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  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom

Definitions

• the present invention is directed towards novel 2', 3'-cyclic carbonate- containing nucleosides and their derivatives, including 5 '-monophosphate derivatives, their preparation and their uses. More specifically, the novel compounds are useful in the treatment of viral infections, including hepatitis C viral infections, as well as cancer and other diseases and disorders for which treatment with nucleoside derivatives is useful or efficacious.
• Hepatitis C is a viral disease that causes inflammation of the liver that may lead to cirrhosis, primary liver cancer and other long-term complications.
• Nucleosides are a well-recognized class of compounds shown to be effective against a variety of viral infections, including those caused by hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), and herpes virus.
• Nucleosides are generally effective as antiviral agents following conversion of the nucleoside to the corresponding nucleoside 5'-triphosphate (NTP). Conversion occurs inside cells through the action of various intracellular kinases.
• the first step i.e., conversion of the nucleoside to the 5'- monophosphate (NMP)
• NMP 5'- monophosphate
• Conversion of the NMP to the NTP is generally catalyzed by host nucleotide kinases.
• the NTP interferes with viral replication through inhibition of viral polymerases and/or via incorporation into a growing strand of DNA or RNA followed by chain termination.
• nucleosides to treat viral liver infections is often complicated by one of two problems.
• the desired nucleoside is a good kinase substrate and accordingly produces NTP in the liver as well as other cells and tissues throughout the body. Since NTP production is often associated with toxicity, efficacy can be limited by extrahepatic toxicities.
• the desired nucleoside is a poor kinase substrate so is not efficiently converted into the NMP and ultimately into the NTP.
• US 6,312,662 discloses the use of certain phosphate prodrugs for the liver-specific delivery of various drugs including nucleosides for the treatment of patients with liver diseases such as hepatitis C, hepatitis B and hepatocellular carcinoma.
• the present invention is directed towards novel nucleoside derivatives, their preparation and their uses for the treatment of diseases and disorders responsive to a pharmaceutical composition comprising a nucleoside as an active pharmaceutical ingredient, including, e.g., viral infections and cancer.
• the invention concerns T, 3 '-cyclic carbonate nucleoside and nucleotide compounds and their derivatives and prodrugs thereof.
• the invention further relates to the treatment of diseases or disorders using the disclosed 2', 3 '-cyclic carbonate nucleoside or nucleotide compounds, derivatives, or prodrugs thereof.
• the present invention relates to a compound of
• X', Y, R 19 , R 18 , R 17 , R 16 , R 15 , B, Z r , and Z" are as defined below.
• the present invention is further directed to a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient or carrier.
• the present invention is further directed to a method of treating a disease or disorder responsive to treatment with a pharmaceutical composition comprising a nucleoside derivative as an active pharmaceutical ingredient.
• the present invention is further directed to a method of treating a viral infection in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of the present invention.
• the present invention is further directed to a method of treating an
• HCV or HBV viral infection in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of the present invention.
• the present invention is also directed to a method of inhibiting viral replication in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of the present invention.
• the present invention is also directed a method of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of the present invention.
• the present invention is also directed a method of treating a platelet disorder or diabetes in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of the present invention, wherein said compound is a P2 receptor antagonist.
• the present invention is also directed a method of treating diabetes or cardiovascular disease in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of the present invention, wherein said compound binds an adenosine receptor.
• the present invention is also directed a method of treating inflammation or a CNS disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of the present invention, wherein said compound acts as an adenosine analogue.
• alkyl refers to saturated aliphatic groups including straight- chain, branched chain and cyclic groups, up to and including 12 carbon atoms, or, more preferably, up to and including 10 carbon atoms, or up to and including 6 carbon atoms.
• Suitable alkyl groups include methyl, ethyl, n- propyl, isopropyl, and cyclopropyl.
• the alkyl may be optionally substituted with 1-3 substituents.
• aryl refers to aromatic groups which have 5-14 ring atoms, and at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted.
• the aryl group may be optionally substituted with 1-6 substituents.
• Carbocyclic aryl groups are groups which have 6-14 ring atoms wherein the ring atoms on the aromatic ring are carbon atoms.
• Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and polycyclic or fused compounds such as optionally substituted naphthyl groups.
• Heterocyclic aryl or heteroaryl groups are groups which have 5-14 ring atoms wherein 1 to 4 heteroatoms are ring atoms in the aromatic ring and the remainder of the ring atoms being carbon atoms.
• Suitable heteroatoms include oxygen, sulfur, and nitrogen.
• Suitable heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, indolyl and the like, all optionally substituted.
• monocyclic aryl refers to aromatic groups which have 5-6 ring atoms and includes carbocyclic aryl and heterocyclic aryl. Suitable aryl groups include phenyl, furanyl, pyridyl, and thienyl. Aryl groups may be substituted.
• heteroaryl refers to aromatic groups which have 5-6 ring atoms wherein 1 to 4 heteroatoms are ring atoms in the aromatic ring and the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen.
• biasing represents aryl groups which have 5-14 atoms containing more than one aromatic ring including both fused ring systems and aryl groups substituted with other aryl groups. Such groups may be optionally substituted. Suitable biaryl groups include naphthyl and biphenyl.
• the term "optionally substituted” or “substituted” includes groups substituted by one to four substituents, independently selected from lower alkyl, lower aryl, lower aralkyl, lower cyclic alkyl, lower heterocycloalkyl, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, lower heteroaryl, lower heteroaryloxy, lower heteroarylalkyl, lower heteroaralkoxy, azido, amino, halogen, lower alkylthio, oxo, lower acyl, lower acylalkyl, lower carboxy esters, sulfonyl, sulfonylamido, carboxyl, -carboxamido, nitro, lower acyloxy, lower aminoalkyl, lower alkylamino, lower alkylaminoaryl, lower alkylaryl, lower alkylaminoalkyl, lower alkoxyaryl, lower arylamino, lower
• Substituted aryl and “substituted heteroaryl” refers to aryl and heteroaryl groups substituted with 1-6 of the substituents listed above. Preferred substituents are those selected from the group consisting of lower alkyl, lower alkoxy, lower perhaloalkyl, halogen, hydroxy, cyano, and amino.
• -aralkyl refers to an alkylene group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl, and the like, and may be optionally substituted. The aryl portion may have 5-14 ring atoms and the alkyl portion may have up to and including 10 carbon atoms. "Heteroarylalkyl” refers to an alkylene group substituted with a heteroaryl group.
• alkylaryl- refers to an aryl group substituted with an alkyl group.
• Lower alkylaryl- refers to such groups where alkyl is lower alkyl.
• the aryl portion may have 5-14 ring atoms and the alkyl portion may have up to and including 10 carbon atoms.
• lower referred to herein in connection with organic radicals or compounds respectively defines such as with up to and including 10, in one aspect up to and including 6, and in another aspect one to four carbon atoms.
• Such groups may be straight chain, branched, or cyclic.
• cyclic alkyl or "cycloalkyl” refers to alkyl groups that are cyclic of 3 to 10 carbon atoms, and in one aspect are 3 to 6 carbon atoms. Suitable cyclic groups include norbornyl and cyclopropyl. Such groups may be substituted.
• heterocyclic refers to cyclic groups of 3 to 10 atoms, and in one aspect are 3 to 6 atoms, containing at least one heteroatom, in a further aspect are 1 to 3 heteroatoms.
• Suitable heteroatoms include oxygen, sulfur, and nitrogen.
• Heterocyclic groups may be attached through a nitrogen or through a carbon atom in the ring.
• the heterocyclic alkyl groups include unsaturated cyclic, fused cyclic and spirocyclic groups. ,.
• Suitable heterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl, and pyridyl.
• arylamino (a), and “aralkylamino” (b), respectively, refer to the group -NRR' wherein respectively, (a) R is aryl and R 1 is hydrogen, alkyl, aralkyl, heterocycloalkyl, or aryl, and (b) R is aralkyl and R' is hydrogen, aralkyl, aryl, alkyl or heterocycloalkyl.
• acyl refers to -C(O)R where R is alkyl, heterocycloalkyl, or aryl.
• lower acyl refers to where R is lower alkyl.
• C 1 -C 4 acyl refers to where R is C 1 -C 4 .
• carboxy esters refers to -C(O)OR where R is alkyl, aryl, aralkyl, cyclic alkyl, or heterocycloalkyl, all optionally substituted.
• amino refers to -NRR' where R and R' are independently selected from hydrogen, alkyl, aryl, aralkyl and heterocycloalkyl, all except H are optionally substituted; and R and R' can form a cyclic ring system.
• -carboxylamido refers to -CONR 2 where each R is independently hydrogen or alkyl.
• halogen refers to -F, -Cl, -Br and -I.
• alkylaminoalkylcarboxy refers to the group alkyl-NR-alk-C(O)-O- where "alk” is an alkylene group, and R is a H or lower alkyl.
• sulphonyl or “sulfonyl” refers to -SO 2 R, where R is H, alkyl, aryl, aralkyl, or heterocycloalkyl.
• sulphonate or “sulfonate” refers to -SO 2 OR, where R is -H, alkyl, aryl, aralkyl, or heterocycloalkyl.
• alkenyl refers to unsaturated groups which have 2 to 12 atoms, 2 to 10 atom, or 2 to 8 atoms, and contain at least one carbon-carbon double bond and includes straight-chain, branched-chain and cyclic groups. Alkenyl groups may be optionally substituted. Suitable alkenyl groups include allyl. "1 -Alkenyl” refers to alkenyl groups where the double bond is between the first and second carbon atom. If the 1 -alkenyl group is attached to another group, e.g. it is a W substituent attached to the cyclic phosphate, it is attached at the first carbon.
• alkynyl refers to unsaturated groups which have 2 to 12 atoms, 2 to 10 atoms, or 2 to 8 atoms, and contain at least one carbon-carbon triple bond and includes straight-chain, branched-chain and cyclic groups. Alkynyl groups may be optionally substituted. Suitable alkynyl groups include ethynyl. "1 -Alkynyl” refers to alkynyl groups where the triple bond is between the first and second carbon atom. If the 1 -alkynyl group is attached to another group, e.g. it is a W substituent attached to the cyclic phosphate, it is attached at the first carbon.
• alkylene refers to a divalent straight chain, branched chain or cyclic saturated aliphatic group. In one aspect the alkylene group contains up to and including 10 atoms. In another aspect, the alkylene chain contains up to and including 6 atoms. In a further aspect, the alkylene groups contains up to and including 4 atoms. The alkylene group can be either straight, branched or cyclic. The alkylene may be optionally substituted with 1-3 substituents.
• acyloxy refers to the ester group -0-C(O)R, where R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, or heterocycloalkyl.
• aminoalkyl- refers to the group NR 2 -alk- wherein “alk” is an alkylene group and R is selected from -H, alkyl, aryl, aralkyl, and heterocycloalkyl.
• alkylamino- refers to the group alkyl-NR- wherein R is H or alkyl.
• “Lower alkylamino-” refers to groups where the alkyl is lower alkyl. [0051]
• alkylaminoalkyl- refers to the group alkyl-NR-alk- wherein each "alk” is an independently selected alkylene, and R is H or lower alkyl.
• “Lower alkylaminoalkyl-” refers to groups where the alkyl and the alkylene group is lower alkyl and alkylene, respectively.
• arylaminoalkyl- refers to the group aryl-NR-alk- wherein
• alk is an alkylene group and R is -H, alkyl, aryl, aralkyl, or heterocycloalkyl.
• alkylene group is lower alkylene.
• alkylaminoaryl- refers to the group alkyl-NR-aryl- wherein
• aryl is a divalent group and R is -H, alkyl, aralkyl, or heterocycloalkyl.
• alkyl group is lower alkyl.
• alkoxyaryl- refers to an aryl group substituted with an alkyloxy group. In “lower alkyloxyaryl-”, the alkyl group is lower alkyl.
• aryloxyalkyl- refers to an alkyl group substituted with an aryloxy group.
• aralkyloxyalkyl- refers to the group aryl-alk-O-alk- wherein “alk” is an alkylene group. "Lower aralkyloxyalkyl-” refers to such groups where the alkylene groups are lower alkylene.
• alkoxy- or “alkyloxy-” refers to the group alkyl-O-.
• each alkyl is lower alkyl.
• alkoxyalkyl- or “alkyloxyalkyl-” refer to the group alkyl-O-alk- wherein “alk” is an alkylene group. In “lower alkoxyalkyl-,” each alkyl and alkylene is lower alkyl and alkylene, respectively.
• alkylthio- refers to the group alkyl-S-.
• alkylthioalkyl- refers to the group alkyl-S-alk- wherein
• alk is an alkylene group.
• each alkyl and alkylene is lower alkyl and alkylene, respectively.
• alkoxycarbonyloxy- refers to alkyl ⁇ 0-C(0)-O.
• aryloxycarbonyloxy- refers to aryl-O-C(O)-O-.
• alkylthiocarbonyloxy- refers to alkyl-S-C(0)-O.
• R and R 1 include -H, alkyl, aryl, aralkyl, and heterocycloalkyl.
• carboxyl refer to NR 2 -C(O)- and RC(O)-NR 1 -, where
• R and R 1 include -H, alkyl, aryl, aralkyl, and heterocycloalkyl. The term does not include urea, -NR-C(O)-NR-.
• carboxylalkylaryl and “carboxamidoaryl” refers to an aryl-alk-NR 1 -C(O), and ar-NR 1 -C(O)-alk-, respectively where "ar” is aryl,
• alk is alkylene, R 1 and R include H, alkyl, aryl, aralkyl, and heterocycloalkyl.
• alk is alkylene, R 1 and R include -H, alkyl, aryl, aralkyl, and heterocycloalkyl.
• hydroxyalkyl refers to an alkyl group substituted with one -OH.
• haloalkyl refers to an alkyl group substituted with one halogen.
• cyano refers to ⁇ C ⁇ N .
• nitro refers to -NO 2 .
• acylalkyl refers to an alkyl-C(O)-alk-, where “alk” is alkylene.
• aminocarboxamidoalkyl- refers to the group
• heteroarylalkyl refers to an alkylene group substituted with a heteroaryl group.
• perhalo refers to groups wherein every C-H bond has been replaced with a C-halo bond on an aliphatic or aryl group.
• Suitable perhaloalkyl groups include -CF 3 and -CFCl 2 .
• purine refers to nitrogenous bicyclic heterocycles.
• pyrimidine refers to nitrogenous monocyclic heterocycles.
• purine or pyrimidine base includes, but is not limited to, adenine, N 6 - alkylpurines, N 6 -acylpurines (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N 6 -benzylpurine, N 6 -halopurine, N 6 -vinylpurine, N 6 -acetylenic purine, N 6 -acyl purine, N 6 -hydroxyalkyl purine, N 6 -thioalkyl purine, N 2 - alkylpurines, N 2 -alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine, 5- methylcytosine, 6-azapyrimidme, including 6-azacytosine, 2-
• Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 2,6- diaminopurine, and 6-chloropurine. Functional oxygen and nitrogen groups on the base can be protected as necessary or desired. Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl, methanesulfonyl, and p- toluenesulfonyl.
• terapéuticaally effective amount means an amount of a compound or a combination of compounds that ameliorates, attenuates or eliminates one or more of the symptoms of a particular disease or condition or prevents, modifies, or delays the onset of one or more of the symptoms of a particular disease or condition.
• salts of a compound of the present invention includes compounds of Formulae I-XVI and its prodrugs derived from the combination of a compound of this invention and an organic or inorganic acid or base.
• Suitable acids include acetic acid, adipic acid, benzenesulfonic acid,
• (+)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-l-methanesulfonic acid citric acid, 1,2-ethanedisulfonic acid, dodecyl sulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, hippuric acid, hydrochloride hemiethanolic acid, HBr, HCl, HI, 2-hydroxyethanesulfonic acid, lactic acid, lactobionic acid, maleic acid, methanesulfonic acid, methylbromide acid, methyl sulfuric acid, 2-naphthalenesulfonic acid, nitric acid, oleic acid, 4,4'-methylenebis [3-hydroxy-2-naphthalenecarboxylic acid], phosphoric acid, polygalacturonic acid, stearic acid, succinic acid, sulfuric acid, sulfosalicylic acid, tannic acid,
• L-amino acid refers to those amino acids routinely found as components of proteinaceous molecules in nature, including alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamme, aspartic acid, glutamic acid, lysine, arginine and histidine.
• this term is intended to encompass L-amino acids having only the amine and carboxylic acid as charged functional groups, i.e., alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine and tyrosine.
• they are alanine, valine, leucine, isoleucine, proline, phenylalanine, and glycine. Ia a further aspect, it is valine.
• esters of an L-amino acid refers to ester formed by coupling of a hydroxyl group of the compound with a carboxylic acid of naturally occurring L-amino acid.
• patient refers to an animal being treated including a mammal, such as a dog, a cat, a cow, a horse, a sheep, and a human. Another aspect includes a mammal, both male and female.
• prodrug refers to any compound that when administered to a biological system generates a biologically active compound as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or metabolic chemical reaction(s), or a combination of each.
• Standard prodrugs are formed using groups attached to a functionality, e.g.
• Standard prodrugs include but are not limited to carboxylate esters where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters of hydroxyl, thiol and amines where the group attached is an acyl group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate.
• phosphonate or monophosphate prodrugs are compounds that breakdown chemically or enzymatically to a phosphonic acid or monophosphate or phosphinic acid group or a monoester thereof in vivo. As employed herein the term includes, but is not limited to, the following groups and combinations of these groups:
• acyloxyalkyl esters are possible in which a cyclic alkyl ring is formed. These esters have been shown to generate phosphorus-containing nucleotides inside cells through a postulated sequence of reactions beginning with deesterification and followed by a series of elimination reactions (e.g.,
• alkyloxycarbonyloxymethyl esters as shown in formula A, where R is alkoxy, aryloxy, alkylthio, arylthio, alkylamino, and arylamino; R', and R" are independently -H, alkyl, aryl, alkylaryl, and heterocycloalkyl have been studied in the area of ⁇ -lactam antibiotics (Nishimura et al, J.
• R, R', and R" are independently H, alkyl, aryl, alkylaryl, and alicyclic (see, e.g., International Publ. Nos. WO 90/08155 and WO 90/10636).
• Other acyloxyalkyl esters are possible in which a cyclic alkyl ring is formed such as shown in Formula B. These esters have been shown to generate phosphorus-containing nucleotides inside cells through a postulated sequence of reactions beginning with deesterification and followed by a series of elimination reactions (see, e.g., Freed et al., Biochem. Pharm. 35:3193- 3198 (1989)).
• R is -H, alkyl, aryl, alkylaryl, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino, or cycloalkyl.
• Aryl esters have also been used as phosphorus prodrugs ⁇ e.g.,
• Phenyl as well as mono and poly- substituted phenyl proesters have generated the parent phosphonic acid in studies conducted in animals and in man (Formula C).
• Y is a carboxylic ester ortho to the phosphate (Khamnei et al, J. Med. Chem. 3P:4109-4115 (1996)).
• Benzyl esters have also been reported to generate the parent phosphonic acid. In some cases, using substituents at the para-position can accelerate the hydrolysis.
• X and Y are independently -H, alkyl, aryl, alkylaryl, alkoxy, acyloxy, hydroxy, cyano, nitro, perhaloalkyl, halo, or alkyloxycarbonyl; and R' and R" are independently -H, alkyl, aryl, alkylaryl, halogen, and cyclic alkyl.
• Thio-containing phosphonate proesters may also be useful in the delivery of drugs to hepatocytes. These proesters contain a protected thioethyl moiety as shown in Formula E. One or more of the oxygens of the phosphonate can be esterified.
• thiol protecting groups are possible.
• the disulfide is reduced by a reductase-mediated process (Puech et al, Antiviral Res. 22:155-174 (1993)).
• Thioesters will also generate free thiolates after esterase-mediated hydrolysis Benzaria, et al, J. Med. Chem. 39 (25) -.4958-4965 (1996)).
• Cyclic analogs are also possible and were shown to liberate phosphonate in isolated rat hepatocytes.
• the cyclic disulfide shown below has not been previously described and is novel.
• Formula E wherein Z is alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, or alkylthio.
• suitable prodrugs include proester classes exemplified by Biller and Magnin (U.S. Patent No. 5,157,027); Serafmowska et al, J. Med. Chem. 38(8): 1372-1379 (1995); Starrett Qt al, J. Med. Chem. 37:1857 (1994); Martin et al, J. Pharm. Sd. 7(5:180 (1987); Alexander et al, Collect. Czech. Chem. Commun. 59:1853 (1994); and EP 0 632 048 Al.
• Formula E-I Formula E-2 Formula E-3 wherein R is -H, alkyl, cycloalkyl, or heterocycloalkyl; and wherein Y is -H, alkyl, aryl, alkylaryl, cyano, alkoxy, acyloxy, halogen, amino, heterocycloalkyl, and alkoxycarbonyl.
• prodrugs of Formula E-3 are an example of "optionally substituted heterocycloalkyl where the cyclic moiety contains a carbonate or thiocarbonate.”
• Propyl phosphonate proesters can also be used to deliver drugs into hepatocytes. These proesters may contain a hydroxyl and hydroxyl group derivatives at the 3-position of the propyl group as shown in Formula F. The R and X groups can form a cyclic ring system as shown in Formula F. One or more of the oxygens of the phosphonate can be esterified.
• R is alkyl, aryl, heteroaryl
• X is hydrogen, alkylcarbonyloxy, alkyloxycarbonyloxy
• Y is alkyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, halogen, hydrogen, hydroxy, acyloxy, amino.
• Phosphoramidate derivatives have been explored as phosphate prodrugs (e.g., McGuigan et ah, J. Med. Chem. 42:393 (1999) and references cited therein) as shown in Formula G and H.
• prodrugs are possible based on literature reports such as substituted ethyls, for example, bis(trichloroethyl)esters as disclosed by McGuigan, et al., Bioorg Med. Chem. Lett. 3:1207-1210 (1993), and the phenyl and benzyl combined nucleotide esters reported by Meier, C. et al, Bioorg. Med. Chem. Lett. 7:99-104 (1997).
• substituted ethyls for example, bis(trichloroethyl)esters as disclosed by McGuigan, et al., Bioorg Med. Chem. Lett. 3:1207-1210 (1993), and the phenyl and benzyl combined nucleotide esters reported by Meier, C. et al, Bioorg. Med. Chem. Lett. 7:99-104 (1997).
• prodrugs of the compounds of Formula I fall within this scope.
• Prodrugs must undergo some form of a chemical transformation to produce the compound that is biologically active or is a precursor of the biologically active compound.
• the prodrug is biologically active, usually less than the drug itself, and serves to improve drug efficacy or safety through improved oral bioavailability, pharmacodynamic half-life, etc.
• Prodrug forms of compounds may be utilized, for example, to improve bioavailability, improve subject acceptability such as by masking or reducing unpleasant characteristics such as bitter taste or gastrointestinal irritability, alter solubility such as for intravenous use, provide for prolonged or sustained release or delivery, improve ease of formulation, or provide site-specific delivery of the compound.
• Prodrugs are described in The Organic Chemistry of Drug Design and Drug Action, by Richard B. Silverman, Academic Press, San Diego (1992); Chapter 8: “Prodrugs and Drug delivery Systems,” pp.352-401; Design of Prodrugs, edited by H. Bundgaard, Elsevier Science, Amsterdam (1985); Design of Biopharmaceutical Properties through Prodrugs and Analogs, Ed. by E.B. Roche, American Pharmaceutical Association, Washington (1977); and Drug Delivery Systems, ed. by R. L. Juliano, Oxford Univ. Press, Oxford (1980).
• prodrugs are preferred at the 6-position of purine analogs. Such substitution may include H, halogen, amino, acetoxy or azido or alkyl carbamoyl groups. Hydrogen substituted prodrugs at the 6- position of guanosine analogs undergo oxidation in vivo by aldehyde oxidase or xanthine oxidase to give the required functionality (Rashidi et at, Drug Metab. Dispos. 25:805 (1997)). While esterases unmask acetoxy groups, amine and halogen substituents are known to be substrates for deaminases. 6- Azido substituted compounds are also known to give the corresponding amino derivatives by the action of reductases (Koudriakova, et at, J. Med Chem. 39:4676 (1996)).
• V and Z are connected together via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, that is fused to an aryl group attached at the beta and gamma position to the O attached to the phosphorus.
• V and Z are connected together via 4 additional atoms.
• W and W are connected together via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
• cyclic phosphate refers to
• the carbon attached to V must have a C-H bond.
• the carbon attached to Z must also have a C-H bond.
• trans stereochemistry refers to the spatial relationship of the V group and the substituent attached to the phosphorus atom via an exocyclic single bond on the six membered 2-oxo-phosphorinane ring.
• the structures M and N below show two possible trans- isomers of 2- and A- substituted 2-oxo-phosphorinane. Structure M shows trans- isomer of (2S, 4S)- configuration whereas structure N shows trans- isomer of (2R, 4R)- configuration.
• ⁇ RI - rsi x 100 %R - %s [R] + [S] where [R] is the amount of the R isomer and [S] is the amount of the S isomer. This formula provides the % ee when R is the dominant isomer.
• enantioenriched or “enantiomerically enriched” refers to a sample of a chiral compound that consists of more of one enantiomer than the other. The extent to which a sample is enantiomerically enriched is quantitated by the enantiomeric ratio or the enantiomeric excess.
• liver refers to liver organ.
• enhancing refers to increasing or improving a specific property.
• liver specificity refers to the ratio: [drug or a drug metabolite in liver tissue!
• the ratio can be determined by measuring tissue levels at a specific time or may represent an AUC based on values measured at three or more time points.
• the term "increased or enhanced liver specificity” refers to an increase in the liver specificity ratio in animals treated with the prodrug relative to animals treated with the parent drug.
• the term "enhanced oral bioavailability" refers to an increase of at least 50% of the absorption of the dose of the parent drug. In an additional aspect the increase in oral bioavailability of the prodrug (compared to the parent drug) is at least 100%, that is a doubling of the absorption. Measurement of oral bioavailability usually refers to measurements of the prodrug, drug, or drug metabolite in blood, plasma, tissues, or urine following oral administration compared to measurements following parenteral administration.
• therapeutic index refers to the ratio of the dose of a drug or prodrug that produces a therapeutically beneficial response relative to the dose that produces an undesired response such as death, an elevation of markers that are indicative of toxicity, and/or pharmacological side effects.
• sustained delivery refers to an increase in the period in which there is a prolongation of therapeutically-effective drug levels due to the presence of the prodrug.
• bypassing drug resistance refers to the loss or partial loss of therapeutic effectiveness of a drug (drug resistance) due to changes in the biochemical pathways and cellular activities important for producing and maintaining the biological activity of the drug and the ability of an agent to bypass this resistance through the use of alternative pathways or the failure of the agent to induce changes that tend to resistance.
• treating or “treatment” of a disease includes inhibiting the disease (slowing or arresting its development), providing relief from the symptoms or side-effects of the disease (including palliative treatment), and relieving the disease (causing regression of the disease).
• the present invention relates to compounds of Formula I, and isomers, hydrates, solvates, prodrugs, co-crystals, and pharmaceutically acceptable salts thereof:
• Y is -O-, -S-, -N-, -C(R 20' )-, or -CH 2 -;
• R 18 is independently H, C 1-4 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl; wherein said C 1-4 alkyl is optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms, C 1-4 alkylamino, dialkylamino, C 3-6 cycloalkylamino, halogen, or alkoxy;
• R 17 is H, halogen, alkyl optionally substituted with 1 to 3 fluorine atoms, Ci -10 alkoxy optionally substituted with C 1-3 alkoxy or 1 to 3 fluorine atoms, C 2-6 alkenyloxy, C 1-4 alkylthio, Ci -8 alkylcarbonyloxy, aryloxycarbonyl, azido, amino, alkylamino, or dialkylamino;
• R 16 and R 15 are independently H, Ci -4 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl; wherein said C 1-4 alkyl is optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms, and said C 2-4 alkenyl and C 2-4 alkynyl are each optionally substituted with one or more of Ci -3 alkoxy, carboxy, C 2-6 alkenyloxy, Ci -4 alkylthio, C 1-8 alkylcarbonyloxy, aryloxycarbonyl, azido, amino, alkylamino, or dialkylamino;
• B is a purine or pyrimidine base or an analogue or derivative thereof
• Z' is -CH(R 23 )-OH, -O-, -CH(R 23 )-O-, Ci -4 cycloalkyl, -OC(R 2 VO 3 H 2 , -CH 2 C(R 2 VO 3 H 2 , C 2-4 alkenyl, C 2-4 alkynyl, Ci -4 cycloalkylene, C 2-4 alkenylene, or C 2-4 alkynylene; wherein R 23 is H, F, methyl, ethyl, hydroxymethyl, fluoromethyl, -CH 2 N 3 , -CH 2 -NR 21 R 22 , -CH 2 -, or -CH 2 -NH 2 ; and
• V, W, and W are independently H, optionally substituted alkyl, optionally substituted aralkyl, cycloalkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1 -alkenyl, or optionally substituted 1 -alkynyl; and
• Z" is P(O)Y 1 R 11 Y 1 R 11 , wherein each R 11 is independently H or C 1-4 alkyl; Y and Y' are each independently selected from the group consisting of -O-, and -NR V -; and when Y' and Y" are both -O-, R 11 attached to -O- is independently selected from the group consisting of optionally substituted aryl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R Z ) 2 OC(O)NR Z 2 ,
• R 11 attached to -NR V - is independently selected from the group consisting of -H, -[C(R z ) 2 ] q -C00R y , -C(R ⁇ 2 COOR 3 ', -[C(R z ) 2 ] q -C(O)SR y , and
• R 11 attached to -O- is independently selected from the group consisting of optionally substituted aryl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R Z ) 2 OC(O)NR Z 2 ,
• R 11 attached to -NR V - is independently selected from the group consisting of -H, -[C(R z ) 2 ] q -C00R y , -C(R x ) 2 C00R y , -[C(R z ) 2 ] q -C(O)SR y , and -cycloalkylene-COOR y ; or when Y' and Y" are independently selected from -O- and -NR V
• V, Z, W, W are not all -H;
• Z when Z is -R z , then at least one of V, W, and W is not -H, alkyl, aralkyl, cycloalkyl, or heterocycloalkyl;
• compounds of Formula I are those in which X' is O or S.
• compounds of Formula I are those in which X' is O.
• compounds of Formula I are those in which X' is S.
• compounds of Formula I are those in which X 1 is
• suitable values of R 20 include H, C 1-1O alkyl, C 6-10 aryl, C 6-10 aryl(C 1-6 )alkyl, or C 3-6 cycloalkyl.
• compounds of Formula I are those in which Y is -O-,
• Y is -C(R 20' )-. In yet other aspects of the invention, Y is -O-.
• R 19 is absent in compounds of Formula I.
• R 19 is present and is H, -OH, -0-lower alkyl, e.g., -OCH 3 , or R 19 is optionally substituted C 1-4 alkyl, e.g., methyl.
• R 19 is joined together with R 17 to form -O-(CH 2 ) P , wherein p is 2 or 3.
• R 18 is H, C 1-4 alkyl, wherein said C 1-4 alkyl is optionallysubstituted with amino, hydroxy, or 1 to 3 fluorine atoms, hi other aspects, R 18 is H or C 1-4 alkyl, e.g., methyl or ethyl.
• R 18 , R 17 , R 15 , and R 15 are independently H or lower alkyl, e.g., C 1-6 alkyl, such as methyl, ethyl, or propyl.
• R 16 is -CH 3 .
• variable B depicted in Formula I above represents a purine or pyrimidine base or analogue or derivative thereof.
• B will be preferably linked to the ribose ring of Formula I at the 9- or 1- position, respectively, of the purine or pyrimidine base B.
• purine or pyrimidine base or analogue or derivative thereof is meant a purine or pyrimidine base found in native nucleosides, or an analogue thereof, which mimics such bases in that their structures (the kinds of atoms and their arrangement) are similar to the native bases but may either possess additional or lack certain of the functional properties of the native bases.
• Such analogues include those derived by replacement of a CH moiety by a nitrogen atom (for example, 5- azapyrimidines such as 5-azacytosine) or vice versa (for example, 7- deazapurines such as 7-deazadenine or 7-deazaguanine) or both (e.g., 7-deaza, 8-azapurines).
• derivatives of such bases or analogues are meant those compounds wherein ring substituents are either incorporated, removed, or modified by conventional substituents known in the art, e.g., halogen, hydroxyl, amino, and C 1-6 alkyl.
• purine or pyrimidine bases, analogues, and derivatives will be well known to those skilled in the art.
• B is selected from:
• A, D, E, J, and G are each independently selected from the group consisting of C and N;
• L is selected from O or S
• M is selected from the group consisting of O, S, and Se;
• X 1 is absent, or X 1 is selected from the group consisting of H, -OH, -SH, -NH 2 , -CO, -COOR 11 , -CONH 2 , -CSNH 2 , alkylamino, dialkylamino, cycloalkylamino, halogen, alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, acyl, alkoxy, CF 3 , and -NHCORx 1 , wherein Rx 1 is H, lower alkyl, or lower alkoxy, and wherein R 11 is H or C 1-4 alkyl;
• X 2 is absent, or X 2 is independently selected from the group consisting of H, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, acyl, and C 1 -C 6 alkyl;
• X 3 , X 4 and X 6 are each independently absent, or X 3 , X 4 and X 6 are each independently selected from the group consisting of H, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, acyl, OH, SH, NH 2 , CF 3 , alkyl, amino, halogen, alkylamino, cycloalkylamino, and dialkylamino; and
• X 5 is absent, or X 5 is selected from the group consisting of H, -CN, -NO 2 , -alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, acyl, -NHCONH 2 , -CONR 11 R 11' , -CSNR 11 R 11' , -COOR 11' , -C( ⁇ NH)NH 2 , -hydroxy, -C 1-3 alkoxy, -amino, -alkylamino, -dialkylamino, halogen, -(l,3-oxazol-2-yl), -(1,3-thiazol- 2-yl), and -(imidazol-2-yl); wherein alkyl is unsubstituted or substituted with one to three groups independently selected from the group consisting of halogen, amino, hydroxy, carboxy, and C 1-3 alkoxy; and wherein R 11 and R 11 are independently H
• R 25 is independently selected from the group consisting of H and NH 2 ; and R 26 is selected from the group consisting of NH 2 , NHCH 3 , N(CH 3 ) 2 , OCH 3 , SCH 3 , OH, Cl, Br, SH, cyclopropyl amino, cyclobutyl amino, and cyclopentyl amino.
• B is selected from:
• B is selected from the following:
• each R 4 and R 5 is independently H, acyl, Cj-C 6 alkyl, alkenyl, alkynyl or cycloalkyl;
• W 2 , W 3 and W 4 are each independently N, CH, CF, Cl, CBr, CCl, CCN, CCH 3 , CCF 3 , CCH 2 CH 3 , CC(O)NH 2 , CC(O)N(R 4 ) S , CC(O)OH, CC(O)OR 4 or CT 3 ; wherein T 3 is as defined below;
• T 2 is H, optionally substituted alkyl (such as, e.g., CH 3 , CF 3 , C(Y 3 ) 3 , 2- Br-ethyl, CH 2 F, CH 2 Cl, CF 2 CF 3 , C(Y 3 ) 2 C(Y 3 ) 3 , or CH 2 OH), optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR 4 , COO- alkyl, COO-aryl, CO-alkoxyalkyl, CONH 2 , CONHR 4 , CON(R 4 ⁇ , chloro, bromo, fluoro, iodo, CN, N 3 , OH, OR 4 , NH 2 , NHR 4 , NR 4 R 5 , SH or SR 5 , wherein Y 3 is as defined below;
• alkyl such as, e.g., CH 3 , CF 3 , C(Y 3 ) 3 , 2- Br-eth
• T 3 is optionally substituted alkyl (including lower alkyl, such as, e.g., CH 3 , CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , CH 2 OH), halogenated alkyl (including halogenated lower alkyl such as, e.g., CF 3 , C(Y 3 ) 3 , 2-Br-ethyl, CH 2 F, CH 2 Cl, CH 2 CF 3 , CF 2 CF 3 , C(Y 3 ) 2 C(Y 3 ) 3 ), optionally substituted alkenyl, haloalkenyl, optionally substituted alkynyl, haloalkynyl, Br-vinyl, N 3 , CN, -C(O)OH, -C(O)OR 4 , -C(O)O(lower alkyl), -C(O)NH 2 , -CON
• Y 1 is H, Br, Cl, I, F, CN, OH, OR 4 , NH 2 , NHR 4 , NR 4 R 5 , SH or SR 4 , wherein R 4 and R 5 are as defined below;
• Y 2 is O, S, NH or NR 4 , wherein R 4 is as defined below;
• Y 3 is H, Br, Cl, I, F;
• Y 4 is H, optionally substituted lower alkyl, cycloalkyl, alkenyl, alkynyl, CH 2 OH, CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , CH 2 F, CH 2 Cl, CH 2 N 2 , CH 2 CN, CH 2 CF 3 , CF 3 , CF 2 CF 3 , CH 2 CO 2 R, (CH 2 ) m COOH, (CH 2 ) m COOR, (CH 2 ) m CONH 2 , (CH 2 ) m CONR 2 , or (CH 2 ) m C0NHR; wherein R is H, alkyl or acyl, and m is 0, 1 or 2; wherein for base (B), W 4 cannot be CH if W 1 , W 2 , and W 3 are N; and wherein for base (E), (F), (K), (L), (W), and (X), W 4 cannot be CH if W 1 is N.
• compounds of Formula I are those in which Z' is -CHR 23 -OH, C 1-4 cycloalkyl, C 2-4 alkenyl, or C 2-4 alkynyl, wherein R 23 is methyl, ethyl, hydroxymethyl, fluoromethyl, -CH 2 N 3 , -CH 2 -NR 21 R 22 , -CH 2 -, or -CH 2 -NH 2 , wherein R 21 and R 22 are independently H or lower alkyl.
• Z' is -CHR 23 -OH, -OC(R 23 ) 2 PO 3 H 2 or -CH 2 C(R 23 ) 2 PO 3 H 2 , wherein R 23 is methyl or ethyl.
• Z' is -O-, -CH(R 23 )-O-, C 1-4 cycloalkylene
• R 23 is H, F, methyl, ethyl, hydroxymethyl, fluoromethyl, -CH 2 N 3 , -CH 2 -NR 21 R 22 , -CH 2 -, or -CH 2 -NH 2 , wherein R 21 and R 22 are independently H or lower alkyl.
• Z" is absent. In other aspects,
• V, W, and W are independently H, optionally substituted alkyl, optionally substituted aralkyl, cycloalkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1 -alkenyl, or optionally substituted 1 -alkynyl; and
• V, Z, W, W, q, R z , and R y are as defined above. [0138] In some aspects of the invention in which Z" is
• V and Z are connected together via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorus.
• V and Z are connected together via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus
• V and W are connected together via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorus.
• Z and W are connected together via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
• W and W are connected together via an additional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
• V, Z, W, W are not all -H; and b) when Z is -R z , then at least one of V, W, and W is not -H, alkyl, aralkyl, cycloalkyl or heterocycloalkyl.
• V is selected from the group consisting of phenyl; substituted phenyl with 1-3 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, -CF 3 , -OR 3 , -OR 12 , -COR 3 , -CO 2 R 3 , -N(R 3 ) 2 , -N(R 12 ) 2 , -CO 2 N(R 2 ) 2 , -SR 3 , -SO 2 R 3 , -SO 2 N(R 2 ) 2 and -CN; monocyclic heteroaryl; and substituted monocyclic heteroaryl with 1-2 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, -CF 3 , -OR 3 , -OR 12 , -COR 3 , -CO 2 R 3 , -N(R 3 ) 2 , -N(R 12 ) 2 , -CO 2
• V and Z together are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus.
• V is selected from the group consisting of phenyl; substituted phenyl with 1-3 substituents independently selected from the group consisting of -Cl, -Br, -F, C 1-3 alkyl, -CF 3 , -COCH 3 , -OMe, -NMe 2 , -OEt, -C0 2 t-butyl, -CO 2 NH 2 , -SMe, -SO 2 Me, -SO 2 NH 2 , and -CN; monocyclic heteroaryl; and substituted monocyclic heteroaryl with 1-2 substituents independently selected from the group consisting of -Cl, -Br, -F, C 1-3 alkyl, -CF 3 , -COCH 3 , -OMe, -NMe 2 , -OEt, -CCt ⁇ -butyl, -CO 2 NH 2 , -SMe, -SO 2 Me, -SO 2
• V and Z are connected together via an additional 4 atoms to form a 6- membered ring that is fused to a phenyl or substituted phenyl at the beta and gamma position to the O attached to the phosphorus.
• V is selected from the group consisting of phenyl; substituted phenyl with 1-2 substituents independently selected from the group consisting of -Cl, -Br, -F, Cj- 3 alkyl, and -CF 3 ; pyridyl; substituted pyridyl with 1 substituent independently selected from the group consisting of -Cl, -Br, -F, C 1-3 alkyl, and -CF 3 ; furanyl; substituted furanyl with 1 substituent independently selected from the group consisting of -Cl, -Br, -F, Ci -3 alkyl, and -CF 3 ; thienyl; and substituted thienyl with 1 substituent independently selected from the group consisting of -Cl, -Br, -F, Ci -3 alkyl, and -CF 3 .
• V is selected from the group consisting of phenyl, 3- chlorophenyl, 3-bromophenyl, 2-bromophenyl, 3,5-dichlorophenyl, 3-bromo- 4-fluorophenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl.
• V is selected from the group consisting of 3-chlorophenyl, 3-bromophenyl, 2- bromophenyl, 3,5-dichlorophenyl, 3-pyridyl, and 4-pyridyl.
• V is selected from the group consisting of phenyl; substituted phenyl with 1-3 substituents independently selected from the group consisting of -Cl, -Br, -F, C 1-3 alkyl, -CF 3 , -COCH 3 , -OH, -OMe, -NH 2 , -NMe 2 , -OEt, -COOH, -C0 2 t-butyl, -CO 2 NH 2 , -SMe, -SO 2 Me, -SO 2 NH 2 and - CN; monocyclic heteroaryl; and substituted monocyclic heteroaryl with 1-2 substituents independently selected from the group consisting of -Cl, -Br, -F, Ci - 3 alkyl, -CF 3 , -COCH 3 , -OH, -OMe, -NH 2 , -NMe 2 , -OEt, -COOH, -C0 2
• V and Z are connected together via an additional 4 atoms to form a 6- membered ring that is fused to a phenyl or substituted phenyl at the beta and gamma position to the O attached to the phosphorus.
• Z is selected from the group consisting of -H, -OMe,
• R 4 is Ci-C 4 alkyl
• R 5 is selected from the group consisting Of Ci-C 4 alkyl, monocyclic aryl, and monocyclic aralkyl
• R 6 is Ci-C 4 acyl.
• Z is selected from the group consisting of H, -OMe, -OEt, and phenyl.
• W and W are independently selected from the group consisting of H, Ci -6 alkyl, and phenyl; or W and W are connected together via an additional 2-5 atoms to form a cyclic group, hi yet other aspects, W and W are independently selected from the group consisting of H, methyl, and V, or W and W are each methyl, with the proviso that when W is V, then W is H.
• V is selected from the group consisting of optionally substituted monocyclic aryl and optionally substituted monocyclic heteroaryl;
• W and W are independently selected from the group consisting of -H, methyl, and V; or W and W are each methyl; with the proviso that when W is V, then W is H; and
• Z is selected from the group consisting of -H, -OMe, -OEt, phenyl, C 1-3 alkyl, -N(R 4 ) 2 , -SR 4 , -(CH 2 ) P -OR 6 , -(CH 2 ) P -SR 6 and -OCOR 5 , wherein R 4 is Ci -4 alkyl; R 5 is selected from the group consisting of Ci -4 alkyl, monocyclic aryl, and monocyclic aralkyl; and R 6 is Ci -4 acyl; or
• Z and V are connected together via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus; or
• Z and W are connected together via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom;
• W and W are connected together via an additional 2-5 atoms to form a cyclic group.
• V is selected from the group consisting of phenyl; substituted phenyl with 1-3 substituents independently selected from the group consisting of halogen, Ci -6 alkyl, -CF 3 , -OR 3 , -OR 12 , -COR 3 , -CO 2 R 3 , -N(R 3 ) 2 , -N(R 12 ) 2 , -CO 2 N(R 2 ) 2 , -SR 3 , -SO 2 R 3 , -SO 2 N(R 2 ) 2 and -CN; monocyclic heteroaryl; and substituted monocyclic heteroaryl with 1-2 substituents independently selected from the group consisting of halogen, Ci -6 alkyl, -CF 3 , -OR 3 , -OR 12 , -COR 3 , -CO 2 R 3 , -N(R 3 ) 2 , -N(R 12 ) 2 , -CO 2 N(R 2
• W and W are independently selected from the group consisting of -H, methyl, and V; or W and W are each methyl, with the proviso that when W is V, then W is H;
• Z is selected from the group consisting of -H, -OMe, -OEt, phenyl, C 1 -C 3 alkyl, -N(R 4 ) 2 , -SR 4 , ⁇ (CH 2 ) P -OR 6 , -(CH 2 ) P -SR 6 and -OCOR 5 ; wherein R 4 is C 1 -C 4 alkyl, R 5 is selected from the group consisting of C 1 -C 4 alkyl, monocyclic aryl, and monocyclic aralkyl, and R 6 is C 1 -C 4 acyl; or
• Z and V are connected together via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorus; or
• Z and W are connected together via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom;
• V is selected from the group consisting of phenyl; substituted phenyl with 1-3 substituents independently selected from the group consisting of -Cl, -Br, -F, C 1-3 alkyl, -CF 3 , -COCH 3 , -OMe, -NMe 2 , -OEt, - CCt ⁇ -butyl, -CO 2 NH 2 , -SMe, -SO 2 Me, -SO 2 NH 2 and -CN; monocyclic heteroaryl; and substituted monocyclic heteroaryl with 1-2 substituents independently selected from the group consisting of -Cl 5 -Br, -F, C 1-3 alkyl, -CF 3 , -COCH 3 , -OMe, -NMe 2 , -OEt, -C0 2 t-butyl, -CO 2 NH 2
• W and W are independently selected from the group consisting of -H, methyl, and V, or W and W are each methyl, with the proviso that when W is V, then W is H;
• Z is selected from the group consisting of -H, -OMe, -OEt, phenyl, C 1-3 alkyl, -N(R 4 ) 2 , -SR 4 , -(CH 2 ) P -OR 6 , -(CH 2 ) P -SR 6 and -OCOR 5 , wherein R 4 is C 1 -C 4 alkyl, R 5 is selected from the group consisting of C 1 -C 4 alkyl, monocyclic aryl, and monocyclic aralkyl, and R 6 is C 1 -C 4 acyl; or
• V and Z are connected together via an additional 4 atoms to form a 6- membered ring that is fused to a phenyl or substituted phenyl at the beta and gamma position to the O attached to the phosphorus; or
• Z and W are connected together via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom;
• W and W are connected together via an additional 2-5 atoms to form a cyclic group.
• V is selected from the group consisting of phenyl; substituted phenyl with 1-2 substituents independently selected from the group consisting of -Cl, -Br, -F, C 1-3 alkyl, and -CF 3 ; pyridyl; substituted pyridyl with 1 substituent independently selected from the group consisting of -Cl, -Br, -F, C 1-3 alkyl, and -CF 3 ; furanyl; substituted furanyl with 1 substituent independently selected from the group consisting of -Cl, -Br, -F, C 1-3 alkyl, and -CF 3 ; thienyl; and substituted thienyl with 1 substituent independently selected from the group consisting of -Cl, -Br, -F, C 1 -C 3 alkyl, and -CF 3 ;
• W and W are independently selected from the group consisting of -H, methyl, and V, or W and W are each methyl, with the proviso that when W is V, then W is H;
• Z is selected from the group consisting of -H, -OMe, -OEt, phenyl, C 1 -C 3 alkyl, -N(R 4 ) 2 , -SR 4 , -(CH 2 ) P -OR 6 , -(CH 2 ) P -SR 6 and -OCOR 5 , wherein R 4 is C 1 -C 4 alkyl, R 5 is selected from the group consisting of C 1 -C 4 alkyl, monocyclic aryl, and monocyclic aralkyl, and R 6 is C 1 -C 4 acyl; or Z and W are connected together via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom; or
• W and W are connected together via an additional 2-5 atoms to form a cyclic group.
• V is selected from the group consisting of phenyl, 3- chlorophenyl, 3-bromophenyl, 2-bromophenyl, 3,5-dichlorophenyl, 3-bromo- 4-fluorophenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl;
• Z is selected from the group consisting of -H, OMe, OEt, and phenyl;
• W and W are independently selected from the group consisting of -H and phenyl, or W and W are each methyl.
• Z, W, and W are each — H.
• V and W are the same and each is selected from the group consisting of optionally substituted monocyclic aryl and optionally substituted monocyclic heteroaryl.
• Z" is:
• V is as defined above.
• Z" is selected from the following non-limiting examples:
• Z" is P(O)Y 1 R 11 YR 11 , wherein each R 11 is independently H or C 1-4 alkyl; Y' and Y" are each independently selected from the group consisting of-O-, and -NR V -; and when Y' and Y" are both -O-, R 11 attached to -O- is independently selected from the group consisting of optionally substituted aryl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R Z ) 2 OC(O)NR Z 2 ,
• R 11 attached to -NR V - is independently selected from the group consisting of -H, -[C(R z ) 2 ] q -COOR y , -C(R x ) 2 COOR y , -[C(R z ) 2 ] q -C(O)SR y , and
• R 11 attached to -O- is independently selected from the group consisting of optionally substituted aryl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R Z ) 2 OC(O)NR Z 2 ,
• R 11 attached to -NR V - is independently selected from the group consisting of -H, -[C(R z ) 2 ] q -C00R y , -C(R x ) 2 C00R y , -[C(R z ) 2 ] q -C(O)SR y , and -cycloalkylene-COOR y ; or when Y' and Y" are independently selected from -O- and -NR V
• Z" is -P(O)Y 1 R 11 Y 11 R 11 .
• Z" is selected from the group consisting of-P(O)[-OCR z 2 OC(O)R y ] 2 , -P(O)[-OCR z 2 OC(O)OR y ] 2 , -P(O)[-N(H)CR z 2 C(O)OR y ] 2 , -P(O)[-N(H)CR z 2 C(O)OR y ][-OR 11 ],
• Z" is selected from the group consisting of -P(O)[-OCR z 2 OC(O)R y ] 2 , -P(O)[-OCR z 2 OC(O)OR y ] 2 , -P(0)[-OCH 2 CH 2 SC(0)Me] 2 , -P(0)[-N(H)CR z 2 C(0)OR y ] 2 , and -P(O)[-N(H)CR z 2 C(O)OR y ][ -OR 11 ].
• Z" is selected from the group consisting of
• Z" is selected from the group consisting of -P(O)[-OCR z 2 OC(O)R y ] 2 , -P(O)[-OCR z 2 OC(O)OR y ] 2 , -P(O)[-N(H)CR z 2 C(O)OR y ] 2 , -P(O)[-N(H)CR z 2 C(O)OR y ][-OR ⁇ ], -P(O)(OH)( OR 11 ), -P(O)(OR e )(OR e ), -P(O)[-OCR z 2 OC(O)R y ](OR e ), -P(O)[-OCR Z 2 OC(O) OR y ](OR e ), and -P(O)[-N(H)CR z 2 C(O)OR y ](OR e ), and -P(O)[-N(
• Z" is selected from the group consisting of -P(O)[-OCR z 2 OC(O)R y ] 2 , -P(O)[-OCR z 2 OC(O)OR y ] 2 , -P(O)[-N(H)CR z 2 C(O)OR y ] 2 , -P(O)[-N(H)CR z 2 C(O)OR y ][-OR ⁇ ], -P(O)(OH)(OR 6 ), -P(O)(OR e )(OR e ), -P(O)[-OCR z 2 OC(O)R y ](OR e ), -P(0)[-0 CR z 2 OC(O)OR y ](OR e ), -P(O)[-N(H)CR z 2 C(O)OR y ](OR e ), and
• Z" is selected from the group consisting of -P(O)[-OCH 2 OC(O)-t-butyl] 2 , -P(0)[-OCH 2 OC(0)0-/-propyl] 2 , -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ] 2 ,
• Z" is selected from the group consisting of -P(O)[-OCH 2 OC(O)-t-butyl] 2 , -P(O)[-OCH 2 OC(O)O-z-propyl] 2 , -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ] 2 , -P(O)[-N(H)C(CH 3 ) 2 C(O)OCH 2 CH 3 ] 2 ,
• Z" is selected from the group consisting of -P(O)[-OCH 2 OC(OH-butyl] 2 and -P(O)[-OCH 2 OC(O)-?-propyl] 2 .
• Z" is selected from the group consisting of-P(O)[-OCH 2 OC(O)-t-butyl] 2 , -P(O)[-OCH 2 OC(O)O-?-propyl] 2 , -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ] 2 ,
• Z" is selected from the group consisting of -P(O)[-OCH 2 OC(O)O-ethyl] 2 and -P(O)[-OCH 2 OC(O)O-z-propyl] 2.
• Z" is selected from the group consisting of -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ] 2 and
• Z" is -P(OX-OCH 2 CH 2 SC(O)Me] 2 .
• Z" is selected from the group consisting of -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ]
• Z" is selected from the group consisting of -P(O)[-OCR z 2 OC(O)R y ] 2 , -P(O)[-OCR z 2 OC(O)OR y ] 2 , -P(O)[-N(H)CR z 2 C(O)OR y ] 2 , -P(O)[-N(H)CR z 2 C(O)OR y ][-OR n ] and -P(O)[-OCH(V)CH 2 CH 2 O-].
• Z" is selected from the group consisting of -P(O)[-OCH 2 OC(O)-t-butyl] 2 , -P(O)[-OCH 2 OC(O)O-z-propyl] 2 , -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ] 2 ,
• compounds of Formula II above include compounds with the following structure:
• keto-enol tautomers may also exist as tautomers such as keto-enol tautomers and imine-enamine tautomers.
• the individual tautomers as well as mixtures thereof are encompassed with compounds of Formulae I- VIII.
• An example of keto-enol tautomers which are intended to be encompassed within the compounds of the present invention is illustrated below:
• a further aspect of this invention includes compounds of Formula XVI and isomers, solvates, hydrates, prodrugs, or pharmaceutically acceptable salts thereof:
• V is selected from the group consisting of optionally substituted monocyclic aryl and optionally substituted monocyclic heteroaryl;
• V and the 5' oxymethylene group of the ribose sugar moiety are cis to one another.
• this invention includes a compound of Formula
• V is selected from the group consisting of optionally substituted monocyclic aryl and optionally substituted monocyclic heteroaryl;
• compounds of Formula XVI are those in which V is selected from the group consisting of phenyl; substituted phenyl with 1-3 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, -CF 3 , -OR 3 , -OR 12 , -COR 3 , -CO 2 R 3 , -N(R 3 ) 2 , -N(R 12 ) 2 , -CO 2 N(R 2 ) 2 , -SR 3 , -SO 2 R 3 , -SO 2 N(R 2 ) 2 and -CN; monocyclic heteroaryl; and substituted monocyclic heteroaryl with 1-2 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, -CF 3 , -OR 3 , -OR 12 , -COR 3 ,
• V of Formula XVI is selected from the group consisting of phenyl; substituted phenyl with 1-3 substituents independently selected from the group consisting of -Cl, -Br, -F, C 1-3 alkyl, -CF 3 , -COCH 3 , -OMe, -NMe 2 , -OEt, -CCt ⁇ -butyl, -CO 2 NH 2 , -SMe, -SO 2 Me, -SO 2 NH 2 and -CN; monocyclic heteroaryl; and substituted monocyclic heteroaryl with 1-2 substituents independently selected from the group consisting of -Cl, -Br, -F, C 1-3 alkyl, -CF 3 , -COCH 3 , -OMe, -NMe 2 , -OEt, -CCt ⁇ -butyl, -CO 2 NH 2 , -SMe, -SO 2 Me, -SO 2
• V of Formula XVI is selected from the group consisting of phenyl; substituted phenyl with 1-2 substituents independently selected from the group consisting of -Cl, -Br, -F, C 1 -C 3 alkyl, and -CF 3 ; pyridyl; substituted pyridyl with 1 substituent independently selected from the group consisting of -Cl, -Br, -F, C 1 -C 3 alkyl, and -CF 3 ; furanyl; substituted furanyl with 1 substituent independently selected from the group consisting of -Cl, -Br, -F, C 1 -C 3 alkyl, and -CF 3 ; thienyl; and substituted thienyl with 1 substituent independently selected from the group consisting of -Cl, -Br, -F, C 1 -C 3 alkyl, and -CF 3 .
• V is selected from the group consisting of phenyl
• V is selected from the group consisting of 3-chlorophenyl, 3-bromophenyl, 2- bromophenyl, 3,5-dichlorophenyl, 3-pyridyl, and 4-pyridyl.
• V of Formula XVI is selected from the group consisting of phenyl; substituted phenyl with 1-3 substituents independently selected from the group consisting of -Cl, -Br, -F, C 1-3 alkyl, -CF 3 , -COCH 3 , -OMe, -NMe 2 , -OEt, -CCt ⁇ -butyl, -CO 2 NH 2 , -SMe, -SO 2 Me, -SO 2 NH 2 and -CN; monocyclic heteroaryl; and substituted monocyclic heteroaryl with 1-2 substituents independently selected from the group consisting of -Cl, -Br, -F, C 1 -C 3 alkyl, -CF 3 , -COCH 3 , -OMe, -NMe 2 , -OEt, -CCt ⁇ -butyl, -CO 2 NH 2 , -SMe, -SO 2 Me,
• V is selected from the group consisting of phenyl, 3-chlorophenyl, 3-bromophenyl, 2-bromophenyl, 3,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 2-pyridyl, 3-pyridyl, and 4- pyridyl.
• the compounds of this invention have R-stereochemistry at the V-attached carbon and have S- stereochemistry at the phosphorus center, hi other aspects, the compounds of this invention have S-stereochemistry at the V-attached carbon and have R- stereochemistry at the phosphoras center.
• M1 is a variable that represents nucleosides of Formulae IX- XIV which are attached via 5'-hydroxyl group that is phosphorylated with a group P(O)(O-CH(V)CH 2 CH 2 -O) to make compounds of Formula XV.
• V is an aryl or heteroaryl group that has 2 substituents, Ll and L2, at the designated positions. V may have additional substituents.
• Variable V Group V2
• Preferred groups of compounds are those listed in Table 1 using variables Ml and Vl and Ll and L2 listed in that order.
• "1.3.6.7” represents structure 1 of variable Ml (for example, where Y is O, R 19 is absent, R 15 -R 18 are each H, and B is 7-deaza-2'-methyl adenine, the 2', 3'- cyclic carbonate form of 7-deaza-2'-methyl adenosine); structure 3 of group Vl ⁇ i.e., 2-(Ll)-5-(L2) phenyl); structure 6 of variable Ll (i.e., trifluoromethyl); and structure 7 of variable L2 ⁇ i.e., methoxy).
• Preferred groups of compounds are also[those listed in Table 1 using variables Ml and V2 wherein the four digit number represents M1.V2.L1.L2.
• Preferred groups of compounds are also those listed in Table 1 using variables Ml and V3 wherein the four digit number represents M1.V3.L1.L2.
• the presence of the carbonate group leads to surprisingly enhanced properties of the compounds of the present invention when compared to the same compounds without a carbonate group at the same location.
• the compounds of the present invention have improved pharmacological properties including one or more of the following: enhanced absorption, increased chemical stability, increased metabolic stability, and increased liver distribution.
• the unexpected improvement in pharmacological properties involved one or more of the following: a) enhanced absorption through improvements in the physical properties of the nucleoside, including one of more of the following: increased lipophilicity, decreased solvation, increased solubility, and increased dissolution in biological fluids; b) decreased chemical instability that limits oral absorption or first pass liver exposure.
• the increased stability results from changes in the physical properties of the compound, including one or more of the following: i) decreased chemical instability in gastrointestinal tract through decreasing the susceptibility for glycosyl bond cleavage through changes in preferred conformation and or electronics in the vicinity of the glycosyl bond; ii) decreased hydrolysis in gastrointestinal tract through decreased water exposure as a result of increased lipophilicity; c) decreased metabolic instability that limits oral absorption or first pass liver exposure.
• Increased stability results from changes in the physical properties of the compound that result in the compound being less susceptible to enzymes that catalyze its metabolism.
• nucleoside and nucleotide degradation that can be affected by a 2',3'-cyclic carbonate include one or more of the following: i) decreased deamination by enzymes known to catalyze purine or pyrimidine base deamination. These enzymes limit absorption of certain nucleosides, especially nucleoside containing adenine- and cytidine-related analogues. Enzymes known to catalyze deamination include cytosine deaminase, adenosine deaminase and adenylate deaminase.
• One or more of the 2' and more often 3' hydroxyls of ribofuranosyl-containing nucleosides and nucleotides interact with protein residues (cytidine deaminase, Marquez 1984), (adenosine deaminase, Sharff, 1992). Cyclic carbonates remove both the 2' and 3' hydroxyl which are known to aid in catalytic efficiency.
• the improved properties of the carbonate compounds of the present invention make them particularly useful for the sustained delivery of nucleoside- and nucleotide-containing compounds.
• Standard prodrugs such as acylated analogues of nucleosides undergo rapid hydrolysis in vivo resulting in the rapid production of the nucleoside.
• Compounds that cleave more slowly are useful for sustained delivery of the active drug (nucleoside or phosphorylated metabolites of the nucleoside).
• the improved properties of the carbonate compounds of the present invention also make them particularly useful for the liver-delivery of nucleoside- and nucleotide- containing compounds.
• Activation of the prodrug in the liver can result in increased drug levels in the liver and improved efficacy, decreased drag levels outside of the liver and therefore improved safety, or both.
• Prodrugs that are efficiently activated by enzymes widely distributed throughout the body often result in wide drug distribution and in the case of nucleosides in a variety of toxicities, including for example neuropathies, myelosuppression, gastrointestinal toxicity, renal toxicity and cardiovascular toxicity.
• the improved properties of the carbonate compounds of the present invention make them particularly useful for the treatment of chronic liver diseases, including viral hepatitis, primary liver cancer, cancers that metastasize to the liver, liver fibrosis, and metabolic diseases that involve pathways in the liver that are sensitive to nucleosides and phosphorylated metabolites of nucleosides, including diabetes, hyperlipidemia, obesity and non-alcoholic steatohepatitis.
• chronic liver diseases including viral hepatitis, primary liver cancer, cancers that metastasize to the liver, liver fibrosis, and metabolic diseases that involve pathways in the liver that are sensitive to nucleosides and phosphorylated metabolites of nucleosides, including diabetes, hyperlipidemia, obesity and non-alcoholic steatohepatitis.
• the compounds of the present invention are also useful for the treatment of nucleoside and nucleotide responsive diseases including the treatment of liver diseases responsive to nucleotides which include hepatitis B, hepatitis C, and other viruses that result in viral hepatitis, primary liver cancer, secondary liver cancer.
• the compounds of the present invention are also useful for the treatment of diseases outside of the liver but responsive to nucleotide analogues, including viral infections, and cancer.
• the compounds of the present invention are also useful for the treatment of diseases outside the liver that are responsive to nucleotides and nucleoside analogues which include respiratory syncytial virus (RSV), herpes simplex type 1 and 2, herpes genitalis, herpes keratitis, herpes encephalitis, herpes zoster, human immunodeficiency virus (HIV), influenza A virus, hantann virus (hemorrhagic fever), human papilloma virus (HPV), measles, fungal infections, protozoan infections, antiplatelet therapy (P2 receptor antagonists), diabetes (e.g., compounds that bind to the adenosine receptor, P2 receptor ligands, AMP- activated protein kinase (“AMPK”) activators, cardiovascular disease (e.g., with adenosine based compounds that are agonists or antagonists for the adenosine receptor), immunostimulants (e.g., inos
• NMP nucleoside monophosphate
• NTP biologically active nucleoside triphosphate
• Drug elimination from the hepatocyte typically entails degradation of phosphorylated metabolites back to a species capable of being transported out of the hepatocyte and into the blood for elimination by the kidney or into the bile for biliary excretion.
• the phosphorylated metabolites are dephosphorylated to the uncharged nucleoside.
• nucleosides that leak back into the systemic circulation result in systemic exposure. If the nucleoside is active systemically, e.g. through entry into virally infected cells and phosphorylation to the active species, escape of the nucleoside from the liver leads to biological activity outside of the liver (i.e. extrahepatic tissues, blood cells).
• prodrugs of the invention can be effective for treating diseases outside of the liver, e.g. viral infections. Since many nucleosides exhibit poor oral bioavailability due to breakdown in the gastrointestinal tract either enzymatically (e.g. deamination by adenosine deaminase) or chemically (e.g. acid instability), the prodrug can be used for oral drug delivery.
• the prodrugs in some cases are broken down slowly relative to e.g. most ester based prodrugs, the prodrugs could advantageously result in slow, sustained systemic release of the nucleoside.
• systemic exposure to the nucleoside can result in toxicity. This can be minimized by selecting nucleosides that are preferentially excreted through the bile or nucleosides that are unable to undergo phosphorylation in tissues or nucleosides that undergo rapid intrahepatic metabolism to a biologically inactive metabolite.
• Some enzymes in the hepatocyte are present that can degrade nucleosides and therefore minimize exposure (e.g. Phase I and Phase II enzymes).
• adenosine deaminase which can deaminate some adenosine-based nucleosides to produce the corresponding inosine analogue. Rapid intracellular deamination of the nucleoside following its dephosphorylation to the nucleoside limits systemic exposure to the nucleoside and diminishes the risk of toxicity.
• Liver specificity of the prodrugs relative to the nucleosides is measured by methods in Example G.
• Tissue distribution can be determined according to methods in
• Example H Oral bioavailability is determined by methods described in Example I. The susceptibility of nucleoside analogs to metabolism can be determined as in Example J.
• the RNA-dependent RNA viral infection is a positive-sense single-stranded RNA-dependent viral infection.
• the positive-sense single-stranded RNA-dependent RNA viral infection is Flaviviridae viral infection or Picornaviridae viral infection.
• the Picornaviridae viral infection is rhinovirus infection, poliovirus infection, or hepatitis A virus infection.
• the Flaviviridae viral infection is selected from the group consisting of hepatitis C virus infection, yellow fever virus infection, dengue virus infection, West Nile virus infection, Japanese encephalitis virus infection, Banzi virus infection, and bovine viral diarrhea virus infection.
• the Flaviviridae viral infections hepatitis C virus infection.
• compounds of the present invention can be used to enhance the oral bioavailability of the parent drug, hi some aspects, compounds of the present invention can be used to enhance the oral bioavailability of the parent drug by at least 5%. hi other aspects, compounds of the present invention can be used to enhance the oral bioavailability of the parent drug by at least 10%. In yet other aspects, oral bioavailability is enhanced by 50% compared to the parent drug administered orally, hi further aspects, the oral bioavailability is enhanced by at least 100%.
• compounds of the present invention can be used to increase the therapeutic index of a drug.
• compounds of the present invention can be used to bypass drug resistance.
• compounds of the present invention can be used to treat cancer.
• the present invention provides methods for inhibiting viral replication comprising the step of administering to a patient a therapeutically effective amount of a compound of the present invention, or a solvate, hydrate, prodrug, or pharmaceutically acceptable salt thereof.
• the present invention also provides methods for inhibiting RNA- dependent RNA viral replication comprising the step of administering to a patient a therapeutically effective amount of a compound of the present invention, or a solvate, hydrate, prodrug, or pharmaceutically acceptable salt thereof.
• the present invention further provides methods for inhibiting HCV replication comprising the step of administering to a patient a therapeutically effective amount of a compound of the present invention, or a solvate, hydrate, prodrug, or pharmaceutically acceptable salt thereof.
• the present invention also provides methods for treating viral infections comprising the step of administering to a patient a therapeutically effective amount of a compound of the present invention, or a solvate, hydrate, prodrug, or pharmaceutically acceptable salt thereof.
• the present invention also provides methods for treating viral infections of the liver comprising the step of administering to a patient a therapeutically effective amount of a compound of the present invention, or a solvate, hydrate, prodrug, or pharmaceutically acceptable salt thereof.
• the present invention also provides methods for treating RNA- dependent RNA viral infection comprising the step of administering to a patient a therapeutically effective amount of a compound of the present invention, or a solvate, hydrate, prodrug, or pharmaceutically acceptable salt thereof.
• the present invention also provides methods for treating hepatitis B virus (HBV) or hepatitis C virus (HCV) infection comprising the step of administering to a patient a therapeutically effective amount of a compound of the present invention, or a solvate, hydrate, prodrug, or pharmaceutically acceptable salt thereof.
• HBV hepatitis B virus
• HCV hepatitis C virus
• the present invention also provides methods for treating chronic liver diseases, including viral hepatitis, primary liver cancer, cancers that metastasize to the liver, liver fibrosis, and metabolic diseases that involve pathways in the liver that are sensitive to nucleosides and phosphorylated metabolites of nucleosides, including diabetes, hyperlipidemia, obesity and non-alcoholic steatohepatitis comprising the step of administering to a patient a therapeutically effective amount of a compound of the present invention, or a solvate, hydrate, prodrug, or pharmaceutically acceptable salt thereof.
• the present invention also provides methods for treating a platelet disorder or diabetes comprising the step of administering to a patient a therapeutically effective amount of a compound of the present invention that is a P2 receptor antagonist, or a solvate, hydrate, prodrug, or pharmaceutically acceptable salt thereof.
• the present invention also provides methods for treating diabetes comprising the step of administering to a patient a therapeutically effective amount of a compound of the present invention that is an AMPK activator, or a solvate, hydrate, prodrug, or pharmaceutically acceptable salt thereof.
• the present invention also provides methods for treating diabetes or cardiovascular disease comprising the step of administering to a patient a therapeutically effective amount of a compound of the present invention that binds an adenosine receptor, or a solvate, hydrate, prodrug, or pharmaceutically acceptable salt thereof.
• the present invention also provides methods for treating an immunodeficiency disease comprising the step of administering to a patient a therapeutically effective amount of a compound of the present invention that acts as an immunostimulant inhibiting EVIPDH, or a solvate, hydrate, prodrug, or pharmaceutically acceptable salt thereof.
• the present invention also provides methods for treating inflammation or a CNS disorder comprising the step of administering to a patient a therapeutically effective amount of a compound of the present invention that acts as an adenosine analogue, or a solvate, hydrate, prodrug, or pharmaceutically acceptable salt thereof.
• the compounds of the present invention are administered in a total daily dose of 0.01 to 1000 mg/kg. In some aspects of the invention, the range is about 0.1 mg/kg to about 100 mg/kg. In other aspects, the range is 0.5 to 20 mg/kg. The dose may be administered in as many divided doses as is convenient.
• Compounds of this invention when used in combination with other antiviral agents may be administered as a daily dose or an appropriate fraction of the daily dose (e.g., bid). Administration of the prodrug compound may occur at or near the time in which the other antiviral is administered or at a different time.
• the compounds of this invention may be used in a multidrug regimen, also known as combination or 'cocktail' therapy, wherein, multiple agents may be administered together, may be administered separately at the same time or at different intervals, or administered sequentially.
• the compounds of this invention may be administered after a course of treatment by another agent, during a course of therapy with another agent, administered as part of a therapeutic regimen, or can be administered prior to therapy by another agent in a treatment program.
• the compounds may be administered by a variety of means including orally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles.
• parenteral as used here includes subcutaneous, intravenous, intramuscular, and intra-arterial injections with a variety of infusion techniques.
• Intra-arterial and intravenous injection as used herein includes administration through catheters. Intravenous administration is generally preferred.
• Pharmaceutically acceptable salts include acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, methylbromide, methylsulfate, napsylate, nitrate, oleate, palmoate, phosphate, polygalacturonate, stearate, succinate, sulfate, subsalicylate, tannate, tartrate, terphthalate, tosylate, and triethiodide.
• compositions containing the active ingredient may be in any form suitable for the intended method of administration.
• tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
• Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
• Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets are acceptable.
• excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or can be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
• inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate
• granulating and disintegrating agents such as maize starch, or alginic acid
• binding agents such as starch, ge
• Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
• an inert solid diluent for example calcium phosphate or kaolin
• an oil medium such as peanut oil, liquid paraffin or olive oil.
• Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
• excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan
• the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
• Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachid oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
• the oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
• Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
• These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
• Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives.
• a dispersing or wetting agent and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
• the pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions.
• the oily phase may be a vegetable oil, such as olive oil or arachid oil, a mineral oil, such as liquid paraffin, or a mixture of these.
• Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
• the emulsion can also contain sweetening and flavoring agents.
• Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
• sweetening agents such as glycerol, sorbitol or sucrose.
• Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
• compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
• a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
• This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
• a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
• acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
• sterile fixed oils may conventionally be employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid may likewise be used in the preparation ofinjectables.
• the amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
• a time-release formulation intended for oral administration to humans may contain 20 to 2000 ⁇ mol (approximately 10 to 1000 mg) of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions. It is preferred that the pharmaceutical composition be prepared which provides easily measurable amounts for administration.
• an aqueous solution intended for intravenous infusion should contain from about 0.05 to about 50 ⁇ mol (approximately 0.025 to 25 mg) of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/h can occur.
• formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non ⁇ aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
• the active ingredient may also be administered as a bolus, electuary or paste.
• a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface active or dispersing agent.
• Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
• the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach. This is particularly advantageous with the compounds of Formula I when such compounds are susceptible to acid hydrolysis.
• Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
• Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
• Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
• Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non ⁇ aqueous sterile suspensions which may include suspending agents and thickening agents.
• the formulations may be presented in unit-dose or multi- dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
• Injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
• Formulations suitable for parenteral administration may be administered in a continuous infusion manner via an indwelling pump or via a hospital bag. Continuous infusion includes the infusion by an external pump. The infusions may be done through a Hickman or PICC or any other suitable means of administering a formulation either parenterally or i.v.
• Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, of a drug.
• Another aspect of the present invention is concerned with a method of inhibiting HCV replication or treating HCV infection with a compound of the present invention in combination with one or more agents useful for treating HCV infection.
• agents active against HCV include, but are not limited to, ribavirin, levovirin, viramidine, thymosin alpha- 1, interferon- ⁇ , interferon- ⁇ , pegylated interferon- ⁇ (peginterferon- ⁇ ), a combination of interferon- ⁇ and ribavirin, a combination of peginterferon- ⁇ and ribavirin, a combination of interferon- ⁇ and levovirin, and a combination of peginterferon- ⁇ and levovirin.
• Interferon- ⁇ includes, but is not limited to, recombinant interferon- ⁇ 2a (such as Roferon interferon available from Hoffmann-LaRoche, Nutley, NJ), pegylated interferon- ⁇ 2a (PegasysTM), interferon- ⁇ 2b (such as Intron-A interferon available from Schering Corp., Kenilworth, NJ), pegylated interferon- ⁇ 2b (PeglntronTM), a recombinant consensus interferon (such as interferon alphacon-1), and a purified interferon- ⁇ product.
• Amgen's recombinant consensus interferon has the brand name Infergen®.
• Levovirin is the L-enantiomer of ribavirin which has shown immunomodulatory activity similar to ribavirin.
• Viramidine is a liver-targeting prodrug analog of ribavirin disclosed in International Publ. No. WO 01/60379 (assigned to ICN Pharmaceuticals).
• the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment, and the term "administering" is to be interpreted accordingly.
• composition comprising a compound of Formula I, solvate, hydrate, prodrug or pharmaceutically acceptable salt thereof, and at least one agent useful for treating a viral infection, particularly an HCV infection.
• the compounds of the present invention may also be administered in combination with an agent that is an inhibitor of HCV NS3 serine protease.
• HCV NS3 serine protease is an essential viral enzyme and has been described to be an excellent target for inhibition of HCV replication. Both substrate and non-substrate based inhibitors of HCV NS3 protease inhibitors are disclosed in International Publ. Nos.
• NS3 protease inhibitors for combination with the compounds of the present invention are BILN 2061 (Boehringer Ingelheim) and VX-950/LY-570310.
• HCV NS3 protease as a target for the development of inhibitors of HCV replication and for the treatment of HCV infection is discussed in Dymock, B.W., "Emerging therapies for hepatitis C virus infection,” Emerging Drugs (5:13-42 (2001).
• Ribavirin, levovirin, and viramidine may exert their anti-HCV effects by modulating intracellular pools of guanine nucleotides via inhibition of the intracellular enzyme inosine monophosphate dehydrogenase (“EVfPDH").
• IMPDH is the rate-limiting enzyme on the biosynthetic route in de novo guanine nucleotide biosynthesis.
• Ribavirin is readily phosphorylated intracellularly and the monophosphate derivative is an inhibitor of EVIPDH.
• inhibition of IMPDH represents another useful target for the discovery of inhibitors of HCV replication. Therefore, the compounds of the present invention may also be administered in combination with an inhibitor of IMPDH, such as VX-497 (merimepodib), which is disclosed in International Publ. Nos. WO 97/41211 and WO 01/00622 (assigned to Vertex); another IMPDH inhibitor, such as that disclosed in International Publ. No. WO 00/25780 (assigned to Bristol-Myers Squibb); or mycophenolate mofetil (see Allison, A.C. and Eugui, E.M., Agents Action 44 (Suppl.):l65 (1993)).
• the compounds of the present invention may also be administered in combination with the antiviral agent amantadine (1-aminoadamantane) and its hydrochloride salt (for a comprehensive description of this agent, see Kirschbaum, J., Anal. Profiles Drug Subs. 72:1-36 (1983)).
• the compounds of the present invention may also be combined for the treatment of HCV infection with antiviral l'-C, 2'-C-, or 3'-C-branched ribonucleosides disclosed in R. E. Harry-O'kuru, et al., J. Org. Chem. 62:1754- 1759 (1997); M. S. Wolfe, et al., Tetrahedron Lett. 36:7611-7614 (1995); U.S. Patent No. 3,480,613 (Nov. 25, 1969); International Publ. No. WO 01/90121 (29 November 2001); International Publ. No. WO 01/92282 (6 December 2001); and International Publ. No.
• branched ribonucleosides include, but are not limited to, 2'-C-methylcytidine, 2'-C-methyluridine, 2'-C-methyladenosine, 2'-C-methylguanosine, and 9-(2-C- methyl- ⁇ -D-ribofuranosyl)-2,6-diaminopurine, and prodrugs thereof.
• the compounds of the present invention may also be combined for the treatment of HCV infection with other nucleosides having anti-HCV properties, such as those disclosed in International Publ. No. WO 02/51425 (4 July 2002), assigned to Mitsubishi Pharma Corp.; International Publ. Nos.WO 01/79246, WO 02/32920 (25 April 2002), and WO 02/48165 (20 June 2002), assigned to Pharmasset, Ltd.; International Publ. No. WO 01/68663 (20 September 2001), assigned to ICN Pharmaceuticals; International Publ. No. WO 99/43691 (2 Sept. 1999); International Publ. No. WO 02/18404 (7 March 2002), assigned to Hoffmann-LaRoche; U.S. 2002/0019363 (14 Feb. 2002); International Publ. No.
• WO 02/057287 25 July 2002
• International Publ. No. WO 02/057425 25 July 2002
• the compounds of the present invention may also be combined for the treatment of HCV infection with non-nucleoside inhibitors of HCV polymerase such as those disclosed in International Publ. No. WO 01/77091 (18 Oct. 2001), assigned to Tularik, hie; International Publ. No. WO 01/47883 (5 July 2001), assigned to Japan Tobacco, Inc.; International Publ. No. WO 02/04425 (17 January 2002), assigned to Boehringer Ingelheim; International Publ. No.
• WO 02/06246 (24 Jan. 2002), assigned to Istituto di Ricerche di Biologia Moleculare P. Angeletti S.P.A.; and International Publ. No. WO 02/20497 (3 March 2002).
• International Publ. No. WO 01/47883 discloses a large number of benzimidazole derivatives, such as JTK-003, which is claimed to be an orally active inhibitor of NS5B that is currently undergoing clinical evaluation.
• Synthesis of 2',3 '-carbonate of nucleoside derivatives of formula I may be organized into two following sections: (i) synthesis of 2',3 '-carbonate of nucleoside analogs; and (ii) synthesis of 2',3 '-carbonate of nucleotide analogs.
• Synthesis of 2',3 '-carbonate of nucleoside analogs may be achieved by a variety of known methods (Greene T.W., Protective Groups in Organic Chemistry, John Wiley & Sons, New York (1999)). Following are two general routes wherein path A is an approach via carbonylation of 2',3 '-vicinal diols of 5 '-hydroxy protected nucleosides and path B is an approach wherein direct carbonylation is attained on unprotected nucleosides.
• Synthesis via path A includes carbonylation of nucleosides with masked 5'-hydroxy group. Protection of the 5'-hydroxy group may be attained by acid labile functionality such as silyl or trityl groups. These nucleoside derivatives containing a protected 5 '-hydroxy then undergo carbonylation via a range of reagents, such as N,N'-carbonyl diimidazole (Kutney et al, Synth. Commun. 5:47 (1975)) or p-nitrophenyl chloroformate (Cook et al, J. Org. Chem. 53:3589 (1968)) under mild conditions. Such methods are applicable to a variety of nucleosides with diverse sugar as well as base substitutions.
• the final step of the sequence (path A) involves removal of the 5 '-protective group under mildly acidic or neutral reaction conditions.
• 2',3'-Carbonate containing nucleotide analogs may be prepared via two different protocols. These compounds can be made starting from 2',3'- carbonate derivative of nucleosides as shown via path A or from path B from phosphorylated nucleoside analogs. As in path A, 2',3 '-carbonate derivative of nucleosides can be phosphorylated to give nucleoside monophosphate (NMP) prodrugs via phosphorylation utilizing P(III) or P(V) intermediates (Mackman et al, Ann. Rep. Med. Chem. 39:305 (2004)). Alternatively, such prodrugs may be prepared via carbonylation as shown in path B following conditions described in the earlier section.
• NMP nucleoside monophosphate
• prodrugs may be prepared via carbonylation as shown in path B following conditions described in the earlier section.
• thionocarbonate formation can be achieved by treatment of vicinal diols of nucleoside derivatives by 1,1 '- thiocarbonyldiimidazole (Yu et al, Org. Lett. 4: ⁇ 9 ⁇ 9 (2002)) or by 1,1 '- thiocarbonyldi-2(lH)- ⁇ yridone (Kim et al, J. Org. Chem. 51:2615 (1986)).
• V, W, Z groups of Z" of Formula II i.e., V, W, and Z groups of Formula II
• V, W, and Z groups of Formula II can be introduced or modified either during synthesis of diols or after the synthesis of prodrugs.
• 1,3-Dihydroxy compounds can be synthesized by several well-known methods from the literature. Substituted aromatic aldehydes are utilized to synthesize racemic l-(aryl)propane-l,3-diols via addition of lithium enolate of alkyl acetate followed by ester reduction (path A) (Turner, J. Org. Chem. 55:4744 (1990)). Alternatively, aryl lithium or aryl Grignard additions to I- hydroxy propan-3-al also give l-(arylsubstituted)propane-l,3-diols (path B).
• This method will enable conversion of various substituted aryl halides to 1- (arylsubstituted)-l,3-propane diols (Coppi, et al, J. Org. Chem. 53:911 (1988)).
• Aryl halides can also be used to synthesize 1-substituted propane diols by Heck coupling of l,3-diox-4-ene followed by reduction and hydrolysis (Sakamoto, et al, Tetrahedron Lett. 55:6845 (1992)).
• Pyridyl-, quinolyl-, isoquinolyl- propan-3-ol derivatives can be hydroxylated to 1- substituted-l,3-diols by N-oxide formation followed by rearrangement in the presence of acetic anhydride (path C) (Yamamoto, et al, Tetrahedron 37:1871 (1981)).
• path C acetic anhydride
• a variety of aromatic aldehydes can also be converted to 1- substituted-l,3-diols by vinyl lithium or vinyl Grignard addition followed by hydroboration reaction (path D).
• V Aryl
• R Alkyl
• R 1 benzyl
• M Mg or Li
• X Halide or null
• the ⁇ -keto acid or ester substrates for high pressure hydrogenation or hydrogen transfer reactions may be prepared by a variety of methods such as condensation of acetophenone with dimethylcarbonate in the presence of a base (Chu, et al, J. Het Chem. 22:1033 (1985)), by ester condensation (Turner, et al, J. Org. Chem. 54:4229 (1989)) or from aryl halides (Kobayashi, et al, Tetrahedron Lett. 27:4745 (1986)).
• 1,3-diols of high enantiomeric purity can be obtained by enantioselective borane reduction of ⁇ -hydroxyethyl aryl ketone derivatives or ⁇ -keto acid derivatives (path B) (Ramachandran, et al, Tetrahedron Lett. 38:761 (1997)).
• path B ⁇ -hydroxyethyl aryl ketone derivatives or ⁇ -keto acid derivatives
• commercially available cinnamyl alcohols may be converted to epoxy alcohols under catalytic asymmetric epoxidation conditions. These epoxy alcohols are reduced by Red- Al to result in 1,3-diols with high ee's (path C) (Gao, et al, J. Org. Chem. 53:4081 (1980)).
• Enantioselective aldol condensation is another well-described method for synthesis of 1,3 -oxygenated functionality with high ee's starting from aromatic aldehydes, (path D) (Mukaiyama, Org. React. 28:203 (1982)).
• Nitrotriol is also known to give triol by reductive elimination (path b) (Latour, et. al, Synthesis 8:742 (1987)).
• the triol can be derivatized by mono acylation or carbonate formation by treatment with alkanoyl chloride, or alkylchloroformate (path d) (Greene and Wuts, Protective groups in organic synthesis , John Wiley, New York (1990)).
• Aryl substitution can be affected by oxidation to aldehyde and aryl Grignard additions (path c).
• Aldehydes can also be converted to substituted amines by reductive animation reaction (path e).
• Compounds of Formula II where V-Z or V-W are fused by four carbons are made from cyclohexane diol derivatives.
• Commercially available cis can be used as is or modified as described in case of 2-substituted propan-l,3-diols to give various analogues. These modifications can either be made before or after ester formation.
• Various 1,3- cyclohexane-diols can be made by Diels-Alder methodology using pyrone as diene (Posner, et. al, Tetrahedron Lett. 32:5295 (1991)).
• Cyclohexanediol derivatives are also made by nitrile oxide-olefm additions (Curran, et. al., J. Am. Chem. Soc. 107:6023 (1985)).
• cyclohexyl precursors are also made from commercially available quinic acid (Rao, et. al., Tetrahedron Lett. 32:541 (1991).)
• 1,3-Diols described in the earlier section can be converted selectively to either hydroxy amines or to corresponding diamines by converting hydroxy functionality to a leaving group and treating with anhydrous ammonia or required primary or secondary amines (Corey, et al., Tetrahedron Lett., 1989, 30, 5207: Gao, et al, J. Org. Chem. 53:4081 (1988)).
• a similar transformation may also be achieved directly from alcohols under Mitsunobu type of reaction conditions (Hughes, D. L., Org. React. 42 (1992)).
• a general synthetic procedure for 3-aryl-3-hydroxy-propan-l-amine type of prodrug moiety involves aldol type condensation of aryl esters with alkyl nitrites followed by reduction of resulting substituted benzoylacetonitrile (Shih et al., Heterocycles 24:1599 (1986)).
• the procedure can also be adapted for formation of 2-substituted aminopropanols by using substituted alkylnitrile.
• 3-aryl-3-amino-propan-l-ol type of prodrug groups are synthesized from aryl aldehydes by condensation of malonic acid in presence of ammonium acetate followed by reduction of resulting substituted ⁇ -amino acids. Both these methods enable to introduce wide variety of substitution of aryl group (Shih, et al., Heterocycles. P: 1277 (1978)).
• ⁇ -substituted organo lithium compounds of 1 -amino- 1 -aryl ethyl dianion generated from styrene type of compounds undergo addition with carbonyl compounds to give variety of W, W substitution by variation of the carbonyl compounds (Barluenga, et al., J.Org. Chem. 4 ⁇ 79S (1979)).
• Substituted 1,3-diamines are synthesized starting from a variety of substrates.
• Arylglutaronitriles can be transformed to 1 -substituted diamines by hydrolysis to amide and Hofmann rearrangement conditions (Bertochio, et al., Bull. Soc. Chim. Fr. 1809 (1962)).
• malononitrile substitution will enable variety of Z substitution by electrophile introduction followed by hydride reduction to corresponding diamines.
• cinnamaldehydes react with hydrazines or substituted hydrazines to give corresponding pyrazolines which upon catalytic hydrogenation result in substituted 1,3-diamines (Weinhardt, et al, J. Med. Chem. 28:694 (1985)).
• High trans-diastereoselectivity of 1,3-substitution is also attainable by aryl Grignard addition on to pyrazolines followed by reduction (Alexakis, et al, J. Org. Chem. 576:4563 (1992)).
• l-Aryl-l,3-diaminopropanes are also prepared by diborane reduction of 3-amino-3-arylacrylonitriles which in turn are made from nitrile substituted aromatic compounds (Dornow, et al, Chem Ber. 82:254 (1949)). Reduction of 1,3-diimines obtained from corresponding 1,3- carbonyl compounds are another source of 1,3-diamine prodrug moiety which allows a wide variety of activating groups V and/or Z (Barluenga, et al, J. Org. Chem. 48:2255 (1983)).
• Enantiomerically pure 3 -aryl-3-hydroxypropan-l -amines are synthesized by CBS enantioselective catalytic reaction of ⁇ - chloropropiophenone followed by displacement of halo group to make secondary or primary amines as required (Corey, et al, Tetrahedron Lett. 30:5207 (1989)).
• Chiral 3-aryl-3-amino propan-1-ol type of prodrug moiety may be obtained by 1,3-dipolar addition of chirally pure olefin and substituted nitrone of arylaldehyde followed by reduction of resulting isoxazolidine (Koizumi, et al, J. Org. Chem.
• Diastereoselective formation of 1,3- aminoalcohols is also achieved by reductive animation of optically pure 3- hydroxy ketones (Haddad et al, Tetrahedron Lett. 35:5981 (1997)).
• 3-aminoketones are transformed to 1,3-disubstituted aminoalcoliols in high stereoselectivity by a selective hydride reduction (Barluenga et al, J. Org. Chem. 57:1219 (1992)).
• Phosphorylation of 5'-alcohol is achieved using cyclic l',3'-propanyl esters of phosphorylating agents where the agent is in the P(III) oxidation state.
• Appropriately substituted phosphoramidites can be prepared by reacting cyclic chlorophospholanes with N,N-dialkylamine (Perich, et al, Aust. J. Chem. 43:1623 (1990); Perich, et al, Synthesis 2:142 (1988)) or by reaction of commercially available dialkylaminophosphorochloridate with substituted propane-l,3-diols. Synthesis of P(V) phosphorylation precursors:
• the activated precursor can be prepared by several well known methods.
• Chlorophosphates useful for synthesis of the prodrugs are prepared from the substituted- 1,3-propanediol (Wissner, et al, J. Med Chem. 35:1650 (1992)). Chlorophosphates are made by oxidation of the corresponding chlorophospholanes (Anderson, et al, J. Org. Chem.
• chlorophosphate agent is made by treating substituted-1,3- diols with phosphorus oxychloride (Patois, et al, J. Chem. Soc. Perkin Trans. /:1577 (1990)).
• Chlorophosphate species may also be generated in situ from corresponding cyclic phosphites (Silverburg, et ah, Tetrahedron Lett. 37:771 (1996)), which in turn can be either made from a chlorophospholane or phosphoramidate intermediate.
• Phosphorofluoridate intermediate prepared either from pyrophosphate or phosphoric acid may also act as precursor in preparation of cyclic prodrugs (Watanabe et al., Tetrahedron Lett. 29:5763 (1988)).

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