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US20090192121A1 - Novel bisamidate phosphonate prodrugs - Google Patents

Novel bisamidate phosphonate prodrugs Download PDF

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Publication number
US20090192121A1
US20090192121A1 US12/411,951 US41195109A US2009192121A1 US 20090192121 A1 US20090192121 A1 US 20090192121A1 US 41195109 A US41195109 A US 41195109A US 2009192121 A1 US2009192121 A1 US 2009192121A1
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alkyl
aryl
aralkyl
alicyclic
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Tao Jiang
Srinivas Rao Kasibhatla
K. Raja Reddy
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/44—Amides thereof
    • C07F9/4461—Amides thereof the amide moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4465—Amides thereof the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring

Definitions

  • the present invention is directed towards novel prodrugs, to their preparation, to their use for the oral delivery of Fructose-1,6-bisphosphatase inhibitors (FBPase), and to their use in the treatment of diabetes and other diseases where the inhibition of gluconeogenesis, control of blood glucose levels, reduction in glycogen storage, or reduction in insulin levels is beneficial.
  • FBPase Fructose-1,6-bisphosphatase inhibitors
  • acyloxyalkyl ester A large number of structurally-diverse prodrugs are described for phosphonic acids. Freeman and Ross in Progress in Medicinal Chemistry 34: 112-147 (1997).
  • the most commonly used prodrug class is the acyloxyalkyl ester, which was first used as a prodrug strategy for carboxylic acids and then applied to phosphates in 1983 by Farquhar et al. J. Pharm. Sci. 72: 324 (1983). Subsequently, the acyloxyalkyl ester was used to deliver phosphonic acids across cell membranes and to enhance oral bioavailability.
  • a close valiant of the acyloxyalkyl ester strategy, the alkoxycarbonyloxyalkyl ester is also reported to enhance oral bioavailability.
  • Aryl esters especially phenyl esters, are reported in a few cases to enhance oral bioavailability. DeLambert et al., J. Med. Chem. 37: 498 (1994). Phenyl esters containing a carboxylic ester ortho to the phosphate have also been described. Khamnei and Torrence, J. Med. Chem. 39:4109-4115 (1996). Benzyl esters are reported to generate the parent phosphonic acid. In some cases using substituents at the ortho- or para-position can accelerate the hydrolysis.
  • Benzyl analogs with an acylated phenol or an alkylated phenol can generate the phenolic compound through the action of enzymes, e.g. esterases, oxidases, etc., which in turn undergoes cleavage at the benzylic C—O bond to generate the phosphoric acid and the quinone methide intermediate.
  • enzymes e.g. esterases, oxidases, etc.
  • this class of prodrugs are described by Mitchell et al., J. Chem. Soc. Perklin Trans. I 2345 (1992); Brook, et al. WO 91/19721.
  • Still other benzylic prodrugs have been described containing a carboxylic ester-containing group attached to the benzylic methylene. Glazier et al. WO 91/19721.
  • Thio-containing prodrugs are reported to be useful for the intracellular delivery of phosphonate drugs.
  • These proesters contain an ethylthio group in which the thiol group is either esterified with an acyl group or combined with another thiol group to form a disulfide. Desterification or reduction of the disulfide generates the free thio intermediate which subsequently breaks down to the phosphoric acid and episulfide.
  • Cyclic phosphonate esters have also been described as prodrugs of phosphorus-containing compounds.
  • Some phosphoramidates are also known prodrugs of phosphonates, but they have shown poor oral bioavailability. In some cases the phosphoramindates were very unstable under acidic conditions which was reported as a potential explanation for their poor oral bioavailability ( J. Med. Chem., 37: 1857-1864 (1994)). Similarly, poor oral bioavailability was reported for a bisamidate of a PMEA analog ( J. Med, Chem., 38: 1372-1379 (1995)). Another PMEA prodrug consists of a mono glycine ester amidate and a phenyl ester (WO 95/07920).
  • prodrugs are unstable to the gastrointestinal tract environment (low pH, esterase activity). In other cases the prodrugs are too stable and are therefore poorly transformed in vivo to the parent drug.
  • WO 98/39344, WO 98/39343, WO 98/139342, and WO 00/14095 describe compounds containing phosphoric acids and esters that inhibit fructose-1,6-bisphosphatase.
  • the present invention is directed towards novel bisamidate phosphonates that are potent FBPase inhibitors. In one aspect these compounds possess superior oral bioavailability compared to the corresponding phosphonic acids. In another aspect, the present invention is directed to the in vitro and in vivo FBPase inhibitory activity of these compounds. Another aspect of the present invention is directed to the clinical use of these FBPase inhibitors as a method of treatment or prevention of diseases responsive to inhibition of gluconeogenesis and in diseases responsive to lowered blood glucose levels.
  • the compounds are also useful in treating or preventing excess glycogen storage diseases and diseases such as cardiovascular diseases including atherosclerosis, myocardial ischemic injury, and diseases such as metabolic disorders such as hypercholesterolemia, hyperlipidemia which are exacerbated by hyperinsulinema and hyperglycemia.
  • cardiovascular diseases including atherosclerosis, myocardial ischemic injury, and diseases such as metabolic disorders such as hypercholesterolemia, hyperlipidemia which are exacerbated by hyperinsulinema and hyperglycemia.
  • the invention also comprises the novel compounds and methods of using them as specified below in formulae I, X, and XI. Also included in the scope of the present invention are standard salts and prodrugs of the compounds of formulae I, X, and XI.
  • the present invention is directed not only to racemic mixtures of these compounds, but also to individual stereoisomers.
  • the present invention also includes pharmaceutically acceptable and/or useful salts of the compounds of formulae I, X, and XI, including acid addition salts.
  • the present inventions also encompass standard prodrugs of compounds of formulae I, X, and XI.
  • X, X′′, X 2 and X 3 group nomenclature as used herein in formulae I and XI describes the group attached to the phosphonate and ends with the group attached to the heteroaromatic ring.
  • X alkylamino
  • A, B, C, D, E, A, B, C′′, D′′, E′′, A 2 , L 2 , E 2 , J 2 , A 3 , L 3 , E, and J 3 groups and other substituents of the heteroaromatic ring are described in such a way that the term ends with the group attached to the heteroaromatic ring.
  • substituents are named such that the term ends with the group at the point of attachment.
  • a hyphen before or after a term indicates a point of attachment.
  • “-alkyl-” refers to divalent alkyl or alkylene.
  • 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. Suitable aryl groups include phenyl and furan-2,5-diyl.
  • Carbocyclic aryl groups are groups 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 having from 1 to 4 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include oxygen, sulfur, nitrogen, and selenium. Suitable heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, and the like, all optionally substituted.
  • annulation refers to the formation of an additional cyclic moiety onto an existing aryl or heteroaryl group. It is a form of optional substitution on an aryl or heteroaryl group.
  • the newly formed ring may be carbocyclic or heterocyclic, saturated or unsaturated, and contains 2-9 new atoms of which 0-3 may be heteroatoms taken from the group of N, O, and S.
  • the annulation may incorporate atoms from the X group as part of the newly formed ring.
  • the phrase “together L 2 and E 2 form an annulated cyclic group” includes
  • biasing represents aryl groups 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.
  • alicyclic means compounds which combine the properties of aliphatic and cyclic compounds. Such cyclic compounds include but are not limited to, aromatic, cycloalkyl and bridged cycloalkyl compounds.
  • the cyclic compound includes heterocycles. Cyclohexenylethyl and cyclohexylethyl are suitable alicyclic groups. Such groups may be optionally substituted.
  • optionally substituted or “substituted” includes groups substituted by one to four substituents, independently selected from lower alkyl, lower aryl, lower aralkyl, lower alicyclic, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, heteroaryl, heterocyclic alkyl, heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, amino, guanidino, amidino, halo, lower alkylthio, oxo, acylalkyl, carboxy esters, carboxyl, -carboxamido, nitro, acyloxy, aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl, arylamino, aralkylamino, phosphono, sulfonyl, -carboxamidoalkylaryl, -carboxamidoaryl
  • Substituted aryl and “substituted heteroaryl” refer to aryl and heteroaryl groups substituted with 1-2; 1-3; or 1-4 substituents.
  • suitable substituents of aryl groups include lower alkyl, lower alkoxy, lower perhaloalkyl, halo, hydroxy, and amino. “Substituted” when describing an R 5 group does not include annulation.
  • aralkyl refers to an alkyl group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl, and the like, and may be optionally substituted.
  • -aralkyl- refers to a divalent group -aryl-alkylene-.
  • Heteroarylalkyl refers to an alkylene group substituted with a heteroaryl group.
  • alkylaryl- refers to the group -alk-aryl- where “alk” is an alkylene group. “Lower -alkylaryl-” refers to such groups where alkylene is lower alkylene.
  • lower referred to herein in connection with organic radicals or compounds respectively defines such as with up to and including 10, or up to and including 6, or one to four carbon atoms.
  • Such groups may be straight chain, branched, or cyclic.
  • arylamino (a), and “aralkylamino” (b), respectively, refer to the group —NRR′ wherein respectively, (a) R is aryl and R′ is hydrogen, alkyl, aralkyl or aryl, and (b) R is aralkyl and R′ is hydrogen or aralkyl, aryl, alkyl.
  • acyl refers to —C(O)R where R is alkyl and aryl.
  • carboxy esters refers to —C(O)OR where R is alkyl, aryl, aralkyl, and alicyclic, all optionally substituted.
  • oxo refers to ⁇ O in an alkyl group.
  • amino refers to —NRR 1 where R and R 1 are independently selected from hydrogen, alkyl, aryl, aralkyl and alicyclic, all except H are optionally substituted; and R and R 1 can form a cyclic ring system.
  • carbonylamino and “-carbonylamino-” refers to RCONR— and —CONR—, respectively, where each R is independently hydrogen or alkyl.
  • halogen refers to —F, —Cl, —Br and —I.
  • -oxyalkylamino- refers to —O-alk-NR—, where “alk” is an alkylene group and R is H or alkyl.
  • alkylaminoalkylcarboxy- refers to the group -alk-NR-alk-C(O)—O where “alk” is an alkylene group, and R is a H or lower alkyl.
  • alkylaminocarbonyl- refers to the group -alk-NR—C(O)— where “alk” is an alkylene group, and R is a H or lower alkyl.
  • -oxyalkyl- refers to the group —O-alk- where “alk” is an alkylene group.
  • alkylcarboxyalkyl- refers to the group -alk-C(O)—O-alk- where each alk is independently an alkylene group.
  • alkyl refers to saturated aliphatic groups including straight-chain, branched chain and cyclic groups. Alkyl groups may be optionally substituted. Suitable alkyl groups include methyl, isopropyl, and cyclopropyl.
  • cyclic alkyl or “cycloalkyl” refers to alkyl groups that are cyclic groups of 3 to 6; or 3 to 10 atoms. Suitable cyclic groups include norbornyl and cyclopropyl. Such groups may be substituted.
  • heterocyclic and “heterocyclic alkyl” refer to cyclic groups of 3 to 6; or 3 to 10 atoms, containing at least one heteroatom. In one aspect, these groups contain 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. Suitable heterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl, and pyridyl. Such groups may be substituted.
  • phosphono refers to —PO 3 R 2 , where R is selected from the group consisting of —H, alkyl, aryl, aralkyl, and alicyclic.
  • sulphonyl or “sulfonyl” refers to —SO 3 R, where R is H, alkyl, aryl, aralkyl, and alicyclic.
  • alkenyl refers to unsaturated groups which 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 phosph(oramid)ate, it is attached at the first carbon.
  • alkynyl refers to unsaturated groups which 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, it is attached at the first carbon.
  • alkylene refers to a divalent straight chain, branched chain or cyclic saturated aliphatic group.
  • -cycloalkylene-COOR 3 refers to a divalent cyclic alkyl group or heterocyclic group containing 4 to 6 atoms in the ring, with 0-1 heteroatoms selected from O, N, and S.
  • the cyclic alkyl or heterocyclic group is substituted with —COOR 3 .
  • acyloxy refers to the ester group —O—C(O)R, where R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, or alicyclic.
  • aminoalkyl- refers to the group NR 2 -alk- wherein “alk” is an alkylene group and R is selected from H, alkyl, aryl, aralkyl, and alicyclic.
  • -alkyl(hydroxy)- refers to an —OH off the alkyl chain.
  • this term is an X group, the —OH is at the position a to the phosphorus atom.
  • 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 each alkylene group is lower alkylene.
  • arylaminoalkyl- refers to the group aryl-NR-alk- wherein “alk” is an alkylene group and R is H, alkyl, aryl, aralkyl, and alicyclic. In “lower arylaminoalkyl-”, the 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, and alicyclic. In “lower alkylaminoaryl-”, the alkylene group is lower alkyl.
  • alkyloxyaryl- refers to an aryl group substituted with an alkyloxy group.
  • 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 -alk-O— wherein “alk” is an alkylene group.
  • alkoxy- refers to the group alkyl-O—.
  • alkoxyalkyl- or “-alkyloxyalkyl-” refer to the group -alk-O-alk- wherein each “alk” is an independently selected alkylene group. In “lower -alkoxyalkyl-”, each alkylene is lower alkylene.
  • alkylthio- and -alkylthio- refer to the groups alkyl-S—, and -alk-S—, respectively, wherein “alk” is alkylene group.
  • alkylthioalkyl- refers to the group -alk-S-alk- wherein each “alk” is an independently selected alkylene group. In “lower -alkylthioalkyl” each alkylene is lower alkylene.
  • alkoxycarbonyloxy- refers to alkyl-O—C(O)—O—.
  • aryloxycarbonyloxy- refers to aryl-O—C(O)—O—.
  • alkylthiocarbonyloxy- refers to alkyl-S—C(O)—O—.
  • alkoxycarbonylamino- refers to -alk-O—C(O)—NR 1 —, where “alk” is alkylene and R 1 , includes —H, alkyl, aryl, alicyclic, and aralkyl.
  • alkylaminocarbonylamino refers to -alk-NR 1 —C(O)—NR 1 —, where “alk” is alkylene and R 1 is independently selected from H, alkyl, aryl, aralkyl, and alicyclic.
  • amido or “carboxamido” refer to NR 2 —C(O)— and RC(O)—NR 1 —, where R and R 1 include H, alkyl, aryl, aralkyl, and alicyclic. The term does not include urea, —NR—C(O)—NR—.
  • carboxamidoalkylaryl and “carboxamidoaryl” refers to an aryl-alk-NR 1 —C(O)—, and ar-NR 1 —C(O)-alk-, respectively, where “ar” is aryl, and “alk” is alkylene, R 1 and R include H, alkyl, aryl, aralkyl, and alicyclic.
  • alkylcarboxamido- or “-alkylcarbonylamino-” refers to the group -alk-C(O)N(R)— wherein “alk” is an alkylene group and R is H or lower alkyl.
  • alkylaminocarbonyl- refers to the group -alk-NR—C(O)— wherein “alk” is an alkylene group and R is H or lower alkyl.
  • aminocarboxamidoalkyl- refers to the group NR 2 —C(O)—N(R)-alk- wherein R is an alkyl group or H and “alk” is an alkylene group. “Lower aminocarboxamidoalkyl-” refers to such groups wherein “alk” is lower alkylene.
  • thiocarbonate refers to —O—C(S)—O— either in a chain or in a cyclic group.
  • hydroxyalkyl refers to an alkyl group substituted with one —OH.
  • haloalkyl refers to an alkyl group substituted with one halo, selected from the group I, Cl, Br, F.
  • cyano refers to —C ⁇ N.
  • nitro refers to —NO 2 .
  • acylalkyl refers to an alkyl-C(O)-alk-, where “alk” is alkylene.
  • heteroarylalkyl refers to an alkyl group substituted with a heteroaryl group.
  • -1,1-dihaloalkyl- refers to an X group where the 1 position and therefore halogens are ⁇ to the phosphorus atom.
  • 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 .
  • guanidino refers to both —NR—C(NR)—NR 2 as well as —N ⁇ C(NR 2 ) 2 where each R group is independently selected from the group of —H, alkyl alkenyl, alkynyl, aryl, and alicyclic, all except —H are optionally substituted.
  • identity refers to an alkyl group that is attached by its terminal ends to the same atom to form a cyclic group.
  • propylene amine contains a bidentate propylene group.
  • naturally occurring amino acid refers to alpha amino acids containing at least one hydrogen at the alpha carbon and when the alpha carbon is chiral, it has S absolute configuration.
  • amino refers to —C(NR)—NR 2 where each R group is independently selected from the group of —H, alkyl, alkenyl, alkynyl, aryl, and alicyclic, all except —H are optionally substituted.
  • pharmaceutically acceptable salt includes salts of compounds of formula IA and its prodrugs derived from the combination of a compound of this invention and an organic or inorganic acid or base.
  • Suitable acids include hydrochloric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and maleic acid.
  • prodrug refers to any compound that when administered to a biological system generates the “drug” substance (a biologically active compound) as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or metabolic chemical reaction(s).
  • Standard prodrugs are formed using groups attached to functionality, e.g. HO—, HS—, HOOC—, R 2 N—, associated with the FBPase inhibitor, that cleave in vivo.
  • 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.
  • the groups illustrated are exemplary, not exhaustive, and one skilled in the art could prepare other known varieties of prodrugs.
  • Such prodrugs of the compounds of formulae I, X, and XI fall within the scope of the present invention.
  • 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 efficacy or safety through improved oral bioavailability, pharmacodynamic half-life, etc.
  • Phosphoramidate derivatives have been explored as phosphate prodrugs (e.g. McGuigan et al., J. Med. Chem., 1999, 42: 393 and references cited therein) and phosphonate prodrugs (Bischofberger, et al., U.S. Pat. No. 5,798,340 and references cited therein) as shown in Formulae G and H.
  • Cyclic phosphoramidates have also been studied as phosphonate prodrugs because of their speculated higher stability compared to non-cyclic phosphoramidates (e.g. Starrett et al., J. Med. Chem., 1994, 37:1857).
  • nucleotide prodrug Another type of nucleotide prodrug was reported as the combination of S-acyl-2-thioethyl ester and phosphoramidate (Egron et al., Nucleosides & Nucleotides, 1999, 18, 981) as shown in Formula J.
  • enhancing refers to increasing or improving a specific property.
  • the term “enhanced oral bioavailability” refers to an increase of at least 50% of the absorption of the dose of the parent drug or prodrug (not of this invention) from the gastrointestinal tract. In one aspect, this increase is at least 100%.
  • Measurement of oral bioavailability usually refers to measurements of the prodrug, drug, or drug metabolite in blood, tissues, or urine following oral administration, compared to measurements following systemic administration.
  • parent drug refers to any compound which delivers the same biologically active compound.
  • the parent drug form is M-P(O)(OH) 2 and standard prodrugs, such as esters.
  • drug metabolite refers to any compound produced in vivo or in vitro from the parent drug, which can include the biologically active drug.
  • pharmacodynamic half-life refers to the time after administration of the drug or prodrug to observe a diminution of one half of the measured pharmacological response. In one aspect, the half-life is enhanced when the half-life is increased by at least 50%.
  • biologically active drug or agent refers to the chemical entity that produces a biological effect.
  • active drugs or agents include compounds which as M-P(O)(OH) 2 are biologically active.
  • inhibitor of fructose-1,6-bisphosphatase refers to chemical entities M-PO 3 H 2 that have an IC 50 of equal to or less than 50 ⁇ M on human liver FBPase.
  • terapéuticaally effective amount refers to an amount that has any beneficial effect in treating a disease or condition.
  • Suitable alkyl groups include groups having from 1 to about 20 carbon atoms.
  • Suitable aryl groups include groups having from 1 to about 20 carbon atoms.
  • Suitable aralkyl groups include groups having from 2 to about 21 carbon atoms.
  • Suitable acyloxy groups include groups having from 1 to about 20 carbon atoms.
  • Suitable alkylene groups include groups having from 1 to about 20 carbon atoms.
  • Suitable alicyclic groups include groups having 3 to about 20 carbon atoms.
  • Suitable heteroaryl groups include groups having from 1 to about 20 carbon atoms and from 1 to 4 heteroatoms, independently selected from nitrogen, oxygen, phosphorous, and sulfur.
  • Suitable heteroalicyclic groups include groups having from 2 to about twenty carbon atoms and from 1 to 5 heteroatoms, independently selected from nitrogen, oxygen, phosphorous, and sulfur.
  • One aspect of the invention is directed to the compound of formula IA
  • n is an integer from 1 to 3;
  • R 2 is selected from the group of —H and —R 3 .
  • R 3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
  • each R 12 and R 13 is independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R 12 and R 13 together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of O, N and S, to form a cyclic group;
  • each R 14 is independently selected from the group consisting of —OR 17 , —N(R 17 ) 2 , —NHR 17 , —NR 2 OR 19 and —SR 17 ;
  • R 15 is selected from the group consisting of —H, lower alkyl, lower aryl, lower aralkyl, or together with R 16 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
  • R 16 is selected from the group consisting of —(CR 12 R 13 ) n —C(O)—R 14 , —H, lower alkyl, lower aryl, lower aralkyl, or together with R 15 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
  • each R 17 is independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or together R 17 and R 17 on N is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
  • R 18 is independently selected from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R 12 is connected via 1-4 carbon atoms to form a cyclic group;
  • each R 19 is independently selected from the group consisting of —H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl, and COR 3 ;
  • Such compounds converted to M-PO 3 H 2 include compounds that have an IC 50 on isolated human liver FBPase enzyme of less than or equal to 10 ⁇ M. Alternatively, the IC 50 is less than or equal to 1 ⁇ M. Such compounds may also bind to the AMP site of FBPase.
  • M is R 5 —X—, wherein R 5 is selected from the group consisting of:
  • each G is independently selected from the group consisting of C, N, O, S, and Se, and wherein only one G may be O, S, or Se, and at most one G is N;
  • each G′ is independently selected from the group consisting of C and N and wherein no more than two G′ groups are N;
  • A is selected from the group consisting of —H, —NR 4 2 , —CONR 4 2 , —CO 2 R 3 , halo, —S(O)R 3 , —SO 2 R 3 , alkyl, alkenyl, alkynyl, perhaloalkyl, haloalkyl, aryl, —CH 2 OH, —CH 2 NR 4 2 , —CH 2 CN, —CN, —C(S)NH 2 , —OR 2 , —SR 2 , —N 3 , —NHC(S)NR 4 2 , —NHAc, and null;
  • each B and D are independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, —C(O)R 11 , —C(O)SR 3 , —SO 2 R 11 , —S(O)R 3 , —CN, —NR 9 2 , —OR 3 , —SR 3 , perhaloalkyl, halo, —NO 2 , and null, all except —H, —CN, perhaloalkyl, —NO 2 , and halo are optionally substituted;
  • E is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, —C(O)OR 3 , —CONR 4 2 , —CN, —NR 9 2 , —NO 2 , —OR 3 , —SR 3 , perhaloalkyl, halo, and null, all except —H, —CN, perhaloalkyl, and halo are optionally substituted;
  • J is selected from the group consisting of —H and null
  • X is an optionally substituted linking group that links R 5 to the phosphorus atom via 2-4 atoms, including 0-1 heteroatoms selected from N, O, and S, except that if X is urea or carbamate there is 2 heteroatoms, measured by the shortest path between R 5 and the phosphorus atom, and wherein the atom attached to the phosphorus is a carbon atom, and wherein X is selected from the group consisting of -alkyl(hydroxy)-, -alkynyl-, -heteroaryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alk
  • R 2 is selected from the group consisting of R 3 and —H;
  • R 3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
  • each R 4 is independently selected from the group consisting of —H, and alkyl, or together R 4 and R 4 form a cyclic alkyl group;
  • each R 9 is independently selected from the group consisting of —H, alkyl, aryl, aralkyl, and alicyclic, or together R 9 and R 9 form a cyclic alkyl group;
  • R 11 is selected from the group consisting of alkyl, aryl, —NR 2 2 , and —OR 2 ;
  • compounds of formula IA have an IC 50 of ⁇ 50 ⁇ M on glucose production in isolated rat hepatocytes.
  • compounds of formula IA can be selected from those compounds where M is attached to
  • R 17 is selected from the group consisting of ethyl, i-propyl, n-propyl and neopentyl and wherein C* has S stereochemistry.
  • R 17 is selected from the group consisting of ethyl, i-propyl, n-propyl and neopentyl and wherein C* has S stereochemistry.
  • the compounds of formula IA can be selected from:
  • compounds of formula IA may be compounds of formulae II or IV:
  • compounds are of Formula IA wherein M is
  • G′′ is selected from the group consisting of —O— and —S—;
  • a 2 is selected from the group consisting of —H, —NR 4 2 , —NHAc, —OR 2 , —SR 2 , —C(O)NR 4 2 , halo, —COR 11 , —CN, perhaloalkyl, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl;
  • L 2 , E 2 , and J 2 are selected from the group consisting of —NR 4 2 , —NHAc, —NO 2 , —H, —OR 2 , —SR 2 , —C(O)NR 4 2 , halo, —COR 11 , —SO 2 R 3 , guanidinyl, amidinyl, aryl, aralkyl, alkyloxyalkyl, —SCN, —NHSO 2 R 3 , —SO 2 NR 4 2 —CN, —S(O)R 3 , perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C6 alkyl(OH), C1-C6 alkyl(SH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl, and lower alicyclic, or together L 2 and E 2 or E 2 and J 2 form an annulated cyclic group;
  • X 2 is selected from the group consisting of —CR 2 2 —, —CF 2 —, —CR 2 2 —O—, —CR 2 2 —S—, —C(O)—O—, —C(O)—S—, —C(S)—O—, —CH 2 —C(O)—O— and —CR 2 2 —NR 20 —, and wherein in the atom attached to the phosphorus is a carbon atom; with the proviso that X 2 is not substituted with —COOR 2 —SO 3 H, or —PO 3 R 2 2 ;
  • R 2 is selected from the group consisting of R 3 and —H;
  • R 3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
  • each R 4 is independently selected from the group consisting of —H, and alkyl, or together R 4 and R 4 form a cyclic alkyl group;
  • R 11 is selected from the group consisting of alkyl, aryl, —NR 2 2 , and —OR 2 ;
  • R 20 is selected from the group consisting of lower alkyl, —H, and —COR 2 ;
  • R 17 is selected from the group consisting of ethyl, i-propyl, n-propyl, n-butyl and neopentyl.
  • C* has S stereochemistry.
  • such compounds may be of the formula:
  • M is N
  • a 3 , E 3 , and L 3 are selected from the group consisting of —NR 8 2 , —NO 2 , —H, —OR 7 , —SR 7 , —C(O)NR 4 2 , halo, —COR 11 , —SO 2 R 3 , guanidine, amidine, —NHSO 2 R 3 , —SO 2 NR 4 2 , —CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or together A 3 and L 3 form a cyclic group, or together L 3 and E 3 form a cyclic group, or together E 3 and J 3 form a cyclic group including aryl, cyclic alkyl, and heterocyclic;
  • J 3 is selected from the group consisting of —NR 8 2 , —NO 2 , —H, —OR 7 , —SR 7 , —C(O)NR 4 2 , halo, —C(O)R 11 , —CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl; alicyclic, aryl, and aralkyl, or together with Y 3 forms a cyclic group including aryl, cyclic alkyl and heterocyclic alkyl;
  • X 3 is selected from the group consisting of -alkyl(hydroxy)-, -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X 3 is not substituted with —COOR 2 , —SO 3 H, or —PO 3 R 2 2 ;
  • Y 3 is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C(O)R 3 , —S(O) 2 R 3 , —C(O)—R 11 , —CONHR 3 , —NR 2 2 , and —OR 3 , all except H are optionally substituted;
  • R 2 is selected from the group consisting of R 3 and —H;
  • R 3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
  • each R 4 is independently selected from the group consisting of —H, and alkyl, or together R 4 and R 4 form a cyclic alkyl group;
  • R 7 is independently selected from the group consisting of —H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and —C(O)R 10 ;
  • R 8 is independently selected from the group consisting of —H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —C(O)R 10 , or together they form a bidentate alkyl;
  • each R 9 is independently selected from the group consisting of —H, -alkyl, aralkyl, and alicyclic, or together R 9 and R 9 form a cyclic alkyl group;
  • R 10 is selected from the group consisting of —H, lower alkyl, —NH 2 , lower aryl, and lower perhaloalkyl;
  • R 11 is selected from the group consisting of alkyl, aryl, —NR 2 2 , and —OR 2 ;
  • provisos may apply:
  • X 3 is not alkylamine and alkylaminoalkyl substituted with phosphonic esters and acids;
  • a 3 , L 3 , E 3 , J 3 , and Y 3 together may only form 0-2 cyclic groups.
  • Compounds of formula IA may have oral bioavailability of at least 5% and some may have oral bioavailability of at least 10%.
  • the prodrugs of the present invention may have two isomeric forms around the phosphorus. In one aspect, the compounds of the invention are not chiral at the phosphorus. In another aspect, there is no chiral center in the amino groups attached to the phosphorus.
  • the prodrugs of the present invention may have isomers at the carbon substituted with R 12 and R 13 .
  • the invention contemplates mixtures of isomers as well as individual stereoisomers. For instance, when n is 1, and R 12 is H, the carbon attached to R 12 and R 13 can have R stereochemistry. In another aspect, when n is 1 and R 12 is —H, the carbon attached to R 12 and R 13 can have S stereochemistry.
  • the present invention includes compounds designated in Table 1 as defined in the following formulae: formula i, formula ii, and formula iii.
  • R 55 may be substituted by A and B.
  • the compounds of formulae i, ii, and iii are listed in Table 1 by designated numbers assigned to R 55 , A, B, Q 1 , and Q 2 in the above formulae i, ii, and iii according to the following convention:
  • Variable R 55 is divided into two groups, each listing four different structures.
  • Variable B moieties are assigned the following numbers:
  • Variables Q 1 and Q 2 are divided into three groups, each listing eight different substituents.
  • Variables Q 1 and Q 2 are divided into three groups, each listing eight different substituents.
  • Variable B is divided into three groups, each listing eight different substituents.
  • B B&D are B&D are B&D are B&D are B&D are B&D are B&D are B&D are B&D are B&D are B&D are B&D are B&D are connected connected connected connected connected connected connected connected connected connected connected connected connected connected connected connected connected connected connected connected to form to form to form to form to form to form to form cyclohexyl phenyl furanyl furanyl cyclohexyl phenyl furanyl furanyl ring ring ring (O ring (O ring ring ring (O ring (O attached at attached at attached at attached at attached at attached at B) D) B) D) B) D) B) D) B) D) B) D)
  • Group 3 for Variable B can only be combined with Group 3 variable for D.
  • Variable D is divided into nine groups, each listing four different substituents.
  • R 14 is selected from the groups consisting of OMe, OEt, OBn, O-tBu, O-nPr, OPh, O-neopentyl, —N(Me) 2 , oxyethylene-N-morpholino, SMe, SEt;
  • R 21 is methyl, ethyl, benzyl, and propyl;
  • R 22 is H, Me, Et, Bn, Pr, and Ph; and
  • R 23 is Me, Et, Bn, Pr and Ph; or R 22 and R 23 is morpholinyl and pyrrolidinyl.
  • Synthesis of compounds encompassed by the present invention typically includes some or all of the following general steps: (1) preparation of a phosphonate prodrug; (2) deprotection of a phosphonate ester; (3) modification of a heterocycle; (4) coupling of a heterocycle with a phosphonate component; (5) construction of a heterocycle; (6) ring closure to construct a heterocycle with a phosphonate moiety present and (7) preparation of useful intermediates.
  • steps are illustrated in the following scheme for compounds of formula I wherein R 5 is a 5-membered heteroaromatic ring.
  • Compounds of formula I wherein R 5 is a 6-member heteroaromatic ring or other heteroaromatic rings are prepared in an analogous manner.
  • the bis-phosphoroamidates of formula I where both —NR 15 R 16 and —N(R 18 )—(CR 12 R 13 ) n —C(O)—R 14 are from the same amino acid residues, can be prepared from the activated phosphonates for example, dichlorophosphonate, by coupling with an amino acid ester for example, glycine ethylester with or without base for example, N-methylimidazole.
  • the reactive dichloridates can be prepared from the corresponding phosphonic acid and a chlorinating agent for example, thionyl chloride (Starrett, et al., J. Med.
  • dichloridates can also be prepared from their corresponding disilyl esters (Bhongle, et al., Synth. Commun., 1987, 17, 1071) and dialkyl esters (Still, et al, Tetrahedron Lett., 1983, 24, 4405; Patois, et al., Bull. Soc. Chim. Fr., 1993, 130, 485).
  • these bis-phosphoroamidates can be prepared by reacting the corresponding phosphonic acid with an amino acid ester for example, glycine ethylester in presence of PPh 3 and 2,2′-dipyridyl disulfide in pyridine as described in WO 95/07920 or Mukaiyama, T. et al, J. Am. Chem. Soc., 1972, 94, 8528.
  • an amino acid ester for example, glycine ethylester in presence of PPh 3 and 2,2′-dipyridyl disulfide in pyridine as described in WO 95/07920 or Mukaiyama, T. et al, J. Am. Chem. Soc., 1972, 94, 8528.
  • Synthesis of mixed bis-phosphoroamidates of formula I, where —NR 15 R 16 and —N(R 18 )—(CR 12 R 13 ) n C(O)—R 14 are different amino acid esters or a combination of an amino acid ester and a substituted amine, can be prepared by direct conversion via dichloridate as described above (sequential addition) followed by purification of the desired product (e.g., by column chromatography).
  • these unsymmetrical bis-phosphoroamidates can be prepared starting with an appropriate phosphonate monoester such as phenyl ester or benzyl ester to give the mixed phosphonoesteramide via the chloridate, followed by ester hydrolysis under conditions where the amide bond is stable.
  • the resultant mono-amide can be converted to a mixed bisamide by condensation with a second amino ester or a substituted amine via the chloridate, as described above. Synthesis of such monoesters can be prepared using the reported procedure (EP 481 214).
  • Compounds of formula 2 may be prepared from phosphonate esters using known phosphate and phosphonate ester cleavage conditions.
  • Silyl halides are generally used to cleave various phosphonate esters, and subsequent mild hydrolysis of the resulting silyl phosphonate esters give the desired phosphonic acids.
  • acid scavengers e.g. 1,1,1,3,3,3-hexamethyldisilazane, 2,6-lutidine, etc.
  • Such silyl halides include chlorotrimethylsilane (Rabinowitz, J. Org.
  • phosphonate esters can be cleaved under strong acidic conditions (e.g. HBr or HCl: Moffatt, et al, U.S. Pat. No. 3,524,846, 1970). These esters can also be cleaved via dichlorophosphonates, prepared by treating the esters with halogenating agents (e.g.
  • phosphorus pentachloride, thionyl chloride, BBr 3 Pelchowicz et al, J. Chem. Soc., 1961, 238) followed by aqueous hydrolysis to give phosphonic acids.
  • Aryl and benzyl phosphonate esters can be cleaved under hydrogenolysis conditions (Lejczak, et al, Synthesis, 1982, 412; Elliott, et al, J. Med. Chem., 1985, 28: 1208; Baddiley, et al, Nature, 1953, 171: 76) or metal reduction conditions (Shafer, et al, J. Am. Chem. Soc., 1977, 99: 5118).
  • Halogens can also be introduced by direct halogenations of various heterocycles.
  • 5-unsubstituted-2-aminothiazoles can be converted to 2-amino-5-halothiazoles using various reagents (e.g. NIS, NBS, NCS).
  • Heteroaryl halides are also useful intermediates and are often readily converted to other substituents (such as A, A′′, B, B′′, C′′, D, D′′, E and E′′) via transition metal assisted coupling reactions such as Suzuki, Heck or Stille reactions (Farina et al, Organic Reactions, Vol 50; Wiley, New York, 1997; Mitchell, Synthesis, 1992, 808; Suzuki, Pure App.
  • HSMe, HOMe, etc. represents still another method for introducing substituents such as A, A′′, B and B′′.
  • substituents such as A, A′′, B and B′′.
  • substitution of a 2-chlorothiazole with methanethiol gives the corresponding 2-methylthiothiazole.
  • alkylation of nitrogen atoms in the heterocycles can be readily performed using for example standard alkylation reactions (with an alkyl halide, an aralkyl halide, an alkyl sulfonate or an aralkyl sulfonate), or Mitsunobu reactions (with an alcohol).
  • Transition metal catalyzed coupling reactions such as Stille or Suzuki reactions are particularly suited for the synthesis of compounds of formula I.
  • Coupling reactions between a heteroaryl halide or triflate e.g. 2-bromopyridine
  • M-PO 3 R′ wherein M is a 2-(5-tributylstannyl)furanyl or a 2-(5-boronyl)furanyl group under palladium catalyzed reaction conditions
  • the Heck reaction may be used to prepare compounds of formula I wherein X is an alkenyl group (Heck Palladium Reagents in Organic Syntiesis ; Academic Press: San Diego, 1985). These reactions are particularly suited for syntheses of various heteroaromatics as R 5 for compounds of formula I given the availability of numerous halogenated heterocycles, and these reactions are particularly suitable for parallel synthesis (e.g. combinatorial synthesis on solid phase (Bunin, B. A., The Combinatorial Index ; Academic Press: San Diego, 1998) or in solution phase (Flynn, D. L. et al., Curr. Op. Drug. Disc. Dev., 1998, 1, 1367)) to generate large combinatorial libraries.
  • X is an alkenyl group
  • ethyl 5-iodo-2-furanylphosphonate can be coupled to Wang's resin under suitable coupling reaction conditions.
  • the resin-coupled 5-iodo-2-[5-(O-ethyl-O-Wang's resin)phosphono]furan can then be subjected to transition metal catalyzed Suzuki and Stille reactions (as described above) with organoboranes and organotins in a parallel manner to give libraries of compounds of formula 3 wherein X is furan-2,5-diyl.
  • Substitution reactions are useful for the coupling of a heterocycle with a phosphonate diester component.
  • cyanuric chloride can be substituted with dialkyl mercaptoalkylphosphonates or dialkyl aminoalkylphosphonates to give compounds of formula I wherein R 5 is a 1,3,5-triazine, X is an alkylthio or an alkylamino group.
  • Alkylation reactions are also used for the coupling of a heterocycle with a phosphonate diester component.
  • a heteroaromatic thiol e.g. a 1,3,4-thiadiazole-2-thiol
  • a dialkyl methylphosphonate derivative e.g.
  • ICH 2 P(O)(OEt) 2 , TsOCH 2 P(O)(OEt) 2 , TfOCH 2 P(O)(OEt) 2 ) to lead to compounds of formula I wherein X is an alkylthio group.
  • alkylation reactions of a heteroaromatic carboxylic acid e.g. a thiazole-4-carboxylic acid
  • a dialkyl methylphosphonate derivative e.g.
  • ICH 2 P(O)(OEt) 2 , TsOCH 2 P(O)(OEt) 2 , TfOCH 2 P(O)(OEt) 2 ) lead to compounds of formula I wherein X is an alkoxycarbonyl group, while alkylation reactions of a heteroaromatic thiocarboxylic acid (e.g. a thiazole-4-thiocarboxylic acid) with a dialkyl methylphosphonate derivative (e.g. ICH 2 P(O)(OEt) 2 , TsOCH 2 P(O)(OEt) 2 , TfOCH 2 P(O)(OEt) 2 ) lead to compounds of formula I wherein X is an alkylthiocarbonyl group.
  • a heteroaromatic thiocarboxylic acid e.g. a thiazole-4-thiocarboxylic acid
  • a dialkyl methylphosphonate derivative e.g. ICH 2 P(O)(
  • haloalkyl heterocycles e.g. 4-haloalkylthiazole
  • nucleophiles containing the phosphonate group diethyl hydroxymethylphosphonate
  • X is an alkoxyalkyl or an alkylthioalkyl group.
  • compounds of formula I where X is a —CH 2 OCH 2 — group can be prepared from 2-chloromethylpyridine or 4-chloromethylthiazole using dialkyl hydroxymethylphosphonates and a suitable base (e.g. sodium hydride). It is possible to reverse the nature of the nucleophiles and electrophiles for the substitution reactions, i.e.
  • haloalkyl- and/or sulfonylalkylphosphonate esters can be substituted with heterocycles containing a nucleophile (e.g. a 2-hydroxyalkylpyridine, a 2-mercaptoalkylpyridine, or a 4-hydroxyalkyloxazole).
  • a nucleophile e.g. a 2-hydroxyalkylpyridine, a 2-mercaptoalkylpyridine, or a 4-hydroxyalkyloxazole.
  • Known amide bond formation reactions can also be used to couple a heteroaromatic carboxylic acid with a phosphonate diester component leading to compounds of formula I wherein X is an alkylaminocarbonyl or an alkoxycarbonyl group.
  • X is an alkylaminocarbonyl or an alkoxycarbonyl group.
  • couplings of a thiazole-4-carboxylic acid with a dialkyl aminoalkylphosphonate or a dialkyl hydroxyalkylphosphonate give compounds of formula I wherein R 5 is a thiazole, and X is an alkylaminocarbonyl or an alkoxycarbonyl group.
  • HOCH 2 P(O)(OEt)(O-resin), H 2 NCH 2 P(O)(OEt)(O-resin) and HOOCCH 2 P(O)(OEt)(O-resin) can be coupled to various heterocycles using the above described reactions to give libraries of compounds of formula 3 wherein X is a —C(O)OCH 2 —, or a —C(O)NHCH 2 —, or a NHC(O)CH 2 —.
  • Rearrangement reactions can also be used to prepare compounds covered in the present invention.
  • Curtius' rearrangement of a thiazole-4-carboxylic acid in the presence of a dialkyl hydroxyalkylphosphonate or a dialkyl aminoalkylphosphonate lead to compounds of formula I wherein X is an alkylaminocarbonylamino or an alkoxycarbonylamino group.
  • These reactions can also be adopted for combinatorial synthesis of various libraries of compounds of formula 3.
  • Curtius' rearrangement reactions between a heterocyclic carboxylic acid and HOCH 2 P(O)(OEt)(O-resin), or H 2 NCH 2 P(O)(OEt)(O-resin) can lead to libraries of compounds of formula I wherein X is a —NHC(O)OCH 2 —, or a NHC(O)NHCH 2 —.
  • the phosphonate group can be introduced using other common phosphonate formation methods such as Michaelis-Arbuzov reaction (Bhattacharya et al., Chem. Rev., 1981, 81: 415), Michaelis-Becker reaction (Blackburn et al., J. Organomet. Chem., 1988, 348: 55), and addition reactions of phosphorus to electrophiles (such as aldehydes, ketones, acyl halides, imines and other carbonyl derivatives).
  • Michaelis-Arbuzov reaction Bhattacharya et al., Chem. Rev., 1981, 81: 415
  • Michaelis-Becker reaction Blackburn et al., J. Organomet. Chem., 1988, 348: 55
  • addition reactions of phosphorus to electrophiles such as aldehydes, ketones, acyl halides, imines and other carbonyl derivatives.
  • Phosphonate component can also be introduced via lithiation reactions.
  • lithiation of an 2-ethynylpyridine using a suitable base followed by trapping the thus generated anion with a dialkyl chlorophosphonate lead to compounds of formula I wherein R 5 is a pyridyl, X is a 1-(2-phosphono)ethynyl group.
  • heterocycles can also be constructed leading to compounds in the current invention.
  • the construction of heterocycles have been well described in the literature using a variety of reaction conditions (Joule et al., Heterocyclic Chemistry ; Chapman hall, London, 1995; Boger, Weinreb, Hetero Diels - Alder Methodology In Organic Synthesis ; Academic press, San Diego, 1987; Padwa, 1,3-Dipolar Cycloaddition Chemistry; Wiley, New York, 1984; Katritzsky et al., Comprehensive Heterocyclic Chemistry; Pergamon press, Oxford; Newkome et al., Contemporary Heterocyclic Chemistry: Syntheses, Reaction and Applications; Wiley, New York, 1982; Syntheses of Heterocyclic Compounds; Consultants Bureau, New York).
  • Thiazoles useful for the present invention can be readily prepared using a variety of well described ring-forming reactions (Metzger, Thiazole and its derivatives, part 1 and part 2; Wiley & Sons, New York, 1979). Cyclization reactions of thioamides (e.g. thioacetamide, thiourea) and alpha-halocarbonyl compounds (such as alpha-haloketones, alpha-haloaldehydes) are particularly useful for the construction of a thiazole ring system.
  • thioamides e.g. thioacetamide, thiourea
  • alpha-halocarbonyl compounds such as alpha-haloketones, alpha-haloaldehydes
  • cyclization reactions between thiourea and 5-diethylphosphono-2-[( ⁇ 2-bromo-1-oxo)alkyl]furans are useful for the synthesis of compounds of formula I wherein R 5 is a thiazole, A is an amino group and X is a furan-2,5-diyl group; cyclization reaction between thiourea and a bromopyruvate alkyl ester give a 2-amino-4-alkoxycarbonylthiazole which is useful for the preparations of compounds of formula I wherein R 5 is a thiazole and X is an alkylaminocarbonyl, an alkoxycarbonyl, an alkylaminocarbonylamino, or an alkoxyacarbonylamino group.
  • Thioamides can be prepared using reactions reported in the literature (Trost, Comprehensive organic synthesis, Vol. 6; Pergamon press, New York, 1991, pages 419-434) and alpha-halocarbonyl compounds are readily accessible via conventional reactions (Larock, Comprehensive organic transformations , VCH, New York, 1989).
  • amides can be converted to thioamides using Lawesson's reagent or P 2 S 5 , and ketones can be halogenated using various halogenating reagents (e.g. NBS, CuBr 2 ).
  • Oxazoles useful for the present invention can be prepared using various methods in the literature (Turchi, Oxazoles ; Wiley & Sons, New York, 1986). Reactions between isocyanides (e.g. tosylmethylisocyanide) and carbonyl compounds (e.g. aldehydes and acyl chlorides) can be used to construct oxazole ring systems (van Leusen et al, Tetrahedron Lett., 1972, 2369). Alternatively, cyclization reactions of amides (e.g. urea, carboxamides) and alpha-halocarbonyl compounds are commonly used for the construction of an oxazole ring system.
  • isocyanides e.g. tosylmethylisocyanide
  • carbonyl compounds e.g. aldehydes and acyl chlorides
  • amides e.g. urea, carboxamides
  • alpha-halocarbonyl compounds are commonly used for the construction of an ox
  • reaction of urea and 5-diethylphosphono-2-[( ⁇ 2-bromo-1-oxo)alkyl]furans are useful for the synthesis of compounds of formula I wherein R 5 is an oxazole, A is an amino group and X is a furan-2,5-diyl group.
  • Reactions between amines and imidates are also used to construct the oxazole ring system (Meyers et al, J. Org. Chem., 1986, 51(26), 5111).
  • Pyridines useful for the synthesis of compounds of formula I can be prepared using various known synthetic methods (Klingsberg, Pyridine and Its Derivatives; Interscience Publishers, New York, 1960-1984). 1,5-Dicarbonyl compounds or their equivalents can be reacted with ammonia or compounds which can generate ammonia to produce 1,4-dihydropyridines which are easily dehydrogenated to pyridines. When unsaturated 1,5-dicarbonyl compounds, or their equivalents (e.g. pyrylium ions) are used to react with ammonia, pyridines can be generated directly. 1,5-Dicarbonyl compounds or their equivalents can be prepared using conventional chemistry.
  • 1,5-diketones are accessible via a number of routes, such as Michael addition of an enolate to an enone (or precursor Mannich base (Gill et al, J. Am. Chem. Soc., 1952, 74, 4923)), ozonolysis of a cyclopentene precursor, or reaction of silyl enol ethers with 3-methoxyallylic alcohols (Duhamel et al, Tetrahedron, 1986, 42, 4777). When one of the carbonyl carbons is at the acid oxidation state, then this type of reaction produces 2-pyridones which can be readily converted to 2-halopyridines (Isler et al, Helv. Chim.
  • a pyridine can be prepared from an aldehyde, a 1,3-dicarbonyl compound and ammonia via the classical Hantzsch synthesis (Bossart et al, Angew. Chem. Int. Ed. Engl., 1981, 20, 762). Reactions of 1,3-dicarbonyl compounds (or their equivalents) with 3-amino-enones or 3-amino-nitriles have also been used to produce pyridines (such as the Guareschi synthesis, Marinella, Org. Synth., Coll, Vol.
  • 1,3-Dicarbonyl compounds can be made via oxidation reactions on corresponding 1,3-diols or aldol reaction products (Mukaiyama, Org, Reactions, 1982, 28, 203). Cycloaddition reactions have also been used for the synthesis of pyridines, for example cycloaddition reactions between oxazoles and alkenes (Naito et al., Chem. Pharm. Bull, 1965, 13, 869), and Diels-Alder reactions between 1,2,4-triazines and enamines (Boger et al., J. Org. Chem., 1981, 46, 2179).
  • Pyrimidine ring systems useful for the synthesis of compounds of formula I are readily available (Brown, The pyrimidines ; Wiley, New York, 1994).
  • One method for pyrimidine synthesis involves the coupling of a 1,3-dicarbonyl component (or its equivalent) with an N—C—N fragment.
  • the selection of the N—C—N component—urea (Sherrnan et al., Org. Synth., Coll. Vol. IV, 1963, 247), amidine (Kenner et al., J. Chem. Soc., 1943, 125) or guanidine (Burgess, J. Org. Chem., 1956, 21, 97; VanAllan, Org. Synth., Coll. Vol.
  • pyrimidines can be prepared via cycloaddition reactions such as aza-Diels-Alder reactions between a 1,3,5-triazine and an enamine or an ynamine (Boger et al., J. Org. Chem., 1992, 57, 4331 and references cited therein).
  • Imidazoles useful for the synthesis of compounds of formula I are readily prepared using a variety of different synthetic methodologies.
  • Various cyclization reactions are generally used to synthesize imidazoles such as reactions between amidines and alpha-haloketones (Mallick et al, J. Am. Chem. Soc., 1984, 106(23), 7252) or alpha-hydroxyketones (Shi et al, Synthetic Comm., 1993, 23(18), 2623), reactions between urea and alpha-haloketones, and reactions between aldehydes and 1,2-dicarbonyl compounds in the presence of amines.
  • Isoxazoles useful for the synthesis of compounds of formula I are readily synthesized using various methodologies (such as cycloaddition reactions between nitrile oxides and alkynes or active methylene compounds, oximation of 1,3-dicarbonyl compounds or alpha, beta-acetylenic carbonyl compounds or alpha,beta-dihalocarbonyl compounds, etc.) can be used to synthesize an isoxazole ring system (Grunanger et al., Isoxazoles ; Wiley & Sons, New York, 1991).
  • reactions between alkynes and 5-diethylphosphono-2-chlorooximidofuran in the presence of base e.g. triethylamine, Hunig's base, pyridine
  • base e.g. triethylamine, Hunig's base, pyridine
  • Pyrazoles useful for the synthesis of compounds of formula I are readily prepared using a variety of methods (Wiley, Pyrazoles, Pyrazolines, Pyrazolidines, Indazoles, and Condensed Rings ; Interscience Publishers, New York, 1967) such as reactions between hydrazines and 1,3-dicarbonyl compounds or 1,3-dicarbonyl equivalents (e.g. one of the carbonyl group is masked as an enamine or ketal or acetal), and additions of hydrazines to acrylonitriles followed by cyclization reactions (Dom et al, Org. Synth., 1973, Coll. Vol. V, 39).
  • Reaction of 2-(2-alkyl-3-N,N-dimethylamino)acryloyl-5-diethylphosphonofurans with hydrazines are useful for the synthesis of compounds of formula I wherein R 5 is a pyrazole, X is a furan-2,5-diyl group and B′′ is an alkyl group.
  • 1,2,4-Triazoles useful for the synthesis of compounds of formula I are readily available via various methodologies (Montgomery, 1,2,4-Triazoles; Wiley, New York, 1981). For example, reactions between hydrazides and imidates or thioimidates (Sui et al., Bioorg. Med. Chem. Lett., 1998, 8, 1929; Catarzi et al., J. Med. Chem., 1995, 38(2), 2196), reactions between 1,3,5-triazine and hydrazines (Grundmann et al., J. Org. Chem., 1956, 21, 1037), and reactions between aminoguanidine and carboxylic esters (Ried et al., Chem. Ber., 1968, 101, 2117) are used to synthesize 1,2,4-triazoles.
  • Compounds of formula 4 can also be prepared using a ring closure reaction to construct the heterocycle from precursors that contain the phosphonate component.
  • a ring closure reaction to construct the heterocycle from precursors that contain the phosphonate component.
  • cyclization reactions between thiourea and 5-diethylphosphono-2-[(-2-bromo-1-oxo)alkyl]furans are useful for the synthesis of compounds of formula I wherein R 5 is a thiazole, A is an amino group and X is a furan-2,5-diyl group.
  • Oxazoles of the present invention can also be prepared using a ring closure reaction.
  • reactions of urea and 5-diethylphosphono-2-[(-2-bromo-1-oxo)alkyl]furans are useful for the synthesis of compounds of formula I wherein R 5 is an oxazole, A is an amino group and X is a furan-2,5-diyl group.
  • Reactions between 5-diethylphosphono-2-furaldehyde, an alkyl amine, a 1,2-diketone and ammonium acetate are useful to synthesize compounds of formula I wherein R 5 is an imidazole and X is a furan-2,5-diyl group.
  • ring closure reactions can also be used for the synthesis of pyridines or pyrimidines useful in the present invention.
  • reaction of 5-diethylphosphono-2-[3-dimethylamino-2-alkyl)acryloyl]furans and cyanoacetamide in the presence of base gives 5-alkyl-3-cyano-6-[2-(5-diethylphosphono)furanyl]-2-pyridones (Jain et al., Tetrahedron Lett., 1995, 36, 3307).
  • aryl phosphonate dialkyl esters are particularly useful for the synthesis of compounds of formula I.
  • compounds of formula I wherein X is a furan-2,5-diyl group can be prepared from a variety of furanyl precursors. It is envisioned that synthesis of other precursors may follow some or all of these reaction steps, and some modifications of these reactions may be required for different precursors.
  • 5-Dialkylphosphono-2-furancarbonyl compounds e.g. 5-diethylphosphono-2-furaldehyde, 5-diethylphosphono-2-acetylfuran
  • 5-diethylphosphono-2-furaldehyde e.g. 5-diethylphosphono-2-acetylfuran
  • aryl phosphonate esters can also be prepared using this approach or a modification of this approach.
  • other methods such as transition metal catalyzed reactions of aryl halides or triflates (Balthazar et al. J. Org. Chem., 1980, 45: 5425; Petrakis et al. J. Am. Chem. Soc., 1987, 109: 2831; Lu et al. Synthesis, 1987, 726) are used to prepare aryl phosphonates.
  • Aryl phosphonate esters can also be prepared from aryl phosphates under anionic rearrangement conditions (Melvin, Tetrahedron Lett., 1981, 22: 3375; Casteel et al.
  • N-Alkoxy aryl salts with alkali metal derivatives of dialkyl phosphonate provide another general synthesis for heteroaryl-2-phosphonate esters (Redmore J. Org. Chem., 1970, 35: 4114).
  • a second lithiation step can be used to incorporate a second group on the aryl phosphonate dialkyl ester such as an aldehyde group, a trialkylstannyl or a halo group, although other methods known to generate these functionalities (e.g. aldehydes) can be envisioned as well (e.g. Vilsmeier-Hack reaction or Reimar-Teimann reaction for aldehyde synthesis).
  • the lithiated aromatic ring is treated with reagents that either directly generate the desired functional group (e.g.
  • 5-keto-2-dialkylphosphonofurans which encompass the following steps: acylations of furan under Friedel-Crafts reaction conditions give 2-ketofuran, subsequent protection of the ketone as ketals (e.g. 1,3-propanediol cyclic ketal) followed by a lithiation step as described above gives the 5-dialkylphosphono-2-furanketone with the ketone being protected as a 1,3-propanediol cyclic ketal, and final deprotection of the ketal under, for example, acidic conditions gives 2-keto-5-dialkylphosphonofurans (e.g. 2-acetyl-5-diethylphosphonofuran).
  • 2-keto-5-dialkylphosphonofurans e.g. 2-acetyl-5-diethylphosphonofuran
  • 2-ketofurans can be synthesized via a palladium catalyzed reaction between 2-trialkylstannylfurans (e.g. 2-tributylstannylfuran) and an acyl chloride (e.g. acetyl chloride, isobutyryl chloride).
  • the phosphonate moiety may be present in the 2-trialkylstannylfurans (e.g. 2-tributylstannyl-5-diethylphosphonofuran).
  • 2-Keto-5-dialkylphosphonofurans can also be prepared from a 5-dialkylphosphono-2-furoic acid (e.g. 5-diethylphosphono-2-furoic acid) by conversion of the acid to the corresponding acyl chloride and followed by additions of a Grignard reagent.
  • a 2-keto-5-dialkylphosphonofuran can be further converted to a 1,3-dicarbonyl derivative which is useful for the preparation of pyrazoles, pyridines or pyrimidines.
  • dimethylformamide dimethyl acetal gives a 1,3-dicarbonyl equivalent as a 2-(3-dialkylamino-2-alkyl-acryloyl)-5-dialkylphosphonofuran (e.g. 2-(3-dimethylaminoacryloyl)-5-diethylphosphonofuran).
  • furan derivatives can be, either directly or with some modifications, applied to syntheses of various other useful intermediates such as aryl phosphonate esters (e.g. thienyl phosphonate esters, phenyl phosphonate esters or pyridyl phosphonate esters).
  • aryl phosphonate esters e.g. thienyl phosphonate esters, phenyl phosphonate esters or pyridyl phosphonate esters.
  • Synthesis of the compounds encompassed by the present invention typically includes some or all of the following general steps: (1) preparation of a phosphonate prodrug; (2) deprotection of a phosphonate ester; (3) construction of a heterocycle; (4) introduction of a phosphonate component; (5) synthesis of an aniline derivative. Step (1) and step (2) were discussed in section 1, and discussions of step (3), step (4) and step (5) are given below. These methods are also generally applicable to compounds of Formula X.
  • One method involves the treatment of a suitably substituted aniline with a mixture of KSCN and CuSO 4 in methanol to give a substituted 2-aminobenzothiazole (Ismail, I. A.; Sharp, D. E; Chedekel, M. R. J. Org. Chem. 45, 2243-2246, 1980).
  • a 2-aminobenzothiazole can also be prepared by the treatment of Br 2 in presence of KSCN in acetic acid (Patil, D. G.; Chedekel, M. R. J. Org. Chem. 49, 997-1000, 1984).
  • This reaction can also be done in two step sequence. For example treatment of substituted phenylthioureas with Br 2 in CHCl 3 gives substituted 2-aminobenzothiazoles (Patil, D. G.; Chedekel, M. R. J. Org. Chem. 49, 997-1000, 1984).
  • 2-Aminobenzothiazoles can also be made by condensation of ortho iodo anilines with thiourea in presence of Ni catalyst (NiCl 2 (PPh 3 ) 2 ) (Takagi, K. Chem. Lett. 265-266, 1986).
  • Benzothiazoles can undergo electrophilic aromatic substitution to give 6-substituted benzothiazoles (Sprague, J. M.; Land, A. H. Heterocycle. Compd. 5, 606-13, 1957).
  • compounds of formula 3 wherein A is a halo, H, alkoxy, alkylthio or an alkyl can be prepared from the corresponding amino compound (Larock, Comprehensive organic transformations , VCH, New York, 1989; Trost, Comprehensive organic synthesis ; Pergamon press, New York, 1991).
  • the alkylation method can also be applied to the precursor compounds to compounds of formula 5 wherein a phenol moiety is present and it can be alkylated with a phosphonate containing component.
  • compounds of formula 4 can also be made from the nucleophilic substitution of the precursor compounds to compounds of formula 5, for example, wherein a halo group, e.g., such as a fluoro or a chloro, is present ortho to a nitro group.
  • aniline derivatives Numerous synthetic methods have been reported for the synthesis of aniline derivatives, these methods can be applied to the synthesis of useful intermediates which can lead to compounds of formula X. For example, various alkenyl or aryl groups can be introduced on to a benzene ring via transition metal catalyzed reactions (Kasibhatla, S. R., et al WO 98/39343 and the references cited in); anilines can be prepared from their corresponding nitro derivatives via reduction reactions (e.g. hydrogenation reactions in presence of 10% Pd/C, or reduction reactions using SnCl 2 in HCl (Patil, D. G.; Chedekel, M. R. J. Org. Chem. 49, 997-1000, 1984)).
  • reduction reactions e.g. hydrogenation reactions in presence of 10% Pd/C, or reduction reactions using SnCl 2 in HCl (Patil, D. G.; Chedekel, M. R. J. Org. Chem. 49
  • WO 98/39343 describes the synthesis of phosphonic acids and esters of the benzimidazoles of Formula XI.
  • the bisamidate phosphonates of the present invention can be prepared by using procedures described supra for compounds of Formula I.
  • Compounds of the invention are administered orally in a total daily dose in a range of about 0.01 mg/kg/dose to about 100 mg/kg/dose; and from about 0.1 mg/kg/dose to about 10 mg/kg/dose.
  • the use of time-release preparations to control the rate of release of the active ingredient is contemplated.
  • the dose may be administered in as many divided doses as is convenient.
  • compounds are administered to the affected tissue at a rate in the range from 0.05 to 10 mg/kg/hour; and from 0:1 to 1 mg/kg/hour. Such rates are easily maintained when these compounds are intravenously administered as discussed below.
  • 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 intraarterial injections with a variety of infusion techniques.
  • Intraarterial and intravenous injection as used herein includes administration through catheters. Oral administration is generally preferred.
  • 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 excipient 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 may 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, hydroxypropyl methylcelluose, 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 monooleate).
  • a suspending agent
  • 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 arachis 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 e.g., sodium tartrate
  • suspending agent e.g., sodium EDTA
  • preservatives e.g., sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate
  • 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 arachis 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 may 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.
  • the 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
  • a time-release formulation intended for oral administration to humans may contain approximately 1 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.
  • the pharmaceutical composition can be prepared to provide easily measurable amounts for administration.
  • an aqueous solution intended for intravenous infusion should contain from about 3 to 330 ⁇ g of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr 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, especially when the active ingredient is 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.
  • Suitable unit dosage formulations include those containing a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, of a fructose 1,6-bisphosphatase inhibitor compound.
  • the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those skilled in the art.
  • One aspect of the invention is directed to novel bis-phosphoramidate prodrugs of FBPase inhibitors to increase the oral bioavailability of the parent drugs.
  • FBPase inhibitors and their prodrugs may be used to treat diabetes mellitus, lower blood glucose levels, and inhibit gluconeogenesis.
  • FBPase inhibitors and their prodrugs may also be used to treat excess glycogen storage diseases. Excessive hepatic glycogen stores are found in patients with some glycogen storage diseases. Since the indirect pathway contributes significantly to glycogen synthesis (Shulman, G. I. Phys. Rev. — 72:1019-1035, 1992), inhibition of the indirect pathway (gluconeogenesis flux) decreases glycogen overproduction.
  • FBPase inhibitors and their prodrugs may also be used to treat or prevent diseases associated with increased insulin levels. Increased insulin levels are associated with an increased risk of cardiovascular complications and atherosclerosis (Folsom, et al., Stroke, 25:66-73, 1994; Howard, G. et al., Circulation, 93:1809-1817, 1996). FBPase inhibitors and their prodrugs are expected to decrease postprandial glucose levels by enhancing hepatic glucose uptake. This effect is postulated to occur in individuals that are non-diabetic (or pre-diabetic, i.e. without elevated hepatic glucose output “hereinafter HGO” or fasting blood glucose levels). Increased hepatic glucose uptake will decrease insulin secretion and thereby decrease the risk of diseases or complications that arise from elevated insulin levels.
  • HGO hepatic glucose output
  • Step A A solution of 2-furaldehyde diethyl acetal (1 mmole) in THF (tetrahydrofuran) was treated with nBuLi (1 mmole) at ⁇ 78° C. After 1 h, diethyl chlorophosphate (1.2 mmole) was added and the reaction was stirred for 40 min. Extraction and evaporation gave a brown oil. Step B. The resulting brown oil was treated with 80% acetic acid at 90° C. for 4 h. Extraction and chromatography gave compound 1 as a clear yellow oil. Alternatively this aldehyde can be prepared from furan as described below. Step C.
  • Step E A solution of 2-furaldehyde (1 mmole) and N,N′-dimethylethylene diamine (1 mmole) in toluene was refluxed while the resulting water being collected through a Dean-Stark trap. After 2 h the solvent was removed in vacuo and the residue was distilled to give. furan-2-(N,N′-dimethylimidazolidine) as a clear colorless oil. bp 59-61° C.
  • Step F A solution of furan-2-(N,N′-dimethylimidazolidine) (1 mmole) and TMEDA (1 mmole) in THF was treated with nBuLi (1.3 mmole) at ⁇ 40 to ⁇ 48° C. The reaction was stirred at 0° C. for 1.5 h and then cooled to ⁇ 55° C. and treated with a solution of diethylchlorophosphate (1.1 mmole) in THF. After stirring at 25° C. for 12 h the reaction mixture was evaporated and subjected to extraction to give 5-diethylphosphono-furan-2-(N,N′-dimethylimidazolidine) as a brown oil.
  • Step G A solution of furan-2-(N,N′-dimethylimidazolidine) (1 mmole) and TMEDA (1 mmole) in THF was treated with nBuLi (1.3 mmole) at ⁇ 40 to ⁇ 48° C. The reaction
  • Step A A solution of furan (1.3 mmole) in toluene was treated with 4-methyl pentanoic acid (1 mmole), trifluoroacetic anhydride (1.2 mmole) and boron trifluoride etherate (0.1 mmole) at 56° C. for 3.5 h. The cooled reaction mixture was quenched with aqueous sodium bicarbonate (1.9 mmole), filtered through a celite pad. Extraction, evaporation and distillation gave 2-[(4-methyl-1-oxo)pentyl]furan as a brown oil (bp 65-77° C., 0.1 mm Hg). Step B.
  • Step E A solution of 2-[(4-methyl-1-oxo)pentyl]furan (1 mmole, prepared as in Step A) in benzene was treated with N,N-dimethyl hydrazine (2.1 mmole) and trifluoroacetic acid (0.05 mmole) at reflux for 6 h. Extraction and evaporation gave 2-[(4-methyl-1-oxo)pentyl]furan N,N-dimethyl hydrazone as a brown liquid.
  • Step F A solution of 2-[(4-methyl-1-oxo)pentyl]furan (1 mmole, prepared as in Step A) in benzene was treated with N,N-dimethyl hydrazine (2.1 mmole) and trifluoroacetic acid (0.05 mmole) at reflux for 6 h. Extraction and evaporation gave 2-[(4-methyl-1-oxo)pentyl]furan N,N-dimethyl hydrazone
  • Step G A solution of compound 1 (1 mmole) and 1,3-propanedithiol (1.1 mmole) in chloroform was treated with borontrifluoride etherate (0.1 mmole) at 25° C. for 24 h. Evaporation and chromatography gave 2-(2-(5-diethylphosphono)furanyl)-1,3-dithiane as a light yellow oil.
  • Step A A solution of compound 2.1 (1 mmole) in ethanol was treated with copper (11) bromide (2.2 mmole) at reflux for 3 h. The cooled reaction mixture was filtered and the filtrate was evaporated to dryness. The resulting dark oil was purified by chromatography to give 5-diethylphosphono-2-[(2-bromo-4-methyl-1-oxo)pentyl]furan as an orange oil.
  • Step B A solution of 5-diethylphosphono-2-[(2-bromo-4-methyl-1-oxo)pentyl]furan (1 mmole) and thiourea (2 mmole) in ethanol was heated at reflux for 2 h.
  • Step C A solution of 2-amino-5-isobutyl-4-[2-(5-diethylphosphono)-furanyl]thiazole (1 mmole) in methylene chloride was treated with bromotrimethylsilane (10 mmole) at 25° C. for 8 h. The reaction mixture was evaporated to dryness and the residue was suspended in water.
  • Step A A solution of 2-amino-4-[2-(5-diethylphosphono)furanyl]thiazole (prepared as in Step B of Example 3) (1 mmole) in chloroform was treated with N-bromo succinimide (NBS) (1.5 mmole) at 25° C. for 1 h. Extraction and chromatography gave 2-amino-5-bromo-4-[2-(5-diethylphosphono)furanyl]-thiazole as a brown solid.
  • NBS N-bromo succinimide
  • Step A A solution of 2-amino-5-isobutyl-4-[2-(5-diethylphosphono)-furanyl]thiazole (prepared as in Step B of Example 3) (1 mmole) in acetonitrile was treated with copper (II) bromide (1.2 mmole) and isoamyl nitlite (1.2 mmole) at 0° C. for 1 h. Extraction and chromatography gave 2-bromo-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole as a brown solid. Step B.
  • Step A A solution of 2-bromo-5-isobutyl-4-[2-(5-diethylphosphono)-furanyl]thiazole (1 mmole, prepared as in the Step A of Example 5) in DMF was treated with tributyl(vinyl)tin (5 mmole) and palladium bis(triphenylphosphine) dichloride (0.05 mmole) at 100° C. under nitrogen. After 5 h the cooled reaction mixture was evaporated and the residue was subjected to chromatography to give 2-vinyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole as a yellow solid. Step B.
  • This method can also be used to prepare various 5-substituted 4-[2-(5-phosphono)furanyl]thiazoles from their corresponding halides.
  • Step C 2-Amino-5-bromo-4-[2-(5-diethylphosphono)furanyl]thiazole was subjected to Step A using 2-tributylstannylfuran as the coupling partner to give 2-amino-5-(2-furanyl)-4-[2-(5-diethylphosphono)furanyl]thiazole.
  • Step D 2-Amino-5-(2-furanyl)-4-[2-(5-diethylphosphono)furanyl]thiazole was subjected to Step C of Example 3 to give 2-amino-5-(2-furanyl)-4-[2-(5-phosphono)furanyl]thiazole (6.2). mp 190-210° C. Anal. calcd. for C 11 H 9 N 2 O 5 PS+0.25HBr: C, 39.74; H, 2.80; N, 8.43. Found: C, 39.83; H, 2.92; N, 8.46.
  • Step A A solution of 2-vinyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]-thiazole (1 mmole, prepared as in the Step A of Example 6) in ethanol was treated with palladium on carbon (0.05 mmole) under 1 atmosphere of hydrogen for 12 h. The reaction mixture was filtered, the filtrate was evaporated and the residue was purified by chromatography to give 2-ethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole as a yellow foam.
  • Step B A solution of 2-vinyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole (1 mmole, prepared as in the Step A of Example 6) in ethanol was treated with palladium on carbon (0.05 mmole) under 1 atmosphere of hydrogen for 12 h. The reaction mixture was filtered, the filtrate was evaporated and the residue was purified by chromat
  • Step A A solution of diethyl hydroxymethylphosphonate (1 mmole) in DMF was treated with sodium hydride (1.2 mmole) followed by 2-methyl-4-chloromethylthiazole (1 mmole) at 0° C. and stirred at 25° C. for 12 h. Extraction and chromatography gave 2-methyl-4-(diethylphosphonomethoxymethyl)thiazole.
  • Step B 2-Methyl-4-diethylphosphonomethoxymethylthiazole was subjected to Step C of Example 3 to give 2-methyl-4-phosphonomethoxymethylthiazole (8.1). Anal. calcd.
  • Step C 2-Methyl-4-diethylphosphonomethoxymethylthiazole was subjected to Step A of Example 4 and followed by Step C of Example 3 to give 5-bromo-2-methyl-4-phosphonomethoxymethylthiazole (8.2).
  • Step A A solution of 2-ethoxycarbonyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole (1 mmole) in saturated methanolic ammonia solution at 25° C. for 12 h. Evaporation and chromatography gave 2-carbamoyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole as a white solid.
  • Step B A solution of 2-ethoxycarbonyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole (1 mmole) in saturated methanolic ammonia solution at 25° C. for 12 h. Evaporation and chromatography gave 2-carbamoyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole as a white solid.
  • Step C A solution of 2-ethoxycarbonyl-4-[2-(5-diethylphosphono)furanyl]thiazole (1 mmole) in methanol was treated with sodium borohydride (1.2 mmole) at 25° C. for 12 h. Extraction and chromatography gave 2-hydroxymethyl-4-[2-(5-diethylphosphono)furanyl]thiazole Step D. 2-Hydroxymethyl-4-[2-(5-diethylphosphono)furanyl]-thiazole was subjected to Step C of Example 3 to give 2-hydroxymethyl-4-[2-(5-phosphono)furanyl]thiazole (9.3). mp 205-207° C. Anal. calcd. for C 8 H 8 NO 5 PS+0.25H 2 O: C, 36.16; H, 3.22; N, 5.27. Found: C, 35.98; H, 2.84; N, 5.15.
  • Step I A solution of 2-bromomethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole (1 mmole) in DMF was treated with potassium phthalimide (1.2 mmole) at 25° C. for 12 h. Extraction and chromatography gave 2-phthalimidomethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole.
  • Step J 2-Phthalimidomethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]-thiazole (1 mmole) in ethanol was treated with hydrazine (1.5 mmole) at 25° C. for 12 h.
  • Step A A solution of 5-diethylphosphono-2-[(2-bromo-4-methyl-1-oxo)pentyl]furanyl (1 mmole) in t-BuOH was treated with urea (10 mmole) at reflux for 72 h. Filtration, evaporation and chromatography gave 2-amino-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]oxazole, and 2-hydroxy-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]imidazole.
  • Step B A solution of 5-diethylphosphono-2-[(2-bromo-4-methyl-1-oxo)pentyl]furanyl (1 mmole) in t-BuOH was treated with urea (10 mmole) at reflux for 72 h. Filtration, evaporation and chromatography gave 2-amino-5-isobutyl-4-[2-(5-die
  • 4-[2-(5-phosphono)furanyl]oxazoles and 4-[2-(5-phosphono)furanyl]imidazoles can be prepared as follows:
  • Step D A solution of 5-diethylphosphono-2-[(2-bromo-4-methyl-1-oxo)pentyl]furan (1 mmole) in acetic acid was treated with sodium acetate (2 mmole) and ammonium acetate (2 mmole) at 100° C. for 4 h.
  • Step F A solution of 5-diethylphosphono-2-(bromoacetyl)furan (1 mmole) in ethanol was treated with trifluoroacetamidine (2 mmole) at 80° C. for 4 h. Evaporation and chromatography gave 2-trifluoromethyl-4-[2-(5-diethylphosphono)furanyl]imidazole as an oil.
  • Step G 2-Trifluoromethyl-4-[2-(5-diethylphosphono)furanyl]imidazole was subjected to Step C of Example 3 to give 2-trifluoromethyl-4-[2-(5-phosphono)-furanyl]imidazole (10.22). mp 188° C. (dec.); Anal. calcd. for C 8 H 6 F 3 N 2 O 4 P+0.5HBr: C, 29.79; H, 2.03; N, 8.68. Found: C, 29.93; H, 2.27; N, 8.30.
  • 4,5-dimethyl-1-isobutyl-2-[2-(5-phosphono)furanyl]-imidazole can be prepared as follows:
  • Step H A solution of 5-diethylphosphono-2-furaldehyde (1 mmole), ammonium acetate (1.4 mmole), 3,4-butanedione (3 mmole) and isobutylamine (3 mmole) in glacial acetic acid was heated at 100° C. for 24 h. Evaporation and chromatography gave 4,5-dimethyl-1-isobutyl-2-[2-(5-diethylphosphono)furanyl]imidazole as an yellow solid.
  • 4,5-Dimethyl-1-isobutyl-2-[2-(5-diethylphosphono)furanyl]-imidazole was subjected to Step C of Example 3 to give 4,5-dimethyl-1-isobutyl-2-[2-(5-phosphono)furanyl]imidazole (10.23); Anal. calcd. for C 13 H 19 N 2 O 4 P+1.35HBr: C, 38.32; H, 5.03; N, 6.87. Found: C, 38.09; H, 5.04; N, 7.20.
  • Step A A suspension of cesium carbonate (1.5 mmole) and 2-methyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]imidazole (1 mmole) in DMF was treated with iodomethane (1.5 mmole) at 25° C. for 16 h. Extraction and chromatography gave 1,2-dimethyl-4-isobutyl-5-[2-(5-diethylphosphono)-fiuanyl]imidazole and 1,2-dimethyl-5-isobutyl-4-[2-(5-diethylphosphono)-furanyl]imidazole.
  • Step B A suspension of cesium carbonate (1.5 mmole) and 2-methyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]imidazole (1 mmole) in DMF was treated with iodomethane (1.5 mmole) at 25° C. for 16 h
  • Step A A solution of 2,2′-bipyridyl (1 mmole) in dichloromethane was treated with m-chloroperoxybenzoic acid (2 mmole) at 0° C., and the reaction mixture was stirred at 25° C. for 2 h. Extraction and chromatography gave 2,2′-bipyridyl-N-oxide.
  • Step B (Redmore, D., J. Org.
  • Step A A solution of 2,4,6-collidine (1 mmole) in carbon tetrachloride was treated with NBS (5 mmole) and dibenzoyl peroxide (0.25 mmole) at 80° C. for 12 h. The reaction mixture was cooled to 0° C. and the precipitate was filtered. The filtrate was concentrated under vacuum. Chromatography gave 2-bromomethyl-4,6-dimethylpyridine.
  • Step B A solution of diethyl hydroxymethylphosphonate (1 mmole) in toluene was treated with sodium hydride (1.1 mmole) at 0° C., and after 15 min 2-bromomethyl-4,6-dimethylpyridine (1 mmole) was added.
  • Step A A solution of 2,6-dichloropyridine (120 mmol) in ethanol was treated with aqueous ammonia solution (28%, excess) at 160-165° C. for 60 h in a sealed tube. Extraction and chromatography gave 2-amino-6-chloropyridine as a white solid.
  • Step B A solution of 2-amino-6-chloropyridine (1 mmole) and compound 14 (1 mmole) in p-xylene was treated with tetrakis(triphenylphosphhine) palladium (0.05 mmole) at reflux for 12 h.
  • Step A A solution of 5-diethylphosphono-2-[(1-oxo)pentyl]furan in N,N-dimethylformamide dimethyl acetal was heated at reflux for 12 h. Evaporation and chromatography gave diethyl 5-(2-propyl-3-N,N-dimethylamino)acryloyl-2-furanphosphonate.
  • Step B A solution of diethyl 5-(2-propyl-3-N,N-dimethylamino)acryloyl-2-furanphosphonate (1 mmole) in ethanol was treated with guanidine hydrogen chloride (1.2 mmole) and sodium ethoxide (1 mmole) at 80° C. for 12 h.
  • Step E Compound 2.2 was subjected to Step A of Example 16 to give diethyl 5-(3-N,N-dimethylamino)acryloyl-2-furanphosphonate as an orange solid.
  • Step F A solution of diethyl 5-(3-N,N-dimethylamino)acryloyl-2-furanphosphonate (1 mmole), sodium ethoxide ethanol solution (2 mmole) and guanidine hydrochloride (1.1 mmole) was heated at 55° C. for 2 h. The reaction mixture was cooled in an ice bath and was neutralized with 1N HCl.
  • Step A The procedures described in Example 16 can also be applied to the synthesis of 2-[2-(5-phosphono)furanyl]pyrazine and 2-[2-(5-phosphono)furanyl]triazine analogs and in some cases with minor modifications of these procedures using conventional chemistry methods.
  • Step A A solution of 2-amino-4-ethoxycarbonylthiazole (1 mmole) in 1,4-dioxane (5 mL) was treated with di-tert-butyl dicarbonate (1.2 mmole), TMEDA (0.1 mmole) and DMAP (0.1 mmole) at room temperature. After the reaction was stirred for 20 h, it was evaporated to dryness. The residue was subjected to extraction to give 2-[N-Boc(amino)]-4-ethoxycarbonyl thiazole as a yellow solid. Step B.
  • ester linkage can be formed using a mixed anhydride method as exemplified in the following procedures:
  • Step D A solution of 2-[N-Boc(amino)]-4-diethylphosphonomethoxycarbonylthiazole (1 mmole) and anisole (0.1 mmole) in methylene chloride (5 mL) and trifluoroacetic acid (5 mL) was stirred at 0° C. for 1 h, and at room temperature for 1 h. Evaporation, extraction and chromatography gave 2-amino-4-diethyllphosphonomethoxycarbonylthiazole as a solid.
  • Step G A solution of 2-[N-Boc(amino)]-5-bromo-4-diethylphosphonomethoxycarbonylthiazole (1 mmole) and dichlorobis(triphenylphosphine)palladium(II) (0.1 mmole) in DMF (5 mL) was treated with tributyl(vinyl)tin (2.5 mmole) and the reaction was stirred at 60° C. for 2 h.
  • Step H A suspension of 2-[N-Boc(amino)]-5-vinyl-4-diethylphosphonomethoxycarbonyl thiazole (1 mmole) and 10% Pd/C (0.5 mmole) in MeOH (5 mL) was stirred under an atmosphere of H 2 (balloon) at room temperature for 15 h.
  • Step L A solution of 2-[N-Boc(amino)]-4-thiazolecarboxylic acid (1 mmole) in DMF (5 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.5 mmole) and 1-hydroxylbenzotriazole hydrate (HOBt, 1.5 mmole) followed by addition of diethyl aminomethylphosphonate (1.5 mmole) at room temperature for 24 h.
  • EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • HOBt 1-hydroxylbenzotriazole hydrate
  • Step M A solution of 2-amino-4,5-dimethylthiazole hydrochloride (2 mmole) and diethyl phosphonoacetica acid (1 mmole) in DMF (5 mL) was treated with EDCI (1.5 mmole), HOBt (1.5 mmole) and triethylamine (2 mmole) at room temperature for 24 h.
  • Step A A solution of diethyl 5-(2-isobutyl-3-N,N-dimethylamino)acryloyl-2-furanphosphonate (1 mmole, prepared according to Step A of Example 17) in ethanol was treated with hydrazine (1.2 mmole) 80° C. for 12 h. Evaporation and chromatography gave 4-isobutyl-3-[2-(5-diethylphosphono)furanyl]pyrazole.
  • Step B 4-Isobutyl-3-[2-(5-diethylphosphono)furanyl]pyrazole was subjected to Step C of Example 3 to give 4-isobutyl-3-[2-(5-phosphono)furanyl]pyrazole (19.1).
  • Step C 4-Isobutyl-3-[2-(5-diethylphosphono)furanyl]pyrazole was subjected to Step A of Example 11 to give 1-methyl-4-isobutyl-3-[2-(5-diethylphosphono)furanyl]pyrazole.
  • Step A A solution of 5-diethylphosphono-2-furaldehyde (1 mmole) in ethanol was treated with hydroxylamine (1.1 mmole) and sodium acetate (2.2 mmole) at 25° C. for 12 h. Extraction and chromatography gave 5-diethylphosphono-2-furaldehyde oxime.
  • Step B A solution of 5-diethylphosphono-2-furaldehyde oxime (1 mmole) in DMF was treated with N-chlorosuccinimide (1.1 mmole) at 25° C. for 12 h. Extraction gave 5-diethylphosphono-2-chlorooximidofuran. Step C.
  • Step A Diethyl 5-tributylstannyl-2-furanphosphonate (14) and 2-bromo-4-ethoxycarbonylthiazole was subjected to Step A of Example 6 to give 4-ethoxycarbonyl-2-[2-(5-diethylphosphono)furanyl]thiazole.
  • Step B 4-Ethoxycarbonyl-2-[2-(5-diethylphosphono)furanyl]thiazole was subjected to Step A of Example 9 followed by Step C of Example 3 to give 4-carbamoyl-2-[2-(5-phosphono)furanyl]thiazole (21.1). mp 239-240° C. Anal. calcd. for C 8 H 7 N 2 O 5 PS+0.2H 2 O: C, 34.59; H, 2.68; N, 10.08. Found: C, 34.65; H, 2.69; N, 9.84.
  • Step A A solution of 3-(tert-butyl-diphenylsilyloxy)-1-propanol (1 mmole) in methylene chloride (7 mL) was treated with powder molecular sieves (4 A, 0.5 equiv. wt/wt) and pyridinium chlorochromate (1.5 mmole) at 0° C. The resulting mixture was stirred at room temperature for 2 h, and diluted with diethyl ether (7 mL) and stirred at room temperature for another 30 min. Filtration, evaporation and chromatography gave 3-(tert-butyldiphenylsilyloxy)-1-propanal as a clear oil.
  • Step B A solution of 3-(tert-butyl-diphenylsilyloxy)-1-propanol (1 mmole) in methylene chloride (7 mL) was treated with powder molecular sieves (4 A, 0.5 equiv. wt/wt) and
  • Step F A solution of diethyl 3-carboxyl-2,3-difluoropropylphosphonate (1 mmole) in thionyl chloride (3 mL) was heated to reflux for 2 h. The reaction was evaporated to dryness, and the residue was dissolved in diethyl ether (1 mL) was treated with an etheral solution of diazomethane (10 mmole) at 0° C. for 30 min.
  • Step A A solution of 2-methylthio-1,3,4-thiadiazole-5-thiol (1 mmole) in THF (5 mL) was treated with sodium hydride (60%, 1.1 mmole) at 0° C. and the resulting mixture was stirred at room temperature for 30 min. The reaction was then cooled to 0° C. and treated with diethylphosphonomethyl trifluoromethanesulfonate (1.1 mmole). After stirring at room temperature for 12 h, the reaction was quenched with saturated ammonium chloride. Extraction and chromatography gave 2-methylthio-5-diethylphosphonomethylthio-1,3,4-thiadiazole as an oil. Step B.
  • phosphonomethylthio substituted heteroaromatics are made using the following method as exemplified by the synthesis of 2-phosphonomethylthiopyridine:
  • Step C A solution of 2,2′-dipyridyl disulfide (1 mmole) in THF was treated with tri-n-butylphosphine (1 mmole) and diethyl hydroxymethylphosphonate at 0° C. The resulting reaction solution was stirred at room temperature for 18 h. Extraction and chromatography gave 2-diethylphosphonomethylthiopyridine as a yellow oil. Step D. 2-Diethylphosphonomethylthiopyridine was subjected to Step C of Example 3 to give 2-phosphonomethylthiopyridine (23.2) as a yellow solid. Anal. calcd. for C 6 H 8 NO 3 PS+0.62 HBr: C, 28.22; H, 3.40; N, 5.49. Found: C, 28.48; H, 3.75; N, 5.14.
  • Step A A solution of 2-ethynylpyridine (1 mmole) in THF (5 mL) was treated with LDA (1.2 mmole) at 0° C. for 40 min. Diethyl chlorophosphate (1.2 mmole) was added to the reaction and the resulting reaction solution was stirred at room temperature for 16 h. The reaction was quenched with saturated ammonium chloride followed by extraction and chromatography to give 2-[(2-diethylphosphono)ethynyl]pyridine as a yellow oil.
  • Step B A solution of 2-ethynylpyridine (1 mmole) in THF (5 mL) was treated with LDA (1.2 mmole) at 0° C. for 40 min. Diethyl chlorophosphate (1.2 mmole) was added to the reaction and the resulting reaction solution was stirred at room temperature for 16 h. The reaction was quenched with saturated ammonium chloride followed by extraction and chromatography to give 2-[(2-diethy
  • Step A To a mixture of tetrazole (1 mmole) and powdered K 2 CO 3 (1.5 mmole) in 1 mL DMF cooled to 0° C. was added benzyl chloromethyl ether (1.2 mmole) and the resulting mixture stirred for 30 min at 0° C. and then for 16 h at rt. The mixture was diluted with water and ether. Extraction and chromatography provided 2-benzyloxymethyltetrazole as a colorless oil.
  • Step B To a solution of 2-benzyloxymethyltetrazole (1 mmole) and TMEDA (2 mmole) in 3 mL diethyl ether at ⁇ 78° C.
  • Step 1 A mixture of 5-[2-(5-diethylphosphono)furanyl]tetrazole (1 mmole), 1-iodo-2-methylpropane (2 mmole) and powdered K 2 CO 3 (2 mmole) in 5 mL DMF was stirred at 80° C. for 48 h and then diluted with CH 2 Cl 2 and water and the layers separated. The CH 2 O 2 layer was evaporated and combined with the product of the following reaction for chromatography. Step 2. The aqueous layer of Step 1 was made acidic and extracted with EtOAc. This extract was evaporated and the residue heated at 80° C. in 2 mL of SOCl 2 for 3 h and then the solvent evaporated.
  • Step A Various 2-(5-diethylphosphono)furanyl substituted heteroaromatic compounds were prepared in a similar manner as Step B of Example 15, and some of these compounds were used for the high throughput synthesis of compounds listed in Table 33.1 and Table 33.2.
  • Step B A mixture of 2-chloro-6-[2-(5-diethylphosphono)furanyl]pyridine (0.01 mmole) and TMSBr (0.1 mL) in CH 2 Cl 2 (0.5 mL) was stirred at room temperature for 16 h and then evaporated and diluted with 0.5 mL of 9:1 CH 3 CN:water. Evaporation provided 2-chloro-6-[2-(5-phosphono)furanyl]pyridine.
  • Step C A mixture of 2-chloro-6-[2-(5-diethylphosphono)furanyl]pyridine (0.01 mmole) and TMSBr (0.1 mL) in CH 2 Cl 2 (0.5 mL) was stirred at room
  • Step G A solution of trimethylphosphonoacetate (30.9 mmol), 2-(trimethylsiyl)ethanol (10.4 mmol) and DMAP (3.1 mmol) in toluene (25 mL) was refluxed for 48 h under N 2 . After cooling, the solution was diluted with EtOAc and washed with 1N HCl followed by water. The organic solution was dried over sodium sulfate and concentrated under vacuum to give an oil. The residue was treated with LiI (10.4 mmol) in 2-butanone (30 mL), and refluxed overnight under N 2 .
  • Step H Hydroxymethylpolystyrene (2.35 mmol) was prepared for coupling by combining with anhydrous THF (40 mL), gently shaking for 20 min. and then removing the excess solvent by cannula. This procedure was repeated 3 times. The swollen resin was then suspended in THF (40 mL) and DIPEA (21.2 mmol).
  • Step J In a 2 mL well, a heteroaromatic amine (0.14 mmol), resin (0.014 mmol), PyBOP (0.14 mmol) and TEA (0.36 mmol) in DMF (1.45 mL) were combined and shaken for 48 h at room temperature. The treated resin was then filtered, washed with DMF (3 ⁇ ) and CH 2 Cl 2 (3 ⁇ ). The isolated resin was resuspended in CH 2 Cl 2 (900 ⁇ L), combined with TMSBr (100 ⁇ L) and mixed for 6 h. The mixture was filtered, the resin washed with anhydrous CH 2 Cl 2 (500 ⁇ L) and the filtrate concentrated under vacuum.
  • Step K To a solution of dimethyl phthalimidomethylphosphonate (37 mmole) in 2-butanone (150 mL) was added LiI (38.9 mmol). After refluxing overnight under N 2 , the solution was diluted with EtOAc, washed with 1N HCl, dried over MgSO 4 and concentrated under vacuum to afford monomethyl phthalimidomethylphosphonate as a white solid.
  • Step L As described above in Step H, monomethyl phthalimidomethyl-phosphonate was coupled to hydroxymethylpolystyrene to give the resin-coupled phthalimidomethylphosphonate monomethyl ester. Step M.
  • Step N In a 2 mL well, a heteroaromatic carboxylic acid (0.2 mmol), resin (0.02 mmol), EDC (0.2 mmol) and HOBT (0.2 mmol) in DMF (0.5 mL) were combined and shaken for 24 h at room temperature. The treated resin was then filtered, washed with DMF (3 ⁇ ) and CH 2 Cl 2 (3 ⁇ ). The isolated resin was resuspended in CH 2 Cl 2 (500 ⁇ L), combined with TMSBr (50 ⁇ L) and mixed for 6 h. The mixture was filtered, the resin washed with anhydrous CH 2 Cl 2 (500 ⁇ L) and the filtrate concentrated under vacuum.
  • HPLC was performed using a YMC ODS-Aq, Aq-303-5, 250 4.6 mm ID, S-5 ⁇ m, 120 A column with the UV detector set at 280 nm.
  • Step A A solution of AlCl 3 (5 mmole) in EtSH (10 mL) was cooled to 0° C. and treated with 2-amino-4-methoxybenzothiazole (1 mmole). The mixture was stirred at 0-5° C. for 2 h. Evaporation and extraction gave 2-amino-4-hydroxybenzothiazole as white solid.
  • Step B A mixture of 2-amino-4-hydroxybenzothiazole (1 mmole) and NaH (1.3 mmole) in DMF (5 mL) was stirred at 0° C. for 10 min, and then treated with diethylphosphonomethyl trifluoromethylsulfonate (1.2 mmole). After being stirred at room temperature for 8 h.
  • Step C A solution of 2-amino-4-(diethylphosphonomethyloxy)benzothiazole (1 mmole) in AcOH (6 mL) was cooled to 10° C. and treated with bromine (1.5 mmole) in AcOH (2 mL). After 5 min the mixture was stirred at room temperature for 2.5 h. The yellow precipitate was collected via filtration and washed with CH 2 Cl 2 to give 2-amino-4-diethylphosphonomethyloxy-6-bromobenzothiazole.
  • Step D A solution of 2-amino-4-(diethylphosphonomethyloxy)benzothiazole (1 mmole) in AcOH (6 mL) was cooled to 10° C. and treated with bromine (1.5 mmole) in AcOH (2 mL). After 5 min the mixture was stirred at room temperature for 2.5 h. The yellow precipitate was collected via filtration and washed with CH 2 Cl 2 to give 2-amino-4-diethylphosphonomethyloxy-6
  • Step A A solution of 1-(2-methoxy-5-chlorophenyl)-2-thiourea (1 mmole) in chloroform (10 mL) was cooled to 10° C. and treated with bromine (2.2 mmole) in chloroform (10 mL). The reaction was stirred at 10° C. for 20 min and at room temperature for 0.5 h. The resulting suspension was heated at reflux for 0.5 h.
  • Step A 3-Amino-2-hydroxy-5,6,7,8-tetrahydronaphthalene was subjected to Step B of Example 27 to give 3-amino-2-diethylphosphonomethyloxy-5,6,7,8-tetrahydronaphthlene.
  • Step B A solution of KSCN (16 mmole) and CuSO 4 (7.7 mmole) in MeOH (10 mL) was treated with a solution of 3-amino-2-diethylphosphonomethyloxy-5,6,7,8-tetrahydronaphthalene (1 mmole) in MeOH (5 mL) at room temperature. The mixture was heated at reflux for 2 h.
  • Step A of Example 33 gave 2-Amino-5,7-dichloro-6-methyl-4-phosphonomethoxybenzothiazole. mp.>230° C. (dec.).
  • Anal. calcd. for C 9 H 9 N 2 O 4 PSCl 2 C, 31.50; H, 2.64; N, 8.16. Found: C, 31.61; H, 2.66; N, 8.08.
  • (29.6) Starting with 2-hydroxy-4-methoxycarbonyl aniline and using the same reaction sequence as above gave 2-Amino-4-phosphonomethoxy-6-carboxybenzothiazole. mp.>230° C. (dec.).
  • Anal. calcd. for C 9 H 9 N 2 O 6 PS C, 35.53; H, 2.98; N, 9.21. Found: C, 35.56; H, 3.26; N, 9.03.
  • Step A 2-Hydroxy-5-methoxynitrobenzene was subjected to Step B of Example 27 to give 2-diethylphosphonomethyloxy-5-methoxynitrobenzene.
  • Step B A solution of SnCl 2 (4 mmole) in freshly prepared methonolic HCl (10 mL) was added to a cold (0° C.) solution of 2-diethylphosphonomethyloxy-5-methoxynitrobenzene (1 mmole) in MeOH (5 mL). The mixture was warmed to room temperature and stirred for 3 h. Evaporation, extraction and chromatography provided 2-diethylphosphonomethyloxy-5-methoxyaniline.
  • Step C A solution of SnCl 2 (4 mmole) in freshly prepared methonolic HCl (10 mL) was added to a cold (0° C.) solution of 2-diethylphosphonomethyloxy-5-methoxynitrobenzene (1 mmole) in MeOH (5 mL). The
  • Step A A solution of 2-fluoro-5-bromonitrobenzene (1 mmole) in DMF (5 mL) was cooled to 0° C., and treated with a solution of freshly prepared sodium salt of diethylhydroxymethylphosphonate (1.2 mmole) in DMF (5 mL). The mixture was stirred at room, temperature for 16 h. Evaporation, extraction and chromatography provided 2-diethylphosphonomethyloxy-5-bromonitrobenzene. Step B.
  • Step A 2-Chloro-5-formylnitrobenzene was subjected to Step A of Example 31 to give 2-diethylphosphonomethyloxy-5-formylnitrobenzene.
  • Step B A solution of 2-diethylphosphonomethyloxy-5-formylnitrobenzene (1 mmole) in methanol (5 mL) was treated with 10% palladium on carbon (0.05 mmole) under 1 atmosphere of hydrogen at room temperature for 12 h.
  • Step A A solution of 2-diethylphosphonomethyloxy-4-bromo-5-fluoroaniline (1 mmole, prepared as in Example 4, Step B) and KSCN (2 mmole) in AcOH (8 mL) was cooled to 10° C., and treated with a solution of bromine (2 mmole) in AcOH (5 mL).
  • Step A A solution of 2-diethylphosphonomethyloxy-5-bromonitrobenzene (1 mmole, prepared as in Example 31, Step A from 2-fluoro-5-bromonitrobenzene) in DMF (5 mL) was treated with tributyl(vinyl)tin (1.2 mmole) and palladium bis(triphenylphosphine) dichloride (0.1 mmole), and the mixture was heated at 60° C. under nitrogen for 6 h.
  • Step A A suspension of 2-diethylphosphonomethyloxy-5-vinylnitrobenzene (1 mmole, prepared as in Step A of Example 33) and Pd(OAc) 2 (0.1 mmole) in ether (8 mL) was treated with a solution of diazomethane (generated from 3.0 g of 1-methyl-3-nitro-1-nitrosoguanidine) in ether at 0° C.
  • Step A 2-Methoxy-4-chloro-5-methylaniline was subjected to Steps A and B of Example 27, Step B of Example 29, and Step D of Example 27 to give 2-amino-4-phosphonomethoxy-6-chloro-7-methyl benzothiazole (36.1). mp>250° C. (dec.). Anal. calcd. for C 9 H 10 N 2 O 4 PS 2 Cl+0.3H 2 O+0.4 HBr: C, 31.20; H, 3.20; N, 8.09. Found: C, 31.37; H, 2.87; N, 7.89.
  • Step A A solution of 2-amino-4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole (1 mmole) in CH 3 CN (4 mL) was cooled to 0° C., and treated with CuBr 2 (1.2 mmole) followed by isoamylnitrite (1.5 mmole) in a dropwise fashion. The resulting dark mixture was stirred for 3.5 h. Evaporation and chromatography gave 2-bromo-4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole as an oil.
  • Step B A solution of 2-amino-4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole 1 mmole) in CH 3 CN (4 mL) was cooled to 0° C., and treated with CuBr
  • Step A A solution of isoamylnitrite (1.5 mmole) in DMF (1 mL) at 65° C. was treated with 2-amino-4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole (1 mmole) in DMF (3 mL).
  • Step A 2-Diethylphosphonomethylthioaniline, prepared according to Step B of Example 27, was subjected to Step B of Example 29 to give 2-amino-4-diethylphosphonomethylhio-benzothiazole.
  • Step B 2-Amino-4-diethylphosphonomethylhiobenzothiazole was subjected to Step D of Example 34 to give 2-amino-4-phosphonomethythiobenzothiazole (39.1) as a foam.
  • Step A A solution of 1 mmole of 2-diethylphosphonomethoxy-5-bromonitrobenzene (prepared as in Example 30, step A) in diethyl amine (5 mL) was treated with 1-hexyne (1.2 mmole), CuI (0.1 mmole) and palladium bis(triphenylphosphine) dichloride (0.1 mmole), and the mixture was heated at 60° C. under nitrogen for 14 h.
  • Step A A solution of 2-chloro-4-floro-5-methylnitrobenzene (1 mmole) in DMF (5 mL) was treated with fresh sodium methoxy (1.1 mmole), and the mixture was stirred for 6 h. Evaporation and chromatography gave 2-chloro-4-methoxy-5-methylnitrobenzene.
  • Step B 2-chloro-4-methoxy-5-methylnitrobenzene was subjected to Step A of Example 31, Step B of Example 32, Step A of Example 33, and Step D of Example 27 to give 2-Amino-6-methoxy-7-methyl-4-phosphonomethoxybenzothiazole 41.1. mp.>250° C. (dec.). Anal. calcd. for C 10 H 13 N 2 O 4 PS: C, 39.48; H, 4.31; N, 9.21. Found: C, 39.39; H, 4.17; N, 8.98.
  • Step A To a solution of 1 mmol of 3-bromo chlorobenzene in 2 mL of con. H 2 SO 4 was added 1.5 mmol of 79% HNO 3 at ⁇ 10° C. After it was stirred for 30 min. the mixture was poured onto ice/water mixture. The yellow precipitate was filtered and dried to give a mixture of 2-chloro-4-bromo nitrobenzene (desired) and 4-chloro-2-bromo nitrobenzene. Step B.
  • Step A A solution of 1 mmol of 2-Amino-6-thio-7-ethyl-4-diethylphosphonomethoxybenzothiazole (for preparation see Example 34) in 3 mL of 48% HBr in AcOH was heated at 90° C. for 16 h. Solvent was removed and the residue was washed with water to give 2-Amino-6-thio-7-ethyl-4-phosphonomethoxybenzothiazole (43.1). mp.>220° C. (dec.). Anal. calcd. for C 10 H 13 N 2 O 4 PS 2 +0.2 HBr: C, 35.69; H, 3.95; N, 8.33. Found: C, 35.49; H, 3.74; N, 8.33.
  • Step A To a solution of 1 mmol of 2-chloro-5-hydroxy nitrobenzene in 5 mL of DMF was added 1.2 mmol of NaH at 0° C. After 30 min, allyl bromide was added and the mixture was stirred at rt for 16 h. Solvent was removed and the residue was washed with water and extracted with EtOAc to give 2-chloro-5-propenyloxy nitrobenzene.
  • Step B 2-Chloro-5-propenyloxy nitrobenzene was subjected to Step A of Example 31, Step B of Example 32, Step A of Example 33, and Step D of Example 27 to give 2-Amino-7-propyloxy-6-thiocyano-4-phosphonomethoxy benzothiazole.
  • Step A 2-Hydroxy-4-methoxy nitrobenzene was subjected to Step B of Example 32, Step B of Example 27, Step B of Example 29, Step D of Example 27 to give 2-Amino-6-methoxy-4-phosphonomethoxybenzothiazole (45.1) mp.>230° C. (dec.).
  • Step A 2-Fluoro-4-methyl nitrobenzene was subjected to Step A of Example 31, Step C of Example 27, Step A of Example 34, Step B of Example 32, Step B of Example 29, Step D of Example 27 to give (46.1) 2-Amino-7-ethyl-6-methyl-4-phosphonomethoxybenzothiazole. mp.>250° C. (dec.).
  • Step A 2-Fluoro-4-methyl nitrobenzene was subjected to Step A of Example 31, Step C of Example 27, Step B of Example 30, Step A of Example 33, Step D of Example 27 to give 2-Amino-7-bromo-6-methyl-4-phosphonomethoxybenzothiazole. (47.1) mp.>250° C. (dec.).
  • Step A 2-Hydroxy-4-methyl-5-fluoro nitrobenzene was subjected to Step B of Example 27, Step B of Example 32, Step A of Example 33, Step D of Example 27 to give (48.1) 2-Amino-7-fluoro-6-methyl-4-phosphonomethoxybenzothiazole. mp.>250° C. (dec.). Anal. calcd. for C 9 H 10 N 2 O 4 PSF+0.1 HBr: C, 35.99; H, 3.39; N, 9.33. Found: C, 35.84; H, 3.32; N, 9.31.
  • Step A 2-Amino-4,7-dimethoxy benzothiazole [prepared from 1-(2,5-dimethoxyphenyl)-2-thiourea using the procedure Step A of Example 28] was subjected to Step C to give 2-Amino-4,7-dimethoxy-6-bromo benzothiazole.
  • Step B To a solution of 1 mmol of 2-Amino-4,7-dimethoxy-6-bromo benzothiazole in CH 2 Cl 2 was added 2.2 mmol of BBr 3 in CH 2 Cl 2 at 0° C. for 16 h. Aqueous work-up and chromatography gave 2-amino-4-hydroxy-6-bromo-7-methoxy benzothiazole.
  • Step C To a solution of 1 mmol of 2-Amino-4,7-dimethoxy-6-bromo benzothiazole in CH 2 Cl 2 was added 2.2 mmol of BBr 3 in CH 2 Cl 2 at 0° C. for 16 h.
  • Method A The crude dichloridate was taken into 5 mL of dry CH 2 Cl 2 , and was added 8 mmol of amino acid ester at 0° C. The resultant mixture was allowed to come to rt where it was stirred for 16 h. The reaction mixture was subjected to aq. work up and chromatography.
  • Method B The crude dichloridate was taken into 5 mL of dry CH 2 Cl 2 , and was added a mixture of 4 mmol of amino acid ester and 4 mmol of N-methylimidazole at 0: ° C. The resultant mixture was allowed to come to rt where it was stirred for 16 h. The reaction mixture was subjected to aq. work up and chromatography.
  • Compound A is 4-Amino-5-fluoro-7-ethyl-1-isobutyl-2-(2-phosphono-5-furanyl)benzimidazole;
  • Compound B is 4-Amino-5-fluoro-1-cyclopropylmethyl-2-(2-phosphono-5-furanyl)benzimidazole.
  • Compound C is 2-Amino-5-isobutyl-4- ⁇ 2-[N-(1-methyl-1-carboxy)ethylmonophosphonamido]furanyl ⁇ thiazole
  • assays that may be useful for identifying compounds which inhibit gluconeogenesis include the following animal models of diabetes:
  • Streptozotocin e.g. the Streptozotocin-treated mouse, rat, dog, and monkey.
  • mice such as the C57BL/Ks db/db, C57BL/Ks ob/ob, and C57BL/6J ob/ob strains from Jackson Laboratory, Bar Harbor, and others such as Yellow Obese, T-KK, and New Zealand Obese.
  • Mutant rats such as the Zucker fa/fa Rat rendered diabetic with Streptozotocin or Dexamethasone, the Zucker Diabetic Fatty Rat, and the Wistar Kyoto Fatty Rat. Stolz, K. J., Martin, R. J. Journal of Nutrition 112, 997-1002 (1982) (Streptozotocin); Ogawa, A., Johnson, J. H., Ohnbeda, M., McAllister, C. T., Inman, L., Alam, T., Unger, R. H., The Journal of Clinical Investigation 90, 497-504 (1992) (Dexamethasone); Clark, J. B., Palmer, C.
  • E. coli strain BL21 transformed with a human liver FBPase-encoding plasmid was obtained from Dr. M. R. El-Maghrabi at the State University of New York at Stony Brook.
  • the enzyme was typically purified from 10 liters of recombinant E. coli culture as described (M. Gidh-Jain et al., 1994, The Journal of Biological Chemistry 269, pp 27732-27738).
  • Enzymatic activity was measured spectrophotometrically in reactions that coupled the formation of product (fructose 6-phosphate) to the reduction of dimethylthiazoldiphenyltetrazolium bromide (MTT) via NADP + and phenazine methosulfate (PMS), using phosphoglucose isomerase and glucose 6-phosphate dehydrogenase as the coupling enzymes.
  • Reaction mixtures (200 ⁇ l) were made up in 96-well microtitre plates, and consisted of 50 mM Tris-HCl, pH 7.4, 100 mM KCl, 5 mM EGTA, 2 mM MgCl 2 , 0.2 mM NADP, 1 mg/ml BSA, 1 mM MTT, 0.6 mM PMS, 1 unit/ml phosphoglucose isomerase, 2 units/ml glucose 6-phosphate dehydrogenase, and 0.150 mM substrate (fructose 1,6-bisphosphate). Inhibitor concentrations were varied from 0.01 ⁇ M to 10 ⁇ M. Reactions were started by the addition of 0.002 units of pure hlFBPase, and were monitored for 7 minutes at 590 nm in a Molecular Devices Plate Reader (37° C.).
  • the table below provides the IC 50 values for several compounds prepared.
  • the IC 50 for AMP is 1 ⁇ LM.
  • E. Coli strain BL21 transformed with a rat liver FBPase-encoding plasmid was obtained from Dr. M. R. El-Maghrabi at the State University of New York at Stony Brook. Recombinant FBPase was purified as described (El-Maghrabi, M. R., and Pilkis, S. J. (1991) BioChem. Biophys. Res. Commun. 176, 137-144) The enzyme assay was identical to that described above for human liver FBPase.
  • the table below provides the IC 50 values for several compounds prepared.
  • the IC 50 for AMP is 20 ⁇ M.
  • the enzyme is incubated with radio-labeled AMP in the presence of a range of test compound concentrations.
  • the reaction mixtures consist of 25 mM 3 H-AMP (54 mCi/mmole) and 0-1000 mM test compound in 25 mM Tris-HCl, pH 7.4, 100 mM KCl and 1 mM MgCl 2 . 1.45 mg of homogeneous FBPase ( ⁇ nmole) is added last.
  • AMP bound to FBPase is separated from unbound AMP by means of a centrifugal ultrafiltration unit (“Ultrafree-MC”, Millipore) used according to the instructions of the manufacturer.
  • Ultrafree-MC centrifugal ultrafiltration unit
  • the radioactivity in aliquots (100 ⁇ l) of the upper compartment of the unit (the retentate, which contains enzyme and label) and the lower compartment (the filtrate, which contains unbound label) is quantified using a Beckman liquid scintillation counter.
  • the amount of AMP bound to the enzyme is estimated by comparing the counts in the filtrate (the unbound label) to the total counts in the retentate.
  • Hepatocytes were prepared from overnight fasted Sprague-Dawley rats (250-300 g) according to the procedure of Berry and Friend (Berry, M. N., Friend, D. S., 1969, J. Cell. Biol. 43, 506-520) as modified by Groen (Groen, A. K., Sips, H. J., Vervoorn, R. C., Tager, J. M., 1982, Eur. J. BioChem. 122, 87-93).
  • Hepatocytes (75 mg wet weight/ml) were incubated in 1 ml Krebs-bicarbonate buffer containing 10 mM Lactate, 1 mM pyruvate, 1 mg/ml BSA, and test compound concentrations from 1 to 500 ⁇ M. Incubations were carried out in a 95% oxygen, 5% carbon dioxide atmosphere in closed, 50-ml Falcon tubes submerged in a rapidly shaking water bath (37° C.). After 1 hour, an aliquot (0.25 ml) was removed, transferred to an Eppendorf tube and centrifuged. 50 ⁇ l of supernatant was then assayed for glucose content using a Sigma Glucose Oxidase kit as per the manufacturer's instructions.
  • Isolated rat hepatocytes are prepared as described in Example C and incubated under the identical conditions described. Reactions are terminated by removing an aliquot (250 ⁇ L) of cell suspension and spinning it through a layer of oil (0.8 ml silicone/mineral oil, 4/1) into a 10% perchloric acid layer (100 ⁇ L). After removal of the oil layer, the acidic cell extract layer is neutralized by addition of 1 ⁇ 3 volume of 3 M KOH/3 M KHCO 3 . After thorough mixing and centrifugation, the supernatant is analyzed for glucose content as described in Example C, and also for fructose-1,6-bisphosphate.
  • Fructose 1,6-bisphosphate is assayed spectrophotometrically by coupling its enzymatic conversion to glycerol 3-phosphate to the oxidation of NADH, which is monitored at 340 nm.
  • Reaction mixtures (1 mL) consist of 200 mM Tris-HCl, pH 7.4, 0.3 mM NADH, 2 units/ml glycerol 3-phosphate dehydrogenase, 2 units/ml triosephosphate isomerase, and 50-100 ⁇ l cell extract. After a 30 minute preincubation at 37° C., 1 unit/ml of aldolase is added and the change in absorbance measured until a stable value is obtained. 2 moles of NADH are oxidized in this reaction per mole of fructose-1,6-bisphosphate present in the cell extract.
  • a dose-dependent inhibition of glucose production accompanied by a dose-dependent accumulation of fructose-1,6-bisphosphate is an indication that the target enzyme in the gluconeogenic pathway, FBPase, is inhibited.
  • Aim To assess the stability of prodrugs 50.6, 50.9, 50.15, and 50.20 in a phosphate buffered, aqueous solution at neutral pH.
  • results The prodrugs evaluated exhibited good stability at neutral pH. Less than 10% decomposition of the prodrugs was noted over a 4 day incubation period. The t90's for 50.6, 50.9, 50.15, and 50.20 at pH 7 were thus >96 hours.
  • Aim To estimate the oral bioavailability of prodrugs by means of the urinary parent compound excretion method in the rat.
  • Prodrugs were dissolved in 10% ethanol/90% polyethylene glycol (mw 400) and administered by oral gavage at doses of 10 to 40 mg/kg parent compound equivalents to 6-hour fasted, Sprague Dawley rats (220-240 g).
  • Parent compounds were typically dissolved in deionized water, neutralized with sodium hydroxide, and then administered via the tail vein at ⁇ 10 mg/kg to rats that were briefly anesthetized with halothane. The rats were subsequently placed in metabolic cages and urine was collected for 24 hours. The quantity of parent compound excreted into urine was determined by HPLC analysis. Analysis was performed as described in Example E. The percentage oral bioavailability was estimated by comparison of the recovery in urine of the parent compound generated from the prodrug administered orally, to that recovered in urine following intravenous administration of unsubstituted parent compound.

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Abstract

Novel bisamidate phosphonate prodrugs of FBPase inhibitors of the Formula IA:
Figure US20090192121A1-20090730-C00001
and their use in the treatment of diabetes and other conditions associated with elevated blood glucose.

Description

    RELATED APPLICATION
  • This application is a continuation of U.S. application Ser. No. 10/900,718, filed Jul. 28, 2004, which is a continuation of U.S. application Ser. No. 09/747,182, filed Dec. 22, 2000, now U.S. Pat. No. 6,965,033, which claims the benefit of priority to U.S. Ser. No. 60/171,862 filed Dec. 22, 1999, which are each incorporated by reference in their entireties.
    • FIELD OF THE INVENTION
  • The present invention is directed towards novel prodrugs, to their preparation, to their use for the oral delivery of Fructose-1,6-bisphosphatase inhibitors (FBPase), and to their use in the treatment of diabetes and other diseases where the inhibition of gluconeogenesis, control of blood glucose levels, reduction in glycogen storage, or reduction in insulin levels is beneficial.
    • BACKGROUND OF THE INVENTION
  • Organic compounds that are charged at physiological pH frequently exhibit limited oral bioavailability, cell penetration, and tissue distribution (e.g. CNS). These properties are attributed to the failure of ionic compounds to cross cell membranes by passive diffusion. One strategy to circumvent this problem is to prepare lipophilic prodrugs which are capable of crossing cell membranes and subsequently undergoing a transformation to generate the charged compound. The transformation could result from either chemical instability or an enzyme-catalyzed reaction.
  • A large number of structurally-diverse prodrugs are described for phosphonic acids. Freeman and Ross in Progress in Medicinal Chemistry 34: 112-147 (1997). The most commonly used prodrug class is the acyloxyalkyl ester, which was first used as a prodrug strategy for carboxylic acids and then applied to phosphates in 1983 by Farquhar et al. J. Pharm. Sci. 72: 324 (1983). Subsequently, the acyloxyalkyl ester was used to deliver phosphonic acids across cell membranes and to enhance oral bioavailability. A close valiant of the acyloxyalkyl ester strategy, the alkoxycarbonyloxyalkyl ester, is also reported to enhance oral bioavailability.
  • Much less success has been achieved with other classes of phosphonate prodrugs. Aryl esters, especially phenyl esters, are reported in a few cases to enhance oral bioavailability. DeLambert et al., J. Med. Chem. 37: 498 (1994). Phenyl esters containing a carboxylic ester ortho to the phosphate have also been described. Khamnei and Torrence, J. Med. Chem. 39:4109-4115 (1996). Benzyl esters are reported to generate the parent phosphonic acid. In some cases using substituents at the ortho- or para-position can accelerate the hydrolysis. Benzyl analogs with an acylated phenol or an alkylated phenol can generate the phenolic compound through the action of enzymes, e.g. esterases, oxidases, etc., which in turn undergoes cleavage at the benzylic C—O bond to generate the phosphoric acid and the quinone methide intermediate. Examples of this class of prodrugs are described by Mitchell et al., J. Chem. Soc. Perklin Trans. I 2345 (1992); Brook, et al. WO 91/19721. Still other benzylic prodrugs have been described containing a carboxylic ester-containing group attached to the benzylic methylene. Glazier et al. WO 91/19721. Thio-containing prodrugs are reported to be useful for the intracellular delivery of phosphonate drugs. These proesters contain an ethylthio group in which the thiol group is either esterified with an acyl group or combined with another thiol group to form a disulfide. Desterification or reduction of the disulfide generates the free thio intermediate which subsequently breaks down to the phosphoric acid and episulfide. Puech et al., Antivircil Res., 22: 155-174 (1993); Benzaria, et al., J. Med. Chem. 39: 4958 (1996). Cyclic phosphonate esters have also been described as prodrugs of phosphorus-containing compounds.
  • Some phosphoramidates are also known prodrugs of phosphonates, but they have shown poor oral bioavailability. In some cases the phosphoramindates were very unstable under acidic conditions which was reported as a potential explanation for their poor oral bioavailability (J. Med. Chem., 37: 1857-1864 (1994)). Similarly, poor oral bioavailability was reported for a bisamidate of a PMEA analog (J. Med, Chem., 38: 1372-1379 (1995)). Another PMEA prodrug consists of a mono glycine ester amidate and a phenyl ester (WO 95/07920).
  • Although numerous phosphoric acid prodrug strategies are reported to achieve high intracellular delivery of phosphoric acids, few are known to result in good oral bioavailability. In some cases, the prodrugs are unstable to the gastrointestinal tract environment (low pH, esterase activity). In other cases the prodrugs are too stable and are therefore poorly transformed in vivo to the parent drug.
  • WO 98/39344, WO 98/39343, WO 98/139342, and WO 00/14095 describe compounds containing phosphoric acids and esters that inhibit fructose-1,6-bisphosphatase.
  • The entire disclosures of the publication and references referred to above and hereafter in this specification are incorporated herein by reference and are not admitted to be prior art.
    • SUMMARY OF THE INVENTION
  • The present invention is directed towards novel bisamidate phosphonates that are potent FBPase inhibitors. In one aspect these compounds possess superior oral bioavailability compared to the corresponding phosphonic acids. In another aspect, the present invention is directed to the in vitro and in vivo FBPase inhibitory activity of these compounds. Another aspect of the present invention is directed to the clinical use of these FBPase inhibitors as a method of treatment or prevention of diseases responsive to inhibition of gluconeogenesis and in diseases responsive to lowered blood glucose levels.
  • In another aspect, the compounds are also useful in treating or preventing excess glycogen storage diseases and diseases such as cardiovascular diseases including atherosclerosis, myocardial ischemic injury, and diseases such as metabolic disorders such as hypercholesterolemia, hyperlipidemia which are exacerbated by hyperinsulinema and hyperglycemia.
  • The invention also comprises the novel compounds and methods of using them as specified below in formulae I, X, and XI. Also included in the scope of the present invention are standard salts and prodrugs of the compounds of formulae I, X, and XI.
  • Figure US20090192121A1-20090730-C00002
  • Since these compounds may have asymmetric centers, the present invention is directed not only to racemic mixtures of these compounds, but also to individual stereoisomers. The present invention also includes pharmaceutically acceptable and/or useful salts of the compounds of formulae I, X, and XI, including acid addition salts. The present inventions also encompass standard prodrugs of compounds of formulae I, X, and XI.
    • DETAILED DESCRIPTION OF THE INVENTION Definitions
  • In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise.
  • X, X″, X2 and X3 group nomenclature as used herein in formulae I and XI describes the group attached to the phosphonate and ends with the group attached to the heteroaromatic ring. For example, when X is alkylamino, the following structure is intended:
      • (heteroaromatic ring)-NR-alk-P(O)(NR15R16)(NR18—(CR12R13)n—(C(O)—R14)
  • Likewise, A, B, C, D, E, A, B, C″, D″, E″, A2, L2, E2, J2, A3, L3, E, and J3 groups and other substituents of the heteroaromatic ring are described in such a way that the term ends with the group attached to the heteroaromatic ring. Generally, substituents are named such that the term ends with the group at the point of attachment. A hyphen before or after a term indicates a point of attachment. For example, “-alkyl-” refers to divalent alkyl or alkylene.
  • The term “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. Suitable aryl groups include phenyl and furan-2,5-diyl.
  • Carbocyclic aryl groups are groups 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 having from 1 to 4 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include oxygen, sulfur, nitrogen, and selenium. Suitable heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, and the like, all optionally substituted.
  • The term “annulation” or “annulated” refers to the formation of an additional cyclic moiety onto an existing aryl or heteroaryl group. It is a form of optional substitution on an aryl or heteroaryl group. The newly formed ring may be carbocyclic or heterocyclic, saturated or unsaturated, and contains 2-9 new atoms of which 0-3 may be heteroatoms taken from the group of N, O, and S. The annulation may incorporate atoms from the X group as part of the newly formed ring. For example, the phrase “together L2 and E2 form an annulated cyclic group”, includes
  • Figure US20090192121A1-20090730-C00003
  • The term “biaryl” represents aryl groups 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 “alicyclic” means compounds which combine the properties of aliphatic and cyclic compounds. Such cyclic compounds include but are not limited to, aromatic, cycloalkyl and bridged cycloalkyl compounds. The cyclic compound includes heterocycles. Cyclohexenylethyl and cyclohexylethyl are suitable alicyclic groups. Such groups may be optionally substituted.
  • The term “optionally substituted” or “substituted” includes groups substituted by one to four substituents, independently selected from lower alkyl, lower aryl, lower aralkyl, lower alicyclic, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, heteroaryl, heterocyclic alkyl, heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, amino, guanidino, amidino, halo, lower alkylthio, oxo, acylalkyl, carboxy esters, carboxyl, -carboxamido, nitro, acyloxy, aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl, arylamino, aralkylamino, phosphono, sulfonyl, -carboxamidoalkylaryl, -carboxamidoaryl, hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxy-, aminocarboxamidoalkyl-, cyano, lower alkoxyalkyl, lower perhaloalkyl, and arylalkyloxyalkyl. “Substituted aryl” and “substituted heteroaryl” refer to aryl and heteroaryl groups substituted with 1-2; 1-3; or 1-4 substituents. In one aspect, suitable substituents of aryl groups include lower alkyl, lower alkoxy, lower perhaloalkyl, halo, hydroxy, and amino. “Substituted” when describing an R5 group does not include annulation.
  • The term “aralkyl” refers to an alkyl group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl, and the like, and may be optionally substituted. The term “-aralkyl-” refers to a divalent group -aryl-alkylene-. “Heteroarylalkyl” refers to an alkylene group substituted with a heteroaryl group.
  • The term “-alkylaryl-” refers to the group -alk-aryl- where “alk” is an alkylene group. “Lower -alkylaryl-” refers to such groups where alkylene is lower alkylene.
  • The term “lower” referred to herein in connection with organic radicals or compounds respectively defines such as with up to and including 10, or up to and including 6, or one to four carbon atoms. Such groups may be straight chain, branched, or cyclic.
  • The terms “arylamino” (a), and “aralkylamino” (b), respectively, refer to the group —NRR′ wherein respectively, (a) R is aryl and R′ is hydrogen, alkyl, aralkyl or aryl, and (b) R is aralkyl and R′ is hydrogen or aralkyl, aryl, alkyl.
  • The term “acyl” refers to —C(O)R where R is alkyl and aryl.
  • The term “carboxy esters” refers to —C(O)OR where R is alkyl, aryl, aralkyl, and alicyclic, all optionally substituted.
  • The term “carboxyl” refers to —C(O)OH.
  • The term “oxo” refers to ═O in an alkyl group.
  • The term “amino” refers to —NRR1 where R and R1 are independently selected from hydrogen, alkyl, aryl, aralkyl and alicyclic, all except H are optionally substituted; and R and R1 can form a cyclic ring system.
  • The term “carbonylamino” and “-carbonylamino-” refers to RCONR— and —CONR—, respectively, where each R is independently hydrogen or alkyl.
  • The term “halogen” or “halo” refers to —F, —Cl, —Br and —I.
  • The term “-oxyalkylamino-” refers to —O-alk-NR—, where “alk” is an alkylene group and R is H or alkyl.
  • The term “-alkylaminoalkylcarboxy-” refers to the group -alk-NR-alk-C(O)—O where “alk” is an alkylene group, and R is a H or lower alkyl.
  • The term “-alkylaminocarbonyl-” refers to the group -alk-NR—C(O)— where “alk” is an alkylene group, and R is a H or lower alkyl.
  • The term “-oxyalkyl-” refers to the group —O-alk- where “alk” is an alkylene group.
  • The term “-alkylcarboxyalkyl-” refers to the group -alk-C(O)—O-alk- where each alk is independently an alkylene group.
  • The term “alkyl” refers to saturated aliphatic groups including straight-chain, branched chain and cyclic groups. Alkyl groups may be optionally substituted. Suitable alkyl groups include methyl, isopropyl, and cyclopropyl.
  • The term “cyclic alkyl” or “cycloalkyl” refers to alkyl groups that are cyclic groups of 3 to 6; or 3 to 10 atoms. Suitable cyclic groups include norbornyl and cyclopropyl. Such groups may be substituted.
  • The term “heterocyclic” and “heterocyclic alkyl” refer to cyclic groups of 3 to 6; or 3 to 10 atoms, containing at least one heteroatom. In one aspect, these groups contain 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. Suitable heterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl, and pyridyl. Such groups may be substituted.
  • The term “phosphono” refers to —PO3R2, where R is selected from the group consisting of —H, alkyl, aryl, aralkyl, and alicyclic.
  • The term “sulphonyl” or “sulfonyl” refers to —SO3R, where R is H, alkyl, aryl, aralkyl, and alicyclic.
  • The term “alkenyl” refers to unsaturated groups which 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 phosph(oramid)ate, it is attached at the first carbon.
  • The term “alkynyl” refers to unsaturated groups which 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, it is attached at the first carbon.
  • The term “alkylene” refers to a divalent straight chain, branched chain or cyclic saturated aliphatic group.
  • The term “-cycloalkylene-COOR3” refers to a divalent cyclic alkyl group or heterocyclic group containing 4 to 6 atoms in the ring, with 0-1 heteroatoms selected from O, N, and S. The cyclic alkyl or heterocyclic group is substituted with —COOR3.
  • The term “acyloxy” refers to the ester group —O—C(O)R, where R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, or alicyclic.
  • The term “aminoalkyl-” refers to the group NR2-alk- wherein “alk” is an alkylene group and R is selected from H, alkyl, aryl, aralkyl, and alicyclic.
  • The term “-alkyl(hydroxy)-” refers to an —OH off the alkyl chain. When this term is an X group, the —OH is at the position a to the phosphorus atom.
  • The term “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 each alkylene group is lower alkylene.
  • The term “arylaminoalkyl-” refers to the group aryl-NR-alk- wherein “alk” is an alkylene group and R is H, alkyl, aryl, aralkyl, and alicyclic. In “lower arylaminoalkyl-”, the alkylene group is lower alkylene.
  • The term “alkylaminoaryl-” refers to the group alkyl-NR-aryl- wherein “aryl” is a divalent group and R is H, alkyl, aralkyl, and alicyclic. In “lower alkylaminoaryl-”, the alkylene group is lower alkyl.
  • The term “alkyloxyaryl-” refers to an aryl group substituted with an alkyloxy group. In “lower alkyloxyaryl-”, the alkyl group is lower alkyl.
  • The term “aryloxyalkyl-” refers to an alkyl group substituted with an aryloxy group.
  • The term “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.
  • The term “-alkoxy-” or “-alkyloxy-” refers to the group -alk-O— wherein “alk” is an alkylene group. The term “alkoxy-” refers to the group alkyl-O—.
  • The term “-alkoxyalkyl-” or “-alkyloxyalkyl-” refer to the group -alk-O-alk- wherein each “alk” is an independently selected alkylene group. In “lower -alkoxyalkyl-”, each alkylene is lower alkylene.
  • The terms “alkylthio-” and “-alkylthio-” refer to the groups alkyl-S—, and -alk-S—, respectively, wherein “alk” is alkylene group.
  • The term “-alkylthioalkyl-” refers to the group -alk-S-alk- wherein each “alk” is an independently selected alkylene group. In “lower -alkylthioalkyl” each alkylene is lower alkylene.
  • The term “alkoxycarbonyloxy-” refers to alkyl-O—C(O)—O—.
  • The term “aryloxycarbonyloxy-” refers to aryl-O—C(O)—O—.
  • The term “alkylthiocarbonyloxy-” refers to alkyl-S—C(O)—O—.
  • The term “-alkoxycarbonylamino-” refers to -alk-O—C(O)—NR1—, where “alk” is alkylene and R1, includes —H, alkyl, aryl, alicyclic, and aralkyl.
  • The term “-alkylaminocarbonylamino” refers to -alk-NR1—C(O)—NR1—, where “alk” is alkylene and R1 is independently selected from H, alkyl, aryl, aralkyl, and alicyclic.
  • The terms “amido” or “carboxamido” refer to NR2—C(O)— and RC(O)—NR1—, where R and R1 include H, alkyl, aryl, aralkyl, and alicyclic. The term does not include urea, —NR—C(O)—NR—.
  • The terms “carboxamidoalkylaryl” and “carboxamidoaryl” refers to an aryl-alk-NR1—C(O)—, and ar-NR1—C(O)-alk-, respectively, where “ar” is aryl, and “alk” is alkylene, R1 and R include H, alkyl, aryl, aralkyl, and alicyclic.
  • The term “-alkylcarboxamido-” or “-alkylcarbonylamino-” refers to the group -alk-C(O)N(R)— wherein “alk” is an alkylene group and R is H or lower alkyl.
  • The term “-alkylaminocarbonyl-” refers to the group -alk-NR—C(O)— wherein “alk” is an alkylene group and R is H or lower alkyl.
  • The term “aminocarboxamidoalkyl-” refers to the group NR2—C(O)—N(R)-alk- wherein R is an alkyl group or H and “alk” is an alkylene group. “Lower aminocarboxamidoalkyl-” refers to such groups wherein “alk” is lower alkylene.
  • The term “thiocarbonate” refers to —O—C(S)—O— either in a chain or in a cyclic group.
  • The term “hydroxyalkyl” refers to an alkyl group substituted with one —OH.
  • The term “haloalkyl” refers to an alkyl group substituted with one halo, selected from the group I, Cl, Br, F.
  • The term “cyano” refers to —C≡N.
  • The term “nitro” refers to —NO2.
  • The term “acylalkyl” refers to an alkyl-C(O)-alk-, where “alk” is alkylene.
  • The term “heteroarylalkyl” refers to an alkyl group substituted with a heteroaryl group.
  • The term “-1,1-dihaloalkyl-” refers to an X group where the 1 position and therefore halogens are α to the phosphorus atom.
  • The term “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 —CF3 and —CFCl2.
  • The term “guanidino” refers to both —NR—C(NR)—NR2 as well as —N═C(NR2)2 where each R group is independently selected from the group of —H, alkyl alkenyl, alkynyl, aryl, and alicyclic, all except —H are optionally substituted.
  • The term “bidentate” refers to an alkyl group that is attached by its terminal ends to the same atom to form a cyclic group. For example, propylene amine contains a bidentate propylene group.
  • The term “naturally occurring amino acid” refers to alpha amino acids containing at least one hydrogen at the alpha carbon and when the alpha carbon is chiral, it has S absolute configuration.
  • The term “amidino” refers to —C(NR)—NR2 where each R group is independently selected from the group of —H, alkyl, alkenyl, alkynyl, aryl, and alicyclic, all except —H are optionally substituted.
  • The term “pharmaceutically acceptable salt” includes salts of compounds of formula IA and its prodrugs derived from the combination of a compound of this invention and an organic or inorganic acid or base. Suitable acids include hydrochloric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and maleic acid.
  • The term “prodrug” as used herein refers to any compound that when administered to a biological system generates the “drug” substance (a biologically active compound) as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or metabolic chemical reaction(s). Standard prodrugs are formed using groups attached to functionality, e.g. HO—, HS—, HOOC—, R2N—, associated with the FBPase inhibitor, that cleave in vivo. 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. The groups illustrated are exemplary, not exhaustive, and one skilled in the art could prepare other known varieties of prodrugs. Such prodrugs of the compounds of formulae I, X, and XI, fall within the scope of the present invention. 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. In some cases, the prodrug is biologically active usually less than the drug itself, and serves to improve efficacy or safety through improved oral bioavailability, pharmacodynamic half-life, etc.
  • Phosphoramidate derivatives have been explored as phosphate prodrugs (e.g. McGuigan et al., J. Med. Chem., 1999, 42: 393 and references cited therein) and phosphonate prodrugs (Bischofberger, et al., U.S. Pat. No. 5,798,340 and references cited therein) as shown in Formulae G and H.
  • Figure US20090192121A1-20090730-C00004
  • Cyclic phosphoramidates have also been studied as phosphonate prodrugs because of their speculated higher stability compared to non-cyclic phosphoramidates (e.g. Starrett et al., J. Med. Chem., 1994, 37:1857).
  • Another type of nucleotide prodrug was reported as the combination of S-acyl-2-thioethyl ester and phosphoramidate (Egron et al., Nucleosides & Nucleotides, 1999, 18, 981) as shown in Formula J.
  • Figure US20090192121A1-20090730-C00005
  • The term “enhancing” refers to increasing or improving a specific property.
  • The term “enhanced oral bioavailability” refers to an increase of at least 50% of the absorption of the dose of the parent drug or prodrug (not of this invention) from the gastrointestinal tract. In one aspect, this increase is at least 100%. Measurement of oral bioavailability usually refers to measurements of the prodrug, drug, or drug metabolite in blood, tissues, or urine following oral administration, compared to measurements following systemic administration.
  • The term “parent drug” refers to any compound which delivers the same biologically active compound. The parent drug form is M-P(O)(OH)2 and standard prodrugs, such as esters.
  • The term “drug metabolite” refers to any compound produced in vivo or in vitro from the parent drug, which can include the biologically active drug.
  • The term “pharmacodynamic half-life” refers to the time after administration of the drug or prodrug to observe a diminution of one half of the measured pharmacological response. In one aspect, the half-life is enhanced when the half-life is increased by at least 50%.
  • The term “biologically active drug or agent” refers to the chemical entity that produces a biological effect. Thus, active drugs or agents include compounds which as M-P(O)(OH)2 are biologically active.
  • The term “inhibitor of fructose-1,6-bisphosphatase” refers to chemical entities M-PO3H2 that have an IC50 of equal to or less than 50 μM on human liver FBPase.
  • The term “therapeutically effective amount” refers to an amount that has any beneficial effect in treating a disease or condition.
    • Compounds
  • Suitable alkyl groups include groups having from 1 to about 20 carbon atoms. Suitable aryl groups include groups having from 1 to about 20 carbon atoms. Suitable aralkyl groups include groups having from 2 to about 21 carbon atoms. Suitable acyloxy groups include groups having from 1 to about 20 carbon atoms. Suitable alkylene groups include groups having from 1 to about 20 carbon atoms. Suitable alicyclic groups include groups having 3 to about 20 carbon atoms. Suitable heteroaryl groups include groups having from 1 to about 20 carbon atoms and from 1 to 4 heteroatoms, independently selected from nitrogen, oxygen, phosphorous, and sulfur. Suitable heteroalicyclic groups include groups having from 2 to about twenty carbon atoms and from 1 to 5 heteroatoms, independently selected from nitrogen, oxygen, phosphorous, and sulfur.
  • One aspect of the invention is directed to the compound of formula IA
  • Figure US20090192121A1-20090730-C00006
  • wherein compounds of formula IA are converted in vivo or in vitro to M-PO3H2 which is an inhibitor of fructose-1,6-bisphosphatase and
  • n is an integer from 1 to 3;
  • R2 is selected from the group of —H and —R3.
  • R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
  • each R12 and R13 is independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R12 and R13 together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of O, N and S, to form a cyclic group;
  • each R14 is independently selected from the group consisting of —OR17, —N(R17)2, —NHR17, —NR2OR19 and —SR17;
  • R15 is selected from the group consisting of —H, lower alkyl, lower aryl, lower aralkyl, or together with R16 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
  • R16 is selected from the group consisting of —(CR12R13)n—C(O)—R14, —H, lower alkyl, lower aryl, lower aralkyl, or together with R15 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
  • each R17 is independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or together R17 and R17 on N is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
  • R18 is independently selected from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R12 is connected via 1-4 carbon atoms to form a cyclic group;
  • each R19 is independently selected from the group consisting of —H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl, and COR3;
  • and pharmaceutically acceptable salts thereof.
  • Such compounds converted to M-PO3H2 include compounds that have an IC50 on isolated human liver FBPase enzyme of less than or equal to 10 μM. Alternatively, the IC50 is less than or equal to 1 μM. Such compounds may also bind to the AMP site of FBPase.
  • In one aspect, M is R5—X—, wherein R5 is selected from the group consisting of:
  • Figure US20090192121A1-20090730-C00007
  • wherein:
  • each G is independently selected from the group consisting of C, N, O, S, and Se, and wherein only one G may be O, S, or Se, and at most one G is N;
  • each G′ is independently selected from the group consisting of C and N and wherein no more than two G′ groups are N;
  • A is selected from the group consisting of —H, —NR4 2, —CONR4 2, —CO2R3, halo, —S(O)R3, —SO2R3, alkyl, alkenyl, alkynyl, perhaloalkyl, haloalkyl, aryl, —CH2OH, —CH2NR4 2, —CH2CN, —CN, —C(S)NH2, —OR2, —SR2, —N3, —NHC(S)NR4 2, —NHAc, and null;
  • each B and D are independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, —C(O)R11, —C(O)SR3, —SO2R11, —S(O)R3, —CN, —NR9 2, —OR3, —SR3, perhaloalkyl, halo, —NO2, and null, all except —H, —CN, perhaloalkyl, —NO2, and halo are optionally substituted;
  • E is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, —C(O)OR3, —CONR4 2, —CN, —NR9 2, —NO2, —OR3, —SR3, perhaloalkyl, halo, and null, all except —H, —CN, perhaloalkyl, and halo are optionally substituted;
  • J is selected from the group consisting of —H and null;
  • X is an optionally substituted linking group that links R5 to the phosphorus atom via 2-4 atoms, including 0-1 heteroatoms selected from N, O, and S, except that if X is urea or carbamate there is 2 heteroatoms, measured by the shortest path between R5 and the phosphorus atom, and wherein the atom attached to the phosphorus is a carbon atom, and wherein X is selected from the group consisting of -alkyl(hydroxy)-, -alkynyl-, -heteroaryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X is not substituted with —COOR2, —SO3H, or —PO3R2 2;
  • R2 is selected from the group consisting of R3 and —H;
  • R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
  • each R4 is independently selected from the group consisting of —H, and alkyl, or together R4 and R4 form a cyclic alkyl group;
  • each R9 is independently selected from the group consisting of —H, alkyl, aryl, aralkyl, and alicyclic, or together R9 and R9 form a cyclic alkyl group;
  • R11 is selected from the group consisting of alkyl, aryl, —NR2 2, and —OR2;
  • and with the proviso that:
      • 1) when G′ is N, then the respective A, B, D, or E is null;
      • 2) at least one of A and B, or A, B, D, and E is not selected from the group consisting of —H or null;
      • 3) when G is N, then the respective A or B is not halogen or a group directly bonded to G via a heteroatom;
  • and pharmaceutically acceptable salts thereof.
  • In one aspect, the following additional provisos may apply:
      • 4) when R is a six-membered ring, then X is not any 2 atom linker, an optionally substituted-alkyloxy-, or an optionally substituted-alkylthio-;
      • 5) when X is not α-heteroaryl- group, then R is not substituted with two or more aryl groups.
  • In one aspect of the present invention, compounds of formula IA have an IC50 of ≦50 μM on glucose production in isolated rat hepatocytes.
  • In one aspect, compounds of formula IA can be selected from those compounds where M is attached to
  • Figure US20090192121A1-20090730-C00008
  • wherein R17 is selected from the group consisting of ethyl, i-propyl, n-propyl and neopentyl and wherein C* has S stereochemistry.
  • In thiazoles where A″ is —NH2, X is furan-2,5-diyl, B″ is —S(CH2)2CH3; or where A″ is —NH2, D is furan-2,5-diyl, B″ is —CH2—CH(CH3)2, then M may be attached to
  • Figure US20090192121A1-20090730-C00009
  • wherein R17 is selected from the group consisting of ethyl, i-propyl, n-propyl and neopentyl and wherein C* has S stereochemistry.
  • In one aspect, the compounds of formula IA can be selected from:
  • Figure US20090192121A1-20090730-C00010
  • Within such a group, compounds of formula IA may be compounds of formulae II or IV:
  • Figure US20090192121A1-20090730-C00011
  • In one aspect, compounds are of Formula IA wherein M is
  • Figure US20090192121A1-20090730-C00012
  • wherein:
  • G″ is selected from the group consisting of —O— and —S—;
  • A2 is selected from the group consisting of —H, —NR4 2, —NHAc, —OR2, —SR2, —C(O)NR4 2, halo, —COR11, —CN, perhaloalkyl, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl;
  • L2, E2, and J2 are selected from the group consisting of —NR4 2, —NHAc, —NO2, —H, —OR2, —SR2, —C(O)NR4 2, halo, —COR11, —SO2R3, guanidinyl, amidinyl, aryl, aralkyl, alkyloxyalkyl, —SCN, —NHSO2R3, —SO2NR4 2—CN, —S(O)R3, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C6 alkyl(OH), C1-C6 alkyl(SH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl, and lower alicyclic, or together L2 and E2 or E2 and J2 form an annulated cyclic group;
  • X2 is selected from the group consisting of —CR2 2—, —CF2—, —CR2 2—O—, —CR2 2—S—, —C(O)—O—, —C(O)—S—, —C(S)—O—, —CH2—C(O)—O— and —CR2 2—NR20—, and wherein in the atom attached to the phosphorus is a carbon atom; with the proviso that X2 is not substituted with —COOR2—SO3H, or —PO3R2 2;
  • R2 is selected from the group consisting of R3 and —H;
  • R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
  • each R4 is independently selected from the group consisting of —H, and alkyl, or together R4 and R4 form a cyclic alkyl group;
  • R11 is selected from the group consisting of alkyl, aryl, —NR2 2, and —OR2;
  • R20 is selected from the group consisting of lower alkyl, —H, and —COR2; and
  • pharmaceutically acceptable salts thereof.
  • In one aspect, the bisphosphoramidate portion of the compounds of the invention,
  • Figure US20090192121A1-20090730-C00013
  • may be selected from the group consisting of
  • Figure US20090192121A1-20090730-C00014
  • wherein R17 is selected from the group consisting of ethyl, i-propyl, n-propyl, n-butyl and neopentyl. In another aspect, C* has S stereochemistry.
  • Alternatively, such compounds may be of the formula:
  • Figure US20090192121A1-20090730-C00015
  • In one aspect of the invention, M is
  • Figure US20090192121A1-20090730-C00016
  • wherein:
  • A3, E3, and L3 are selected from the group consisting of —NR8 2, —NO2, —H, —OR7, —SR7, —C(O)NR4 2, halo, —COR11, —SO2R3, guanidine, amidine, —NHSO2R3, —SO2NR4 2, —CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or together A3 and L3 form a cyclic group, or together L3 and E3 form a cyclic group, or together E3 and J3 form a cyclic group including aryl, cyclic alkyl, and heterocyclic;
  • J3 is selected from the group consisting of —NR8 2, —NO2, —H, —OR7, —SR7, —C(O)NR4 2, halo, —C(O)R11, —CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl; alicyclic, aryl, and aralkyl, or together with Y3 forms a cyclic group including aryl, cyclic alkyl and heterocyclic alkyl;
  • X3 is selected from the group consisting of -alkyl(hydroxy)-, -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X3 is not substituted with —COOR2, —SO3H, or —PO3R2 2;
  • Y3 is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C(O)R3, —S(O)2R3, —C(O)—R11, —CONHR3, —NR2 2, and —OR3, all except H are optionally substituted;
  • R2 is selected from the group consisting of R3 and —H;
  • R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
  • each R4 is independently selected from the group consisting of —H, and alkyl, or together R4 and R4 form a cyclic alkyl group;
  • R7 is independently selected from the group consisting of —H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and —C(O)R10;
  • R8 is independently selected from the group consisting of —H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —C(O)R10, or together they form a bidentate alkyl;
  • each R9 is independently selected from the group consisting of —H, -alkyl, aralkyl, and alicyclic, or together R9 and R9 form a cyclic alkyl group;
  • R10 is selected from the group consisting of —H, lower alkyl, —NH2, lower aryl, and lower perhaloalkyl;
  • R11 is selected from the group consisting of alkyl, aryl, —NR2 2, and —OR2; and
  • pharmaceutically acceptable salts thereof.
  • In one aspect, the following provisos may apply:
  • a) when X3 is alkyl or alkene, then A3 is —N(R8 2);
  • b) X3 is not alkylamine and alkylaminoalkyl substituted with phosphonic esters and acids; and
  • c) A3, L3, E3, J3, and Y3 together may only form 0-2 cyclic groups.
  • In the following table, the inventors contemplate any combination of the following Markush groups and those described above for the various variables.
  • TABLE A
    Table of Markush Groups by Variable
    Markush Markush Markush Markush
    Group A Group B Group C Group D
    R2 R3 and —H —H, lower alkyl, —H, C1-C4 alkyl,
    lower aryl, lower C2-C7 alicyclic,
    alicyclic and C4-C6 aryl, and
    lower aralkyl C5-C7 aralkyl,
    wherein said alicyclic,
    aryl, aralkyl may be
    optionally substituted
    with 1-2 heteroatoms
    R3 alkyl, aryl, lower alkyl, C1-C4 alkyl,
    alicyclic, and lower aryl, lower C2-C7 alicyclic,
    aralkyl alicyclic and C4-C6 aryl, and
    lower aralkyl C5-C7 aralkyl,
    wherein said alicyclic,
    aryl, aralkyl may be
    optionally substituted
    with 1-2 heteroatoms
    R4 —H, and —H, and
    C1-C4 alkyl, C1-C2 alkyl
    or
    R4 and R4 are
    connected by 4-5
    atoms to form a
    cyclic group
    R5 pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4- thiadiazolyl, pyrazolyl, isoxazolyl, 1,2,3- oxadiazolyl, 1,2,4- oxadiazolyl, 1,2,5- oxadiazolyl, 1,3,4 oxadiazolyl, 1,2,4- thiadiazolyl, 1,3,4- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, and 1,3- selenazolyl, all of which contain at least one substituent pyrrolyl, imidazolyl, isothiazolyl, 1,2,4- thiadiazolyl, pyrazolyl, isoxazolyl, 1,2,3- oxadiazolyl, 1,2,4- oxadiazolyl, 1,2,5- oxadiazolyl, 1,3,4- oxadiazolyl, 1,2,4- thiadiazolyl, 1,3,4- thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, and 1,3- selenazolyl, all of which contain at least one substituent
    Figure US20090192121A1-20090730-C00017
    Figure US20090192121A1-20090730-C00018
    Figure US20090192121A1-20090730-C00019
    Figure US20090192121A1-20090730-C00020
    Figure US20090192121A1-20090730-C00021
    Figure US20090192121A1-20090730-C00022
    Figure US20090192121A1-20090730-C00023
    Figure US20090192121A1-20090730-C00024
    Figure US20090192121A1-20090730-C00025
    Figure US20090192121A1-20090730-C00026
    thiazolyl, oxazolyl, and selenazolyl
    Figure US20090192121A1-20090730-C00027
    Figure US20090192121A1-20090730-C00028
    Figure US20090192121A1-20090730-C00029
    Figure US20090192121A1-20090730-C00030
    Figure US20090192121A1-20090730-C00031
    R7 —H, lower alkyl, —H, C(O)R10, C1-
    lower alicyclic, C4 alkyl, C2-C7
    lower aralkyl, alicyclic, C4-C6
    lower aryl, and aryl, and C5-C7
    C(O)R10 aralkyl, wherein
    said alicyclic,
    aryl, aralkyl may
    be optionally
    substituted with
    1-2 heteroatoms
    R8 —H, lower alkyl, H, C(O)R10, C1-
    lower alicyclic, C4 alkyl, C2-C7
    lower aralkyl, alicyclic, C4-C6
    lower aryl, and aryl, and C5-C7
    C(O)R10; or aralkyl, wherein
    said alicyclic,
    aryl, aralkyl may
    be optionally
    substituted with
    1-2 heteroatoms;
    or
    together R8 and together R8 and
    R8 form a R8 form a C2-C5
    bidentate alkyl bidentate alkyl
    R9 —H, lower alkyl, —H, C1-C4 alkyl,
    lower aralkyl, C5-C7 aralkyl,
    and lower and C2-C7
    alicyclic; or aliycylic,
    wherein said
    alicyclic, and
    aralkyl may be
    optionally
    substituted with
    1-2 heteroatoms;
    or
    together R9 and together R9 and
    R9 form a cyclic R9 form a C2-C6
    alkyl group cyclic alkyl
    R10 —H, —NH2, lower —H, —NH2, C1-C4
    alkyl, lower aryl, alkyl, C4-C6
    and lower aryl, and C1-C4
    perhaloalkyl perhaloalkyl,
    wherein said
    aryl, may be
    optionally
    substituted with
    1-2 heteroatoms
    R11 —NR2 2, —OR2, —NR2 2, —OR2,
    lower alkyl, and C1-C4 alkyl, and
    lower aryl C4-C6 aryl,
    wherein said aryl
    may be
    optionally
    substituted with
    1-2 heteroatoms
    R12 —H, lower alkyl, —H, C1-C6 —H, —H,lower —H, C1-C4 —H and
    lower alkyl, -lower C1-C4 alkyl, lower alkyl, methyl,
    perhaloalkyl, alkoxyalkyl, alkyl, perhaloalkyl, —CH2—O—C(CH3)3,
    lower aralkyl, lower phenyl, and lower phenyl,
    lower aryl, alkylthioalkyl, and aryl, and
    optionally phenyl, and benzyl; optionally benzyl; or
    substituted with benzyl, or or substituted
    —OR19, —NR19 2, with —OR19, methyl
    —SR19, —NR19 2,
    —C(O)—NR2R3, —SR19,
    halo, —CO2R2, —C(O)—NR2R3,
    3-indolyl, halogen,
    4-imidazolyl, or —CO2R2, H
    guandinyl; or 3-indolyl, 4-
    imidazolyl,
    or
    guanidinyl;
    or
    together R12 and R12 and R13 are R12 and R13 are R12 and R12 and
    R13are connected via 2- connected via 2-5 R13 are R13 are
    connected via 2- 5 carbon atoms carbon atoms to form connectd connect-
    5 carbon atoms to form a a cycloalkyl group via 2 or 4 ed via 4
    to form a cycloalkyl group carbon carbon
    cycloalkyl group atoms to atoms to
    form a form
    cyclopro- cyclo-
    pyl or pentyl
    cyclopent- group
    yl group
    R13 —H, lower alkyl, —H, C1-C6 alkyl, —H, —H, lower —H, Cl-C4 —H,
    lower -lower C1-C4 alkyl, lower alkyl, methyl,
    perhaloalkyl, alkoxyalkyl, alkyl, perhaloalkyl, —CH2—O—C(CH3)3, i-propyl,
    lower aralkyl, lower phenyl, and lower phenyl, and
    lower aryl, alkylthioalkyl, and aryl, option- and benzyl,
    optionally phenyl, and benzyl; ally substi- benzyl; or
    substituted with benzyl, or or tuted with
    —OR19, —OR19,
    —NR19 2, NR19 2SR19,
    —SR19, C(O)NR2R3,
    —C(O)—NR2R3, halogen,
    halogen, —CO2R2, 3-
    —CO2R2, indolyl, 4-
    3-indolyl, imidazolyl,
    4-imidazolyl, or or guani-
    guandinyl; or dinyl; or
    together and R12 and R12 and R13 are R12 and R13 are R12 and R12 and
    R13 are connected via 2- connected via 2-5 R13 are R13 are
    connected via 2- 5 carbon atoms carbon atoms to form connected connect-
    5 carbon atoms to form a a cycloalkyl group via 2 or 4 ed via 4
    to form a cycloalkyl group carbon carbon
    cycloalkyl group atoms to atoms to
    form a form
    cyclopropyl cyclo-
    or pentyl
    cyclo- group
    pentyl
    group
    R14 —OR17, —SR17 and —OR17
    —NR2OR19
    R15 —H, lower alkyl, —H, and C1-C6 —H and C1-C3 alkyl —H, methyl, ethyl,
    lower aryl, and alkyl, or and propyl
    lower aralkyl, or
    together R15and together R15 and —NR15R16 is a cyclic NR15R16 is
    R16 are R16 are amine morpholinyl and
    connected via 2- connected via 2- pyrrolidinyl
    6 atoms, 6 atoms
    optionally optionally
    including 1 including 1
    heteroatom heteroatom
    selected from the selected from the
    group consisting group consisting
    of O, N, and S of, O, N, and S
    R16 —H, lower alkyl, —H, and C1-C6 —H and C1-C3 alkyl —(CR12R13)n—C(O)—R14
    lower aryl, and alkyl, or
    lower aralkyl, or
    together R15 and together R15 and —NR15R16 is a cyclic NR15R16 is
    R16 are R16 are amine morpholinyl and
    connected via 2- connected via 2- pyrrolidinyl
    6 atoms 6 atoms, —H, C1-C6 alkyl and
    optionally optionally —(CR12R13)n—C(O)—R14
    including 1 including 1 or
    heteroatom heteroatom
    selected from the selected from the together R15 and R16
    group consisting group consisting are connected via 2-6
    of O, N, and S of, O, N, and S atoms, optionally
    including 1
    heteroatom selected
    from the group
    consisting of, 0, N,
    and S
    R17 C1-C7 alkyl, methyl, ethyl, methyl, ethyl, ethyl, n-propyl, i-
    phenyl, indolyl, i-propyl i-propyl, n-propyl, propyl, and neopentyl
    sesimol and n-propyl, t-butyl, t-butyl, cyclopentyl,
    benzyl, wherein isobutyl neo- neopentyl, phenyl and
    said phenyl, pentyl, cyclo- benzyl ethyl, i-propyl, n-
    indolyl, sesimol pentyl and propyl, n-butyl, and
    and benzyl may unsubstituted neopentyl
    be optionally benzyl
    substituted with ethyl
    1-3 groups
    selected from the
    group consisting
    of —CO2R2,
    —OR3, halo,
    —NHC(O)R3, and
    lower alkyl
    R18 —H, C1-C6 alkyl —H and C1-C6 —H and methyl —H
    and benzyl alkyl
    R19 —H, —COR3, —H, —COR3,
    lower alkyl, C1-C4 alkyl, C4-
    lower aryl, lower C6 aryl, C2-C7
    alicyclic, and alicyclic, and
    lower aralkyl C5-C7 aralkyl
    R20 —H, —COR2, and —H, —COR2, and
    lower alkyl C1-C4 alkyl
    A —H, —NR4 2, —CONR4 2, —CO2R3, halo,
    C1-C6 alkyl, C2-C6 alkenyl, C2-C6
    alkynyl, C1-C6 perhaloalkyl, C1-C6
    haloalkyl, aryl, —CH2OH, —CH2NR4 2,
    CH2CN, —CN, —C(S)NH2, —OR2,
    —SR2, —N3, —NHC(S)NR4 2, —NHAc,
    and null
    B —H, alkyl, alkenyl, alkynyl, aryl,
    heteroaryl. alicyclic, aralkyl,
    alkoxyalkyl, —C(O)R11, —C(O)SR3,
    SO2R11, —S(O)R3, —CN, —NR9 2, —OR3,
    —SR3, perhaloalkyl, halo, and null,
    all except —H, —CN, perhalo-alkyl,
    and halo are optionally substituted
    D —H, alkyl, alkenyl, alkynyl, aryl,
    heteroaryl, alicyclic, aralkyl,
    alkoxyalkyl, —C(O)R11, —C(O)SR3,
    SO2R11, —S(O)R3, —CN, —NR2, —OR3,
    —SR3, perhaloalkyl, halo, and null,
    all except —H, —CN, perhalo-alkyl,
    and halo are optionally substituted
    E —H, C1-C6 alkyl, C2-C6 alkenyl, C2-
    C6 alkynyl, aryl, C4-C6 alicyclic,
    alkoxyalkyl, —C(O)OR3, —CONR4 2,
    —CN, —NR9 2, —OR3, —SR3, C1-C6
    perhaloalkyl, halo, and null, all
    except —H, —CN, perhaloalkyl, and
    halo are optionally substituted
    X -heteroaryl-, -heteroaryl-, methylenoxycarbonyl furan-2,5-diyl
    -alkylcarbonyl- -alkylamino- and furan-2,5-diyl
    amino-, -alkyl- carbonyl-, and
    aminocarbonyl-, -alkoxy-
    and alkoxy- carbonyl-, all
    carbonyl- optionally sub-
    stituted
    -heteroaryl-, -heteroaryl- and methylenoxycarbonyl
    -alkoxyalkyl- -alkoxy-
    -alkylcarbonyl- carbonyl-
    amino-, -alkyl-
    aminocarbonyl-,
    -alkoxyalkyl and
    -alkoxy-
    carbonyl-
    G′ C, and N
    A″ —H, —NR4 2, —NH2, —CONH2, —H, —NH2, —Cl, —NH2
    —CONR4 2, halo, —Br, and
    —CO2R3, halo, —CH3, —CF3, —CH3
    C1-C6 alkyl, C2- —CH2-halo, —CN,
    C6 alkenyl, C2- —OCH3, —SCH3,
    C6 alkynyl, C1- and —H
    C6 perhaloalkyl,
    C1-C6 haloalkyl,
    aryl, —CH2OH,
    —CH2NR4 2,
    —CH2CN, —CN,
    —C(S)NH2, —OR2,
    —SR2, —N3,
    —NHC(S)NR4 2,
    and —NHAc
    B″ —H, alkyl, —H, —C(O)R11, —H, —C(O)OR3, —S(CH2)2CH3
    alkenyl, alkynyl, —C(O)SR3, alkyl, —C(O)SR3, C1-C6
    aryl, heteroaryl, aryl, heteroaryl, alkyl, alicyclic, aryl, —SMe
    alicyclic, aralkyl, alicyclic, halo, heteroaryl, and SR3
    alkoxyalkyl, —CN, —SR3, OR3
    —C(O)R11, and —NR9 2 —S(CH2)2CH3, —CH(CH3)2
    —C(O)SR3, —CH2—CH(CH3)2,
    —SO2R11, —COOEt,
    —S(O)R3, —CN, —SMe, —CH(CH3)2 —CH2—CH(CH3)2
    —NR9 2, —OR3, cyclopropyl and —COOEt
    —SR3, perhalo- n-propyl
    alkyl, and halo,
    all except —H,
    —CN, perhalo-
    alkyl, and halo
    are optionally
    substituted
    D″ —H, alkyl, —H, —C(O)R11, —H, —C(O)OR3, lower —H
    alkenyl, alkynyl, —C(O)SR3, alkyl, alkyl, alicyclic, and
    aryl, heteroaryl, aryl, heteroaryl, halo
    alicyclic, aralkyl, alicyclic, halo,
    alkoxyalkyl, —NR9 2, and —SR3
    —C(O)R11,
    —C(O)SR3,
    —SO2R11, —CN,
    —S(O)R3, —NR9 2,
    —OR3, —SR3,
    perhaloalkyl, and
    halo, all except
    —H, —CN, per-
    haloalkyl, and
    halo are
    optionally
    substituted
    E″ —H, C1-C6 alkyl, —H, C1-C6 alkyl, —H, C1—C6 alkyl, —H
    C2-C6 alkenyl, lower alicyclic, lower alicyclic, halo,
    C2-C6 alkynyl, halo, —CN, —CN, —C(O)OR3, and
    aryl, C4-C6 —C(O)OR3, —SR3, —SR3
    alicyclic, and —CONR4 2
    alkoxyalkyl,
    —C(O)OR3, H, —Br, and —Cl
    —CONR4 2, —CN,
    —NR9 2, —OR3,
    —SR3, C1-C6
    perhaloalkyl, and
    halo, all except
    H, —CN, perhalo-
    alkyl, and halo
    are optionally
    substituted
    G″ —S—
    A2 —H, —NR4 2, —CN, —H, —NR4 2, —NH2, —H, —NH2
    —NHAc, halogen, halogen, and C1- —H, —NH2,
    —OR3, perhalo- C5 alkyl, halo, and —Cl,
    alkyl, C1-C5 alkyl —Br,
    —C(O)—NR4 2, and
    C1-C6 —CH3
    alkyl, C2-C6
    alkenyl, C2-C6
    alkynyl
    E2 —H, —NR4 2, —NO2, —H, —H, —NR4 2, —H, H, lower —SCN,
    —NHAc, —S—C≡N, —NR4 2, —S—C≡N, —SCN, alkyl, C1-C6
    —CN, halogen, —S—C≡N, —CN, halo- halogen, alkyl,
    —OR3, hydroxy, —C(O)OH, —C(O)OH, gen, —SCN, C1-C6
    lower alkoxy- halogen, lower lower —CN, —OR3, alkoxy,
    methylene, alkoxy, lower alkoxy, C1-C6 lower C1-C6
    -alkyl(OH), aryl, alkylthio, lower alkyl, alkyloxy- alkylthio,
    alkyloxy- hydroxy, lower alkylthio, C1-C6 carbonyl, and —Br
    carbonyl, alkyl(hydroxy), C1-C5 alkoxy, lower Me
    —CO(OH), —SR3, lower alkoxy- alkyl, lower or alkyloxy,
    —SH, lower methylene, lower alkyl(hydroxy), —CN, OMe
    perhaloalkyl, aryl, lower lower lower OEt
    heteroaryl, lower heteroaryl, and aryl, and alkylthio,
    alicyclic and C1- C1-C5 alkyl, or halogen, or or —(O)—CH2—CH—CH—(CH3)2
    C6 alkyl, or
    together L2 and together L2 and together L2 and E2 together
    E2 form an E2 form an form an annulated L2 and E2
    annulated cyclic annulated cyclic cyclic group form a
    group group containing an cyclic
    additional 4 carbon group
    atoms including
    aryl,
    cyclic
    alkyl,
    hetero-
    aryl, or
    hetero-
    cyclic
    alkyl
    J2 —H,—NR4 2, —NO2, —H, —NR4 2, —H, halo, H, Cl, —H
    —NHAc, —S—C≡N, —S—C≡N, and C1-C5 and
    —CN, halogen, —C(O)OH, alkyl —CH3
    —OR3, hydroxy, halogen, lower
    lower alkoxy- alkoxy, lower
    methylene, alkylthio,
    -alkyl(OH), aryl, hydroxy, lower
    alkyloxy- alkyl(hydroxy),
    carbonyl, lower alkoxy-
    —CO(OH), —SR3, methylene, lower
    —SH, lower aryl, lower
    perhaloalkyl, heteroaryl, and
    heteroaryl, lower C1-C5 alkyl
    alicyclic and C1-
    C6 alkyl
    L2 —H, —NR4 2, —NO2, —H, —NR4 2, —H, —NR4 2, —H, —H, —CN, —H,
    —NHAc, —S—C≡N, —S—C≡N, —S—C≡N, —CN, —SCN, methyl,
    —CN, halogen, —C(O)OH, —CN, —SCN, lower ethyl,
    —OR3, hydroxy, halogen, lower —C(O)OH, C1-C6 alkyl, propyl,
    lower alkoxy- alkoxy, lower lower alkyl, alicyclic, —SCN and
    methylene, alkylthio, alkoxy, halo- aryl, —Cl
    -alkyl(OH), aryl, hydroxy, lower lower gen, halogen,
    alkyloxy- alkyl(hydroxy), alkylthio, and lower
    carbonyl, lower alkoxy- C1-C5 lower alkyloxy,
    —CO(OH), —SR3, methylene, lower alkyl, alkoxy, hydroxy,
    —SH, lower aryl, lower lower or and
    perhaloalkyl, heteroaryl, and alkyl- alken-
    heteroaryl, lower C1-C5 alkyl; or (hydroxy), ylene-
    alicyclic and C1- lower aryl, OH, or
    C6 alkyl, or and
    halogen,
    or
    together L2 and together L2 and together L2 and E2 together L2
    E2 form an E2 form an form an annulated and E2 form
    annulated cyclic annulated cyclic cyclic group a cyclic
    group group containing an group
    additional 4 carbon including
    atoms aryl, cyclic
    alkyl,
    heteroaryl,
    or hetero-
    cyclic alkyl
    X2 —CR2 2—, —CF2—, —CH2—O— and —CH2—O—
    —CR2 2—O—, —CH2—S—
    —CR2 2—S—,
    —C(O)—O—,
    —C(O)—S—,
    —C(S)—O—,
    —CH2—C(O)—O—
    and —CR2 2—NR20—
    A3 —H, —NR8 2, —NO2, —H, —NH2, —F, —NH2
    hydroxy, and —CH3
    halogen, —OR7,
    alkylamino-
    earbonyl, —SR7,
    lower perhalo-
    alkyl, and C1-C5
    alkyl
    E —H, —NR8 2, —NO2, —H and —Cl —H
    hydroxy,
    halogen, —OR7,
    alkylamino-
    earbonyl, —SR7,
    lower perhalo-
    alkyl, and C1-C5
    alkyl, or
    together E3 and
    J3 together form
    a cyclic group
    J3 —H, halogen, —H, halo, C1-C5 -ethyl
    lower alkyl, hydroxyalkyl,
    lower hydroxy- C1-C5 haloalkyl,
    alkyl, —NR8 2, R8 2N-C1-C5
    lower R8 2N- alkyl, C1-C5 -N,N-dimethylamino-
    alkyl, lower alicyclic, and propyl
    haloalkyl, lower C1-C5 alkyl
    perhaloalkyl,
    lower alkenyl,
    lower alkynyl,
    lower aryl,
    heterocyclic, and
    alicyclic or
    together E3 and
    J3 together form
    a cyclic group
    L3 —H, —NR8 2,—NO2, —H, —F, —OCH3, —F
    hydroxy, —Cl, and —CH3
    halogen, —OR7 ,
    alkylaminocar-
    bonyl, —SR7,
    lower perhalo-
    alkyl, and C1-C5
    alkyl
    Y3 alicyclic and lower alkyl -i-butyl
    lower alkyl
    X3 -heteroaryl-, —CH2OCH2-, -furan-2,5-diyl-
    -alkylcarbonyl- -methyleneoxy-
    amino-, carbonyl- and
    -alkylamino- -furan-2,5-diyl-
    carbonyl-, and
    -alkoxycarbonyl-
    n 1,2 1
  • Compounds of formula IA may have oral bioavailability of at least 5% and some may have oral bioavailability of at least 10%.
  • The prodrugs of the present invention may have two isomeric forms around the phosphorus. In one aspect, the compounds of the invention are not chiral at the phosphorus. In another aspect, there is no chiral center in the amino groups attached to the phosphorus. The prodrugs of the present invention may have isomers at the carbon substituted with R12 and R13. The invention contemplates mixtures of isomers as well as individual stereoisomers. For instance, when n is 1, and R12 is H, the carbon attached to R12 and R13 can have R stereochemistry. In another aspect, when n is 1 and R12 is —H, the carbon attached to R12 and R13 can have S stereochemistry.
  • The present invention includes compounds designated in Table 1 as defined in the following formulae: formula i, formula ii, and formula iii.
  • Figure US20090192121A1-20090730-C00032
  • In the above formulae i, ii, and iii, R55 may be substituted by A and B. The compounds of formulae i, ii, and iii are listed in Table 1 by designated numbers assigned to R55, A, B, Q1, and Q2 in the above formulae i, ii, and iii according to the following convention:
  • Q1.Q2.R5.B.A. For each moiety, structures assigned to a number shown in the following tables for R55, A, B, Q1 and Q2.
  • Variable R55 is divided into two groups, each listing four different structures.
  • Compounds named in Table 1 of formulae i, ii, and iii wherein the R55 moieties are assigned the following numbers:
  • Group 1:
  • 1 2 3 4
    R55 =
    Figure US20090192121A1-20090730-C00033
    Figure US20090192121A1-20090730-C00034
    Figure US20090192121A1-20090730-C00035
    Figure US20090192121A1-20090730-C00036
  • Group 2:
  • 1 2 3 4
    R55 =
    Figure US20090192121A1-20090730-C00037
    Figure US20090192121A1-20090730-C00038
    Figure US20090192121A1-20090730-C00039
    Figure US20090192121A1-20090730-C00040
  • Variable A moieties are assigned the following numbers:
  • 1 2 3 4
    A = NH2 H Me Cl
  • Variable B moieties are assigned the following numbers:
  • 1 2 3 4 5 6 7 8
    B = —SCH3 -iBu -cPr —S-nPr —SEt -iPr -nPr —CH2cPr
  • Variables Q1 and Q2 are divided into three groups, each listing eight different substituents.
  • Q1 and Q2 moieties are assigned the following numbers:
    • Group 1: Q1 and Q2
    • 1. —NH—CH2—C(O)R14
    • 2. —NH—CH(CH3)—C(O)R14
    • 3. —NH—C(CH3)2—C(O)R14
    • 4. —NH—C(CH3)2CH2—C(O)R14
    • 5. —NH—CH(CH(CH3)2))—C(O)R14
    • 6. —NH—CH(CH2(CH(CH3)2)))—C(O)R14
    • 7. —NH—CH(CH2CH2SCH3)—C(O)R14
    • 8. —NH—CH(CH2SCH2Ph)—C(O)R14
    Group 2: Q1 and Q2
    • 1.—NH—CH2CH2—C(O)R14
    • 2. —NH—CH(CH2CH2COR4)—C(O)R14
    • 3. —NH—CH(CH2COR14)—C(O)R14
    • 4. —NH—CH(CH2CONH2)—C(O)R14
    • 5. —NH—CH(COR4)CH2—C(O)R14
    • 6. —NH—CH(CH2OR21)—C(O)R14
    • 7. —NH—CH(CH2CH2COR14)—C(O)R14
    • 8. —NH—CH(CH2OH)—C(O)R14
    Group 3: Q1 and Q2
    • 1. —NH—CH(CH2—C6H5OH)—C(O)R14
    • 2. —NH—C(c-propyl)-C(O)R14
    • 3. —NH—C(c-pentyl)-C(O)R14
    • 4. —NH—C(c-hexyl)-C(O)R14
    • 5. —NH—CH(CH2Ph)-C(O)R14
    • 6. —N(CH3)—CH2—C(O)R4
  • Figure US20090192121A1-20090730-C00041
    • 8. —NR22R23
      where R14 is selected from the groups consisting of OMe, OEt, OBn, O-iPr, O-neopentyl, O-tBu, O-nPr, OPh, —N(Me)2, oxyethylene-N-morpholino, SMe, SEt; R21 is methyl, ethyl, benzyl, and propyl; R22 is H, Me, Et, Bn, Pr and Ph; and R23 is Me, Et, Bn, Pr and Ph; or R22 and R23 is morpholinyl and pyrrolidinyl.
  • Thus, the compound 3.3.1.2.1 in Group 1 corresponds to the structure below for formula i:
  • Figure US20090192121A1-20090730-C00042
  • and when R14 is ethoxy the structure would be:
  • Figure US20090192121A1-20090730-C00043
  • The numbers designated in Table 1 also refer to benzothiazole and benzoxazole compounds of formula X. These compounds are shown in formulae iv and v.
  • Figure US20090192121A1-20090730-C00044
  • The compounds of formulae iv and formula v are listed in Table 1 by designated numbers assigned to A, B, D, Q1, and Q2 in the above formulae iv and v according to the following convention: Q1.Q2.A.B.D. For each moiety, structures assigned to a number shown in the following tables for A, B, D, Q1 and Q2.
  • Variables Q1 and Q2 are divided into three groups, each listing eight different substituents.
    • Group 1:
  • Q1 and Q2 moieties are assigned the following numbers:
    • Q1 and Q2
    • 1. —NH—CH2—C(O)R14
    • 2. —NH—CH(CH3)—C(O)R14
    • 3. —NH—C(CH3)2—C(O)R14
    • 4. —NH—C(CH3)2CH2—C(O)R14
    • 5. —NH—CH(CH(CH3)2))—C(O)R14
    • 6. —NH—CH(CH2(CH(CH3)2)))—C(O)R14
    • 7. —NH—CH(CH2CH2SCH3)—C(O)R14
    • 8. —NH—CH(CH2SCH2Ph)-C(O)R14
    Group 2: Q1 and Q2
    • 1. —NH—CH2CH2—C(O)R14
    • 2. —NH—CH(CH2CH2COR14)—C(O)R14
    • 3. —NH—CH(CH2COR14)—C(O)R14
    • 4. —NH—CH(CH2CONH2)—C(O)R14
    • 5. —NH—CH(COR14)CH2—C(O)R14
    • 6. —NH—CH(CH2OR21)—C(O)R14
    • 7. —NH—CH(CH2CH2COR14)—C(O)R14
    • 8. —NH—CH(CH2OH)—C(O)R14
    Group 3: Q1 and Q2
    • 1. —NH—CH(CH2—C6H5OH)—C(O)R14
    • 2. —NH—C(c-propyl)-C(O)R14
    • 3. —NH—C(c-pentyl)-C(O)R14
    • 4. —NH—C(c-hexyl)-C(O)R14
    • 5. —NH—CH(CH2Ph)-C(O)R14
    • 6. —N(CH3)—CH2—C(O)R14
  • Figure US20090192121A1-20090730-C00045
    • 8. —NR22R23
  • Variable B is divided into three groups, each listing eight different substituents.
    • Group 1:
  • B moieties are assigned the following numbers:
  • 1 2 3 4 5 6 7 8
    B = H Me Et nPr Br iPr SCN cPr
    • Group 2:
  • 1 2 3 4 5 6 7 8
    B = CN F OMe OEt SMe SEt 2-furanyl C(O)OEt
    • Group 3:
  • 1 2 3 4 5 6 7 8
    B = B&D are B&D are B&D are B&D are B&D are B&D are B&D are B&D are
    connected connected connected connected connected connected connected connected
    to form to form to form to form to form to form to form to form
    cyclohexyl phenyl furanyl furanyl cyclohexyl phenyl furanyl furanyl
    ring ring ring (O ring (O ring ring ring (O ring (O
    attached at attached at attached at attached at
    B) D) B) D)
  • Group 3 for Variable B can only be combined with Group 3 variable for D.
  • Variable D is divided into nine groups, each listing four different substituents.
    • Group 1:
  • 1 2 3 4
    D = H Me Et SCN
    • Group 2:
  • Variable D is replaced with the moieties assigned in the following numbers:
  • 1 2 3 4
    D = SMe SEt CH2OMe OMe
    • Group 3:
  • 1 2 3 4
    D = null null null null
    • Group 4:
  • 1 2 3 4
    D = Pr O-Et O—Pr O-isopropyl
    • Group 5:
  • 1 2 3 4
    D = O-Bu O-isobutyl O-cyclopropyl O-pentyl
    • Group 6,
  • 1 2 3 4
    D = O-neopentyl O-cyclopentyl O-cyclohexyl O-benzyl
    • Group 7:
  • 1 2 3 4
    D = S—Pr S-isopropyl S-Bu S-isobutyl
    • Group 8:
  • 1 2 3 4
    D = S-cyclopropyl S-pentyl S-neopentyl S-cyclopentyl
    • Group 9:
  • 1 2 3 4
    D = cyclohexyl S-benzyl OCH2OCH3 OCH2SCH3
  • Compounds named in Table 1 of formulae iv and v wherein the A moieties are assigned the following numbers:
  • 1 2 3 4
    A = NH2 H Me Cl

    where R14 is selected from the groups consisting of OMe, OEt, OBn, O-tBu, O-nPr, OPh, O-neopentyl, —N(Me)2, oxyethylene-N-morpholino, SMe, SEt; R21 is methyl, ethyl, benzyl, and propyl; R22 is H, Me, Et, Bn, Pr, and Ph; and R23 is Me, Et, Bn, Pr and Ph; or R22 and R23 is morpholinyl and pyrrolidinyl.
  • Thus, the compound 2.2.1.7.4 from Group 1 for B, D, Q1 and Q2 corresponds to the structure below for formula iv
  • Figure US20090192121A1-20090730-C00046
  • and when R14 is ethoxy the structure would be
  • Figure US20090192121A1-20090730-C00047
  • Similarly, in group 3 for variable B, the compound 2.2.1.7.4 corresponds to the structure below for formula iv
  • Figure US20090192121A1-20090730-C00048
  • and when R14 is ethoxy the structure would be
  • Figure US20090192121A1-20090730-C00049
  • TABLE 1
    1.1.1.1.1 1.1.1.1.2 1.1.1.1.3 1.1.1.1.4 1.1.1.2.1 1.1.1.2.2 1.1.1.2.3 1.1.1.2.4
    1.1.1.3.1 1.1.1.3.2 1.1.1.3.3 1.1.1.3.4 1.1.1.4.1 1.1.1.4.2 1.1.1.4.3 1.1.1.4.4
    1.1.1.5.1 1.1.1.5.2 1.1.1.5.3 1.1.1.5.4 1.1.1.6.1 1.1.1.6.2 1.1.1.6.3 1.1.1.6.4
    1.1.1.7.1 1.1.1.7.2 1.1.1.7.3 1.1.1.7.4 1.1.1.8.1 1.1.1.8.2 1.1.1.8.3 1.1.1.8.4
    1.1.2.1.1 1.1.2.1.2 1.1.2.1.3 1.1.2.1.4 1.1.2.2.1 1.1.2.2.2 1.1.2.2.3 1.1.2.2.4
    1.1.2.3.1 1.1.2.3.2 1.1.2.3.3 1.1.2.3.4 1.1.2.4.1 1.1.2.4.2 1.1.2.4.3 1.1.2.4.4
    1.1.2.5.1 1.1.2.5.2 1.1.2.5.3 1.1.2.5.4 1.1.2.6.1 1.1.2.6.2 1.1.2.6.3 1.1.2.6.4
    1.1.2.7.1 1.1.2.7.2 1.1.2.7.3 1.1.2.7.4 1.1.2.8.1 1.1.2.8.2 1.1.2.8.3 1.1.2.8.4
    1.1.3.1.1 1.1.3.1.2 1.1.3.1.3 1.1.3.1.4 1.1.3.2.1 1.1.3.2.2 1.1.3.2.3 1.1.3.2.4
    1.1.3.3.1 1.1.3.3.2 1.1.3.3.3 1.1.3.3.4 1.1.3.4.1 1.1.3.4.2 1.1.3.4.3 1.1.3.4.4
    1.1.3.5.1 1.1.3.5.2 1.1.3.5.3 1.1.3.5.4 1.1.3.6.1 1.1.3.6.2 1.1.3.6.3 1.1.3.6.4
    1.1.3.7.1 1.1.3.7.2 1.1.3.7.3 1.1.3.7.4 1.1.3.8.1 1.1.3.8.2 1.1.3.8.3 1.1.3.8.4
    1.1.4.1.1 1.1.4.1.2 1.1.4.1.3 1.1.4.1.4 1.1.4.2.1 1.1.4.2.2 1.1.4.2.3 1.1.4.2.4
    1.1.4.3.1 1.1.4.3.2 1.1.4.3.3 1.1.4.3.4 1.1.4.4.1 1.1.4.4.2 1.1.4.4.3 1.1.4.4.4
    1.1.4.5.1 1.1.4.5.2 1.1.4.5.3 1.1.4.5.4 1.1.4.6.1 1.1.4.6.2 1.1.4.6.3 1.1.4.6.4
    1.1.4.7.1 1.1.4.7.2 1.1.4.7.3 1.1.4.7.4 1.1.4.8.1 1.1.4.8.2 1.1.4.8.3 1.1.4.8.4
    1.2.1.1.1 1.2.1.1.2 1.2.1.1.3 1.2.1.1.4 1.2.1.2.1 1.2.1.2.2 1.2.1.2.3 1.2.1.2.4
    1.2.1.3.1 1.2.1.3.2 1.2.1.3.3 1.2.1.3.4 1.2.1.4.1 1.2.1.4.2 1.2.1.4.3 1.2.1.4.4
    1.2.1.5.1 1.2.1.5.2 1.2.1.5.3 1.2.1.5.4 1.2.1.6.1 1.2.1.6.2 1.2.1.6.3 1.2.1.6.4
    1.2.1.7.1 1.2.1.7.2 1.2.1.7.3 1.2.1.7.4 1.2.1.8.1 1.2.1.8.2 1.2.1.8.3 1.2.1.8.4
    1.2.2.1.1 1.2.2.1.2 1.2.2.1.3 1.2.2.1.4 1.2.2.2.1 1.2.2.2.2 1.2.2.2.3 1.2.2.2.4
    1.2.2.3.1 1.2.2.3.2 1.2.2.3.3 1.2.2.3.4 1.2.2.4.1 1.2.2.4.2 1.2.2.4.3 1.2.2.4.4
    1.2.2.5.1 1.2.2.5.2 1.2.2.5.3 1.2.2.5.4 1.2.2.6.1 1.2.2.6.2 1.2.2.6.3 1.2.2.6.4
    1.2.2.7.1 1.2.2.7.2 1.2.2.7.3 1.2.2.7.4 1.2.2.8.1 1.2.2.8.2 1.2.2.8.3 1.2.2.8.4
    1.2.3.1.1 1.2.3.1.2 1.2.3.1.3 1.2.3.1.4 1.2.3.2.1 1.2.3.2.2 1.2.3.2.3 1.2.3.2.4
    1.2.3.3.1 1.2.3.3.2 1.2.3.3.3 1.2.3.3.4 1.2.3.4.1 1.2.3.4.2 1.2.3.4.3 1.2.3.4.4
    1.2.3.5.1 1.2.3.5.2 1.2.3.5.3 1.2.3.5.4 1.2.3.6.1 1.2.3.6.2 1.2.3.6.3 1.2.3.6.4
    1.2.3.7.1 1.2.3.7.2 1.2.3.7.3 1.2.3.7.4 1.2.3.8.1 1.2.3.8.2 1.2.3.8.3 1.2.3.8.4
    1.2.4.1.1 1.2.4.1.2 1.2.4.1.3 1.2.4.1.4 1.2.4.2.1 1.2.4.2.2 1.2.4.2.3 1.2.4.2.4
    1.2.4.3.1 1.2.4.3.2 1.2.4.3.3 1.2.4.3.4 1.2.4.4.1 1.2.4.4.2 1.2.4.4.3 1.2.4.4.4
    1.2.4.5.1 1.2.4.5.2 1.2.4.5.3 1.2.4.5.4 1.2.4.6.1 1.2.4.6.2 1.2.4.6.3 1.2.4.6.4
    1.2.4.7.1 1.2.4.7.2 1.2.4.7.3 1.2.4.7.4 1.2.4.8.1 1.2.4.8.2 1.2.4.8.3 1.2.4.8.4
    1.3.1.1.1 1.3.1.1.2 1.3.1.1.3 1.3.1.1.4 1.3.1.2.1 1.3.1.2.2 1.3.1.2.3 1.3.1.2.4
    1.3.1.3.1 1.3.1.3.2 1.3.1.3.3 1.3.1.3.4 1.3.1.4.1 1.3.1.4.2 1.3.1.4.3 1.3.1.4.4
    1.3.1.5.1 1.3.1.5.2 1.3.1.5.3 1.3.1.5.4 1.3.1.6.1 1.3.1.6.2 1.3.1.6.3 1.3.1.6.4
    1.3.1.7.1 1.3.1.7.2 1.3.1.7.3 1.3.1.7.4 1.3.1.8.1 1.3.1.8.2 1.3.1.8.3 1.3.1.8.4
    1.3.2.1.1 1.3.2.1.2 1.3.2.1.3 1.3.2.1.4 1.3.2.2.1 1.3.2.2.2 1.3.2.2.3 1.3.2.2.4
    1.3.2.3.1 1.3.2.3.2 1.3.2.3.3 1.3.2.3.4 1.3.2.4.1 1.3.2.4.2 1.3.2.4.3 1.3.2.4.4
    1.3.2.5.1 1.3.2.5.2 1.3.2.5.3 1.3.2.5.4 1.3.2.6.1 1.3.2.6.2 1.3.2.6.3 1.3.2.6.4
    1.3.2.7.1 1.3.2.7.2 1.3.2.7.3 1.3.2.7.4 1.3.2.8.1 1.3.2.8.2 1.3.2.8.3 1.3.2.8.4
    1.3.3.1.1 1.3.3.1.2 1.3.3.1.3 1.3.3.1.4 1.3.3.2.1 1.3.3.2.2 1.3.3.2.3 1.3.3.2.4
    1.3.3.3.1 1.3.3.3.2 1.3.3.3.3 1.3.3.3.4 1.3.3.4.1 1.3.3.4.2 1.3.3.4.3 1.3.3.4.4
    1.3.3.5.1 1.3.3.5.2 1.3.3.5.3 1.3.3.5.4 1.3.3.6.1 1.3.3.6.2 1.3.3.6.3 1.3.3.6.4
    1.3.3.7.1 1.3.3.7.2 1.3.3.7.3 1.3.3.7.4 1.3.3.8.1 1.3.3.8.2 1.3.3.8.3 1.3.3.8.4
    1.3.4.1.1 1.3.4.1.2 1.3.4.1.3 1.3.4.1.4 1.3.4.2.1 1.3.4.2.2 1.3.4.2.3 1.3.4.2.4
    1.3.4.3.1 1.3.4.3.2 1.3.4.3.3 1.3.4.3.4 1.3.4.4.1 1.3.4.4.2 1.3.4.4.3 1.3.4.4.4
    1.3.4.5.1 1.3.4.5.2 1.3.4.5.3 1.3.4.5.4 1.3.4.6.1 1.3.4.6.2 1.3.4.6.3 1.3.4.6.4
    1.3.4.7.1 1.3.4.7.2 1.3.4.7.3 1.3.4.7.4 1.3.4.8.1 1.3.4.8.2 1.3.4.8.3 1.3.4.8.4
    1.4.1.1.1 1.4.1.1.2 1.4.1.1.3 1.4.1.1.4 1.4.1.2.1 1.4.1.2.2 1.4.1.2.3 1.4.1.2.4
    1.4.1.3.1 1.4.1.3.2 1.4.1.3.3 1.4.1.3.4 1.4.1.4.1 1.4.1.4.2 1.4.1.4.3 1.4.1.4.4
    1.4.1.5.1 1.4.1.5.2 1.4.1.5.3 1.4.1.5.4 1.4.1.6.1 1.4.1.6.2 1.4.1.6.3 1.4.1.6.4
    1.4.1.7.1 1.4.1.7.2 1.4.1.7.3 1.4.1.7.4 1.4.1.8.1 1.4.1.8.2 1.4.1.8.3 1.4.1.8.4
    1.4.2.1.1 1.4.2.1.2 1.4.2.1.3 1.4.2.1.4 1.4.2.2.1 1.4.2.2.2 1.4.2.2.3 1.4.2.2.4
    1.4.2.3.1 1.4.2.3.2 1.4.2.3.3 1.4.2.3.4 1.4.2.4.1 1.4.2.4.2 1.4.2.4.3 1.4.2.4.4
    1.4.2.5.1 1.4.2.5.2 1.4.2.5.3 1.4.2.5.4 1.4.2.6.1 1.4.2.6.2 1.4.2.6.3 1.4.2.6.4
    1.4.2.7.1 1.4.2.7.2 1.4.2.7.3 1.4.2.7.4 1.4.2.8.1 1.4.2.8.2 1.4.2.8.3 1.4.2.8.4
    1.4.3.1.1 1.4.3.1.2 1.4.3.1.3 1.4.3.1.4 1.4.3.2.1 1.4.3.2.2 1.4.3.2.3 1.4.3.2.4
    1.4.3.3.1 1.4.3.3.2 1.4.3.3.3 1.4.3.3.4 1.4.3.4.1 1.4.3.4.2 1.4.3.4.3 1.4.3.4.4
    1.4.3.5.1 1.4.3.5.2 1.4.3.5.3 1.4.3.5.4 1.4.3.6.1 1.4.3.6.2 1.4.3.6.3 1.4.3.6.4
    1.4.3.7.1 1.4.3.7.2 1.4.3.7.3 1.4.3.7.4 1.4.3.8.1 1.4.3.8.2 1.4.3.8.3 1.4.3.8.4
    1.4.4.1.1 1.4.4.1.2 1.4.4.1.3 1.4.4.1.4 1.4.4.2.1 1.4.4.2.2 1.4.4.2.3 1.4.4.2.4
    1.4.4.3.1 1.4.4.3.2 1.4.4.3.3 1.4.4.3.4 1.4.4.4.1 1.4.4.4.2 1.4.4.4.3 1.4.4.4.4
    1.4.4.5.1 1.4.4.5.2 1.4.4.5.3 1.4.4.5.4 1.4.4.6.1 1.4.4.6.2 1.4.4.6.3 1.4.4.6.4
    1.4.4.7.1 1.4.4.7.2 1.4.4.7.3 1.4.4.7.4 1.4.4.8.1 1.4.4.8.2 1.4.4.8.3 1.4.4.8.4
    1.5.1.1.1 1.5.1.1.2 1.5.1.1.3 1.5.1.1.4 1.5.1.2.1 1.5.1.2.2 1.5.1.2.3 1.5.1.2.4
    1.5.1.3.1 1.5.1.3.2 1.5.1.3.3 1.5.1.3.4 1.5.1.4.1 1.5.1.4.2 1.5.1.4.3 1.5.1.4.4
    1.5.1.5.1 1.5.1.5.2 1.5.1.5.3 1.5.1.5.4 1.5.1.6.1 1.5.1.6.2 1.5.1.6.3 1.5.1.6.4
    1.5.1.7.1 1.5.1.7.2 1.5.1.7.3 1.5.1.7.4 1.5.1.8.1 1.5.1.8.2 1.5.1.8.3 1.5.1.8.4
    1.5.2.1.1 1.5.2.1.2 1.5.2.1.3 1.5.2.1.4 1.5.2.2.1 1.5.2.2.2 1.5.2.2.3 1.5.2.2.4
    1.5.2.3.1 1.5.2.3.2 1.5.2.3.3 1.5.2.3.4 1.5.2.4.1 1.5.2.4.2 1.5.2.4.3 1.5.2.4.4
    1.5.2.5.1 1.5.2.5.2 1.5.2.5.3 1.5.2.5.4 1.5.2.6.1 1.5.2.6.2 1.5.2.6.3 1.5.2.6.4
    1.5.2.7.1 1.5.2.7.2 1.5.2.7.3 1.5.2.7.4 1.5.2.8.1 1.5.2.8.2 1.5.2.8.3 1.5.2.8.4
    1.5.3.1.1 1.5.3.1.2 1.5.3.1.3 1.5.3.1.4 1.5.3.2.1 1.5.3.2.2 1.5.3.2.3 1.5.3.2.4
    1.5.3.3.1 1.5.3.3.2 1.5.3.3.3 1.5.3.3.4 1.5.3.4.1 1.5.3.4.2 1.5.3.4.3 1.5.3.4.4
    1.5.3.5.1 1.5.3.5.2 1.5.3.5.3 1.5.3.5.4 1.5.3.6.1 1.5.3.6.2 1.5.3.6.3 1.5.3.6.4
    1.5.3.7.1 1.5.3.7.2 1.5.3.7.3 1.5.3.7.4 1.5.3.8.1 1.5.3.8.2 1.5.3.8.3 1.5.3.8.4
    1.5.4.1.1 1.5.4.1.2 1.5.4.1.3 1.5.4.1.4 1.5.4.2.1 1.5.4.2.2 1.5.4.2.3 1.5.4.2.4
    1.5.4.3.1 1.5.4.3.2 1.5.4.3.3 1.5.4.3.4 1.5.4.4.1 1.5.4.4.2 1.5.4.4.3 1.5.4.4.4
    1.5.4.5.1 1.5.4.5.2 1.5.4.5.3 1.5.4.5.4 1.5.4.6.1 1.5.4.6.2 1.5.4.6.3 1.5.4.6.4
    1.5.4.7.1 1.5.4.7.2 1.5.4.7.3 1.5.4.7.4 1.5.4.8.1 1.5.4.8.2 1.5.4.8.3 1.5.4.8.4
    1.6.1.1.1 1.6.1.1.2 1.6.1.1.3 1.6.1.1.4 1.6.1.2.1 1.6.1.2.2 1.6.1.2.3 1.6.1.2.4
    1.6.1.3.1 1.6.1.3.2 1.6.1.3.3 1.6.1.3.4 1.6.1.4.1 1.6.1.4.2 1.6.1.4.3 1.6.1.4.4
    1.6.1.5.1 1.6.1.5.2 1.6.1.5.3 1.6.1.5.4 1.6.1.6.1 1.6.1.6.2 1.6.1.6.3 1.6.1.6.4
    1.6.1.7.1 1.6.1.7.2 1.6.1.7.3 1.6.1.7.4 1.6.1.8.1 1.6.1.8.2 1.6.1.8.3 1.6.1.8.4
    1.6.2.1.1 1.6.2.1.2 1.6.2.1.3 1.6.2.1.4 1.6.2.2.1 1.6.2.2.2 1.6.2.2.3 1.6.2.2.4
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    8.5.1.1.1 8.5.1.1.2 8.5.1.1.3 8.5.1.1.4 8.5.1.2.1 8.5.1.2.2 8.5.1.2.3 8.5.1.2.4
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    8.5.1.7.1 8.5.1.7.2 8.5.1.7.3 8.5.1.7.4 8.5.1.8.1 8.5.1.8.2 8.5.1.8.3 8.5.1.8.4
    8.5.2.1.1 8.5.2.1.2 8.5.2.1.3 8.5.2.1.4 8.5.2.2.1 8.5.2.2.2 8.5.2.2.3 8.5.2.2.4
    8.5.2.3.1 8.5.2.3.2 8.5.2.3.3 8.5.2.3.4 8.5.2.4.1 8.5.2.4.2 8.5.2.4.3 8.5.2.4.4
    8.5.2.5.1 8.5.2.5.2 8.5.2.5.3 8.5.2.5.4 8.5.2.6.1 8.5.2.6.2 8.5.2.6.3 8.5.2.6.4
    8.5.2.7.1 8.5.2.7.2 8.5.2.7.3 8.5.2.7.4 8.5.2.8.1 8.5.2.8.2 8.5.2.8.3 8.5.2.8.4
    8.5.3.1.1 8.5.3.1.2 8.5.3.1.3 8.5.3.1.4 8.5.3.2.1 8.5.3.2.2 8.5.3.2.3 8.5.3.2.4
    8.5.3.3.1 8.5.3.3.2 8.5.3.3.3 8.5.3.3.4 8.5.3.4.1 8.5.3.4.2 8.5.3.4.3 8.5.3.4.4
    8.5.3.5.1 8.5.3.5.2 8.5.3.5.3 8.5.3.5.4 8.5.3.6.1 8.5.3.6.2 8.5.3.6.3 8.5.3.6.4
    8.5.3.7.1 8.5.3.7.2 8.5.3.7.3 8.5.3.7.4 8.5.3.8.1 8.5.3.8.2 8.5.3.8.3 8.5.3.8.4
    8.5.4.1.1 8.5.4.1.2 8.5.4.1.3 8.5.4.1.4 8.5.4.2.1 8.5.4.2.2 8.5.4.2.3 8.5.4.2.4
    8.5.4.3.1 8.5.4.3.2 8.5.4.3.3 8.5.4.3.4 8.5.4.4.1 8.5.4.4.2 8.5.4.4.3 8.5.4.4.4
    8.5.4.5.1 8.5.4.5.2 8.5.4.5.3 8.5.4.5.4 8.5.4.6.1 8.5.4.6.2 8.5.4.6.3 8.5.4.6.4
    8.5.4.7.1 8.5.4.7.2 8.5.4.7.3 8.5.4.7.4 8.5.4.8.1 8.5.4.8.2 8.5.4.8.3 8.5.4.8.4
    8.6.1.1.1 8.6.1.1.2 8.6.1.1.3 8.6.1.1.4 8.6.1.2.1 8.6.1.2.2 8.6.1.2.3 8.6.1.2.4
    8.6.1.3.1 8.6.1.3.2 8.6.1.3.3 8.6.1.3.4 8.6.1.4.1 8.6.1.4.2 8.6.1.4.3 8.6.1.4.4
    8.6.1.5.1 8.6.1.5.2 8.6.1.5.3 8.6.1.5.4 8.6.1.6.1 8.6.1.6.2 8.6.1.6.3 8.6.1.6.4
    8.6.1.7.1 8.6.1.7.2 8.6.1.7.3 8.6.1.7.4 8.6.1.8.1 8.6.1.8.2 8.6.1.8.3 8.6.1.8.4
    8.6.2.1.1 8.6.2.1.2 8.6.2.1.3 8.6.2.1.4 8.6.2.2.1 8.6.2.2.2 8.6.2.2.3 8.6.2.2.4
    8.6.2.3.1 8.6.2.3.2 8.6.2.3.3 8.6.2.3.4 8.6.2.4.1 8.6.2.4.2 8.6.2.4.3 8.6.2.4.4
    8.6.2.5.1 8.6.2.5.2 8.6.2.5.3 8.6.2.5.4 8.6.2.6.1 8.6.2.6.2 8.6.2.6.3 8.6.2.6.4
    8.6.2.7.1 8.6.2.7.2 8.6.2.7.3 8.6.2.7.4 8.6.2.8.1 8.6.2.8.2 8.6.2.8.3 8.6.2.8.4
    8.6.3.1.1 8.6.3.1.2 8.6.3.1.3 8.6.3.1.4 8.6.3.2.1 8.6.3.2.2 8.6.3.2.3 8.6.3.2.4
    8.6.3.3.1 8.6.3.3.2 8.6.3.3.3 8.6.3.3.4 8.6.3.4.1 8.6.3.4.2 8.6.3.4.3 8.6.3.4.4
    8.6.3.5.1 8.6.3.5.2 8.6.3.5.3 8.6.3.5.4 8.6.3.6.1 8.6.3.6.2 8.6.3.6.3 8.6.3.6.4
    8.6.3.7.1 8.6.3.7.2 8.6.3.7.3 8.6.3.7.4 8.6.3.8.1 8.6.3.8.2 8.6.3.8.3 8.6.3.8.4
    8.6.4.1.1 8.6.4.1.2 8.6.4.1.3 8.6.4.1.4 8.6.4.2.1 8.6.4.2.2 8.6.4.2.3 8.6.4.2.4
    8.6.4.3.1 8.6.4.3.2 8.6.4.3.3 8.6.4.3.4 8.6.4.4.1 8.6.4.4.2 8.6.4.4.3 8.6.4.4.4
    8.6.4.5.1 8.6.4.5.2 8.6.4.5.3 8.6.4.5.4 8.6.4.6.1 8.6.4.6.2 8.6.4.6.3 8.6.4.6.4
    8.6.4.7.1 8.6.4.7.2 8.6.4.7.3 8.6.4.7.4 8.6.4.8.1 8.6.4.8.2 8.6.4.8.3 8.6.4.8.4
    8.7.1.1.1 8.7.1.1.2 8.7.1.1.3 8.7.1.1.4 8.7.1.2.1 8.7.1.2.2 8.7.1.2.3 8.7.1.2.4
    8.7.1.3.1 8.7.1.3.2 8.7.1.3.3 8.7.1.3.4 8.7.1.4.1 8.7.1.4.2 8.7.1.4.3 8.7.1.4.4
    8.7.1.5.1 8.7.1.5.2 8.7.1.5.3 8.7.1.5.4 8.7.1.6.1 8.7.1.6.2 8.7.1.6.3 8.7.1.6.4
    8.7.1.7.1 8.7.1.7.2 8.7.1.7.3 8.7.1.7.4 8.7.1.8.1 8.7.1.8.2 8.7.1.8.3 8.7.1.8.4
    8.7.2.1.1 8.7.2.1.2 8.7.2.1.3 8.7.2.1.4 8.7.2.2.1 8.7.2.2.2 8.7.2.2.3 8.7.2.2.4
    8.7.2.3.1 8.7.2.3.2 8.7.2.3.3 8.7.2.3.4 8.7.2.4.1 8.7.2.4.2 8.7.2.4.3 8.7.2.4.4
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    8.7.3.1.1 8.7.3.1.2 8.7.3.1.3 8.7.3.1.4 8.7.3.2.1 8.7.3.2.2 8.7.3.2.3 8.7.3.2.4
    8.7.3.3.1 8.7.3.3.2 8.7.3.3.3 8.7.3.3.4 8.7.3.4.1 8.7.3.4.2 8.7.3.4.3 8.7.3.4.4
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    8.8.1.1.1 8.8.1.1.2 8.8.1.1.3 8.8.1.1.4 8.8.1.2.1 8.8.1.2.2 8.8.1.2.3 8.8.1.2.4
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  • The best mode of practicing the invention is with Compounds of Example numbers 50.6, 50.9, 50.15, and 50.20.
    • Section 1 Synthesis of Compounds of Formula I
  • Synthesis of compounds encompassed by the present invention typically includes some or all of the following general steps: (1) preparation of a phosphonate prodrug; (2) deprotection of a phosphonate ester; (3) modification of a heterocycle; (4) coupling of a heterocycle with a phosphonate component; (5) construction of a heterocycle; (6) ring closure to construct a heterocycle with a phosphonate moiety present and (7) preparation of useful intermediates. These steps are illustrated in the following scheme for compounds of formula I wherein R5 is a 5-membered heteroaromatic ring. Compounds of formula I wherein R5 is a 6-member heteroaromatic ring or other heteroaromatic rings are prepared in an analogous manner.
  • Figure US20090192121A1-20090730-C00050
    • (1) Preparation of a Bisamidate Phosphonate
  • General synthesis of bis-phosphoroamidate prodrugs:
  • In general, the bis-phosphoroamidates of formula I, where both —NR15R16 and —N(R18)—(CR12R13)n—C(O)—R14 are from the same amino acid residues, can be prepared from the activated phosphonates for example, dichlorophosphonate, by coupling with an amino acid ester for example, glycine ethylester with or without base for example, N-methylimidazole. The reactive dichloridates, can be prepared from the corresponding phosphonic acid and a chlorinating agent for example, thionyl chloride (Starrett, et al., J. Med. Chem., 1994, 1857), oxalyl chloride (Stowell, et al., Tetrahedron Lett., 1990, 31, 3261), or phosphorous pentachloride (Quast, et al., Synthesis, 1974, 490). These dichloridates can also be prepared from their corresponding disilyl esters (Bhongle, et al., Synth. Commun., 1987, 17, 1071) and dialkyl esters (Still, et al, Tetrahedron Lett., 1983, 24, 4405; Patois, et al., Bull. Soc. Chim. Fr., 1993, 130, 485).
  • Alternatively, these bis-phosphoroamidates can be prepared by reacting the corresponding phosphonic acid with an amino acid ester for example, glycine ethylester in presence of PPh3 and 2,2′-dipyridyl disulfide in pyridine as described in WO 95/07920 or Mukaiyama, T. et al, J. Am. Chem. Soc., 1972, 94, 8528.
  • Synthesis of mixed bis-phosphoroamidates of formula I, where —NR15R16 and —N(R18)—(CR12R13)nC(O)—R14 are different amino acid esters or a combination of an amino acid ester and a substituted amine, can be prepared by direct conversion via dichloridate as described above (sequential addition) followed by purification of the desired product (e.g., by column chromatography). Alternatively, these unsymmetrical bis-phosphoroamidates can be prepared starting with an appropriate phosphonate monoester such as phenyl ester or benzyl ester to give the mixed phosphonoesteramide via the chloridate, followed by ester hydrolysis under conditions where the amide bond is stable. The resultant mono-amide can be converted to a mixed bisamide by condensation with a second amino ester or a substituted amine via the chloridate, as described above. Synthesis of such monoesters can be prepared using the reported procedure (EP 481 214).
    • (2) Deprotection of a Phosphonate Ester
  • Compounds of formula 2 may be prepared from phosphonate esters using known phosphate and phosphonate ester cleavage conditions. Silyl halides are generally used to cleave various phosphonate esters, and subsequent mild hydrolysis of the resulting silyl phosphonate esters give the desired phosphonic acids. When required, acid scavengers (e.g. 1,1,1,3,3,3-hexamethyldisilazane, 2,6-lutidine, etc.) can be used for the synthesis of acid labile compounds. Such silyl halides include chlorotrimethylsilane (Rabinowitz, J. Org. Chem., 1963, 28: 2975), and bromotrimethylsilane (McKenna, et al, Tetrahedron Lett., 1977, 155), and iodotrimethylsilane (Blackburn, et al, J. Chem. Soc., Chem. Commun., 1978, 870). Alternately, phosphonate esters can be cleaved under strong acidic conditions (e.g. HBr or HCl: Moffatt, et al, U.S. Pat. No. 3,524,846, 1970). These esters can also be cleaved via dichlorophosphonates, prepared by treating the esters with halogenating agents (e.g. phosphorus pentachloride, thionyl chloride, BBr3: Pelchowicz et al, J. Chem. Soc., 1961, 238) followed by aqueous hydrolysis to give phosphonic acids. Aryl and benzyl phosphonate esters can be cleaved under hydrogenolysis conditions (Lejczak, et al, Synthesis, 1982, 412; Elliott, et al, J. Med. Chem., 1985, 28: 1208; Baddiley, et al, Nature, 1953, 171: 76) or metal reduction conditions (Shafer, et al, J. Am. Chem. Soc., 1977, 99: 5118). Electrochemical (Shono, et al, J. Org. Chem., 1979, 44: 4508) and pyrolysis (Gupta, et al, Synth. Commun., 1980, 10: 299) conditions have also been used to cleave various phosphonate esters.
    • (3) Modification of an Existing Heterocycle
  • Syntheses of the heterocycles encompassed in the disclosed compounds have been well studied and described in numerous reviews (see section 4). Although it is advantageous to have the desired substituents present in these heterocycles before synthesis of compounds of formula 4, in some cases, the desired substituents are not compatible with subsequent reactions, and therefore modifications of an existing heterocycle are required late in the synthetic scheme using conventional chemistry (Larock, Comprehensive organic transformations, VCH, New York, 1989; Trost, Comprehensive organic synthesis; Pergamon press, New York, 1991). For example, compounds of formula I wherein A, A″, or B is a halo or a cyano group can be prepared from the corresponding amine group by conversion to the diazonium group and reaction with various copper (I) salts (e.g. CuI, CuBr, CuCl, CuCN). Halogens can also be introduced by direct halogenations of various heterocycles. For example, 5-unsubstituted-2-aminothiazoles can be converted to 2-amino-5-halothiazoles using various reagents (e.g. NIS, NBS, NCS). Heteroaryl halides are also useful intermediates and are often readily converted to other substituents (such as A, A″, B, B″, C″, D, D″, E and E″) via transition metal assisted coupling reactions such as Suzuki, Heck or Stille reactions (Farina et al, Organic Reactions, Vol 50; Wiley, New York, 1997; Mitchell, Synthesis, 1992, 808; Suzuki, Pure App. Chem., 1991, 63, 419; Heck Palladium Reagents in Organic Synthesis; Academic Press: San Diego, 1985). Compounds of formula I wherein A is a carbamoyl group can be made from their corresponding alkyl carboxylate esters via aminolysis with various amines, and conventional functional group modifications of the alkyl carboxylate esters are useful for syntheses of compounds of formula I wherein A is a —CH2OH group or a —CH2-halo group. Substitution reactions of haloheterocycles (e.g. 2-bromothiazole, 5-bromothiazole) with various nucleophiles (e.g. HSMe, HOMe, etc.) represents still another method for introducing substituents such as A, A″, B and B″. For example, substitution of a 2-chlorothiazole with methanethiol gives the corresponding 2-methylthiothiazole.
  • It is envisioned that when necessary alkylation of nitrogen atoms in the heterocycles (e.g. imidazoles, 1,2,4-triazoles and 1,2,3,4-tetrazoles) can be readily performed using for example standard alkylation reactions (with an alkyl halide, an aralkyl halide, an alkyl sulfonate or an aralkyl sulfonate), or Mitsunobu reactions (with an alcohol).
  • (4) Coupling of a Heterocycle with a Phosphonate Component
  • When feasible compounds disclosed in the present invention are prepared via a convergent synthetic route entailing the coupling of a heterocycle with a phosphonate diester component.
  • Transition metal catalyzed coupling reactions such as Stille or Suzuki reactions are particularly suited for the synthesis of compounds of formula I. Coupling reactions between a heteroaryl halide or triflate (e.g. 2-bromopyridine) and a M-PO3R′ wherein M is a 2-(5-tributylstannyl)furanyl or a 2-(5-boronyl)furanyl group under palladium catalyzed reaction conditions (Farina et al, Organic Reactions, Vol. 50; Wiley, New York, 1997; Mitchell, Synthesis, 1992, 808; Suzuki, Pure App. Chem., 1991, 63, 419) yield compounds of formula I wherein X is a furan-2,5-diyl group. It is envisioned that the nature of the coupling partners for these reactions can also be reversed (e.g. coupling of trialkylstannyl or boronyl heterocycles with a halo-X—P(O)(O-alkyl)2). Other coupling reactions between organostannes and an alkenyl halide or an alkenyl triflate are also reported which may be used to prepared compounds of formula I wherein X is an alkenyl group. The Heck reaction may be used to prepare compounds of formula I wherein X is an alkenyl group (Heck Palladium Reagents in Organic Syntiesis; Academic Press: San Diego, 1985). These reactions are particularly suited for syntheses of various heteroaromatics as R5 for compounds of formula I given the availability of numerous halogenated heterocycles, and these reactions are particularly suitable for parallel synthesis (e.g. combinatorial synthesis on solid phase (Bunin, B. A., The Combinatorial Index; Academic Press: San Diego, 1998) or in solution phase (Flynn, D. L. et al., Curr. Op. Drug. Disc. Dev., 1998, 1, 1367)) to generate large combinatorial libraries. For example, ethyl 5-iodo-2-furanylphosphonate can be coupled to Wang's resin under suitable coupling reaction conditions. The resin-coupled 5-iodo-2-[5-(O-ethyl-O-Wang's resin)phosphono]furan can then be subjected to transition metal catalyzed Suzuki and Stille reactions (as described above) with organoboranes and organotins in a parallel manner to give libraries of compounds of formula 3 wherein X is furan-2,5-diyl.
  • Substitution reactions are useful for the coupling of a heterocycle with a phosphonate diester component. For example, cyanuric chloride can be substituted with dialkyl mercaptoalkylphosphonates or dialkyl aminoalkylphosphonates to give compounds of formula I wherein R5 is a 1,3,5-triazine, X is an alkylthio or an alkylamino group. Alkylation reactions are also used for the coupling of a heterocycle with a phosphonate diester component. For example, a heteroaromatic thiol (e.g. a 1,3,4-thiadiazole-2-thiol) can be alkylated with a dialkyl methylphosphonate derivative (e.g. ICH2P(O)(OEt)2, TsOCH2P(O)(OEt)2, TfOCH2P(O)(OEt)2) to lead to compounds of formula I wherein X is an alkylthio group. In another aspect, alkylation reactions of a heteroaromatic carboxylic acid (e.g. a thiazole-4-carboxylic acid) with a dialkyl methylphosphonate derivative (e.g. ICH2P(O)(OEt)2, TsOCH2P(O)(OEt)2, TfOCH2P(O)(OEt)2) lead to compounds of formula I wherein X is an alkoxycarbonyl group, while alkylation reactions of a heteroaromatic thiocarboxylic acid (e.g. a thiazole-4-thiocarboxylic acid) with a dialkyl methylphosphonate derivative (e.g. ICH2P(O)(OEt)2, TsOCH2P(O)(OEt)2, TfOCH2P(O)(OEt)2) lead to compounds of formula I wherein X is an alkylthiocarbonyl group. Substitutions of haloalkyl heterocycles (e.g. 4-haloalkylthiazole) with nucleophiles containing the phosphonate group (diethyl hydroxymethylphosphonate) are useful for the preparation of compounds of formula I wherein X is an alkoxyalkyl or an alkylthioalkyl group. For example, compounds of formula I where X is a —CH2OCH2— group can be prepared from 2-chloromethylpyridine or 4-chloromethylthiazole using dialkyl hydroxymethylphosphonates and a suitable base (e.g. sodium hydride). It is possible to reverse the nature of the nucleophiles and electrophiles for the substitution reactions, i.e. haloalkyl- and/or sulfonylalkylphosphonate esters can be substituted with heterocycles containing a nucleophile (e.g. a 2-hydroxyalkylpyridine, a 2-mercaptoalkylpyridine, or a 4-hydroxyalkyloxazole).
  • Known amide bond formation reactions (e.g. the acyl halide method, the mixed anhydride method, the carbodiimide method) can also be used to couple a heteroaromatic carboxylic acid with a phosphonate diester component leading to compounds of formula I wherein X is an alkylaminocarbonyl or an alkoxycarbonyl group. For example, couplings of a thiazole-4-carboxylic acid with a dialkyl aminoalkylphosphonate or a dialkyl hydroxyalkylphosphonate give compounds of formula I wherein R5 is a thiazole, and X is an alkylaminocarbonyl or an alkoxycarbonyl group. Alternatively, the nature of the coupling partners can be reversed to give compounds of formula I wherein X is an alkylcarbonylamino group. For example, 2-aminothiazoles can be coupled with (RO)2P(O)-alkyl-CO2H (e.g. diethylphosphonoacetic acid) under these reaction conditions to give compounds of formula I wherein R5 is a thiazole and X is an alkylcarbonylamino group. These reactions are also useful for parallel synthesis of compound libraries through combinatorial chemistry on solid phase or in solution phase. For example, HOCH2P(O)(OEt)(O-resin), H2NCH2P(O)(OEt)(O-resin) and HOOCCH2P(O)(OEt)(O-resin) (prepared using known methods) can be coupled to various heterocycles using the above described reactions to give libraries of compounds of formula 3 wherein X is a —C(O)OCH2—, or a —C(O)NHCH2—, or a NHC(O)CH2—.
  • Rearrangement reactions can also be used to prepare compounds covered in the present invention. For example, the Curtius' rearrangement of a thiazole-4-carboxylic acid in the presence of a dialkyl hydroxyalkylphosphonate or a dialkyl aminoalkylphosphonate lead to compounds of formula I wherein X is an alkylaminocarbonylamino or an alkoxycarbonylamino group. These reactions can also be adopted for combinatorial synthesis of various libraries of compounds of formula 3. For example, Curtius' rearrangement reactions between a heterocyclic carboxylic acid and HOCH2P(O)(OEt)(O-resin), or H2NCH2P(O)(OEt)(O-resin) can lead to libraries of compounds of formula I wherein X is a —NHC(O)OCH2—, or a NHC(O)NHCH2—.
  • For compounds of formula I wherein X is an alkyl group, the phosphonate group can be introduced using other common phosphonate formation methods such as Michaelis-Arbuzov reaction (Bhattacharya et al., Chem. Rev., 1981, 81: 415), Michaelis-Becker reaction (Blackburn et al., J. Organomet. Chem., 1988, 348: 55), and addition reactions of phosphorus to electrophiles (such as aldehydes, ketones, acyl halides, imines and other carbonyl derivatives).
  • Phosphonate component can also be introduced via lithiation reactions. For example, lithiation of an 2-ethynylpyridine using a suitable base followed by trapping the thus generated anion with a dialkyl chlorophosphonate lead to compounds of formula I wherein R5 is a pyridyl, X is a 1-(2-phosphono)ethynyl group.
    • (5) Construction of a Heterocycle
  • Although existing heterocycles are useful for the synthesis of compounds of formula I, when required, heterocycles can also be constructed leading to compounds in the current invention. The construction of heterocycles have been well described in the literature using a variety of reaction conditions (Joule et al., Heterocyclic Chemistry; Chapman hall, London, 1995; Boger, Weinreb, Hetero Diels-Alder Methodology In Organic Synthesis; Academic press, San Diego, 1987; Padwa, 1,3-Dipolar Cycloaddition Chemistry; Wiley, New York, 1984; Katritzsky et al., Comprehensive Heterocyclic Chemistry; Pergamon press, Oxford; Newkome et al., Contemporary Heterocyclic Chemistry: Syntheses, Reaction and Applications; Wiley, New York, 1982; Syntheses of Heterocyclic Compounds; Consultants Bureau, New York). Some of the methods which are useful to prepare compounds in the present invention are given as examples in the following discussion.
    • (i) Construction of a Thiazole Ring System
  • Thiazoles useful for the present invention can be readily prepared using a variety of well described ring-forming reactions (Metzger, Thiazole and its derivatives, part 1 and part 2; Wiley & Sons, New York, 1979). Cyclization reactions of thioamides (e.g. thioacetamide, thiourea) and alpha-halocarbonyl compounds (such as alpha-haloketones, alpha-haloaldehydes) are particularly useful for the construction of a thiazole ring system. For example, cyclization reactions between thiourea and 5-diethylphosphono-2-[(−2-bromo-1-oxo)alkyl]furans are useful for the synthesis of compounds of formula I wherein R5 is a thiazole, A is an amino group and X is a furan-2,5-diyl group; cyclization reaction between thiourea and a bromopyruvate alkyl ester give a 2-amino-4-alkoxycarbonylthiazole which is useful for the preparations of compounds of formula I wherein R5 is a thiazole and X is an alkylaminocarbonyl, an alkoxycarbonyl, an alkylaminocarbonylamino, or an alkoxyacarbonylamino group. Thioamides can be prepared using reactions reported in the literature (Trost, Comprehensive organic synthesis, Vol. 6; Pergamon press, New York, 1991, pages 419-434) and alpha-halocarbonyl compounds are readily accessible via conventional reactions (Larock, Comprehensive organic transformations, VCH, New York, 1989). For example, amides can be converted to thioamides using Lawesson's reagent or P2S5, and ketones can be halogenated using various halogenating reagents (e.g. NBS, CuBr2).
    • (ii) Construction of an Oxazole Ring System
  • Oxazoles useful for the present invention can be prepared using various methods in the literature (Turchi, Oxazoles; Wiley & Sons, New York, 1986). Reactions between isocyanides (e.g. tosylmethylisocyanide) and carbonyl compounds (e.g. aldehydes and acyl chlorides) can be used to construct oxazole ring systems (van Leusen et al, Tetrahedron Lett., 1972, 2369). Alternatively, cyclization reactions of amides (e.g. urea, carboxamides) and alpha-halocarbonyl compounds are commonly used for the construction of an oxazole ring system. For example, the reactions of urea and 5-diethylphosphono-2-[(−2-bromo-1-oxo)alkyl]furans are useful for the synthesis of compounds of formula I wherein R5 is an oxazole, A is an amino group and X is a furan-2,5-diyl group. Reactions between amines and imidates are also used to construct the oxazole ring system (Meyers et al, J. Org. Chem., 1986, 51(26), 5111).
    • (III) Construction of a Pyridine Ring System
  • Pyridines useful for the synthesis of compounds of formula I can be prepared using various known synthetic methods (Klingsberg, Pyridine and Its Derivatives; Interscience Publishers, New York, 1960-1984). 1,5-Dicarbonyl compounds or their equivalents can be reacted with ammonia or compounds which can generate ammonia to produce 1,4-dihydropyridines which are easily dehydrogenated to pyridines. When unsaturated 1,5-dicarbonyl compounds, or their equivalents (e.g. pyrylium ions) are used to react with ammonia, pyridines can be generated directly. 1,5-Dicarbonyl compounds or their equivalents can be prepared using conventional chemistry. For example, 1,5-diketones are accessible via a number of routes, such as Michael addition of an enolate to an enone (or precursor Mannich base (Gill et al, J. Am. Chem. Soc., 1952, 74, 4923)), ozonolysis of a cyclopentene precursor, or reaction of silyl enol ethers with 3-methoxyallylic alcohols (Duhamel et al, Tetrahedron, 1986, 42, 4777). When one of the carbonyl carbons is at the acid oxidation state, then this type of reaction produces 2-pyridones which can be readily converted to 2-halopyridines (Isler et al, Helv. Chim. Acta, 1955, 38, 1033) or 2-aminopyridines (Vorbruggen et al, Chem. Ber., 1984, 117, 1523). Alternatively, a pyridine can be prepared from an aldehyde, a 1,3-dicarbonyl compound and ammonia via the classical Hantzsch synthesis (Bossart et al, Angew. Chem. Int. Ed. Engl., 1981, 20, 762). Reactions of 1,3-dicarbonyl compounds (or their equivalents) with 3-amino-enones or 3-amino-nitriles have also been used to produce pyridines (such as the Guareschi synthesis, Marinella, Org. Synth., Coll, Vol. IV, 1963, 210). 1,3-Dicarbonyl compounds can be made via oxidation reactions on corresponding 1,3-diols or aldol reaction products (Mukaiyama, Org, Reactions, 1982, 28, 203). Cycloaddition reactions have also been used for the synthesis of pyridines, for example cycloaddition reactions between oxazoles and alkenes (Naito et al., Chem. Pharm. Bull, 1965, 13, 869), and Diels-Alder reactions between 1,2,4-triazines and enamines (Boger et al., J. Org. Chem., 1981, 46, 2179).
    • (iv) Construction of a Pyrimidine Ring System
  • Pyrimidine ring systems useful for the synthesis of compounds of formula I are readily available (Brown, The pyrimidines; Wiley, New York, 1994). One method for pyrimidine synthesis involves the coupling of a 1,3-dicarbonyl component (or its equivalent) with an N—C—N fragment. The selection of the N—C—N component—urea (Sherrnan et al., Org. Synth., Coll. Vol. IV, 1963, 247), amidine (Kenner et al., J. Chem. Soc., 1943, 125) or guanidine (Burgess, J. Org. Chem., 1956, 21, 97; VanAllan, Org. Synth., Coll. Vol. IV, 1963, 245)—governs the substitution at C-2 in the pyrimidine products. This method is particular useful for the synthesis of compounds of formula I with various A groups. In another method, pyrimidines can be prepared via cycloaddition reactions such as aza-Diels-Alder reactions between a 1,3,5-triazine and an enamine or an ynamine (Boger et al., J. Org. Chem., 1992, 57, 4331 and references cited therein).
    • (v) Construction of an Imidazole Ring System
  • Imidazoles useful for the synthesis of compounds of formula I are readily prepared using a variety of different synthetic methodologies. Various cyclization reactions are generally used to synthesize imidazoles such as reactions between amidines and alpha-haloketones (Mallick et al, J. Am. Chem. Soc., 1984, 106(23), 7252) or alpha-hydroxyketones (Shi et al, Synthetic Comm., 1993, 23(18), 2623), reactions between urea and alpha-haloketones, and reactions between aldehydes and 1,2-dicarbonyl compounds in the presence of amines.
    • (vi) Construction of an Isoxazole Ring System
  • Isoxazoles useful for the synthesis of compounds of formula I are readily synthesized using various methodologies (such as cycloaddition reactions between nitrile oxides and alkynes or active methylene compounds, oximation of 1,3-dicarbonyl compounds or alpha, beta-acetylenic carbonyl compounds or alpha,beta-dihalocarbonyl compounds, etc.) can be used to synthesize an isoxazole ring system (Grunanger et al., Isoxazoles; Wiley & Sons, New York, 1991). For example, reactions between alkynes and 5-diethylphosphono-2-chlorooximidofuran in the presence of base (e.g. triethylamine, Hunig's base, pyridine) are useful for the synthesis of compounds of formula I wherein R5 is an isoxazole and X is a furan-2,5-diyl group.
  • (vii) Construction of a Pyrazole Ring System
  • Pyrazoles useful for the synthesis of compounds of formula I are readily prepared using a variety of methods (Wiley, Pyrazoles, Pyrazolines, Pyrazolidines, Indazoles, and Condensed Rings; Interscience Publishers, New York, 1967) such as reactions between hydrazines and 1,3-dicarbonyl compounds or 1,3-dicarbonyl equivalents (e.g. one of the carbonyl group is masked as an enamine or ketal or acetal), and additions of hydrazines to acrylonitriles followed by cyclization reactions (Dom et al, Org. Synth., 1973, Coll. Vol. V, 39). Reaction of 2-(2-alkyl-3-N,N-dimethylamino)acryloyl-5-diethylphosphonofurans with hydrazines are useful for the synthesis of compounds of formula I wherein R5 is a pyrazole, X is a furan-2,5-diyl group and B″ is an alkyl group.
  • (viii) Construction of a 1,2,4-triazole Ring System
  • 1,2,4-Triazoles useful for the synthesis of compounds of formula I are readily available via various methodologies (Montgomery, 1,2,4-Triazoles; Wiley, New York, 1981). For example, reactions between hydrazides and imidates or thioimidates (Sui et al., Bioorg. Med. Chem. Lett., 1998, 8, 1929; Catarzi et al., J. Med. Chem., 1995, 38(2), 2196), reactions between 1,3,5-triazine and hydrazines (Grundmann et al., J. Org. Chem., 1956, 21, 1037), and reactions between aminoguanidine and carboxylic esters (Ried et al., Chem. Ber., 1968, 101, 2117) are used to synthesize 1,2,4-triazoles.
  • (6) Ring Closure to Construct a Heterocycle with a Phosphonate
  • Compounds of formula 4 can also be prepared using a ring closure reaction to construct the heterocycle from precursors that contain the phosphonate component. For example, cyclization reactions between thiourea and 5-diethylphosphono-2-[(-2-bromo-1-oxo)alkyl]furans are useful for the synthesis of compounds of formula I wherein R5 is a thiazole, A is an amino group and X is a furan-2,5-diyl group. Oxazoles of the present invention can also be prepared using a ring closure reaction. In this case, reactions of urea and 5-diethylphosphono-2-[(-2-bromo-1-oxo)alkyl]furans are useful for the synthesis of compounds of formula I wherein R5 is an oxazole, A is an amino group and X is a furan-2,5-diyl group. Reactions between 5-diethylphosphono-2-furaldehyde, an alkyl amine, a 1,2-diketone and ammonium acetate are useful to synthesize compounds of formula I wherein R5 is an imidazole and X is a furan-2,5-diyl group. These types of ring closure reactions can also be used for the synthesis of pyridines or pyrimidines useful in the present invention. For example, reaction of 5-diethylphosphono-2-[3-dimethylamino-2-alkyl)acryloyl]furans and cyanoacetamide in the presence of base gives 5-alkyl-3-cyano-6-[2-(5-diethylphosphono)furanyl]-2-pyridones (Jain et al., Tetrahedron Lett., 1995, 36, 3307). Subsequent conversion of these 2-pyridones to the corresponding 2-halopyridines (see references cited in section 3 for the modifications of heterocycles) will lead to compounds of formula I wherein R5 is a pyridine, A is a halo group, X is a furan-2,5-diyl group, and B is an alkyl group. Reactions of 5-diethylphosphono-2-[3-dimethylamino-2-alkyl)acryloyl]furans and amidines in the presence of base give 5-alkyl-6-[2-(5-diethylphosphono)-furanyl]pyrimidines which will lead to compounds of formula I wherein R5 is a pyrimidine, X is a furan-2,5-diyl group and B is an alkyl group.
    • (7) Preparation of Various Precursors Useful for Cyclization Reactions
  • Intermediates required for the synthesis of compounds in the present invention are generally prepared using either an existing method in the literature or a modification of an existing method. Syntheses of some of the intermediates useful for the synthesis of compounds in the present invention are described herein.
  • Various aryl phosphonate dialkyl esters are particularly useful for the synthesis of compounds of formula I. For example, compounds of formula I wherein X is a furan-2,5-diyl group can be prepared from a variety of furanyl precursors. It is envisioned that synthesis of other precursors may follow some or all of these reaction steps, and some modifications of these reactions may be required for different precursors. 5-Dialkylphosphono-2-furancarbonyl compounds (e.g. 5-diethylphosphono-2-furaldehyde, 5-diethylphosphono-2-acetylfuran) are well suited for the synthesis of compounds of formula I wherein X is a furan-2,5-diyl group. These intermediates are prepared from furan or furan derivatives using conventional chemistry such as lithiation reactions, protection of carbonyl groups and deprotection of carbonyl groups. For example, lithiation of furan using known methods (Gschwend Org. React., 1979, 26: 1) followed by addition of phosphorylating agents (e.g. CLPO3R2) gives 2-dialkylphosphono-furans (e.g. 2-diethylphosphonofuran). This method can also be applied to a 2-substituted furan (e.g. 2-furoic acid) to give a 5-dialkylphosphono-2-substituted furan (e.g. 5-diethylphosphono-2-furoic acid). It is envisioned that other aryl phosphonate esters can also be prepared using this approach or a modification of this approach. Alternatively, other methods such as transition metal catalyzed reactions of aryl halides or triflates (Balthazar et al. J. Org. Chem., 1980, 45: 5425; Petrakis et al. J. Am. Chem. Soc., 1987, 109: 2831; Lu et al. Synthesis, 1987, 726) are used to prepare aryl phosphonates. Aryl phosphonate esters can also be prepared from aryl phosphates under anionic rearrangement conditions (Melvin, Tetrahedron Lett., 1981, 22: 3375; Casteel et al. Synthesis, 1991, 691). N-Alkoxy aryl salts with alkali metal derivatives of dialkyl phosphonate provide another general synthesis for heteroaryl-2-phosphonate esters (Redmore J. Org. Chem., 1970, 35: 4114).
  • A second lithiation step can be used to incorporate a second group on the aryl phosphonate dialkyl ester such as an aldehyde group, a trialkylstannyl or a halo group, although other methods known to generate these functionalities (e.g. aldehydes) can be envisioned as well (e.g. Vilsmeier-Hack reaction or Reimar-Teimann reaction for aldehyde synthesis). In the second lithiation step, the lithiated aromatic ring is treated with reagents that either directly generate the desired functional group (e.g. for an aldehyde using DMF, HCO2R, etc.) or with reagents that lead to a group that is subsequently transformed into the desired functional group using known chemistry (e.g. alcohols, esters, nitrites, alkenes can be transformed into aldehydes). For example, lithiation of a 2-dialkylphosphonofuran (e.g. 2-diethylphosphonofuran) under normal conditions (e.g. LDA in THF) followed by trapping of the thus generated anion with an electrophile (e.g. tributyltin chloride or iodine) produces a 5-functionalized-2-dialkylphosphonofuran (e.g. 5-tributylstannyl-2-diethylphosphonofuran or 5-iodo-2-diethylphosphonofuran). It is also envisioned that the sequence of these reactions can be reversed, i.e. the aldehyde moiety can be incorporated first followed by the phosphorylation reaction. The order of the reaction will be dependent on reaction conditions and protecting groups. Prior to the phosphorylation, it is also envisioned that some of these functional groups may be protected using a number of well-known methods (e.g. protection of aldehydes as acetals, animals; protection of ketones as ketals). The protected functional group is then unmasked after phosphorylation. (Protective groups in Organic Synthesis, Greene, T. W., 1991, Wiley, New York). For example, protection of 2-furaldehyde as 1,3-propanediol acetal followed by a lithiation step (using for example LDA) and trapping the anion with a dialkyl chlorophosphate (e.g. diethyl chlorophosphate), and subsequent deprotection of the acetal functionality under normal deprotection conditions produces the 5-dialkylphosphono-2-furaldehyde (e.g. 5-diethylphosphono-2-furaldehyde). Another example is the preparation of 5-keto-2-dialkylphosphonofurans which encompass the following steps: acylations of furan under Friedel-Crafts reaction conditions give 2-ketofuran, subsequent protection of the ketone as ketals (e.g. 1,3-propanediol cyclic ketal) followed by a lithiation step as described above gives the 5-dialkylphosphono-2-furanketone with the ketone being protected as a 1,3-propanediol cyclic ketal, and final deprotection of the ketal under, for example, acidic conditions gives 2-keto-5-dialkylphosphonofurans (e.g. 2-acetyl-5-diethylphosphonofuran). Alternatively, 2-ketofurans can be synthesized via a palladium catalyzed reaction between 2-trialkylstannylfurans (e.g. 2-tributylstannylfuran) and an acyl chloride (e.g. acetyl chloride, isobutyryl chloride). The phosphonate moiety may be present in the 2-trialkylstannylfurans (e.g. 2-tributylstannyl-5-diethylphosphonofuran). 2-Keto-5-dialkylphosphonofurans can also be prepared from a 5-dialkylphosphono-2-furoic acid (e.g. 5-diethylphosphono-2-furoic acid) by conversion of the acid to the corresponding acyl chloride and followed by additions of a Grignard reagent.
  • Some of the above described intermediates can also be used for the synthesis of other useful intermediates. For example, a 2-keto-5-dialkylphosphonofuran can be further converted to a 1,3-dicarbonyl derivative which is useful for the preparation of pyrazoles, pyridines or pyrimidines. Reaction of a 2-keto-5-dialkylphosphonofuran (e.g. 2-acetyl-5-diethylphosphonofuran) with a dialkylformamide dialkyl acetal (e.g. dimethylformamide dimethyl acetal) gives a 1,3-dicarbonyl equivalent as a 2-(3-dialkylamino-2-alkyl-acryloyl)-5-dialkylphosphonofuran (e.g. 2-(3-dimethylaminoacryloyl)-5-diethylphosphonofuran).
  • It is envisioned that the above described methods for the synthesis of furan derivatives can be, either directly or with some modifications, applied to syntheses of various other useful intermediates such as aryl phosphonate esters (e.g. thienyl phosphonate esters, phenyl phosphonate esters or pyridyl phosphonate esters).
  • It is conceivable that when applicable the above described synthetic methods can be adopted for parallel synthesis either on solid phase or in solution to provide rapid SAR (structure activity relationship) exploration of FBPase inhibitors encompassed in the current invention, provided method development for these reactions are successful.
    • Section 2 Synthesis of Compounds of Formula X
  • Synthesis of the compounds encompassed by the present invention typically includes some or all of the following general steps: (1) preparation of a phosphonate prodrug; (2) deprotection of a phosphonate ester; (3) construction of a heterocycle; (4) introduction of a phosphonate component; (5) synthesis of an aniline derivative. Step (1) and step (2) were discussed in section 1, and discussions of step (3), step (4) and step (5) are given below. These methods are also generally applicable to compounds of Formula X.
  • Figure US20090192121A1-20090730-C00051
    • (3) Construction of a Heterocycle (i) Benzothiazole Ring System
  • Compounds of formula 3 wherein G″═S, i.e. benzothiazoles, can be prepared using various synthetic methods reported in the literature. Two of these methods are given as examples as discussed below. One method is the modification of commercially available benzothiazole derivatives to give the appropriate functionality on the benzothiazole ring. Another method is the annulation of various anilines (e.g. compounds of formula 4) to construct the thiazole portion of the benzothiazole ring. For example, compounds of formula 3 wherein G″═S, A2=NH2, L2, E2, J2=H, X2═CH2O, and R′=Et can be prepared from the commercially available 4-methoxy-2-amino thiazole via a two-step sequence: conversion 4-methoxy-2-aminobenzothiazole to 4-hydroxy-2-aminobenzothiazole with reagents such as BBr3 (Node, M.; et al. J. Org. Chem. 45, 2243-2246, 1980) or AlCl3 in presence of a thiol (e.g. EtSH) (McOmie, J. F. W.; et al. Org. Synth., Collect. Vol. V, 412, 1973) followed alkylation of the phenol group with diethylphosphonomethyl trifluoromethylsulfonate (Phillion, D. P.; et al. Tetrahedron Lett. 27, 1477-1484, 1986) in presence of a suitable base (e.g. NaH) in polar aprotic solvents (e.g. DMF) provide the required compound.
  • Several methods can be used to convert various anilines to benzothiazoles (Sprague, J. M.; Land, A. H. Heterocycle. Compd. 5, 506-13, 1957). For example, 2-aminobenzothiazoles (formula 3 wherein A=NH2) can be prepared by annulation of compounds of formula 4 wherein W2═H, using various common methods. One method involves the treatment of a suitably substituted aniline with a mixture of KSCN and CuSO4 in methanol to give a substituted 2-aminobenzothiazole (Ismail, I. A.; Sharp, D. E; Chedekel, M. R. J. Org. Chem. 45, 2243-2246, 1980). Alternatively, a 2-aminobenzothiazole can also be prepared by the treatment of Br2 in presence of KSCN in acetic acid (Patil, D. G.; Chedekel, M. R. J. Org. Chem. 49, 997-1000, 1984). This reaction can also be done in two step sequence. For example treatment of substituted phenylthioureas with Br2 in CHCl3 gives substituted 2-aminobenzothiazoles (Patil, D. G.; Chedekel, M. R. J. Org. Chem. 49, 997-1000, 1984). 2-Aminobenzothiazoles can also be made by condensation of ortho iodo anilines with thiourea in presence of Ni catalyst (NiCl2 (PPh3)2) (Takagi, K. Chem. Lett. 265-266, 1986).
  • Benzothiazoles can undergo electrophilic aromatic substitution to give 6-substituted benzothiazoles (Sprague, J. M.; Land, A. H. Heterocycle. Compd. 5, 606-13, 1957). For example bromination of formula 3 wherein G″=S, A2=NH2, L2, E2, J2=H, X2═CH2O and R′=Et with bromine in polar solvents such as AcOH gave compound of formula 3 wherein E2=Br.
  • Furthermore, compounds of formula 3 wherein A is a halo, H, alkoxy, alkylthio or an alkyl can be prepared from the corresponding amino compound (Larock, Comprehensive organic transformations, VCH, New York, 1989; Trost, Comprehensive organic synthesis; Pergamon press, New York, 1991).
    • (ii) Benzoxazoles
  • Compounds of formula 3 wherein G″=O, i.e. benzoxazoles, can be prepared by the annulation of ortho aminophenols with suitable reagent (e.g. cyanogen halide (A=NH2; Alt, K. O.; et al J. Heterocyclic Chem. 12, 775, 1975) or acetic acid (A=CH3; Saa, J. M.; J. Org. Chem. 57, 589-594, 1992) or trialkyl orthoformate (A=H; Org. Prep. Proced. Int., 22, 613, 1990)).
    • (4) Introduction of a Phosphonate Component
  • Compounds of formula 4 (wherein X2═CH2O and R′=alkyl) can made in different ways (e.g. using alkylation and nucleophilic substitution reactions). Typically, compounds of formula 5 wherein M′=OH is treated with a suitable base (e.g. NaH) in polar aprotic solvent (e.g. DMF, DMSO) and the resulting phenoxide anion can be alkylated with a suitable electrophile often with a phosphonate component present (e.g. diethyl iodomethylphosphonate, diethyl trifluoromethylsulphonomethyl phosphonate, diethyl p-methyltoluenesulphonomethylphosphonate). The alkylation method can also be applied to the precursor compounds to compounds of formula 5 wherein a phenol moiety is present and it can be alkylated with a phosphonate containing component. Alternately, compounds of formula 4 can also be made from the nucleophilic substitution of the precursor compounds to compounds of formula 5, for example, wherein a halo group, e.g., such as a fluoro or a chloro, is present ortho to a nitro group. For example, a compound of formula 4 (wherein X2═CH2O and R′=Et) can be prepared from a 2-chloro-1-nitrobenzene derivative by treatment with NaOCH2P(O)(OEt)2 in DMF. Similarly, compounds of formula 4 where X2=-alkyl-S— or -alkyl-N— can also be made.
    • (5) Synthesis of an Aniline Derivative
  • Numerous synthetic methods have been reported for the synthesis of aniline derivatives, these methods can be applied to the synthesis of useful intermediates which can lead to compounds of formula X. For example, various alkenyl or aryl groups can be introduced on to a benzene ring via transition metal catalyzed reactions (Kasibhatla, S. R., et al WO 98/39343 and the references cited in); anilines can be prepared from their corresponding nitro derivatives via reduction reactions (e.g. hydrogenation reactions in presence of 10% Pd/C, or reduction reactions using SnCl2 in HCl (Patil, D. G.; Chedekel, M. R. J. Org. Chem. 49, 997-1000, 1984)).
    • Section 3 Synthesis of Compounds of Formula XI
  • WO 98/39343 describes the synthesis of phosphonic acids and esters of the benzimidazoles of Formula XI. The bisamidate phosphonates of the present invention can be prepared by using procedures described supra for compounds of Formula I.
    • Formulations
  • Compounds of the invention are administered orally in a total daily dose in a range of about 0.01 mg/kg/dose to about 100 mg/kg/dose; and from about 0.1 mg/kg/dose to about 10 mg/kg/dose. The use of time-release preparations to control the rate of release of the active ingredient is contemplated. The dose may be administered in as many divided doses as is convenient. When other methods are used (e.g. intravenous administration), compounds are administered to the affected tissue at a rate in the range from 0.05 to 10 mg/kg/hour; and from 0:1 to 1 mg/kg/hour. Such rates are easily maintained when these compounds are intravenously administered as discussed below.
  • For the purposes of this invention, 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. The term parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques. Intraarterial and intravenous injection as used herein includes administration through catheters. Oral administration is generally preferred.
  • Pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, 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 excipient which are suitable for manufacture of tablets are acceptable. These 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 may 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.
  • 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.
  • Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, 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 monooleate). 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 arachis 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. Suitable dispersing or wetting agents 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 arachis 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 may 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.
  • The pharmaceutical compositions of the invention may be in the form of 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. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • 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. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 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. The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion should contain from about 3 to 330 μg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
  • As noted above, 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, especially when the active ingredient is 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.
  • Suitable unit dosage formulations include those containing a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, of a fructose 1,6-bisphosphatase inhibitor compound.
  • It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those skilled in the art.
    • Utility
  • One aspect of the invention is directed to novel bis-phosphoramidate prodrugs of FBPase inhibitors to increase the oral bioavailability of the parent drugs.
  • FBPase inhibitors and their prodrugs may be used to treat diabetes mellitus, lower blood glucose levels, and inhibit gluconeogenesis.
  • FBPase inhibitors and their prodrugs may also be used to treat excess glycogen storage diseases. Excessive hepatic glycogen stores are found in patients with some glycogen storage diseases. Since the indirect pathway contributes significantly to glycogen synthesis (Shulman, G. I. Phys. Rev. —72:1019-1035, 1992), inhibition of the indirect pathway (gluconeogenesis flux) decreases glycogen overproduction.
  • FBPase inhibitors and their prodrugs may also be used to treat or prevent diseases associated with increased insulin levels. Increased insulin levels are associated with an increased risk of cardiovascular complications and atherosclerosis (Folsom, et al., Stroke, 25:66-73, 1994; Howard, G. et al., Circulation, 93:1809-1817, 1996). FBPase inhibitors and their prodrugs are expected to decrease postprandial glucose levels by enhancing hepatic glucose uptake. This effect is postulated to occur in individuals that are non-diabetic (or pre-diabetic, i.e. without elevated hepatic glucose output “hereinafter HGO” or fasting blood glucose levels). Increased hepatic glucose uptake will decrease insulin secretion and thereby decrease the risk of diseases or complications that arise from elevated insulin levels.
  • These aspects are described in greater detail below.
    • EXAMPLES 1. Synthesis of Compounds of Formula IA Example 1 Preparation of 5-diethylnhosphono-2-furaldehyde (1)
  • Step A. A solution of 2-furaldehyde diethyl acetal (1 mmole) in THF (tetrahydrofuran) was treated with nBuLi (1 mmole) at −78° C. After 1 h, diethyl chlorophosphate (1.2 mmole) was added and the reaction was stirred for 40 min. Extraction and evaporation gave a brown oil.
    Step B. The resulting brown oil was treated with 80% acetic acid at 90° C. for 4 h. Extraction and chromatography gave compound 1 as a clear yellow oil. Alternatively this aldehyde can be prepared from furan as described below.
    Step C. A solution of furan (1 mmole) in diethyl ether was treated with TMEDA (N,N,N′N′-tetramethylethylenediamine) (1 mmole) and nBuLi (2 mmole) at −78° C. for 0.5 h. Diethyl chlorophosphate (1.2 mmole) was added to the reaction mixture and stirred for another hour. Extraction and distillation gave diethyl 2-furanphosphonate as a clear oil.
    Step D. A solution of diethyl 2-furanphosphonate (1 mmole) in THF was treated with LDA (1.12 mmole, lithium N,N-diisopropylamide) at −78° C. for 20 min. Methyl formate (1.5 mmole) was added and the reaction was stirred for 1 h. Extraction and chromatography gave compound 1 as a clear yellow oil. Preferably this aldehyde can be prepared from 2-furaldehyde as described below.
    Step E. A solution of 2-furaldehyde (1 mmole) and N,N′-dimethylethylene diamine (1 mmole) in toluene was refluxed while the resulting water being collected through a Dean-Stark trap. After 2 h the solvent was removed in vacuo and the residue was distilled to give. furan-2-(N,N′-dimethylimidazolidine) as a clear colorless oil. bp 59-61° C. (3 mm Hg).
    Step F. A solution of furan-2-(N,N′-dimethylimidazolidine) (1 mmole) and TMEDA (1 mmole) in THF was treated with nBuLi (1.3 mmole) at −40 to −48° C. The reaction was stirred at 0° C. for 1.5 h and then cooled to −55° C. and treated with a solution of diethylchlorophosphate (1.1 mmole) in THF. After stirring at 25° C. for 12 h the reaction mixture was evaporated and subjected to extraction to give 5-diethylphosphono-furan-2-(N,N′-dimethylimidazolidine) as a brown oil.
    Step G. A solution of 5-diethylphosphonofuran-2-(N,N′-dimethyl- imidazolidine) (1 mmole) in water was treated with concentrated sulfuric acid until pH=1. Extraction and chromatography gave compound 1 as a clear yellow oil.
    • Example 2 Preparation of 5-diethylphosphono-2-1[(1-oxo)alkyl]furans and 6-diethylphosphono-2-[(1-oxo)alkyl]pyridines
  • Step A. A solution of furan (1.3 mmole) in toluene was treated with 4-methyl pentanoic acid (1 mmole), trifluoroacetic anhydride (1.2 mmole) and boron trifluoride etherate (0.1 mmole) at 56° C. for 3.5 h. The cooled reaction mixture was quenched with aqueous sodium bicarbonate (1.9 mmole), filtered through a celite pad. Extraction, evaporation and distillation gave 2-[(4-methyl-1-oxo)pentyl]furan as a brown oil (bp 65-77° C., 0.1 mm Hg).
    Step B. A solution of 2-[(4-methyl-1-oxo)pentyl]furan (1 mmole) in benzene was treated with ethylene glycol (2.1 mmole) and p-toluenesulfonic acid (0.05 mmole) at reflux for 60 h while removing water via a Dean-Stark trap. Triethyl orthoformate (0.6 mmole) was added and resulting mixture was heated at reflux for an additional hour. Extraction and evaporation gave 2-(2-furanyl)-2-[(3-methyl)butyl]-1,3-dioxolane as an orange liquid.
    Step C. A solution of 2-(2-furanyl)-2-[(3-methyl)butyl]-1,3-dioxolane (1 mmole) in THF was treated with TMEDA (1 mmole) and nBuLi (1.1 mmole) at −45° C., and the resulting reaction mixture was stirred at −5 to 0° C. for 1 h. The resulting reaction mixture was cooled to −45° C., and cannulated into a solution of diethyl chlorophosphate in THF at −45° C. The reaction mixture was gradually warmed to ambient temperature over 1.25 h. Extraction and evaporation gave 2-[2-(5-diethylphosphono)furanyl]-2-[(3-methyl)butyl]-1,3-dioxolane as a dark oil.
    Step D. A solution of 2-[2-(5-diethylphosphono)furanyl]-2-[(3-methyl)butyl]-1,3-dioxolane (1 mmole) in methanol was treated with 1 N hydrochloric acid (0.2 mmole) at 60° C. for 18 h. Extraction and distillation gave 5-diethylphosphono-2-[(4-methyl-1-oxo)pentyl]furan (2.1) as a light orange oil (bp 152-156° C., 0.1 mm Hg).
  • The following compounds were prepared according to this procedure:
  • (2.2) 5-diethylphosphono-2-acetylfuran: by 125-136° C., 0.1 mm Hg.
    (2.3) 5-diethylphosphono-2-[(1-oxo)butyl]furan: by 130-145° C., 0.08 mm Hg.
  • Alternatively these compounds can be prepared using the following procedures:
  • Step E. A solution of 2-[(4-methyl-1-oxo)pentyl]furan (1 mmole, prepared as in Step A) in benzene was treated with N,N-dimethyl hydrazine (2.1 mmole) and trifluoroacetic acid (0.05 mmole) at reflux for 6 h. Extraction and evaporation gave 2-[(4-methyl-1-oxo)pentyl]furan N,N-dimethyl hydrazone as a brown liquid.
    Step F. 2-[(4-Methyl-1-oxo)pentyl]furan N,N-dimethyl hydrazone was subjected to the procedures of Step C to give 2-[(4-methyl-1-oxo)pentyl]-5-diethylphosphonofuran N,N-dimethyl hydrazone as a brown liquid which was treated with copper (II) chloride (1.1 equivalent) in ethanol-water at 25° C. for 6 h. Extraction and distillation gave compound 2.1 as a light orange oil.
  • Some of 5-diethylphosphono-2-[(1-oxo)alkyl]furans are prepared using the following procedures:
  • Step G. A solution of compound 1 (1 mmole) and 1,3-propanedithiol (1.1 mmole) in chloroform was treated with borontrifluoride etherate (0.1 mmole) at 25° C. for 24 h. Evaporation and chromatography gave 2-(2-(5-diethylphosphono)furanyl)-1,3-dithiane as a light yellow oil.
  • A solution of 2-(2-(5-diethylphosphono)furanyl)-1,3-dithiane (1 mmole) in THF was cooled to −78° C. and treated with nBuLi (1.2 mmole). After 1 h. at −78° C. the reaction mixture was treated with cyclopropanemethyl bromide and reaction was stirred at −78° C. for another hour. Extraction and chromatography gave 2-(2-(5-diethylphosphono)furanyl)-2-cyclopropanemethyl-1,3-dithiane as an oil.
  • A solution of 2-(2-(5-diethylphosphono)furanyl)-2-cyclopropanemethyl-1,3-dithiane (1 mmole) in acetonitrile—water was treated with [bis(trifluoroacetoxy)iodo]benzene (2 mmole) at 25° C. for 24 h. Extraction and chromatography gave 5-diethylphosphono-2-(2-cyclopropylacetyl)furan as a light orange oil.
  • The following compounds were prepared according to this procedure:
  • (2.4) 5-Diethylphosphono-2-(2-ethoxycarbonylacetyl)furan
    (2.5) 5-Diethylphosphono-2-(2-methylthioacetyl)furan
    (2.6) 6-Diethylphosphono-2-acetylpyridine
    • Example 3 Preparation of 4-[2-(5-phosphono)furanyl]thiazoles. 4-[2-(6-phosphono)pyridyl]thiazoles and 4-[2-(5-phosphono)furanyl]selenazoles
  • Step A. A solution of compound 2.1 (1 mmole) in ethanol was treated with copper (11) bromide (2.2 mmole) at reflux for 3 h. The cooled reaction mixture was filtered and the filtrate was evaporated to dryness. The resulting dark oil was purified by chromatography to give 5-diethylphosphono-2-[(2-bromo-4-methyl-1-oxo)pentyl]furan as an orange oil.
    Step B. A solution of 5-diethylphosphono-2-[(2-bromo-4-methyl-1-oxo)pentyl]furan (1 mmole) and thiourea (2 mmole) in ethanol was heated at reflux for 2 h. The cooled reaction mixture was evaporated to dryness and the resulting yellow foam was suspended in saturated sodium bicarbonate and water (pH=8). The resulting yellow solid was collected through filtration to give 2-amino-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole.
    Step C. A solution of 2-amino-5-isobutyl-4-[2-(5-diethylphosphono)-furanyl]thiazole (1 mmole) in methylene chloride was treated with bromotrimethylsilane (10 mmole) at 25° C. for 8 h. The reaction mixture was evaporated to dryness and the residue was suspended in water. The resulting solid was collected through filtration to give 2-amino-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole (3.1) as an off-white solid. mp>250° C. Anal. calcd. for C11H15N2O4PS+1.25HBr: C, 32.75; H, 4.06; N, 6.94. Found: C, 32.39; H, 4.33; N, 7.18.
  • According to the above procedures or in some cases with minor modifications of these procedures using conventional chemistry the following compounds were prepared:
  • (3.2) 2-Methyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for C12H16NO4PS+HBr+0.1CH2Cl2: C, 37.20; H, 4.44; N, 3.58. Found: C, 37.24; H, 4.56; N, 3.30.
    (3.3) 4-[2-(5-Phosphono)furanyl]thiazole. Anal. calcd. for C7H6NO4PS+0.65 HBr: C, 29.63; H, 2.36; N, 4.94. Found: C, 29.92; H, 2.66; N, 4.57.
    (3.4) 2-Methyl-4-[2-(5-phosphono)furanyl]thiazole. mp 235-236° C. Anal. calcd. for C8H8NO4PS+0.25H2O: C, 38.48; H, 3.43; N, 5.61. Found: C, 38.68; H, 3.33; N, 5.36.
    (3.5) 2-Phenyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for C17H18NO4PS+HBr: C, 45.96; H, 4.31; N, 3.15. Found: C, 45.56; H, 4.26; N, 2.76.
    (3.6) 2-Isopropyl-4-[2-(5-phosphono)furanyl]thiazole. mp 194-197° C. Anal. calcd. for C10H12NO4PS: C, 43.96; H, 4.43; N, 5.13. Found: C, 43.70; H, 4.35; N, 4.75.
    (3.7) 5-Isobutyl-4-[2-(5-phosphono)furanyl]thiazole. mp 164-166° C. Anal. calcd. for C11H14NO4PS: C, 45.99; H, 4.91; N, 4.88. Found: C, 45.63; H, 5.01; N, 4.73.
    (3.8) 2-Aminothiocarbonyl-4-[2-(5-phosphono)furanyl]thiazole. mp 189-191° C. Anal. calcd. for C8H7N2O4PS2: C, 33.10; H, 2.43; N, 9.65. Found: C, 33.14; H, 2.50; N, 9.32.
    (3.9) 2-(1-Piperidyl)-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for C16H23N2O4PS+1.3HBr: C, 40.41; H, 5.15; N, 5.89. Found: C, 40.46; H, 5.36; N, 5.53.
    (3.10) 2-(2-Thienyl)-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for C15H16NO4PS2+0.75H2O: C, 47.05; H, 4.61; N, 3.66. Found: C, 47.39; H, 4.36; N, 3.28.
    (3.11) 2-(3-Pyridyl)-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for C16H17N2O4PS+3.75HBr: C, 28.78; H, 3.13; N, 4.20. Found: C, 28.73; H, 2.73; N, 4.53.
    (3.12) 2-Acetamido-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. mp 179-181° C. Anal. calcd. for C13H17N2O5PS+0.25H2O: C, 44:76; H, 5.06; N, 8.03. Found: C, 44.73; H, 5.07; N, 7.89.
    (3.13) 2-Amino-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for C7H7N2O4PS: C, 34.15; H, 2.87; N, 11.38. Found: C, 33.88; H, 2.83; N, 11.17.
    (3.14) 2-Methylamino-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. mp 202-205° C. Anal. calcd. for C12H17N2O4PS+0.5H2O: C, 44.30; H, 5.58; N, 8.60. Found: C, 44.67; H, 5.27; N, 8.43.
    (3.15) 2-(N-amino-N-methyl)amino-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. mp 179-181° C. Anal. calcd. for C12H18N3O4PS+1.25HBr: C, 33.33; H, 4.49; N, 9.72. Found: C, 33.46; H, 4.81; N, 9.72.
    (3.16) 2-Amino-5-methyl-4-[2-(5-phosphono)furanyl]thiazole. mp 200-220° C. Anal. calcd. for C8H9N2O4PS+0.65HBr: C, 30.72; H, 3.11; N, 8.96. Found: C, 30.86; H, 3.33; N, 8.85.
    (3.17) 2,5-Dimethyl-4-[2-(5-phosphono)furanyl]thiazole. mp 195° C. (decomp). Anal. calcd. for C9H10NO4PS+0.7HBr: C, 34.22; H, 3.41; N, 4.43. Found: C, 34.06; H, 3.54; N, 4.12.
    (3.18) 2-Aminothiocarbonyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for C12H15N2O4PS2+O.1HBr+0.3EtOAc: C, 41.62; H, 4.63; N, 7.35. Found: C, 41.72; H, 4.30; N, 7.17.
    (3.19) 2-Ethoxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. mp 163-165° C. Anal. calcd. for C10H10NO6PS+0.5H2O: C, 38.47; H, 3.55; N, 4.49. Found: C, 38.35; H, 3.30; N, 4.42.
    (3.20) 2-Amino-5-isopropyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for C10H13N2O4PS+1HBr: C, 32.53; H, 3.82; N, 7.59. Found: C, 32.90; H, 3.78; N, 7.65.
    (3.21) 2-Amino-5-ethyl-4-[2-(5-phosphono)furanyl]thiazole. mp>250° C. Anal. calcd. for C9H11N2O4PS: C, 39.42; H, 4.04; N, 10.22. Found: C, 39.02; H, 4.15; N, 9.92.
    (3.22) 2-Cyanomethyl-4-[2-(5-phosphono)furanyl]thiazole. mp 204-206° C. Anal. calcd. for C9H7N2O4PS: C, 40.01; H, 2.61; N, 10.37. Found: C, 39.69; H, 2.64; N, 10.03.
    (3.23) 2-Aminothiocarbonylamino-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. mp 177-182° C. Anal. calcd. for C12H16N3O4PS2+0.2hexane+0.3HBr: C, 39.35; H, 4.78; N, 10.43. Found: C, 39.61; H, 4.48; N, 10.24.
    (3.24) 2-Amino-5-propyl-4-[2-(5-phosphono)furanyl]thiazole. mp 235-237° C. Anal. calcd. for C10H13N2O4PS+0.3H2O: C, 40.90; H, 4.67; N, 9.54. Found: C, 40.91; H, 4.44; N, 9.37.
    (3.25) 2-Amino-5-ethoxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. mp 248-250° C. Anal. calcd. for C10H11N2O6PS+O.1HBr: C, 36.81; H, 3.43; N, 8.58. Found: C, 36.99; H, 3.35; N, 8.84.
    (3:26) 2-Amino-5-methylthio-4-[2-(5-phosphono)furanyl]thiazole. mp 181-184° C. Anal. calcd. for C8H9N2O4PS2+0.4H2O: C, 32.08; H, 3.30; N, 9.35. Found: C, 32.09; H, 3.31; N, 9.15.
    (3.27) 2-Amino-5-cyclopropyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for C10H11N2O4PS+1H2O+0.75HBr: C, 32.91; H, 3.80; N, 7.68. Found: C, 33.10; H, 3.80; N, 7.34.
    (3.28) 2-Amino-5-methanesulfinyl-4-[2-(5-phosphono)furanyl]thiazole. mp>250° C. Anal. calcd. for C8H9N2O5PS2+0.35NaCl: C, 29.23; H, 2.76; N, 8.52. Found: C, 29.37; H, 2.52; N, 8.44.
    (3.29) 2-Amino-5-benzyloxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for C15H13N2O6PS+0.2H2O: C, 46.93; H, 3.52; N, 7.30. Found: C, 46.64; H, 3.18; N, 7.20.
    (3.30) 2-Amino-5-cyclobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for C11H13N2O4PS+0.15 HBr+0.15H2O: C, 41.93; H, 4.30; N, 8.89. Found: C, 42.18; H, 4.49; N, 8.53.
    (3.31) 2-Amino-5-cyclopropyl-4-[2-(5-phosphono)furanyl]thiazole hydrobromide. Anal. calcd. for C10H11N2O4PSBr+0.73HBr+0.15MeOH+0.5H2O: C, 33.95; H, 3.74; N, 7.80; S: 8.93; Br: 16.24. Found: C, 33.72; H, 3.79; N, 7.65; S: 9.26; Br: 16.03.
    (3.32) 2-Amino-5-[(N,N-dimethyl)aminomethyl]-4-[2-(5-phosphono)furanyl]thiazole dihydrobromide. Anal. calcd. for C10H16N3O4Br2 PS+0.8CH2Cl2: C, 24.34; H, 3.33; N, 7.88. Found: C, 24.23; H, 3.35; N, 7.64.
    (3.33) 2-Amino-5-methoxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. Mp 227° C. (decomp). Anal. calcd. for C9H9N2O6PS+0.1H2O+0.2HBr: C, 33.55; H, 2.94; N, 8.69. Found: C, 33.46; H, 3.02; N, 8.49.
    (3.34) 2-Amino-5-ethylthiocarbonyl-4-[2-(5-phosphono)furanyl]thiazole. Mp 245° C. (decomp). Anal. calcd. for C10H11N2O5PS2: C, 35.93; H, 3.32; N, 8.38. Found: C, 35.98; H, 3.13; N, 8.17.
    (3.35) 2-Amino-5-propyloxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. Mp 245° C. (decomp). Anal. calcd. for C11H13N2O6PS: C, 39.76; H, 3.94; N, 8.43. Found: C, 39.77; H, 3.72; N, 8.19.
    (3.36) 2-Amino-5-benzyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for C14H13N2O4PS+H2O: C, 47.46; H, 4.27; N, 7.91. Found: C, 47.24; H, 4.08; N, 7.85.
    (3.37) 2-Amino-5-[(N,N-diethyl)aminomethyl]-4-[2-(5-phosphono)furanyl]thiazole dihydrobromide. Anal. calcd. for C12H20N3O4Br2PS+0.1HBr+1.4 MeOH: C, 29.47; H, 4.74; N, 7.69. Found: C, 29.41; H, 4.60; N, 7.32.
    (3.38) 2-Amino-5-[(N,N-dimethyl)carbamoyl]-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for C10H12N3O5PS+1.3HBr+1.0H2O+0.3 Acetone: C, 28.59; H, 3.76; N, 9.18. Found: C, 28.40; H, 3.88; N, 9.01.
    (3.39) 2-Amino-5-carboxyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for C8H7N2O6PS+0.2HBr+0.1H2O: C, 31.18; H, 2.42; N, 9.09. Found: C, 31.11; H, 2.42; N, 8.83.
    (3.40) 2-Amino-5-isopropyloxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. Mp 240° C. (decomp). Anal. calcd. for C11H13N2O6PS: C, 39.76; H, 3.94; N, 8.43. Found: C, 39.42; H, 3.67; N, 8.09.
    (3.41) 2-Methyl-5-ethyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for C10H12O4PNS+0.75HBr+0.35H2O: C, 36.02; H, 4.13; N, 4.06. Found: C, 36.34; H, 3.86; N, 3.69.
    (3.42) 2-Methyl-5-cyclopropyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for C11H12NO4PS+0.3HBr+0.5CHCl3: C, 37.41; H, 3.49; N, 3.79. Found: C, 37.61; H, 3.29; N, 3.41.
    (3.43) 2-Methyl-5-ethoxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for C11H12NO6PS: C, 41.64; H, 3.81; N, 4.40. Found: C, 41.61; H, 3.78; N, 4.39.
    (3.44) 2-[(N-acetyl)amino]-5-methoxymethyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for C11H13N2O6PS+0.15HBr: C, 38.36; H, 3.85; N, 8.13. Found: C, 38.74; H, 3.44; N, 8.13.
    (3.45) 2-Amino-5-(4-morpholinyl)methyl-4-[2-(5-phosphono)furanyl]thiazole dihydrobromide. Anal. calcd. for C12H18Br2N3O5PS+0.25HBr: C, 27.33; H, 3.49; N, 7.97. Found: C, 27.55; H, 3.75; N, 7.62.
    (3.46) 2-Amino-5-cyclopropylmethoxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. Mp 238° C. (decom p). Anal. calcd. for C12H13N2O6PS: C, 41.86; H, 3.81; N, 8.14. Found: C, 41.69; H, 3.70; N, 8.01.
    (3.47) 2-Amino-5-methylthio-4-[2-(5-phosphono)furanyl]thiazole N,N-dicyclohexylammonium salt. Mp>250° C. Anal. calcd. for C8H9N2O4PS2+1.15 C12H23N, C, 52.28; H, 7.13; N, 8.81. Found: C, 52.12; H, 7.17; N, 8.81.
    (3.48) 2-[(N-Dansyl)amino]-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for C23H26N3O6PS2+0.5HBr: C, 47.96; H, 4.64; N, 7.29. Found: C, 48.23; H, 4.67; N, 7.22.
    (3.49) 2-Amino-5-(2,2,2-trifluoroethyl)-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for C9H8N2F3O4PS: C, 32.94; H, 2.46; N, 8.54. Found: C, 32.57; H, 2.64; N, 8.14.
    (3.50) 2-Methyl-5-methylthio-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for C9H10NO4PS2 C, 37.11; H, 3.46; N, 4.81. Found: C, 36.72; H, 3.23; N, 4.60.
    (3.51) 2-Amino-5-methylthio-4-[2-(5-phosphono)furanyl]thiazole ammonium salt. Anal. calcd for C8H12N3O4PS2: C, 31.07; H, 3.91; N, 13.59. Found: C, 31.28; H, 3.75; N, 13.60.
    (3.52) 2-Cyano-5-ethyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for C10H9N2O4PS: C, 42.26; H, 3.19; N, 9.86. Found: C, 41.96; H, 2.95; N, 9.76.
    (3.53) 2-Amino-5-hydroxymethyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for C8H9N2O5PS: C, 34.79; H, 3.28; N, 10.14. Found: C, 34.57; H, 3.00; N, 10.04.
    (3.54) 2-Cyano-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for C12H13N2O4SP+0.09HBr: C, 46.15; H, 4.20; N, 8.97. Found: C, 44.81; H, 3.91; N, 8.51.
    (3.55) 2-Amino-5-isopropylthio-4-[2-(5-phosphono)furanyl]thiazole hydrobromide. Anal. calcd for C10H14BrN2O4PS2: C, 29.94; H, 3.52; N, 6.98. Found: C, 30.10; H, 3.20; N, 6.70.
    (3.56) 2-Amino-5-phenylthio-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for C13H11N2O4PS2: C, 44.07; H, 3.13; N, 0.91. Found: C, 43.83; H, 3.07; N, 7.74.
    (3.57) 2-Amino-5-tert-butylthio-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for C11H15N2O4PS2+0.6CH2Cl2: C, 36.16; H, 4.24; N, 7.27. Found: C, 36.39; H, 3.86; N, 7.21.
    (3.58) 2-Amino-5-propylthio-4-[2-(5-phosphono)furanyl]thiazole hydrobromide. Anal. calcd for C10H14BrN2O4PS2: C, 29.94; H, 3.52; N, 6.98. Found: C, 29.58; H, 3.50; N, 6.84.
    (3.59) 2-Amino-5-ethylthio-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for C9H11N2O4PS2+0.25HBr: C, 33.11; H, 3.47; N, 8.58. Found: C, 33.30; H, 3.42; N, 8.60.
    (3.60) 2-[(N-tert-butyloxycarbonyl)amino]-5-methoxymethyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for C14H19N2O7PS: C, 43.08; H, 4.91; N, 7.18. Found: C, 42.69; H, 4.58; N, 7.39.
    (3.61) 2-Hydroxyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for C7H6NO5PS: C, 34.02; H, 2.45; N, 5.67. Found: C, 33.69; H, 2.42; N, 5.39.
    (3.62) 2-Hydroxyl-5-ethyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for C9H10NO5PS: C, 39.28; H, 3.66; N, 5.09. Found: C, 39.04; H, 3.44; N, 4.93.
    (3.63) 2-Hydroxyl-5-isopropyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for C10H12NO5PS+0.1HBr: C, 40.39; H, 4.10; N, 4.71. Found: C, 40.44; H, 4.11; N, 4.68.
    (3.64) 2-Hydroxyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for C11H14NO5PS: C, 43.57; H, 4.65; N, 4.62. Found: C, 43.45; H, 4.66; N, 4.46.
    (3.65) 5-Ethoxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for C10H10NO6PS: C, 39.61; H, 3.32; N, 4.62. Found: C, 39.60; H, 3.24; N, 4.47.
    (3.66) 2-Amino-5-vinyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for C9H9N2O4PS+0.28HCl: C, 37.66; H, 3.26; N, 9.46. Found: C, 37.96; H, 3.37; N, 9.10.
    (3.67) 2-Amino-4-[2-(6-phosphono)pyridyl]thiazole hydrobromide.
    (3.68) 2-Methylthio-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for C12H16NO4PS2: C, 43.24; H, 4.84; N, 4.20. Found: C, 43.55; H, 4.63; N, 4.46.
    (3.69) 2-Amino-5-isobutyl-4-[2-(3-phosphono)furanyl]thiazole. Anal. calcd for C11H15N2O4PS+0.1H2O: C, 43.45; H, 5.04; N, 9.21. Found: C, 43.68; H, 5.38; N, 8.98.
    (3.70) 2-Amino-5-isobutyl-4-[2-(5-phosphono)furanyl]selenazole. Anal. calcd for C11H15N2O4PSe+0.14HBr+0.6 EtOAc: C, 38.93; H, 4.86; N, 6.78. Found: C, 39.18; H, 4.53; N, 6.61.
    (3.71) 2-Amino-5-methylthio-4-[2-(5-phosphono)furanyl]selenazole. Anal. calcd for C8H9N2O4PSSe+0.7 HBr+0.2 EtOAc: C, 25.57; H, 2.75; N, 6.78. Found: C, 25.46; H, 2.49; N, 6.74.
    (3.72) 2-Amino-5-ethyl-4-[2-(5-phosphono)furanyl]selenazole. Anal. calcd for C9H11N2O4PSe+HBr: C, 26.89; H, 3.01; N, 6.97. Found: C, 26.60; H, 3.16; N, 6.81.
    • Example 4 Preparation of 5-halo-4-[2-(5-phosphono)furanyl]thiazoles
  • Step A. A solution of 2-amino-4-[2-(5-diethylphosphono)furanyl]thiazole (prepared as in Step B of Example 3) (1 mmole) in chloroform was treated with N-bromo succinimide (NBS) (1.5 mmole) at 25° C. for 1 h. Extraction and chromatography gave 2-amino-5-bromo-4-[2-(5-diethylphosphono)furanyl]-thiazole as a brown solid.
    Step B. 2-Amino-5-bromo-4-[2-(5-diethylphosphono)furanyl]thiazole was subjected to Step C of Example 3 to give 2-amino-5-bromo-4-[2-(5-phosphono)furanyl]thiazole (4.1) as a yellow solid. mp>230° C. Anal. calcd. for C7H6N2O4PSBr: C, 25.86; H, 1.86; N, 8.62.
  • Found: C, 25.93; H, 1.64; N, 8.53.
  • The following compounds were prepared according to this procedure:
  • (4.2) 2-Amino-5-chloro-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for C7H6N2O4PSCl: C, 29.96; H, 2.16; N, 9.98. Found: C, 29.99; H, 1.97; N, 9.75.
    (4.3) 2-Amino-5-iodo-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for C7H6N2O4PSI: C, 22.42; H, 2.28; N, 6.70. Found: C, 22.32; H, 2.10; N, 6.31.
    (4.4) 2,5-Dibromo-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for C7H4NO4PSBr2: C, 21.62; H, 1.04; N, 3.60. Found: C, 21.88; H, 0.83; N, 3.66.
    • Example 5 Preparation of 2-halo-4-[2-(5-phosphono)furanyl]thiazoles
  • Step A. A solution of 2-amino-5-isobutyl-4-[2-(5-diethylphosphono)-furanyl]thiazole (prepared as in Step B of Example 3) (1 mmole) in acetonitrile was treated with copper (II) bromide (1.2 mmole) and isoamyl nitlite (1.2 mmole) at 0° C. for 1 h. Extraction and chromatography gave 2-bromo-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole as a brown solid.
    Step B. 2-Bromo-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole was subjected to Step C of Example 3 to give 2-bromo-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole (5.1) as a yellow hygroscopic solid. Anal. calcd. for C11H13NO4PSBr: C, 36.08; H, 3.58; N, 3.83. Found: C, 36.47; H, 3.66; N, 3.69.
  • The following compounds were prepared according to this procedure:
  • (5.2) 2-Chloro-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole: Anal. calcd. for C11H13NO4PSCl: C, 41.07; H, 4.07; N, 4.35. Found: C, 40.77; H, 4.31; N, 4.05.
    (5.3) 2-Bromo-5-methylthio-4-[2-(5-phosphono)furanyl]thiazole: Anal. calcd. for C8H7NO4PS2Br: C, 26.98; H, 1.98; N, 3.93. Found: C, 27.21; H, 1.82; N, 3.84.
    • Example 6 Preparation of Various 2- and 5-substituted 4-[2-(5-phosphono)furanyl]thiazoles
  • Step A. A solution of 2-bromo-5-isobutyl-4-[2-(5-diethylphosphono)-furanyl]thiazole (1 mmole, prepared as in the Step A of Example 5) in DMF was treated with tributyl(vinyl)tin (5 mmole) and palladium bis(triphenylphosphine) dichloride (0.05 mmole) at 100° C. under nitrogen. After 5 h the cooled reaction mixture was evaporated and the residue was subjected to chromatography to give 2-vinyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole as a yellow solid.
    Step B. 2-Vinyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole was subjected to Step C of Example 3 to give 2-vinyl-5-isobutyl-4-[2-(5-phosphono)-furanyl]thiazole (6.1) as a yellow solid. Anal. calcd. for C13H16NO4PS+1HBr+0.1H2O: C, 39.43; H, 4.38; N, 3.54. Found: C, 39.18; H, 4.38; N, 3.56.
  • This method can also be used to prepare various 5-substituted 4-[2-(5-phosphono)furanyl]thiazoles from their corresponding halides.
  • Step C. 2-Amino-5-bromo-4-[2-(5-diethylphosphono)furanyl]thiazole was subjected to Step A using 2-tributylstannylfuran as the coupling partner to give 2-amino-5-(2-furanyl)-4-[2-(5-diethylphosphono)furanyl]thiazole.
    Step D. 2-Amino-5-(2-furanyl)-4-[2-(5-diethylphosphono)furanyl]thiazole was subjected to Step C of Example 3 to give 2-amino-5-(2-furanyl)-4-[2-(5-phosphono)furanyl]thiazole (6.2). mp 190-210° C. Anal. calcd. for C11H9N2O5PS+0.25HBr: C, 39.74; H, 2.80; N, 8.43. Found: C, 39.83; H, 2.92; N, 8.46.
  • The following compound was prepared according to this procedure:
  • (6.3) 2-Amino-5-(2-thienyl)-4-[2-(5-diethylphosphono)furanyl]thiazole. Anal. calcd. for C11H9N2O4PS2+0.3EtOAc+0.11HBr: C, 40.77; H, 3.40; N, 7.79. Found: C, 40.87; H, 3.04; N, 7.45.
    • Example 7 Preparation of 2-ethyl-4-[2-(5-phosphono)furanyl]-thiazoles
  • Step A. A solution of 2-vinyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]-thiazole (1 mmole, prepared as in the Step A of Example 6) in ethanol was treated with palladium on carbon (0.05 mmole) under 1 atmosphere of hydrogen for 12 h. The reaction mixture was filtered, the filtrate was evaporated and the residue was purified by chromatography to give 2-ethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole as a yellow foam.
    Step B. 2-Ethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole was subjected to Step C of Example 3 to give 2-ethyl-5-isobutyl-4-[2-(5-phosphono)-furanyl]thiazole (7.1) as a yellow solid. Anal. calcd. for C13H18NO4PS+1HBr: C, 39.41; H, 4.83; N, 3.53. Found: C, 39.65; H, 4.79; N, 3.61.
    • Example 8 Preparation of 4-phosphonomethoxymethylthiazoles
  • Step A. A solution of diethyl hydroxymethylphosphonate (1 mmole) in DMF was treated with sodium hydride (1.2 mmole) followed by 2-methyl-4-chloromethylthiazole (1 mmole) at 0° C. and stirred at 25° C. for 12 h. Extraction and chromatography gave 2-methyl-4-(diethylphosphonomethoxymethyl)thiazole.
    Step B. 2-Methyl-4-diethylphosphonomethoxymethylthiazole was subjected to Step C of Example 3 to give 2-methyl-4-phosphonomethoxymethylthiazole (8.1). Anal. calcd. for C6H10NO4PS+0.5HBr+0.5H2O: C, 26.43; H, 4.25; N, 5.14. Found: C, 26.52; H, 4.22; N, 4.84.
    Step C. 2-Methyl-4-diethylphosphonomethoxymethylthiazole was subjected to Step A of Example 4 and followed by Step C of Example 3 to give 5-bromo-2-methyl-4-phosphonomethoxymethylthiazole (8.2). Anal. calcd. for C6H9NO4PSBr+0.5HBr: C, 21.04; H, 2.80; N, 4.09. Found: C, 21.13; H, 2.69; N, 4.01.
    Step D. A solution of ethyl 2-[(N-Boc)amino]-4-thiazolecarboxylate (1 mmole) in CH2Cl2 (10 mL) was cooled to −78° C., and treated with DIBAL-H (1M, 5 mL). The reaction was stirred at −60° C. for 3 h, and quenched with a suspension of NaF/H2O (1 g/1 mL). The resulting mixture was filtered and the filtrate was concentrated to give 2-[(N-Boc)amino]-4-hydroxymethylthiazole as a solid.
    Step E. A solution of 2-[(N-Boc)amino]-4-hydroxymethylthiazole (1 mmole) in DMF (10 mL) was cooled to 0° C., and treated with NaH (1.1 mmole). The mixture was stirred at room temperature for 30 min, then phosphonomethyl trifluoromethanesulfonate (1.1 mmole) was added. After stirring at room temperature for 4 h, the reaction was evaporated to dryness. Chromatography of the residue gave 2-[(N-Boc)amino]-4-diethylphosphonomethoxylmethylthiazole as a solid.
    Step F. 2-[(N-Boc)amino]-4-diethylphosphonomethoxylmethylthiazole was subjected to Step C of Example 3 to give 2-amino-4-phosphonomethoxymethylthiazole (8.3) as a solid. Anal. calcd. for C5H9N2O4PS+0.16 HBr+0.1 MeOH: C, 25.49; H, 4.01; N, 11.66. Found: C, 25.68; H, 3.84; N, 11.33.
    • Example 9 Preparation of 2-carbamoyl-4-[2-(5-phosphono)furanyl]thiazoles
  • Step A. A solution of 2-ethoxycarbonyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole (1 mmole) in saturated methanolic ammonia solution at 25° C. for 12 h. Evaporation and chromatography gave 2-carbamoyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole as a white solid.
    Step B. 2-Carbamoyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole was subjected to Step C of Example 3 to give 2-carbamoyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole (9.1) as a solid. mp 185-186° C. Anal. calcd. for C12H15N2O5PS: C, 43.64; H, 4.58; N, 8.48. Found: C, 43.88; H, 4.70; N, 8.17.
  • The following compound was prepared according to this procedure:
  • (9.2) 2-Carbamoyl-4-[2-(5-phosphono)furanyl]thiazole. mp 195-200° C. Anal. calcd. for C8H7N2O5PS+0.25H2O: C, 34.48; H, 2.71; N, 10.05. Found: C, 34.67; H, 2.44; N, 9.84.
  • 2-Ethoxycarbonyl-4-[2-(5-diethylphosphono)furanyl]thiazoles can also be converted to other 2-substituted 4-[2-(5-phosphono)furanyl]thiazoles.
  • Step C. A solution of 2-ethoxycarbonyl-4-[2-(5-diethylphosphono)furanyl]thiazole (1 mmole) in methanol was treated with sodium borohydride (1.2 mmole) at 25° C. for 12 h. Extraction and chromatography gave 2-hydroxymethyl-4-[2-(5-diethylphosphono)furanyl]thiazole
    Step D. 2-Hydroxymethyl-4-[2-(5-diethylphosphono)furanyl]-thiazole was subjected to Step C of Example 3 to give 2-hydroxymethyl-4-[2-(5-phosphono)furanyl]thiazole (9.3). mp 205-207° C. Anal. calcd. for C8H8NO5PS+0.25H2O: C, 36.16; H, 3.22; N, 5.27. Found: C, 35.98; H, 2.84; N, 5.15.
  • The following compound was prepared according to this procedure:
  • (9.4) 2-Hydroxymethyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. mp 160-170° C. Anal. calcd. for C12H16NO5PS+0.75HBr: C, 38.13; H, 4.47; N, 3.71. Found: C, 37.90; H, 4.08; N, 3.60.
    Step E. A solution of 2-hydroxymethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole (1 mmole) in methylene chloride was treated with phosphorus tribromide (1.2 mmole) at 25° C. for 2 h. Extraction and chromatography gave 2-bromomethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole.
    Step F. 2-Bromomethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]-thiazole was subjected to Step C of Example 3 to give 2-bromomethyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole (9.5). mp 161-163° C. Anal. calcd. for C12H15BrNO4PS+0.25HBr: C, 35.99; H, 3.84; N, 3.50. Found: C, 36.01; H, 3.52; N, 3.37.
  • The following compound was prepared according to this procedure:
  • (9.6) 2-Bromomethyl-4-[2-(5-phosphono)furanyl]thiazole. mp>250° C. Anal. calcd. for C8H7BrNO4PS: C, 29.65; H, 2.18; N, 4.32. Found: C, 29.47; H, 1.99; N, 4.16.
    Step G. A solution of 2-hydroxymethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole (1 mmole) in methylene chloride was treated with thionyl chloride (1.2 mmole) at 25° C. for 2 h. Extraction and chromatography gave 2-chloromethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole.
    Step H. 2-Chloromethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]-thiazole was subjected to Step C of Example 3 to give 2-chloromethyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole (9.7). mp 160-162° C. Anal. calcd. for C12H15ClNO4PS+0.45HBr: C, 38.73; H, 4.18; N, 3.76. Found: C, 38.78; H, 4.14; N, 3.73.
    Step I. A solution of 2-bromomethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole (1 mmole) in DMF was treated with potassium phthalimide (1.2 mmole) at 25° C. for 12 h. Extraction and chromatography gave 2-phthalimidomethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole.
    Step J. 2-Phthalimidomethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]-thiazole (1 mmole) in ethanol was treated with hydrazine (1.5 mmole) at 25° C. for 12 h. Filtration, evaporation and chromatography gave 2-aminomethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole.
    Step K. 2-Aminomethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]-thiazole was subjected to Step C of Example 3 to give 2-aminomethyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole (9.8). mp 235-237° C. Anal. calcd. for Cl2H17N2O4PS+0.205HBr: C, 43.30; H, 5.21; N, 8.41. Found: C, 43.66; H, 4.83; N, 8.02.
  • According to the above procedures or in some cases with some minor modifications of the above procedures, the following compounds were prepared:
  • (9.9) 2-Carbamoyl-5-cyclopropyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for C11H11N2O5PS+0.15HBr: C, 40.48; H, 3.44; N, 8.58. Found: C, 40.28; H, 3.83; N, 8.34.
    (9.10) 2-Carbamoyl-5-ethyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for C10H11N2O5PS+0.75H2O: C, 38.04; H, 3.99; N, 8.87. Found: C, 37.65; H, 3.93; N, 8.76.
    • Example 10 Preparation of 4-[2-(5-phosphono)furanyl]oxazoles and 4-[2-(5-phosphono)furanyl]imidazoles
  • Step A. A solution of 5-diethylphosphono-2-[(2-bromo-4-methyl-1-oxo)pentyl]furanyl (1 mmole) in t-BuOH was treated with urea (10 mmole) at reflux for 72 h. Filtration, evaporation and chromatography gave 2-amino-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]oxazole, and 2-hydroxy-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]imidazole.
    Step B. 2-Amino-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]oxazole was subjected to Step C of Example 3 to give 2-amino-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole (10.1). mp 250° C. (decomp.). Anal. calcd. for C11H15N2O5P: C, 46.16; H, 5.28; N, 9.79. Found: C, 45.80; H, 5.15; N, 9.55.
    Step C. 2-Hydroxy-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]imidazole was subjected to Step C of Example 3 to give 2-hydroxy-5-isobutyl-4-[2-(5-phosphono)furanyl]imidazole (10.14). mp 205° C. (decomp). Anal. calcd. for C11H15N2O5P: C, 46.16; H, 5.28; N, 9.79. Found: C, 45.80; H, 4.90; N, 9.73:
  • Alternatively 4-[2-(5-phosphono)furanyl]oxazoles and 4-[2-(5-phosphono)furanyl]imidazoles can be prepared as follows:
  • Step D. A solution of 5-diethylphosphono-2-[(2-bromo-4-methyl-1-oxo)pentyl]furan (1 mmole) in acetic acid was treated with sodium acetate (2 mmole) and ammonium acetate (2 mmole) at 100° C. for 4 h. Evaporation and chromatography gave 2-methyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]-oxazole, 2-methyl-4-isobutyl-5-[2-(5-diethylphosphono)furanyl]oxazole and 2-methyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]imidazole.
    Step E. 2-Methyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]oxazole, 2-methyl-4-isobutyl-5-[2-(5-diethylphosphono)furanyl]oxazole and 2-methyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]imidazole were subjected to Step C of Example 3 to give the following compounds:
    (10.18) 2-Methyl-4-isobutyl-5-[2-(5-phosphono)furanyl]oxazole hydrogen bromide. mp>230° C.; Anal. calcd. for C12H17BrNO5P+0.4H2O: C, 38.60; H, 4.81; N, 3.75. Found: C, 38.29; H, 4.61; N, 3.67.
    (10.19) 2-Methyl-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole hydrogen bromide. Anal. Calcd. for C12H17BrNO5P: C, 39.36; H, 4.68; N, 3.83. Found: C, 39.33; H, 4.56; N, 3.85.
    (10.21) 2-Methyl-5-isobutyl-4-[2-(5-phosphono)furanyl]imidazole hydrogen bromide. Anal. Calcd. for C12H18BrN2O4P+0.2NH4Br: C, 37.46; H, 4.93; N, 8.01. Found: C, 37.12; H, 5.11; N, 8.28.
  • Alternatively 4-[2-(5-phosphono)furanyl]imidazoles can be prepared as follows:
  • Step F. A solution of 5-diethylphosphono-2-(bromoacetyl)furan (1 mmole) in ethanol was treated with trifluoroacetamidine (2 mmole) at 80° C. for 4 h. Evaporation and chromatography gave 2-trifluoromethyl-4-[2-(5-diethylphosphono)furanyl]imidazole as an oil.
    Step G. 2-Trifluoromethyl-4-[2-(5-diethylphosphono)furanyl]imidazole was subjected to Step C of Example 3 to give 2-trifluoromethyl-4-[2-(5-phosphono)-furanyl]imidazole
    (10.22). mp 188° C. (dec.); Anal. calcd. for C8H6F3N2O4P+0.5HBr: C, 29.79; H, 2.03; N, 8.68. Found: C, 29.93; H, 2.27; N, 8.30.
  • Alternatively 4,5-dimethyl-1-isobutyl-2-[2-(5-phosphono)furanyl]-imidazole can be prepared as follows:
  • Step H. A solution of 5-diethylphosphono-2-furaldehyde (1 mmole), ammonium acetate (1.4 mmole), 3,4-butanedione (3 mmole) and isobutylamine (3 mmole) in glacial acetic acid was heated at 100° C. for 24 h. Evaporation and chromatography gave 4,5-dimethyl-1-isobutyl-2-[2-(5-diethylphosphono)furanyl]imidazole as an yellow solid.
    Step I. 4,5-Dimethyl-1-isobutyl-2-[2-(5-diethylphosphono)furanyl]-imidazole was subjected to Step C of Example 3 to give 4,5-dimethyl-1-isobutyl-2-[2-(5-phosphono)furanyl]imidazole (10.23); Anal. calcd. for C13H19N2O4P+1.35HBr: C, 38.32; H, 5.03; N, 6.87. Found: C, 38.09; H, 5.04; N, 7.20.
  • According to the above procedures or in some cases with some minor modifications of the above procedures, the following compounds were prepared:
  • (10.2) 2-Amino-5-propyl-4-[2-(5-phosphono)furanyl]oxazole. mp 250° C. (decomp.); Anal. Calcd. for C10H13N2O5P: C, 44.13; H, 4.81; N, 10.29. Found: C, 43.74; H, 4.69; N, 9.92.
    (10.3) 2-Amino-5-ethyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd. for C9H11N2O5P+0.4H2O: C, 40.73; H, 4.48; N, 10.56. Found: C, 40.85; H, 4.10; N, 10.21.
    (10.4) 2-Amino-5-methyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd. for C8H9N2O5P+0.1H2O: C, 39.07; H, 3.77 N, 11.39. Found: C, 38.96; H, 3.59; N, 11.18.
    (10.5) 2-Amino-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd. for C7H7N2O5P+0.6H2O: C, 34.90; H, 3.43; N, 11.63. Found: C, 34.72; H, 3.08; N, 11.35.
    (10.6) 2-Amino-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole hydrogen bromide. Anal. calcd. for C11H16N2O5BrP+0.4H2O: C, 35.29; H, 4.52; N, 7.48. Found: C, 35.09; H, 4.21; N, 7.34.
    (10.7) 2-Amino-5-phenyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd. for C13H11N2O5P: C, 50.99; H, 3.62; N, 9.15. Found: C, 50.70; H, 3.43; N, 8.96.
    (10.8) 2-Amino-5-benzyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd. for C14H13N2O5P+1.1H2O: C, 49.45; H, 4.51; N, 8.24. Found: C, 49.35; H, 4.32; N, 8.04.
    (10.9) 2-Amino-5-cyclohexylmethyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd. for C14H19N2O5P+0.3H2O: C, 50.70; H, 5.96; N, 8.45. Found: C, 50.60; H, 5.93; N, 8.38.
    (10.10) 2-Amino-5-allyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd. for C10H11N2O5P+0.4HBr+0.3H2O: C, 39.00; H, 3.93; N, 9.10. Found: C, 39.31; H, 3.83; N, 8.76.
    (10:11) 5-Isobutyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd. for C11H14NO5P: C, 48.72; H, 5.20; N, 5.16. Found: C, 48.67; H, 5.02; N, 5.10.
    (10.12) 2-Amino-5-butyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd. for C11H5N2O5P+0.2H2O: C, 45.59; H, 5.36; N, 9.67. Found: C, 45.32; H, 5.29; N, 9.50.
    (10.13) 5-Isobutyl-4-[2-(5-phosphono)furanyl]oxazole-2-one. Anal. calcd. for C11H14NO6P+0.39HBr: C, 41.45; H, 4.55; N, 4.39. Found: C, 41.79; H, 4.22; N, 4.04.
    (10.15) 5-Cyclohexylmethyl-2-hydroxy-4-[2-(5-phosphono)furanyl]imidazole. Anal. calcd. for C14H19N2O5P+0.05HBr: C, 50.90; H, 5.81; N, 8.48. Found: C, 51.06; H, 5.83; N, 8.25.
    (10.16) 5-Butyl-2-hydroxy-4-[2-(5-phosphono)furanyl]. Anal. calcd. for C11H15N2O5P+0.2H2O: C, 45.59; H, 5.36; N, 9.67. Found: C, 45.77; H, 5.34; N, 9.39.
    (10.17) 5-Benzyl-2-hydroxy-4-[2-(5-phosphono)furanyl]imidazole. Anal. calcd. for C14H13N2O5P: C, 52.51; H, 4.09; N, 8.75. Found: C, 52.29; H, 4.15; N, 8.36.
    (10.20) 2-Methyl-5-propyl-4-[2-(5-phosphono)furanyl]imidazole hydrogen bromide. Anal. calcd. for C11H16BrN2O4P+0.5H2O: C, 36.69; H, 4.76; N, 7.78. Found: C, 36.81; H, 4.99; N, 7.42.
    (10.24) 2-Amino-5-(2-thienylmethyl)-4-[2-(5-phosphono)fluranyl]oxazole. Anal. calcd for C12H11N2O5PS+0.9HBr: C, 36.12; H, 3.01; N, 7.02. Found: C, 36.37; H, 2.72; N, 7.01.
    (10.25) 2-Dimethylamino-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole hydrogen bromide. Anal. Calcd for C13H20BrN2O5P+0.05HBr: C, 39.11; H, 5.06; N, 7.02. Found: C, 39.17; H, 4.83; N, 6.66
    (10.26) 2-Isopropyl-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. Calcd for C14H20NO5P+0.8HBr: C, 44.48; H, 5.55; N, 3.71. Found: C, 44.45; H, 5.57; N, 3.73.
    (10.27) 2-Amino-5-ethoxycarbonyl-4-[2-(5-phosphono)furanyl]oxazole. mp 245° C. (decomp.). Anal. Calcd for C10H11N2O7P: C, 39.75; H, 3.67; N, 9.27. Found: C, 39.45; H, 3.71; N, 8.87
    (10.28) 2-Methylamino-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole hydrogen bromide. Anal. Calcd for C12H18BrN2O5P+0.7H2O: C, 36.60; H, 4.97; N, 7.11. Found: C, 36.50; H, 5.09; N, 7.04.
    (10.29) 2-Ethyl-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole hydrogen bromide. Anal. Calcd for C13H19BrNO5P: C, 41.07; H, 5.04; N, 3.68. Found: C, 41.12; H, 4.84; N, 3:62.
    (10.30) 2-Ethylamino-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole hydrogen bromide. Anal. Calcd for C13H20BrN2O5P: C, 39.51; H, 5.10; N, 7.09. Found: C, 39.03; H, 5.48; N, 8.90.
    (10.31) 2-Vinyl-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. Calcd for C13H16NO5P+0.25HBr: C, 49.18; H, 5.16; N, 4.41. Found: C, 48.94; H, 5.15; N, 4.40.
    (10.32) 2-Amino-5-pentyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. Calcd for C12H17N2O5P+0.5H2O: C, 46.61; H, 5.87; N, 9.06. Found: C, 46.38; H, 5.79; N, 9.07.
    (10.33) 5-Pentyl-2-hydroxy-4-[2-(5-phosphono)furanyl]imidazole. Anal. calcd. for C12H17N2O5P: C, 48.00; H, 5.71; N, 9.33. Found: C, 48.04; H, 5.58; N, 9.26.
    (10.45) 2-Amino-5-methylthio-4-[2-(5-phosphono)furanyl]oxazole. mp 196° C. (decomp). Anal. calcd. for C8H9N2O5PS: C, 34.79; H, 3.28; N, 10.14. Found: C, 34.60; H, 2.97; N, 10.00.
    (10.35) 2-Amino-5-benzyloxycarbonyl-4-[2-(5-phosphono)furanyl]oxazole. mp 230° C. (decomp). Anal. calcd for C15H13N2O7P+0.7H2O: C, 47.81; H, 3.85; N, 7.43. Found: C, 47.85; H, 3.88; N, 7.21.
    (10.36) 2-Amino-5-isopropyloxycarbonyl-4-[2-(5-phosphono)furanyl]oxazole. mp 221° C. (decomp). Anal. calcd for C11H13N2O7P+0.9H2O: C, 39.75; H, 4.49; N, 8.43. Found: C, 39.72; H, 4.25; N, 8.20.
    (10.37) 2-Amino-5-methoxycarbonyl-4-[2-(5-phosphono)furanyl]oxazole. mp 240° C. (decomp). Anal. calcd for C9HgN2O7P+0.3H2O+0.1 Acetone: C, 37.31; H, 3.43; N, 9.36.
  • Found: C, 37.37; H, 3.19; N, 9.01.
  • (10.38) 2-Amino-5-[(N-methyl)carbamoyl]-4-[2-(5-phosphono)furanyl]oxazole. mp 235° C. (decomp). Anal. calcd for C9H10N3O6P: C, 37.64; H, 3.51; N, 14.63. Found: C, 37.37; H, 3.22; N, 14.44.
    (10.39) 2-Amino-5-ethylthiocarbonyl-4-[2-(5-phosphono)furanyl]oxazole. mp 225° C. (decomp). Anal. calcd for C10H11N2O6PS: C, 37.74; H, 3.48; N, 8.80. Found: C, 37.67; H, 3.27; N, 8.46.
    (10.40) 2-Amino-5-isopropylthio-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd for C10H13N2O5PS+0.2HBr: C, 37.48; H, 4.15; N, 8.74. Found: C, 37.39; H, 4.11; N, 8.56.
    (10.41) 2-Amino-5-phenylthio-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd for C13H11N2O5PS+0.25 HBr: C, 43.55; H, 3.16; N, 7.81. Found: C, 43.82; H, 3.28; N, 7.59.
    (10.42) 2-Amino-5-ethylthio-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd for C9H11N2O5PS+0.85HBr: C, 30.11; H, 3.33; N, 7.80. Found: C, 30.18; H, 3.44; N, 7.60.
    (10.43) 2-Amino-5-propylthio-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd for C10H13N2O5+H2O: C, 37.27; H, 4.69; N, 8.69; H2O: 5.59. Found: C, 37.27; H, 4.67; N, 8.60; H2O: 5.66.
    (10.44) 2-Amino-5-tert-butylthio-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd for C11H15N2O5PS+0.25HBr: C, 39.03; H, 4.54; N, 8.28. Found: C, 39.04; H, 4.62; N, 8.06.
    (10.34) 4,5-Dimethyl-2-[2-(5-phosphono)furanyl]imidazole. Anal. calcd. for C9H11N2O4P+1.25H2O: C, 40.84; H, 5.14; N, 10.58. Found: C, 41.02; H, 5.09; N, 10.27.
    • Example 11 Preparation of N-alkylated 4-[2-(5-phosphono)furanyl]imidazoles and 4-[2-(5-phosphono)furanyl]oxazoles
  • Step A. A suspension of cesium carbonate (1.5 mmole) and 2-methyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]imidazole (1 mmole) in DMF was treated with iodomethane (1.5 mmole) at 25° C. for 16 h. Extraction and chromatography gave 1,2-dimethyl-4-isobutyl-5-[2-(5-diethylphosphono)-fiuanyl]imidazole and 1,2-dimethyl-5-isobutyl-4-[2-(5-diethylphosphono)-furanyl]imidazole.
    Step B. 1,2-Dimethyl-4-isobutyl-5-[2-(5-diethylphosphono)furanyl]-imidazole and 1,2-dimethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]-imidazole were subjected to Step C of Example 3 to give the following compounds:
    (11.1) 1,2-Dimethyl-5-isobutyl-4-[2-(5-phosphono)furanyl]imidazole hydrogen bromide. Anal. calcd. for C13H20N2O4PBr+0.8H2O: C, 39.67; H, 5.53; N, 7.12. Found: C, 39.63; H, 5.48; N, 7.16.
    • Example 12 Preparation of 2-[2-(6-phosphono)pyridyl]pyridine
  • Step A. A solution of 2,2′-bipyridyl (1 mmole) in dichloromethane was treated with m-chloroperoxybenzoic acid (2 mmole) at 0° C., and the reaction mixture was stirred at 25° C. for 2 h. Extraction and chromatography gave 2,2′-bipyridyl-N-oxide.
    Step B. (Redmore, D., J. Org. Chem., 1970, 35, 4114) A solution of 2,2′-bipyridyl-N-oxide methyl ether (1 mmole, prepared from dimethyl sulfate and 2,2′-bipyridyl-N-oxide in diethyl phosphite) was added slowly at −30° C. to a solution of n-butyl lithium (1 mmole) in diethyl phosphite at −30° C. The resulting reaction mixture was stirred at 25° C. for 12 h. Extraction and chromatography gave 2-[2-(6-diethylphosphono)pyridyl]pyridine.
    Step C. 2-[2-(6-Diethylphosphono)pyridyl]pyridine was subjected to Step C of Example 3 to give 2-[2-(6-phosphono)pyridyl]pyridine (12.1). mp 158-162° C. Anal. calcd. for C10H9N2O3P+0.5H2O+O.1HBr: C, 47.42; H, 4.02; N, 11.06. Found: C, 47.03; H, 3.67; N, 10.95.
    • Example 13 Preparation of 4,6-dimethyl-2-(phosphonomethoxymethyl)pyridine
  • Step A. A solution of 2,4,6-collidine (1 mmole) in carbon tetrachloride was treated with NBS (5 mmole) and dibenzoyl peroxide (0.25 mmole) at 80° C. for 12 h. The reaction mixture was cooled to 0° C. and the precipitate was filtered. The filtrate was concentrated under vacuum. Chromatography gave 2-bromomethyl-4,6-dimethylpyridine.
    Step B. A solution of diethyl hydroxymethylphosphonate (1 mmole) in toluene was treated with sodium hydride (1.1 mmole) at 0° C., and after 15 min 2-bromomethyl-4,6-dimethylpyridine (1 mmole) was added. After 3 h the reaction mixture was subjected to extraction and chromatography to give 2-diethylphosphonomethyl-4,6-dimethylpyridine.
    Step C. 2-Diethylphosphonomethyl-4,6-dimethylpyridine was subjected to Step C of Example 3 to give 4,6-dimethyl-2-(phosphonomethoxymethyl)pyridine (13.1). mp 109-112° C. Anal. calcd. for C9H14NO4P+1.0H2O+0.5HBr: C, 37.32; H, 5.74; N, 4.84. Found: C, 37.18; H, 5.38; N, 4.67.
  • The following compound was prepared similarly:
  • (13.2) 2-Amino-4-methyl-5-propyl-6-phosphonomethoxymethylpyrimidine. mp 153-156° C. Anal. calcd. for C10H18N3O4P+1.25H2O+1.6HBr: C, 28.11; H, 5.21; N, 9.84. Found: C, 28.25; H, 4.75; N, 9.74.
    • Example 14 Preparation of diethyl 5-tributylstannyl-2-furanphosphonate
  • A solution of diethyl 2-furanphosphonate (1 mmole, prepared as in Step C of Example 1) in THF was cooled at −78° C. and cannulated to a solution of lithium N-isopropyl-N-cyclohexylamide in THF at −78° C. over 15 min. The resulting mixture was stirred at −78° C. for 2 h and cannulated into a solution of tributyltin chloride (1 mmole) in THF at −78° C. over 20 min. The mixture was then stirred at −78° C. for 1 h, and at 25° C. for 12 h. Extraction and chromatography gave compound (14) as a light yellow oil.
    • Example 15 Preparation of 6-[2-(5-phosphono)furanyl]pyridines
  • Step A. A solution of 2,6-dichloropyridine (120 mmol) in ethanol was treated with aqueous ammonia solution (28%, excess) at 160-165° C. for 60 h in a sealed tube. Extraction and chromatography gave 2-amino-6-chloropyridine as a white solid.
    Step B. A solution of 2-amino-6-chloropyridine (1 mmole) and compound 14 (1 mmole) in p-xylene was treated with tetrakis(triphenylphosphhine) palladium (0.05 mmole) at reflux for 12 h. Extraction and chromatography gave 2-amino-6-[2-(5-diethylphosphono)furanyl]pyridine as a light yellow solid.
    Step C. 2-Amino-6-[2-(5-diethylphosphono)furanyl]pyridine was subjected to Step C of Example 3 to give 2-amino-6-[2-(5-phosphono)furanyl]pyridine (15.1). mp 186-187° C. Anal. calcd. for C9H9N2O4P+0.4HBr: C, 39.67; H, 3.48; N, 10.28. Found: C, 39.95, H, 3.36; N, 10.04.
    Step D. A solution of 2-amino-6-[2-(5-diethylphosphono)furanyl]pyridine (1 mmole) in acetic acid was treated with a solution of bromine in acetic acid (1N, 1 mmole) at 25° C. for 0.5 h. Evaporation and chromatography gave 2-amino-5-bromo-6-[2-(5-diethylphosphono)furanyl]pyridine and 2-amino-3,5-dibromo-6-[2-(5-diethylphosphono)furanyl]pyridine.
    Step E. 2-Amino-5-bromo-6-[2-(5-diethylphosphono)furanyl]pyridine and 2-amino-3,5-dibromo-6-[2-(5-diethylphosphono)furanyl]pyridine were subjected to Step C of Example 3 to give the following compounds:
    (15.2) 6-Amino-3-bromo-2-[2-(5-phosphono)furanyl]pyridine. Anal. calcd. for C9H8BrN2O4P+0.7H2O+0.9HBr+0.12PhCH3: C, 28.44; H, 2.73; N, 6.74. Found: C, 28.64; H, 2.79; N, 6.31.
    (15.3) 6-Amino-3,5-dibromo-2-[2-(5-phosphono)furanyl]pyridine. mp 233-235° C. Anal. calcd. for C9H7Br2N2O4P+1.2HBr: C, 21.84; H, 1.67; N, 5.66. Found: C, 21.90; H, 1.52; N, 5.30.
    Step F. A solution of 2-amino-3,5-dibromo-6-[2-(5-diethylphosphono)-furanyl]pyridine (1 mmole) in DMF was treated with tributyl(vinyl)tin (1.2 mmole) and tetrakis(triphenylphosphine) palladium (0.2 mmole) at 85° C. for 4 h. Evaporation and chromatography gave 2-amino-3,5-bis(vinyl)-6-[2-(5-diethylphosphono)furanyl]pyridine.
    Step G. A solution of 2-amino-3,5-bis(vinyl)-6-[2-(5-diethylphosphono)-furanyl]pyridine (1 mmole) in ethyl acetate was treated with palladium on carbon (10%) at 25° C. under 1 atmosphere of hydrogen for 12 h. Filtration, evaporation and chromatography gave 2-amino-3,5-diethyl-6-[2-(5-diethylphosphono)furanyl]pyridine.
    Step H. 2-Amino-3,5-diethyl-6-[2-(5-diethylphosphono)furanyl]pyridine was subjected to Step C of Example 3 to give 2-amino-3,5-diethyl-6-[2-(5-phosphono)furanyl]pyridine
    (15.4). mp 217-218° C. Anal. calcd. for C13H17N2O4P+0.7H2O+1.0HBr: C, 40.06; H, 5.02; N, 7.19. Found: C, 40.14; H, 4.70; N, 6.87.
    Step 1. A solution of 2-amino-6-picoline (1 mmole) in 48% hydrobromic acid (4.4 mmole) was treated with bromine (3 mmole) at 0° C. for 1 h. An aqueous solution of sodium nitrite (2.5 mmole) was then added and the reaction mixture was stirred at 0° C. for 0.5 h. An aqueous solution of sodium hydroxide (9.4 mmole) was then added and the reaction mixture was stirred at 25° C. for 1 h. Extraction and chromatography gave 2,3-dibromo-6-picoline and 2,3,5-tribromo-6-picoline.
    Step J. 2,3-Dibromo-6-picoline was subjected to Step B of Example 15 and followed by Step C of Example 3 to give 5-bromo-2-methyl-6-[2-(5-phosphono)furanyl]pyridine
    (15.5). mp 207-208° C. Anal. calcd. for C10H9BrNO4P+0.6HBr: C, 32.76; H, 2.64; N, 3.88. Found: C, 32.62; H, 2.95; N, 3.55.
  • Following compounds were prepared according to the above described procedures or with some minor modifications of these procedures using conventional chemistry.
  • (15.6) 2-[2-(5-Phosphono)furanyl]pyridine. mp 220-221° C. Anal. calcd. for C9H8NO4P+0.1H2O+0.45HBr: C, 41.05; H, 3.31; N, 5.32. Found: C, 41.06; H, 3.10; N, 5.10.
    (15.7) 2-Amino-3-nitro-6-[2-(5-phosphono)furanyl]pyridine. mp 221-222° C. Anal. calcd. for C9H8N3O6P+0.55HBr+0.02PhCH3: C, 33.12; H, 2.65; N, 12.68. Found: C, 33.22; H, 2:43; N, 12.26.
    (15.8) 2,3-Diamino-6-[2-(5-phosphono)furanyl]pyridine. mp 150-153° C. Anal. calcd. for C9H10N3O4P+1.5HBr+0.05PhCH3: C, 29.46; H, 3.15; N, 11.02. Found: C, 29.50; H, 3.29; N, 10.60.
    (15.9) 2-Chloro-6-[2-(5-phosphono)furanyl]pyridine. mp 94-96° C. Anal. calcd. for C9H7ClNO4P+0.25HBr: C, 38.63; H, 2.61; N, 5.01. Found: C, 38.91; H, 3.00; N, 5.07.
    (15.10) 3,5-Dichloro-2-[2-(5-phosphono)furanyl]pyridine. mp 180-181° C. Anal. calcd. for C9H6Cl2NO4P+0.7HBr: C, 31.61; H, 2.01; N, 3.94. Found: C, 31.69; H, 2.09; N, 3.89.
    (15.11) 3-Chloro-5-trifluoromethyl-2-[2-(5-phosphono)furanyl]pyridine. mp 253-254° C. Anal. calcd. for C10H6ClF3NO4P: C, 36.67; H, 1.85; N, 4.28. Found: C, 36.69; H, 1.89; N, 4.30.
    (15.12) 2-Amino-3-ethyl-6-[2-(5-phosphono)furanyl]pyridine. mp 220-221° C. Anal. calcd. for C11H13N2O4P+0.6HBr+0.2H2O: C, 41.24; H, 4.40; N, 8.74. Found: C, 41.02; H, 4.57; N, 8.68.
    (15.13) 6-Amino-3-ethyl-2-[2-(5-phosphono)furanyl]pyridine. Anal. calcd. for C11H13N2O4P+1.0HBr+0.3H2O: C, 37.27; H, 4.15; N, 7.90. Found: C, 37.27; H, 4.19; N, 7.51.
    (15.14) 6-Amino-3-propyl-2-[2-(5-phosphono)furanyl]pyridine. mp 252-253° C. Anal. calcd. for C12H15N2O4P+1.0HBr+1.0H2O+0.32PhCH3: C, 41.65; H, 5.05; N, 6.82. Found: C, 41.97; H, 5.19; N, 6.83.
    (15.15) 2,4-Dimethyl-3-bromo-6-[2-(5-phosphono)furanyl]pyridine. mp 232-233° C. Anal. Calcd. for C11H1BrNO4P+0.45HBr: C, 35.85; H, 3.13; N, 3.80. Found: C, 35.98; H, 3.10; N, 3.71.
    (15.16) 2-Chloro-4-amino-6-[2-(5-phosphono)furanyl]pyridine. Anal. calcd. for C9H8N2O4PCl+HBr+0.5H2O+MeOH: C, 30.99; H, 3.38; N, 7.23. Found: C, 31.09; H, 3.21; N, 6.96.
    (15.17) 3-Hydroxyl-2-[2-(5-phosphono)furanyl]pyridine. Anal. calcd. for C9H8NO5P+1.1HBr+0.3 CH3Ph: C, 37.26; H, 3.24; N, 3.91. Found: C, 37.66; H, 3.55; N, 3.84.
    (15.19) 2-Amino-3-cyclopropyl-6-[2-(5-phosphono)furanyl]pyridine. Anal. calcd. for C12H13N2O4PCl+HBr+0.4H2O: C, 39.13; H, 4.05; N, 7.61. Found: C, 39.06; H, 3.85; N, 7.37.
    (15.20) 2-Amino-5-cyclopropyl-6-[2-(5-phosphono)furanyl]pyridine. Anal. calcd. for C12H13N2O4P+HBr+0.7 CH3Ph: C, 47.69; H, 4.64; N, 6.58. Found: C, 47.99; H, 4.62; N, 6.91.
    (15.21) 5-Amino-2-methoxy-6-[2-(5-phosphono)furanyl]pyridine. Anal. calcd. for C10H11N2O5P+0.2H2O: C, 43.87; H, 4.20; N, 10.23. Found: C, 43.71; H, 3.77; N, 9.77.
    (15.22) 2-Methyl-5-cyano-6-[2-(5-phosphono)furanyl]pyridine. Anal. Calcd. for C11H9N2O4P+0.75 HBr+0.5H2O+0.5 MePh: C, 45.84; H, 3.91; N, 7.37. Found: C, 45.93; H, 3.56; N, 7.36.
    (15.23) 2-Amino-3,5-bis(cyano)-4-methyl-6-[2-(5-phosphono)furanyl]pyridine. Anal. calcd. for C12H9N4O4P+0.7H2O: C, 45.49; H, 3.31; N, 17.68. Found: C, 45.48; H, 3.06; N, 17.51.
    (15.24) 2-Chloro-4-cyano-6-[2-(5-phosphono)furanyl]pyridine. Anal. calcd. for C10H6N2O4PCl: C, 42.20; H, 2.13; N, 9.84. Found: C, 41.95; H, 2.10; N, 9.47.
    • Example 16 Preparation of 2-[2-(5-phosphono)furanyl]pyrimidines and 4-[2-(5-phosphono)furanyl]pyrimidines
  • Step A. A solution of 5-diethylphosphono-2-[(1-oxo)pentyl]furan in N,N-dimethylformamide dimethyl acetal was heated at reflux for 12 h. Evaporation and chromatography gave diethyl 5-(2-propyl-3-N,N-dimethylamino)acryloyl-2-furanphosphonate.
    Step B. A solution of diethyl 5-(2-propyl-3-N,N-dimethylamino)acryloyl-2-furanphosphonate (1 mmole) in ethanol was treated with guanidine hydrogen chloride (1.2 mmole) and sodium ethoxide (1 mmole) at 80° C. for 12 h. The reaction mixture was evaporated, and residue was dissolved in water. The aqueous solution was neutralized with HCl (2 N), and concentrated under reduced pressure. The residue was co-evaporated with toluene to give 2-amino-5-propyl-4-[2-(5-ethylphosphono)-furanyl]pyrimidine as a yellow solid.
    Step C. 2-Amino-5-propyl-4-[2-(5-ethylphosphono)furanyl]pyrimidine (1 mmole) and thionyl chloride was heated at reflux for 2 h. The reaction mixture was evaporated to dryness and the residue was dissolved in methylene chloride, and treated with excess pyridine and ethanol at 25° C. for 12 h. Evaporation and chromatography gave 2-amino-5-propyl-4-[2-(5-diethylphosphono)furanyl]pyrimidine.
    Step D. 2-Amino-5-propyl-4-[2-(5-diethylphosphono)furanyl]pyrimidine was subjected to Step C of Example 3 to give 2-amino-5-propyl-4-[2-(5-phosphono)furanyl]pyrimidine (16.1). mp 258-259° C. Anal. calcd. for C11H14N3O4P+1.33H2O: C, 43.01; H, 5.47; N, 13.68. Found: C, 43.18; H, 5.31; N, 13.30.
  • The following compound was prepared according to this procedure:
  • (16.2) 2-Amino-5-isobutyl-4-[2-(5-phosphono)furanyl]pyrimidine. mp 218-220° C. Anal. calcd. for C12H16N3O4P+0.75HBr+0.3PhCH3: C, 43.92; H, 5.01; N, 10.90. Found: C, 44.02; H, 4.62; N, 10.69.
  • Alternatively other 4-[2-(5-phosphono)furanyl]pyrimidines can be prepared according to the following procedures:
  • Step E. Compound 2.2 was subjected to Step A of Example 16 to give diethyl 5-(3-N,N-dimethylamino)acryloyl-2-furanphosphonate as an orange solid.
    Step F. A solution of diethyl 5-(3-N,N-dimethylamino)acryloyl-2-furanphosphonate (1 mmole), sodium ethoxide ethanol solution (2 mmole) and guanidine hydrochloride (1.1 mmole) was heated at 55° C. for 2 h. The reaction mixture was cooled in an ice bath and was neutralized with 1N HCl. Evaporation and chromatography gave 2-amino-4-[2-(5-diethylphosphono)-furanyl]pyrimidine as a yellow solid.
    Step G. 2-Amino-4-[2-(5-diethylphosphono)furanyl]pyrimidine was subjected to Step C of Example 3 to give 2-amino-4-[2-(5-phosphono)furanyl]-pyrimidine (16.3). mp>230° C. Anal. calcd. for C8H8N3O4P+0.75H2O+0.2HBr: C, 35.48; H, 3.61; N, 15.51. Found: C, 35.42; H, 3.80; N, 15.30.
    Step H. A solution of 2-amino-4-[2-(5-diethylphosphono)furanyl]pyrimidine (1 mmole) in methanol and chloroform was treated with NBS (1.5 mmole) at 25° C. for 1 h. Extraction and chromatography gave 2-amino-5-bromo-4-[2-(5-diethylphosphono)furanyl]pyrimidine as a yellow solid.
    Step I. 2-Amino-5-bromo-4-[2-(5-diethylphosphono)furanyl]pyrimidine was subjected to Steps F and G of Example 15 followed by Step C of Example 3 to give 2-amino-5-ethyl-4-[2-(5-phosphono)furanyl]pyrimidine (16.4). mp>225° C. Anal. calcd. for C10H12N3O4P+1.4H2O+0.2HBr+0.25PhCH3: C, 42.30; H, 5.14; N, 12.59. Found: C, 42.74; H, 4.94; N, 12.13.
  • The following compounds were prepared according to the above described procedures or with some minor modifications using conventional chemistry:
  • (16.5) 2-[2-(5-Phosphono)furanyl]pyrimidine. mp 194-196° C. Anal. calcd. for C8H7N2O4P+0.1H2O+0.55HBr: C, 35.27; H, 2.87; N, 10.28. Found: C, 35.26; H, 2.83; N, 9.89.
    (16.6) 2-Amino-6-methyl-4-[2-(5-phosphono)furanyl]pyrimidine. mp 238-239° C. Anal. calcd. for C9H10N3O4P+0.9HBr: C, 32.96; H, 3.35; N, 12.81. Found: C, 33.25; H, 3.34; N, 12.46.
    (16.7) 2-Methylthio-4-[2-(5-phosphono)furanyl]pyrimidine. mp 228-229° C. Anal. calcd. for C9H9N2O4PS+0.5H2O: C, 38.44; H, 3.58; N, 9.96. Found: C, 38.19; H, 3.25; N, 9.66.
    (16.8) 2-Methyl-4-[2-(5-phosphono)furanyl]pyrimidine. mp 206-212° C. Anal. calcd. for C9H9N2O4P+0.9H2O+0.25HBr: C, 34.05; H, 3.30; N, 8.82. Found: C, 34.02; H, 3.06: N, 8.75.
    (16.9) 4,6-Dimethyl-5-bromo-2-[2-(5-phosphono)furanyl]pyrimidine. mp 251-252° C. Anal. calcd. for C10H10BrN2O4P: C, 36.06; H, 3.03; N, 8.41. Found: C, 35.89; H, 2.82; N, 8.11.
    (16.10) 2-Amino-5-chloro-4-[2-(5-phosphono)furanyl]pyrimidine. Anal. calcd. for C8H7ClN3O4P+0.5H2O: C, 33.76; H, 2.83; N, 14.76. Found: C, 33.91; H, 2.86; N, 14.20.
    (16.11) 2-Amino-6-methylthio-4-[2-(5-phosphono)furanyl]pyrimidine. Anal. calcd. for C9H10N3O4PS+HBr: C, 29.36; H, 3.01; N, 11.41. Found: C, 29.63; H, 3.02; N, 11.27.
    (16.12) 2-Amino-5-bromo-6-methylthio-4-[2-(5-phosphono)furanyl]pyrimidine. Anal. calcd. for C9H9N3O4PSBr+0.8 HBr+0.2 MePh: C, 27.80; H, 2.56; N, 9.35. Found: C, 27.74; H, 2.40; N, 8.94.
    (16.13) 2-Amino-(4-morpholino)-4-[2-(5-phosphono)furanyl]pyrimidine. Mp>230° C. Anal. calcd. for C12H15N4O5P+HBr+0.05 MePh: C, 36.02; H, 4.01; N, 13.61. Found: C, 35.98; H, 4.04; N, 13.33.
    (16.14) 6-Amino-4-chloro-2-[2-(5-phosphono)furanyl]pyrimidine. Mp>230° C. Anal. calcd. for C8H7N3O4PCl+0.5H2O: C, 33.76; H, 2.83; N, 14.76. Found: C, 33.83; H, 2.54; N, 14.48.
    • Example 17 Preparation of 2-[2-(5-phosphono)furanyl]pyrazines and 2-[2-(5-phosphono)furanyl]triazines
  • Step A. The procedures described in Example 16 can also be applied to the synthesis of 2-[2-(5-phosphono)furanyl]pyrazine and 2-[2-(5-phosphono)furanyl]triazine analogs and in some cases with minor modifications of these procedures using conventional chemistry methods.
  • The following compounds were prepared accordingly:
  • (17.1) 2,5-Dimethyl-3-[2-(5-phosphono)furanyl]pyrazine. mp 212-213° C. Anal. calcd. for C10H11N2O4P+0.75HBr: C, 38.15; H, 3.76; N, 8.90. Found: C, 38.41; H, 3.93; N, 8.76.
    (17.2) 2-Chloro-6-[2-(5-phosphono)furanyl]pyrazine. mp 204-205° C. Anal. calcd. for C8H6ClN2O4P+0.3HBr+0.02PhCH3: C, 34.10; H, 2.27; N, 9.77. Found: C, 34.36; H, 2.07; N, 9.39.
    (17.3) 2-Amino-3-propyl-6-[2-(5-phosphono)furanyl]pyrazine. mp 227-228° C. Anal. calcd. for C11H14N3O4P+0.7HBr: C, 38.87; H, 4.36; N, 12.36. Found: C, 39.19; H, 4.36; N, 11.92.
    (17.4) 2-Amino-6-[2-(5-phosphono)furanyl]pyrazine. mp 235-236° C. Anal. calcd. for C8H8N3O4P+1.15H2O+0.03PhCH3; C, 37.26; H, 4.01; N, 15.88. Found: C, 37.09; H, 3.67; N, 15.51.
    (17.5) 2-Amino-3-bromo-6-[2-(5-phosphono)furanyl]pyrazine. Anal. calcd. for C8H7N3O4PBr+1HBr: C, 23.97; H, 2.01; N, 10.48. Found: C, 24.00; H, 2.00; N, 10.13.
    (17.6) 3-Methylthio-2-[2-(5-phosphono)furanyl]pyrazine. Anal. calcd. for C9H9N2O4PS+0.3H2O: C, 38.94; H, 3.49; N, 10.09. Found: C, 38.99; H, 3.11; N, 9.67.
    (17.7) 6-Amino-3-methylthio-2-[2-(5-phosphono)furanyl]pyrazine. Anal. calcd. for C9H10N3O4PS+1.5H2O+1.7 HBr+0.25 MePh: C, 27.19; H, 3.54; N, 8.85. Found: C, 27.10; H, 3.85; N, 8.49.
    (17.8) 6-Amino-5-methylthio-2-[2-(5-phosphono)furanyl]pyrazine. Anal. calcd. for C9H10N3O4PS+1.1 HBr+0.05 MePh: C, 29.49; H, 3.04; N, 11.03. Found: C, 29.23; H, 2.79; N, 10.87.
    (17.9) 6-Amino-5-methoxycarbonyl-3-chloro-2-[2-(5-phosphono)furanyl]pyrazine. Anal. calcd. for C10H9N3O6PCl+0.3 HBr+0.04 MePh: C, 34.15; H, 2.68; N, 11.62. Found: C, 34.20; H, 2.90; N, 11.21.
    (17.10) 6-Amino-3-methylthio-2-[2-(5-phosphono)furanyl]pyrazine ammonium salt. Anal. calcd. for C9H13N4O4PS+0.8 HBr: C, 29.30; H, 3.77; N, 15.18. Found: C, 29.03; H, 3.88; N, 15.08.
    (17.11) 2-Amino-4-phenyl-6-[2-(5-phosphono)furanyl]triazine. Anal. calcd. for C13H11N4O4P+HBr+0.1 EtOAc: C, 39.45; H, 3.16; N, 13.73. Found: C, 39.77; H, 3.26; N, 13.48.
    • Example 18 Preparation of Analogs with X being Methoxycarbonyl Methylthiocarbonyl, Methylaminocarbonyl and Methylcarbonylamino Preparations of 4-phosphonomethoxycarbonylthiazoles and 4-phosphonomethoxycarbonyloxazoles
  • Step A. A solution of 2-amino-4-ethoxycarbonylthiazole (1 mmole) in 1,4-dioxane (5 mL) was treated with di-tert-butyl dicarbonate (1.2 mmole), TMEDA (0.1 mmole) and DMAP (0.1 mmole) at room temperature. After the reaction was stirred for 20 h, it was evaporated to dryness. The residue was subjected to extraction to give 2-[N-Boc(amino)]-4-ethoxycarbonyl thiazole as a yellow solid.
    Step B. A solution of 2-[N-Boc(amino)]-4-ethoxycarbonylthiazole (1 mmole) in a 2:1 mixture of EtOH:H2O (10 mL) was treated with NaOH (3N, 3 mmole) and the reaction was stirred at 60° C. for 4 h. The reaction was cooled to 0° C. and neutralized to pH 5 with 3 N HCl, and the resulting solid was collected via filtration to give 2-[N-Boc(amino)]-4-carboxylthiazole as a white solid.
    Step C. A suspension of 2-[N-Boc(amino)]-4-carboxylthiazole (1 mmole) in CH2Cl2 (5 mL) was treated with thionyl chloride (4 mmole) at room temperature. After stirring for 4 h the reaction was evaporated to dryness. The residue was dissolved in CH2Cl2 (5 mL) and added to a solution of diethyl(hydroxymethyl)phosphonate (1.5 mmole) and pyridine (2 mmole) in CH2Cl2 (5 mL) at 0° C. The reaction was warmed to room temperature and stirred for 4 h. The reaction was quenched with water and the mixture was subjected to extraction to give 2-[N-Boc(amino)]-4-diethylphosphonomethoxycarbonylthiazole as a thick yellow oil.
  • Alternatively the ester linkage can be formed using a mixed anhydride method as exemplified in the following procedures:
  • A solution of 2-[N-Boc(amino)]-4-carboxylthiazole (1 mmole) in pyridine (5 mL) was treated with para-toluenesulfonyl chloride (2 mmole) followed by diethyl (hydroxymethyl)phosphonate (2 mmole) at room temperature for 4 h. Evaporation, extraction and chromatography gave 2-[N-Boc(amino)]-4-diethylphosphonomethoxycarbonylthiazole as a thick yellow oil.
  • Step D. A solution of 2-[N-Boc(amino)]-4-diethylphosphonomethoxycarbonylthiazole (1 mmole) and anisole (0.1 mmole) in methylene chloride (5 mL) and trifluoroacetic acid (5 mL) was stirred at 0° C. for 1 h, and at room temperature for 1 h. Evaporation, extraction and chromatography gave 2-amino-4-diethyllphosphonomethoxycarbonylthiazole as a solid.
    Step E. 2-Amino-4-diethyllphosphonomethoxycarbonylthiazole was subjected to Step C of Example 3 to give 2-amino-4-phosphonomethoxycarbonylthiazole (18.1) as a solid. Mp>240° C. (decomp). Anal. calcd. for C5H7N2O5PS: C, 25.22: H, 2.96; N, 11.76. Found: C, 25.30; H, 2.86; N, 11.77.
    Step F. A solution of 2-[N-Boc(amino)]-4-diethylphosphonomethoxycarbonylthiazole (1 mmole) in CH2Cl2 (5 mL) was treated with bromine (2 mmole) at room, temperature for 4 h. Evaporation and extraction gave 2-[N-Boc(amino)]-5-bromo-4-diethylphosphonomethoxycarbonylthiazole as an orange oil which was subjected to Step D of Example 18 followed by Step C of Example 3 to give 2-amino-5-bromo-4-phosphonomethoxycarbonylthiazole (18.2) as a solid. Mp>230° C. (decomp). Anal. calcd. for C5H6N2O5PSBr: C, 18.94; H, 1.91; N, 8.84. Found: C, 19.08; H, 1.76; N, 8.67.
    Step G. A solution of 2-[N-Boc(amino)]-5-bromo-4-diethylphosphonomethoxycarbonylthiazole (1 mmole) and dichlorobis(triphenylphosphine)palladium(II) (0.1 mmole) in DMF (5 mL) was treated with tributyl(vinyl)tin (2.5 mmole) and the reaction was stirred at 60° C. for 2 h. The solvent was removed and the residue taken up in EtOAc and stirred with 2 mmol NaF in 5 ml water for 1 h. Extraction and chromatography gave 2-[N-Boc(amino)]-5-vinyl-4-diethylphosphonomethoxycarbonylthiazole as a yellow solid.
    Step H. A suspension of 2-[N-Boc(amino)]-5-vinyl-4-diethylphosphonomethoxycarbonyl thiazole (1 mmole) and 10% Pd/C (0.5 mmole) in MeOH (5 mL) was stirred under an atmosphere of H2 (balloon) at room temperature for 15 h. Filtration and evaporation gave 2-[N-Boc(amino)]-5-ethyl-4-diethylphosphonomethoxycarbonylthiazole as a yellow solid, which was subjected to Step D of Example 18 followed by Step C of Example 3 to give 2-amino-5-ethyl-4-phosphonomethoxycarbonylthiazole (18.3) as a solid. Mp>230° C. (decomp). Anal. Calcd. for C7H11N2O5PS: 31.58; H, 4.16; N, 10.52. Found: C, 31.80; H, 4.04; N, 10.18.
    Step I. A solution of N-[Bis(methylthio)methylene]glycine methyl ester (1 mmole) in anhydrous THF (2 mL) was added to a solution of t-BuOK (1.4 mmole) in anhydrous THF (10 mL) at −78° C. and the mixture was stirred for 30 min. Then a solution of ethyl isothiocyanate (1 mmole) in anhydrous THF (2 mL) was added and the reaction was stirred at −78° C. for 30 min and at room temperature for 2 h. The reaction was quenched with water. Extraction and chromatography gave 2-methylthio-5-(N-ethylamino)-4-methoxycarbonylthiazole as a yellow solid, which was subjected to Step B and C of Example 18 followed by Step C of Example 3 to give 2-methylthio-5-(N-ethylamino)-4-phosphonomethoxycarbonylthiazole (18.4) as a solid. Mp>200° C. (decomp). Anal. calcd. for C8H13N2O5PS2+0.1 HBr: C, 29.99; H, 4.12; N, 8.74. Found: C, 29.71; H, 4.10; N, 8.60.
    Step J. A solution of 1 mmol of 2-[N-Boc(amino)]-4-thiazolecarboxylate acid chloride (1 mmole) and pyridine (2 mmole) in CH2Cl2 (5 mL) was cooled to −78° C. and H2S(g) was bubbled through the solution for 10 min. The reaction was stirred at −78° C. for 30 min and then warmed to room temperature. The mixture was washed with 3 N HCl. The organic phase was separated, dried and concentrated to give 2-[N-Boc(amino)]-4-thiazolethiocarboxylic acid as a yellow solid.
    Step K. A solution of give 2-[N-Boc(amino)]-4-thiazolethiocarboxylic acid (1 mmole) in THF (5 mL) was cooled to −78° C. and treated with NaH (2 mmole) in small portions. After 10 min the reaction was treated with a solution of diethylphosphonomethyl triflate in THF (5 mL). The reaction was stirred at −78° C. for 1 h, and then quenched with H2O. Extraction and chromatography gave 2-[N-Boc(amino)]-4-diethylphosphonomethylthiocarbonylthiazole as a thick oil, which was subjected to Step D of Example 18 followed by Step C of Example 3 to give 2-amino-4-phosphonomethylthiocarbonylthiazole (18.5) as a solid. Mp>230° C. (decomp). Anal. calcd. for C5H7N2O4PS2: C, 23.62; H, 2.78; N, 11.02. Found: C, 23.77; H, 2.61; N, 10.73.
    • Preparation of 4-[(N-phosphonomethyl)carbamoyl]thiazole, 3-[N-phosphonomethyl)-carbamoyl]isothiazole and 2-[N-phosphonomethyl)carbamoyl]pyridine
  • Step L. A solution of 2-[N-Boc(amino)]-4-thiazolecarboxylic acid (1 mmole) in DMF (5 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.5 mmole) and 1-hydroxylbenzotriazole hydrate (HOBt, 1.5 mmole) followed by addition of diethyl aminomethylphosphonate (1.5 mmole) at room temperature for 24 h. The reaction was subjected to evaporation, extraction and chromatography to give 2-[N-Boc(amino)]-4-[(N-diethylphosphonomethyl)carbamoyl]thiazole as a white solid, which was subjected to Step D of Example 18 followed by Step C of Example 3 to give 2-amino-4-[(N-phosphonomethyl)carbamoyl]thiazole (18.6) as a light brown solid. Mp>245° C. (decomp). Anal. calcd. for C5H8N3O4PS+1.05 HBr: C, 18.64; H, 2.83; N, 13.04. Found: C, 18.78; H, 2.43; N, 12.97.
    • Preparation of 2-[(N-phosphonoacetyl)amino]thiazole and 2-[(N-phosphonoacetyl)amino]pyridine
  • Step M. A solution of 2-amino-4,5-dimethylthiazole hydrochloride (2 mmole) and diethyl phosphonoacetica acid (1 mmole) in DMF (5 mL) was treated with EDCI (1.5 mmole), HOBt (1.5 mmole) and triethylamine (2 mmole) at room temperature for 24 h. The reaction was subjected to evaporation, extraction and chromatography to give 2-[(N-diethylphosphonoacetyl)amino]-4,5-dimethylthiazole as a yellow solid, which was subjected to Step D of Example 18 followed by Step C of Example 3 to give 4,5-dimethyl-2-[(N-phosphonoacetyl)amino]thiazole (18.7) as a light brown solid. Mp>250° C. Anal. calcd. for C7H11N2O4PS: C, 33.60; H, 4.43; N, 11.20. Found: C, 33.62; H, 4.29; N, 10.99.
  • The following compounds were prepared using some of the above described procedures or some of the above procedures with some minor modifications using conventional chemistry:
  • (18.8) 2-[(N-phosphonomethyl)carbamoyl]pyridine. Anal. calcd. for C7H9N2O4P+HBr+0.67H2O: C, 27.20; H, 3.70; N, 9.06. Found: C, 27.02; H, 3.71; N, 8.92.
    (18.9) 2-[(N-phosphonoacetyl)amino]pyridine. Anal. calcd. for C7H9N2O4P+HBr+0.67H2O: C, 27.20; H, 3.70; N, 9.06. Found: C, 27.05; H, 3.59; N, 8.86.
    (18.10) 4-Ethoxycarbonyl-2-[(N-phosphonoacetyl)amino]thiazole. Anal. calcd. for C8H11N2O6PS: C, 32.66; H, 3.77; N, 9.52. Found: C, 32.83; H, 3.58; N, 9.20.
    (18.11) 2-Amino-5-bromo-4-[(N-phosphonomethyl)carbamoyl]thiazole. Mp 232° C. (decomp). Anal. calcd. for C5H7N3O4PSBr+0.15HBr+0.1 hexane: C, 19.97; H, 2.56; N, 12.48. Found: C, 19.90; H, 2.29; N, 12.33.
    (18.12) 2-Amino-5-(2-thienyl)-4-[(N-phosphonomethyl)carbamoyl]thiazole. Mp 245° C. (decomp). Anal. calcd. for C9H10N3O4PS2+HBr+0.1 EtOAc: C, 27.60; H, 2.91; N, 10.27. Found: C, 27.20; H, 2.67; N, 9.98.
    (18.13) 4,5-Dichloro-3-[(N-phosphonomethyl)carbamoyl]isothiazole. Mp 189-191° C. Anal. calcd. for C5H5N2O4PSCl2: C, 20.63; H, 1.73; N, 9.62. Found: C, 20.43; H, 1.54; N, 9.51.
    (18.14) 2-Amino-5-bromo-4-{[N-(1-phosphono-1-phenyl)methyl]carbamoyl}thiazole. Mp>250° C. Anal. calcd. for C11H11N3O4PSBr: C, 33.69; H, 2.83; N, 10.71. Found: C, 33.85; H, 2.63; N, 10.85.
    (18.15) 2-Amino-5-(2-thienyl)-4-phosphonomethoxycarbonylthiazole. Mp>230° C. (decomp). Anal. calcd. for C9H9N2O5PS2: C, 33.75; H, 2.83; N, 8.75. Found: C, 33.40; H, 2.74; N, 8.51.
    (18.16) 2-Amino-5-benzyl-4-phosphonomethoxycarbonylthiazole. Mp>230° C. (decomp). Anal. calcd. for C12H13N2O5PS: C, 43.91; H, 3.99; N, 8.53. Found: C, 43.77; H, 4.03; N, 8.25.
    (18.17) 2-Methylthio-5-methylamino-4-phosphonomethoxycarbonylthiazole. Anal. calcd. for C7H11N2O5PS2+0.2 HBr: C, 26.74; H, 3.59; N, 8.91. Found: C, 26.79; H, 3.89; N, 8.89.
    (18.18) 2-Amino-5-ethyl-4-[(N-phosphonomethyl)carbamoyl]thiazole. Mp 180° C. (decomp). Anal. calcd. for C7H12N3O4PS+HBr+0.4 CH2Cl2: C, 23.49; H, 3.67; N, 11.18. Found: C, 23.73; H, 3.29; N, 11.42.
    (18.19) 2-Amino-5-isopropyl-4-[(N-phosphonomethyl)carbamoyl]thiazole. Mp 247-250° C. Anal. calcd. for C8H14N3O4PS: C, 34.41; H, 5.05; N, 15.05. Found: C, 34.46; H, 4.80; N, 14.68.
    (18.20) 2-Amino-5-isopropyl-4-phosphonomethoxycarbonylthiazole. Mp>230° C. Anal. calcd. for C8H13N2O5PS: C, 34.29; H, 4.68; N, 10.00. Found: C, 33.97; H, 4.49; N, 9.70.
    (18.21) 2-Amino-5-phenyl-4-phosphonomethoxycarbonylthiazole. Mp>230° C. Anal. calcd. for C11H11N2O5PS: C, 42.04; H, 3.53; N, 8.91. Found: C, 42.04; H, 3.40; N, 8.72.
    (18.22) 2-Amino-4-phosphonomethoxycarbonyloxazole. Anal. calcd. for C5H7N2O6P+0.09−HBr: C, 26.18; H, 3.12; N, 12.21. Found: C, 26.29; H, 3.04; N, 11.90.
    (18.23) 2-Amino-6-[(N-phosphonoacetyl)amino]pyridine. Anal. calcd. for C7H10N3O4P+1.1 HBr+0.25 MeOH: C, 26.54; H, 3.72; N, 12.80. Found: C, 26.79; H, 3.63; N, 12.44.
    (18.24) 2-Amino-5-methyl-4-[(N-phosphonomethyl)carbamoyl]thiazole. Mp>250° C. Anal. calcd. for C6H10N3O4PS+0.06 EtOAc: C, 29.22; H, 4.12; N, 16.38. Found: C, 29.03; H, 3.84; N, 16.01.
    (18.25) 2-Amino-3-bromo-6-[(N-phosphonoacetyl)amino]pyridine. Anal. calcd. for C7H9N3O4PBr+1.25 HBr+0.8 EtOAc: C, 25.43; H, 3.48; N, 8.72. Found: C, 25.58; H, 3.71; N, 8.56.
    (18.26) 2-Amino-3,5-dibromo-6-[(N-phosphonoacetyl)amino]pyridine. Anal. calcd. for C7H8N3O4PBr2+HBr+0.5 EtOAc: C, 21.03; H, 2.55; N, 8.18. Found: C, 21.28; H, 2.55; N, 7.91.
    (18.27) 2-Amino-5-methyl-4-phosphonomethoxycarbonylthiazole. Mp 230° C. (decomp). Anal. calcd. for C6H9N2O5PS: C, 28.58; H, 3.60; N, 11.11. Found: C, 28.38; H, 3.49; N, 11.10.
    (18.28) 2-Amino-3,5-diethyl-6-[(N-phosphonoacetyl)amino]pyridine. MS calcd. for C11H18N3O4P+H: 288, found 288.
    (18.29) 2-Amino-3,5-dibromo-6-{[N-(2,2-dibromo-2-phosphono)acetyl]amino}pyridine. Anal. calcd. for C7H6N3O4PBr4+0.5 HBr+EtOAc: C, 19.56; H, 2.16; N, 6.22. Found: C, 19.26; H, 2.29; N, 5.91.
    (18.30) 2-Amino-5-isopropyl-4-phosphonomethoxycarbonyloxazole. Anal. calcd. for C8H13N2O6P+0.2 HBr: C, 34.27; H, 4.75; N, 9.99. Found: C, 34.47; H, 4.84; N, 9.83.
    (18.31) 2-Amino-5-[1-(2-cyclohexylmethyl)ethynyl]-4-phosphonomethoxycarbonylthiazole. Mp 230° C. (decomp). Anal. calcd. for C14H19N2O5PS+0.1 HBr: C, 45.89; H, 5.25; N, 7.64. Found: C, 45.85; H, 4.96; N, 7.44.
    (18.32) 2-Amino-5-[1-(4-cyano)butynyl]-4-phosphonomethoxycarbonylthiazole. Mp 230° C. (decomp). Anal. calcd. for C10H10N3O5PS+0.25 HBr: C, 35.80; H, 3.08; N, 12.53. Found: C, 35.92; H, 2.99; N, 12.20.
    (18.33) 2-Amino-5-methyl-4-phosphonomethoxycarbonyloxazole. Anal. calcd. for C6H9N2O6P+0.15 HBr: C, 29.03; H, 3.71; N, 11.28. Found: C, 28.98; H, 3.66; N, 11.21.
    (18.34) 2-Amino-5-[1-(4-cyano)butyl]-4-phosphonomethoxycarbonylthiazole. Mp 230° C. (decomp). Anal. calcd. for C10H14N3O5PS: C, 37.62; H, 4.42; N, 13.16. Found: C, 37.23; H, 4.18; N, 12.79.
    (18.35) 2-Amino-5-pentyl-4-phosphonomethoxycarbonyloxazole. Anal. calcd. for C10H17N2O6P: C, 41.10; H, 5.86; N, 9.59. Found: C, 41.16; H, 5.75; N, 9.50.
    (18.36) 2-[N-Boc(amino)]-4-[(2-phosphono)ethoxycarbonyl]thiazole. Anal. calcd. for C11H17N2O7PS: C, 37.50; H, 4.86; N, 7.95. Found: C, 37.10; H, 4.59; N, 7.84.
    (18.37) 2-Amino-4-[(2-phosphono)ethoxycarbonyl]thiazole hydrobromide. Anal. calcd. for C6H9N2O5PS+HBr: C, 21.63; H, 3.03; N, 8.41. Found: C, 22.01; H, 2.99; N, 8.15.
    (18.38) 2-Amino-5-butyl-4-phosphonomethoxycarbonyloxazole. Anal. calcd. for C9H15N2O6P: C, 38.86; H, 5.43; N, 10.07. Found: C, 38.59; H, 5.43; N, 9.96.
    (18.39) 2-Amino-5-[1-(1-oxo-2,2-dimethyl)propyl]-4-phosphonomethoxycarbonylthiazole. Anal. Calcd. for C10H15N2O6PS: C, 37.27; H, 4.69; N, 8.69. Found: C, 37.03; H, 4.69; N, 8.39.
    (18.40) 2-Amino-5-propyl-4-phosphonomethoxycarbonyloxazole. Anal. calcd. for C8H13N2O6P+0.35 EtOAc+0.05 HBr: C, 37.75; H, 5.34; N, 9.37. Found: C, 37.69; H, 5.21; N, 9.03.
    (18.41) 2-Amino-5-propyl-4-phosphonomethoxycarbonylthiazole. Mp 134° C. (decomp). Anal. calcd. for C8H13N2O5PS: C, 34.29; H, 4.68; N, 10.00. Found: C, 33.90; H, 4.30; N, 9.61.
    (18.42) 2-Amino-5-pentyl-4-phosphonomethoxycarbonylthiazole. Mp 130° C. (decomp). Anal. calcd. for C10H17N2O5PS: C, 38.96; H, 5.56; N, 9.09. Found: C, 38.69; H, 5.25; N, 8.85.
    (18.43) 2-Amino-5-bromo-4-phosphonomethylthiocarbonylthiazole. Mp 230° C. (decomp). Anal. calcd. for C5H6N2O5PS2Br: C, 18.03; H, 1.82; N, 8.41. Found: C, 18.40; H, 1.93; N, 8.18.
    (18.44) 2-Amino-5-(2-furanyl)-4-phosphonomethoxycarbonylthiazole. Mp 230° C. (decomp). Anal. calcd. for C9H9N2O6PS: C, 35.53; H, 2.98; N, 9.21. Found: C, 35.78; H, 3.05; N, 8.11.
    (18.45) 2-Amino-5-ethyl-4-phosphonomethoxycarbonyloxazole. Mp 141° C. (decomp). Anal. calcd. for C7H11N2O6P: C, 33.61; H, 4.43; N, 11.20. Found: C, 33.79; H, 4.47; N, 11.09.
    (18.46) 5-Methyl-4-[(N-phosphonomethyl)carbamoyl]imidazole. Anal. calcd. for C6H10N3O4P: C, 32.89; H, 4.60; N, 19.18. Found; C, 33.04; H, 4.65; N, 18.84.
    • Example 19 Preparation of 3-[2-(5-phosphono)furanyl]pyrazoles
  • Step A. A solution of diethyl 5-(2-isobutyl-3-N,N-dimethylamino)acryloyl-2-furanphosphonate (1 mmole, prepared according to Step A of Example 17) in ethanol was treated with hydrazine (1.2 mmole) 80° C. for 12 h. Evaporation and chromatography gave 4-isobutyl-3-[2-(5-diethylphosphono)furanyl]pyrazole.
    Step B. 4-Isobutyl-3-[2-(5-diethylphosphono)furanyl]pyrazole was subjected to Step C of Example 3 to give 4-isobutyl-3-[2-(5-phosphono)furanyl]pyrazole (19.1). mp 210-215° C. Anal. calcd. for C11H15N2O4P: C, 48.89; H, 5.60; N, 10.37. Found: C, 48.67; H, 5.55; N, 10.20.
    Step C. 4-Isobutyl-3-[2-(5-diethylphosphono)furanyl]pyrazole was subjected to Step A of Example 11 to give 1-methyl-4-isobutyl-3-[2-(5-diethylphosphono)furanyl]pyrazole.
    Step D. 1-Methyl-4-isobutyl-3-[2-(5-diethylphosphono)furanyl]pyrazole was subjected to Step C of Example 3 to give 1-methyl-4-isobutyl-3-[2-(5-phosphono)furanyl]pyrazole
    (19.2). Anal. calcd. for Cl2H17N2O4P+0.85HBr+0.75H2O: C, 39.32; H, 5.32; N, 7.64.
  • Found: C, 39.59; H, 5.30; N, 7.47.
    • Example 20 Preparation of 3-[2-(5-phosphono)furanyl]isoxazoles
  • Step A. A solution of 5-diethylphosphono-2-furaldehyde (1 mmole) in ethanol was treated with hydroxylamine (1.1 mmole) and sodium acetate (2.2 mmole) at 25° C. for 12 h. Extraction and chromatography gave 5-diethylphosphono-2-furaldehyde oxime.
    Step B. A solution of 5-diethylphosphono-2-furaldehyde oxime (1 mmole) in DMF was treated with N-chlorosuccinimide (1.1 mmole) at 25° C. for 12 h. Extraction gave 5-diethylphosphono-2-chlorooximidofuran.
    Step C. A solution of 5-diethylphosphono-2-chlorooximidofuran (1 mmole) and ethyl propiolate (5 mmole) in diethyl ether was treated with triethylamine (2 mmole) at 25° C. for 12 h. Extraction and chromatography gave 5-ethoxycarbonyl-3-{2-(5-diethylphosphono)furanyl]isoxazole.
    Step D. 5-Ethoxycarbonyl-3-{2-(5-diethylphosphono)furanyl]isoxazole was subjected to Step A of Example 9 followed by Step C of Example 3 to give 5-carbamoyl-3-[2-(5-phosphono)furanyl]isoxazole (20.1). mp 221-225° C. Anal. calcd. for C8H7N2O6P+0.25EtOH: C, 37.86; H, 3.18; N, 10.39. Found: C, 37.90; H, 3.02; N, 10.05.
  • The following compound was prepared according to this procedure:
  • (20.2) 5-Ethoxycarbonyl-4-methyl-3-[2-(5-phosphono)furanyl]isoxazole. mp 150-152° C. Anal. calcd. for C11H12NO7P+0.25H2O+0.15HBr: C, 41.57; H, 4.01; N, 4.41. Found: C, 41.57; H, 4.20; N, 4.54.
    (20.3) 4,5-Bis(ethoxycarbonyl)-3-[2-(5-phosphono)furanyl]isoxazole. Anal. calcd for C13H14NO9P: C, 43.47; H, 3.93; N, 3.90. Found: C, 43.26; H, 3.92; N, 3.97.
    (20.4) 5-Amino-4-ethoxycarbonyl-3-[2-(5-phosphono)furanyl]isoxazole. mp 190° C. (decomp). Anal. calcd for C10H11N2O7P+0.25HBr: C, 37.25; H, 3.52; N, 8.69. Found: C, 37.56; H, 3.50; N, 8.85.
    (20.5) 4,5-bis(carbamoyl)-3-[2-(5-phosphono)furanyl]isoxazole. mp>220° C. Anal. calcd for C9H8N3O7P: C, 35.90; H, 2.68; N, 13.95. Found: C, 35.67; H, 2.55; N, 13.62.
    (20.6) 4-Ethoxycarbonyl-5-trifluoromethyl-3-[2-(5-phosphono)furanyl]isoxazole. Anal. calcd for C11H9F3NO7P+0.25HBr: C, 35.20; H, 2.48; N, 3.73. Found: C, 35.25; H, 2.34; N, 3.98.
    (20.7) 5-Amino-4-(2-furyl)-3-[2-(5-phosphono)furanyl]isoxazole. mp>220° C. Anal. calcd for C12H9N2O7P+0.1AcOEt: C, 44.73; H, 2.97; N, 8.41. Found: C, 45.10; H, 2.58; N, 8.73.
    (20.8) 4-Amino-5-cyano-3-[2-(5-phosphono)furanyl]isoxazole. Anal. calcd for C8H6N3O5P+0.1H2O+0.2HBr: C, 35.18; H, 2.36; N, 15.39. Found: C, 35.34; H, 2.50; N, 15.08.
    (20.9) 4-Cyano-5-phenyl-3-[2-(5-phosphono)furanyl]isoxazole. Anal. calcd for C14H9N2O5P+0.15HBr: C, 51.21; H, 2.81; N, 8.53. Found: C, 51.24; H, 3.09; N, 8.33.
    • Example 21 Preparation of 2-[2-(5-phosphono)furanyl]thiazoles
  • Step A. Diethyl 5-tributylstannyl-2-furanphosphonate (14) and 2-bromo-4-ethoxycarbonylthiazole was subjected to Step A of Example 6 to give 4-ethoxycarbonyl-2-[2-(5-diethylphosphono)furanyl]thiazole.
    Step B. 4-Ethoxycarbonyl-2-[2-(5-diethylphosphono)furanyl]thiazole was subjected to Step A of Example 9 followed by Step C of Example 3 to give 4-carbamoyl-2-[2-(5-phosphono)furanyl]thiazole (21.1). mp 239-240° C. Anal. calcd. for C8H7N2O5PS+0.2H2O: C, 34.59; H, 2.68; N, 10.08. Found: C, 34.65; H, 2.69; N, 9.84.
    • Example 22 Preparation of 4-(3,3-difluoro-3-phosphono-1-propyl)thiazoles
  • Step A. A solution of 3-(tert-butyl-diphenylsilyloxy)-1-propanol (1 mmole) in methylene chloride (7 mL) was treated with powder molecular sieves (4 A, 0.5 equiv. wt/wt) and pyridinium chlorochromate (1.5 mmole) at 0° C. The resulting mixture was stirred at room temperature for 2 h, and diluted with diethyl ether (7 mL) and stirred at room temperature for another 30 min. Filtration, evaporation and chromatography gave 3-(tert-butyldiphenylsilyloxy)-1-propanal as a clear oil.
    Step B. A solution of LDA (1.06 mmole) in THF was treated with a solution of diethyl difluoromethylphosphonate (1 mmole) at −78° C. for 45 min. The reaction was then treated with a THF solution of 3-(tert-butyldiphenylsilyloxy)-1-propanal (1.07 mmole) and the resulting solution was stirred at −78° C. for another 4 h. The reaction was quenched with phenyl chlorothioformate (2.14 mmole), and the reaction mixture was subjected to extraction and chromatography to give diethyl 4-(tert-butyldiphenylsilyloxy)-3-phenoxythiocarbonyloxy-2,2-difluorobutylphosphonate as a clear oil.
    Step C. A solution of diethyl 4-(tert-butyldiphenylsilyloxy)-3-phenoxythiocarbonyloxy-2,2-difluorobutylphosphonate (1 mmole) in toluene (1 mL) was treated with tri-n-butyltin hydride (1.5 mmole) and AIBN (0.1 mmole), and the resulting reaction mixture was heated to reflux for 2 h. Evaporation and chromatography gave diethyl 4-(tert-butyldiphenylsilyloxy)-272-difluorobutylphosphonate as a clear oil.
    Step D. A solution of diethyl 4-(tert-butyldiphenylsilyloxy)-2,2-difluorobutylphosphonate (1 mmole) in methanol (1 mL) was treated with hydrochloric acid (4 N, 4 mmole) at 0° C., and the resulting reaction was stirred at room temperature for 2 h. Evaporation and chromatography gave diethyl 4-hydroxy-2,2-difluorobutylphosphonate as a clear oil.
    Step E. A solution of gave diethyl 4-hydroxy-2,2-difluorobutylphosphonate (1 mmole) in acetone (10 mL) was treated with Jones's reagent (10 mmole) at 0° C. for 30 min. The reaction was quenched with 2-propanol (10 mL), and the resulting mixture was filtered through a Celite pad. Evaporation of the filtrate followed by extraction gave diethyl 3-carboxyl-2,3-difluoropropylphosphonate as an oil.
    Step F. A solution of diethyl 3-carboxyl-2,3-difluoropropylphosphonate (1 mmole) in thionyl chloride (3 mL) was heated to reflux for 2 h. The reaction was evaporated to dryness, and the residue was dissolved in diethyl ether (1 mL) was treated with an etheral solution of diazomethane (10 mmole) at 0° C. for 30 min. A solution of HBr in acetic acid (30%, 1 mL) was added to the reaction, and the resulting solution was stirred at room temperature for 1 h. The reaction was evaporated to dryness and the residue was dissolved in THF-EtOH (1:1, 5 mL) and treated with thiourea (1 mmole). The resulting reaction mixture was heated to 75° C. for 1 h. Evaporation followed by extraction and chromatography gave 2-amino-4-[1-(3-diethylphosphono-3,3-difluoro)propyl]thiazole as a solid, which was subjected to Step C of Example 3 to give gave 2-amino-4-[1-(3-phosphono-3,3-difluoro)propyl]thiazole (22.1) as a solid. Anal. calcd. for C6H9N2O3PSF2+HBr: C, 21.25; H, 2.97; N, 8.26. Found: C, 21.24; H, 3.25; N, 8.21.
  • The following compound was prepared in a similar manner: 2-Amino-5-methylthio-4-[1-(3-phosphono-3,3-difluoro)propyl]thiazole (22.2). MS m/e 305 (M+H).
    • Example 23 Preparation of 2-methylthio-5-phosphonomethylthio-1,3,4-thiadiazole and 2-phosphonomethylthiopyridine
  • Step A. A solution of 2-methylthio-1,3,4-thiadiazole-5-thiol (1 mmole) in THF (5 mL) was treated with sodium hydride (60%, 1.1 mmole) at 0° C. and the resulting mixture was stirred at room temperature for 30 min. The reaction was then cooled to 0° C. and treated with diethylphosphonomethyl trifluoromethanesulfonate (1.1 mmole). After stirring at room temperature for 12 h, the reaction was quenched with saturated ammonium chloride. Extraction and chromatography gave 2-methylthio-5-diethylphosphonomethylthio-1,3,4-thiadiazole as an oil.
    Step B. 2-Methylthio-5-diethylphosphonomethylthio-1,3,4-thiadiazole was subjected to Step C of Example 3 to give 2-methylthio-5-phosphonomethylthio-1,3,4-thiadiazole (23.1) as a yellow solid. Anal. calcd. for C4H7N2O3PS3+0.2 HBr: C, 17.50; H, 2.64; N, 10.21. Found: C, 17.64; H, 2.56; N, 10.00.
  • Alternatively, phosphonomethylthio substituted heteroaromatics are made using the following method as exemplified by the synthesis of 2-phosphonomethylthiopyridine:
  • Step C. A solution of 2,2′-dipyridyl disulfide (1 mmole) in THF was treated with tri-n-butylphosphine (1 mmole) and diethyl hydroxymethylphosphonate at 0° C. The resulting reaction solution was stirred at room temperature for 18 h. Extraction and chromatography gave 2-diethylphosphonomethylthiopyridine as a yellow oil.
    Step D. 2-Diethylphosphonomethylthiopyridine was subjected to Step C of Example 3 to give 2-phosphonomethylthiopyridine (23.2) as a yellow solid. Anal. calcd. for C6H8NO3PS+0.62 HBr: C, 28.22; H, 3.40; N, 5.49. Found: C, 28.48; H, 3.75; N, 5.14.
    • Example 24 Preparation of 2-[(2-phosphono)ethynyl]pyridine
  • Step A. A solution of 2-ethynylpyridine (1 mmole) in THF (5 mL) was treated with LDA (1.2 mmole) at 0° C. for 40 min. Diethyl chlorophosphate (1.2 mmole) was added to the reaction and the resulting reaction solution was stirred at room temperature for 16 h. The reaction was quenched with saturated ammonium chloride followed by extraction and chromatography to give 2-[(2-diethylphosphono)ethynyl]pyridine as a yellow oil.
    Step B. 2-[(2-Diethylphosphono)ethynyl]pyridine was subjected to Step C of Example 3 to give 2-[1-(2-phosphono)ethynyl]pyridine (24.1) as a brown solid. Mp 160° C. (decomp). MS m/e 184 (M+H).
    • Example 25 Preparation of 5-[2-(5-phosphono)furanyl]tetrazole
  • Step A. To a mixture of tetrazole (1 mmole) and powdered K2CO3 (1.5 mmole) in 1 mL DMF cooled to 0° C. was added benzyl chloromethyl ether (1.2 mmole) and the resulting mixture stirred for 30 min at 0° C. and then for 16 h at rt. The mixture was diluted with water and ether. Extraction and chromatography provided 2-benzyloxymethyltetrazole as a colorless oil.
    Step B. To a solution of 2-benzyloxymethyltetrazole (1 mmole) and TMEDA (2 mmole) in 3 mL diethyl ether at −78° C. was added n-BuLi in hexanes (1 mmole). This was let stir for 5 min at −78° C. and then it was added to a precooled (−78° C.) solution of (n-Bu)3SnCl (1 mmole) in 2 mL of diethyl ether. After stirring at −78° C. for 30 min it was diluted with water and diethyl ether. Extraction and chromatography provided 2-benzyloxymethyl-5-(tributylstannyl)tetrazole as a colorless oil.
    Step C. A mixture of 5-iodo-2-diethylphosphonofuran (1 mmole), 2-benzyloxymethyl-5-(tributylstannyl)tetrazole (1.05 nmole), tetrakis(triphenylphosphine) palladium(0) (0.03 mmole) and copper(I) iodide (0.07 mmole) in 3 mL of toluene was refluxed at 1110° C. for 20 h. Evaporation and chromatography provided 2-benzyloxymethyl-5-[2-(5-diethylphosphono)furanyl]tetrazole as an oil.
    Step D. A mixture of 2-benzyloxymethyl-5-[2-(5-diethylphosphono)furanyl]tetrazole (1 mmole) and 6 M HCl (1 mL) in 10 mL ethanol was heated at 70° C. for 20 h and then the solvent concentrated by evaporation, made basic with 1 N NaOH and extracted with EtOAc. The aqueous layer was made acidic and extracted with EtOAc. This EtOAc extract was evaporated to provide 5-[2-(5-diethylphosphono)furanyl]tetrazole as a solid, which was subjected to Step C of Example 3 to give 5-[2-(5-phosphono)furanyl]tetrazole (25.1) as a solid: mp 186-188° C. Anal. calcd. for C5H5N4O4P+1.5H2O: C, 24.70; H, 3.32; N, 23.05. Found: C, 24.57; H, 2.57; N, 23.05.
    • Step E.
  • Step 1. A mixture of 5-[2-(5-diethylphosphono)furanyl]tetrazole (1 mmole), 1-iodo-2-methylpropane (2 mmole) and powdered K2CO3 (2 mmole) in 5 mL DMF was stirred at 80° C. for 48 h and then diluted with CH2Cl2 and water and the layers separated. The CH2O2 layer was evaporated and combined with the product of the following reaction for chromatography.
    Step 2. The aqueous layer of Step 1 was made acidic and extracted with EtOAc. This extract was evaporated and the residue heated at 80° C. in 2 mL of SOCl2 for 3 h and then the solvent evaporated. The residue was dissolved in 5 mL CH2Cl2 and 0.3 mL NEt3 and 0.5 mL of EtOH was added. After stirring for 1 h at rt the mixture was diluted with CH2Cl2 and water. This organic extract was combined with that kept from Step 1 and chromatography provided 1-isobutyl-5-[2-(5-diethylphosphono)furanyl]tetrazole and 2-isobutyl-5-[2-(5-diethylphosphono)furanyl]tetrazole each as an oil.
    Step 3. 1-Isobutyl-5-[2-(5-diethylphosphono)furanyl]tetrazole was subjected to Step C of Example 3 to give 1-isobutyl-5-[2-(5-phosphono)furanyl]tetrazole (25.2) as a solid: mp 200-202° C. Anal. calcd. for C9H13N4O4P: C, 39.71; H, 4.81; N, 20.58. Found: C, 39.64; H, 4.63; N, 20.21.
    Step F. A mixture of 2-isobutyl-5-[2-(5-diethylphosphono)furanyl]tetrazole (1 mmole) and TMSBr (10 mmole) in 10 mL of CH2Cl2 was stirred at room temperature for 16 h. The solvent was evaporated and the residue dissolved in 10:1 CH3CN:water, the solvent evaporated and the residue precipitated from acetone by addition of dicyclohexylamine (2 mmole) to provide 2-isobutyl-5-[2-(5-phosphono)furanyl]tetrazole N,N-dicyclohexyl ammonium salt.
    (25.3) as a solid: mp 226-228° C. Anal. calcd. for C9H13N4O4P+C12H23N: C, 55.62; H, 8.00; N, 15.44. Found: C, 55.55; H, 8.03; N, 15.07.
    • Example 26 High Throughput Synthesis of Various 2-(5-phosphono)furanyl Substituted Heteroaromatic Compounds
  • Step A. Various 2-(5-diethylphosphono)furanyl substituted heteroaromatic compounds were prepared in a similar manner as Step B of Example 15, and some of these compounds were used for the high throughput synthesis of compounds listed in Table 33.1 and Table 33.2.
    Step B. A mixture of 2-chloro-6-[2-(5-diethylphosphono)furanyl]pyridine (0.01 mmole) and TMSBr (0.1 mL) in CH2Cl2 (0.5 mL) was stirred at room temperature for 16 h and then evaporated and diluted with 0.5 mL of 9:1 CH3CN:water. Evaporation provided 2-chloro-6-[2-(5-phosphono)furanyl]pyridine.
    Step C. A mixture of 2-chloro-6-[2-(5-diethylphosphono)furanyl]pyridine (0.01 mmole) and a solution of freshly prepared sodium propoxide in propanol (0.25 M, 0.4 mL) was let sit at 85° C. for 14 h. The reaction mixture was evaporated and the residue was subjected to Step B of Example 33 to give 2-propyloxy-6-[2-(5-phosphono)furanyl]pyridine.
    Step D. A mixture of 2-chloro-6-[2-(5-diethylphosphono)furanyl]pyridine (0.01 mmol) and 1-methylpiperazine (0.2 mL) in ethylene glycol (0.2 mL) was heated at 145° C. for 24 h. The mixture was further diluted with 0.5 mL of CH3CN and 0.1 mL of water and then 150 mg of Dowex 1 2-100 formate resin was added. After stirring this mixture 30 min it was filtered and the resin washed with DMF (2×10 mL), CH3CN (2×10 mL) and then 9:1 CH3CN:water (1×10 mL). Finally the resin was stirred with 9:1 TFA:water for 30 min, filtered and the filtrate evaporated. The residue obtained subjected to Step B of example to give 2-[1-(4-methyl)piperazinyl]-6-[2-(5-phosphono)furanyl]pyridine.
    Step E. A mixture of 3-chloro-5-[2-(5-diethylphosphono)furanyl]pyrazine (0.01 mmole), 5-tributylstannylthiophene (0.04 mmole), Pd(PPh3)4 (0.001 mmole) and CuI (0.002 mmole) in dioxane (0.5 mL) was heated at 85° C. for 16 h then the solvent was evaporated. The resulting residue and TMSBr (0.1 mL) in 0.5 mL CH2Cl2 was stirred at rt for 16 h and then evaporated and diluted with 0.5 mL of 9:1 CH3CN:water. To this solution 150 mg of Dowex 1 2-100 formate resin was added and after stirring 30 min it was filtered and the resin washed with DMF (2×10 mL), CH3CN (2×10 mL) and then 9:1 CH3CN:water (1×10 mL). Finally the resin was stirred with 9:1 TFA:water for 30 min, filtered and the filtrate evaporated to give 3-(2-thienyl)-5-[2-(5-phosphono)furanyl]pyrazine.
    Step F. A mixture of 3-chloro-5-[2-(5-diethylphosphono)furanyl]pyrazine (0.01 mmole), 1-hexyne (0.04 mmole), diisopropylethylamine (0.1 mmole), Pd(PPh3)4 (0.001 mmole) and CuI (0.002 mmole) in dioxane (0.5 mL) was heated at 85° C. for 16 h then the solvent was evaporated. The resulting residue was subjected to Step B to give 3-(1-hexyn-1-yl)-5-[2-(5-phosphono)furanyl]pyrazine.
    • Preparation of the Carboxymethylphosphonate Resin
  • Step G. A solution of trimethylphosphonoacetate (30.9 mmol), 2-(trimethylsiyl)ethanol (10.4 mmol) and DMAP (3.1 mmol) in toluene (25 mL) was refluxed for 48 h under N2. After cooling, the solution was diluted with EtOAc and washed with 1N HCl followed by water. The organic solution was dried over sodium sulfate and concentrated under vacuum to give an oil. The residue was treated with LiI (10.4 mmol) in 2-butanone (30 mL), and refluxed overnight under N2. The solution was diluted with EtOAc, washed with 1N HCl, dried over Na2SO4 and concentrated under vacuum to afford the SEM protected carboxy monomethylphosphonate as a colorless oil.
    Step H. Hydroxymethylpolystyrene (2.35 mmol) was prepared for coupling by combining with anhydrous THF (40 mL), gently shaking for 20 min. and then removing the excess solvent by cannula. This procedure was repeated 3 times. The swollen resin was then suspended in THF (40 mL) and DIPEA (21.2 mmol). To this mixture was added, by cannula, a solution of the SEM protected carboxy monomethylphosphonate (prepared in Step G) (7.1 mmol), DIAD (7.1 mmol) and tris(4-chlorophenyl)phosphine (7.1 mmol) in THF (15 mL) which had been stirred for 15 min. prior to addition. After shaking the mixture overnight under a blanket of N2, the resin was filtered, rinsed with THF (3×40 mL), DMF (3×40 mL), and THF again (3×40 mL) before drying under vacuum to afford 3.8 g of the coupled phosphonate resin.
    Step I. To coupled phosphonate resin (2.41 mmol) in THF (100 mL) was added 1 M TBAF in THF solution (12 mL). The mixture was shaken overnight before being filtered and the resin rinsed with THF (3×40 mL) to afford the desired carboxymethylphosphonate resin as the tetrabutylammonium salt.
    • Coupling of the Carboxymethylphosphonate Resin to a Heteroaromatic Amine
  • Step J. In a 2 mL well, a heteroaromatic amine (0.14 mmol), resin (0.014 mmol), PyBOP (0.14 mmol) and TEA (0.36 mmol) in DMF (1.45 mL) were combined and shaken for 48 h at room temperature. The treated resin was then filtered, washed with DMF (3×) and CH2Cl2 (3×). The isolated resin was resuspended in CH2Cl2 (900 μL), combined with TMSBr (100 μL) and mixed for 6 h. The mixture was filtered, the resin washed with anhydrous CH2Cl2 (500 μL) and the filtrate concentrated under vacuum. To the isolated residue was added a solution of CH3CN/H2O (9:1, 300 μL). After shaking for 30 min. the solvents were removed to provide the desired [{N-(phosphono)acetyl]amino} substituted heteroaromatic analogs. Compounds 26.97-26.119 and 26.146-26.164 were synthesized according to these procedures and they are listed in Table 33.1 and Table 33.2.
    • Preparation of the Aminomethylphosphonate Resin
  • Step K. To a solution of dimethyl phthalimidomethylphosphonate (37 mmole) in 2-butanone (150 mL) was added LiI (38.9 mmol). After refluxing overnight under N2, the solution was diluted with EtOAc, washed with 1N HCl, dried over MgSO4 and concentrated under vacuum to afford monomethyl phthalimidomethylphosphonate as a white solid.
    Step L. As described above in Step H, monomethyl phthalimidomethyl-phosphonate was coupled to hydroxymethylpolystyrene to give the resin-coupled phthalimidomethylphosphonate monomethyl ester.
    Step M. To the resin-coupled phthalimidomethylphosphonate monomethyl ester (6.8 mmol) in DMF (7 mL) was added anhydrous hydrazine (3 mL). After shaking at room temperature for 24 h the resin was filtered, rinsed with DMF (3×10 mL), CH2Cl2 (3×10 mL) and then dried under vacuum to afford 832 mg the desired resin-coupled aminomethylphosphonate monomethyl ester.
    • Coupling of Various Heteroaromatic Carboxylic Acids to the Resin-Coupled Aminomethylphosphonate Monomethyl Ester.
  • Step N. In a 2 mL well, a heteroaromatic carboxylic acid (0.2 mmol), resin (0.02 mmol), EDC (0.2 mmol) and HOBT (0.2 mmol) in DMF (0.5 mL) were combined and shaken for 24 h at room temperature. The treated resin was then filtered, washed with DMF (3×) and CH2Cl2 (3×). The isolated resin was resuspended in CH2Cl2 (500 μL), combined with TMSBr (50 μL) and mixed for 6 h. The mixture was filtered, the resin washed with anhydrous CH2Cl2 (500 μL) and the filtrate concentrated under vacuum. To the isolated residue was added a solution of CH3CN/H2O (9:1, 300 μL). After shaking for 30 min the solvents were evaporated to provide the desired (N-phosphonomethyl)carbamoyl substituted heteroaromatic analogs. Compounds 26.120-26.145 were synthesized according to these procedures and they are listed in Table 33.2.
  • The following compounds were prepared according to some or all of the above described procedures. These compounds were characterized by HPLC (as described below) and mass spectroscopy (APCI negative ion), and these characterization data are listed in Table 33.1 and Table 33.2.
  • HPLC was performed using a YMC ODS-Aq, Aq-303-5, 250 4.6 mm ID, S-5 μm, 120 A column with the UV detector set at 280 nm.
  • HPLC Elution Program: 1.5 mL/min flow rate
  • Time (min) % Acetonitrile (A) % Buffereda (B)
    0 10 90
    7.5 90 10
    12.4 90 10
    12.5 10 90
    15 10 90
    aBuffer = 95:5:0.1 water:methanol:acetic acid
  • TABLE 26.1
    Figure US20090192121A1-20090730-C00052
    syn-
    thetic HPLC
    example Rt M-1
    number A B X Y′ (min.) found
    26.146 H Br NHC(O)CH2 S 6.58 299/
    301
    26.147 H Ph NHC(O)CH2 S 6.57 297
    26.148 Ph H NHC(O)CH2 S 6.06 297
    26.149 Ph Et NHC(O)CH2 O 309
    26.150 H H NHC(O)CH2 S 4.22 221
    26.151 adaman- Me NHC(O)CH2 S 6.59 369
    tyl
    26.152 Bu-t Br NHC(O)CH2 S 6.62 355/
    357
    26.153 H Ph(-4-Br) NHC(O)CH2 S 6.62 375/
    377
    Figure US20090192121A1-20090730-C00053
    syn-
    thetic HPLC
    example Rt M-1
    number A* B* X Y′ (min.) found
    26.154 H H NHC(O)CH2 O 6.68 205
    26.155 null NH2 NHC(O)CH2 O 6.6 221
    26.156 NHMe null NHC(O)CH2 S 3.82 251
    26.157 Me H NHC(O)CH2 NH
    26.158 H H NHC(O)CH2 NH
    26.159 OH H NHC(O)CH2 NH
    26.160 Bu-t H NHC(O)CH2 O 6.62 261
    26.161 null 3-pyridyl NHC(O)CH2 O 6.58 283
    26.162 CH2- null NHC(O)CH2 O
    Ph-(2,6-
    dichloro)
    26.163 Br null furan-2,5-diyl NH 4.46 292/
    294
    26.164 Br null furan-2,5-diyl S 5.96 309/
    311
    *when A or B is null, then the corresponding G is N.
  • TABLE 26.2
    Figure US20090192121A1-20090730-C00054
    synthetic HPLC
    example Rt M-1
    number A* B* X D* E* (min.) found
    26.1 NH2 Cl furan-2,5-diyl Me null 11.06 288
    26.2 H OC(O)(Ph- furan-2,5-diyl H H 3.99 413
    2,6-
    dichloro)
    26.3 OMe H furan-2,5-diyl CH2OH H 8.34 284
    26.4 OMe H furan-2,5-diyl C(O)NH2 H 8.23 297
    26.5 OMe H furan-2,5-diyl CO2H H 9.54 298
    26.6 OH H furan-2,5-diyl CF3 C(O)NH2 3.91 351
    26.7 OMe H furan-2,5-diyl CF3 C(O)NH2 9.14 365
    26.8 null H furan-2,5-diyl H OMe 9.72 255
    26.9 null H furan-2,5-diyl H OH 4.52 241
    26.10 OH H furan-2,5-diyl Me null 3.79 255
    26.11 OMe H furan-2,5-diyl Me null 6.44 269
    26.12 NH2 null furan-2,5-diyl OH H 3.96 256
    26.13 NH2 null furan-2,5-diyl OMe H 8.02 270
    26.14 H OMe furan-2,5-diyl null H 7.22 255
    26.15 H OH furan-2,5-diyl null H 4.82 241
    26.16 OMe H furan-2.5-diyl null H 7.48 255
    26.17 OEt H furan-2.5-diyl H H 9.72 268
    26.18 OEt H furan-2,5-diyl CH2OH H 5.26 298
    26.19 null H furan-2,5-diyl Me OEt 7.80 283
    26.20 null H furan-2,5-diyl Me OH 3.80 255
    26.21 OH H furan-2,5-diyl Me null 3.77 255
    26.22 OEt H furan-2,5-diyl Me null 7.33 283
    26.23 NH2 null furan-2,5-diyl OH H 3.94 256
    26.24 NH2 null furan-2,5-diyl OEt H 5.66 284
    26.25 NH2 H furan-2,5-diyl OEt null 5.90 284
    26.26 NH2 H furan-2,5-diyl OH null 3.78 256
    26.27 H OEt furan-2,5-diyl null H 9.74 269
    26.28 H OH furan-2,5-diyl null H 4.81 241
    26.29 OEt H furan-2,5-diyl null H 9.78 269
    26.30 Br H furan-2,5-diyl H NO2 7.78 347/349
    26.31 Cl H furan-2,5 -diyl H C(O)OEt 9.69 330
    26.32 Br H furan-2,5-diyl H C(O)OEt 9.69 374/376
    26.33 Cl H furan-2,5-diyl Me C(O)NH2 3.72 315
    26.34 Cl CF3 furan-2,5-diyl H CF3 9.04 394
    26.35 Cl H furan-2,5-diyl NH2 H 4.89 273
    26.36 Cl H furan-2,5-diyl CN H 7.93 283
    26.37 Cl H furan-2,5-diyl CH2OH H 5.38 288
    26.38 Cl H furan-2,5-diyl C(O)NH2 H 5.57 301
    26.39 Cl H furan-2,5-diyl C(O)OEt H 8.54 330
    26.40 Cl 1- furan-2,5-diyl H H 8.91 398
    triazinyl-
    (3-amino-
    5-methyl-
    thio)
    26.41 Cl H furan-2,5-diyl Me CN 8.22 297
    26.42 Cl H furan-2,5-diyl CF3 NH2 8.60 341
    26.43 Cl H furan-2,5-diyl CF3 CN 8.66 351
    26.44 null CH3 furan-2,5-diyl Me Br 9.25 331/333
    26.45 null CH3 furan-2,5-diyl Me Cl 9.25 287
    26.46 Br CH3 furan-2,5-diyl H null 5.62 317/319
    26.47 Br Br furan-2,5-diyl H null 3.54 381/
    383/
    385
    26.48 Br H furan-2,5-diyl Me null 5.55 317/319
    26.49 H NH2 furan-2,5-diyl Br null 4.78 318/320
    26.50 Br Cl furan-2,5-diyl Br null 8.38 417/419
    26.51 SMe Ph furan-2,5-diyl Br null 9.26 425/427
    26.52 NH2 H furan-2,5-diyl Br null 4.87 318/320
    26.53 NH2 H furan-2,5-diyl OH null 3.70 256
    26.54 Br H furan-2,5-diyl Br null 9.64 381/
    383/385
    26.55 Br H furan-2,5-diyl Cl null 9.64 337/339
    26.56 H Br furan-2,5-diyl null H 5.08 303/305
    26.57 NH2 Cl furan-2,5-diyl null C(O)OMe 3.34 332
    26.58 OPr-n H furan-2,5-diyl Me null 8.14 297
    26.59 H OPr-n furan-2,5-diyl null H 8.45 283
    26.60 H O(CH2)2-OEt furan-2,5-diyl null H 7.82 313
    26.61 NH2 null furan-2,5-diyl OH H 3.97 256
    26.62 NH2 null furan-2,5-diyl OPr-n H 7.84 298
    26.63 OPr-n H furan-2,5-diyl CH2OH H 4.36 312
    26.64 OBu-n H furan-2,5-diyl CH2OH H 8.58 326
    26.65 O—(CH2)2-OEt H furan-2,5-diyl CH2OH H 4.13 342
    26.66 NH2 H furan-2,5-diyl OPr-n null 7.96 298
    26.67 NH2 H furan-2,5-diyl OBu-n null 3.86 312
    26.68 H OBu-i furan-2,5-diyl null H 8.80 297
    26.69 H O(CH2)2-OEt furan-2,5-diyl null H 7.14 299
    26.70 H O(CH2)2—NMe2 furan-2,5-diyl null H 4.57 312
    26.71 NH2 null furan-2,5-diyl OBu-i H 8.06 312
    26.72 NH2 null furan-2,5-diyl O(CH2)2OMe H 4.84 314
    26.73 NH2 H furan-2,5-diyl OBu-i null 8.70 312
    26.74 Br H furan-2,5-diyl C(O)NH2 H 7.68 346/348
    26.75 NH2 null furan-2,5-diyl Cl H 4.77 274
    26.76 NH—(CH2)2—OH H furan-2,5-diyl Me null 4.56 298
    26.77 H NH(CH2)2OH furan-2,5-diyl null H 4.55 284
    26.78 NH2 null furan-2,5-diyl NH—(CH)2OH H 4.58 299
    26.79 NH—(CH2)2—OH H furan-2,5-diyl NH2 null 4.58 299
    26.80 NH—(CH2)2—OH H furan-2,5-diyl CH2OH H 4.44 313
    26.81 NH2 H furan-2,5-diyl NH—(CH2)2OH null 4.33 299
    26.82 NH—CH—CH—(OH)-Me H furan-2,5-diyl CH null 4.65 312
    26.83 NH2 null furan-2,5-diyl NHCH2—CH(OH)-Me H 4.63 313
    26.84 NH—CH2—CH—(OH)-Me H furan-2,5-diyl NH2 null 4.63 313
    26.85 NH—CH2—CH—(OH)-Me H furan-2,5-diyl CH2OH H 4.52 327
    26.86 NH2 H furan-2,5-diyl NHCH2—CH(OH)-Me null 4.65 313
    26.87 NH—(CH2)3—OH H furan-2,5-diyl Me null 4.62 312
    26.88 NH2 null furan-2,5-diy1 NH—(CH2)3OH H 4.48 313
    26.89 NH—(CH2)3—OH H furan-2,5-diyl NH2 null 4.48 313
    26.90 NH2 NH—(CH2)3OH furan-2,5-diyl null C(O)NH—(CH2)3OH 4.76 414
    26.91 H 4- furan-2,5-diyl null H 6.46 310
    morpho-
    linyl
    26.92 4- H furan-2,5-diyl Me null 6.53 324
    morpho-
    linyl
    26.93 NH2 null furan-2,5-diyl 4-morpho- H 6.15 325
    linyl
    26.94 4- H furan-2,5-diyl NH2 null 4.84 325
    morpho-
    linyl
    26.95 NH2 4 -morpho- furan-2,5-diyl null C(O)-(4- 7.47 438
    linyl morpho-
    linyl)
    26.96 NH2 H furan-2,5-diyl 4-morph- null 5.30 325
    olinyl
    26.97 Me H NHC(O)CH2 H H 6.58 229
    26.98 H Me NHC(O)CH2 H H 6.60 229
    26.99 NH2 H NHC(O)CH2 H Cl 6.63 264
    26.100 NH2 Cl NHC(O)CH2 H H 6.63 264
    26.101 H OH NHC(O)CH2 H H 6.54 231
    26.102 Me H NHC(O)CH2 Me H 6.59 243
    26.103 H H NHC(O)CH2 H Cl 7.02 249
    26.104 H H NHC(O)CH2 H Br 8.01 293/295
    26.105 Me H NHC(O)CH2 H Br 6.64 307/309
    26.106 H H NHC(O)CH2 H H 6.72 215
    26.107 H H NHC(O)CH2 H Me 6.54 229
    26.108 H H NHC(O)CH2 Me H 6.53 229
    26.109 Me Cl NHC(O)CH2 Me null 3.93 279
    26.110 Cl H NHC(O)CH2 null H 4.20 251
    26.111 H Br NHC(O)CH2 H Me 6.44 307/309
    26.112 NH2 H NHC(O)CH2 NH-(Ph- null 4.42 401/403
    4-Br)
    26.113 NH2 Bn NHC(O)CH2 H Bn 6.49 410
    26.114 H H NHC(O)CH2 Et H 6.57 243
    26.115 Me Et NHC(O)CH2 H H 6.54 257
    26.116 Me H NHC(O)CH2 H Br 6.55 307/309
    26.117 H Br NHC(O)CH2 H Me 6.51 307/309
    26.118 H Me NHC(O)CH2 H Br 6.52 307/309
    26.119 Me Br NHC(O)CH2 H Br 6.19 385/
    387/
    389
    26.120 H H C(O)NHCH2 H H 3.74 215
    26.121 Me H C(O)NHCH2 H H 229
    26.122 OH H C(O)NHCH2 H H 3.72 231
    26.123 Br H C(O)NHCH2 H H 5.02 293/295
    26.124 Cl H C(O)NHCH2 H H 4.60 249/251
    26.125 H H C(O)NHCH2 Cl H 5.18 249/251
    26.126 H Br C(O)NHCH2 OH H 3.60 310/312
    26.127 H H C(O)NHCH2 null H 3.70 216
    26.128 H H C(O)NHCH2 NO2 H 5.00 260
    26.129 H H C(O)NHCH2 H Bu-n 8.35 271
    26.130 H OPr-n C(O)NHCH2 H H 7.46 273
    26.131 Cl Cl C(O)NHCH2 H H 4.23 283/
    285/
    287
    26.132 Cl CF3 C(O)NHCH2 H H 8.05 317/319
    26.133 H Cl C(O)NHCH2 H CF3 6.49 317/319
    26.134 H Cl C(O)NHCH2 Cl Cl 7.20 318/
    320/
    322
    26.135 H C(O)Ph C(O)NHCH2 H H 7.00 319
    26.136 H OEt C(O)NHCH2 H CF3 6.65 327
    26.137 SMe Cl C(O)NHCH2 H null 5.82 296/298
    26.138 SMe Br C(O)NHCH2 H null 5.40 340/342
    26.139 H O(Ph-3- C(O)NHCH2 null H 376
    CF3)
    26.140 H H C(O)NHCH2 null Me 3.75 230
    26.141 H Me C(O)NHCH2 H H 4.96 229
    26.142 Cl Cl C(O)NHCH2 Cl Cl 9.18 351/
    353/
    355/357
    26.143 H F C(O)NHCH2 OH null 250
    26.144 Me F C(O)NHCH2 OH null 264
    26.145 OH F C(O)NHCH2 OH null 3.93 266
    *When A, B, D or E is null, then the corresponding G′ is N.
    • Section 2 Synthesis of Compounds of Formula X Example 27 Preparation of 2-amino-4-phosphonomethyloxy-6-bromobenzothiazole
  • Step A. A solution of AlCl3 (5 mmole) in EtSH (10 mL) was cooled to 0° C. and treated with 2-amino-4-methoxybenzothiazole (1 mmole). The mixture was stirred at 0-5° C. for 2 h. Evaporation and extraction gave 2-amino-4-hydroxybenzothiazole as white solid.
    Step B. A mixture of 2-amino-4-hydroxybenzothiazole (1 mmole) and NaH (1.3 mmole) in DMF (5 mL) was stirred at 0° C. for 10 min, and then treated with diethylphosphonomethyl trifluoromethylsulfonate (1.2 mmole). After being stirred at room temperature for 8 h. the reaction was subjected to extraction and chromatography to give 2-amino-4-diethylphosphonomethyloxybenzothiazole as an oil.
    Step C. A solution of 2-amino-4-(diethylphosphonomethyloxy)benzothiazole (1 mmole) in AcOH (6 mL) was cooled to 10° C. and treated with bromine (1.5 mmole) in AcOH (2 mL). After 5 min the mixture was stirred at room temperature for 2.5 h. The yellow precipitate was collected via filtration and washed with CH2Cl2 to give 2-amino-4-diethylphosphonomethyloxy-6-bromobenzothiazole.
    Step D. A solution of 2-amino-4-diethylphosphonomethyloxy-6-bromobenzothiazole (1 mmole) in CH2Cl2 (4 mL) was treated with TMSBr (10 mmole) at 0° C. After stirred for 8 h at room temperature the reaction was evaporated to dryness and the residue was taken into water (5 mL). The resulting precipitate was collected via filtration and washed with water to give 2-amino-4-phosphonomethyloxy-6-bromobenzothiazole (27.1) as white solid. mp>220° C. (dec.). Anal. calcd. for C8H8N2O4PSBr: C, 28.34; H, 2.38; N, 8.26. Found: C, 28.32; H, 2.24; N, 8.06,
  • Similarly, the following compounds were prepared according to the above described procedures:
  • (27.2) 2-Amino-4-phosphonomethyloxybenzothiozole. mp>250° C. Anal. calcd. for C8H9N2O4PS+0.4H2O: C, 35.93; H, 3.69; N, 10.48. Found: C, 35.90; H, 3.37; N, 10.37.
    • Example 28 Preparation of 2-amino-4-phosphonomethyloxy-6-bromo-7-chlorobenzothiazole
  • Step A. A solution of 1-(2-methoxy-5-chlorophenyl)-2-thiourea (1 mmole) in chloroform (10 mL) was cooled to 10° C. and treated with bromine (2.2 mmole) in chloroform (10 mL). The reaction was stirred at 10° C. for 20 min and at room temperature for 0.5 h. The resulting suspension was heated at reflux for 0.5 h. The precipitate was collected via filtration (washed with CH2Cl2) to give 2-amino-4-methoxy-7-chlorobenzothiazole which was subjected to Steps A, B, C and D of Example 27 to give 2-amino-4-phosphonomethoxy-6-bromo-7-chloro benzothiazole (28.1). mp>220° C. (dec.). Anal. calcd. for C8H7N2O4PSClBr: C, 25.72; H, 1.89; N, 7.50. Found: C, 25.66; H, 1.67; N, 7.23.
  • Similarly, the following compounds were prepared according to the above described procedures:
  • (28.2) 2-Amino-4-phosphonomethoxy-6-bromo-7-methyl benzothiazole. mp>220° C. (dec.). Anal. calcd. for C9H10N2O4PSBr: C, 30.61; H, 2.85; N, 7.93 Found: 030.25; H, 2.50; N, 7.77.
    (28.3) 2-Amino-4-phosphonomethoxy-7-methylbenzothiazole. mp>220° C. (dec.). Anal: calcd. for C9H11N2O4PS+1.0 H2O: C, 36.99; H, 4.48; N, 9.59. Found: C, 36.73; H, 4.23; N, 9.38.
    (28.4) 2-Amino-4-phosphonomethoxy-7-chlorobenzothiazole. mp>220° C. (dec.). Anal. calcd. for C8H8N2O4PSCl+0.1H2O: C, 32.41; H, 2.79; N, 9.45. Found: C, 32.21; H, 2.74; N, 9.22.
    • Example 29 Preparation of 2-Amino-4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole
  • Step A. 3-Amino-2-hydroxy-5,6,7,8-tetrahydronaphthalene was subjected to Step B of Example 27 to give 3-amino-2-diethylphosphonomethyloxy-5,6,7,8-tetrahydronaphthlene.
    Step B. A solution of KSCN (16 mmole) and CuSO4 (7.7 mmole) in MeOH (10 mL) was treated with a solution of 3-amino-2-diethylphosphonomethyloxy-5,6,7,8-tetrahydronaphthalene (1 mmole) in MeOH (5 mL) at room temperature. The mixture was heated at reflux for 2 h. Filtration, extraction and chromatography provided 2-amino-4-diethylphosphonomethyloxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole as light brown solid.
    Step C. 2-Amino-4-diethylphosphonomethyloxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole was subjected to Step D of Example 27 to give 2-Amino-4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole (29.1). mp>220° C. (dec.). Anal. calcd. for Cl2H15N2O4PS+0.5H2O: C, 45.86; H, 4.81; N, 8.91 Found: C, 44.68; H, 4.77; N, 8.73.
  • The following compounds were also prepared according to above procedures:
  • (29.2) 2-Amino-4-phosphonomethoxy-[1,2-d]naphthothiazole. mp>240° C. (dec.). Anal. calcd. for C12H11N2O4PS+0.2HBr: C, 44.15; H, 3.46; N, 8.58. Found: C, 44.13; H, 3.46; N, 8.59.
    (29.3) 2-Amino-5,7-dimethyl-6-thiocyanato-4-phosphonomethoxybenzothiazole. mp>240° C. (dec.). Anal. calcd. for C11H12N3O4PS2+0.2CH2Cl2: C, 37.13; H, 3.45; N, 11.60. Found: C, 37.03; H, 3.25; N, 11.65.
    (29.4) Starting with 2-hydroxy-5-phenyl aniline and using the same reaction sequence as above gave 2-Amino-7-phenyl-6-thiocyanato-4-phosphonomethoxybenzothiazole. mp.>250° C. (dec.). Anal. calcd. for C11H12N3O4PS2+0.2H2O: C, 45.38; H, 3.15; N, 10.58. Found: C, 45.25; H, 3.21; N, 10.53.
    (29.5) Starting with 2-hydroxy-3,5-dichloro-4-methyl aniline and using the same reaction sequence as above (except the cyclization step was done using B2, AcOH method i.e. Step A of Example 33) gave 2-Amino-5,7-dichloro-6-methyl-4-phosphonomethoxybenzothiazole. mp.>230° C. (dec.). Anal. calcd. for C9H9N2O4PSCl2: C, 31.50; H, 2.64; N, 8.16. Found: C, 31.61; H, 2.66; N, 8.08.
    (29.6) Starting with 2-hydroxy-4-methoxycarbonyl aniline and using the same reaction sequence as above gave 2-Amino-4-phosphonomethoxy-6-carboxybenzothiazole. mp.>230° C. (dec.). Anal. calcd. for C9H9N2O6PS: C, 35.53; H, 2.98; N, 9.21. Found: C, 35.56; H, 3.26; N, 9.03.
    • Example 30 Preparation of 2-Amino-7-methoxy-6-thiocyanato-4-phosphonomethoxy-benzothiazole
  • Step A. 2-Hydroxy-5-methoxynitrobenzene was subjected to Step B of Example 27 to give 2-diethylphosphonomethyloxy-5-methoxynitrobenzene.
    Step B. A solution of SnCl2 (4 mmole) in freshly prepared methonolic HCl (10 mL) was added to a cold (0° C.) solution of 2-diethylphosphonomethyloxy-5-methoxynitrobenzene (1 mmole) in MeOH (5 mL). The mixture was warmed to room temperature and stirred for 3 h. Evaporation, extraction and chromatography provided 2-diethylphosphonomethyloxy-5-methoxyaniline.
    Step C. 2-Diethylphosphonomethyloxy-5-methoxyaniline was subjected to Step B of Example 29 to give 2-amino-4-diethylphosphonomethyloxy-6-thiocyano-7-methoxybenzothiazole, which was subjected to Step D of Example 27 to give 2-amino-7-methoxy-6-thiocyanato-4-phosphonomethoxybenzothiazole (30.1). mp>170° C. (dec.). Anal.calcd. for C10H10N3O5PS2: C, 34.58; H, 2.90; N, 12.10. Found: C, 34.23; H, 2.68; N, 11.77.
  • Similarly, the following compounds were prepared according to above procedures:
  • (30.2) 2-Amino-5,6-difluoro-4-phosphonomethoxybenzothiazole. mp>240° C. (dec.). Anal. calcd. for C8H7N2O4PSF2: C, 32.44; H, 2.38; N, 9.46. Found: C, 32.30; H, 2.26; N, 9.17.
    (30.3) 2-Amino-5-fluoro-7-bromo-4-phosphonomethoxybenzothiazole. mp>190° C. (dec.). Anal. calcd. for C8H7N2O4PSBrF: C, 26.91; H, 1.98; N, 7.84. Found: C, 27.25; H, 1.92; N, 7.54.
    (30.4) 2-Amino-7-ethoxycarbonyl-4-phosphonomethoxybenzothiazole. mp>240° C. (dec.). Anal. calcd. for C11H13N2O6PS+0.2HBr+0.1DMF: C, 38.15; H, 3.94; N, 8.27. Found: C, 38.51; H, 3.57; N, 8.66.
    • Example 31 Preparation of 2-Amino-7-bromo-6-thiocyanato-4-phosphonomethoxy benzothiazole
  • Step A. A solution of 2-fluoro-5-bromonitrobenzene (1 mmole) in DMF (5 mL) was cooled to 0° C., and treated with a solution of freshly prepared sodium salt of diethylhydroxymethylphosphonate (1.2 mmole) in DMF (5 mL). The mixture was stirred at room, temperature for 16 h. Evaporation, extraction and chromatography provided 2-diethylphosphonomethyloxy-5-bromonitrobenzene.
    Step B. 2-Diethylphosphonomethyloxy-5-bromonitrobenzene was subjected to Step B of Example 30, Step B of Example 29, and Step D of Example 27 to give 2-amino-7-bromo-6-thiocyanato-4-phosphonomethoxybenzothiazole (31.1). mp>250° C. (dec.). Anal. calcd. for C9H7N3O4PS2 Br: C, 27.29; H, 1.78; N, 10.61. Found: C, 26.90; H, 1.58; N, 10.54.
  • Similarly, the following compounds were prepared according to above procedures:
  • (31.2) 2-Amino-7-fluoro-6-thiocyanato-4-phosphonoinethoxybenzothiazole. mp>136° C. (dec.). Anal. calcd. for C9H7N3O4 PFS2+0.3HBr: C, 30.07; H, 2.05; N, 11.69. Found: C, 30.27; H, 2.01; N, 11:38.
    (31.3) Starting with 2-fluoro-4-chloro nitrobenzene and using the same reaction sequence as above gave 2-Amino-6-chloro-4-phosphonomethoxybenzothiazole. mp.>250° C. (dec.). Anal. calcd. for C8H8N2O4PSCl: C, 32.61; H, 2.74; N, 9.51. Found: C, 32.27; H, 2.67; N, 9.18.
    (31.4) Starting with 2-fluoro-4,5-dichloro nitrobenzene and using the same reaction sequence as above gave 2-Amino-6,7-dichloro-4-phosphonomethoxybenzothiazole. mp.>250° C. (dec.). Anal. calcd. for C8H7N2O4PSCl2: C, 29.20; H, 2.14; N, 8.51. Found: C, 29.11; H, 2.11; N, 8.36.
    • Example 32 Preparation of 2-Amino-7-hydroxymethyl-6-thiocyano-4-phosphonomethoxy benzothiazole
  • Step A. 2-Chloro-5-formylnitrobenzene was subjected to Step A of Example 31 to give 2-diethylphosphonomethyloxy-5-formylnitrobenzene.
    Step B. A solution of 2-diethylphosphonomethyloxy-5-formylnitrobenzene (1 mmole) in methanol (5 mL) was treated with 10% palladium on carbon (0.05 mmole) under 1 atmosphere of hydrogen at room temperature for 12 h. Filtration followed by evaporation gave 2-diethylphosphonomethyloxy-5-hydroxymethylaniline which was subjected to Step B of Example 29 followed by Step D of Example 27 to give 2-amino-7-hydroxymethyl-6-thiocyanato-4-phosphonomethoxybenzothiazole (32.1). mp 181-184° C. Anal. calcd. for C10H10N3O5PS2+0.35H2O: C, 33.97; 11:3.05; N, 11.88. Found: C, 33.76; 11:2.66; N, 11.61.
  • A similar procedure was used to prepare the following compounds:
  • (32.2) Starting with 2-fluoro-4-methyl nitrobenzene and using the same reaction sequence as above gave 2-Amino-6-methyl-4-phosphonomethoxybenzothiazole. mp.>250° C. (dec.). Anal. calcd. for C9H11N2O4PS+0.2 CH2Cl2: C, 37.94; H, 3.95; N, 9.62. Found: C, 38.16; H, 4.18; N, 9.39.
    (32.3) Starting with 2-chloro-5-cyano nitrobenzene and using the same reaction sequence as above gave 2-Amino-7-cyano-4-phosphonomethoxybenzothiazole. mp.>250° C. (dec.). Anal. calcd. for C9H8N3O4PS+0.9H2O: C, 35.86; H, 3.28; N, 13.94. Found: C, 35.07; H, 2.88; N, 13.58.
    • Example 33 Preparation of 2-Amino-6-bromo-7-fluoro-4-phosphonomethoxybenzothiazole
  • Step A. A solution of 2-diethylphosphonomethyloxy-4-bromo-5-fluoroaniline (1 mmole, prepared as in Example 4, Step B) and KSCN (2 mmole) in AcOH (8 mL) was cooled to 10° C., and treated with a solution of bromine (2 mmole) in AcOH (5 mL). After being stirred at room temperature for 0.5 h, the reaction mixture was evaporated to dryness and the residue was purified by chromatography to provide 2-amino-7-fluorol-6-bromo-4-diethylphosphonomethyloxybenzothiazole which was subjected to Step D of Example 27 to give 2-amino-6-bromo-7-fluoro-4-phosphonomethoxybenzothiazole (33.1). Anal. calcd. for C8H7N2O4PSBrF+0.1HBr: 0:26.31; 11:1.96; N, 7.67. Found: 0:25.96; 11:1.94; N, 7.37.
    • Example 34 Preparation of 2-Amino-7-ethyl-6-thiocyano-4-phosphonomethoxybenzothiazole
  • Step A. A solution of 2-diethylphosphonomethyloxy-5-bromonitrobenzene (1 mmole, prepared as in Example 31, Step A from 2-fluoro-5-bromonitrobenzene) in DMF (5 mL) was treated with tributyl(vinyl)tin (1.2 mmole) and palladium bis(triphenylphosphine) dichloride (0.1 mmole), and the mixture was heated at 60° C. under nitrogen for 6 h. Evaporation and chromatography gave 2-diethylphosphonomethyloxy-5-vinylnitrobenzene as an oil which was subjected to Step B of Example 31, Step B of Example 29, and Step D of Example 27 to give 2-amino-7-ethyl-6-thiocyano-4-phosphonomethoxybenzothiazole (34.1). mp>167° C. (dec.). Anal. calcd. for C11H12N3O4PS2: C, 38.26; H, 3.50; N, 12.17. Found: C, 37.87; H, 3.47; N, 11.93.
  • A similar procedure was used to prepare the following compounds:
  • (34.2) 2-Amino-7-propyl-6-thiocyanato-4-phosphonomethoxybenzothiazole. mp.>250° C. (dec.). Anal. calcd. for C12H14N3O4PS2: C, 40.11; H, 3.93; N, 11.69. Found: C, 39.72; H, 3.82; N, 11.50. Using allyl tributyltin.
    (34.3) 2-Amino-7-(2-furyl)-6-thiocyanato-4-phosphonomethoxybenzothiazole. Anal. calcd. for C14H11N3O5BrPS2+0.6 MeOH: C, 33.79; H, 2.79; N, 8.69. Found: C, 34.10; H, 2.83; N, 8.35. Using 2-furanyl tlibutyltin.
    (34.4) 2-Amino-6-thiocyanato-7-(2-thienyl)-4-phosphonomethoxybenzothiazole. mp.>250° C. (dec.). Anal. calcd. for C13H10N3O4PS3: C, 39.09; H, 2.52; N, 10.52. Found: C, 38.91; H, 2.41; N, 10.34. Using 2-thienyl tributyltin.
    (34.5) 2,5-Difluoro-4-bromo nitrobenzene was treated the same way to give 2-Amino-6-ethyl-7-fluoro-4-phosphonomethoxybenzothiazole. mp.>250° C. (dec.). Anal. calcd. for C10H12N2O4PSF: C, 39.22; H, 3.95; N, 9.15. Found: C, 38.83; H, 3.55; N, 9.02.
    (34.6) 2,5-Difluoro-4-bromo nitrobenzene was treated with 2-thienyl tributyltin in the second step to give 2-Amino-7-fluoro-6-[2-(5-thiocyanato)thienyl]-4-phosphonomethoxybenzothiazole. mp.>250° C. (dec.). Anal. calcd. for C13H9N3O4PS3F+0.6H2O: C, 36.46; H, 2.40; N, 9.81. Found: C, 36.16; H, 2.10; N, 9.68.
    • Example 35 Preparation of 2-Amino-7-cyclopropyl-6-thiocyanato-4-phosphonomethoxy Benzothiazole
  • Step A. A suspension of 2-diethylphosphonomethyloxy-5-vinylnitrobenzene (1 mmole, prepared as in Step A of Example 33) and Pd(OAc)2 (0.1 mmole) in ether (8 mL) was treated with a solution of diazomethane (generated from 3.0 g of 1-methyl-3-nitro-1-nitrosoguanidine) in ether at 0° C. After being stirred at room temperature for 20 h the reaction was evaporated to dryness and the residue was chromatographed to give 2-diethylphosphonomethyloxy-5-cyclopropylnitrobenzene which was subjected to Step B of Example 30, Step B of Example 29, and Step D of Example 27 to give 2-amino-7-cyclopropyl-6-thiocyanato-4-phosphonomethoxybenzothiazole hydrogen bromide (35.1). Anal. calcd. for C12H13N3O4PS2Br+0.1HBr: C, 27.76; H, 2.72; N, 8.09. Found: C, 27.54; H, 3.05; N, 7.83.
    • Example 36 Preparation of 2-Amino-4-phosphonomethoxy-6-chloro-7-methyl Benzothiazole
  • Step A. 2-Methoxy-4-chloro-5-methylaniline was subjected to Steps A and B of Example 27, Step B of Example 29, and Step D of Example 27 to give 2-amino-4-phosphonomethoxy-6-chloro-7-methyl benzothiazole (36.1). mp>250° C. (dec.). Anal. calcd. for C9H10N2O4PS2Cl+0.3H2O+0.4 HBr: C, 31.20; H, 3.20; N, 8.09. Found: C, 31.37; H, 2.87; N, 7.89.
  • Similarly, the following compounds were prepared according to above procedures:
  • (36.2) 2-Amino-7-phenyl-6-thiocyanato-4-phosphonomethoxybenzothiazole. mp>250° C. (dec.). Anal. calcd. for C15H12N3O4PS2+0.2H2O: C, 45.38; H, 3.15; N, 10.58. Found: C, 45.25; H, 3.21; N, 10.53.
    • Example 37 Preparation of 2-bromo-4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole
  • Step A. A solution of 2-amino-4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole (1 mmole) in CH3CN (4 mL) was cooled to 0° C., and treated with CuBr2 (1.2 mmole) followed by isoamylnitrite (1.5 mmole) in a dropwise fashion. The resulting dark mixture was stirred for 3.5 h. Evaporation and chromatography gave 2-bromo-4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole as an oil.
    Step B. 2-Bromo-4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole was subjected to Step D of Example 27 to give 2-bromo-4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole (37.1) as a solid. Mp 220-230° C. Anal. calcd. for C12H13NO4PSBr: C, 38.11; H, 3.46; N, 3.70. Found: C, 37.75; H, 3.26; N, 3.69.
    (37.2) The same procedure was used to react 2-amino-4-diethylphosphonomethoxy-6-chloro-7-methyl benzothiazole with CuCl2 to give 2-Chloro-4-phosphonomethoxy-6-chloro-7-methyl benzothiazole. mp.>250° C. (dec.). Anal. calcd. for C9H8NO4PSCl2+0.7 HBr: C, 28.10; H, 2.28; N, 3.64. Found: C, 28.23; H, 2.20; N, 3.79.
    • Example 38 Preparation of 4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole
  • Step A. A solution of isoamylnitrite (1.5 mmole) in DMF (1 mL) at 65° C. was treated with 2-amino-4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole (1 mmole) in DMF (3 mL). After 30 min, the cooled reaction solution was subjected to evaporation and chromatography to provide 4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole as an oil, which was subjected to Step D of Example 27 to give 4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole (38.1) as a solid. Mp 215-220° C. Anal. calcd. for C12H14NO4PS+1.3HBr: C, 35.63; H, 3.81; N, 3.46. Found: C, 35.53; H, 3.46; N, 3.40.
    (38.2) The same reaction sequence was used to transform 2-amino-4-diethylphosphonomethoxy-6-chloro-7-methyl benzothiazole to 4-Phosphonomethoxy-6-chloro-7-methyl benzothiazole. mp. 195-198° C. Anal. calcd. for C9H9NO4PSCl+0.5H2O: C, 35.71; H, 3.33; N, 4.63. Found: C, 35.49; H, 3.19; N, 4.65.
    • Example 39 Preparation of 2-Amino-4-phosphonomethythio Benzothiazole
  • Step A. 2-Diethylphosphonomethylthioaniline, prepared according to Step B of Example 27, was subjected to Step B of Example 29 to give 2-amino-4-diethylphosphonomethylhio-benzothiazole.
    Step B. 2-Amino-4-diethylphosphonomethylhiobenzothiazole was subjected to Step D of Example 34 to give 2-amino-4-phosphonomethythiobenzothiazole (39.1) as a foam. Anal. calcd. for C8H10N2O3PS2+0.4H2O: C, 35.63; H, 3.81; N, 3.46. Found: C, 35.53; H, 3.46; N, 3.40.
    • Example 40 Preparation of 2-Amino-7-hexyl-6-thiocyano-4-phosphonomethoxy Benzothiazole
  • Step A. A solution of 1 mmole of 2-diethylphosphonomethoxy-5-bromonitrobenzene (prepared as in Example 30, step A) in diethyl amine (5 mL) was treated with 1-hexyne (1.2 mmole), CuI (0.1 mmole) and palladium bis(triphenylphosphine) dichloride (0.1 mmole), and the mixture was heated at 60° C. under nitrogen for 14 h. Evaporation and chromatography gave 2-diethylphosphonomethoxy-5-(1-hexyn) benzene as an oil, which was subjected to Step B of Example 32, Step B of Example 29, and Step D of Example 27 to give 2-amino-7-hexyl-6-thiocyano-4-phosphonomethoxybenzothiazole.
    (40.1) 2-Amino-6-thiocyanato-7-(n-hexyl)-4-phosphonomethoxybenzothiazole. mp.>250° C. (dec.). Anal. calcd. for C15H20N3O4PS2: C, 44.88; H, 5.02; N, 10.47. Found: C, 44.54; H, 4.75; N, 10.37.
  • Similarly, the following compounds were prepared:
  • (40.2) A solution of 1 mmole of 2-diethylphosphonomethoxy-5-bromonitrobenzene (prepared as in Example 30, step A) was subjected to Step C of Example 27, followed a similar sequence as compound 40.1 to give 2-Amino-6-methyl-7-(n-hexyl)-4-phosphonomethoxybenzothiazole. mp.>250° C. (dec.). Anal. calcd. for C15H23N2O4PS+0.25HBr: C, 47.58; H, 6.19; N, 7.40. Found: C, 47.40; H, 6.07; N, 7.54.
    • Example 41 Preparation of 2-Amino-6-methoxy-7-methyl-4-phosphonomethoxybenzothiazole
  • Step A. A solution of 2-chloro-4-floro-5-methylnitrobenzene (1 mmole) in DMF (5 mL) was treated with fresh sodium methoxy (1.1 mmole), and the mixture was stirred for 6 h. Evaporation and chromatography gave 2-chloro-4-methoxy-5-methylnitrobenzene.
    Step B. 2-chloro-4-methoxy-5-methylnitrobenzene was subjected to Step A of Example 31, Step B of Example 32, Step A of Example 33, and Step D of Example 27 to give 2-Amino-6-methoxy-7-methyl-4-phosphonomethoxybenzothiazole 41.1. mp.>250° C. (dec.). Anal. calcd. for C10H13N2O4PS: C, 39.48; H, 4.31; N, 9.21. Found: C, 39.39; H, 4.17; N, 8.98.
  • Similarly, the following compounds were prepared:
  • (41.2) 2-Amino-7-methyl-6-methylthio-4-phosphonomethoxybenzothiazole. mp.>250° C. (dec.). Anal. calcd. for C10H13N2O4PS2+0.45 HBr: C, 33.67; H, 3.80; N, 7.85. Found: C, 33.62; H, 3.86; N, 7.76.
    (41.3) 2-Amino-6-ethoxy-7-methyl-4-phosphonomethoxybenzothiazole. mp.>250° C. (dec.). Anal. calcd. for C11H15N2O5PS: C, 41.51; H, 4.75; N, 8.80. Found: C, 41.80; H, 4.59; N, 8.95.
    (41.4) 2-Amino-6-isobutoxy-7-methyl-4-phosphonomethoxybenzothiazole.
  • mp.>250° C. (dec.). Anal. calcd. for C13H19N2O5PS+0.15 HBr: C, 43.56; H, 5.38; N, 7.81. Found: C, 43.59; H, 5.38; N, 7.86.
    • Example 42 Preparation of 2-Amino-6-ethyl-4-phosphonomethoxybenzothiazole
  • Step A. To a solution of 1 mmol of 3-bromo chlorobenzene in 2 mL of con. H2SO4 was added 1.5 mmol of 79% HNO3 at −10° C. After it was stirred for 30 min. the mixture was poured onto ice/water mixture. The yellow precipitate was filtered and dried to give a mixture of 2-chloro-4-bromo nitrobenzene (desired) and 4-chloro-2-bromo nitrobenzene.
    Step B. 2-Chloro-4-bromo nitrobenzene was subjected to Step A of Example 34, Step B of Example 32, Step B of Example 29, and Step D of Example 27 to give 2-Amino-6-ethyl-4-phosphonomethoxybenzothiazole (42.1) mp.>220° C. (dec.). Anal. calcd. for C10H13N2O4PS+0.3 HBr: C, 38.43; H, 4.29; N, 8.96. Found: C, 38.35; H, 4.44; N, 8.75.
  • Similarly, the following compound was prepared:
  • (42.2) 2-Amino-6-propyl-4-phosphonomethoxybenzothiazole. mp.>220° C. (dec.). Anal. calcd. for C11H15N2O4PS+0.2 HBr: C, 41.49; H, 4.81; N, 8.80. Found: C, 41.85; H, 4.12; N, 8.31.
    • Example 43 Preparation of 2-Amino-6-thio-7-ethyl-4-phosphonomethoxybenzothiazole
  • Step A. A solution of 1 mmol of 2-Amino-6-thio-7-ethyl-4-diethylphosphonomethoxybenzothiazole (for preparation see Example 34) in 3 mL of 48% HBr in AcOH was heated at 90° C. for 16 h. Solvent was removed and the residue was washed with water to give 2-Amino-6-thio-7-ethyl-4-phosphonomethoxybenzothiazole (43.1). mp.>220° C. (dec.). Anal. calcd. for C10H13N2O4PS2+0.2 HBr: C, 35.69; H, 3.95; N, 8.33. Found: C, 35.49; H, 3.74; N, 8.33.
    • Example 44 Preparation of 2-Amino-7-propyloxy-6-thiocyano-4-phosphonomethoxybenzothiazole
  • Step A. To a solution of 1 mmol of 2-chloro-5-hydroxy nitrobenzene in 5 mL of DMF was added 1.2 mmol of NaH at 0° C. After 30 min, allyl bromide was added and the mixture was stirred at rt for 16 h. Solvent was removed and the residue was washed with water and extracted with EtOAc to give 2-chloro-5-propenyloxy nitrobenzene.
    Step B. 2-Chloro-5-propenyloxy nitrobenzene was subjected to Step A of Example 31, Step B of Example 32, Step A of Example 33, and Step D of Example 27 to give 2-Amino-7-propyloxy-6-thiocyano-4-phosphonomethoxy benzothiazole. (44.1). mp.>220° C. (dec.). Anal. calcd. for C12H14N3O5PS2+0.15 HBr+0.08H2O: C, 37.06; H, 3.71; N, 10.8. Found: C, 37.46; H, 3.48; N, 10.38.
    • Example 45 Preparation of 2-Amino-6-methoxy-4-phosphonomethoxybenzothiazole
  • Step A. 2-Hydroxy-4-methoxy nitrobenzene was subjected to Step B of Example 32, Step B of Example 27, Step B of Example 29, Step D of Example 27 to give 2-Amino-6-methoxy-4-phosphonomethoxybenzothiazole (45.1) mp.>230° C. (dec.). Anal. calcd. for C9H11N2O5PS+0.5H2O: C, 36.12; H, 4.04; N, 9.36. Found: C, 36.18; H, 3.81; N, 9.47.
    • Example 46 2-Amino-7-ethyl-6-methyl-4-phosphonomethoxybenzothiazole
  • Step A. 2-Fluoro-4-methyl nitrobenzene was subjected to Step A of Example 31, Step C of Example 27, Step A of Example 34, Step B of Example 32, Step B of Example 29, Step D of Example 27 to give (46.1) 2-Amino-7-ethyl-6-methyl-4-phosphonomethoxybenzothiazole. mp.>250° C. (dec.). Anal. calcd, for C11H15N2O4PS+0.1 HBr: C, 42.57; H, 4.90; N, 9.03. Found: C, 42.32; H, 4.71; N, 8.87.
    • Example 47 2-Amino-7-bromo-6-methyl-4-phosphonomethoxybenzothiazole
  • Step A. 2-Fluoro-4-methyl nitrobenzene was subjected to Step A of Example 31, Step C of Example 27, Step B of Example 30, Step A of Example 33, Step D of Example 27 to give 2-Amino-7-bromo-6-methyl-4-phosphonomethoxybenzothiazole. (47.1) mp.>250° C. (dec.). Anal. calcd. for C9H10N2O4PSBr+0.3HBr: C, 28.64; H, 2.75; N, 7.42. Found: C, 28.62; H, 2.60; N, 7.42.
    • Example 48 2-Amino-7-fluoro-6-methyl-4-phosphonomethoxybenzothiazole
  • Step A. 2-Hydroxy-4-methyl-5-fluoro nitrobenzene was subjected to Step B of Example 27, Step B of Example 32, Step A of Example 33, Step D of Example 27 to give
    (48.1) 2-Amino-7-fluoro-6-methyl-4-phosphonomethoxybenzothiazole. mp.>250° C. (dec.). Anal. calcd. for C9H10N2O4PSF+0.1 HBr: C, 35.99; H, 3.39; N, 9.33. Found: C, 35.84; H, 3.32; N, 9.31.
    (48.2) Starting with 2-hydroxy-5-chloro-4-methyl aniline and using the same reaction sequence as above (except the reduction of NO2 step was done using SnCl2 method i.e. Step B of Example 30) gave 2-Amino-7-chloro-6-methyl-4-phosphonomethoxybenzothiazole. (48.2) mp.>250° C. (dec.). Anal. calcd. for C9H10N2O4PSCl+0.6H2O: C, 34.62; H, 3.36; N, 8.97. Found: C, 34.48; H, 3.40; N, 8.72.
    • Example 49 2-Amino-6-bromo-7-methoxy-4-phosphonomethoxybenzothiazole
  • Step A. 2-Amino-4,7-dimethoxy benzothiazole [prepared from 1-(2,5-dimethoxyphenyl)-2-thiourea using the procedure Step A of Example 28] was subjected to Step C to give 2-Amino-4,7-dimethoxy-6-bromo benzothiazole.
    Step B. To a solution of 1 mmol of 2-Amino-4,7-dimethoxy-6-bromo benzothiazole in CH2Cl2 was added 2.2 mmol of BBr3 in CH2Cl2 at 0° C. for 16 h. Aqueous work-up and chromatography gave 2-amino-4-hydroxy-6-bromo-7-methoxy benzothiazole.
    Step C. 2-amino-4-hydroxy-6-bromo-7-methoxy benzothiazole was subjected to Step B of Example 27, Step D of Example 27 to give (49.1) 2-Amino-6-bromo-7-methoxy-4-phosphonomethoxybenzothiazole. mp.>250° C. (dec.). Anal. calcd. for C9H10N2O5PSBr: C, 29.28; H, 2.73; N, 7.59. Found: C, 28.90; H, 3.05; N, 7.20.
    • Example 50 General Procedure for Bis-Phosphoroamide Prodrugs Dichloridate Formation
  • To a suspension of 1 mmol of phosphonic acid in 5 mL of dichloroethane was added 0.1 mmol of pyridine (or 0.1 mmol of DMF) followed by 6 mmol of thionyl chloride and was heated to reflux for 2.5 h. Solvent and excess thionyl chloride were removed under reduced pressure and dried to give the dichloridate.
    • Coupling Reaction:
  • Method A: The crude dichloridate was taken into 5 mL of dry CH2Cl2, and was added 8 mmol of amino acid ester at 0° C. The resultant mixture was allowed to come to rt where it was stirred for 16 h. The reaction mixture was subjected to aq. work up and chromatography.
  • Method B: The crude dichloridate was taken into 5 mL of dry CH2Cl2, and was added a mixture of 4 mmol of amino acid ester and 4 mmol of N-methylimidazole at 0: ° C. The resultant mixture was allowed to come to rt where it was stirred for 16 h. The reaction mixture was subjected to aq. work up and chromatography.
  • The following compounds were prepared in this manner.
  • (50.1) 2-Amino-5-isobutyl-4-[2-(5-N,N-bis(L-glutamic acid diethylester) phosphonoamido)furanyl]thiazole. Anal. calcd. for C29H45N4O10PS: C, 51:78; H, 6.74; N, 8.33. Found: C, 51.70; H, 6.64; N, 8.15.
    (50.2) 2-Amino-5-isobutyl-4-[2-(5-N,N-bis(L-alanine acid dibenzyl ester)phosphonoamido)furanyl]thiazole. Anal. calcd. for C31H37N4O6PS: C, 59.60; H, 5.97; N, 8.97. Found: C, 59.27; H, 5.63; N, 8.74.
    (50.3) 2-Amino-5-isobutyl-4-{2-[5-(N,N-bis(benzyloxycarbonylmethyl)phosphonodiamido]furanyl}thiazole. Anal. calcd. for C19H25N4O6PS+0.3 CH2Cl2: C, 46.93; H, 5.22; N, 11.34. Found: C, 46.92; H, 5.00; N, 11.22.
    (50.4) 2-Amino-5-isobutyl-4-{2-[5-(N,N-bis(benzyloxycarbonylmethyl)phosphonodiamido]furanyl}thiazole. Anal. calcd. for C29H33N4O6PS: C, 58.38; H, 5.57; N, 9.39. Found: C, 58.20; H, 5.26; N, 9.25.
    (50.5) 2-Amino-5-isobutyl-4-{2-[5-(N,N′-bis((R)-1-methoxycarbonyl)ethyl)phosphonamido]furanyl}thiazole. Anal. calcd. for C19H29N4O6PS+0.6 CH2Cl2: C, 44.97; H, 5.82; N, 10.70. Found: C, 44.79; H, 5.46; N, 10.48.
    (50.6) 2-Amino-5-isobutyl-4-{2-[5-(N,N′-bis((S)-1-ethoxycarbonyl)ethyl)phosphonamido]furanyl}thiazole. mp. 164-165° C.: Anal. calcd. for C21H33N4O6PS+0.61 CH2Cl2: C, 46.99; H, 6.24; N, 10.14. Found: C, 47.35; H, 5.85; N, 9.85.
    (50.7) 2-Amino-5-isobutyl-4-{2-[5-(N,N′-bis((t-butoxycarbonyl)methyl)phosphonamido]furanyl}thiazole. Anal. calcd. for C23H37N4O6PS+0.15 CH2Cl2: C, 51.36; H, 6.94; N, 10.35. Found: C, 51.34; H, 6.96; N, 10.06.
    (50.8) 2-Amino-5-isobutyl-4-{2-[5-(N,N′-bis(ethoxycarbonyl)methyl)phosphonamido)]furanyl}thiazole. Anal. calcd. for C19H29N4O6PS+0.1 EtOAc+0.47 CH2Cl2: C, 45.79; H, 5.94; N, 10.75. Found: C, 46.00; H, 5.96; N, 10.46.
    (50.9) 2-Amino-5-isobutyl-4-{2-[5-(O-(2-bis(N-(1-methyl-1-ethoxycarbonyl)ethyl)phosphonamido]furanyl}thiazole. mp. 142-145° C.: Anal. calcd. for C23H37N4O6PS: C, 52.26; 7.06; 10.60. Found: C, 52.21; 6.93; 10.62.
    (50.10) 2-Amino-5-isobutyl-4-{2-[5-(N,N′-bis(ethoxycarbonylmethyl)-N,N′-dimethylphosphonamido)]furanyl}thiazole. Anal. calcd. for C21H33N4O6PS: C, 50.39; H, 6.65; N, 11.19. Found: C, 50.57; H, 6.56; N, 11.06.
    (50.11) 2-Amino-5-isobutyl-4-{2-[5-(N,N′-bis((S)-1-benzyloxycarbonyl-2-methyl)propyl)phosphonamido]furanyl}thiazole. Anal. calcd. for C35H45N4O6PS+0.5H2O: C, 60.94; H, 6.72; N, 8.12. Found: C, 61.01: H, 6.48; N, 7.82.
    (50.12) 2-Amino-5-isobutyl-4-{2-[5-(N,N′-bis((S)-1-methoxycarbonyl-3-methyl)butyl)phosphonamido]furanyl}thiazole. Anal. calcd. for C25H41N4O6PS: C, 53.94; H, 7.42; N, 10.06. Found: C, 54.12; H, 7.62; N, 9.82.
    (50.13) 2-Amino-5-isobutyl-4-{2-[5-(N,N′-bis((R)-1-ethoxycarbonyl-2-(S-benzyl))ethyl)phosphonamido]furanyl)thiazole. Anal. calcd. for C35H45N4O6PS3+0.4 toluene: C, 58.07; H, 6.21; N, 7.17. Found: C, 57.87; H, 6.14; N, 6.81.
    (50.14) 2-Amino-5-isobutyl-4-{2-[5-(N,N′-bis((S)-1-ethoxycarbonyl-3-(S-methyl))butyl)phosphonamido]furanyl}thiazole. Anal. calcd. for C23H37N4O6PS3: C, 46.61; H, 6.92; N, 9.45. Found: C, 46.26; H, 6.55; N, 9.06.
    (50.15) 2-Amino-5-propylthio-4-{2-[5-(N,N′-(1-(S)ethoxycarbonyl)ethyl)phosphonamido]furanyl}thiazole. Anal. calcd. for C20H31N4O6PS2: C, 46.32; H, 6.03; N, 10.80. Found: C, 46.52; H, 6.18; H, 10.44.
    (50.16) 2-Amino-5-isobutyl-4-{2-[5-(N,N′-bis((S)-1-benzyloxycarbonyl-2-methyl)isobutyl)phosphonamido]furanyl}thiazole. Anal. calcd. for C37H49N4O6PS: C, 62.69; H, 6.97; H, 7.90. Found: C, 62.85; h 7.06, 7.81.
    (50.17) 2-Amino-5-isobutyl-4-{2-[5-(N,N′-bis((S)-1-ethoxycarbonyl-3-methyl)butyl)phosphonamido]furanyl}thiazole. Anal. calcd. for C27H45N4O6PS: C, 55.46; H, 7.76; N, 9.58. Found: C, 55.35; H, 7.94; N, 9.41.
    (50.18) 2-Amino-5-isobutyl-4-{2-[5-(N N′-bis((S)-1-ethoxycarbonyl-2-methyl)propyl)phosphonamido]furanyl}thiazole. Anal. calcd. for C25H41N4O6PS: C, 53.94; H, 7.42; N, 10.06. Found: C, 54.01; H, 7.58; N, 9.94.
    (50.19) 2-Amino-5-isobutyl-4-{2-[5-(N,N′-bis((S)-1-ethoxycarbonyl-2-phenyl)ethyl)phosphonamido]furanyl}thiazole. Anal. calcd. for C33H41N4O6PS+0.15 CH2Cl2: C, 59.83; H, 6.26; H, 8.42. Found: C, 59.88; H, 6.28; H, 8.32.
    (50.20) 2-Amino-5-propylthio-4-{2-[5-(N,N′-(1-methyl-ethoxycarbonyl)ethyl)phosphonamido]furanyl}thiazole. mp. 110-115° C.: Anal. calcd. for C22H35N4O6PS2+0.4HCl+0.5Et2O: C, 48.18; H, 6.81; N, 9.36. Found: C, 48.38; H, 6.60; H, 8.98.
    (50.21) 2-Amino-5-methylthio-4-{2-[5-(N,N′-bis(1-methyl-1-ethoxycarbonyl)ethyl)phosphonamido]furanyl}thiazole. Anal. calcd. for C20H31N4O6PS2+0.5H2O: C, 45.53; H, 6.11; N, 10.62. Found: C, 45.28; H, 5.85: N, 10.56.
    • Example 51 General Procedure for Mixed Bis-Phosphoroamidate Prodrugs
  • To a solution of crude dichloridate (1 mmol, prepared as described in Example 50) in 5 mL of dry CH2Cl2 was added amine (1 mmol) followed by 4-dimethylaminopyridine (3 mmol) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was cooled back to 0° C. before adding amino acid ester (2 mmol) and left at room temperature for 16 h. The reaction mixture was subjected to aq. work up and the mixed bis-phosphoroamidate prodrug was purified by column chromatography.
  • The following compounds were prepared in this manner.
  • (51.1) 2-Amino-5-isobutyl-4-{2-[5-(N-morpholino-N′-(1-methyl-1-ethoxycarbonyl)ethyl)phosphonamido]furanyl}thiazole. mp. 182-183° C.: Anal. calcd. for C21H33N4O5PS: C, 52.05; H, 6.86; N, 11.56. Found: C, 51.66; H, 6.68; N, 11.31.
    (51.2) 2-Amino-5-isobutyl-4-{2-[5-(N-pyrrolidino-N′-(1-methyl-1-ethoxycarbonyl)ethyl)phosphonamido]furanyl}thiazole. mp. 189-190° C.: Anal. calcd. for C21H33N4O4PS: C, 53.83; H, 7.10; N, 11.96. Found: C, 54.15; H, 7.48; N, 12.04.
    • Example 52 Bis-phosphoroamide Prodrug Synthesis using Mukaiyama's Method with Some Modifications
  • J. Am. Chem. Soc. 1972, 94, 8528.
  • To a suspension of 1.0 mmol. phosphonic acid and 2.0 mmol of amino acid ester salt (for example alanine ethyl ester HCl salt) in 9 mL of pyridine, Et3N and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidione (DMPU) (1:1:1) was added a premixed solution of 4 mmol of aldrithiol and 4 mmol of PPh3 in 3 mL of pyridine. After 16 h at 90° C., the solvents pyridine and Et3N were removed under reduced pressure. The remaining solution upon dilution with hexane (100 mL) the crude product was oiled out and was subjected to chromatography purification.
  • The following compounds were prepared using this method.
  • (52.1) 2-Amino-4-[(N,N′-(1-(S)-ethoxycarbonyl)ethyl)phosphonodiamidomethoxy]-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole. Mp. 153-156° C.: Anal. calcd. for C22H33N4O6PS: C, 51.55; H, 6.49; N, 10.93. Found: C, 51.39; H, 6.24; N, 10.96.
    (52.2) 2-Amino-5-isopropyl-4-[(N,N′-(1-(S)-ethoxycarbonyl)ethyl)phosphonodiamidomethoxycarbonyl]-thiazole. Anal. calcd. for C18H31N4O7PS: C, 45.18; H, 6.53; N, 11.71. Found: C, 45.33; H, 6.56; N, 11.46.
    (52.3) 4-Amino-7-ethyl-5-fluoro-1-isobutyl-2-[5-({N,N′-(1-(S) ethoxycarbonyl)ethyl}phosphonodiamido) furanyl]benzimidazole. Anal. calcd. for C27H39N5O6 PF: C, 55.95; H, 6.78; N, 12.08. Found: C, 55.73; H, 6.65; N, 11.72.
    (52.4) 2-Amino-5-ethoxycarbonyl-4-[2-(5-({N,N′-(1-(S)ethoxycarbonyl)ethyl}phosphono)furanyl]thiazole. Anal. calcd. for C20H29N4O8PS+0.3 CH2Cl2: C, 44.99; H, 5.50; N, 10.34. Found: C, 44.68; H, 5.30; N, 10.37.
    (52.5) 2-Amino-4-[(N,N′-(1-(S)-ethoxycarbonyl)methyl)phosphonodiamidomethoxy]-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole. Mp. 177-178° C.: Anal. calcd. for C20H29N4O6PS: C, 49.58; H, 6.03; N, 11.56. Found: C, 49.20; H, 5.95; N, 11.51.
    (52.6) 2-Amino-5-isopropyl-4-[(N,N′-(1-(S)-ethoxycarbonyl)methyl)phosphonodiamidomethoxycarbonyl]-thiazole. Mp. 122-125° C.: Anal. calcd. for C16H27N4O7PS: C, 42.66; H, 6.04; N, 12.44. Found: C, 42.60; H, 6.08; N, 12.43.
    (52.7) 2-Amino-4-{N,N′-(1-(S)-ethoxycarbonyl)ethyl}phosphonomethoxy-6-bromo-7-chloro-benzothiazole. Mp. 210-212° C.: Anal. calcd. for C18H25N4O6PSBrCl: C, 37.81; H, 4.41; N, 9.80. Found: C, 37.88; H, 4.35; N, 9.84.
    (52.8) 2-Amino-5-propylthio-4-{2-[5-(N,N′-bis(S)-1-methoxycarbonyl-2-(t-butoxy)ethyl)phosphonamido]furanyl}thiazole. Anal. calcd. for C26H43N4O8PS2: C, 49.20; H, 6.83; N, 8.83. Found: C, 49.38; H, 6.68; N, 8.65.
    (52.9) 2-Amino-5-propylthio-4-{2-[5-(N,N′-bis(S)-1-ethoxycarbonyl-2-methylbutyl)phosphonamido]furanyl}thiazole. Anal. calcd. for C26H43N4O6PS2: C, 51.81; H, 7.19; N, 9.30. Found: C, 52.03; H, 6.78; N, 9.04.
    (52.10) 2-Amino-5-propylthio-4-[2-{5-(N,N′-bis(S)-1-ethoxycarbonyl-2-methylpropyl)phosphonamido]furanyl}thiazole. Anal. calcd for C24H39N4O6PS2: C, 50.16; H, 6.84; N, 9.75. Found: C, 50.01; H, 6.76; N, 9.66.
    (52.11) 2-Amino-5-propylthio-4-[2-{5-(N,N′-bis(S)-1-methoxycarbonyl-2-(t-butoxy)propyl)phosphonamido}furanyl]thiazole. Anal. calcd. for C28H47N4O8PS2: C, 50.74; H, 7.15; N, 8.45. Found: C, 51.08; H, 7.33; N, 8.25.
    (52.12) 2-Amino-propylthio-4-[2-{5-(N,N′-bis(1-ethoxycarbonyl)cyclopentyl)phosphonamido}furanyl]thiazole. Anal. calcd. for C26H39N4O6PS2: C, 52.16; H, 6.57; N, 9.36. Found: C, 52.55; H, 6.53; N, 9.31.
    (52.13) 2-Amino-5-propylthio-4-[2-{5-(N,N′-bis(S)-1-ethoxycarbonyl)propylphosphonamido}furanyl]thiazole. Anal. calcd. for C22H35N4O6PS2: C, 48.34; H, 6.45; N, 10.25. Found: C, 48.65; H, 6.29; N, 10.23.
    (52.14) 2-Amino-4-{N,N′-(1-(S)-ethoxycarbonyl)ethyl}phosphonomethoxy-6-chloro-7-methyl-benzothiazole. Mp. 178-180° C.: Anal. calcd. for C19H28N4O6PSCl: C, 45.02; H, 5.57; N, 11.05. Found: C, 45.12; H, 5.49; N, 10.92.
    (52.15) 2-Amino-5-methylthio-4-{2-[5-(N,N′-bis((S)-1-ethoxycarbonyl)ethyl)phosphonamido]furanyl}thiazole. Mp. 94-95° C.: Anal. calcd. for C18H27N4O6PS2: C, 44.07; H, 5.55; N, 11.42. Found: C, 44.42; H, 5.44; N, 11.29.
    (52.16) 2-Amino-propylthio-4-[2-{5-(N,N′-bis((S)1-ethoxycarbonyl)butyl)phosphonamido)}furanyl]thiazole.: Anal. calcd. for C24H39N4O6PS2: C, 50.16; H, 6.84; N, 9.75. Found: C, 49.96; H, 6.91; N, 9.68.
    (52.17) 2-Amino-propylthio-4-[2-{5-(N,N′-bis((S) 1-ethoxycarbonyl)cyclohexanylmethyl)phosphonamido)}furanyl]thiazole. Anal. calcd. for C30H47N4O6PS2: C, 55.03; H, 7.23; N, 8.56. Found: C, 54.89; H, 7.14; N, 8.42.
    (52.18) 2-Amino-4-{N,N′-(1-(S)-ethoxycarbonyl)ethyl}phosphonomethoxy-6-methoxy-benzothiazole. Mp. 144-146° C.: Anal. calcd. for C19H29N4O7PS: C, 46.72; H, 5.98; N, 11.47. Found: C, 46.76; H, 5.72; N, 11.33.
    (52.19) 2-Amino-4-{N,N′-(ethoxycarbonyl)methyl}phosphonomethoxy-6-methoxy-benzothiazole. Mp. 150-152° C.: Anal. calcd. for C17H25N4O7PS: C, 44.35; H, 5.47: N, 12.17. Found: C, 44.74; H, 5.45; N, 11.99.
    (52.20) 2-Amino-7-ethyl-4-{N,N′-(1-(S)-ethoxycarbonyl)ethyl}phosphonomethoxy-6-methyl-benzothiazole. Anal. calcd. for C21H33N4O6PS: C, 50.39; H, 6.65; N, 11.19. Found: C, 50.22; H, 6.34; N, 11.30.
    (52.21) 2-Amino-4-{N,N′-(1-(S)-ethoxycarbonyl)ethyl}phosphonomethoxy-6-methyl-benzothiazole. Anal. calcd. for C19H29N4O6PS: C, 48.30; H, 6.19; N, 11.86. Found: C, 48.67; H, 5.90; N, 11.86.
    (52.22) 2-Amino-4-{N,N′-(1-methyl-1-ethoxycarbonyl)ethyl}phosphonomethoxy-6-chloro-7-methyl-benzothiazole. Mp. 170-172° C.: Anal. calcd. for C21H32N4O6PSCl: C, 47.15; H, 6.03; N, 10.47. Found: C, 47.22; H, 5.87; N, 10.08.
    (52.23) 2-Amino-7-ethyl-4-{N,N′-bis(ethoxycarbonylmethyl)}phosphonomethoxy-6-methyl-benzothiazole. Anal. calcd. for C19H29N4O6PS: C, 48.30; H, 6.19; N, 11.86. Found: C, 47.98; H, 6.36; N, 11.88.
    (52.24) 2-Amino-4-{N,N′-bis(ethoxycarbonylmethyl)}phosphonomethoxy-6-methyl-benzothiazole. Anal. calcd. for C17H25N4O6PS+0.5H2O: C, 45.03; H, 5.78; N, 12.36. Found: C, 44.80; H, 6.10; N, 12.40.
    (52.25) 2-Amino-5-propylthio-4-[2-{5-(N,N′-bis((S)1-t-butoxycarbonyl)ethyl)phosphonamido)}furanyl]thiazole. Anal. calcd. for C24H39N4O6PS2: C, 50.16; H, 6.84; N, 9.75. Found: C, 50.26; H, 6.71; N, 9.51.
    (52.26) 2-Amino-5-propylthio-4-[2-{5-(N,N′-bis((S)1-n-butoxycarbonyl)ethyl)phosphonamido)}furanyl]thiazole. Anal. calcd. for C24H39N4O6PS2: C, 50.16; H, 6.84; N, 9.75. Found: C, 50.38; H, 6.64; N, 9.64.
    (52.27) 2-Amino-5-ethoxycarbonyl-4-[2-(5-({N,N′-(1-(S)-ethoxycarbonyl)propyl}phosphono)furanyl]thiazole. Anal. calcd. for C22H33N4O8PS: C, 48.52; H, 6.11; N, 10.29. Found: C, 48.62; H, 6.02; N, 10.26.
    (52.28) 2-Amino-5-ethoxycarbonyl-4-[2-(5-({N,N′-(1-(S)-ethoxycarbonyl)butyl}phosphono)furanyl]thiazole. Anal. calcd. for C24H37N4O8PS: C, 50.34; H, 6.51; N, 9.78. Found: C, 50.34; H, 6.57; N, 9.65.
    (52.29) 2-Amino-5-ethoxycarbonyl-4-[2-(5-({N,N′-(1-ethoxycarbonyl)cyclopentyl}phosphono)furanyl]thiazole. Anal. calcd. for C26H37N4O8PS: C, 52.34; H, 6.25; N, 9.39. Found: C, 52.02; H, 6.20; N, 9.34.
    (52.30) 2-Amino-5-ethoxycarbonyl-4-[2-{5-(N,N′-bis(S)-1-ethoxycarbonyl-2-methylpropyl)phosphonamido}furanyl]thiazole. Anal. calcd. for C24H37N4O8PS: C, 50.34; H, 6.51; N, 9.78. Found: C, 50.56; H, 6.40; N, 9.65.
    (52.31) 2-Amino-5-propylthio-4-[2-{5-(N,N′-bis-coumarin)phosphonamido}furanyl]thiazole. Anal. calcd. for C28H23N4O6PS2: C, 55.44; H, 3.82; N, 9.24. Found: C, 55.52; H, 3.66; N, 9.01.
    (52.32) 2-Amino-5-propylthio-4-[2-{5-(N,N′-bis((S)1-iso-propoxycarbonyl)ethyl)phosphonamido)}furanyl]thiazole. Anal. calcd. For C22H35N4O6PS2: C, 48.34; H, 6.45; N, 10.25. Found: C, 48.03; H, 6.45; N, 10.09.
    (52.33) 2-Amino-5-propylthio-4-[2-{5-(N,N′-bis((S)1-n-propoxycarbonyl)ethyl)phosphonamido)}furanyl]thiazole. Anal. calcd. for C22H35N4O6PS2: C, 48.34; H, 6.45; N, 10.25. Found: C, 48.39; H, 6.27; N, 10.20.
    (52.34) 2-Amino-5-propylthio-4-[2-{5-(N,N′-bis((S)1-cycloheptoxycarbonyl)ethyl)phosphonamido)}furanyl]thiazole. Anal. calcd. for C26H39N4O6PS2: C, 52.16; H, 6.57; N, 9.36. Found: C, 52.07; H, 6.51; N, 9.10.
    (52.35) 2-Amino-6-ethyl-7-fluoro-4-{N,N′-(1-(S)-ethoxycarbonyl)ethyl}phosphonomethoxy-benzothiazole. Anal. calcd. for C20H30N4O6PSF: C, 47.61; H, 5.99; N, 11.10. Found: C, 47.59; H, 5.79; N, 10.90.
    (52.36) 2-Amino-6-ethyl-7-fluoro-4-{N,N′-(1-ethoxycarbonyl)methyl}phosphonomethoxy-benzothiazole. Anal. calcd. for C18H26N4O6PSF: C, 45.38; H, 5.50; N, 11.76. Found: C, 45.07; H, 5.25; N, 11.49.
    (52.37) 2-Amino-7-bromo-4-{N,N′-(1-(S)-ethoxycarbonyl)ethyl}phosphonomethoxy-6-methylbenzothiazole. Anal. calcd. for C19H28N4O6PSBr: C, 41.39; H, 5.12; N, 10.16. Found: C, 41.40; H, 5.05; N, 9.94.
    (52.38) 2-Amino-4-{N,N′-(1-ethoxycarbonyl)methylethyl}phosphonomethoxy-6-methylbenzothiazole. Anal. calcd. for C21H33N4O6PS+0.5H2O: C, 49.50; H, 6.73; N, 11.00. Found: C, 49.18; H, 6.61; N, 11.39.
    (52.39) 2-Amino-5-isobutyl-4-[2-{5-(N,N′-bis((S)-1-(1-ethoxycarbonyl)propyl)phosphonamido)}furanyl]thiazole. Anal. calcd. for C23H37N4O6PS: C, 52.26; H, 7.06; N, 10.60. Found: C, 52.47; H, 7.29; N, 10.77.
    (52.40) 2-Amino-5-propylthio-4-[2-{5-(N,N′-bis((S)-1-cyclohexylmethoxycarbonyl)ethyl)phosphonamido)}furanyl]thiazole. Anal. calcd. for C30H47N4O6PS2: C, 55.03; H, 7.23; N, 8.56. Found: C, 55.08; H, 7.35; N, 8.39.
    (52.41) 2-Amino-5-isobutyl-4-[2-{5-(1-ethoxycarbonyl)cyclopentyl)phosphonamido)}furanyl]thiazole. Anal. calcd. for C27H41N4O6PS: C, 55.85; H, 7.12; N, 9.65. Found: C, 55.62; H, 6.81; N, 9.66.
    (52.42) 2-Amino-4-{N,N′-(1-ethoxycarbonyl)cyclopentyl}phosphonomethoxy-7-fluoro-6-methyl benzothiazole. Anal. calcd. for C26H38N4O6PSF+0.15 Et2O: C, 53.63; H, 6.68; N, 9.40. Found: C, 53.93; H, 6.39; N, 9.50.
    (52.43) 2-Amino-5-isobutyl-4-[2-{5-(N,N′-bis((S)-1-(1-neopentoxycarbonyl)ethyl)phosphonamido)}furanyl]thiazole. Anal. calcd. for C27H45N4O6PS+0.1H2O: C, 55.29; H, 7.77; N, 9.55. Found: C, 54.90; H, 7.68; N, 9.44.
    (52.44) 2-Amino-5-isobutyl-4-{2-[5-(N,N′-bis((R,S)-1-(1-ethoxycarbonyl)ethyl)phosphonamido)]furanyl}thiazole. Mp. 143-146° C.: Anal. calcd. for C21H33N4O6PS: C, 50.39; H, 6.65; N, 11.19. Found: C, 50.33; H, 6.58; N, 11.00.
    (52.45) 2-Amino-5-isobutyl-4-[2-{5-(N,N′-bis((S)-1-(1-isopropoxycarbonyl)ethyl)phosphonamido)}furanyl]thiazole. Anal. calcd. for C23H37N4O6PS: C, 52.26; H, 7.06; N, 10.60. Found: C, 52.34; H, 7.02; N, 10.50.
    (52.46) 2-Amino-5-isobutyl-4-[2-{5-(N,N′-bis((S)-1-(1-propoxycarbonyl)ethyl)phosphonamido)}furanyl]thiazole. Anal. calcd. for C23H37N4O6PS+0.1 CH2Cl2: C, 51.66; H, 6.98; N, 10.43. Found: C, 51.50; H, 7.01; N, 10.63.
    (52.47) 2-Amino-5-isobutyl-4-[2-{5-(N,N′-bis((S)-1-(1-isobutoxycarbonyl)ethyl)phosphonamido)}furanyl]thiazole. Anal. calcd. for C25H41N4O6PS: C, 53.94; H, 7.42; N, 10.06. Found: C, 53.59; H, 7.64; N, 9.98.
    (52.48) 2-Amino-5-propylthio-4-{2-[5-(N,N′-bis((S)-1-ethoxycarbonyl)ethyl)phosphonamido]furanyl}oxazole. Anal. calcd. for C20H31N4O7PS: C, 47.80; H, 6.22; N, 11.15. Found: C, 47.90; H, 6.17; N, 10.92.
    (52.49) 2-Amino-5-propylthio-4-{2-[5-(N,N′-bis-1-ethoxycarbonyl)methyl)phosphonamido]furanyl}oxazole. Anal. calcd. for C18H27N4O7PS: C, 45.57; H, 5.74; N, 11.81. Found: C, 45.87; H, 5.68; N, 11.68.
    (52.50) 2-Amino-5-(isobutyl-d9)-4-[2-{5-(N,N′-bis(S)-1-(1-ethoxycarbonyl)ethylphosphonamido}furanyl]thiazole. Anal. calcd. for C21H24D9N4O6SP: C, 49.50; H, 4.75; N, 10.99. Found: C, 49.89; H, 6.55; N, 10.97.
  • Examples of use of the method of the invention include the following. It will be understood that these examples are exemplary and that the method of the invention is not limited solely to these examples.
  • For the purposes of clarity and brevity, chemical compounds are referred to by synthetic Example number in the biological examples below.
  • Compound A is 4-Amino-5-fluoro-7-ethyl-1-isobutyl-2-(2-phosphono-5-furanyl)benzimidazole;
  • Compound B is 4-Amino-5-fluoro-1-cyclopropylmethyl-2-(2-phosphono-5-furanyl)benzimidazole.
  • Compound C is 2-Amino-5-isobutyl-4-{2-[N-(1-methyl-1-carboxy)ethylmonophosphonamido]furanyl}thiazole
  • Besides the following Examples, assays that may be useful for identifying compounds which inhibit gluconeogenesis include the following animal models of diabetes:
  • i. Animals with pancreatic b-cells destroyed by specific chemical cytotoxins such as
  • Alloxan or Streptozotocin (e.g. the Streptozotocin-treated mouse, rat, dog, and monkey). Kodama, H., Fujita, M., Yamaguchi, I., Japanese Journal of Pharmacology 66, 331-336 (1994) (mouse); Youn, J. H., Kim, J. K., Buchanan, T. A., Diabetes 43, 564-571 (1994) (rat); Le Marchand, Y., Loten, E. G., Assimacopoulos-Jannet, F., et al., Diabetes 27, 1182-88 (1978) (dog); and Pitkin, R. M., Reynolds, W. A., Diabetes 19, 70-85 (1970) (monkey).
  • ii. Mutant mice such as the C57BL/Ks db/db, C57BL/Ks ob/ob, and C57BL/6J ob/ob strains from Jackson Laboratory, Bar Harbor, and others such as Yellow Obese, T-KK, and New Zealand Obese. Coleman, D. L., Hummel, K. P., Diabetologia 3, 238-248 (1967) (C57BL/Ks db/db); Coleman, D. L., Diabetologia 14, 141-148 (1978) (C57BL/6J ob/ob); Wolff, G. L., Pitot, H. C., Genetics 73, 109-123 (1973) (Yellow Obese); Dulin, W. E., Wyse, B. M., Diabetologia 6, 317-323 (1970) (T-KK); and Bielschowsky, M., Bielschowsky, F. Proceedings of the University of Otago Medical School 31, 29-31 (1953) (New Zealand Obese).
  • iii. Mutant rats such as the Zucker fa/fa Rat rendered diabetic with Streptozotocin or Dexamethasone, the Zucker Diabetic Fatty Rat, and the Wistar Kyoto Fatty Rat. Stolz, K. J., Martin, R. J. Journal of Nutrition 112, 997-1002 (1982) (Streptozotocin); Ogawa, A., Johnson, J. H., Ohnbeda, M., McAllister, C. T., Inman, L., Alam, T., Unger, R. H., The Journal of Clinical Investigation 90, 497-504 (1992) (Dexamethasone); Clark, J. B., Palmer, C. J., Shaw, W N., Proceedings of the Society for Experimental Biology and Medicine 173, 68-75 (1983) (Zucker Diabetic Fatty Rat); and Idida, H., Shino, A., Matsuo, T., et al., Diabetes 30, 1045-1050 (1981) (Wistar Kyoto Fatty Rat).
  • iv. Animals with spontaneous diabetes such as the Chinese Hamster, the Guinea Pig, the New Zealand White Rabbit, and non-human primates such as the Rhesus monkey and Squirrel monkey. Gerritsen, G. C., Connel, M. A., Blanks, M. C., Proceedings of the Nutrition Society 40, 237 245 (1981) (Chinese Hamster); Lang, C. M., Munger, B. L., Diabetes 25, 434-443 (1976) (Guinea Pig); Conaway, H. H., Brown, C. J., Sanders, L. L. et al, Journal of Heredity 71, 179-186 (1980) (New Zealand White Rabbit); Hansen, B. C., Bodkin, M. L., Diabetologia 29, 713-719 (1986) (Rhesus monkey); and Davidson, I. W., Lang, C. M., Blackwell, W. L., Diabetes 16, 395-401 (1967) (Squirrel monkey).
  • v. Animals with nutritionally induced diabetes such as the Sand Rat, the Spiny Mouse, the Mongolian Gerbil, and the Cohen Sucrose-Induced Diabetic Rat. Schmidt-Nielsen, K., Hainess, H. B., Hackel, D. B., Science 143, 689-690 (1964) (Sand Rat); Gonet, A. E., Stauffacher, W., Pictet, R., et al., Diabetologia 1, 162-171 (1965) (Spiny Mouse); Boquist, L., Diabetologia 8, 274-282 (1972) (Mongolian Gerbil); and Cohen, A. M., Teitebaum, A., Saliternik, R., Metabolism 21, 235-240 (1972) (Cohen Sucrose-Induced Diabetic Rat).
  • vi. Any other animal with one of the following or a combination of the following characteristics resulting from a genetic predisposition, genetic engineering, selective breeding, or chemical or nutritional induction: impaired glucose tolerance, insulin resistance, hyperglycemia, obesity, accelerated gluconeogenesis, increased hepatic glucose output.
    • Example A Inhibition of Human Liver FBPase
  • E. coli strain BL21 transformed with a human liver FBPase-encoding plasmid was obtained from Dr. M. R. El-Maghrabi at the State University of New York at Stony Brook. The enzyme was typically purified from 10 liters of recombinant E. coli culture as described (M. Gidh-Jain et al., 1994, The Journal of Biological Chemistry 269, pp 27732-27738). Enzymatic activity was measured spectrophotometrically in reactions that coupled the formation of product (fructose 6-phosphate) to the reduction of dimethylthiazoldiphenyltetrazolium bromide (MTT) via NADP+ and phenazine methosulfate (PMS), using phosphoglucose isomerase and glucose 6-phosphate dehydrogenase as the coupling enzymes. Reaction mixtures (200 μl) were made up in 96-well microtitre plates, and consisted of 50 mM Tris-HCl, pH 7.4, 100 mM KCl, 5 mM EGTA, 2 mM MgCl2, 0.2 mM NADP, 1 mg/ml BSA, 1 mM MTT, 0.6 mM PMS, 1 unit/ml phosphoglucose isomerase, 2 units/ml glucose 6-phosphate dehydrogenase, and 0.150 mM substrate (fructose 1,6-bisphosphate). Inhibitor concentrations were varied from 0.01 μM to 10 μM. Reactions were started by the addition of 0.002 units of pure hlFBPase, and were monitored for 7 minutes at 590 nm in a Molecular Devices Plate Reader (37° C.).
  • The table below provides the IC50 values for several compounds prepared. The IC50 for AMP is 1 μLM.
  • Compound # IC50 (hlFBPase), μM
    3.1  0.025
    3.2  0.1
    3.25 0.014
    3.26 0.015
     3.58* 0.018
    (*non-HBr salt)
    3.67 2
    3.69 1
    3.70 0.04
    6.3  0.044
    10.1  0.12
    10.27  0.038
    10.43  0.07
    15.20  0.04
    15.14  0.032
    16.1  0.06
    17.6  0.62
    17.11  0.78
    18.3  0.05
    18.11  0.33
    18.20  0.039
    18.25  2
    19.2  0.4
    22.2  2.8
    34.1  0.022
    A 0.055
    B 0.055
    • Inhibition of Rat Liver FBPase
  • E. Coli strain BL21 transformed with a rat liver FBPase-encoding plasmid was obtained from Dr. M. R. El-Maghrabi at the State University of New York at Stony Brook. Recombinant FBPase was purified as described (El-Maghrabi, M. R., and Pilkis, S. J. (1991) BioChem. Biophys. Res. Commun. 176, 137-144) The enzyme assay was identical to that described above for human liver FBPase.
  • The table below provides the IC50 values for several compounds prepared. The IC50 for AMP is 20 μM.
  • Compound # IC50 (rlFBPase), μM
     3.1 0.18
     3.2 2.5
     3.25 0.5
     3.26 0.25
      3.58* 0.05
    (*non-HBr salt)
     3.70 0.15
     6.3 0.5
    10.1 2
    10.2 2.5
     10.27 2.9
     10.43 0.8
    15.2 1.3
    15.4 4.1
    15.6 7
     15.20 0.6
     15.14 0.68
    16.1 1.8
     18.20 0.28
    18.3 0.49
    34.1 0.16
    A 0.55
    B 2.1
    • Example B AMP Site Binding
  • To assess whether compounds bind to the allosteric AMP binding site of hlFBPase, the enzyme is incubated with radio-labeled AMP in the presence of a range of test compound concentrations. The reaction mixtures consist of 25 mM 3H-AMP (54 mCi/mmole) and 0-1000 mM test compound in 25 mM Tris-HCl, pH 7.4, 100 mM KCl and 1 mM MgCl2. 1.45 mg of homogeneous FBPase (±nmole) is added last. After a 1 minute incubation, AMP bound to FBPase is separated from unbound AMP by means of a centrifugal ultrafiltration unit (“Ultrafree-MC”, Millipore) used according to the instructions of the manufacturer. The radioactivity in aliquots (100 μl) of the upper compartment of the unit (the retentate, which contains enzyme and label) and the lower compartment (the filtrate, which contains unbound label) is quantified using a Beckman liquid scintillation counter. The amount of AMP bound to the enzyme is estimated by comparing the counts in the filtrate (the unbound label) to the total counts in the retentate.
    • Example C Inhibition of Gluconeogenesis in Rat Hepatocytes
  • Hepatocytes were prepared from overnight fasted Sprague-Dawley rats (250-300 g) according to the procedure of Berry and Friend (Berry, M. N., Friend, D. S., 1969, J. Cell. Biol. 43, 506-520) as modified by Groen (Groen, A. K., Sips, H. J., Vervoorn, R. C., Tager, J. M., 1982, Eur. J. BioChem. 122, 87-93). Hepatocytes (75 mg wet weight/ml) were incubated in 1 ml Krebs-bicarbonate buffer containing 10 mM Lactate, 1 mM pyruvate, 1 mg/ml BSA, and test compound concentrations from 1 to 500 μM. Incubations were carried out in a 95% oxygen, 5% carbon dioxide atmosphere in closed, 50-ml Falcon tubes submerged in a rapidly shaking water bath (37° C.). After 1 hour, an aliquot (0.25 ml) was removed, transferred to an Eppendorf tube and centrifuged. 50 μl of supernatant was then assayed for glucose content using a Sigma Glucose Oxidase kit as per the manufacturer's instructions.
  • IC50's for select compounds in this assay are shown in the table below.
  • Compound IC50 Glucose Production, μM
     3.1 2.5
     3.2 26
     3.26 10
      3.58* 2.0
    (*non-HBr salt)
    10.1 15
    10.2 16
    16.1 10
    50.6 2.0
    50.9 2.2
    50.2 2.1
    • Example D Glucose Production Inhibition and Fructose-1,6-bisphosphate Accumulation in Rat Hepatocytes
  • Isolated rat hepatocytes are prepared as described in Example C and incubated under the identical conditions described. Reactions are terminated by removing an aliquot (250 μL) of cell suspension and spinning it through a layer of oil (0.8 ml silicone/mineral oil, 4/1) into a 10% perchloric acid layer (100 μL). After removal of the oil layer, the acidic cell extract layer is neutralized by addition of ⅓ volume of 3 M KOH/3 M KHCO3. After thorough mixing and centrifugation, the supernatant is analyzed for glucose content as described in Example C, and also for fructose-1,6-bisphosphate. Fructose 1,6-bisphosphate is assayed spectrophotometrically by coupling its enzymatic conversion to glycerol 3-phosphate to the oxidation of NADH, which is monitored at 340 nm. Reaction mixtures (1 mL) consist of 200 mM Tris-HCl, pH 7.4, 0.3 mM NADH, 2 units/ml glycerol 3-phosphate dehydrogenase, 2 units/ml triosephosphate isomerase, and 50-100 μl cell extract. After a 30 minute preincubation at 37° C., 1 unit/ml of aldolase is added and the change in absorbance measured until a stable value is obtained. 2 moles of NADH are oxidized in this reaction per mole of fructose-1,6-bisphosphate present in the cell extract.
  • A dose-dependent inhibition of glucose production accompanied by a dose-dependent accumulation of fructose-1,6-bisphosphate (the substrate of FBPase) is an indication that the target enzyme in the gluconeogenic pathway, FBPase, is inhibited.
    • Example E Chemical Stability
  • Aim: To assess the stability of prodrugs 50.6, 50.9, 50.15, and 50.20 in a phosphate buffered, aqueous solution at neutral pH.
  • Methods: A 50 or 100 μg/mL solution of prodrug in potassium phosphate buffer at pH 7 (room temperature) was sampled daily for up to 10 days. Samples were analyzed by reverse phase HPLC with use of a Beckman Ultrasphere C18 column (4.6×250 mm). The column was equilibrated and eluted with a gradient from 50 mM sodium phosphate pH 5.5 to 70% acetonitrile at a flow rate of 1.5 mL/min. Detection was at 300 or 315 nm, column temperature at 40° C. Under these conditions, the prodrugs were well separated from parent compound standards; the retention time for the prodrugs was between 16 and 18 minutes, whereas the parent compounds, 3.1 and 3.58 (non-HBr salt), eluted at 9 and 10 minutes, respectively.
  • Results: The prodrugs evaluated exhibited good stability at neutral pH. Less than 10% decomposition of the prodrugs was noted over a 4 day incubation period. The t90's for 50.6, 50.9, 50.15, and 50.20 at pH 7 were thus >96 hours.
    • Example F Estimation of Oral Bioavailability in the Rat
  • Aim: To estimate the oral bioavailability of prodrugs by means of the urinary parent compound excretion method in the rat.
  • Methods: Prodrugs were dissolved in 10% ethanol/90% polyethylene glycol (mw 400) and administered by oral gavage at doses of 10 to 40 mg/kg parent compound equivalents to 6-hour fasted, Sprague Dawley rats (220-240 g). Parent compounds were typically dissolved in deionized water, neutralized with sodium hydroxide, and then administered via the tail vein at ˜10 mg/kg to rats that were briefly anesthetized with halothane. The rats were subsequently placed in metabolic cages and urine was collected for 24 hours. The quantity of parent compound excreted into urine was determined by HPLC analysis. Analysis was performed as described in Example E. The percentage oral bioavailability was estimated by comparison of the recovery in urine of the parent compound generated from the prodrug administered orally, to that recovered in urine following intravenous administration of unsubstituted parent compound.
  • Results: The estimated % oral bioavailability of select prodrugs is shown below.
  • Parent Oral
    Prodrug compound Bioavailability, %
    50.2 3.1 11
    50.3 3.1 7
    50.4 3.1 17
    50.5 3.1 22
    50.6 3.1 21.5
    50.8 3.1 26
    50.9 3.1 40
    50.15 3.8 22
    50.20 3.8 42
    50.17 3.1 7
    50.21 3.26 45
    51.2 3.1 37
    52.1 29.1 16
    52.4 3.25 30
    52.15 3.26 23
    52.18 45.1 22
    52.21 32.2 24
    52.22 36.1 18
    52.32 3.58 17
    52.33 3.58 19
    52.38 32.2 30
    52.41 3.1 27
    52.43 3.1 18
    52.44 3.1 28
    52.45 3.1 31
    52.46 3.1 16
    • Example G Oral Pharmacokinetics in the Rat
  • Aim: To determine the pharmacokinetic parameters of 50.6 and 50.9 (prodrugs of 3.1), and of 50.2 (prodrug of 3.58) following oral administration in the rat.
  • Methods: Prodrugs were administered orally at 10 mg/kg to fed rats instrumented with tail artery catheters. At appropriate time points following drug administration, blood samples were removed via the tail vein catheters. Plasma was prepared from the samples by centrifugation and plasma protein subsequently precipitated by addition of methanol to 60%. The methanolic extracts were clarified by centrifugation and then analyzed for prodrug and parent compound content by HPLC as described in Example E. Pharmacokinetic parameters were calculated from the parent compound plasma concentration-time profiles using non-compartmental analysis (WinNonLin v. 1.1 software).
  • Results: Prodrugs were not detected in plasma indicating rapid in vivo conversion to their respective parent compounds. Pharmacokinetic parameters are summarized below.
  • Parent Compound
    Cmax Tmax Clearance Half-life
    Compound (μg/ml) (h) (L/kg/h) (h)
    50.6 0.78 1.5 1.31 5.1
    50.9 0.99 1.1 1.6 2.5
    50.2 1 3.1 0.54 7.0
    • Example H Acute Oral Efficacy in the ZDF Rat
  • Aim: To determine the blood glucose lowering effect of acute 50.6, 50.9 and 50.2 administration in the Zucker Diabetic Fatty (ZDF rat).
  • Methods: ZDF rats were purchased from Genetics Inc (Indianapolis, Ind.) at 8 weeks of age. Animals were maintained under standard vivarium conditions and provided with Purina 5008 chow and water ad libitum. At 10-12 weeks of age, rats with blood glucose levels >500 mg/dl were selected and dosed orally either with vehicle (PEG 400), or prodrug (60 mg/kg). Blood glucose levels were monitored at regular intervals for 6 hours following dosing. Blood samples were taken from tail vein nicks and analyzed by means of a HemoCue glucose analyzer (Hemocue, Mission Viejo, Calif.). Statistical analysis was performed using the Student's t test. Means±standard error of the means are shown.
  • Results: The three prodrugs were orally efficacious as indicated by the significant blood glucose lowering effects observed (see table below).
  • Blood Glucose, mg/dl
    Treatment Tbaseline T6h % Change
    Vehicle (n = 8) 562 ± 38 528 ± 29  −6%
    50.6 (n = 8) 544 ± 25 406 ± 12* −25%
    50.9 (n = 8) 602 ± 26 410 ± 18* −32%
    50.2 (n = 8) 591 ± 35 415 ± 15* −30%
    *P < 0.005 versus vehicle
    • Example I Chronic Oral Efficacy in the ZDF Rat
  • Aim: To determine the glucose lowering effects of 50.6 in the ZDF rat during 3 weeks of chronic, oral treatment.
  • Methods: ZDF rats (10 weeks of age) were maintained either on powdered Purina 5008 rat chow (n=10) or the same powdered chow supplemented with 0.4% 50.6 (n=8). Blood glucose measurements were made as described in Example E at baseline and at weekly intervals thereafter for a total of 3 weeks. Statistical analysis was performed using the Student's t test. Means±standard error of the means are shown.
  • Results: As illustrated in the table below, efficacy was maintained throughout the 3-week treatment period, with 45% blood glucose lowering evident in the drug treated group (relative to vehicle) at the end of the study.
  • Blood glucose, mg/dl,
    Treatment tbaseline t21 days
    Vehicle 678 ± 19 776 ± 28 
    50.6 674 ± 20 436 ± 41*
    *p < 0.0001 versus vehicle
    • Example J Identification of the Intermediate Formed During Activation 50.6
  • The metabolism of 50.6 was evaluated in rat, monkey, and human plasma by reverse phase HPLC with use of a Beckman Ultrasphere ODS column (4.6×150 mm) equipped with an Alltech All-Guard column. The column was equilibrated with 20 mM potassium phosphate, pH 6.2 and eluted with a linear gradient of 0-60% acetonitrile over 20 minutes at a flow rate of 1.5 mL/min and at a temperature of 40° C. UV absorbance was monitored at 300 nM. Exposure of 50.6 (100 μM) to the plasma samples resulted in the formation of a single metabolite. This metabolite had the same retention time and UV spectrum as a product formed following incubation of the prodrug with pig liver esterase (Sigma Chemical Co, MO), suggesting that it was a product of an esterase-catalyzed reaction. The metabolite formed in rat plasma was collected and subjected to mass spectrum analysis at Mass Consortium Corporation (San Diego, Calif.). The sample yielded a negative ion peak at 372, indicating that the metabolite formed had a molecular weight of 373. This molecular weight is consistent with that of a monophosphoramidate intermediate. This intermediate is likely formed via a reaction mechanism in which the prodrug first undergoes full de-esterification followed by intramolecular, hydrolytic cleavage of one of the amino acyl substituents. Formation of the postulated monophosphoramidate intermediate was confirmed following the synthesis of a synthetic standard, Compound C. The standard had the identical HPLC and UV profile as the metabolite formed in plasma samples.
    • Example K Metabolism of 50.6 in Human Hepatocytes
  • Cryopreserved human hepatocytes were obtained from In Vitro Technologies and thawed according to the vendor's recommendations. Cells were incubated at 37° C. in a Krebs-bicarbonate based buffer containing 50.6 at 10 μM. At various time points over the course of 4 hours, aliquots of cells were removed and extracted by addition of methanol to 60%. Cell extracts were clarified by centrifugation and analyzed by reverse phase HPLC with use of a Beckman Ultrasphere ODS column (4.6×150 mm) equipped with an Alltech All-Guard column. The column was equilibrated with 20 mM potassium phosphate, pH 6.2 and eluted with a linear gradient of 0-60% acetonitrile over 20 minutes at a flow rate of 1.5 mL/min and at a temperature of 40° C. UV absorbance was monitored at 300 nM. 50.6, Compound C, and 3.1 were quantified by comparison to authentic standards. Disappearance of 50.6 was rapid and essentially complete within 60 minutes of incubation. Two metabolites of 50.6 were detected: Compound C and 3.1. The initial rate of 3.1 formation was 24 pmol/million cells/minute. This study indicates that 50.6 is converted to the active FBPase inhibitor, 3.1, in intact human hepatocytes.
    • Example L Structure Activity Relationship of Human Liver Phosphoramidase
  • Human liver, purchased from the Anatomic Gift Foundation (Laurel, Md.), was homogenized in Krebs-bicarbonate buffer and clarified by a slow-speed centrifugation. Prodrug metabolism was evaluated in reaction mixtures containing human liver homogenate (4 mgs protein), 50 mM Tris-HCl, pH 7.4, 10 mM MgCl2, and 10 mM dithiothreitol. At various time intervals over the course of 2 hours, aliquots were removed from the reaction mixtures and deproteinated by addition of methanol to 60%. Following clarification by centrifugation, metabolites were analyzed by reverse phase HPLC with use of a Beckman Ultrasphere ODS column (4.6×150 mm) equipped with an Alltech All-Guard column. The column was equilibrated with 20 mM potassium phosphate, pH 6.2 and eluted with a linear gradient of 0-60% acetonitrile over 20 minutes at a flow rate of 1.5 mL/min and at a temperature of 40° C. UV absorbance was monitored at 300 nM. Most of the prodrugs evaluated were metabolized via a non-rate limiting, esterase-catalyzed step to their monophosphoramidate form within 5 minutes of incubation. The rate of phosphonic acid appearance was therefore essentially a reflection of the rate of the final phosphoramidate-catalyzed cleavage step. Results for representative prodrugs for which the esterase-catalyzed step was non-rate limiting are shown below:
  • Phosphoramidase Activity
    (Rate of 3.1 or 3.58 production,
    Prodrug nmoles/mn/mg liver protein)
    50.6  0.022
    50.8  0.019
    50.10 0.005
    50.12 0.022
    50.20 0.085
    50.19 0.029
    52.8  0.025
    52.12 0.032
    52.16 0.033
  • The results indicate that human liver phosphoramidase readily cleaves the phosphorus-nitrogen bond of a variety of phosphonic acid-monoamidate substrates, thereby liberating the free phosphonic acid FBPase inhibitor. The lowest P—N cleavage rate was observed with a secondary amine substrate, the monophosphoramidate of 50.10. The first step in prodrug activation, esterase-catalyzed de-esterification, was not rate-limiting for the majority of substrates evaluated.
  • While in accordance with the patent statures, description of the various embodiments and processing conditions have been provided, the scope of the invention is not to be limited thereto or thereby. Modifications and alterations of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the present invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims, rather than by the specific examples which have been presented by way of example.

Claims (11)

1. A compound of formula IA
Figure US20090192121A1-20090730-C00055
wherein compounds of formula IA are converted in vivo or in vitro to M-PO3H2 which is an inhibitor of fructose-1,6-bisphosphatase and
n is an integer from 1 to 3;
each R12 and R13 is independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R12 and R13 together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of O, N and S, to form a cyclic group;
each R14 is independently selected from the group consisting of —OR17, —N(R17)2, —NHR17, —NR2OR19 and —SR17;
R15 is selected from the group consisting of —H, lower alkyl, lower aryl, lower aralkyl, or together with R16 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
R16 is selected from the group consisting of —(CR12R13)n—C(O)—R14, —H, lower alkyl, lower aryl, lower aralkyl, or together with R15 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
each R17 is independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or together R17 and R17 on N is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
R18 is independently selected from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R12 is connected via 1-4 carbon atoms to form a cyclic group;
each R19 is independently selected from the group consisting of —H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl, and COR3;
M is
Figure US20090192121A1-20090730-C00056
wherein:
A3, E3, and L3 are selected from the group consisting of —NR8 2, —NO2, —H, —OR7, —SR7, —C(O)NR4 2, halo, —COR11, —SO2R3, guanidine, amidine, —NHSO2R3, —SO2NR4 2, —CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or together A3 and L3 form a cyclic group, or together L3 and E3 form a cyclic group, or together E3 and J3 form a cyclic group including aryl, cyclic alkyl, and heterocyclic;
J3 is selected from the group consisting of —NR8 2, —NO2, —H, —OR7, —SR7, —C(O)NR4 2, halo, —C(O)R11, —CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl; alicyclic, aryl, and aralkyl, or together with Y3 forms a cyclic group including aryl, cyclic alkyl and heterocyclic alkyl;
X3 is selected from the group consisting of -alkyl(hydroxy)-, -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-,
-alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X3 is not substituted with —COOR2, —SO3H, or —PO3R2 2;
Y3 is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C(O)R3, —S(O)2R3, —C(O)—R11, —CONHR3, —NR2 2, and
—OR3, all except H are optionally substituted;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
each R4 is independently selected from the group consisting of —H, and alkyl, or together R4 and R4 form a cyclic alkyl group;
R7 is independently selected from the group consisting of —H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and —C(O)R10;
R8 is independently selected from the group consisting of —H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —C(O)R10, or together they form a bidentate alkyl;
each R9 is independently selected from the group consisting of —H, -alkyl, aralkyl, and alicyclic, or together R9 and R9 form a cyclic alkyl group;
R10 is selected from the group consisting of —H, lower alkyl, —NH2, lower aryl, and lower perhaloalkyl;
R11 is selected from the group consisting of alkyl, aryl, —NR2 2, and —OR2; and
pharmaceutically acceptable salts thereof.
2. The compound of claim 1, wherein A3, L3, and E3 are independently selected from the group consisting of —H, —NR8 2, —NO2, hydroxy, halogen, —OR7, alkylaminocarbonyl, —SR7, lower perhaloalkyl, and C1-C5 alkyl, or together E3 and J3 together form a cyclic group; and wherein J3 is selected from the group consisting of —H, halogen, lower alkyl, lower hydroxyalkyl, —NR8 2, lower R8 2N-alkyl, lower haloalkyl, lower perhaloalkyl, lower alkenyl, lower alkynyl, lower aryl, heterocyclic, and alicyclic; and wherein Y3 is selected from the group consisting of alicyclic and lower alkyl; wherein X3 is selected from the group consisting of -heteroaryl-, -alkylcarbonylamino-, -alkylaminocarbonyl-, and -alkoxycarbonyl-.
3. The compounds of claim 1, wherein
n is 1;
R12 and R13 are independently selected from the group consisting of —H, lower alkyl, lower perhaloalkyl, and lower aryl, optionally substituted with —OR19, —NR19 2, —SR19, —C(O)NR2R3, halo, —CO2R2, 3-indolyl, 4-imidazolyl, and guanidinyl, or R2 and R13 are connected via 2-5 carbon atoms to form a cycloalkyl group;
R14 is selected from the group consisting of —OR17, —SR17, and —NR2OR19
R15 is selected from the group consisting of —H and C1-C6 alkyl;
R16 is selected from the group consisting of —H, C1-C6 alkyl, and —(CR12R13)n—C(O)—R4; or together R15 and R16 are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of N, O and S.
R17 is selected from the group consisting of C1-C7 alkyl, phenyl, indolyl, sesimol, and benzyl, wherein said phenyl, indolyl, sesimol, and benzyl may be optionally substituted with 1-3 groups selected from the group of —CO2R2, —OR3, —NHC(O)R3, halo and lower alkyl; and
R18 is selected from the group consisting of —H, C1-C6 alkyl, and benzyl.
4. The compound of claim 1, wherein A3 is selected from the group consisting of —H, —NH2, —F, and —CH3;
L3 is selected from the group consisting of —H, —F, —OCH3, Cl and —CH3;
E3 is selected from the group consisting of —H, and —Cl;
J3 is selected from the group consisting of —H, halo, C1-C5 hydroxyalkyl, C1-C5 haloalkyl, R8 2N—C1-C5 alkyl, C1-C5 alicyclic, and C1-C5 alkyl;
X3 is selected from the group consisting of —CH2OCH2—, -methyleneoxycarbonyl- and -furan-2,5-diyl-; and
Y3 is lower alkyl.
5. The compound of claim 4, where A3 is —NH2, L3 is —F, E3 is —H, J3 is ethyl, Y3 is isobutyl, and X3 is -furan-2,5-diyl-.
6. The compound of claim 4, where A3 is —NH2, L3 is —F, E3 is —H, J3 is N,N-dimethylaminopropyl, Y3 is isobutyl, and X3 is -furan-2,5-diyl-.
7. The compound of claim 5, wherein
Figure US20090192121A1-20090730-C00057
is selected from the group consisting of
Figure US20090192121A1-20090730-C00058
wherein C* has S stereochemistry.
8. The compounds of claim 6, wherein
Figure US20090192121A1-20090730-C00059
is selected from the group consisting of
Figure US20090192121A1-20090730-C00060
wherein C* has S stereochemistry.
9. A method of treating an animal for diabetes comprising administering to said animal a therapeutically effective amount of a compound of formula XI:
Figure US20090192121A1-20090730-C00061
wherein:
A3, E3, and L3 are selected from the group consisting of —NR8 2, —NO2, —H, —OR7, —SR7, —C(O)NR4 2, halo, —COR11, —SO2R3, guanidine, amidine, —NHSO2R3, —SO2NR4 2, —CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or together A3 and L3 form a cyclic group, or together L3 and E3 form a cyclic group, or together E3 and J3 form a cyclic group including aryl, cyclic alkyl, and heterocyclic;
J3 is selected from the group consisting of —NR8 2, —NO2, —H, —OR7, —SR7, —C(O)NR4 2, halo, —C(O)R11, —CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl; alicyclic, aryl, and aralkyl, or together with Y3 forms a cyclic group including aryl, cyclic alkyl and heterocyclic alkyl;
X3 is selected from the group consisting of -alkyl(hydroxy)-, -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-,
-alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X3 is not substituted with —COOR2, —SO3H, or —PO3R2 2;
Y3 is selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, —C(O)R3, —S(O)2R3, —C(O)—R11, —CONHR3, —NR2 2, and —OR3, all except H are optionally substituted;
n is an integer from 1 to 3;
R2 is selected from the group consisting of R3 and —H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
each R4 is independently selected from the group consisting of —H, and alkyl, or together R4 and R4 form a cyclic alkyl group;
R7 is independently selected from the group consisting of —H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and —C(O)R10;
R8 is independently selected from the group consisting of —H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —C(O)R10, or together they form a bidentate alkyl;
each R9 is independently selected from the group consisting of —H.-alkyl, aralkyl, and alicyclic, or together R9 and R9 form a cyclic alkyl group;
R10 is selected from the group consisting of —H, lower alkyl, —NH2, lower aryl, and lower perhaloalkyl;
R11 is selected from the group consisting of alkyl, aryl, —NR2 2, and —OR2;
each R12 and R13 is independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R12 and R13 together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of O, N and S, to form a cyclic group;
each R14 is independently selected from the group consisting of —OR17, —N(R17)2, —NHR17, —NR2OR19 and —SR17;
R15 is selected from the group consisting of —H, lower alkyl, lower aryl, lower aralkyl, or together with R16 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
R16 is selected from the group consisting of —(CR12R13)n—C(O)—R14, —H lower alkyl, lower aryl, lower aralkyl, or together with R15 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
each R17 is independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or together R17 and R17 on N is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
R18 is independently selected from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R12 is connected via 1-4 carbon atoms to form a cyclic group;
each R19 is independently selected from the group consisting of —H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl, and COR3;
and pharmaceutically acceptable salts thereof.
10. A method of lowering blood glucose levels in an animal in need thereof, comprising administering to said animal a pharmaceutically acceptable amount of a compound of claim 1.
11. A method of inhibiting gluconeogenesis in an animal in need thereof comprising administering to said animal a pharmaceutically effective amount of a compound of claim 1.
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Families Citing this family (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU6452098A (en) 1997-03-07 1998-09-22 Metabasis Therapeutics, Inc. Novel purine inhibitors of fructose-1,6-bisphosphatase
US6489476B1 (en) 1998-09-09 2002-12-03 Metabasis Therapeutics, Inc. Heteroaromatic compounds containing a phosphonate group that are inhibitors of fructose-1,6-bisphosphatase
US6756360B1 (en) * 1998-12-24 2004-06-29 Metabasis Therapeutics, Inc. Combination of FBPase inhibitors and insulin sensitizers for the treatment of diabetes
SK8892002A3 (en) * 1999-12-22 2003-04-01 Metabasis Therapeutics Inc Novel bisamidate phosphonate prodrugs, process for their preparation and use thereof
CN1699383A (en) * 2000-03-08 2005-11-23 症变治疗公司 Novel aryl fructose-1,6-bisphosphatase inhibitors
MY164523A (en) 2000-05-23 2017-12-29 Univ Degli Studi Cagliari Methods and compositions for treating hepatitis c virus
AP2006003708A0 (en) 2000-05-26 2006-08-31 Idenix Cayman Ltd Methods and compositions for treating flavivirusesand pestiviruses
US7563774B2 (en) * 2000-06-29 2009-07-21 Metabasis Therapeutics, Inc. Combination of FBPase inhibitors and antidiabetic agents useful for the treatment of diabetes
CN100348607C (en) 2002-06-28 2007-11-14 埃迪尼克斯(开曼)有限公司 For the treatment of Flaviviridae viral infection in 2 'and 3'-nucleoside prodrugs
US7608600B2 (en) 2002-06-28 2009-10-27 Idenix Pharmaceuticals, Inc. Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections
RS113904A (en) 2002-06-28 2007-02-05 Idenix (Cayman) Limited 2'-c-methyl-3'-o-l-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections
EP1535630A1 (en) * 2002-07-23 2005-06-01 Sankyo Company, Limited Preventive for the onset of diabetes
ES2624353T3 (en) 2002-11-15 2017-07-13 Idenix Pharmaceuticals Llc 2'-Methyl nucleosides in combination with interferon and Flaviviridae mutation
CN100335492C (en) * 2002-12-23 2007-09-05 埃迪尼克斯(开曼)有限公司 Process for the production of 3'-nucleoside prodrugs
DK1611112T3 (en) * 2003-02-11 2012-11-19 Cancer Res Inst ISOXAZOLE COMPOUNDS AS INHIBITORS OF HEAT SHOCK PROTEINS
JP5069463B2 (en) 2003-04-25 2012-11-07 ギリアード サイエンシーズ， インコーポレイテッド Antiviral phosphonate analogues
WO2005030236A1 (en) * 2003-09-26 2005-04-07 Sky International Co. Ltd Substance having intrahepatic glyconeogenesis inhibiting activity and food or food additive containing the substance
US7129049B2 (en) * 2003-12-22 2006-10-31 Regents Of The University Of Minnesota Method of detecting equine glycogen storage disease IV
LT3002283T (en) * 2003-12-26 2017-09-11 Kyowa Hakko Kirin Co., Ltd. Thiazole derivatives
CA2571498A1 (en) 2004-07-02 2006-01-12 U.S. Filter Wastewater Group, Inc. Gas transfer membrane
EP1773477B1 (en) 2004-07-05 2011-09-07 Siemens Water Technologies Corp. Hydrophilic membranes
CA2577373A1 (en) * 2004-08-18 2006-03-02 Metabasis Therapeutics, Inc. Novel thiazole inhibitors of fructose 1,6-bisphosphatase
CA2588675A1 (en) 2004-12-03 2006-06-08 Siemens Water Technologies Corp. Membrane post treatment
CA2590883A1 (en) * 2004-12-13 2006-06-22 Daiichi Sankyo Company, Limited Medicinal composition for treating diabetes
CA2591416A1 (en) * 2004-12-15 2006-06-22 Daiichi Sankyo Company Limited Medicinal composition containing fbpase inhibitor
KR101318032B1 (en) * 2005-05-20 2013-10-14 다이이찌 산쿄 가부시키가이샤 Film coated preparation
EP1894930A4 (en) 2005-06-23 2010-06-23 Kyowa Hakko Kirin Co Ltd Thiazole derivative
WO2007006104A1 (en) 2005-07-14 2007-01-18 Siemens Water Technologies Corp. Monopersulfate treatment of membranes
EP1752450A1 (en) 2005-08-01 2007-02-14 Merck Sante Imidazole derivatives as fructose-1,6-bisphosphatase inhibitors and pharmaceutical compositions containing them
EP1976382B1 (en) 2005-12-23 2013-04-24 IDENIX Pharmaceuticals, Inc. Process for preparing a synthetic intermediate for preparation of branched nucleosides
CA2652162A1 (en) 2006-06-01 2007-12-06 Marcel Gubler Thiazole derivatives
EA200900392A1 (en) 2006-09-07 2010-06-30 Никомед Гмбх COMBINED TREATMENT OF DIABETES MELLITUS
WO2008057930A2 (en) 2006-11-02 2008-05-15 Aestus Therapeutics, Inc. Methods of treating neuropathic pain with retinoic acid receptor agonists
EP2152663B1 (en) 2007-06-04 2014-03-19 Ben Gurion University of the Negev Research and Development Authority Tri-aryl compounds and compositions comprising the same
EP2058308A1 (en) 2007-11-12 2009-05-13 Merck Sante Benzimidazoledihydrothiadiazinone derivatives used as fructose-1,6-biphosphatase inhibitors and pharmaceutical compositions containing same.
BRPI0821106A2 (en) * 2007-11-29 2015-06-16 Ligand Pharm Inc Nucleoside prodrugs and uses thereof
EP2227452A2 (en) * 2007-11-30 2010-09-15 F. Hoffmann-La Roche AG Pyridine compounds
US8415321B2 (en) 2008-04-15 2013-04-09 Raymond F. Schinazi Nucleoside derivatives for treatment of Caliciviridae infections, including Norovirus infections
EP2403860B1 (en) * 2009-03-04 2015-11-04 IDENIX Pharmaceuticals, Inc. Phosphothiophene and phosphothiazole as hcv polymerase inhibitors
DK3366686T3 (en) 2009-03-20 2020-11-23 Metabasis Therapeutics Inc INHIBITORS OF DIACYLGLYCEROL-O-ACYLTRANSFERASE 1 (DGAT-1) AND USES THEREOF
CR20160207A (en) 2013-11-05 2016-08-10 Ben Gurion Univ Of The Negev Res And Dev Authority COMPOUNDS FOR THE TREATMENT OF DIABETES AND COMPLICATIONS THAT COME FROM THE SAME DISEASE
EP3078378B1 (en) 2015-04-08 2020-06-24 Vaiomer Use of factor xa inhibitors for regulating glycemia
EP3334743B1 (en) 2015-08-10 2023-11-29 Merck Sharp & Dohme LLC Antiviral beta-amino acid ester phosphodiamide compounds
EP3386512B1 (en) 2015-12-10 2023-11-22 Merck Sharp & Dohme LLC Antiviral phosphodiamide prodrugs of tenofovir
US10450335B2 (en) 2015-12-15 2019-10-22 Merck Sharp & Dohme Corp. Antiviral oxime phosphoramide compounds
WO2018080903A1 (en) 2016-10-26 2018-05-03 Merck Sharp & Dohme Corp. Antiviral aryl-amide phosphodiamide compounds
KR20190100249A (en) 2016-12-22 2019-08-28 머크 샤프 앤드 돔 코포레이션 Antiviral benzyl-amine phosphodiamide compounds
EP3823629A4 (en) 2018-07-19 2022-05-04 Merck Sharp & Dohme Corp. Phosphinic amide prodrugs of tenofovir
EP4364798A3 (en) 2018-10-05 2024-06-19 Annapurna Bio Inc. Compounds and compositions for treating conditions associated with apj receptor activity

Citations (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3454635A (en) * 1965-07-27 1969-07-08 Hoechst Ag Benzenesulfonyl-ureas and process for their manufacture
US3551422A (en) * 1968-03-27 1970-12-29 Stevens & Co Inc J P N-(oxymethyl) derivatives of phosphonopolyamino-s-triazines
US3657282A (en) * 1969-01-23 1972-04-18 Merck & Co Inc Carboxyepoxyethyl-1-phosphonic acid and derivatives
US3822296A (en) * 1969-01-23 1974-07-02 Merck & Co Inc 1-trifluoromethyl-1,2-epoxyethyl-1-phosphonic acid and its salts
US3931206A (en) * 1972-09-27 1976-01-06 Imperial Chemical Industries Limited Prostanoic acid derivatives
US4000305A (en) * 1972-09-27 1976-12-28 Imperial Chemical Industries Limited 15-, 16- AND 17-Indolyl or indolinyl nor prostanoic acid derivatives
US4046841A (en) * 1975-09-16 1977-09-06 Imperial Chemical Industries Limited Phosphonates containing protected ketone group
US4092323A (en) * 1975-09-16 1978-05-30 Imperial Chemical Industries Limited Hydrazine derivatives of pyridyl-ketones
US4278791A (en) * 1978-12-22 1981-07-14 Bayer Aktiengesellschaft Benzimidazolyl-2-alkane-phosphonic acids
US4587256A (en) * 1983-06-23 1986-05-06 Hoffmann-La Roche Inc. Novel thiazolidine derivatives
US4728739A (en) * 1987-06-15 1988-03-01 American Home Products Corporation Hypoglycemic thiazolidinediones
US4746654A (en) * 1982-07-29 1988-05-24 Sanofi Anti-inflammatory products derived from methylene-diphosphonic acid, and process for their preparation
US4791125A (en) * 1987-12-02 1988-12-13 Pfizer Inc. Thiazolidinediones as hypoglycemic and anti-atherosclerosis agents
US4939130A (en) * 1986-11-21 1990-07-03 Ciba-Geigy Corporation Substituted alkanediphosphonic acids and pharmaceutical use
US4968790A (en) * 1988-08-12 1990-11-06 American Cyanamid Company Antidiabetic phosphates
US5116919A (en) * 1990-12-05 1992-05-26 E. I. Du Pont De Nemours And Company Process for increasing the relative viscosity of polyamides with reduced thermal degradation
US5133972A (en) * 1989-07-07 1992-07-28 Ciba-Geigy Corporation Topically administrable pharmaceutical preparations
US5142000A (en) * 1991-08-28 1992-08-25 E. I. Du Pont De Nemours And Company Process for increasing polyamide molecular weight with organophosphonic acid or ester catalysts in the presence of alumina-containing titanium dioxide
US5236941A (en) * 1992-06-30 1993-08-17 American Home Products Corporation 5-(2-hydroxy-1-arylethylidene)- and 5-(2-oxo-1-arylethylidene)-2,4-thiazolidinediones and derivatives thereof
US5342850A (en) * 1991-02-25 1994-08-30 Kyorin Pharmaceutical Co., Ltd. Thiazolidine-2,4-dione derivatives, their salts and their preparation processes
US5457109A (en) * 1993-09-15 1995-10-10 Warner-Lambert Company Use of thiazolidinedione derivatives and related antihyperglycemic agents in the treatment of disease states at risk for progressing to noninsulin-dependent diabetes mellitus
US5468762A (en) * 1994-05-18 1995-11-21 American Home Products Corporation Azolidinediones as antihyperglycemic agents
US5478853A (en) * 1992-10-12 1995-12-26 Adir Et Compagnie Thazolidinedione compounds
US5532256A (en) * 1994-05-18 1996-07-02 American Home Products Corporation New azolidinediones and thiadiazolidinediones as antihyperglycemic agents
US5550276A (en) * 1990-01-18 1996-08-27 Ciba-Geigy Corporation Phosphonic acid derivatives and thionophosphonic acid derivatives
US5610210A (en) * 1993-02-09 1997-03-11 Basf Aktiengesellschaft Aminovinylphosphonic ester stabilizers for organic material
US5658889A (en) * 1989-01-24 1997-08-19 Gensia Pharmaceuticals, Inc. Method and compounds for aica riboside delivery and for lowering blood glucose
US5728650A (en) * 1993-10-07 1998-03-17 Zeneca Limited Herbicidal aza bisphosphonic acids and compositions containing the same
US5728704A (en) * 1992-09-28 1998-03-17 Pfizer Inc. Substituted pyridmidines for control of diabetic complications
US5731299A (en) * 1992-05-29 1998-03-24 The Procter & Gamble Company Phosphonosulfonate compounds, pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism
US5798340A (en) * 1993-09-17 1998-08-25 Gilead Sciences, Inc. Nucleotide analogs
US5925656A (en) * 1995-04-10 1999-07-20 Dr. Reddy's Research Foundation Compounds having antidiabetic, hypolipidemic, antihypertensive properties, process for their preparation and pharmaceutical compositions containing them
US5958904A (en) * 1991-12-19 1999-09-28 G.D. Searle & Co. Phosphonomethyl-imidazo 1,2-A! pyrimidine-2-carboxylic acid compounds for treatment of neurotoxic injury
US5985858A (en) * 1995-12-27 1999-11-16 Otsuka Pharmaceutical Factory, Inc. Phosphonic diester derivatives
US6001862A (en) * 1995-06-02 1999-12-14 Kyorin Pharameuticals Co., Ltd. N-benzyldioxothiazolidylbenzamide derivatives and processes for preparing the same
US6008237A (en) * 1997-12-19 1999-12-28 Merck & Co., Inc. Arylthiazolidinedione derivatives
US6028052A (en) * 1995-09-18 2000-02-22 Ligand Pharmaceuticals Incorporated Treating NIDDM with RXR agonists
US6030990A (en) * 1995-06-02 2000-02-29 Kyorin Pharmaceutical Co., Ltd. N-benzyldioxothiazolidylbenzamide derivatives and process for producing the same
US6037335A (en) * 1993-06-29 2000-03-14 Mitsubishi Chemical Corporation Phosphonate-nucleotide ester derivatives
US6054587A (en) * 1997-03-07 2000-04-25 Metabasis Therapeutics, Inc. Indole and azaindole inhibitors of fructose-1,6-bisphosphatase
US6110903A (en) * 1997-03-07 2000-08-29 Sankyo Company Ltd. Benzimidazole inhibitors of fructose 1,6-bisphosphatase
US6147101A (en) * 1995-06-02 2000-11-14 Kyorin Pharmaceutical Co., Ltd. N-benzyldioxothiazolidylbenzamide derivatives and process for producing the same
US6284748B1 (en) * 1997-03-07 2001-09-04 Metabasis Therapeutics, Inc. Purine inhibitors of fructose 1,6-bisphosphatase
US6284672B1 (en) * 1999-03-02 2001-09-04 Advanced Micro Devices, Inc. Method of forming a super-shallow amorphous layer in silicon
US6312662B1 (en) * 1998-03-06 2001-11-06 Metabasis Therapeutics, Inc. Prodrugs phosphorus-containing compounds
US6489476B1 (en) * 1998-09-09 2002-12-03 Metabasis Therapeutics, Inc. Heteroaromatic compounds containing a phosphonate group that are inhibitors of fructose-1,6-bisphosphatase
US20030073728A1 (en) * 2000-06-29 2003-04-17 Van Poelje Paul D. Combination of FBPase inhibitors and antidiabetic agents useful for the treatment of diabetes
US6756360B1 (en) * 1998-12-24 2004-06-29 Metabasis Therapeutics, Inc. Combination of FBPase inhibitors and insulin sensitizers for the treatment of diabetes
US20050004077A1 (en) * 1999-12-22 2005-01-06 Tao Jiang Novel bisamidate phosphonate prodrugs
US6919322B2 (en) * 2000-03-08 2005-07-19 Metabasis Therapeutics, Inc. Phenyl Phosphonate Fructose-1,6-Bisphosphatase Inhibitors

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2083386C (en) 1990-06-13 1999-02-16 Arnold Glazier Phosphorous prodrugs
BR9407510A (en) * 1993-09-17 1997-01-07 Gilead Sciences Inc Nucleotide analogues
US6249316B1 (en) * 1996-08-23 2001-06-19 Flashpoint Technology, Inc. Method and system for creating a temporary group of images on a digital camera
US5861918A (en) * 1997-01-08 1999-01-19 Flashpoint Technology, Inc. Method and system for managing a removable memory in a digital camera
JP3610195B2 (en) * 1997-07-04 2005-01-12 キヤノン株式会社 Imaging device
ES2401070T3 (en) * 1998-03-06 2013-04-16 Metabasis Therapeutics, Inc. New prodrugs for phosphorus-containing compounds
EP1070084A4 (en) 1998-03-16 2001-09-12 Ontogen Corp PIPERAZINES AS INHIBITORS OF FRUCTOSE-1,6-BISPHOSPHATASE (FBPase)
PL352756A1 (en) * 1998-12-24 2003-09-08 Metabasis Therapeutics, Inc. A combination of fbpase inhibitors and insulin sensitizers for the treatment of diabetes
JP2000278573A (en) * 1999-03-23 2000-10-06 Minolta Co Ltd Drive system for data storage medium
JP4393652B2 (en) * 1999-03-30 2010-01-06 株式会社リコー Imaging apparatus and document photographing method
JP3914705B2 (en) * 2000-11-29 2007-05-16 富士フイルム株式会社 Digital camera and operation control method thereof
KR100814426B1 (en) * 2001-07-14 2008-03-18 삼성전자주식회사 multi-channel image processer and system employing the same
US7015941B2 (en) * 2001-10-12 2006-03-21 Malloy Desormeaux Stephen G Hybrid cameras that download electronic images in selected geometric formats and methods
JP2003304482A (en) * 2002-02-08 2003-10-24 Nikon Corp Electronic camera
JP2004038515A (en) * 2002-07-03 2004-02-05 Sanyo Electric Co Ltd Data recording device
JP3781017B2 (en) * 2002-07-22 2006-05-31 カシオ計算機株式会社 Image management system, image management method, and digital camera
US20040156615A1 (en) * 2002-07-25 2004-08-12 Fuji Photo Film Co., Ltd Method and apparatus for image reproduction, method and apparatus for image recording, and programs therefor
US20050093998A1 (en) * 2003-11-03 2005-05-05 Haas William R. Digital camera with variable size delete buffer

Patent Citations (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3454635A (en) * 1965-07-27 1969-07-08 Hoechst Ag Benzenesulfonyl-ureas and process for their manufacture
US3551422A (en) * 1968-03-27 1970-12-29 Stevens & Co Inc J P N-(oxymethyl) derivatives of phosphonopolyamino-s-triazines
US3650670A (en) * 1968-03-27 1972-03-21 Stevens & Co Inc J P N-(oxymethyl) derivatives of phosphonopolyamino-s-triazines used as flame retardants for cellulosic materials
US3657282A (en) * 1969-01-23 1972-04-18 Merck & Co Inc Carboxyepoxyethyl-1-phosphonic acid and derivatives
US3822296A (en) * 1969-01-23 1974-07-02 Merck & Co Inc 1-trifluoromethyl-1,2-epoxyethyl-1-phosphonic acid and its salts
US3931206A (en) * 1972-09-27 1976-01-06 Imperial Chemical Industries Limited Prostanoic acid derivatives
US4000305A (en) * 1972-09-27 1976-12-28 Imperial Chemical Industries Limited 15-, 16- AND 17-Indolyl or indolinyl nor prostanoic acid derivatives
US4046841A (en) * 1975-09-16 1977-09-06 Imperial Chemical Industries Limited Phosphonates containing protected ketone group
US4092323A (en) * 1975-09-16 1978-05-30 Imperial Chemical Industries Limited Hydrazine derivatives of pyridyl-ketones
US4278791A (en) * 1978-12-22 1981-07-14 Bayer Aktiengesellschaft Benzimidazolyl-2-alkane-phosphonic acids
US4746654A (en) * 1982-07-29 1988-05-24 Sanofi Anti-inflammatory products derived from methylene-diphosphonic acid, and process for their preparation
US4876248A (en) * 1982-07-29 1989-10-24 Sanofi Anti-inflammatory products derived from methylene-diphosphonic acid, and process for their preparation
US4587256A (en) * 1983-06-23 1986-05-06 Hoffmann-La Roche Inc. Novel thiazolidine derivatives
US4939130A (en) * 1986-11-21 1990-07-03 Ciba-Geigy Corporation Substituted alkanediphosphonic acids and pharmaceutical use
US4728739A (en) * 1987-06-15 1988-03-01 American Home Products Corporation Hypoglycemic thiazolidinediones
US4791125A (en) * 1987-12-02 1988-12-13 Pfizer Inc. Thiazolidinediones as hypoglycemic and anti-atherosclerosis agents
US4968790A (en) * 1988-08-12 1990-11-06 American Cyanamid Company Antidiabetic phosphates
US5658889A (en) * 1989-01-24 1997-08-19 Gensia Pharmaceuticals, Inc. Method and compounds for aica riboside delivery and for lowering blood glucose
US5133972A (en) * 1989-07-07 1992-07-28 Ciba-Geigy Corporation Topically administrable pharmaceutical preparations
US5550276A (en) * 1990-01-18 1996-08-27 Ciba-Geigy Corporation Phosphonic acid derivatives and thionophosphonic acid derivatives
US5116919A (en) * 1990-12-05 1992-05-26 E. I. Du Pont De Nemours And Company Process for increasing the relative viscosity of polyamides with reduced thermal degradation
US5342850A (en) * 1991-02-25 1994-08-30 Kyorin Pharmaceutical Co., Ltd. Thiazolidine-2,4-dione derivatives, their salts and their preparation processes
US5142000A (en) * 1991-08-28 1992-08-25 E. I. Du Pont De Nemours And Company Process for increasing polyamide molecular weight with organophosphonic acid or ester catalysts in the presence of alumina-containing titanium dioxide
US5958904A (en) * 1991-12-19 1999-09-28 G.D. Searle & Co. Phosphonomethyl-imidazo 1,2-A! pyrimidine-2-carboxylic acid compounds for treatment of neurotoxic injury
US5731299A (en) * 1992-05-29 1998-03-24 The Procter & Gamble Company Phosphonosulfonate compounds, pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism
US5236941A (en) * 1992-06-30 1993-08-17 American Home Products Corporation 5-(2-hydroxy-1-arylethylidene)- and 5-(2-oxo-1-arylethylidene)-2,4-thiazolidinediones and derivatives thereof
US5728704A (en) * 1992-09-28 1998-03-17 Pfizer Inc. Substituted pyridmidines for control of diabetic complications
US5478853A (en) * 1992-10-12 1995-12-26 Adir Et Compagnie Thazolidinedione compounds
US5610210A (en) * 1993-02-09 1997-03-11 Basf Aktiengesellschaft Aminovinylphosphonic ester stabilizers for organic material
US6037335A (en) * 1993-06-29 2000-03-14 Mitsubishi Chemical Corporation Phosphonate-nucleotide ester derivatives
US5457109A (en) * 1993-09-15 1995-10-10 Warner-Lambert Company Use of thiazolidinedione derivatives and related antihyperglycemic agents in the treatment of disease states at risk for progressing to noninsulin-dependent diabetes mellitus
US5798340A (en) * 1993-09-17 1998-08-25 Gilead Sciences, Inc. Nucleotide analogs
US5728650A (en) * 1993-10-07 1998-03-17 Zeneca Limited Herbicidal aza bisphosphonic acids and compositions containing the same
US5532256A (en) * 1994-05-18 1996-07-02 American Home Products Corporation New azolidinediones and thiadiazolidinediones as antihyperglycemic agents
US5468762A (en) * 1994-05-18 1995-11-21 American Home Products Corporation Azolidinediones as antihyperglycemic agents
US5925656A (en) * 1995-04-10 1999-07-20 Dr. Reddy's Research Foundation Compounds having antidiabetic, hypolipidemic, antihypertensive properties, process for their preparation and pharmaceutical compositions containing them
US6001862A (en) * 1995-06-02 1999-12-14 Kyorin Pharameuticals Co., Ltd. N-benzyldioxothiazolidylbenzamide derivatives and processes for preparing the same
US6147101A (en) * 1995-06-02 2000-11-14 Kyorin Pharmaceutical Co., Ltd. N-benzyldioxothiazolidylbenzamide derivatives and process for producing the same
US6030990A (en) * 1995-06-02 2000-02-29 Kyorin Pharmaceutical Co., Ltd. N-benzyldioxothiazolidylbenzamide derivatives and process for producing the same
US6028052A (en) * 1995-09-18 2000-02-22 Ligand Pharmaceuticals Incorporated Treating NIDDM with RXR agonists
US5985858A (en) * 1995-12-27 1999-11-16 Otsuka Pharmaceutical Factory, Inc. Phosphonic diester derivatives
US6399782B1 (en) * 1997-03-07 2002-06-04 Metabasis Therapeutics, Inc. Benzimidazole inhibitors of fructose 1,6-bisphosphatase
US6110903A (en) * 1997-03-07 2000-08-29 Sankyo Company Ltd. Benzimidazole inhibitors of fructose 1,6-bisphosphatase
US6054587A (en) * 1997-03-07 2000-04-25 Metabasis Therapeutics, Inc. Indole and azaindole inhibitors of fructose-1,6-bisphosphatase
US6284748B1 (en) * 1997-03-07 2001-09-04 Metabasis Therapeutics, Inc. Purine inhibitors of fructose 1,6-bisphosphatase
US6294672B1 (en) * 1997-03-07 2001-09-25 Metabasis Therapeutics, Inc. Indole and azaindole inhibitors of Fructose-1,6-biphosphatase
US6967193B1 (en) * 1997-03-07 2005-11-22 Metabasis Therapeutics, Inc. Purine inhibitors of fructose-1,6-bisphosphatase
US6200998B1 (en) * 1997-12-19 2001-03-13 Merck & Co., Inc. Arylthiazolidinedione derivitives
US6008237A (en) * 1997-12-19 1999-12-28 Merck & Co., Inc. Arylthiazolidinedione derivatives
US6312662B1 (en) * 1998-03-06 2001-11-06 Metabasis Therapeutics, Inc. Prodrugs phosphorus-containing compounds
US6489476B1 (en) * 1998-09-09 2002-12-03 Metabasis Therapeutics, Inc. Heteroaromatic compounds containing a phosphonate group that are inhibitors of fructose-1,6-bisphosphatase
US20040058892A1 (en) * 1998-09-09 2004-03-25 Qun Dang Novel heteroaromatic inhibitors of fructose 1,6-bisphosphatase
US20040167178A1 (en) * 1998-12-24 2004-08-26 Erion Mark D. Combination of FBPase inhibitors and insulin sensitizers for the treatment of diabetes
US6756360B1 (en) * 1998-12-24 2004-06-29 Metabasis Therapeutics, Inc. Combination of FBPase inhibitors and insulin sensitizers for the treatment of diabetes
US6284672B1 (en) * 1999-03-02 2001-09-04 Advanced Micro Devices, Inc. Method of forming a super-shallow amorphous layer in silicon
US20050004077A1 (en) * 1999-12-22 2005-01-06 Tao Jiang Novel bisamidate phosphonate prodrugs
US6965033B2 (en) * 1999-12-22 2005-11-15 Metabasis Therapeutics, Inc. Bisamidate phosphonate prodrugs
US6919322B2 (en) * 2000-03-08 2005-07-19 Metabasis Therapeutics, Inc. Phenyl Phosphonate Fructose-1,6-Bisphosphatase Inhibitors
US20050176684A1 (en) * 2000-03-08 2005-08-11 Bookser Brett C. Novel aryl fructose-1,6-bisphosphatase inhibitors
US20030073728A1 (en) * 2000-06-29 2003-04-17 Van Poelje Paul D. Combination of FBPase inhibitors and antidiabetic agents useful for the treatment of diabetes

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