Methanocarba cycloakyl nucleoside analogues
AssigneeThe United States of America as represented by the Department of Health and Human Services
Inventorskenneth A Jacobson, Victor E Marquez
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Abstract
The present invention provides novel nucleoside and nucleotide derivatives that are useful agonists or antagonists of P1 or P2 receptors. For example, the present invention provides a compound of formula A-M, wherein A is modified adenine or uracil and M is a constrained cycloalkyl group. The adenine or uracil is bonded to the constrained cycloakyl group. The compounds of the present invention are useful in the treatment or prevention of various diseases including airway diseases (through A2B, A3, P2Y2 receptors), cancer (through A3, P2 receptors), cardiac arrhythmias (through A1 receptors), cardiac ischemia (through A1, A3 receptors), epilepsy (through A1, P2X receptors), and Huntington's Disease (through A2A receptors).
Claims40
A compound having the formula A-M, wherein A is a chemically modified adenine or uracil and M is a constrained cycloalkyl group, said adenine or uracil is bonded to said constrained cycloalkyl group, and said compound binds a receptor;
- or a salt of said compound.
A compound selected from the group consisting of
- 15
- wherein
- R1 is hydrogen, alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, arylalkyl, acyl, sulfonyl, arylsulfonyl, thiazolyl or bicyclic alkyl;
- R2 is hydrogen, halo, alkyl, aryl, arylamino, aryloxide, alkynyl, alkenyl, thiol, cyano, or;
- R3, R4, and R5, are each independently hydrogen, hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, aryl, acyl, alkylamino, arylamino, phosphoryl, diphosphoryl, triphosphoryl, phosphonyl, boronyl, thiophosphoryl, thiodiphosphoryl, thiotriphosphoryl or vanadyl, and can be the same or different;
- R6 is hydrogen, alkyl, alkenyl, alkynyl, heteroaryl or aminoalkyl;
- R7 is methylene, dihalomethyl, carbonyl, sulfoxide;
- and at least one of R1, R2, and R6 is other than hydrogen;
- R8 is carbon or nitrogen;
- or a salt of said compound.
A compound selected from the group consisting of:
- 19
- wherein
- R1, R2, R9 is hydrogen, alkyl, alkenyl, alkynyl, aminoalkyl and
- R3, R4, and R5, are each independently hydrogen, hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, aryl, acyl, alkylamino, arylamino, phosphoryl, phosphonyl, boronyl, or vanadyl, and can be the same or different;
- R6 and R7 are each independently sulfur or oxygen;
- and R10 is methylene, dihalomethyl, carbonyl, sulfoxide;
- or a salt of said compound.
A compound comprising a methanocarbocyclic analog of a chemically modified adenosine or uradine wherein said compound is a P2 receptor ligand;
- or a salt of said compound.
A compound comprising a methanocarbocyclic analog of a chemically modified adenosine or uradine wherein said compound is a P1 receptor ligand;
- or a salt of said compound.
The use of a compound of any of claims 1-36 as a medicament.
The use of a methanocarba analog in the manufacture of a medicament for the treatment or prevention in a mammal a disease state, or condition that responds to an adenosine, ATP, UTP receptor agonist or antagonist.
A method for the treatment of airway diseases, cancer, cardiac arrhythmia, cardiac ischemia, epilepsy, Huntington's Disease, immunodeficient disorders, inflammatory disorders, neonatal hypoxia, neurodegenerative, pain, Parkinson's Disease, renal failure, schizophrenia, sleep disorders, stroke, thrombosis, urinary incontinence, diabetes, psoriasis, septic shock, brain trauma, glaucoma, or congestive heart failure in individuals in need of such treatment comprising contacting an effective quantity of a compound of any of claims 1-36.
A method of treating or preventing in a mammal a disease, state, or condition that responds to an adenosine, ATP, or UTP receptor agonist or antagonist comprising administering to the mammal a compound of any of any of claims 1-36.
Dependencies are inferred from the claim text.