King Pharmaceuticals Research and Development, Inc.

King Pharmaceuticals, Inc.

Allan R Moorman

Pier Giovanni Baraldi

Romeo Romagnoli

Pier Andrea Borea

Edward Leung

Michael Scannell

Mojgan Aghazadeh Tabrizi

Delia Preti

Russell Outcalt

Thiagarajan Balasubramanian

The present invention provides compounds of formula (I) wherein R, R, R, Rand Q have a meaning as defined herein in the specification. The compounds of formula (I) are allosteric modulators of the Aadenosine receptor and, thus, may be employed for the treatment of conditions mediated by the Aadenosine receptor. Accordingly, the compounds of formula (I) may be employed for treatment of pain, in particular, chronic pain such as neuropathic pain; cardiac disease or disorder such as cardiac disarrhythmias, e.g., peroxysmal supraventricular tachycardia, angina, myocardial infarction and stroke; neurological disease or injury; sleep disorder; epilepsy; and depression.

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The present invention provides compounds of the formula which are adenosine Areceptor antagonists and, thus, may be employed for the treatment of conditions and diseases mediated by the adenosine Areceptor activity. Such conditions include, but are not limited to, chronic and acute inflammatory diseases involving degranulation of mast cells, e.g., asthma, allergic rhinitis and allergic dermatitis; impaired sensitivity to insulin, e.g., type 2 diabetes, pre-diabetic state, and impaired glucose tolerance; diseases in which angiogenesis is a key component of pathogenesis, e.g., solid tumors and angiogenic retinopathies; apnea of preterm infants; myocardial reperfusion injury; inflammatory bowel disease; autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, and lupus erythematosis; diseases involving microvascular abnormalities of the retina that are mediated by adenosine Areceptors, e.g., retinopathy of prematurity, macular degeneration, and diabetic retinopathy; and cardiac diseases including hyperplasia consequent to hypertension, arteriosclerosis, and heart attack.

Adenosine A2B receptor antagonists

The present invention provides compounds of the formula wherein Rand Rhave meaning as defined herein in the specification. The compounds of formula (I) are adenosine Areceptor antagonists and, thus, may be employed for the treatment of conditions and diseases mediated by the adenosine Areceptor activity. Such conditions include, but are not limited to, diseases of the central nervous system such as depression, cognitive function diseases and neurodegenerative diseases such as Parkinson's disease, senile dementia as in Alzheimer's disease or psychoses and stroke. The compounds of the present invention may also be employed for the treatment of attention related disorders such as attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD), extra pyramidal syndrome, e.g., dystonia, akathisia, pseudoparkinsonism and tardive dyskinesia, and disorders of abnormal movement such as restless leg syndrome (RLS) and periodic limb movement in sleep (PLMS); cirrhosis, and fibrosis and fatty liver; dermal fibrosis in diseases such as scleroderma; and the mitigation of addictive behavior. In particular, the compounds of the present invention may be employed to improve motor-impairment due to neurodegenerative diseases such as Parkinson's disease.

The present invention provides compounds of the formula wherein R, R, Rand n have meaning as described in the specification, methods for their preparation, and pharmaceutical compositions containing them. The compounds of formula (I) are adenosine Areceptor agonists and, thus, may be employed for the treatment of diseases in mammals that are mediated by the Areceptor including, but not limited to, septic shock, cystic fibrosis, impotence, diarrhea, and cardiac diseases. Cardiac diseases include hyperplasia consequent to hypertension, arteriosclerosis, and heart attack. The present invention also provides methods for the induction of pharmacological stress to facilitate coronary imaging of areas of ischemia by employing compounds of formula (I). The compounds of formula (I) may be labeled, e.g., with radioactive isotopes, and therefore are useful in kinetic binding experiments.

New fused thiophene compounds are provided and methods of using those compounds for a variety of therapeutic indications. Compounds of the invention are particularly useful for treatment of neuropathic pain.

Pharmaceutically active compounds and methods of use

Provided is a method for the synthesis of an aralkyloxyadenosine or an alkoxyadenosine. The method includes protecting the hydroxyl sugar groups with a protecting group to produce a protected halogenated adenosine. The protected halogenated adenosine is alkoxylated, and the hydroxyl sugar groups of the protected halogenated adenosine are deprotected to provide the aralkyloxyadenosine or alkoxyadenosine.

Synthesis of 2-aralkyloxyadenosines, 2-alkoxyadenosines, and their analogs

The invention provides new methods for synthesis of 2-aralkyloxyadenosines and 2-alkoxyadenosines. The invention is particularly useful for synthesis of 2-[2-(4-chlorophenyl)ethoxy]adenosine. Preferred methods of the invention include activating a guanosine compound followed by hydrolysis; alkylating the hydrolyzed compound with subsequent animation to provide a 2-aralkyloxyadenosine or a 2-alkoxyadenosine compound.

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Durham, NC, United States of America

Allan R Moorman