine in place of aniline as described in Example 1. 1H NMR (CHLOROFORM-d, 300MHz): δ = 8.67 (s, 1 H), 8.58 (d, J=7.9 Hz, 1 H), 7.63 (d, J=7.9 Hz, 1 H), 7.50 (t, J=7.9 Hz, 1 H), 7.30 - 7.39 (m, 2 H), 6.96 - 7.07 (m, 2 H), 5.70 (s, 1 H), 5.00 (br. s., 2 H), 3.84 (s, 3 H), 3.35 ppm (s, 3 H); MS m/e 388 (M+H).
Example 4: 3-[4-Amino-6-(pyridin-2-ylamino)-thieno[2,3-d]pyrimidin-2-yl]-benzonitrile
Figure imgf000018_0003
PRD 3029 US and PCT
The title compound was prepared using pyridin-2-ylamine in place of aniline as described in Example 1. 1H NMR (Acetone, 300MHz): δ = 9.58 (s, 1 H), 8.45 - 8.77 (m, 2 H), 8.19 (d, J=4.1 Hz, 1 H), 7.67 (d, J=7.5 Hz, 1 H), 7.45 - 7.59 (m, 2 H), 6.69 - 6.87 (m, 3 H), 6.50 ppm (br. s., 2 H); MS m/e 345 (M+H).
Example 5: 3-[4-Amino-6-(methyl-phenyl-amino)-thieno[2,3-d]pyrimidin-2-yl]- benzonitrile
Figure imgf000019_0001
The title compound was prepared using N-methylaniline in place of aniline as described in Example 1. 1H NMR (CHLOROF ORM-d, 300MHz): δ = 8.70 (s, 1 H), 8.60 (d, J=8.3 Hz, 1 H), 7.65 (d, J=7.9 Hz, 1 H), 7.52 (t, J=7.7 Hz, 1 H), 7.35 - 7.45 (m, 2 H), 7.23 - 7.33 (m, 3 H), 7.12 - 7.23 (m, 1 H), 5.14 (br. s., 2 H), 3.45 ppm (s, 3 H); MS m/e 358 (M+H).
Example 6: 3-[4-Amino-6-(3-methoxy-phenylamino)-thieno[2,3-d]pyrimidin-2-yl]- benzonitrile-hydrochloride
Figure imgf000019_0002
The title compound was prepared using 3-methoxy-phenylamine in place of aniline as described in Example 1. 1H NMR (DMSO-d6, 300MHz): δ = 8.55 - 8.72 (m, 2 H), 7.94 (d, J=7.9 Hz, 1 H), 7.72 (t, J=7.9 Hz, 2 H), 7.16 - 7.29 (m, 1 H), 7.06 (s, 1 H), 6.71 - 6.83 (m, 2 H), 6.47 - 6.59 (m, 1 H), 3.76 ppm (s, 3 H); MS m/e 374 (M+H).
Example 7 : 3-[4-Amino-6-(2-chloro-phenylamino)-thieno[2,3-d]pyrimidin-2-yl]- benzonitrile-hydrochloride PRD 3029 US and PCT
Figure imgf000020_0001
The title compound was prepared using 2-chloro-phenylamine in place of aniline as described in Example 1. 1H NMR (DMSO-d6, 300MHz): δ = 8.64 (s, 2 H), 7.96 (s, 1 H), 7.60 - 7.85 (m, 2 H), 7.46 (s, 1 H), 7.38 (s, 1 H), 7.18 - 7.31 (m, 2 H), 6.66 (s, 1 H), 3.17 ppm (s, 2 H); MS m/e 378 (M+H). ro-phenyl)-methyl-amino]-thieno[2,3-d]pyrimidin-2-
Figure imgf000020_0002
The title compound was prepared using (2-chloro-phenyl)-methyl-amine in place of aniline as described in Example 1. 1H NMR (DMSO-d6, 300MHz): δ = 8.66 (s, 1 H), 8.57 (s, 1 H), 7.99 (s, 1 H), 7.67 - 7.77 (m, 2 H), 7.62 (d, J=I.9 Hz, 1 H), 7.45 - 7.51 (m, 2 H), 7.31 (s, 1 H), 6.56 (s, 2 H), 3.37 ppm (s, 3 H); MS m/e 392 (M+H).
Example 9: 3-{4-Amino-6-[(3-methoxy-phenyl)-methyl-amino]-thieno[2,3-d]pyrimidin- 2-yl}-benzonitrile-hydrochloride
Figure imgf000020_0003
The title compound was prepared using (3-methoxy-phenyl)-methyl-amine in place of aniline as described in Example 1. 1H NMR (DMSO-d6, 300MHz): δ = 8.51 - 8.66 (m, 2 H), 7.93 (d, PRD 3029 US and PCT
J=I.5 Hz, 1 H), 7.71 (d, J=7.9 Hz, 1 H), 7.29 (d, J=7.9 Hz, 1 H), 6.82 - 6.94 (m, 4 H), 6.73 (d, J=2.3 Hz, 1 H), 3.76 (s, 3 H), 3.40 ppm (s, 3 H); MS m/e 388 (M+H).
Example 10: 3- [4-Amino-6-(2-fluoro-phenylamino)-thieno [2,3-d] pyrimidin-2-yl] - benzonitrile
Figure imgf000021_0001
The title compound was prepared using 2-fluoro-phenylamine in place of aniline as described in Example 1. 1H NMR (DMSO-d6, 300MHz): δ = 9.17 (br. s., 1 H), 8.52 - 8.75 (m, 2 H), 7.96 (d, J=7.9 Hz, 1 H), 7.62 - 7.82 (m, 2 H), 6.93 - 7.33 ppm (m, 6 H); MS m/e 362 (M+H).
Example 11: 3-{4-Amino-6-[(3-fluoro-phenyl)-methyl-amino]-thieno[2,3-d]pyrimidin-2- yl}-benzonitrile
Figure imgf000021_0002
The title compound was prepared using (3-fluoro-phenyl)-methyl-amine in place of aniline as described in Example 1. 1H NMR (CHLOROFORM-d, 300MHz): δ = 8.73 (s, 1 H), 8.64 (d, J=7.9 Hz, 1 H), 7.68 (d, J=7.5 Hz, 1 H), 7.54 (t, J=7.9 Hz, 1 H), 7.30 (d, J=6.8 Hz, 1 H), 6.86 - 7.03 (m, 2 H), 6.79 (s, 1 H), 6.38 (s, 1 H), 5.18 (br. s., 2 H), 3.45 ppm (s, 3 H); MS m/e 376 (M+H).
Example 12: 3-(4-Amino-6-benzenesulfonyl-thieno [2,3-d] pyrimidin-2-yl)-benzonitrile
Example 12: step a
[2-(3-Cyano-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-bis-carbamic acid tert-butyl ester PRD 3029 US and PCT
Figure imgf000022_0001
Solid DMAP (42 mg, 0.3 mmol) was added to a THF solution (17 mL) of 3-(4-Amino- thieno[2,3-d]pyrimidin-2-yl)-benzonitrile(850 mg, 3.4 mmol) and (Boc)2θ (1.8 g, 8.4 mmol). After 4 h the mixture was diluted with EtOAc and then washed consecutively with water and brine, dried (TS^SO4), concentrated and purified via column chromatography to give 1.2 g of the title compound.
Example 12: step b
Figure imgf000022_0002
A 1.8 M LDA solution (0.675 ml, 1.2 mmol) was added dropwise a -78 0C THF solution (5 mL) of [2-(3-Cyano-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-bis-carbamic acid tert-butyl ester (0.5 g, 1.1 mmol). After 5 minutes a THF solution (2 ml) of diphenyldisulfide (361 mg, 1.6 mmol) was added. After 30 minutes 10 ml of saturated aqueous NH4Cl solution was added and the aqueous layer was extracted with EtOAc, dry packed onto silica gel and then purified via column chromatography to give 371 mg of the phenylsulfide adduct. Solid Oxone (0.986 g, 1.6 mmol) was added to 50:50 THF/water solution (6 mL) of the phenylsulfide compound (300 mg, 0.53 mmol). After 8 hours the mixture was diluted with EtOAc and then washed consecutively with saturated aqueous NaHCθ3 solution, water and brine, dried (Na2SO4), concentrated and used without further purification. This material was dissolved in a 50:50 CH2CI2/TFA (6 mL) and stirred. After 30 minutes the solution was neutralized with saturated aqueous NaHCθ3 solution and the aqueous layer was extracted with EtOAc, dry packed onto silica gel and then purified via column chromatography to give 200 mg of of the title. 1H NMR (DMSO-d6, 300MHz): δ = 8.61 (s, 1 H), 8.50 (s, 1 H), 8.21 (br. s., 2 H), 7.95 - 8.05 (m, 3 H), 7.65 - 7.82 ppm (m, 5 H); MS m/e 393 (M+H). PRD 3029 US and PCT
Biological Assays and Activity
Ligand Binding Assay for Adenosine A2a Receptor
Ligand binding assay of adenosine A2a receptor was performed using plasma membrane of HEK293 cells containing human A2a adenosine receptor (PerkinElmer, RB- HA2a) and radioligand [3H]CGS21680 (PerkinElmer, NET1021). Assay was set up in 96- well polypropylene plate in total volume of 200 μL by sequentially adding 20 μLl :20 diluted membrane, 130 μLassay buffer (50 mM TrisΗCl, pH7.4 10 mM MgCl2, 1 mM EDTA) containing [3H] CGS21680, 50 μL diluted compound (4X) or vehicle control in assay buffer. Nonspecific binding was determined by 80 mM NECA. Reaction was carried out at room temperature for 2 hours before filtering through 96-well GF/C filter plate pre-soaked in 50 mM TrisΗCl, pH7.4 containing 0.3% polyethylenimine. Plates were then washed 5 times with cold 50 mM TrisΗCl, pH7.4, dried and sealed at the bottom. Microscintillation fluid 30 μL was added to each well and the top sealed. Plates were counted on Packard Topcount for [3H]. Data was analyzed in Microsoft Excel and GraphPad Prism programs. (Varani, K.; Gessi, S.; Dalpiaz, A.; Borea, P.A. British Journal of Pharmacology, 1996, 117, 1693)
Adenosine A2a Receptor Functional Assay (A2AGAL2)
To initiate the functional assay, cryopreserved CHO-Kl cells overexpressing the human adenosine A2a receptor and containing a cAMP inducible beta-galactosidase reporter gene were thawed, centrifuged, DMSO containing media removed, and then seeded with fresh culture media into clear 384-well tissue culture treated plates (BD #353961) at a concentration of 1OK cells/well. Prior to assay, these plates were cultured for two days at 37°C, 5% CO2, 90% Rh. On the day of the functional assay, culture media was removed and replaced with 45uL assay medium (Hams/F-12 Modified (Mediatech # 10-080CV) supplemented w/ 0.1% BSA). Test compounds were diluted and 11 point curves created at a 100Ox concentration in 100% DMSO. Immediately after addition of assay media to the cell plates, 5OnL of the appropriate test compound antagonist or agonist control curves were added to cell plates using a Cartesian Hummingbird. Compound curves were allowed to incubate at room temperature on cell plates for approximately 15 minutes before addition of a 15nM NECA (Sigma E2387) agonist challenge (5uL volume). A control curve of NECA, a DMSO/Media control, and a single dose of Forskolin (Sigma F3917) were also included on PRD 3029 US and PCT
each plate. After additions, cell plates were allowed to incubate at 37°C, 5% CO2, 90% Rh for 5.5 - 6 hours. After incubation, media was removed, and cell plates were washed Ix 5OuL with DPBS w/o Ca & Mg (Mediatech 21 -031-CV). Into dry wells, 2OuL of Ix Reporter Lysis Buffer (Promega E3971 (diluted in dEtO from 5x stock)) was added to each well and plates frozen at -200C overnight. For β-galactosidase enzyme colorimetric assay, plates were thawed out at room temperature and 20 μL 2X assay buffer (Promega) was added to each well. Color was allowed to develop at 37°C, 5% CO2, 90% Rh for 1 - 1.5 h or until reasonable signal appeared. The colorimetric reaction was stopped with the addition of 60 μL/well IM sodium carbonate. Plates were counted at 405 nm on a SpectraMax Microplate Reader (Molecular Devices). Data was analyzed in Microsoft Excel and IC/EC50 curves were fit using a standardized macro.
Adenosine Al Receptor Functional Assay (A1 GAL2)
To initiate the functional assay, cryopreserved CHO-Kl cells overexpressing the human adenosine Al receptor and containing a cAMP inducible beta-galactosidase reporter gene were thawed, centrifuged, DMSO containing media removed, and then seeded with fresh culture media into clear 384-well tissue culture treated plates (BD #353961) at a concentration of 1OK cells/well. Prior to assay, these plates were cultured for two days at 37°C, 5% CO2, 90% Rh. On the day of the functional assay, culture media was removed and replaced with 45uL assay medium (Hams/F-12 Modified (Mediatech # 10-080CV) supplemented w/ 0.1% BSA). Test compounds were diluted and 11 point curves created at a 100Ox concentration in 100% DMSO. Immediately after addition of assay media to the cell plates, 5OnL of the appropriate test compound antagonist or agonist control curves were added to cell plates using a Cartesian Hummingbird. Compound curves were allowed to incubate at room temperature on cell plates for approximately 15 minutes before addition of a 4nM r-PIA (Sigma P4532)/luM Forskolin (Sigma F3917) agonist challenge (5uL volume). A control curve of r-PIA inluM Forskolin, a DMSO/Media control, and a single dose of Forskolin were also included on each plate. After additions, cell plates were allowed to incubate at 37°C, 5% CO2, 90% Rh for 5.5 - 6 hours. After incubation, media was removed, and cell plates were washed Ix 5OuL with DPBS w/o Ca & Mg (Mediatech 21-031-CV). Into dry wells, 2OuL of Ix Reporter Lysis Buffer (Promega E3971 (diluted in dH2θ from 5x PRD 3029 US and PCT
stock)) was added to each well and plates frozen at -200C overnight. For β-galactosidase enzyme colorimetric assay, plates were thawed out at room temperature and 20 μL 2X assay buffer (Promega) was added to each well. Color was allowed to develop at 37°C, 5% CO2, 90% Rh for 1 - 1.5 h or until reasonable signal appeared. The colorimetric reaction was stopped with the addition of 60 μL/well IM sodium carbonate. Plates were counted at 405 nm on a SpectraMax Microplate Reader (Molecular Devices). Data was analyzed in Microsoft Excel and IC/EC50 curves were fit using a standardized macro.
A2a ASSAY DATA
Figure imgf000025_0001
While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.
All publications disclosed in the above specification are hereby incorporated by reference in full.

Claims

PRD 3029 US and PCTWe Claim:
1. The compounds of Formula A.
Figure imgf000026_0001
wherein:
R1 is phenyl wherein said phenyl is optionally substituted with up to three substituents independently selected from the group consisting of F, Cl, Br, and OCH3, or a single substituent selected from the group consisting of: OH, OCH2CF3, OC(i_4)alkyl, C(i_4)alkyl,
CHF2, OCF3, CF3, cyclopropyl and CN; or R1 is heteroaryl optionally substituted with one substituent selected from the group consisting of: -OH, OC(i_4)alkyl, CF3, OCF3, Cl, Br, -CN,
F, CHF2, cyclopropyl, and C(i_4)alkyl;
R2 is an aromatic ring selected from the group consisting of phenyl and heteroaryl, wherein said aromatic ring is optionally substituted with -CN, F, Cl, Br, NO2, -CF3, OC(1-4)alkyl,
OCF3, C(i_4)alkyl, or cyclopropyl;
X is NH, NC(i_4)alkyl, S, S(O), or S(O)2; and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof.
2. A compound of Claiml wherein:
R1 is an aromatic ring selected from the group consisting of phenyl, furyl, oxazolyl, isoxazolyl, pyridyl, and thiazolyl, wherein said aromatic ring is optionally substituted with -
CN, F, Cl, Br, -CF3, OC(i_4)alkyl, OCF3, C(i_4)alkyl, or cyclopropyl;
R2 is an aromatic ring selected from the group consisting of phenyl, furyl, oxazolyl, isoxazolyl, pyridyl, and thiazolyl, wherein said aromatic ring is optionally substituted with -
CN, F, Cl, Br, NO2, -CF3, OC(1-4)alkyl, OCF3, C(1-4)alkyl, or cyclopropyl; and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof.
3. A compound of Claim 2 wherein: PRD 3029 US and PCT
R1 is an aromatic ring selected from the group consisting of phenyl, furyl, oxazolyl, isoxazolyl, pyridyl, and thiazolyl, wherein said aromatic ring is optionally substituted with -
CN, F, -CF3, OC(1-4)alkyl, OCF3, C(i-4)alkyl, or cyclopropyl;
R is an aromatic ring selected from the group consisting of phenyl, furyl, oxazolyl, isoxazolyl, pyridyl, and thiazolyl, wherein said aromatic ring is optionally substituted with -
CN, F, Cl, -CF3, OC(i_4)alkyl, OCF3, C(i_4)alkyl, or cyclopropyl; and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof.
4. A compound of Claim 3 wherein:
R1 is phenyl, wherein said phenyl is optionally substituted with -CN, -CF3, OC(i-4)alkyl,
OCF3, C(i_4)alkyl, or cyclopropyl;
R2 is phenyl, or pyridyl, wherein said phenyl, or pyridyl is optionally substituted with -CN,
F, Cl, -CF3, OC(i_4)alkyl, OCF3, C(i_4)alkyl, or cyclopropyl;
X is NH, NC(i_4)alkyl, or S(O)2; and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof.
5. A compound of Claim 4 wherein:
R1 is phenyl, wherein said phenyl is substituted with -CN;
R2 is phenyl, or pyridyl, wherein said phenyl, or pyridyl is optionally substituted with OCH3,
Cl, or F;
X is NH, NCH3, or S(O)2; and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof.
6. A compound selected from the group consisting of:
Figure imgf000027_0001
PRD 3029 US and PCT
Figure imgf000028_0001
PRD 3029 US and PCT
Figure imgf000029_0001
PRD 3029 US and PCT
Figure imgf000030_0001
and solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof.
7. A pharmaceutical composition comprising the compound of Claim 1, and a pharmaceutically acceptable carrier.
8. A method of treating a subject having a disorder ameliorated by antagonizing Adenosine A2a receptors in appropriate cells in the subject, which comprises administering to the subject a therapeutically effective dose of the compound of Claim 1.
9. A method of preventing a disorder ameliorated by antagonizing Adenosine A2a receptors in appropriate cells in the subject, comprising administering to the subject a prophylactically effective dose of the compound of Claim 1, either preceding or subsequent to an event anticipated to cause a disorder ameliorated by antagonizing Adenosine A2a receptors in appropriate cells in the subject.
10. The method of Claim 8, comprising administering to the subject a therapeutically or prophylactically effective dose of the pharmaceutical composition of Claim 7.
11. The method of Claim 9 comprising administering to the subject a therapeutically or prophylactically effective dose of the pharmaceutical composition of Claim 7.
12. The method of Claim 8, wherein the disorder is a neurodegenerative disorder or a movement disorder. PRD 3029 US and PCT
13. The method of Claim 8, 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.
14. The method of Claim 9, wherein the disorder is a neurodegenerative disorder or a movement disorder.
15. The method of Claim 9, 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.
16. The method of Claim 8, wherein the disorder is Parkinson's Disease.
17. The method of Claim 8, wherein the disorder is addiction.
18. The method of Claim 8, wherein the disorder is Attention Deficit Hyperactivity Disorder (ADHD).
19. The method of Claim 8, wherein the disorder is depression.
20. The method of Claim 8, wherein the disorder is anxiety.
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