US20060115815A1 - Method and compositions for identifying anti-hiv therapeutic compounds - Google Patents

Method and compositions for identifying anti-hiv therapeutic compounds Download PDF

Info

Publication number
US20060115815A1
US20060115815A1 US10/511,183 US51118305A US2006115815A1 US 20060115815 A1 US20060115815 A1 US 20060115815A1 US 51118305 A US51118305 A US 51118305A US 2006115815 A1 US2006115815 A1 US 2006115815A1
Authority
US
United States
Prior art keywords
compound
candidate
phosphonate
hiv
compounds
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/511,183
Other languages
English (en)
Inventor
Gabriel Birkus
James Chen
Xiaowu Chen
Tomas Cihlar
Eugene Eisenberg
Marcos Hatada
Gong-Xi He
Choung Kim
William Lee
Martin McDermott
Sundaramoorthi Swaminathan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gilead Sciences Inc
Original Assignee
Gilead Sciences Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gilead Sciences Inc filed Critical Gilead Sciences Inc
Priority to US10/511,183 priority Critical patent/US20060115815A1/en
Assigned to GILEAD SCIENCES, INC. reassignment GILEAD SCIENCES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BIRKUS, GABRIEL, KIM, CHOUNG U., LEE, WILLIAM A., CIHLAR, TOMAS, EISENBERG, EUGENE J., HATADA, MARCOS, CHEN, JAMES M., CHEN, XIAOWU, HE, GONG-XIN, MCDERMOTT, MARTIN J., SWAMINATHAN, SUNDARAMOORTHI
Publication of US20060115815A1 publication Critical patent/US20060115815A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • 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)]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/42—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C07D239/49—Two nitrogen atoms with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/80—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/04—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • 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)]
    • C07F9/40—Esters thereof
    • 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)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • 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
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings
    • 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
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen 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
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
    • 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
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/650905—Six-membered rings having the nitrogen atoms in the positions 1 and 2
    • 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
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/650905—Six-membered rings having the nitrogen atoms in the positions 1 and 2
    • C07F9/650947—Six-membered rings having the nitrogen atoms in the positions 1 and 2 condensed with carbocyclic rings or carbocyclic ring systems
    • 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
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
    • 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
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
    • C07F9/65128—Six-membered rings having the nitrogen atoms in positions 1 and 3 condensed with carbocyclic rings or carbocyclic ring systems
    • 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
    • C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07F9/6533—Six-membered rings
    • C07F9/65335—Six-membered rings condensed with carbocyclic rings or carbocyclic ring systems
    • 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
    • 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
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
    • C12Q1/18—Testing for antimicrobial activity of a material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • C12Q1/37—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving peptidase or proteinase
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • C12Q1/44—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving esterase
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
    • G01N33/5038—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects involving detection of metabolites per se
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/005—Assays involving biological materials from specific organisms or of a specific nature from viruses
    • G01N2333/08—RNA viruses
    • G01N2333/15—Retroviridae, e.g. bovine leukaemia virus, feline leukaemia virus, feline leukaemia virus, human T-cell leukaemia-lymphoma virus
    • G01N2333/155—Lentiviridae, e.g. visna-maedi virus, equine infectious virus, FIV, SIV
    • G01N2333/16—HIV-1, HIV-2
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)

Definitions

  • the invention relates generally to methods and compositions for identifying compounds having therapeutic activity against human immunodeficiency virus (HIV).
  • HIV human immunodeficiency virus
  • Anti-HIV compounds are well established and have achieved significant therapeutic benefit. However, existing therapeutics remain less than optimal. Conspiring to reduce patient compliance and therapeutic efficacy are toxicity, resistant HIV, poor bioavailability, low potency, and frequent and inconvenient dosing schedules, among other failings. The need to administer very large tablets and requirements for frequent dosing characterize a number of important anti-HIV therapeutics, most particularly the HIV protease inhibitors. While significant advances have been made in preparing improved nucleotide analogue anti-HIV therapeutics (see WO 02/08241, EP 820,461 and WO 95/07920, all of which are hereby incorporated by reference), other anti-HIV therapeutic drug classes remain encumbered with severe deficiencies.
  • the present invention provides methods and compositions for identifying therapeutic anti-HIV compounds having improved pharmacological and therapeutic properties.
  • this invention provides for novel candidate therapeutic anti-HIV compounds and methods for screening them to identify compounds having such beneficial properties.
  • determining the anti-HIV activity of the candidate compound comprises determining the anti-HIV activity of a carboxylic acid or phosphonic acid-containing metabolite of the candidate compound, which carboxyl acid or phosphonic acid-containing metabolite is produced by esterolytic metabolic cleavage of the esterified carboxyl or phosphonate-containing group.
  • determining anti-HIV activity comprises determining the tissue selectivity and/or the intracellular residence time of at least one of said intracellular carboxylic acid or phosphonic acid-containing metabolites.
  • a library of anti-HIV candidate compounds comprises at least one non-nucleotide prototype compound substituted by an esterified carboxyl or phosphonate group.
  • Such libraries facilitate large-scale screening of candidate compounds.
  • This invention is an improvement in the conventional methods for identifying therapeutic anti-HIV compounds.
  • the improvement comprises substituting a prototype compound with an esterified carboxyl or phosphonate and assaying the resulting candidate compound for its anti-HIV activity.
  • ester(s) mask the charge of the carboxyl or phosphonate and permit the candidate to enter HIV infected cells, in particular peripheral blood mononuclear cells (PBMCs).
  • PBMCs peripheral blood mononuclear cells
  • the candidate Once the candidate has entered the cells it is processed by biological mechanisms (most notably, it is believed, by a newly discovered PBMC enzyme which we designate GS-7340 Ester Hydrolase) to produce at least one metabolite containing a free carboxylic acid and/or phosphonic acid. This metabolite is antivirally active against HIV.
  • esterified carboxyl or phosphonate substituent may direct the selective distribution of the prototype to tissues (most particularly lymphoid tissues such as PBMCs) which are noted sites of HIV infection, thereby potentially reducing systemic dose and toxicity.
  • assaying for anti-HIV activity optionally comprises screening the candidate compounds for their susceptibility to esterolytic cleavage by isolated GS-7340 Ester Hydrolase.
  • isolated Hydrolase is a further embodiment of this invention.
  • another embodiment of this invention is a method comprising obtaining a substantially pure organic molecule, optionally contacting the organic molecule with another molecule to produce a composition, contacting GS-7340 Ester Hydrolase with said organic molecule or composition, and optionally determining whether the organic molecule has been cleaved by the Hydrolase.
  • a method comprising contacting GS-7340 Ester Hydrolase with an organic compound in a cell-free environment.
  • a method comprising contacting GS-7340 Ester Hydrolase with an organic compound in an in vitro or cell culture environment.
  • composition comprising a substantially pure organic compound and isolated GS-7340 Ester Hydrolase.
  • composition comprising an organic compound and GS-7340 Ester Hydrolase in an in vitro or cell culture environment.
  • Anti-HIV activity of candidates is determined by any method for assaying the HIV inhibitory activity of a substance. Many such methods are well known, and range from in vitro enzyme assays (e.g., HIV reverse transcriptase or integrase assays) to animal studies (e.g., SIV in chimps) and human clinical trials. Included with this term are any assays bearing on the therapeutic anti-HIV efficacy of a substance, e.g., HIV resistance determinations, biodistribution, and intracellular persistence.
  • in vitro enzyme assays e.g., HIV reverse transcriptase or integrase assays
  • animal studies e.g., SIV in chimps
  • human clinical trials include any assays bearing on the therapeutic anti-HIV efficacy of a substance, e.g., HIV resistance determinations, biodistribution, and intracellular persistence.
  • candidate compound is an organic compound containing an esterified carboxylate or phosphonate.
  • candidate compounds excluded compounds heretofore known to have anti-HIV activity.
  • the candidate compounds herein exclude compounds that are anticipated under 35 USC ⁇ 102 or obvious under 35 USC ⁇ 103 over the prior art.
  • the candidate compounds exclude compounds not novel or which lack inventive step over the prior art.
  • libraries containing candidate compounds optionally comprise known compounds. These may be, for example, reference compounds having known anti-HIV activity.
  • Non-nucleotide means any compound that has all of the following characteristics: It does not already contain an esterified carboxyl or phosphonate, it is not a phosphonate or phosphate-containing compound disclosed in WO 02/08241, EP 820,461 or WO 95/07920 and it does not already contain a phosphonate group.
  • GS-7340 is an example of a nucleotide anti-HIV compound. Many other examples of such compounds are known. These compounds are excluded from the scope of prototype compounds and are not employed in the candidate compound screening method or candidate compound compositions of this invention.
  • the nucleotide analogues comprise the substructure —OC(H) 2 P(O) ⁇ coupled (usually at the 9 position of purine bases or the 1 position of pyrimidine bases) via a sugar or cyclic or acyclic sugar analogue (aglycon) to a nucleotide base or an analogue thereof.
  • the base analogues typically are substituted, usually at extracyclic N atoms, or are the aza or deaza analogues of the naturally occuring base scaffolds. They are fully set forth in the above described art and are well known in the field. See for example U.S. Pat. No. 5,641,763 and related patents and publications by Antonin Holy.
  • such compounds shall be considered candidate compounds.
  • the act of making and screening the phosphonates of such filings to determine their intracellular persistence falls within the scope hereof, as does obtaining regulatory approval to market one of them and selling the selected phosphonate.
  • Non-nucleoside means any compound that is not a nucleotide base linked to a sugar or aglycon (cyclic or acyclic) and terminating at the 5′ position (or the analogous position in nucleosides containing sugar analogues) by hydroxyl or a group which is metabolized in vivo to hydroxyl.
  • the nucleosides are distinguishable from the nucleotides in not containing a phosphate or, in the case of relevant nucleotide analogues, a phosphonate.
  • “Phosphonate-containing group” is a group comprising a phosphorus atom singly bonded to carbon, double bonded to oxygen and singly bonded to two other groups through oxygen, sulfur, or nitrogen.
  • the carbon bond is to a carbon atom of the prototype or a linking group to the prototype and the single bonds to oxygen, nitrogen or sulfur are bonds to oxy or thioesters or are amino acid amidates in which the terminal carboxyl group(s) are esterified.
  • Carboxyl-containing groups are any group having a free carboxyl serving as the site for esterification.
  • An “organic acid” is any compound containing carboxyl and at least one additional carbon atom.
  • esterified carboxyl or esterified phosphonate group is any group capable of intracellular processing to yield a free carboxyl and/or free phosphonic acid.
  • the structure of these groups is not important other than that the free acid be produced intracellularly.
  • systemic or digestive esterolysis is minimized in preference to intracellular hydrolysis. This permits maximum migration of the candidate into target cells and maximum intracellular retention of the acid metabolites.
  • Y 1 is independently O, S, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), or N(N(R x )(R x ));
  • Y 2 is independently a bond, O, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), N(N(R x )(R x )), —S(O) M2 —, or —S(O) M2 —S(O) M2 —;
  • R x is independently H, W 3 , a protecting group, or a group of the formula:
  • R y is independently H, W 3 , R 2 or a protecting group
  • R 1 is independently H or alkyl of 1 to 18 carbon atoms
  • R 2 is independently H, R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups;
  • R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a heteroatom, then R 3 is R 3c or R 3d ;
  • R 3a is F, Cl, Br, I, —CN, N 3 or —NO 2 ;
  • R 3b is Y 1 ;
  • R 3c is —R x , —N(R x )(R x ), —SR x , —S(O)R x , —S(O) 2 R x , —S(O)(OR x ), —S(O) 2 (OR x ).
  • R 3d is —C(Y 1 )R x , —C(Y 1 )OR x or —C(Y 1 )(N(R x )(R x ));
  • R 4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
  • R 5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups;
  • R 5a is independently alkylene of 1 to 18 carbon atoms, alkenylene of 2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R 3 groups;
  • W 3 is W 4 or W 5 ;
  • W 4 is R 5 , —C(Y 1 )R 5 , —C(Y 1 )W 5 , —SO 2 R 5 , or —SO 2 W 5 ;
  • W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;
  • M2 is 0, 1 or 2;
  • M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • M1a, M1c, and M1d are independently 0 or 1;
  • M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
  • the esterified group is attached to the prototype through a bond or via intermediary linking groups such as the A 1 subgroup —[Y 2 —(C(R 2 ) 2 ) m12a ] m12b Y 2 W 6 — defined below.
  • Candidates optionally are substituted with a single substituent which contains both an esterified carboxyl and an esterified phosphonate.
  • the candidate contains separate substituents bearing esterified carboxyl and/or phosphonate groups.
  • An example of a combined group would a phosphonate in which a free valence of the phosphorus atom is bonded to the hydroxy of an hydroxyorganic acid or to the amino group of an amino acid wherein the carboxyl groups of the organic acid or amino acid are esterifed.
  • “Esterified” means that the phosphonate or carboxyl is bonded to a carbon atom-containing group through oxygen or sulfur, as in —P(O)(OR)— or —COOR for example, where R is a carbon containing group such as alkyl or aryl.
  • Protecting group is a group covalently bonded to a labile site on the candidate compound, which site is expected to be labile under the conditions to be encountered by the candidate, for example during synthetic procedures, during exposure to ambient conditions, and the conditions found in in vivo environments.
  • the protecting group serves to prevent degradation or otherwise undesired conversions at the labile site. Extensive disclosure of various exemplary protecting groups is found infra.
  • “Intracellular depot metabolite” is an esterolytic metabolite of the esterified carboxyl or phosphonate whereby a charged carboxyl or phosphonic acid is revealed.
  • An example is Metabolite X, further described in the examples.
  • tissue selectivity of candidate compounds is determined by procedures set forth in WO02/08241. The object of this determination is to find whether or not the candidate (and by extension its depot forms) are enriched in one tissue or another. It is expected that compounds containing the carboxyl or phosphonate groups as described herein will be preferentially enriched in lymphoid tissue such as PBMCs.
  • Intracellular residence time refers to a measure of the time that a candidate molecule or its anti-HIV active metabolite is found within a given cell after introduction of the esterified candidate into the cell. Any technique is suitable that demonstrates how long a candidate or its anti-HIV active metabolite(s) remain in a cell. Further description of suitable assay procedures are set forth infra. Ideally, the method for measuring residence time will measure the retention time of the metabolite at a concentration adequate to inhibit HIV.
  • a “prototype compound” is any organic compound.
  • the prototype compound will be one that has, or at least is suspected, to have anti-HIV activity.
  • the prototype compound since the prototype compound is serving only as a starting point for preparing candidate compounds to be screened, it is not essential that it have, or be known or suspected to have, preexisting anti-HIV activity.
  • the prototype compound need not be published or known generally to the public.
  • the method of this invention is advantageously practiced in on-going proprietary research programs where anti-HIV compounds are continually identified and optimized. It also should be understood that identification or selection of the prototype compound need not be temporally related to that of the candidate compound.
  • the prototype might be identified after one or more related candidate compounds are made, or the prototype might be an early version of a compound class that has advanced further into development before the candidate based on the early prototype is actually synthesized.
  • the prototype compound also may be entirely conceptual or may be in various phases of development. No actual prototype need to have been made, nor tested for activity or any other properties. This is often the case with candidates that are the product of truncating an existing compound and then inserting a linker group in place of all or a part of the omitted portion.
  • the conception of the candidate compound optionally is a single act.
  • the candidate compound may be based on a prototype which is in fact a previously made candidate compound and the subsequent candidate is multiply substituted with the carboxyl or phosphonate ester.
  • a candidate or group of candidates compounds optionally are based on an original prototype even though intervening candidates or libraries of candidates have been made.
  • the prototypes generally serve as the starting point for designing and identifying candidate compounds. Generally a prototype will not contain a phosphonate or carboxyl group, but it may do so if the phosphonate or carboxyl are not esterified (since candidates contain esterified phosphonate or carboxyl groups). It is most efficient to start with prototypes already known to have anti-HIV activity (preferably compounds active against anti-HIV protease, HIV integrase or HIV polymerase), but it is not essential to do so. For example, a prototype optionally is a subsegment or fragment of a compound known to possess anti-HIV activity, even though the fragment need not be active against HIV in its own right. In this instance, the phosphonate or carboxyl group restores anti-HIV activity to the candidate.
  • anti-HIV activity preferably compounds active against anti-HIV protease, HIV integrase or HIV polymerase
  • Linker or “link” is a bond or an assembly of atoms binding the prototype to the the esterified phosphonate or carboxyl-containing group.
  • the nature of the linker is not critical. The linker need not be involved in the interactions of the esterified carboxyl or phosphonate group with GS-7340 Ester Hydrolase or other processing enzymes, nor need it be involved in the therapeutic interaction of the prototype with its target protein. This is not to say that these functions could not be enhanced or influenced by the linker, but it is not necessary that the linker perform or contribute to such functions. Thus, it is a straight-forward matter of elemental organic chemistry to devise suitable linkergroups and methods for joining the esterified groups.
  • linker groups Some general principles are useful in selecting suitable linkergroups, despite their lack of criticality. First, they will not be so bulky as to interfere with the interaction of the remainder of the prototype with its target protein, e.g., HIV protease inhibitor, nor will they bear reactive or unstable groups once the linkage has been accomplished. Such chemically reactive groups will be well known to the artisan, and the parameters of bulky linkers can be evaluated by molecular modeling. Resources are available to model proteins involved in a number of diseases and disorders of lymphoid tissues, in particular HIV protease. In general, the linker will be relatively small, on the order of about 16-500 MW, typically about 16-250, ordinarily about 16-200, although as noted the linker can be as small as a bond. It generally will be substantially linear, containing less than about 40% of the total MW of the linkeratoms being found in branching groups, typically less than 30% and ordinarily less than about 20%.
  • the backbone of such linkergroups ideally will not contain any atom that is known to be labile to cleavage by biological processes or otherwise subject to hydrolysis in biological fluids. Typical suspect groups would be esters or amides in the backbone of the linker. The object is for the carboxyl or phosphonate to survive intracellular processing, with only the ester(s) being hydrolyzed, and the presence of labile groups in the backbone would jeopardize this function. However, if enzymatic access to labile atoms or groups is sterically hindered, e.g., by a cycloalkyl group or branched alkyl group, then labile sites optionally may be used in the linker.
  • Labile groups also optionally are can be found in locations other than backbone positions, e.g. on branching groups or cyclic substituents, where their potential cleavage would not result in the loss of the free acid functionality.
  • Backbone alkyls, alkyl ethers (S or O), or alkyl containing N in any oxidation state are usually satisfactory.
  • the linker backbone is linear rather than branched or cyclic (although it may be desired to use branching or cyclic backbones when multiple esterified groups are substituted onto the prototype).
  • the linker generally is chosen to permit substantial rotational freedom to the esterified group, and for this reason backbone double or triple bonds are not favored unless it is expected that they would be metabolized to less rotationally confined structures in vivo (e.g., oxidized to hydroxyl substituents). If it is desired to avoid interactions with the target protein then the linker optimally will have neither highly charged nor strongly hydrophobic character, although as noted such properties can have advantages in enhancing anti-HIV activity.
  • the typical linker to phosphonate will comprise at least the group —OCH 2 — (wherein the carbon is linked to the phosphorous atom), but many others will be apparent to the artisan or are described elsewhere herein.
  • linkers will contain a backbone or chain heteroatom such as 1 to 3 S, N or O.
  • the prototype compound will contain a convenient site for insertion of the linker, e.g., a pendant hydroxyl, thus enabling a small linkergroup because the phosphorous atom can be linked directly, or virtually directly, to the prototype.
  • Synthetic routes also can be devised readily that permit direct linkage of the phosphorous atom to the prototype, in which case the linker is merely a bond.
  • the linker optionally is grafted onto the prototype, or the prototype compound is optionally is modified to remove group(s) which then are replaced with linker(s). This may facilitate the synthesis of the candidate compound or, in some instances, may fortuitously improve the properties of the candidate. This may or may not be more efficient that simply grafting A 3 onto the prototype.
  • the starting point in devising a facile synthetic route for a candidate compound is to analyze the synthons employed in known methods for preparing the remainder of the prototype compound, concentrating on synthons which could contribute at least a part of the esterified group.
  • Such synthons optionally are modified to contain the esterified group or a portion thereof (e.g., the acid, which is then esterified in a later step). They are then introduced into the remainder of the candidate in substantially the same fashion as the prototype or antecedent compound.
  • a reactive group is introduced into the synthon before it is assembled into the precursor, and it is this group that is reacted with an intermediate for the carboxyl or phosphonate group. If necessary, suitable protecting groups are employed to facilitate the synthesis.
  • the site for insertion of the esterified carboxyl or phosphonate group on the prototype will vary widely.
  • the esterified group preferably is substituted at any location on the prototype that does not bind substantially with the target protein or affect the functioning of a group that does interact with the target protein. These sites are identified by molecular modeling, by consulting systematic SAR studies or by preparing pilot candidate compounds. However, it is also within the scope of this invention to insert the esterified groups at a site which is involved in binding the prototype to the target protein.
  • Such sites optionally are used if (a) the linker reasonably replicates the function of the group on the prototype that it is displacing, e.g., it possesses a side chain containing the group, (b) if the loss in binding affinity is not critical to the functioning of the prototype or (c) if other substitutents are introduced into the prototype that compensate for any loss in activity caused by the insertion of the linker.
  • the linker generally will contain at least two free valences (1 for the prototype and 1-3 for the esterified groups). Multivalent linkergroups can be employed to form a cyclic structure, being joined at 2 or more sites on the prototype and forming a bridge, the bridge in turn being subsituted with one or more esterified carboxyl or phosphonate groups or including at least one atom encompassed within such groups.
  • the linker does not need to be bound to the esterified group and/or the remainder of the prototype by a covalent bond, nor need it consist solely of covalently bonded atoms. Any bond meeting the basic criteria herein will be satisfactory, as for example linkage by chelation or other stable non-covalent attachment systems are included within the scope of the term “bond” as used herein.
  • Linkers also include polymers, e.g., those containing repeating units of alkyloxy (e.g. polyethylenoxy, PEG, polymethyleneoxy) and/or alkylamino (e.g. polyethyleneamnino, JeffamineTM).
  • alkyloxy e.g. polyethylenoxy, PEG, polymethyleneoxy
  • alkylamino e.g. polyethyleneamnino, JeffamineTM
  • Other linker groups include diacid ester and amides including succinate, succinamide, diglycolate, malonate, and caproamide.
  • Suitable linker groups optionally are prescreened by testing model candidates in the same fashion set forth herein for disclosed candidate compounds, e.g., screening using the Ester Hydrolase described herein, or by studying the effect of a model linker-containing candidate compound in PBMCs.
  • Typical linkers have the A 1 substructure —[Y 2 —(C(R 2 ) 2 ) m12a ] m12b Y 2 W 6 — wherein Y 2 , R 2 , m12a and m12b are defined elsewhere herein, W 6 is W 3 having from 1 to 3 free valences and the prototype is bound to the Y 2 with free valence.
  • W 6 is W 3 having from 1 to 3 free valences and the prototype is bound to the Y 2 with free valence.
  • many other structures would be apparent to the ordinary artisan and can be prepared by conventional means using the guidance herein.
  • Alkyl is C1-C18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples are methyl (Me, —CH 3 ), ethyl (Et, —CH 2 CH 3 ), 1-propyl ( n -Pr, n -propyl, —CH 2 CH 2 CH 3 ), 2-propyl ( i -Pr, i -propyl —CH(CH 3 ) 2 ), 1-butyl ( n -Bu, n -butyl, —CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl ( i -Bu, i -butyl, —CH 2 CH(CH 3 ) 2 ), 2-butyl ( s -Bu, s -butyl, —CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl ( t -Bu, t -butyl, —C(CH 3 ) 3
  • Alkenyl is C 2 -C 18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp 2 double bond. Examples include, but are not limited to: ethylene or vinyl (—CH ⁇ CH 2 ), allyl (—CH 2 CH ⁇ CH 2 ), cyclopentenyl (—C 5 H 7 ), and 5-hexenyl (—CH 2 CH 2 CH 2 CH 2 CH ⁇ CH 2 )
  • Alkynyl is C 2 -C 18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond. Examples include, but are not limited to: acetylenic (—C ⁇ CH) and propargyl (—CH 2 C ⁇ H),
  • Alkylene refers to a saturated, branched or straight chain or cyclic hydrocarbon radical of 1-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane.
  • Typical alkylene radicals include, but are not limited to: methylene (—CH 2 —-) 1,2-ethyl (—CH 2 CH 2 —), 1,3-propyl (—CH 2 CH 2 CH 2 —), 1,4-butyl (—CH 2 CH 2 CH 2 CH 2 —), and the like.
  • Alkenylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene.
  • Typical alkenylene radicals include, but are not limited to: 1,2-ethylene (—CH ⁇ CH—).
  • Alkynylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne.
  • Typical alkynylene radicals include, but are not limited to: acetylene (—C ⁇ C—), propargyl (—CH 2 C ⁇ C—), and 4-pentynyl (—CH 2 CH 2 CH 2 C ⁇ CH—).
  • Aryl means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl, and the like.
  • Arylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with an aryl radical.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like.
  • the arylalkyl group comprises 6 to 20 carbon atoms, e.g. the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms.
  • Substituted alkyl mean alkyl, aryl, and arylalkyl respectively, in which one or more hydrogen atoms are each independently replaced with a substituent.
  • Typical substituents include, but are not limited to, —X, —R, —O ⁇ , —OR, —SR, —S ⁇ , —NR 2 , —NR 3 , ⁇ NR, —CX 3 , —CN, —OCN, —SCN, —N ⁇ C ⁇ O, —NCS, —NO, —NO 2 , ⁇ N 2 , —N 3 , NC( ⁇ O)R, —C( ⁇ O)R, —C( ⁇ O)NRR, —S( ⁇ O) 2 O ⁇ , —S( ⁇ O) 2 OH, —S( ⁇ O) 2 R, —OS( ⁇ O) 2 OR, —S( ⁇ O) 2 NR, —S( ⁇ O)R, —OP( ⁇ O)O 2 RR, —P( ⁇ O)O 2 RR, —P( ⁇ O)(O ⁇ ) 2 , —P( ⁇ O)(OH
  • Heterocycle as used herein includes by way of example and not limitation these heterocycles described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566.
  • heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, pyr
  • carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.
  • carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl.
  • nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ -carboline.
  • nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
  • Carbocycle means a saturated, unsaturated or aromatic ring having 3 to 7 carbon atoms as a monocycle or 7 to 12 carbon atoms as a bicycle.
  • Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms.
  • Bicyclic carbocycles have 7 to 12 ring atoms, e.g. arranged as a bicyclo (4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system.
  • Examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spiryl and naphthyl.
  • chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.
  • Enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • the prefixes d and the linkeror (+) and ( ⁇ ) are employed to designate the sign of rotation of plane-polarized light by the compound, with ( ⁇ ) or 1 meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • these stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • Candidate compounds contain at least one A 1 (which in turn contains 1-3 A 3 groups) but also may contain at least one A 2 group.
  • a 1 is:
  • a 2 is:
  • a 3 is:
  • Y 1 is independently O, S, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), or N(N(R x )(R x ));
  • Y 2 is independently a bond, O, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), N(N(R x )(R x )), —S(O) M2 —, or —S(O) M2 —S(O) M2 —;
  • R x is independently H, R 1 , W 3 , a protecting group, or the formula:
  • R y is independently H, W 3 , R 2 or a protecting group
  • R 1 is independently H or an alkyl of 1 to 18 carbon atoms
  • R 2 is independently H, R 1 , R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups;
  • R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a heteroatom, then R 3 is R 3c or R 3d ;
  • R 3a is F, Cl, Br, I, —CN, N 3 or —NO 2 ;
  • R 3b is Y 1 ;
  • R 3c is —R x , —N(R x )(R x ), —SR x , —S(O)R x , —S(O) 2 R x , —S(O)(OR x ), —S(O) 2 (OR x ), —OC(Y 1 )R x , —OC(Y 1 )OR x , —OC(Y 1 )(N(R x )(R x )), —SC(Y 1 )R x , —SC(Y 1 )OR x , —SC(Y 1 )(N(R x )(R x )), —N(R x )C(Y 1 )R x , —N(R x )C(Y 1 )OR x , or —N(R x )C(Y 1 )(N(R x )(R x ));
  • R 3d is —C(Y 1 )R x , —C(Y 1 )OR x or —C(Y 1 )(N(R x )(R x ));
  • R 4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
  • R 5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups;
  • W 3 is W 4 or W 5 ;
  • W 4 is R 5 , —C(Y 1 )R 5 , —C(Y 1 )W 5 , —SO 2 R 5 , or —SO 2 W 5 ;
  • W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;
  • W 6 is W 3 independently substituted with 1, 2, or 3 A 3 groups
  • W 7 is a heterocycle bonded through a nitrogen atom of said heterocycle and independently substituted with 0, 1 or 2 A 0 groups;
  • M2 is 0, 1 or 2;
  • M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • M1a, M1c, and M1d are independently 0 or 1;
  • M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
  • W 5 carbocycles and W 5 heterocycles may be independently substituted with 0 to 3 R 2 groups.
  • W 5 may be a saturated, unsaturated or aromatic ring comprising a mono- or bicyclic carbocycle or heterocycle.
  • W 5 may have 3 to 10 ring atoms, e.g., 3 to 7 ring atoms.
  • the W 5 rings are saturated when containing 3 ring atoms, saturated or mono-unsaturated when containing 4 ring atoms, saturated, or mono- or di-unsaturated when containing 5 ring atoms, and saturated, mono- or di-unsaturated, or aromatic when containing 6 ring atoms.
  • a W 5 heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S).
  • W 5 heterocyclic monocycles may have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S); or 5 or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selected from N and S).
  • W 5 heterocyclic bicycles have 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S) arranged as a bicyclo [4,5], [5,5), [5,6], or [6,6] system; or 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2 hetero atoms selected from N and S) arranged as a bicyclo [5,6] or [6,6] system.
  • the W 5 heterocycle may be bonded to Y 2 through a carbon, nitrogen, sulfur or other atom by a stable covalent bond.
  • W 5 heterocycles include for example, pyridyl, dihydropyridyl isomers, piperidine, pyridazinyl pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, and pyrrolyl.
  • W 5 also includes, but is not limited to, examples such as:
  • W 5 carbocycles and heterocycles may be independently substituted with 0 to 3 R 2 groups, as defined above.
  • substituted W 5 carbocycles include:
  • substituted phenyl carbocycles include:
  • each embodiment is to be construed as representing the enumerated substituent (or assembly of substituents) in combination with each and every other substituent that is not enumerated in the embodiment. For example, if W 3 is specified in an embodiment, then W 3 is locked but the remaining substituents can be set in any combination possible within the definition of A 3 .
  • a 1 is
  • a 1 is
  • An embodiment of A 3 includes where M2 is 0, such as: and where M12b is 1, Y 1 is oxygen, and Y 2b is oxygen (O) or nitrogen (N(R x )) such as:
  • Another embodiment of A 3 is:
  • Embodiments of A 2 include where W 3 is W 5 , such as: Alternatively, A 2 is phenyl, substituted phenyl, benzyl, substituted benzyl, pyridyl or substituted pyridyl.
  • W 4 may be R 4
  • W 5a is a carbocycle or heterocycle and W 5a is optionally and independently substituted with 1, 2, or 3 R 2 groups.
  • W 5a may be 3,5-dichlorophenyl.
  • a 1 is: n is an integer from 1 to 18;
  • An embodiment of A 3 optionally is of the formula: where W 5 is a carbocycle such as phenyl or substituted phenyl. Such embodiments include: where Y 2b is O or N(R x ); M12d is 1, 2, 3, 4, 5, 6, 7 or 8; and the phenyl carbocycle is substituted with 0 to 3 R 2 groups.
  • Such embodiments of A 3 include phenyl phosphonamidate-alanate esters and phenyl phosphonate-lactate esters:
  • Embodiments of R x include esters, carbamates, carbonates, thioesters, amides, thioamides, and urea groups: and Y 2c is O, N(R y ) or S.
  • R 1 may be H and n may be 1.
  • An embodiment of A 1 optionally comprises a phosphonate group attached to an imidazole nitrogen through a heterocycle linker, such as: where Y 2b is O or N(R 2 ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • the A 3 unit may be attached at any of the W 5 carbocycle or heterocycle ring atoms, e.g. ortho, meta, or para on a disubstituted W 5 .
  • a 1 optionally is —(X 2 —(C(R 2 )(R 2 )) m1 —X 3 ) m1 -W 3 , and W 3 is substituted with 1 to 3 A 3 groups.
  • a 2 optionally is —(X 2 —(C(R 2 )(R 2 )) m1 —X 3 ) m1 —W 3 .
  • a 3 optionally is —(X 2 —(C(R 2 )(R 2 )) m1 —X 3 ) m1 —P(Y 1 )(Y 1 R 6a )(Y 1 R 6a ).
  • X 2 and X 3 optionally are independently a bond, —O—, —N(R 2 )—, —N(OR 2 )—, —N(N(R 2 )(R 2 ))—, —S—, —SO—, or —SO2—.
  • Each Y 1 optionally is independently O, N(R 2 ), N(OR 2 ), or N(N(R 2 )(R 2 )), wherein each Y 1 is bound by two single bonds or one double bond.
  • R 1 optionally is independently H or alkyl of 1 to 12 carbon atoms.
  • R 2 optionally is independently H, R 3 or R 4 wherein each R4 is independently substituted with 0 to 3 R 3 groups.
  • R 3 optionally is independently F, Cl, Br, I, —CN, N 3 , —NO 2 , —OR 6a , —OR 1 , —N(R 1 ) 2 , —N(R 1 )(R 6b ), —N(R 6b ) 2 , —SR 1 , —SR 6a , —S(O)R 1 , —S(O) 2 R 1 , —S(O)OR 1 , —S(O)OR 6a , —S(O) 2 OR 1 , —S(O) 2 OR 6a , —C(O)OR 1 , —C(O)R 6c , —C(O)OR 6a , —OC(O)R 1 , —N(R 1 )(C(O)R 1 ), —N(R 6 b)(C(O)R 1 ), —N(R 1 )(C(O)OR 1 ), —N(
  • R 4 optionally is independently alkyl of 1 to 12 carbon atorns, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms.
  • R 5 optionally is independently R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups; or Rs is independently alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, or alkynylene of 2-12 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R 3 groups.
  • R 6a is independently H or an ether- or ester-forming group.
  • R 6b is independently H, a protecting group for amino or the residue of a carboxyl-containing compound.
  • R 6c is independently H or the residue of an amino-containing compound.
  • W 4 is R 5 , —C(Y 1 )R 5 , —C(Y 1 )W 5 , —SO 2 R 5 , or —SO 2 W 5 .
  • W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups.
  • m1 is independently an integer from 0 to 12, wherein the sum of all m1's within each individual embodiment of A 1 , A 2 or A 3 is 12 or less.
  • n2 is independently an integer from 0 to 2.
  • a 1 is —(C(R 2 )(R 2 )) m1 —W 3 , wherein W 3 is substituted with 1 A 3 group,
  • a 2 is —(C(R 2 )(R 2 )) m1 —W 3 , and
  • a 3 is —(C(R 2 )(R 2 )) m1 P(Y 1 )(Y 1 R 6a )(Y 1 R 6a ).
  • a 1 is of the formula:
  • a 1 is of the formula:
  • a 1 is of the formula:
  • a 1 is of the formula:
  • W 5a is a carbocycle or a heterocycle where W 5a is independently substituted with 0 or 1 R 2 groups.
  • M12a is 1.
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • Y 1a is O or S
  • Y 2a is O, N(R x ) or S.
  • a 3 is of the formula:
  • Y 2b is O or N(R x ).
  • a 3 is of the formula:
  • Y 2b is O or N(R x );
  • M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • Y 2b is O or N(R x );
  • M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • M12d is 1.
  • a 3 is of the formula:
  • a 3 is of the formula:
  • W 5 is a carbocycle.
  • a 3 is of the formula:
  • W 5 is phenyl
  • M12b is 1.
  • Y 1a is O or S
  • Y 2a is O, N(R x ) or S.
  • a 3 is of the formula: and Y 2b is O or N(R x ).
  • a 3 is of the formula:
  • Y 2b is O or N(R x );
  • M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • R 1 is H.
  • M12d is 1.
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • Y 1a is O or S
  • Y 2c is O, N(R y ) or S.
  • Y 1a is O or S
  • Y 2d is O or N(R x ).
  • a 3 is of the formula:
  • a 3 is of the formula:
  • R x is of the formula:
  • a 3 is of the formula:
  • Y 1a is O or S
  • Y 2a is O, N(R 2 ) or S.
  • a 3 is of the formula:
  • Y 1a is O or S
  • Y 2b is O or N(R 2 );
  • Y 2c is O, N(R y ) or S.
  • a 3 is of the formula:
  • Y 1a is O or S
  • Y 2b is O or N(R 2 );
  • Y 2d is O or N(R y );
  • M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • a 3 is of the formula:
  • Y 2b is O or N(R 2 );
  • M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • a 3 is of the formula:
  • Y 2b is O or N(R 2 ).
  • a 3 is of the formula:
  • a 3 is of the formula:
  • R x is of the formula:
  • a 3 is of the formula:
  • Y 1a is O or S
  • Y 2a is O, N(R 2 ) or S.
  • a 3 is of the formula:
  • Y 1a is O or S
  • Y 2b is O or N(R 2 );
  • Y 2c is O, N(R y ) or S.
  • a 3 is of the formula:
  • Y 1a is O or S
  • Y 2b is O or N(R 2 );
  • Y 2d is O or N(R y );
  • M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • a 3 is of the formula:
  • Y 2b is O or N( 2 );
  • M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • a 3 is of the formula:
  • Y 2b is O or N(R 2 ).
  • a 1 is of the formula:
  • a 3 is of the formula:
  • a 1 is of the formula:
  • a 3 is of the formula:
  • R x is of the formula:
  • a 1 is of the formula:
  • a 3 is of the formula:
  • Y 1a is O or S
  • Y 2a is O, N(R 2 ) or S.
  • a 1 is of the formula:
  • W 5a is a carbocycle independently substituted with 0 or 1 R 2 groups
  • a 3 is of the formula:
  • Y 1a is O or S
  • Y 2b is O or N(R 2 );
  • Y 2c is O, N(R y ) or S.
  • a 1 is of the formula:
  • W 5a is a carbocycle independently substituted with 0 or 1 R 2 groups
  • a 3 is of the formula:
  • Y 1a is O or S
  • Y 2b is O or N(R 2 );
  • Y 2d is O or N(R y );
  • M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • a 1 is of the formula:
  • Y 2b is O or N(R 2 );
  • M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • a 1 is of the formula:
  • a 3 is of the formula:
  • a 1 is of the formula:
  • a 3 is of the formula:
  • R x is of the formula:
  • a 1 is of the formula:
  • a 3 is of the formula:
  • Y 1a is O or S
  • Y 2a is O, N(R 2 ) or S.
  • a 1 is of the formula:
  • W 5a is a carbocycle independently substituted with 0 or 1 R 2 groups
  • a 3 is of the formula:
  • Y 1a is O or S
  • Y 2b is O or N(R 2 );
  • Y 2c is O, N(R y ) or S.
  • a 3 is of the formula:
  • a 1 is of the formula:
  • W 5a is a carbocycle or heterocycle where W 5a is independently substituted with 0 or 1 R 2 groups;
  • a 3 is of the formula:
  • Y 1a is O or S
  • Y 2b is O or N(R 2 );
  • Y 2d is O or N(R y );
  • M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • a 1 is of the formula:
  • Y 2b is O or N(R 2 );
  • M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • a 2 is of the formula:
  • a 2 is of the formula:
  • M12b is 1.
  • M12b is 0, Y 2 is a bond and W 5 is a carbocycle or heterocycle where W 5 is optionally and independently substituted with 1, 2, or 3 R 2 groups.
  • a 2 is of the formula: and W 5a is a carbocycle or heterocycle where W 5a is optionally and independently substituted with 1, 2, or 3 R 2 groups.
  • M12a is 1.
  • a 2 is selected from phenyl, substituted phenyl, benzyl, substituted benzyl, pyridyl and substituted pyridyl.
  • a 2 is of the formula:
  • a 2 is of the formula:
  • M12b is 1.
  • a 1 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • R 4 is isopropyl.
  • a 1 is of the formula:
  • a 3 is of the formula:
  • Y 1a is O or S.
  • a 3 is of the formula:
  • Y 2a is O, N(R 2 ) or S.
  • a 3 is of the formula:
  • Y 2b is O or N(R 2 );
  • Y 2c is O, N(R y ) or S.
  • a 3 is of the formula:
  • Y 1a is O or S
  • Y 2b is O or N(R 2 );
  • Y 2d is O or N(R y );
  • M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • a 1 is of the formula:
  • Y 2b is O or N(R 2 );
  • M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • a 1 is of the formula:
  • Y 2b is O or N(R 2 );
  • M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • a 1 is of the formula:
  • n is an integer from 1 to 18;
  • a 3 is of the formula:
  • Y 2c is O, N(R y ) or S.
  • R 1 is H and n is 1.
  • a 1 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 2 is selected from:
  • W 5 is a carbocycle or a heterocycle and where W 5 is independently substituted with 0 to 3 R 2 groups.
  • a 3 is of the formula:
  • Y 2a is O, N(R 2 ) or S.
  • a 3 is of the formula:
  • Y 2c is O, N(R y ) or S.
  • a 1 is of the formula:
  • a 3 is of the formula:
  • W 5a is a carbocycle or a heterocycle where the carbocycle or heterocycle is independently substituted with 0 to 3 R 2 groups;
  • Y 2b is O or N(R 2 );
  • Y 2c is O, N(R y ) or S.
  • a 1 is of the formula:
  • a 3 is of the formula:
  • Y 1a is O or S
  • Y 2b is O or N(R 2 );
  • Y 2d is O or N(R y );
  • M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • a 1 is of the formula:
  • Y 2b is O or N(R 2 );
  • M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • a 1 is of the formula:
  • Y 2b is O or N(R 2 );
  • M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • a 2 is a phenyl substituted with 0 to 3 R 2 groups.
  • W 4 is of the formula:
  • n is an integer from 1 to 18; and Y 2b is O or N(R 2 ).
  • a 1 is —(X 2 —(C(R 2 )(R 2 )) m1 —X 3 ) m1 —W 3 , wherein W 3 is substituted with 1 to 3 A 3 groups;
  • a 2 is —(X 2 —(C(R 2 )(R 2 )) m1 —X 3 ) m1 —W 3 ;
  • a 3 is —(X 2 —(C(R 2 )(R 2 )) m1 —X 3 ) m1 —P(Y 1 )(Y 1 R 6a )(Y 1 R 6a );
  • X 2 and X 3 are independently a bond, —O—, —N(R 2 )—, —N(OR 2 )—, —N(N(R 2 )(R 2 ))—, —S—, —SO—, or —SO2—;
  • each Y 1 is independently O, N(R 2 ), N(OR 2 ), or N(N(R 2 )(R 2 )), wherein each Y 1 is bound by two single bonds or one double bond;
  • R 1 is independently H or alkyl of 1 to 12 carbon atoms
  • R 2 is independently H, R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups;
  • R 3 is independently F, Cl, Br, I, —CN, N 3 , —NO 2 , —OR 6a , —OR 1 , —N(R 1 ) 2 , —N(R 1 )(R 6b ), —N(R 6b ) 2 , —SR 1 , —SR 6a , —S(O)R 1 , —S(O) 2 R 1 , —S(O)OR 1 , —S(O)OR 6a , —S(O) 2 OR 1 , —S(O) 2 OR 6a , —C(O)OR 1 , —C(O)R 6c , —C(O)OR 6a , —OC(O)R 1 , —N(R 1 )(C(O)R 1 ), —N(R 6b )(C(O)R 1 ), —N(R 1 )(C(O)OR 1 ), —N(R 6
  • R 4 is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;
  • R 5 is independently R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups;
  • R 5a is independently alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, or alkynylene of 2-12 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R 3 groups;
  • R 6a is independently H or an ether- or ester-forming group
  • R 6b is independently H, a protecting group for amino or the residue of a carboxyl-containing compound
  • R 6c is independently H or the residue of an amino-containing compound
  • W 3 is W 4 or W 5 ;
  • W 4 is R 5 , —C(Y 1 )R 5 , —C(Y 1 )W 5 , —SO 2 R 5 , or —SO 2 W 5 ;
  • W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;
  • m1 is independently an integer from 0 to 12, wherein the sum of all m1's within each individual embodiment of A 1 , A 2 or A 3 is 12 or less;
  • n2 is independently an integer from 0 to 2.
  • a 1 is —(C(R 2 )(R 2 )) m1 —W 3 , wherein W 3 is substituted with 1 A 3 group;
  • a 2 is —(C(R 2 )(R 2 )) m1 —W 3 ;
  • a 3 is —(C(R 2 )(R 2 )) m1 —P(Y 1 )(Y 1 R 6a )(Y 1 R 6a ).
  • the chemical substructure of a protecting group varies widely.
  • One function of a protecting group is to serve as intermediates in the synthesis of the parental drug substance.
  • Chemical protecting groups and strategies for protection/deprotection are well known in the art. See: “Protective Groups in Organic Chemistry”, Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991.
  • Protecting groups are often utilize to mask the reactivity of certain functional groups, to assist in the efficiency of desired chemical reactions, e.g. making and breaking chemical bonds in an ordered and planned fashion. Protection of functional groups of nal group, such as the polarity, lipophilicity (hydrophobicity), and other properties which can be measured by common analytical tools.
  • Chemically protected intermediates may themselves be biologically active or inactive.
  • Protected compounds may also exhibit altered, and in some cases, optimized properties in vitro and in vivo, such as passage through cellular membranes and resistance to enzymatic degradation or sequestration. In this role, protected compounds may in themselves exhibit therapeutic activity and need not be limited to the role of chemical intermediates or precursors.
  • the protecting group need not be physiologically acceptable upon deprotection, although in general it is more desirable if such products are pharmacologically innocuous a compound alters other physical properties besides the reactivity of the protected function.
  • protecting groups include prodrug moieties and chemical protecting groups.
  • Protecting groups are available, commonly known and used, and are optionally used to prevent side reactions with the protected group during synthetic procedures, i.e. routes or methods to prepare the compounds of the invention. For the most part the decision as to which groups to protect, when to do so, and the nature of the chemical protecting group “PRT” will be dependent upon the chemistry of the reaction to be protected against (e.g., acidic, basic, oxidative, reductive or other conditions) and the intended direction of the synthesis. The PRT groups do not need to be, and generally are not, the same if the compound is substituted with multiple PRT. In general, PRT will be used to protect functional groups such as carboxyl, hydroxyl or amino groups and to thus prevent side reactions or to otherwise facilitate the synthetic efficiency. The order of deprotection to yield free, deprotected groups is dependent upon the intended direction of the synthesis and the reaction conditions to be encountered, and may occur in any order as determined by the artisan.
  • Various functional groups of the compounds of the invention may be protection.
  • protecting groups for —OH groups are embodiments of “ether- or ester-forming groups”.
  • Ether- or ester-forming groups are capable of functioning as chemical protecting groups in the synthetic schemes set forth herein.
  • some hydroxyl and thio protecting groups are neither ether- nor ester-forming groups, as will be understood by those skilled in the art, and are included with amides, discussed below.
  • Ester-forming groups include: (1) phosphonate ester-forming groups, such as phosphonamidate esters, phosphorothioate esters, phosphonate esters, and phosphon-bis-amidates; (2) carboxyl ester-forming groups, and (3) sulphur ester-forming groups, such as sulphonate, sulfate, and sulfinate.
  • phosphonate ester-forming groups such as phosphonamidate esters, phosphorothioate esters, phosphonate esters, and phosphon-bis-amidates
  • carboxyl ester-forming groups such as sulphonate, sulfate, and sulfinate.
  • the phosphonate moieties of the compounds of the invention may or may not be prodrug moieties, i.e. they may or may be susceptible to hydrolytic or enzymatic cleavage or modification. Certain phosphonate moieties are stable under most or nearly all metabolic conditions. For example, a dialkylphosphonate, where the alkyl groups are two or more carbons, may have appreciable stability in vivo due to a slow rate of hydrolysis.
  • phosphonate prodrug moieties a large number of structurally-diverse prodrugs have been described for phosphonic acids (Freeman and Ross in Progress in Medicinal Chemistry 34: 112-147 (1997) and are included within the scope of the present invention.
  • An exemplary embodiment of a phosphonate ester-forming group is the phenyl carbocycle in substructure A 3 having the formula:
  • m1 is 1, 2, 3, 4, 5, 6, 7 or 8, and the phenyl carbocycle is substituted with 0 to 3 R 2 groups.
  • Y 1 is O
  • a lactate ester is formed.
  • R 1 may be H or C 1 -C 12 alkyl.
  • a protecting group typically is bound to any acidic group such as, by way of example and not limitation, a —CO 2 H or —C(S)OH group, thereby resulting in —CO 2 R x where R x is defined herein.
  • R x for example includes the enumerated ester groups of WO 95/07920.
  • protecting groups include:
  • C 3 -C 12 heterocycle (described above) or aryl.
  • aromatic groups optionally are polycyclic or monocyclic. Examples include phenyl, spiryl, 2- and 3-pyrrolyl, 2- and 3-thienyl, 2- and 4-imidazolyl, 2-, 4- and 5-oxazolyl, 3- and 4-isoxazolyl, 2-, 4- and 5-thiazolyl, 3-, 4- and 5-isothiazolyl, 3- and 4-pyrazolyl, 1-, 2-, 3- and 4-pyridinyl, and 1-, 2-, 4- and 5-pyrimidinyl, C 3 -C 12 heterocycle or aryl substituted with halo, R 1 , R 1 —O—C 1 -C 12 alkylene, C 1 -C 12 alkoxy, CN, NO 2 , OH, carboxy, carboxyester, thiol, thioester, C 1 -C 12 haloalkyl (1-6 halogen atoms), C 2 -C 12 alken
  • Such groups include 2-, 3- and 4-alkoxyphenyl (C 1 -C 12 alkyl), 2-, 3- and 4-methoxyphenyl, 2-, 3- and 4-ethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-diethoxyphenyl.
  • triglycerides such as ⁇ -D- ⁇ -diglycerides (wherein the fatty acids composing glyceride lipids generally are naturally occurring saturated or unsaturated C 6-26 , C 6-18 or C 6-10 fatty acids such as linoleic, lauric, myristic, palnitic, stearic, oleic, palmitoleic, linolenic and the like fatty acids) linked to acyl of the parental compounds herein through a glyceryl oxygen of the triglyceride;
  • cyclic carbonates such as (5-R d -2-oxo-1,3-dioxolen-4-yl) methyl esters (Sakamoto et al., Chem. Pharm. Bull (1984) 32(6)2241-2248) where R d is R 1 , R 4 or aryl; and
  • hydroxyl groups of the compounds of this invention optionally are substituted with one of groups III, IV or V disclosed in WO 94/21604, or with isopropyl.
  • Table A lists examples of protecting group ester moieties that for example can be bonded via oxygen to —C(O)O— and —P(O)(O—) 2 groups. Several amidates also are shown, which are bound directly to —C(O)— or —P(O) 2 .
  • Esters of structures 1-5, 8-10 and 16, 17, 19-22 are synthesized by reacting the compound herein having a free hydroxyl with the corresponding halide (chloride or acyl chloride and the like) and N,N-dicyclohexyl-N-morpholine carboxamidine (or another base such as DBU, triethylamine, CsCO 3 , N,N-dimethylaniline and the like) in DMF (or other solvent such as acetonitrile or N-methylpyrrolidone).
  • halide chloride or acyl chloride and the like
  • N,N-dicyclohexyl-N-morpholine carboxamidine or another base such as DBU, triethylamine, CsCO 3 , N,N-dimethylaniline and the like
  • DMF or other solvent such as acetonitrile or N-methylpyrrolidone
  • the esters of structures 5-7, 11, 12, 21, and 23-26 are synthesized by reaction of the alcohol or alkoxide salt (or the corresponding amines in the case of compounds such as 13, 14 and 15) with the monochlorophosphonate or dichlorophosphonate (or another activated phosphonate).
  • TABLE A 1. —CH 2 —C(O)—N(R 1 ) 2 * 2. —CH 2 —S(O)(R 1 ) 3. —CH 2 —S(O) 2 (R 1 ) 4. —CH 2 —O—C(O)—H 2 —C 6 H 5 5.
  • —CH 2 —O—C(O)—C 6 H 5 9. —CH 2 —O—C(O)—CH 2 CH 3 10. —CH 2 —O—C(O)—C(CH 3 ) 3 11. —CH 2 —CCl 3 12. —C 6 H 5 13. —NH—CH 2 —C(O)O—CH 2 CH 3 14. —N(CH 3 )—CH 2 —C(O)O—CH 2 CH 3 15. —NHR 1 16. —CH 2 —O—C(O)—C 10 H 15 17. —CH 2 —O—C(O)—CH(CH 3 ) 2 18.
  • Protecting groups also includes “double ester” forming profunctionalities such as —CH 2 OC(O)OCH 3 , —CH 2 SCOCH 3 , —CH 2 OCON(CH 3 ) 2 , or alkyl- or aryl-acyloxyalkyl groups of the structure —CH(R 1 or W 5 )O((CO)R 37 ) or —CH(R 1 or W 5 )((CO)OR 38 ) (linked to oxygen of the acidic group) wherein R 37 and R 38 are alkyl, aryl, or alkylaryl groups (see U.S. Pat. No. 4,968,788).
  • R 37 and R 38 are bulky groups such as branched alkyl, ortho-substituted aryl, meta-substituted aryl, or combinations thereof, including normal, secondary, iso- and tertiary alkyls of 1-6 carbon atoms.
  • An example is the pivaloyloxymethyl group.
  • alkylacyloxymethyl esters and their derivatives including —CH(CH 2 CH 2 OCH 3 )OC(O)C(CH 3 ) 3 , CH 2 OC(O)C 10 H 15 , —CH 2 OC(O)C(CH 3 ) 3 , —CH(CH 2 OCH 3 )OC(O)C(CH 3 ) 3 , —CH(CH(CH 3 ) 2 )OC(O)C(CH 3 ) 3 , —CH 2 OC(O)CH 2 CH(CH 3 ) 2 , —CH 2 OC(O)C 6 H 11 , —CH 2 OC(O)C 6 H 5 , —CH 2 OC(O)C 10 H 15 , —CH 2 OC(O)CH 2 CH 3 , —CH 2 OC(O)CH(CH 3 ) 2 , —CH 2 OC(O)C(CH 3 ) 3 and —CH 2 OC(O)CH 2
  • the ester typically chosen is one heretofore used for antibiotic drugs, in particular the cyclic carbonates, double esters, or the phthalidyl, aryl or alkyl esters.
  • the protected acidic group is an ester of the acidic group and is the residue of a hydroxyl-containing functionality.
  • an amino compound is used to protect the acid functionality.
  • the residues of suitable hydroxyl or amino-containing functionalities are set forth above or are found in WO 95/07920.
  • residues of amino acids, amino acid esters, polypeptides, or aryl alcohols are described on pages 11-18 and related text of WO 95/07920 as groups L1 or L2.
  • WO 95/07920 expressly teaches the amidates of phosphonic acids, but it will be understood that such amidates are formed with any of the acid groups set forth herein and the amino acid residues set forth in WO 95/07920.
  • Typical esters for protecting acidic functionalities are also described in WO 95/07920, again understanding that the same esters can be formed with the acidic groups herein as with the phosphonate of the '920 publication.
  • Typical ester groups are defined at least on WO 95/07920 pages 89-93 (under R 31 or R 35 ), the table on page 105, and pages 21-23 (as R).
  • esters of unsubstituted aryl such as phenyl or arylalkyl such benzyl, or hydroxy-, halo-, alkoxy-, carboxy- and/or alkylestercarboxy-substituted aryl or alkylaryl especially phenyl, ortho-ethoxyphenyl, or C 1 -C 4 alkylestercarboxyphenyl (salicylate C 1 -C 12 alkylesters).
  • the protected acidic groups are useful as prodrugs for oral administration. However, it is not essential that the acidic group be protected in order for the compounds of this invention to be effectively administered by the oral route.
  • the compounds of the invention having protected groups in particular amino acid amidates or substituted and unsubstituted aryl esters are administered systemically or orally they are capable of hydrolytic cleavage in vivo to yield the free acid.
  • One or more of the acidic hydroxyls are protected. If more than one acidic hydroxyl is protected then the same or a different protecting group is employed, e.g., the esters may be different or the same, or a mixed amidate and ester may be used.
  • Typical hydroxy protecting groups described in Greene include substituted methyl and alkyl ethers, substituted benzyl ethers, silyl ethers, esters including sulfonic acid esters, and carbonates.
  • substituted methyl and alkyl ethers include substituted methyl and alkyl ethers, substituted benzyl ethers, silyl ethers, esters including sulfonic acid esters, and carbonates.
  • 1,2-diol protecting groups include those shown in Table B, still more typically, epoxides, acetonides, cyclic ketals and aryl acetals. TABLE B wherein R 9 is C 1 -C 6 alkyl.
  • Another set of protecting groups include any of the typical amino protecting groups described by Greene at pages 315-385. They include:
  • protected amino groups include carbamates and amides, still more typically, —NHC(O)R 1 or —N ⁇ CR 1 N(R 1 ) 2 .
  • Another protecting group, also useful as a prodrug for amino or —NH(R 5 ), is: See for example Alexander, J. et al (1996) J. Med. Chem. 39:480486.
  • An amino acid or polypeptide protecting group of a compound of the invention has the structure R 15 NHCH(R 16 )C(O)—, where R 15 is H, an amino acid or polypeptide residue, or R 5 , and R 16 is defined below.
  • R 16 is lower alkyl or lower alkyl (C 1 -C 6 ) substituted with amino, carboxyl, amide, carboxyl ester, hydroxyl, C 6 -C 7 aryl, guanidinyl, imidazolyl, indolyl, sulfhydryl, sulfoxide, and/or alkylphosphate.
  • R 10 also is taken together with the amino acid ⁇ N to form a proline residue (R 10 ⁇ —CH 2 ) 3 —).
  • R 10 is generally the side group of a naturally-occurring amino acid such as H, —CH 3 , —CH(CH 3 ) 2 , —CH 2 —CH(CH 3 ) 2 , —CHCH 3 —CH 2 —CH 3 , —CH 2 —C 6 H 5 , —CH 2 CH 2 —S—CH 3 , —CH 2 OH, —CH(OH)—CH 3 , —CH 2 —SH, —CH 2 —C 6 H 4 OH, —CH 2 —CO—NH 2 , —CH 2 —CH 2 —CO—NH 2 , —CH 2 —COOH, —CH 2 —CH 2 —COOH, —(CH 2 ) 4 —NH 2 and —(CH 2 ) 3 —NH—C(NH 2 )—NH 2 .
  • R 10 also includes 1-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl, imidazol-4-y
  • Another set of protecting groups include the residue of an amino-containing compound, in particular an amino acid, a polypeptide, a protecting group, —NHSO 2 R, NHC(O)R, —N(R) 2 , NH 2 or —NH(R)(H), whereby for example a carboxylic acid is reacted, i.e. coupled, with the amine to form an amide, as in C(O)NR 2 .
  • a phosphonic acid may be reacted with the amine to form a phosphonamidate, as in —P(O)(OR)(NR 2 ).
  • amino acids have the structure R 17 C(O)CH(R 16 )NH—, where R 17 is —OH, —OR, an amino acid or a polypeptide residue.
  • Amino acids are low molecular weight compounds, on the order of less than about 1000 MW and which contain at least one amino or imino group and at least one carboxyl group. Generally the amino acids will be found in nature, i.e., can be detected in biological material such as bacteria or other microbes, plants, animals or man.
  • Suitable amino acids typically are alpha amino acids, i.e. compounds characterized by one amino or imino nitrogen atom separated from the carbon atom of one carboxyl group by a single substituted or unsubstituted alpha carbon atom.
  • hydrophobic residues such as mono-or di-alkyl or aryl amino acids, cycloalkylamino acids and the like. These residues contribute to cell permeability by increasing the partition coefficient of the parental drug. Typically, the residue does not contain a sulfhydryl or guanidino substituent.
  • Naturally-occurring amino acid residues are those residues found naturally in plants, animals or microbes, especially proteins thereof. Polypeptides most typically will be substantially composed of such naturally-occurring amino acid residues. These amino acids are glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, glutamic acid, aspartic acid, lysine, hydroxylysine, arginine, histidine, phenylalanine, tyrosine, tryptophan, proline, asparagine, glutamine and hydroxyproline. Additionally, unnatural amino acids, for example, valanine, phenylglycine and homoarginine are also included.
  • amino acids that are not gene-encoded may also be used in the present invention. All of the amino acids used in the present invention may be either the D- or L-optical isomer. In addition, other peptidomimetics are also useful in the present invention. For a general review, see Spatola, A. F., in Chemistry and Biochemistry of Amino Acids, Peptides and Proteins, B. Weinstein, eds., Marcel Dekker, New York, p. 267 (1983).
  • protecting groups are single amino acid residues or polypeptides they optionally are substituted at R 3 of substituents A 1 , A 2 or A 3 , or substituted at R 3 of substituents A 1 , A 2 or A 3 .
  • These conjugates are produced by forming an amide bond between a carboxyl group of the amino acid (or C-terminal amino acid of a polypeptide for example).
  • conjugates are formed between R 3 or R 3 and an amino group of an amino acid or polypeptide.
  • only one of any site in the parental molecule is amidated with an amino acid as described herein, although it is within the scope of this invention to introduce amino acids at more than one permitted site.
  • a carboxyl group of R 3 is amidated with an amino acid.
  • the ⁇ -amino or ⁇ -carboxyl group of the amino acid or the terminal amino or carboxyl group of a polypeptide are bonded to the parental functionalities, i.e., carboxyl or amino groups in the amino acid side chains generally are not used to form the amide bonds with the parental compound (although these groups may need to be protected during synthesis of the conjugates as described further below).
  • carboxyl-containing side chains of amino acids or polypeptides it will be understood that the carboxyl group optionally will be blocked, e.g. by R 1 , esterified with R 5 or amidated. Similarly, the amino side chains R 16 optionally will be blocked with R 1 or substituted with R 5 .
  • esters or amide bonds with side chain amino or carboxyl groups like the esters or amides with the parental molecule, optionally are hydrolyzable in vivo or in vitro under acidic (pH ⁇ 3) or basic (pH>10) conditions. Alternatively, they are substantially stable in the gastrointestinal tract of humans but are hydrolyzed enzymatically in blood or in intracellular environments.
  • the esters or amino acid or polypeptide amidates also are useful as intermediates for the preparation of the parental molecule containing free amino or carboxyl groups.
  • the free acid or base of the parental compound for example, is readily formed from the esters or amino acid or polypeptide conjugates of this invention by conventional hydrolysis procedures.
  • any of the D, L, meso, threo or erythro (as appropriate) racemates, scalemates or mixtures thereof may be used.
  • the intermediates are to be hydrolyzed non-enzymatically (as would be the case where the amides are used as chemical intermediates for the free acids or free amines)
  • D isomers are useful.
  • the linkerisomers are more versatile since they can be susceptible to both non-enzymatic and enzymatic hydrolysis, and are more efficiently transported by amino acid or dipeptidyl transport systems in the gastrointestinal tract.
  • R x or R y examples include the following:
  • Aminopolycarboxylic acids e.g., aspartic acid, ⁇ -hydroxyaspartic acid, glutamic acid, ⁇ -hydroxyglutamic acid, ⁇ -methylaspartic acid, ⁇ -methylglutamic acid, ⁇ , ⁇ -dimethylaspartic acid, ⁇ -hydroxyglutamic acid, ⁇ , ⁇ -dihydroxyglutamic acid, ⁇ -phenylglutamic acid, ⁇ -methyleneglutamic acid, 3-aminoadipic acid, 2-aminopimelic acid, 2-aminosuberic acid and 2-aminosebacic acid;
  • Amino acid amides such as glutamine and asparagine
  • Polyamino- or polybasic-monocarboxylic acids such as arginine, lysine, ⁇ -aminoalanine, ⁇ -aminobutyrine, ornithine, citruline, homoarginine, homocitrulline, hydroxylysine, allohydroxylsine and diaminobutyric acid;
  • Diaminodicarboxylic acids such as ⁇ , ⁇ ′-diaminosuccinic acid, ⁇ , ⁇ ′-diaminoglutaric acid, ⁇ , ⁇ ′-diaminoadipic acid, ⁇ , ⁇ ′-diamninopimelic acid, ⁇ , ⁇ ′-diamino- ⁇ -hydroxypimelic acid, ⁇ , ⁇ ′-diaminosuberic acid, ⁇ , ⁇ ′-diaminoazelaic acid, and ⁇ , ⁇ ′-diaminosebacic acid;
  • Imino acids such as proline, hydroxyproline, allohydroxyproline, ⁇ -methylproline, pipecolic acid, 5-hydroxypipecolic acid, and azetidine-2-carboxylic acid;
  • a mono- or di-alkyl (typically C 1 -C 8 branched or normal) amino acid such as alanine, valine, leucine, allylglycine, butyrine, norvaline, norleucine, heptyline, ⁇ -methylserine, ⁇ -amino- ⁇ -methyl- ⁇ -hydroxyvaleric acid, ⁇ -amino- ⁇ -methyl- ⁇ -hydroxyvaleric acid, ⁇ -amino- ⁇ -methyl- ⁇ -hydroxycaproic acid, isovaline, ⁇ -methylglutamic acid, ⁇ -aaminoisobutyric acid, ⁇ -aminodiethylacetic acid, ⁇ -aminodiisopropylacetic acid, ⁇ -aminodi-n-propylacetic acid, ⁇ -aminodiisobutylacetic acid, ⁇ -amninodi-n-butylacetic acid, ⁇ -aminoethylisopropylacetic acid
  • Aliphatic ⁇ -amino- ⁇ -hydroxy acids such as serine, ⁇ -hydroxyleucine, ⁇ -hydroxynorleucine, ⁇ -hydroxynorvaline, and ⁇ -amino- ⁇ -hydroxystearic acid;
  • ⁇ -Amino, ⁇ -, ⁇ -, ⁇ - or ⁇ -hydroxy acids such as homoserine, ⁇ -hydroxynorvaline, ⁇ -hydroxynorvaline and ⁇ -hydroxynorleucine residues; canavine and canaline; ⁇ -hydroxyornithine;
  • 2-hexosaminic acids such as D-glucosaminic acid or D-galactosaminic acid
  • ⁇ -Amino- ⁇ -thiols such as penicillamine, ⁇ -thiolnorvaline or ⁇ -thiolbutyrine;
  • cysteine Other sulfur containing amino acid residues including cysteine; homocystine, ⁇ -phenylmethionine, methionine, S-allyl-L-cysteine sulfoxide, 2-thiolhistidine, cystathionine, and thiol ethers of cysteine or homocysteine;
  • Phenylalanine, tryptophan and ring-substituted a-amino acids such as the phenyl- or cyclohexylamino acids ⁇ -aminophenylacetic acid, ⁇ -aminocyclohexylacetic acid and ⁇ -amino- ⁇ -cyclohexylpropionic acid; phenylalanine analogues and derivatives comprising aryl, lower alkyl, hydroxy, guanidino, oxyalkylether, nitro, sulfur or halo-substituted phenyl (e.g., tyrosine, methyltyrosine and o-chloro-, p-chloro-, 3,4-dichloro, o-, m- or p-methyl-, 2,4,6-trimethyl-, 2-ethoxy-5-nitro-, 2-hydroxy-5-nitro- and p-nitro-phenylalanine); furyl-, thienyl-,
  • ⁇ -Amino substituted amino acids including sarcosine (N-methylglycine), N-benzylglycine, N-methylalanine, N-benzylalanine, N-methylphenylalanine, N-benzylphenylalanine, N-methylvaline and N-benzylvaline; and
  • ⁇ -Hydroxy and substituted ⁇ -hydroxy amino acids including serine, threonine, allothreonine, phosphoserine and phosphothreonine.
  • Polypeptides are polymers of amino acids in which a carboxyl group of one amino acid monomer is bonded to an amino or imino group of the next amino acid monomer by an amide bond.
  • Polypeptides include dipeptides, low molecular weight polypeptides (about 1500-5000 MW) and proteins. Proteins optionally contain 3, 5, 10, 50, 75, 100 or more residues, and suitably are substantially sequence-homologous with human, animal, plant or microbial proteins. They include enzymes (e.g., hydrogen peroxidase) as well as immunogens such as KLH, or antibodies or proteins of any type against which one wishes to raise an immune response. The nature and identity of the polypeptide may vary widely.
  • polypeptide amidates are useful as immunogens in raising antibodies against either the polypeptide (if it is not immunogenic in the animal to which it is administered) or against the epitopes on the remainder of the compound of this invention.
  • Antibodies capable of binding to the parental non-peptidyl compound are used to separate the parental compound from mixtures, for example in diagnosis or manufacturing of the parental compound.
  • the conjugates of parental compound and polypeptide generally are more immunogenic than the polypeptides in closely homologous animals, and therefore make the polypeptide more immunogenic for facilitating raising antibodies against it. Accordingly, the polypeptide or protein may not need to be immunogenic in an animal typically used to raise antibodies, e.g., rabbit, mouse, horse, or rat, but the final product conjugate should be immunogenic in at least one of such animals.
  • the polypeptide optionally contains a peptidolytic enzyme cleavage site at the peptide bond between the first and second residues adjacent to the acidic heteroatom. Such cleavage sites are flanked by enzymatic recognition structures, e.g. a particular sequence of residues recognized by a peptidolytic enzyme.
  • Peptidolytic enzymes for cleaving the polypeptide conjugates of this invention are well known, and in particular include carboxypeptidases.
  • Carboxypeptidases digest polypeptides by removing C-terminal residues, and are specific in many instances for particular C-terminal sequences.
  • Such enzymes and their substrate requirements in general are well known.
  • a dipeptide (having a given pair of residues and a free carboxyl terminus) is covalently bonded through its a-amino group to the phosphorus or carbon atoms of the compounds herein.
  • W 1 is phosphonate it is expected that this peptide will be cleaved by the appropriate peptidolytic enzyme, leaving the carboxyl of the proximal amino acid residue to autocatalytically cleave the phosphonoamidate bond.
  • Suitable dipeptidyl groups are AA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK, AM, AF, AP, AS, AT, AW, AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, RM, RF, RP, RS, RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL, NK, NM, NF, NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG, DH, DI, DL, DK, DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, C
  • Tripeptide residues are also useful as protecting groups.
  • the sequence —X 4 -pro-X 5 — (where X 4 is any amino acid residue and X 5 is an amino acid residue, a carboxyl ester of proline, or hydrogen) will be cleaved by luminal carboxypeptidase to yield X 4 with a free carboxyl, which in turn is expected to autocatalytically cleave the phosphonoamidate bond.
  • the carboxy group of X 5 optionally is esterified with benzyl.
  • Dipeptide or tripeptide species can be selected on the basis of known transport properties and/or susceptibility to peptidases that can affect transport to intestinal mucosal or other cell types.
  • Dipeptides and tripeptides lacking an a-amino group are transport substrates for the peptide transporter found in brush border membrane of intestinal mucosal cells (Bai, J. P. F., (1992) Pharm. Res. 9:969-978.
  • Transport competent peptides can thus be used to enhance bioavailability of the amidate compounds.
  • Di- or tripeptides having one or more amino acids in the D configuration are also compatible with peptide transport and can be utilized in the amidate compounds of this invention.
  • Amino acids in the D configuration can be used to reduce the susceptibility of a di- or tripeptide to hydrolysis by proteases common to the brush border such as aminopeptidase N.
  • di- or tripeptides alternatively are selected on the basis of their relative resistance to hydrolysis by proteases found in the lumen of the intestine.
  • tripeptides or polypeptides lacking asp and/or glu are poor substrates for aminopeptidase A
  • di- or tripeptides lacking amino acid residues on the N-terminal side of hydrophobic amino acids are poor substrates for endopeptidase
  • peptides lacking a pro residue at the penultimate position at a free carboxyl terminus are poor substrates for carboxypeptidase P.
  • Similar considerations can also be applied to the selection of peptides that are either relatively resistant or relatively susceptible to hydrolysis by cytosolic, renal, hepatic, serum or other peptidases.
  • Such poorly cleaved polypeptide amidates are immunogens or are useful for bonding to proteins in order to prepare immunogens.
  • Prototype compounds contain at least one functional group capable of bonding to the phosphorus atom in the phosphonate moiety.
  • the phosphonate candidate compounds are cleaved intracellularly after they have reached the desired site of action, e.g., inside a lymphoid cell. The mechanism by which this occurs is further described below in the examples. As noted, the free acid of the phosphonate is phosphorylated in the cell.
  • the prototype compound contains multiple reactive hydroxyl functions, a mixture of intermediates and final products may be obtained.
  • all hydroxy groups are approximately equally reactive, there is not expected to be a single, predominant product, as each mono-substituted product will be obtained in approximately equal amounts, while a lesser amount of multiple-substituted candidate compound will also result.
  • one of the hydroxyl groups will be more susceptible to substitution than the other(s), e.g. a primary hydroxyl will be more reactive than a secondary hydroxyl, an unhindered hydroxyl will be more reactive than a hindered one. Consequently, the major product will be a mono-substituted one in which the most reactive hydroxyl has been derivatized while other mono-substituted and multiply-substituted products may be obtained as minor products.
  • the candidate compounds may have chiral centers, e.g. chiral carbon or phosphorus atoms.
  • the compounds thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers.
  • the compounds include enriched or resolved optical isomers at any or all asynmmetric, chiral atoms.
  • the chiral centers apparent from the depictions are provided as the chiral isomers or racemic mixtures. Both racemic and diastereomeric mixtures, as well as the individual optical isomers isolated or synthesized, substantially free of their enantiomeric or diastereomeric partners, are all suitable for use as candidate compounds.
  • racemic mixtures are separated into their individual substantially optically pure isomers through well-known techniques such as, for example, the separation of diastereomeric salts formed with optically active adjuncts, e.g., acids or bases followed by conversion back to the optically active substances.
  • optically active adjuncts e.g., acids or bases
  • the desired optical isomer is synthesized by means of stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material.
  • the compounds can also exist as tautomeric isomers in certain cases. All though only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention.
  • ene-amine tautomers can exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and all their possible tautomeric forms are within the scope of the invention.
  • the optimal absolute configuration at the phosphorus atom for use in candidate compounds is that of GS-7340, depicted in the examples.
  • any reference to any of the compounds of the invention also includes a reference to a physiologically acceptable salt thereof.
  • physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX 4 + (wherein X is C 1 -C 4 alkyl).
  • Physiologically acceptable salts of a hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
  • organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids
  • organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids
  • Physiologically acceptable salts of a compound of an hydroxy group include the anion of said compound in combination with a suitable cation such as Na + and NX 4 + (wherein X is independently selected from H or a C 1 -C 4 alkyl group).
  • salts of active ingredients of the candidate compounds will be physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base.
  • salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present invention.
  • non-toxic salts of candidate compounds containing, for example, Na + , Li + , K + , Ca +2 and Mg +2 fall within the scope herein.
  • Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid.
  • Monovalent salts are preferred if a water soluble salt is desired.
  • Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention.
  • metal salts which are prepared in this way are salts containing Li + , Na + , and K + .
  • a less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
  • compositions herein comprise compounds of the invention in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
  • Salts of the candidate compounds with amino acids also fall within the scope of this invention.
  • Any of the amino acids described above are suitable, especially the naturally-occurring amino acids found as protein components, although the amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
  • the anti-HIV activity of a candidate compound is assayed by any method heretofore known for determining inhibition of growth, replication, or other characteristic of HIV infection, including direct and indirect methods of detecting HIV activity. Quantitative, qualitative, and semiquantitative methods of determining HIV activity are all contemplated. Typically any one of the in vitro or cell culture screening methods known to the art are employed, as are clinical trials in humans, studies in animal models (SIV), and the like. In screening candidate compounds it should be kept in mind that the results of enzyme assays may not correlate with cell culture assays. Thus, a cell based assay is often the primary screening tool.
  • Candidate compounds having an in vitro Ki (inhibitory constant) of less then about 5 ⁇ 10 ⁇ 6 M, typically less than about 1 ⁇ 10 ⁇ 7 M and preferably less than about 5 ⁇ 10 ⁇ 8 M are preferred for in vivo development, but the analytical point of selection of a candidate compound for further development is essentially a matter of choice.
  • Candidate compounds selected for further development in vivo are formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as those set forth in the “Handbook of Pharmaceutical Excipients” (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. The pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10.
  • the formulations both for veterinary and for human use, of the invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients.
  • the carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
  • the formulations include those suitable for the foregoing administration routes.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remnington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of candidate compounds 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 is 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, lubricant, inert diluent, preservative, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.
  • the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w.
  • the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax
  • the wax together with the oil and fat make up the so-called emulsifyng ointment base which forms the oily dispersed phase of the cream formulations.
  • Emulgents and emulsion stabilizers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used.
  • compositions according to the present invention comprise a combination according to the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
  • Pharmaceutical formulations 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.
  • 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 candidate compounds 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.
  • the pharmaceutical compositions of the candidate compounds may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • 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 (weight:weight).
  • the pharmaceutical composition can be prepared to provide easily measurable amounts for administration.
  • an aqueous solution intended for intravenous infusion may contain from about 3 to 500 ⁇ 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 suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • the active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis 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 intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range between 0.1 and 500 microns in increments microns such as 0.5, 1, 30 microns, 35 microns, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.
  • Suitable formulations include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of HIV infections as described below.
  • 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 sterile injection solutions which may contain anti-oxidants, 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 are presented in unit-dose or multi-dose containers, for example sealed 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 injection, immediately prior to use.
  • sterile liquid carrier for example water for injection
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
  • formulations of candidate compounds may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.
  • controlled release formulations in which the release of the active ingredient are controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient.
  • An effective dose of candidate compound depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses) or against an active HIV infection, the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. It can be expected to be from about 0.0001 to about 100 mg/kg body weight per day. Typically, from about 0.01 to about 10 mg/kg body weight per day. More typically, from about 0.01 to about 5 mg/kg body weight per day. More typically, from about 0.05 to about 0.5 mg/kg body weight per day.
  • the daily candidate dose for an adult human of approximately 70 kg body weight will range from 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and may take the form of single or multiple doses.
  • One or more candidate compounds are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the recipient.
  • An advantage of the compounds of this invention is that they are orally bioavailable and can be dosed orally.
  • Candidate compound are also used in combination with other active ingredients. Such combinations are selected based on the condition to be treated, cross-reactivities of ingredients and pharmaco- compounds.
  • Other active ingredients include adefovir dipivoxil and/or any other product currently marketed for therapy of HIV infection.properties. It is also possible to combine any compound of the invention with one or more other active ingredients in a unitary dosage form for simultaneous or sequential administration to an HIV infected patient.
  • the combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.
  • Second and third active ingredients in the combination may have anti-HIV activity and include HIV.
  • the combination therapy may be synergistic, i.e. the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.
  • a synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen.
  • a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g. in separate tablets, pills or capsules, or by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e. serially
  • effective dosages of two or more active ingredients are administered together.
  • a synergistic anti-viral effect denotes an antiviral effect which is greater than the predicted purely additive effects of the individual compounds of the combination.
  • the candidate compounds are metabolized in vivo.
  • the group R x is hydrolytically cleaved to produce a charged metabolite, and in some cases the substituents on the phosphonate such as —Y 2 [P(( ⁇ Y 1 )(Y 2 )) m2 R x ] 2 are hydrolyzed as well.
  • An example showing exemplary metabolites is found in the examples herein. While this example is concerned with the metabolites of GS-7340, a nucleotide analogue, the metabolic changes to be found with candidate compounds are believed to be substantially the same at the phosphonate substituent.
  • This charged metabolite functions as an intracellular depot form of the candidate.
  • candidate compounds include metabolites of candidate compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.
  • Such products typically are identified by preparing a radiolabelled (e.g. C 14 or H 3 ) compound of the invention, administering it parenterally in a detectable dose (e.g.
  • metabolite structures are determined in conventional fashion, e.g. by MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well-known to those skilled in the art.
  • the conversion products so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the candidate compounds even if they possess no HIV inhibitory activity of their own.
  • the candidate compounds are prepared by any of the applicable techniques of organic synthesis. Many such techniques are well known in the art. However, many of the known techniques are elaborated in “Compendium of Organic Synthetic Methods” (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6, Michael B. Smith; as well as March, J., “Advanced Organic Chemistry, Third Edition”, (John Wiley & Sons, New York, 1985), “Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency in Modern Organic Chemistry. In 9 Volumes”, Barry M. Trost, Editor-in-Chief (Pergamon Press, New York, 1993 printing).
  • Dialkyl phosphonates may be prepared according to the methods of: Quast etal (1974) Synthesis 490; Stowell et al (1990) Tetrahedron Lett. 3261; U.S. Pat. No. 5,663,159.
  • synthesis of phosphonate esters is achieved by coupling a nucleophile amine or alcohol with the corresponding activated phosphonate electrophilic precursor.
  • chlorophosphonate addition on to 5′-hydroxy of nucleoside is a well known method for preparation of nucleoside phosphate monoesters.
  • the activated precursor can be prepared by several well known methods.
  • Chlorophosphonates useful for synthesis of the prodrugs are prepared from the substituted-1,3-propanediol (Wissner, etal, (1992) J. Med Chem. 35:1650). Chlorophosphonates are made by oxidation of the corresponding chlorophospholanes (Anderson, et al, (1984) J. Org. Chem.
  • chlorophosphonate agent is made by treating substituted-1,3-diols with phosphorusoxychloride (Patois, etal, (1990) J. Chem. Soc. Perkin Trans. I, 1577). Chlorophosphonate species may also be generated in situ from corresponding cyclic phosphites (Silverburg, etal., (1996) Tetrahedron Lett., 37:771-774), which in turn can be either made from chlorophospholane or phosphoramidate intermediate.
  • the phosphoroflouridate intermediate prepared either from pyrophosphate or phosphoric acid may also act as precursor in preparation of cyclic prodrugs (Watanabe etal., (1988) Tetrahedron Lett., 29:5763-66).
  • Candidate compounds comprising a prodrug functionality may also be prepared from the free acid by Mitsunobu reactions (Mitsunobu, (1981) Synthesis, 1; Campbell, (1992) J. Org. Chem., 52:6331), and other acid coupling reagents including, but not limited to, carbodiimides (Alexander, etal, (1994) Collect. Czech. Chem. Commun. 59:1853; Casara, etal (1992) Bioorg. Med. Chem.
  • Aryl halides undergo Ni +2 catalyzed reaction with phosphite derivatives to give aryl phosphonate containing compounds (Balthazar, etal (1980) J. Org. Chem. 45:5425).
  • Phosphonates may also be prepared from the chlorophosphonate in the presence of a palladium catalyst using aromatic triflates (Petrakis, etal, (1987) J. Am. Chem. Soc. 109:2831; Lu, etal, (1987) Synthesis, 726).
  • aryl phosphonate esters are prepared from aryl phosphates under anionic rearrangement conditions (Melvin (1981) Tetrahedron Lett.
  • N-Alkoxy aryl salts with alkali metal derivatives of cyclic alkyl phosphonate provide general synthesis for heteroaryl-2-phosphonate linkers-(Redmore (1970) J. Org. Chem. 35:4114). These above mentioned methods can also be extended to compounds where the W 5 group is a heterocycle.
  • Cyclic-1,3-propanyl prodrugs of phosphonates are also synthesized from phosphonic diacids and substituted propane-1,3-diols using a coupling reagent such as 1,3-dicyclohexylcarbodiimide (DCC) in presence of a base (e.g., pyridine).
  • a coupling reagent such as 1,3-dicyclohexylcarbodiimide (DCC) in presence of a base (e.g., pyridine).
  • DCC 1,3-dicyclohexylcarbodiimide
  • EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • the carbamoyl group may be formed by reaction of a hydroxy group according to the methods known in the art, including the teachings of Ellis, U.S. 2002/0103378 A1 and Hajima, U.S. Pat. No. 6,018,049.
  • a number of exemplary methods for the preparation of the candidate compounds are provided below. These methods are intended to illustrate the nature of such preparations and do not limit the scope of this invention. Many of the compounds set forth below have been screened and demonstrated to have anti-HIV activity. In view of this these compounds are no longer candidate compounds for use in the screening method of this invention. However, they are illustrative of the manner in which the artisan can substitute prototype compounds with A 3 in various ways. In addition, taken cumulatively, they are illustrative of the typical component candidate compounds to be found in a screening library.
  • reaction conditions such as temperature, reaction time, solvents, work-up procedures, and the like, will be those common in the art for the particular reaction to be performed.
  • the cited reference material, together with material cited therein, contains detailed descriptions of such conditions.
  • temperatures will be ⁇ 100° C. to 200° C.
  • solvents will be aprotic or protic
  • reaction times will be 10 seconds to 10 days.
  • Work-up typically consists of quenching any unreacted reagents followed by partition between a water/organic layer system (extraction) and separating the layer containing the product.
  • Oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20° C.), although for metal hydride reductions frequently the temperature is reduced to 0° C. to ⁇ 100° C., solvents are typically aprotic for reductions and may be either protic or aprotic for oxidations. Reaction times are adjusted to achieve desired conversions.
  • Condensation reactions are typically carried out at temperatures near room temperature, although for non-equilibrating, kinetically controlled condensations reduced temperatures (0° C. to ⁇ 100° C.) are also common.
  • Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled reactions).
  • Standard synthetic techniques such as azeotropic removal of reaction by-products and use of anhydrous reaction conditions (e.g. inert gas environments) are common in the art and will be applied when applicable.
  • treated means contacting, mixing, reacting, allowing to react, bringing into contact, and other terms common in the art for indicating that one or more chemical entities is treated in such a manner as to convert it to one or more other chemical entities.
  • treating compound one with compound two is synonymous with “allowing compound one to react with compound two”, “contacting compound one with compound two”, “reacting compound one with compound two”, and other expressions common in the art of organic synthesis for reasonably indicating that compound one was “treated”, “reacted”, “allowed to react”, etc., with compound two.
  • “Treating” indicates the reasonable and usual manner in which organic chemicals are allowed to react. Normal concentrations (0.01M to 10M, typically 0.1M to 1M), temperatures ( ⁇ 100° C. to 250° C., typically ⁇ 78° C. to 150° C., more typically ⁇ 78° C. to 100° C., still more typically 0° C. to 100° C.), reaction vessels (typically glass, plastic, metal), solvents, pressures, atmospheres (typically air for oxygen and water insensitive reactions or nitrogen or argon for oxygen or water sensitive), etc., are intended unless otherwise indicated.
  • the knowledge of similar reactions known in the art of organic synthesis are used in selecting the conditions and apparatus for “treating” in a given process. In particular, one of ordinary skill in the art of organic synthesis selects conditions and apparatus reasonably expected to successfully carry out the chemical reactions of the described processes based on the knowledge in the art.
  • reaction products from one another and/or from starting materials.
  • the desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art.
  • separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.
  • Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium, and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
  • SMB simulated moving bed
  • reagents selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like.
  • reagents include adsorbents such as activated carbon, molecular sieves, ion exchange media, or the like.
  • the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LIX), or the like.
  • a single stereoisomer, e.g. an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (“Stereochemistry of Carbon Compounds,” (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113:(3) 283-302).
  • Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions.
  • diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, ⁇ -methyl- ⁇ -phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid.
  • the diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography.
  • addition of chiral carboxylic or sulfonic acids such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.
  • the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair
  • Diastereomeric compounds can be formed by reacting asynmmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched xanthene.
  • a method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g.
  • a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (“Chiral Liquid Chromatography” (1989) W. J. Lough, Ed. Chapman and Hall, New York; Okamoto, (1990) J. of Chromatogr. 513:375-378).
  • Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.
  • This invention includes all novel and unobvious compounds disclosed herein, whether or not such compounds are described in the context of methods or other disclosure and whether or not such compounds are claimed upon filing or are set forth in the summary of invention.
  • compositions of the invention are prepared by any of the applicable techniques of organic synthesis. Many such techniques are well known in the art. Such as those elaborated in “Compendium of Organic Synthetic Methods” (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6, Michael B.
  • Dialkyl phosphonates may be prepared according to the methods of: Quast et al (1974) Synthesis 490; Stowell et al (1990) Tetrahedron Lett. 3261; U.S. Pat. No. 5,663,159.
  • synthesis of phosphonate esters is achieved by coupling a nucleophile amine or alcohol with the corresponding activated phosphonate electrophilic precursor for example, Chlorophosphonate addition on to 5′-hydroxy of nucleoside is a well known method for preparation of nucleoside phosphate monoesters.
  • the activated precursor can be prepared by several well known methods.
  • Chlorophosphonates useful for synthesis of the prodrugs are prepared from the substituted-1,3-propanediol (Wissner, et al, (1992) J. Med Chem. 35:1650). Chlorophosphonates are made by oxidation of the corresponding chlorophospholanes (Anderson, et al. (1984) J. Org.
  • chlorophosphonate agent is made by treating substituted-1,3-diols with phosphorusoxychloride (Patois, et al, (1990) J. Chem. Soc. Perkin Trans. I, 1577). Chlorophosphonate species may also be generated in situ from corresponding cyclic phosphites (Silverburg, et al., (1996) Tetrahedron Lett., 37:771-774), which in turn can be either made from chlorophospholane or phosphoramidate intermediate.
  • Phosphoroflouridate intermediate prepared either from pyrophosphate or phosphoric acid may also act as precursor in preparation of cyclic prodrugs (Watanabe et al., (1988) Tetrahedron Lett., 29:5763-66). Caution: fluorophosphonate compounds may be highly toxic!
  • compositions of the invention are provided below. These methods are intended to illustrate the nature of such preparations are not intended to limit the scope of applicable methods.
  • treated means contacting, mixing, reacting, allowing to react, bringing into contact, and other terms common in the art for indicating that one or more chemical entities is treated in such a manner as to convert it to one or more other chemical entities.
  • treating compound one with compound two is synonymous with “allowing compound one to react with compound two”, “contacting compound one with compound two”, “reacting compound one with compound two”, and other expressions common in the art of organic synthesis for reasonably indicating that compound one was “treated”, “reacted”, “allowed to react”, etc., with compound two.
  • “Treating” indicates the reasonable and usual manner in which organic chemicals are allowed to react. Normal concentrations (0.01M to 10M, typically 0.1M to 1M), temperatures ( ⁇ 100° C. to 250° C., typically ⁇ 78° C. to 150° C., more typically ⁇ 78° C. to 100° C., still more typically 0° C. to 100° C.), reaction vessels (typically glass, plastic, metal), solvents, pressures, atmospheres (typically air for oxygen and water insensitive reactions or nitrogen or argon for oxygen or water sensitive), etc., are intended unless otherwise indicated.
  • the knowledge of similar reactions known in the art of organic synthesis are used in selecting the conditions and apparatus for “treating” in a given process. In particular, one of ordinary skill in the art of organic synthesis selects conditions and apparatus reasonably expected to successfully carry out the chemical reactions of the described processes based on the knowledge in the art.
  • reaction products from one another and/or from starting materials.
  • the desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art.
  • separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.
  • Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium, and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
  • SMB simulated moving bed
  • reagents selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like.
  • reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like.
  • the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LIX), or the like.
  • a single stereoisomer, e.g. an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (“Stereochemistry of Carbon Compounds,” (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113:(3) 283-302).
  • Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions.
  • diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, x-methyl-p-phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid.
  • the diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography.
  • addition of chiral carboxylic or sulfonic acids such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.
  • the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair
  • Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched xanthene.
  • a method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g.
  • a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (“Chiral Liquid Chromatography” (1989) W. J. Lough, Ed. Chapman and Hall, New York; Okamoto, (1990) J. of Chromatogr. 513:375-378).
  • Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism
  • Scheme A shows the general interconversions of certain phosphonate compounds: acids —P(O)(OH) 2 ; mono-esters —P(O)(OR 1 )(OH); and diesters —P(O)(OR 1 ) 2 in which the R 1 groups are independently selected, and defined herein before, and the phosphorus is attached through a carbon moiety (link, i.e. linker), which is attached to the rest of the molecule, e.g. drug or drug intermediate (R).
  • the R 1 groups attached to the phosphonate esters in Scheme 1 may be changed using established chemical transformations.
  • the interconversions may be carried out in the precursor compounds or the final products using the methods described below.
  • the conversion of a phosphonate diester 27.1 into the corresponding phosphonate monoester 27.2 can be accomplished by a number of methods.
  • the ester 27.1 in which R 1 is an arylalkyl group such as benzyl can be converted into the monoester compound 27.2 by reaction with a tertiary organic base such as diazabicyclooctane (DABCO) or quinuclidine, as described in J. Org. Chem., 1995, 60:2946.
  • DABCO diazabicyclooctane
  • the reaction is performed in an inert hydrocarbon solvent such as toluene or xylene, at about 110° C.
  • the conversion of the diester 27.1 in which R 1 is an aryl group such as phenyl, or an alkenyl group such as allyl, into the monoester 27.2 can be effected by treatment of the ester 27.1 with a base such as aqueous sodium hydroxide in acetonitrile or lithium hydroxide in aqueous tetrahydrofuran.
  • Phosphonate diesters 27.2 in which one of the groups R 1 is arylalkyl, such as benzyl and the other is alkyl can be converted into the monoesters 27.2 in which R 1 is alkyl by hydrogenation, for example using a palladium on carbon catalyst.
  • Phosphonate diesters in which both of the groups R 1 are alkenyl, such as allyl can be converted into the monoester 27.2 in which R 1 is alkenyl, by treatment with chlorotris(triphenylphosphine)rhodium (Willcinson's catalyst) in aqueous ethanol at reflux, optionally in the presence of diazabicyclooctane, for example by using the procedure described in J. Org. Chem., 38:3224 1973 for the cleavage of allyl carboxylates.
  • a phosphonate monoester 27.2 in which R 1 is alkenyl such as, for example, allyl, can be converted into the phosphonic acid 27.3 by reaction with Wilkinson's catalyst in an aqueous organic solvent, for example in 15% aqueous acetonitrile, or in aqueous ethanol, for example using the procedure described in Helv. Chim Acta., 68:618, 1985.
  • the conversion of a phosphonate monoester 27.2 into a phosphonate diester 27.1 (Scheme A, Reaction 4) in which the newly introduced R 1 group is alkyl arylalkyl, or haloalkyl such as chloroethyl, can be effected by a number of reactions in which the substrate 27.2 is reacted with a hydroxy compound R 1 OH, in the presence of a coupling agent.
  • Suitable coupling agents are those employed for the preparation of carboxylate esters, and include a carbodiimide such as dicyclohexylcarbodiimide, in which case the reaction is preferably conducted in a basic organic solvent such as pyridine, or (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PYBOP, Sigma), in which case the reaction is performed in a polar solvent such as dimethylformamide, in the presence of a tertiary organic base such as diisopropylethylamine, or Aldrithiol-2 (Aldrich) in which case the reaction is conducted in a basic solvent such as pyridine, in the presence of a triaryl phosphine such as triphenylphosphine.
  • a carbodiimide such as dicyclohexylcarbodiimide
  • PYBOP benzotriazol-1-yloxy)tripyrrolidinophosphonium
  • the conversion of the phosphonate monoester 27.1 to the diester 27.1 can be effected by the use of the Mitsunobu reaction.
  • the substrate is reacted with the hydroxy compound R 1 OH, in the presence of diethyl azodicarboxylate and a triarylphosphine such as triphenyl phosphine.
  • the phosphonate monoester 27.2 can be transformed into the phosphonate diester 27.1, in which the introduced R 1 group is alkenyl or arylalkyl, by reaction of the monoester with the halide R 1 Br, in which R 1 is as alkenyl or arylalkyl.
  • the alkylation reaction is conducted in a polar organic solvent such as dimethylformamiide or acetonitrile, in the presence of a base such as cesium carbonate.
  • a polar organic solvent such as dimethylformamiide or acetonitrile
  • a base such as cesium carbonate.
  • the phosphonate monoester can be transformed into the phosphonate diester in a two step procedure. In the first step, the phosphonate monoester 27.2 is transformed into the chloro analog —P(O)(OR 1 )Cl by reaction with thionyl chloride or oxalyl chloride and the like, as described in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p.
  • a phosphonic acid —P(O)(OH) 2 can be transformed into a phosphonate monoester —P(O)(OR 1 )(OH) (Scheme A, Reaction 5) by means of the methods described above of for the preparation of the phosphonate diester —P(O)(OR 1 ) 2 27.1, except that only one molar proportion of the component R 1 OH or R 1 Br is employed.
  • a phosphonic acid —P(O)(OH) 2 27.3 can be transformed into a phosphonate diester —P(O)(OR 1 ) 2 27.1 (Scheme A, Reaction 6) by a coupling reaction with the hydroxy compound R 1 OH, in the presence of a coupling agent such as Aldrithiol-2 (Aldrich) and triphenylphosphine.
  • the reaction is conducted in a basic solvent such as pyridine.
  • phosphonic acids 27.3 can be transformed into phosphonic esters 27.1 in which R 1 is aryl, such as phenyl, by means of a coupling reaction employing, for example, phenol and dicyclohexylcarbodiimide in pyridine at about 70° C.
  • phosphonic acids 27.3 can be transformed into phosphonic esters 27.1 in which R 1 is alkenyl by means of an alkylation reaction. The phosphonic acid is reacted with the alkenyl bromide R 1 Br in a polar organic solvent such as acetonitrile solution at reflux temperature, in the presence of a base such as cesium carbonate, to afford the phosphonic ester 27.1.
  • Phosphonate prodrugs of the present invention may also be prepared from the precursor free acid by Mitsunobu reactions (Mitsunobu, (1981) Synthesis, 1; Campbell, (1992) J. Org. Chem., 52:6331), and other acid coupling reagents including, but not limited to, carbodiimides (Alexander, et al, (1994) Collect. Czech. Chem. Commun. 59:1853; Casara, et al, (1992) Bioorg. Med. Chem.
  • a number of methods are available for the conversion of phosphonic acids into amidates and esters.
  • the phosphonic acid is either converted into an isolated activated intermediate such as a phosphoryl chloride, or the phosphonic acid is activated in situ for reaction with an amine or a hydroxy compound.
  • the conversion of phosphonic acids into phosphoryl chlorides is accomplished by reaction with thionyl chloride, for example as described in J. Gen. Chem. USSR, 1983, 53, 480, Zh. Obschei Chim., 1958, 28, 1063, or J. Org. Chem., 1994, 59, 6144, or by reaction with oxalyl chloride, as described in J. Am. Chem. Soc., 1994, 116, 3251, or J. Org. Chem., 1994, 59, 6144, or by reaction with phosphorus pentachloride, as described in J. Org. Chem., 2001, 66, 329, or in J. Med. Chem., 1995, 38, 1372.
  • the resultant phosphoryl chlorides are then reacted with amines or hydroxy compounds in the presence of a base to afford the amidate or ester products.
  • Phosphonic acids are converted into activated imidazolyl derivatives by reaction with carbonyl dimidazole, as described in J. Chem. Soc., Chem. Comm., 1991, 312, or Nucleosides Nucleotides 2000, 19, 1885.
  • Activated sulfonyloxy derivatives are obtained by the reaction of phosphonic acids with trichloromethylsulfonyl chloride, as described in J. Med. Chem. 1995, 38, 4958, or with triisopropylbenzenesulfonyl chloride, as described in Tet. Lett., 1996, 7857, or Bioorg. Med. Chem. Lett., 1998, 8, 663.
  • the activated sulfonyloxy derivatives are then reacted with amines or hydroxy compounds to afford amidates or esters.
  • the phosphonic acid and the amine or hydroxy reactant are combined in the presence of a diimide coupling agent.
  • the preparation of phosphonic amidates and esters by means of coupling reactions in the presence of dicyclohexyl carbodiimide is described, for example, in J. Chem. Soc., Chem. Comm., 1991, 312, or J. Med. Chem, 1980, 23, 1299 or Coll. Czech. Chem. Comm, 1987, 52, 2792.
  • the agents include Aldrithiol-2, and PYBOP and BOP, as described in J. Org. Chem., 1995, 60, 5214, and J. Med. Chem., 1997, 40, 3842, mesitylene-2-sulfonyl-3-nitro-1,2,4-triazole (MSNT), as described in J. Med. Chem., 1996, 39, 4958, diphenylphosphoryl azide, as described in J. Org.
  • Phosphonic acids are converted into amidates and esters by means of the Mitsonobu reaction, in which the phosphonic acid and the amine or hydroxy reactant are combined in the presence of a triaryl phosphine and a dialkyl azodicarboxylate.
  • the procedure is described in Org. Lett., 2001, 3, 643, or J. Med. Chem., 1997, 40, 3842.
  • Phosphonic esters are also obtained by the reaction between phosphonic acids and halo compounds, in the presence of a suitable base.
  • the method is described, for example, in Anal. Chem., 1987, 59, 1056, or J. Chem. Soc. Perkin Trans., I, 1993, 19, 2303, or J. Med. Chem., 1995, 38, 1372, or Tet. Lett., 2002, 43, 1161.
  • Schemes 1-4 illustrate the conversion of phosphonate esters and phosphonic acids into carboalkoxy-substituted phosphorobisamidates (Scheme 1), phosphoroamidates (Scheme 2), phosphonate monoesters (Scheme 3) and phosphonate diesters, (Scheme 4).
  • Scheme 1 illustrates various methods for the conversion of phosphonate diesters 1.1 into phosphorobisamidates 1.5.
  • the diester 1.1 prepared as described previously, is hydrolyzed, either to the monoester 1.2 or to the phosphonic acid 1.6. The methods employed for these transformations are described above.
  • the monoester 1.2 is converted into the monoamidate 1.3 by reaction with an aminoester 1.9, in which the group R 2 is H or alkyl, the group R 4 is an alkylene moiety such as, for example, CHCH 3 , CHPr 1 , CH(CH 2 Ph), CH 2 CH(CH 3 ) and the like, or a group present in natural or modified aminoacids, and the group R 5 is alkyl.
  • the reactants are combined in the presence of a coupling agent such as a carbodiimide, for example dicyclohexyl carbodiimide, as described in J. Am. Chem. Soc., 1957, 79, 3575, optionally in the presence of an activating agent such as hydroxybenztriazole, to yield the amidate product 1.3.
  • a coupling agent such as a carbodiimide, for example dicyclohexyl carbodiimide, as described in J. Am. Chem. Soc., 1957, 79, 3575
  • an activating agent such as hydroxybenztriazole
  • the amidate-forming reaction is also effected in the presence of coupling agents such as BOP, as described in J. Org. Chem., 1995, 60, 5214, Aldrithiol, PYBOP and similar coupling agents used for the preparation of amides and esters.
  • the reactants 1.2 and 1.9 are transformed into the monoamidate 1.3 by means of a Mitson
  • the phosphonic acid 1.6 is converted into the bisamidate 1.5 by use of the coupling reactions described above.
  • the reaction is performed in one step, in which case the nitrogen-related substituents present in the product 1.5 are the same, or in two steps, in which case the nitrogen-related substituents can be different.
  • the phosphonic acid 1.6 is converted into the mono or bis-activated derivative 1.7, in which Lv is a leaving group such as chloro, immidazolyl, triisopropylbenzenesulfonyloxy etc.
  • Lv is a leaving group such as chloro, immidazolyl, triisopropylbenzenesulfonyloxy etc.
  • the conversion of phosphonic acids into chlorides 1.7 is effected by reaction with thionyl chloride or oxalyl chloride and the like, as described in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p. 17.
  • the phosphonic acid is activated by reaction with triisopropylbenzenesulfonyl chloride, as described in Nucleosides and Nucleotides, 2000, 10, 1885.
  • the activated product is then reacted with the aminoester 1.9, in the presence of a base, to give the bisamidate 1.5.
  • the reaction is performed in one step, in which case the nitrogen substituents present in the product 1.5 are the same, or in two steps, via the intermediate 1.11, in which case the nitrogen substituents can be different.
  • Example 5 the phosphonic acid 1.6 is reacted, as described in J. Chem. Soc. Chem. Comm., 1991, 312, with carbonyl dimidazole to give the imidazolide 1.32.
  • the product is then reacted in acetonitrile solution at ambient temperature, with one molar equivalent of ethyl alaninate 1.33 to yield the monodisplacement product 1.34.
  • the latter compound is then reacted with carbonyl diimidazole to produce the activated intermediate 1.35, and the product is then reacted, under the same conditions, with ethyl N-methylalaninate 1.33a to give the bisamidate product 1.36.
  • the intermediate monoamidate 1.3 is also prepared from the monoester 1.2 by first converting the monoester into the activated derivative 1.8 in which Lv is a leaving group such as halo, imidazolyl etc, using the procedures described above.
  • the product 1.8 is then reacted with an aminoester 1.9 in the presence of a base such as pyridine, to give an intermediate monoamidate product 1.3.
  • the latter compound is then converted, by removal of the R 1 group and coupling of the product with the aminoester 1.9, as described above, into the bisamidate 1.5.
  • the product is subjected to a Mitsonobu coupling procedure, with equimolar amounts of butyl alaninate 1.30, triphenyl phosphine, diethylazodicarboxylate and triethylamine in tetrahydrofuran, to give the bisamidate product 1.31.
  • the activated phosphonic acid derivative 1.7 is also converted into the bisamidate 1.5 via the diamino compound 1.10.
  • the conversion of activated phosphonic acid derivatives such as phosphoryl chlorides into the corresponding amino analogs 1.10, by reaction with ammonia, is described in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976.
  • the diamino compound 1.10 is then reacted at elevated temperature with a haloester 1.12, in a polar organic solvent such as dimethylformamide, in the presence of a base such as dimethylaminopyridine or potassium carbonate, to yield the bisamidate 1.5.
  • a haloester 1.12 in a polar organic solvent such as dimethylformamide
  • a base such as dimethylaminopyridine or potassium carbonate
  • a dichlorophosphonate 1.23 is reacted with ammonia to afford the diamide 1.37.
  • the reaction is performed in aqueous, aqueous alcoholic or alcoholic solution, at reflux temperature.
  • the resulting diamino compound is then reacted with two molar equivalents of ethyl 2-bromo-3-methylbutyrate 1.38, in a polar organic solvent such as N-methylpyrrolidinone at ca. 150° C., in the presence of a base such as potassium carbonate, and optionally in the presence of a catalytic amount of potassium iodide, to afford the bisamidate product 1.39.
  • Scheme 1 illustrates the preparation of bisamidates derived from tyrosine.
  • the monoimidazolide 1.32 is reacted with propyl tyrosinate 1.40, as described in Example 5, to yield the monoamidate 1.41.
  • the product is reacted with carbonyl diimidazole to give the imidazolide 1.42, and this material is reacted with a further molar equivalent of propyl tyrosinate to produce the bisamidate product 1.43.
  • aminoesters 1.9 Using the above procedures, but employing, in place of propyl tyrosinate 1.40, different aminoesters 1.9, the corresponding products 1.5 are obtained.
  • the aminoesters employed in the two stages of the above procedure can be the same or different, so that bisamidates with the same or different amino substituents are prepared.
  • Scheme 2 illustrates methods for the preparation of phosphonate monoamidates.
  • a phosphonate monoester 1.1 is converted, as described in Scheme 1, into the activated derivative 1.8.
  • This compound is then reacted, as described above, with an aminoester 1.9, in the presence of a base, to afford the monoamidate product 2.1.
  • the procedure is illustrated in Scheme 2, Example 1.
  • a monophenyl phosphonate 2.7 is reacted with, for example, thionyl chloride, as described in J. Gen. Chem. USSR., 1983, 32, 367, to give the chloro product 2.8.
  • the product is then reacted, as described in Scheme 1, with ethyl alaninate 2.9, to yield the amidate 2.10.
  • the phosphonate monoester 1.1 is coupled, as described in Scheme 1, with an aminoester 1.9 to produce the amidate 2.1. If necessary, the R 1 substituent is then altered, by initial cleavage to afford the phosphonic acid 2.2. The procedures for this transformation depend on the nature of the R 1 group, and are described above.
  • the phosphonic acid is then transformed into the ester amidate product 2.3, by reaction with the hydroxy compound R 3 OH, in which the group R 3 is aryl, heteroaryl, alkyl, cycloalkyl, haloalkyl etc, using the same coupling procedures (carbodiimide, Aldrithiol-2, PYBOP, Mitsonobu reaction etc) described in Scheme 1 for the coupling of amines and phosphonic acids.
  • Example 2 Examples of this method are shown in Scheme 2, Examples and 2 and 3.
  • a monobenzyl phosphonate 2.11 is transformed by reaction with ethyl alaninate, using one of the methods described above, into the monoamidate 2.12.
  • the benzyl group is then removed by catalytic hydrogenation in ethyl acetate solution over a 5% palladium on carbon catalyst, to afford the phosphonic acid amidate 2.13.
  • the product is then reacted in dichloromethane solution at ambient temperature with equimolar amounts of 1-(dimethylaminopropyl)-3-ethylcarbodiimide and trifluoroethanol 2.14, for example as described in Tet. Lett., 2001, 42, 8841, to yield the amidate ester 2.15.
  • Example 3 the monoamidate 2.13 is coupled, in tetrahydrofuran solution at ambient temperature, with equimolar amounts of dicyclohexyl carbodiimide and 4-hydroxy-N-methylpiperidine 2.16, to produce the amidate ester product 2.17.
  • the activated phosphonate ester 1.8 is reacted with ammonia to yield the amidate 2.4.
  • the product is then reacted, as described in Scheme 1, with a haloester 2.5, in the presence of a base, to produce the amidate product 2.6.
  • the nature of the R 1 group is changed, using the procedures described above, to give the product 2.3.
  • the method is illustrated in Scheme 2, Example 4. In this sequence, the monophenyl phosphoryl chloride 2.18 is reacted, as described in Scheme 1, with ammonia, to yield the amino product 2.19.
  • the monoamidate products 2.3 are also prepared from the doubly activated phosphonate derivatives 1.7.
  • the intermediate 1.7 is reacted with a limited amount of the aminoester 1.9 to give the mono-displacement product 1.11.
  • the latter compound is then reacted with the hydroxy compound R 3 OH in a polar organic solvent such as dimethylformamide, in the presence of a base such as diisopropylethylamine, to yield the monoamidate ester 2.3.
  • Scheme 3 illustrates methods for the preparation of carboalkoxy-substituted phosphonate diesters in which one of the ester groups incorporates a carboalkoxy substituent.
  • a phosphonate monoester 1.1 prepared as described above, is coupled, using one of the methods described above, with a hydroxyester 3.1, in which the groups R 4 and R 5 are as described in Scheme 1.
  • equimolar amounts of the reactants are coupled in the presence of a carbodiimide such as dicyclohexyl carbodiimide, as described in Aust. J. Chem., 1963, 609, optionally in the presence of dimethylaminopyridine, as described in Tet., 1999, 55, 12997.
  • the reaction is conducted in an inert solvent at ambient temperature.
  • the conversion of a phosphonate monoester 1.1 into a mixed diester 3.2 is also accomplished by means of a Mitsonobu coupling reaction with the hydroxyester 3.1, as described in Org. Lett., 2001, 643.
  • the reactants 1.1 and 3.1 are combined in a polar solvent such as tetrahydrofuran, in the presence of a triarylphosphine and a dialkyl azodicarboxylate, to give the mixed diester 3.2.
  • the R 1 substituent is varied by cleavage, using the methods described previously, to afford the monoacid product 3.3.
  • the product is then coupled, for example using methods described above, with the hydroxy compound R 3 OH, to give the diester product 3.4.
  • the mixed diesters 3.2 are also obtained from the monoesters 1.1 via the intermediacy of the activated monoesters 3.5.
  • the resultant activated monoester is then reacted with the hydroxyester 3.1, as described above, to yield the mixed diester 3.2.
  • the mixed phosphonate diesters are also obtained by an alternative route for incorporation of the R 3 O group into intermediates 3.3 in which the hydroxyester moiety is already incorporated.
  • the monoacid intermediate 3.3 is converted into the activated derivative 3.6 in which Lv is a leaving group such as chloro, imidazole, and the like, as previously described.
  • the activated intermediate is then reacted with the hydroxy compound R 3 OH, in the presence of a base, to yield the mixed diester product 3.4.
  • the phosphonate esters 3.4 are also obtained by means of alkylation reactions performed on the monoesters 1.1.
  • the reaction between the monoacid 1.1 and the haloester 3.7 is performed in a polar solvent in the presence of a base such as diisopropylethylamine, as described in Anal. Chem, 1987, 59, 1056, or triethylamine, as described in J. Med. Chem., 1995, 38, 1372, or in a non-polar solvent such as benzene, in the presence of 18-crown-6, as described in Syn. Comm., 1995, 25, 3565.
  • a base such as diisopropylethylamine, as described in Anal. Chem, 1987, 59, 1056, or triethylamine, as described in J. Med. Chem., 1995, 38, 1372
  • a non-polar solvent such as benzene
  • Scheme 4 illustrates methods for the preparation of phosphonate diesters in which both the ester substituents incorporate carboalkoxy groups.
  • the compounds are prepared directly or indirectly from the phosphonic acids 1.6.
  • the phosphonic acid is coupled with the hydroxyester 4.2, using the conditions described previously in Schemes 1-3, such as coupling reactions using dicyclohexyl carbodiimide or similar reagents, or under the conditions of the Mitsonobu reaction, to afford the diester product 4.3 in which the ester substituents are identical.
  • the diesters 4.3 are obtained by alkylation of the phosphonic acid 1.6 with a haloester 4.1.
  • the alkylation reaction is performed as described in Scheme 3 for the preparation of the esters 3.4.
  • the diesters 4.3 are also obtained by displacement reactions of activated derivatives 1.7 of the phosphonic acid with the hydroxyesters 4.2.
  • the displacement reaction is performed in a polar solvent in the presence of a suitable base, as described in Scheme 3.
  • the displacement reaction is performed in the presence of an excess of the hydroxyester, to afford the diester product 4.3 in which the ester substituents are identical, or sequentially with limited amounts of different hydroxyesters, to prepare diesters 4.3 in which the ester substituents are different.
  • the methods are illustrated in Scheme 4, Examples 3 and 4.
  • Example 3 the phosphoryl dichloride 2.22 is reacted with three molar equivalents of ethyl 3-hydroxy-2-(hydroxymethyl)propionate 4.9 in tetrahydrofuran containing potassium carbonate, to obtain the diester product 4.10.
  • Example 4 depicts the displacement reaction between equimolar amounts of the phosphoryl dichloride 2.22 and ethyl 2-methyl-3-hydroxypropionate 4.11, to yield the monoester product 4.12.
  • the reaction is conducted in acetonitrile at 70° C. in the presence of diisopropylethylamine.
  • the product 4.12 is then reacted, under the same conditions, with one molar equivalent of ethyl lactate 4.13, to give the diester product 4.14.
  • Aryl halides undergo Ni +2 catalyzed reaction with phosphite derivatives to give aryl phosphonate containing compounds (Balthazar, et al (1980) J. Org. Chem. 45:5425).
  • Phosphonates may also be prepared from the chlorophosphonate in the presence of a palladium catalyst using aromatic triflates (Petrakis, et al, (1987) J. Am Chem. Soc. 109:2831; Lu, et al, (1987) Synthesis, 726).
  • aryl phosphonate esters are prepared from aryl phosphates under anionic rearrangement conditions (Melvin (1981) Tetrahedron Lett.
  • N-Alkoxy aryl salts with alkali metal derivatives of cyclic alkyl phosphonate provide general synthesis for heteroaryl-2-phosphonate linkers (Redmore (1970) J. Org. Chem. 35:4114). These above mentioned methods can also be extended to compounds where the W 5 group is a heterocycle.
  • Cyclic-1,3-propanyl prodrugs of phosphonates are also synthesized from phosphonic diacids and substituted propane-1,3-diols using a coupling reagent such as 1,3-dicyclohexylcarbodiimide (DCC) in presence of a base (e.g., pyridine).
  • a coupling reagent such as 1,3-dicyclohexylcarbodiimide (DCC) in presence of a base (e.g., pyridine).
  • DCC 1,3-dicyclohexylcarbodiimide
  • EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • the carbamoyl group may be formed by reaction of a hydroxy group according to the methods known in the art, including the teachings of Ellis, US 2002/0103378 A1 and Hajima, U.S. Pat. No. 6,018,049.
  • reaction conditions such as temperature, reaction time, solvents, work-up procedures, and the like, will be those common in the art for the particular reaction to be performed.
  • the cited reference material, together with material cited therein, contains detailed descriptions of such conditions.
  • temperatures will be ⁇ 100° C. to 200° C.
  • solvents will be aprotic or protic
  • reaction times will be 10 seconds to 10 days.
  • Work-up typically consists of quenching any unreacted reagents followed by partition between a water/organic layer system (extraction) and separating the layer containing the product.
  • Oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20° C.), although for metal hydride reductions frequently the temperature is reduced to 0° C. to ⁇ 100° C., solvents are typically aprotic for reductions and may be either protic or aprotic for oxidations. Reaction times are adjusted to achieve desired conversions.
  • Condensation reactions are typically carried out at temperatures near room temperature, although for non-equilibrating, kinetically controlled condensations reduced temperatures (0° C. to ⁇ 100° C.) are also common.
  • Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled reactions).
  • Standard synthetic techniques such as azeotropic removal of reaction by-products and use of anhydrous reaction conditions (e.g. inert gas environments) are common in the art and will be applied when applicable.
  • Amino alkyl phosphonate compounds 809 are a generic representative of compounds 811, 813, 814, 816 and 818 (Scheme 2).
  • Commercial amino phosphonic acid 810 was protected as carbamate 811.
  • the phosphonic acid 811 was converted to phosphonate 812 upon treatment with ROH in the presence of DCC or other conventional coupling reagents. Coupling of phosphonic acid 811 with esters of amino acid 820 provided bisamidate 817.
  • Lactates 823 are useful intermediates to form the phosphonate compounds of the invention.
  • Alcohol 825 was converted to bromide 826 by first transformed to its mesylate and then treated with NaBr, this conversion was also realized by reacting alcohol 825 with Ph 3 P and CBr 4 (Scheme 8). Upon treating with P(OR) 3 , phosphonate 827 was produced. Esters was then removed to form acid, and following the similar procedure described in Scheme 2 and 3, desired phosphonate, bisphosphoamidate, mono-phosphoamidate, and monophospholactate were produced.
  • alcohol 830 was converted to carbonate 831 by reacting with either p-nitrophenyl chloroformate or p-nitrophenyl carboxy anhyride.
  • Phosphorus compound 838 was produced according to the procedures described in Scheme 10. Replacement of chloride group in compound 833 with azide followed by reduction with triphenylphosphine provided amine 834. Replacement of chloride group in compound 833 with cyanide, e.g. sodium cyanide, provided amine 835. Reduction of nitrile 835 furnished amine 836. Reaction of amines, e.g. 834 or 836, with triflate 841 in the presence of a base afforded phosphonate 837. Removal of benzyl group of 837 gave its corresponding phosphonic acid, e.g. 838 where R 1 ⁇ H, which was converted to various phosphorus compounds according to the procedure described in the previous Schemes.
  • Phosphorus compound 840 was produced in a similar way as described in Scheme 10 except by replacing amines with alcohols 801, or generally, 807 (Scheme 11).
  • Phosphorus compound 848 was synthesized according to procedures described in Scheme 12. Iodoimidazole 842 was converted to imidazole phenyl thioether 843 by reacting with LiH and substituted phenyl disulfide (Scheme 12). Treatment of imidazole with NaH and 4-picolyl chloride gave imidazole 844. Benzyl and methyl groups were removed by treating with strong acid to provide alcohol 845. Conversion of phenol 845 to phosphonate 846 was accomplished by reacting phenol 845 with triflate 841 in the presence of base. Alcohol 846 was reacting with trichloroacetyl isocyanate followed by treatment of alumina afforded carbamate 847. Phosphonate 847 was transformed to all kinds of phosphorus compound 848 followed the procedure described for 838 in Scheme 10.
  • Phosphorus compound 854 was prepared as shown in Scheme 13. Imidazole 849 (prepared according to U.S. Pat. Nos. 5,910,506 and 6,057,448) was converted to 850 by reacting with chloride in the presence of base. Benzyl and methyl groups were removed by treating ether 850 with strong protonic or Lewis acid to furnish phenol 851. Treatment of phenol 851 with base followed by triflate 841 gave phosphonate 852. Following similar procedures described in Scheme 12 transforming alcohol 846 to phosphorus compound 848, alcohol 852 was converted to phosphorus compound 854.
  • Scheme 17 describes synthesis of phosphorus compound 672.
  • Mesylate 862 was transformed to bromide 867 by reacting with NaBr.
  • Arbusov reaction gave phosphonate 868.
  • Both benzyl and ethyl groups were cleaved when treated with TMSBr to yield compound 869.
  • Coupling of phosphonic acid 869 with PhOH provided bisphenyl phosphonate 670.
  • Compound 670 was converted to various phosphorus compounds 671 according to the procedures described in Schemes 1, 2 and 3.
  • Phosphorus compound 672 was obtained by repeating the procedures shown before.
  • reaction mixture was filtered, rinsed with CH 3 CN, and concentrated under reduced pressure to give ⁇ 2-[5-(3,5-dichloro-phenylsulfanyl)-4-isopropyl-1-pyridin-4-ylmethyl-1H-imidazol-2-ylmethoxycarbonylamino]-ethyl ⁇ -phosphonic acid monophenyl ester 32 (10 mg, 100%) as a colorless oil.
  • iodide 35 also denoted previously as compound 842, (1.21 g, 3.39 mmol) and lithium hydride (32 mg, 4.07 mmol).
  • iodide 35 also denoted previously as compound 842, (1.21 g, 3.39 mmol) and lithium hydride (32 mg, 4.07 mmol).
  • the reaction mixture was warmed to 60° C. and stirred for 16 h, the mixture was partitioned between EtOAc and water. The organic phase was washed with brine, dried over Na 2 SO 4 , filtered, and evaporated under reduced pressure.
  • Scheme 25 describes preparation of compound 880.
  • Compound 875 was synthesized from compound 842 using the procedures described in U.S. Pat. No. 5,326,780.
  • Treatment of 875 with HCl removed the benzyl group to give alcohol 876, which was then introduced phenyl group with substitution of Y.
  • Y is a function which can be converted to alcohol, aldehyde or amine, for example —NO 2 , —COOMe, N 3 , and etc. Conversion of Y to the amine or alcohol gave compound 878 and/or 879, which were then used as attachment site of phosphorus to afford phosphorus compound 880.
  • Hydroxyl group in compound 880 was then converted to the desired side chain including but not limit to carbamate 881, urea 882, substituted amine 883.
  • phosphorus compound 887 is shown in Scheme 26.
  • Compound 877 was converted to amine 884 and/or aldehyde 885, which then reacted with aldehyde and/or amine respectively to provide phosphorus compound 886.
  • Treatment of compound 886 with Cl 3 CCONCO provide the carbamate 887.
  • the title compound 49 was prepared following the sequence of steps described in Example 22, except for using scalmeric mixture 46 (around 13:1 ratio). Purification of the crude final product on silica gel eluted with 3-4% MeOH/CH 2 Cl 2 provided 40 mg of the title compound.
  • Amidate 49 A solution of phosphonic acid 45 (66 mg, 0.19 mmol) in CH 3 CN (5 mL) was treated with thionyl chloride (42 ⁇ L, 0.57 mmol). After the reaction mixture was warmed to 70° C. and stirred for 2 h, the mixture was concentrated under reduced pressure. The residue was dissolved in CH 2 Cl 2 (5 mL) and cooled to 0° C. Triethylamine (0.11 mL, 0.76 mmol) and L-alanine n-butyl ester (104 mg, 0.57 mmol) were added. After stirring for 1 h at 0° C. and 1 h at room temperature, the reaction mixture was neutralized with sat.
  • Amine 50 A mixture of benzyl carbamate 49 (35 mg, 0.073 mmol), trifluoroacetic acid (8 ⁇ L, 0.11 mmol) and 10% Pd/C (7 mg) in isopropyl alcohol (2 mL) was stirred under H 2 atmosphere (balloon) for 1 h. The mixture was then filtered through Celite. The filtrate was evaporated under reduced pressure to give amine 50 (33 mg, 99%) as a colorless oil.
  • the title compound was prepared following the sequence of steps described in Example 24, except for substituting alanine ethyl ester for alanine n-butyl ester. Purification of the crude final product on a preparative TLC plate (5% CH 3 OH/CH 2 Cl 2 ) provided 5 mg (75%) of the title compound.
  • Imidazole 54 A solution of imidazole 53 (267 mg, 0.655 mmol) in THF (10 mL) was treated with 4-methoxybenzyl chloride (0.18 mL, 1.31 mmol), powder NaOH (105 mg, 2.62 mmol), lithium iodide (88 mg, 0.655 mmol), and tetrabutylammonium bromide (105 mg, 0.327 mmol). After stirring for 4 days at room temperature, the resulting mixture was partitioned between EtOAc and sat. NH 4 Cl. The organic phase was dried over Na 2 SO 4 , filtered, and evaporated under reduced pressure. The crude product was purified on silica gel (eluting 20-40% EtOAc/hexane) to give imidazole 54 (289 mg, 84%) as a colorless oil.
  • Phenol 55 A solution of benzyl ether 54 (151 mg, 0.286 mmol) in EtOH (5 mL) was treated with conc. HCl (5 mL). After the reaction mixture was warmed to 80° C. and stirred for 2 d, the mixture was concentrated under reduced pressure and partitioned between EtOAc and sat. aqueous NaHCO 3 . The organic phase was dried over Na 2 SO 4 , filtered, and evaporated under reduced pressure. The crude product was purified on silica gel (eluting 60-70% EtOAc/hexane) to give the alcohol (99 mg, 79%) as a colorless solid.
  • Diethylphosphonate 56 To a solution of phenol 55 (21 mg, 0.050 mmol) in CH 3 CN (1 mL) and THF (1 mL) was added trifluoro-methanesulfonic acid diethoxy-phosphorylmethyl ester (18 mg, 0.060 mmol) in CH 3 CN (1 mL). After the addition of Cs 2 CO 3 (20 mg, 0.060 mmol), the reaction mixture was stirred for 2 h at room temperature. Additional triflate (18 mg, 0.060 mmol) and Cs 2 CO 3 (20 mg, 0.060 mmol) were introduced. After the reaction mixture was stirred for another 2 h at room temperature, the mixture was concentrated under reduced pressure.
  • the title compound 58 was prepared following the sequence of steps described in Example 27 with substitution of trifluoro-methanesulfonic acid bis-benzyloxy-phosphorylmethyl ester for trifluoro-methanesulfonic acid diethoxy-phosphorylmethyl ester. Purification of the crude final product on silica gel eluted with 3-4% MeOH/CH 2 Cl 2 provided 33 mg of the title compound.
  • the title compound 60 was prepared following the sequence of steps described in Example 25, except for substituting 3-methoxy benzyl chloride for 4-methoxyl benzyl chloride. Purification of the crude final product on preparative thin layer chromatography eluted with 5% MeOH/CH 2 Cl 2 provided 28 mg of the title compound.
  • the title compound 61 was prepared following the sequence of steps described in Example 26, except for substituting 3-methoxy benzyl chloride for 4-methoxyl benzyl chloride. Purification of the crude final product on silica gel eluted with 3-4% MeOH/CH 2 Cl 2 provided 36 mg of the title compound.
  • the title compound 62 was prepared following the sequence of steps described in Example 29, except for substituting compound 61 for compound 58. Purification of the crude final product with HPLC (eluting 30-40% CH 3 CN/H 2 O) provided 7 mg of the title compound.
  • Alcohol 64 A solution of methyl 6-methoxynicotinate 63 (2.0 g, 12 mmol) in Et 2 O (50 mL) was treated with 1.5M DIBAL-H in toluene (16.8 mL, 25.1 mmol) at 0° C. After the reaction mixture was stirred for 1 h at 0° C., the mixture was quenched with 1M sodium potassium tartrate and stirred for an additional 2 h. The aqueous phase was extracted with Et 2 O and concentrated to give alcohol 64 (1.54 g, 92%) as a pale yellow oil.
  • Bromide 65 A solution of alcohol 64 (700 mg, 5.0 mmol) in CH 2 Cl 2 (50 mL) was treated with carbon tetrabromide (2.49 g, 7.5 mmol) and triphenylphosphine (1.44 g, 5.5 mmol) at 0° C. After the reaction mixture was stirred for 30 min at room temperature, the mixture was partitioned between CH 2 Cl 2 and sat. aqueous NaHCO 3 . The organic phase was dried over Na 2 SO 4 , filtered, and evaporated under reduced pressure. The crude product was purified on silica gel (eluting 5-10% MeOH/CH 2 Cl 2 ) to give bromide 65 (754 mg, 75%) as colorless crystals.
  • Imidazole 66 A solution of imidazole 53 (760 mg, 1.86 mmol) and bromide 65 (752 mg, 3.72 mmol) in THF (10 mL) was treated with powder NaOH (298 mg, 7.44 mmol), lithium iodide (249 mg, 1.86 mmol), and tetrabutylammonium bromide (300 mg, 0.93 mmol). After stirring for 14 h at room temperature, the mixture was partitioned between EtOAc and sat. NH 4 Cl. The organic phase was dried over Na 2 SO 4 , filtered, and evaporated under reduced pressure. The crude product was purified on silica gel (eluting 20-30% EtOAc/hexane) to give imidazole 66 (818 mg, 83%) as a pale yellow oil.
  • Diol 67 A solution of benzyl ether 66 (348 mg, 0.658 mmol) in EtOH (3 mL) was treated with conc. HCl (3 mL). After the reaction mixture was warmed to 80° C. and stirred for 18 h, the mixture was concentrated under reduced pressure. The crude product was chromatographed on silica gel (eluting 5-10% MeOH/CH 2 Cl 2 ) to give diol 67 (275 mg, 98%) as a colorless solid.
  • the title compound 70 was prepared following the sequence of steps described in Example 32, except for substituting trifluoro-methanesulfonic acid bis-benzyloxy-phosphorylmethyl ester for trifluoro-methanesulfonic acid diethoxy-phosphorylmethyl ester. Purification of the crude final product on silica gel eluted with 50-60% CH 3 CN/H 2 O provided 12 mg of the title compound.
  • the title compound 74 was prepared following the sequence of steps described in Example 33, except for substituting 6-bromomethyl-3-methoxy pyridine for 5-bromomethyl-2-methoxy pyridine 65. Purification of the crude final product on silica gel with 4-5% MeOH/CH 2 Cl 2 provided 66 mg of the title compound.
  • the title compound 76 was prepared following the sequence of steps described in Example 39, except for substituting trifluoro-methanesulfonic acid bis-benzyloxy-phosphorylmethyl ester for trifluoro-methanesulfonic acid diethoxy-phosphorylmethyl ester. Purification of the crude final product on silica gel eluted with 4% MeOH/CH 2 Cl 2 provided 67 mg of the title compound.
  • the title compound 78 was prepared following the sequence of steps described in Example 29, except for substituting compound 77 for compound 28. Purification of the crude final product on a C-18 column eluted with 30% CH 3 CN/H 2 O provided 6 mg of the title compound.
  • Diphenylphosphonate 79 A solution of phosphonic acid 59 (389 mg, 0.694 mmol) in pyridine (5 mL) was treated with phenol (653 mg, 6.94 mmol) and 1,3-dicyclohexylcarbodiimide (573 mg, 2.78 mmol). After stirring at 70° C. for 2 h, the mixture was diluted with CH 3 CN and filtered through a fritted funnel. The filtrate was partitioned between EtOAc and sat. NH 4 Cl, and extracted with EtOAc. The organic phase was dried over Na 2 SO 4 , filtered, and evaporated under reduced pressure. The crude product was purified on silica gel (eluting 60-80% EtOAc/hexane) to give diphenylphosphonate 79 (278 mg, 56%) as a colorless oil.
  • Phosphonic acid 80 A solution of diphenylphosphonate 79 (258 mg, 0.362 mmol) in CH 3 CN (20 mL) was treated with 1N NaOH (0.72 mL, 0.724 mmol) at 0° C. After the reaction mixture was stirred for 3 h at 0° C., the mixture was filtered through Dowex 50WX8-400 acidic resin (380 mg), rinsed with MeOH, and concentrated under reduced pressure to give phosphonic acid 80 (157 mg, 68%) as a colorless solid.
  • the title compound 82 was prepared following the sequence of steps described in Example 44, except for reacting monophosphonic acid 80 with isopropyl lactate. Purification of the crude final product on silica gel eluted with 70-90% EtOAc/hexane provided 5.4 mg of the title compound.
  • the title compound 83 was prepared following the sequence of steps described in Example 44, except for reacting monophosphonic acid 80 with methyl lactate. Purification of the crude final product on silica gel eluted with 70-90% EtOAc/hexane provided 2.7 mg of the title compound.
  • the title compound 85 was prepared following the sequence of steps described in Example 44, except for reacting monophosphonic acid 80 with L-alanine ethyl ester. Purification of the crude final product on preparative thin layer chromatography eluted with 80% EtOAc/hexane provided 7 mg of the title compound.
  • the title compound 86 was prepared following the sequence of steps described in Example 44, except for reacting monophosphonic acid 80 with L-alanine methyl ester. Purification of the crude final product on preparative thin layer chromatography eluted with 80% EtOAc/hexane provided 8 mg of the title compound.
  • the title compound 87 was prepared following the sequence of steps described in Example 44, except for reacting monophosphonic acid 80 with L-alanine isopropyl ester. Purification of the crude final product on preparative thin layer chromatography eluted with 80% EtOAc/hexane provided 7 mg of the title compound.
  • the title compound 88 was prepared following the sequence of steps described in Example 44, except for reacting monophosphonic acid 80 with L-alanine n-butyl ester. Purification of the crude final product on preparative thin layer chromatography eluted with 80% EtOAc/hexane provided 6 mg of the title compound.
  • the title compound 89 was prepared following the sequence of steps described in Example 44, except for reacting monophosphonic acid 80 with L-alanine n-butyl ester. Purification of the crude final product on preparative thin layer chromatography eluted with 80% EtOAc/hexane provided 4 mg of the title compound.
  • Diethylphosphonate 93 A solution of alcohol 92 (200 mg, 0.609 mmol) in THF (5 mL) was treated with 60% NaH in mineral oil (37 mg, 0.914 mmol) at 0° C. After the reaction mixture was stirred for 5 min at 0° C., trifluoro-methanesulfonic acid diethoxy-phosphorylmethyl ester (219 mg, 0.731 mmol) was added in THF (3 mL). After the reaction mixture was stirred for an additional 30 min, the mixture was quenched with sat. NH 4 Cl and extracted with EtOAc. The organic phase was dried over Na 2 SO 4 , filtered, and evaporated under reduced pressure to give crude diethylphosphonate 93 as a colorless oil.
  • Alcohol 94 A solution of diethylphosphonate 93 (291 mg, 0.609 mmol) in CH 2 Cl 2 (5 mL) was treated with trifluoroacetic acid (0.5 mL). After the reaction mixture was stirred for 30 min at room temperature, the mixture was concentrated under reduced pressure. The crude product was purified on silica gel (eluting 4-5% MeOH/CH 2 Cl 2 ) to give alcohol 94 (135 mg, 94% over 2 steps) as a colorless oil.
  • Bromide 95 A solution of alcohol 94 (134 mg, 0.567 mmol) in CH 2 Cl 2 (5 mL) was treated with carbon tetrabromide (282 mg, 0.851 mmol) and triphenylphosphine (164 mg, 0.624 mmol). After stirring at room temperature for 1 h, the mixture was partitioned between CH 2 Cl 2 and sat. NaHCO 3 . The organic phase was dried over Na 2 SO 4 , filtered, and evaporated under reduced pressure.
  • Imidazole 96 A solution of benzyl ether 53 (2.58 g, 6.34 mmol) in EtOH (60 mL) was treated with conc. HCl (60 mL). After the reaction mixture was warmed to 100° C. and stirred for 18 h, the mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and sat. NaHCO 3 . The organic phase was dried over Na 2 SO 4 , filtered, and evaporated under reduced pressure. The crude product was chromatographed on silica gel (eluting 8-9% MeOH/CH 2 Cl 2 ) to give imidazole 96 (1.86 g, 93%) as a colorless solid.
  • the title compound 97a was prepared following the sequence of steps described in Example 32 by substituting compound 97a for compound 68. Purification of the crude final product on silica gel eluted with 34% MeOH/CH 2 Cl 2 provided 13 mg of the title compound.
  • Monophenol Allylphosphonate 99c To a solution of allylphosphonic dichloride 99a (4 g, 25.4 mmol) and phenol (5.2 g, 55.3 mmol) in CH 2 Cl 2 (40 mL) at 0° C. was added TEA (8.4 mL, 60 mmol). After stirred at room temperature for 1.5 h, the mixture was diluted with hexane-ethyl acetate and washed with HCl (0.3 N) and water. The organic phase was dried over MgSO 4 , filtered and concentrated under reduced pressure.
  • the aqueous phase was acidified with concentrated HCl at 0° C. and extracted with ethyl acetate.
  • the organic phase was dried over MgSO 4 , filtered, evaporated and co-evaporated with toluene under reduced pressure to yield desired monophenol allylphosphonate 99c (4.75 g. 95%) as an oil.
  • Monolactate Allylphosphonate 99e A solution of monophenol allylphosphonate 99c (4.75 g, 24 mmol) in toluene (30 mL) was treated with SOCl 2 (5 mL, 68 mmol) and DMF (0.05 mL). After stirred at 65° C. for 4 h, the reaction was completed as shown by 31 P NMR. The reaction mixture was evaporated and co-evaporated with toluene under reduced pressure to give mono chloride 99d (5.5 g) as an oil. A solution of chloride 99d in CH 2 Cl 2 (25 mL) at 0° C. was added ethyl (s)-lactate (3.3 mL, 28.8 mmol), followed by TEA.
  • Aldehyde 99f A solution of allylphosphonate 99e (2.5 g, 8.38 mmol) in CH 2 Cl 2 (30 mL) was bubbled with ozone air at ⁇ 78° C. until the solution became blue, then bubbled with nitrogen until the blue color disappeared. Methyl sulfide (3 mL) was added at ⁇ 78° C. The mixture was warmed up to room temperature, stirred for 16 h and concentrated under reduced pressure to give desired aldehyde 99f (3.2 g, as a 1:1 mixture of DMSO).
  • Compound 98 was prepared from compound 29 following the sequence of steps described in Example 22.
  • Compound 99 was prepared from compound 96 following the sequence of steps described in Example 54 and 55, except for substituting 4-nitro benzyl bromide for compound 95.
  • Aniline 100 To a solution of compound 99 (100 mg, 0.202 mmol) in EtOH (2 mL) was added acetic acid (2 mL) and zinc dust (40 mg, 0.606 mmol). After the reaction mixture was stirred for 30 min at room temperature, the mixture was concentrated under reduced pressure. The crude product was purified on silica gel (eluting 5-6% MeOH/CH 2 Cl 2 ) to give aniline 100 (43 mg, 41%) as a yellow oil.
  • Compound 102 was prepared from compound 96 following the sequence of steps described in Example 54, except for substituting methyl 4-bromomethyl benzoate for compound 95.
  • Aldehyde 104 A solution of amide 103 (106 mg, 0.214 mmol) in THF (5 mL) was treated with 1.5M DIBAL-H in toluene (0.43 mL, 0.642 mmol) at 0° C. After the reaction mixture was stirred for 1 h at 0° C., the mixture was quenched with 1M sodium potassium tartrate and stirred for an additional 3 d. The aqueous phase was extracted with EtOAc, and the organic phase was dried over Na 2 SO 4 , filtered, and evaporated under reduced pressure to give crude aldehyde 104 as a colorless oil.
  • the title compound 106 was prepared following the sequence of steps described in Example 34, except for substituting compound 105 for compound 68. Purification of the crude final product on preparative thin layer chromatography eluted with 7% MeOH/CH 2 Cl 2 provided 6 mg of the title compound.
  • Compound 109 was prepared from compound 29 following the sequence of steps described in Example 22.
  • the title compound was prepared following the sequence of steps described in Example 58, except for substituting compound 109 for aminoethyl phosphonic acid diethyl ester. Purification of the crude final product on silica gel eluted with 5-6% MeOH/CH 2 Cl 2 provided 8 mg of the title compound.
  • Alcohol 112a A solution of 112 (1.94 g, 6.42 mmol) in Et 2 O (40 mL) was treated with LiBH 4 (0.699 g, 32.1 mmol) and THF (10 mL). After the reaction mixture was stirred for 12 h at room temperature, the mixture was quenched with water and extracted with EtOAc (3 ⁇ ). The organic phase was dried over Na 2 SO 4 and evaporated under reduced pressure. The crude product was purified on silica gel (eluted with 2-5% MeOH/CH 2 Cl 2 ) to give 1.48 g (84%) of alcohol compound 112a as a colorless oil.
  • Alcohol compound 113 A solution of benzyl ether 36 (120 mg, 0.326 mmol) in EtOH (2 mL) was treated with conc. HCl (2 mL). After the reaction mixture was refluxed at 100° C. for 1 day, the mixture was concentrated under reduced pressure, partitioned between EtOAc and sat. NaHCO 3 , and extracted with EtOAc (3 ⁇ ). The organic phase was dried over Na 2 SO 4 and evaporated under reduced pressure to provide the crude alcohol compound 113 (90 mg, 99%) as a white solid.
  • Title compound 119 was prepared following the sequence of steps described in Example 62 by substituting trifluoro-methanesulfonic acid bis-benzyloxy-phosphorylmethyl ester for trifluoro-methanesulfonic acid diethoxy-phosphorylmethyl ester. Purification of the crude final product on silica gel eluted with (2.5%-5% CH 3 OH/CH 2 Cl 2 ) provided 71 mg (65%) of the title compound.
  • Compound 121 was prepared following the sequence of steps described in Example 62 by substituting trifluoro-methanesulfonic acid dimethoxy-phosphorylethyl ester for trifluoro-methanesulfonic acid diethoxy-phosphorylmethyl ester. Purification of the crude final product on TLC plate eluted with (5% CH 3 OH/CH 2 Cl 2 ) provided 11 mg (65%) of the title compound.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Microbiology (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biophysics (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Toxicology (AREA)
  • Urology & Nephrology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pathology (AREA)
  • Cell Biology (AREA)
  • Food Science & Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Virology (AREA)
  • General Physics & Mathematics (AREA)
  • AIDS & HIV (AREA)
US10/511,183 2002-04-26 2003-04-25 Method and compositions for identifying anti-hiv therapeutic compounds Abandoned US20060115815A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US10/511,183 US20060115815A1 (en) 2002-04-26 2003-04-25 Method and compositions for identifying anti-hiv therapeutic compounds

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US37566502P 2002-04-26 2002-04-26
US37562202P 2002-04-26 2002-04-26
US37577902P 2002-04-26 2002-04-26
US37583402P 2002-04-26 2002-04-26
PCT/US2003/012943 WO2003090691A2 (en) 2002-04-26 2003-04-25 Method and compositions for identifying anti-hiv therapeutic compounds
US10/511,183 US20060115815A1 (en) 2002-04-26 2003-04-25 Method and compositions for identifying anti-hiv therapeutic compounds

Publications (1)

Publication Number Publication Date
US20060115815A1 true US20060115815A1 (en) 2006-06-01

Family

ID=29273807

Family Applications (7)

Application Number Title Priority Date Filing Date
US10/511,998 Abandoned US20070010489A1 (en) 2002-04-26 2003-04-25 Cellular accumulation of phosphonate analogs of hiv protease inhibitor compounds
US10/511,183 Abandoned US20060115815A1 (en) 2002-04-26 2003-04-25 Method and compositions for identifying anti-hiv therapeutic compounds
US10/423,496 Active 2025-05-15 US7649015B2 (en) 2002-04-26 2003-04-25 Cellular accumulation of phosphonate analogs of HIV protease inhibitor compounds
US10/424,130 Active 2025-04-30 US7462608B2 (en) 2002-04-26 2003-04-25 Non nucleoside reverse transcriptase inhibitors
US10/424,186 Abandoned US20040121316A1 (en) 2002-04-26 2003-04-25 Method and compositions for identifying anti-HIV therapeutic compounds
US10/511,182 Abandoned US20060128692A1 (en) 2002-04-26 2003-04-25 Non nucleoside reverse transcriptase inhibitors
US10/554,287 Abandoned US20070190523A1 (en) 2002-04-26 2003-11-06 Method and compositions for identifying anti-hiv therapeutic compounds

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US10/511,998 Abandoned US20070010489A1 (en) 2002-04-26 2003-04-25 Cellular accumulation of phosphonate analogs of hiv protease inhibitor compounds

Family Applications After (5)

Application Number Title Priority Date Filing Date
US10/423,496 Active 2025-05-15 US7649015B2 (en) 2002-04-26 2003-04-25 Cellular accumulation of phosphonate analogs of HIV protease inhibitor compounds
US10/424,130 Active 2025-04-30 US7462608B2 (en) 2002-04-26 2003-04-25 Non nucleoside reverse transcriptase inhibitors
US10/424,186 Abandoned US20040121316A1 (en) 2002-04-26 2003-04-25 Method and compositions for identifying anti-HIV therapeutic compounds
US10/511,182 Abandoned US20060128692A1 (en) 2002-04-26 2003-04-25 Non nucleoside reverse transcriptase inhibitors
US10/554,287 Abandoned US20070190523A1 (en) 2002-04-26 2003-11-06 Method and compositions for identifying anti-hiv therapeutic compounds

Country Status (28)

Country Link
US (7) US20070010489A1 (no)
EP (4) EP1575486A4 (no)
JP (5) JP4942915B2 (no)
KR (2) KR100987815B1 (no)
CN (4) CN101041669A (no)
AT (1) ATE367394T1 (no)
AU (4) AU2003231766A1 (no)
BR (2) BR0309557A (no)
CA (3) CA2481285A1 (no)
CY (1) CY1108036T1 (no)
DE (1) DE60315023T2 (no)
DK (1) DK1509537T3 (no)
EA (2) EA200401437A1 (no)
ES (1) ES2290485T3 (no)
HK (1) HK1073467A1 (no)
HR (2) HRP20041114A2 (no)
IL (2) IL164491A0 (no)
IS (2) IS7555A (no)
MX (2) MXPA04010528A (no)
NO (2) NO336469B1 (no)
NZ (1) NZ535828A (no)
PL (2) PL211979B1 (no)
PT (1) PT1509537E (no)
SI (1) SI1509537T1 (no)
TW (2) TWI332956B (no)
UA (1) UA80819C2 (no)
WO (4) WO2003091264A2 (no)
ZA (2) ZA200409377B (no)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011002523A1 (en) * 2009-07-02 2011-01-06 Kanionusa Inc. Phosphorus containing quinazoline compounds and methods of use
US9012462B2 (en) 2008-05-21 2015-04-21 Ariad Pharmaceuticals, Inc. Phosphorous derivatives as kinase inhibitors
US9273077B2 (en) 2008-05-21 2016-03-01 Ariad Pharmaceuticals, Inc. Phosphorus derivatives as kinase inhibitors
US9611283B1 (en) 2013-04-10 2017-04-04 Ariad Pharmaceuticals, Inc. Methods for inhibiting cell proliferation in ALK-driven cancers
US9834571B2 (en) 2012-05-05 2017-12-05 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in EGFR-driven cancers
US9834518B2 (en) 2011-05-04 2017-12-05 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in EGFR-driven cancers
US9919939B2 (en) 2011-12-06 2018-03-20 Delta Faucet Company Ozone distribution in a faucet
US11458214B2 (en) 2015-12-21 2022-10-04 Delta Faucet Company Fluid delivery system including a disinfectant device

Families Citing this family (122)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL211979B1 (pl) 2002-04-26 2012-07-31 Gilead Sciences Pochodne fosfonianowe, ich zastosowanie w leczeniu zakażenia wirusem HIV i chorób wpływających na białe krwinki, oraz kompozycje farmaceutyczne zawierające te związki
US20050239054A1 (en) * 2002-04-26 2005-10-27 Arimilli Murty N Method and compositions for identifying anti-HIV therapeutic compounds
MXPA05005649A (es) * 2002-11-27 2005-08-16 Elan Pharm Inc Ureas y carbamatos sustituidos.
SI1583542T1 (sl) * 2003-01-14 2008-12-31 Gilead Sciences Inc Sestavki in postopki za kombinacijsko antivirusnoterapijo
US20050261237A1 (en) * 2003-04-25 2005-11-24 Boojamra Constantine G Nucleoside phosphonate analogs
WO2004096286A2 (en) 2003-04-25 2004-11-11 Gilead Sciences, Inc. Antiviral phosphonate analogs
US20090247488A1 (en) * 2003-04-25 2009-10-01 Carina Cannizzaro Anti-inflammatory phosphonate compounds
US7432261B2 (en) 2003-04-25 2008-10-07 Gilead Sciences, Inc. Anti-inflammatory phosphonate compounds
US7470724B2 (en) 2003-04-25 2008-12-30 Gilead Sciences, Inc. Phosphonate compounds having immuno-modulatory activity
CN101410120A (zh) * 2003-04-25 2009-04-15 吉里德科学公司 抗炎的膦酸酯化合物
EP1620110A2 (en) * 2003-04-25 2006-02-01 Gilead Sciences, Inc. Immunomodulator phosphonate conjugates
MXPA05011296A (es) 2003-04-25 2006-01-24 Gilead Sciences Inc Conjugados de fosfonato inhibidores de la cinasa.
US7300924B2 (en) * 2003-04-25 2007-11-27 Gilead Sciences, Inc. Anti-infective phosphonate analogs
US7452901B2 (en) * 2003-04-25 2008-11-18 Gilead Sciences, Inc. Anti-cancer phosphonate analogs
WO2004096237A2 (en) * 2003-04-25 2004-11-11 Gilead Sciences, Inc. Phosphonate analogs for treating metabolic diseases
US7427636B2 (en) 2003-04-25 2008-09-23 Gilead Sciences, Inc. Inosine monophosphate dehydrogenase inhibitory phosphonate compounds
WO2004096233A2 (en) * 2003-04-25 2004-11-11 Gilead Sciences, Inc. Nucleoside phosphonate conjugates
WO2005002626A2 (en) 2003-04-25 2005-01-13 Gilead Sciences, Inc. Therapeutic phosphonate compounds
US7407965B2 (en) * 2003-04-25 2008-08-05 Gilead Sciences, Inc. Phosphonate analogs for treating metabolic diseases
US7491794B2 (en) * 2003-10-14 2009-02-17 Intermune, Inc. Macrocyclic compounds as inhibitors of viral replication
US7427624B2 (en) 2003-10-24 2008-09-23 Gilead Sciences, Inc. Purine nucleoside phosphorylase inhibitory phosphonate compounds
EP1678321A1 (en) 2003-10-24 2006-07-12 Gilead Sciences, Inc. Methods and compositions for identifying therapeutic compounds
US7432273B2 (en) 2003-10-24 2008-10-07 Gilead Sciences, Inc. Phosphonate analogs of antimetabolites
US20050153990A1 (en) * 2003-12-22 2005-07-14 Watkins William J. Phosphonate substituted kinase inhibitors
US7432272B2 (en) * 2003-12-22 2008-10-07 Gilead Sciences, Inc. Antiviral analogs
BRPI0418031A (pt) * 2003-12-22 2007-04-17 Gilead Sciences Inc inibidores de quinase fosfonato-substituìdos
MXPA06007095A (es) * 2003-12-22 2006-09-04 Gilead Sciences Inc Conjugados de fosfonato inhibidores de cinasa.
CN1934093A (zh) * 2004-01-12 2007-03-21 吉里德科学公司 嘧啶基膦酸酯抗病毒化合物和使用方法
ES2315922T3 (es) * 2004-04-14 2009-04-01 Gilead Sciences, Inc. Analogos de fosfonato de compuestos inhibidores de la integrasa del vih.
AU2011218664B2 (en) * 2004-07-27 2014-08-21 Gilead Sciences, Inc. Antiviral compounds
WO2006110157A2 (en) * 2004-07-27 2006-10-19 Gilead Sciences, Inc. Nucleoside phosphonate conjugates as anti hiv agents
PT1799696E (pt) * 2004-09-17 2009-02-16 Idenix Pharmaceuticals Inc Fosfoindoles como inibidores de hiv
UA88325C2 (en) * 2004-09-17 2009-10-12 Айденикс Фармасьютикалз, Инк. Phosphoindoles as hiv inhibitors
NZ554374A (en) 2004-10-07 2010-11-26 Vitae Pharmaceuticals Inc Diaminoalkane aspartic protease inhibitors
US7504389B2 (en) 2004-11-15 2009-03-17 Ceptyr, Inc. Protein tyrosine phosphatase inhibitors and methods of use thereof
ES2401285T3 (es) 2004-12-16 2013-04-18 The Regents Of The University Of California Fármacos con el pulmón como diana
DK1856125T3 (da) 2005-02-25 2009-12-07 Tibotec Pharm Ltd Syntese af proteasehæmmerforstadie
JP2008535862A (ja) * 2005-04-08 2008-09-04 キメリクス，インコーポレイテッド ポックスウイルス感染の治療のための化合物、組成物および方法
WO2006110656A2 (en) * 2005-04-08 2006-10-19 Chimerix, Inc. Compounds, compositions and methods for the treatment of viral infections and other medical disorders
AR053845A1 (es) 2005-04-15 2007-05-23 Tibotec Pharm Ltd 5-tiazolilmetil[(1s,2r)-3-[[(2-amino-6-benzoxazolil)sulfonil)](2-metilpropil)amino]-2-hidroxi-1-(fenilmetil)propil]carbamato como mejorador de farmacos metabolizados por el citocromo p450
TWI471145B (zh) 2005-06-13 2015-02-01 Bristol Myers Squibb & Gilead Sciences Llc 單一式藥學劑量型
TWI375560B (en) * 2005-06-13 2012-11-01 Gilead Sciences Inc Composition comprising dry granulated emtricitabine and tenofovir df and method for making the same
EP2305697A3 (en) * 2005-07-25 2011-07-27 Intermune, Inc. Macrocyclic inhibitors of Hepatitis C virus replication
EP1906971A2 (en) * 2005-07-27 2008-04-09 Gilead Sciences, Inc. Antiviral compounds
NZ568135A (en) * 2005-10-11 2011-06-30 Array Biopharma Inc Macrocyclic compounds and methods for inhibiting hepatitis C viral replication
TWI411607B (zh) 2005-11-14 2013-10-11 Vitae Pharmaceuticals Inc 天門冬胺酸蛋白酶抑制劑
TWI385173B (zh) 2005-11-28 2013-02-11 Tibotec Pharm Ltd 作為ｈｉｖ蛋白酶抑制劑之經取代的胺基苯基磺醯胺化合物
AR058238A1 (es) 2005-11-28 2008-01-23 Tibotec Pharm Ltd Compuestos y derivados de aminofenilsulfonamida sustituida como inhibidores de proteasa del vih
AP2008004533A0 (en) * 2005-12-14 2008-08-31 Cipla Ltd Pharmaceutical combination
US20070167422A1 (en) * 2006-01-18 2007-07-19 Yu Kwok S Pharmaceutical compositions comprising 17-allylamino-17-demethoxygeldanamycin
AP2013006690A0 (en) 2006-03-29 2013-01-31 Gilead Sciences Inc Process for preparation of HIV protease inhibitors
US20090312318A1 (en) * 2006-07-24 2009-12-17 Desai Manoj C Therapeutic compounds and methods
CL2007002689A1 (es) 2006-09-18 2008-04-18 Vitae Pharmaceuticals Inc Compuestos derivados de piperidin-1-carboxamida, inhibidores de la renina; compuestos intermediarios; composicion farmaceutica; y uso en el tratamiento de enfermedades tales como hipertension, insuficiencia cardiaca, fibrosis cardiaca, entre otras.
CA2664396A1 (en) 2006-09-29 2008-04-10 Idenix Pharmaceuticals, Inc. Enantiomerically pure phosphoindoles as hiv inhibitors
EP2121589A2 (en) * 2006-12-18 2009-11-25 University of Massachusetts Crystal structures of hiv-1 protease inhibitors bound to hiv-1 protease
WO2008115894A1 (en) * 2007-03-16 2008-09-25 Sequoia Pharmaceuticals Benzofuran-derived hiv protease inhibitors
WO2008118849A2 (en) * 2007-03-23 2008-10-02 University Of Massachusetts Hiv-1 protease inhibitors
AP2009005053A0 (en) * 2007-05-03 2009-12-31 Intermune Inc Novel macrocyclic inhibitors of hepatitis c virus replication
WO2008151306A1 (en) * 2007-06-05 2008-12-11 Arizona Board Of Regents, A Body Corporate Of The State Of Arizona, Acting For And On Behalf Of Arizona State University Synthesis of cyclodepsipeptide compounds having antineoplastic and/or antimicrobial activity
KR20100041798A (ko) 2007-06-29 2010-04-22 한국화학연구원 신규 ｈｉｖ 역전사효소 억제제
US8334295B2 (en) 2007-06-29 2012-12-18 Korea Research Institute Of Chemical Technology Pyrimidine derivatives as HIV reverse transcriptase inhibitors
US8901487B2 (en) * 2007-07-20 2014-12-02 George Washington University Subcellular analysis by laser ablation electrospray ionization mass spectrometry
US20100285446A1 (en) * 2007-07-20 2010-11-11 Akos Vertes Methods for Detecting Metabolic States by Laser Ablation Electrospray Ionization Mass Spectrometry
US7964843B2 (en) 2008-07-18 2011-06-21 The George Washington University Three-dimensional molecular imaging by infrared laser ablation electrospray ionization mass spectrometry
US8067730B2 (en) 2007-07-20 2011-11-29 The George Washington University Laser ablation electrospray ionization (LAESI) for atmospheric pressure, In vivo, and imaging mass spectrometry
US8119800B2 (en) 2007-12-21 2012-02-21 Korea Research Institute Of Chemical Technology Processes for preparing HIV reverse transcriptase inhibitors
CN105055432A (zh) * 2008-01-25 2015-11-18 奇默里克斯公司 治疗病毒感染的方法
AU2009249443A1 (en) * 2008-04-15 2009-11-26 Intermune, Inc. Novel macrocyclic inhibitors of hepatitis C virus replication
US8173621B2 (en) 2008-06-11 2012-05-08 Gilead Pharmasset Llc Nucleoside cyclicphosphates
CA2729052A1 (en) * 2008-06-26 2009-12-30 Vitae Pharmaceuticals, Inc. Salts of methyl 2-((r)-(3-chlorophenyl)((r)-1-((s)-2-(methylamino)-3((r)-tetrahydro-2h-pyran-3-yl)propylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate
PL2307435T3 (pl) 2008-07-08 2012-11-30 Gilead Sciences Inc Sole związków inhibitorów HIV
JP2012505897A (ja) * 2008-10-15 2012-03-08 インターミューン・インコーポレーテッド 治療用抗ウイルス性ペプチド
EP2376515A1 (en) 2008-12-23 2011-10-19 Pharmasset, Inc. Synthesis of purine nucleosides
AR074897A1 (es) 2008-12-23 2011-02-23 Pharmasset Inc Fosforamidatos de nucleosidos
SG172361A1 (en) 2008-12-23 2011-07-28 Pharmasset Inc Nucleoside analogs
AR075584A1 (es) * 2009-02-27 2011-04-20 Intermune Inc COMPOSICIONES TERAPEUTICAS QUE COMPRENDEN beta-D-2'-DESOXI-2'-FLUORO-2'-C-METILCITIDINA Y UN DERIVADO DE ACIDO ISOINDOL CARBOXILICO Y SUS USOS. COMPUESTO.
TWI576352B (zh) 2009-05-20 2017-04-01 基利法瑪席特有限責任公司 核苷磷醯胺
EP2270021A1 (en) 2009-06-18 2011-01-05 Centre National de la Recherche Scientifique Phosphonates synthons for the synthesis of phosphonates derivatives showing better bioavailability
WO2010151476A2 (en) 2009-06-25 2010-12-29 Gilead Sciences, Inc. Crystalline forms of (3r, 3as, 6ar) - hexahydrofuro [2,3-b] furan-3-yl (1s,2r) - (1-{4-[ (diethoxyphosphoryl) methoxy] pheny1}-3-hydroxy-4- [4-methoxy-n- (2-methylpropyl) benzenesul - fonamido] butan-2-yl) carbamate
US7924650B2 (en) * 2009-06-30 2011-04-12 Oracle America, Inc. Dynamically controlled voltage regulator for a memory
US8614200B2 (en) 2009-07-21 2013-12-24 Chimerix, Inc. Compounds, compositions and methods for treating ocular conditions
AR077692A1 (es) 2009-08-06 2011-09-14 Vitae Pharmaceuticals Inc Sales de 2-((r)-(3-clorofenil) ((r)-1-((s) -2-(metilamino)-3-((r)-tetrahidro-2h-piran-3-il) propilcarbamoil) piperidin -3-il) metoxi) etilcarbamato de metilo
DE102009041443A1 (de) * 2009-09-16 2011-03-31 Archimica Gmbh Salze des 6-Chlor-4-(cyclopropylethinyl)-1,4-dihydro-4-(trifluormethyl)-2H-3,1-benzoxazin-2-ons und deren Synthese, Aufreinigung und Anwendung als Vorstufen für Efavirenz
KR20120110090A (ko) * 2009-09-28 2012-10-09 에프. 호프만-라 로슈 리미티드 Ｃ형 간염 바이러스 복제의 신규한 마크로시클릭 저해제
TW201116540A (en) * 2009-10-01 2011-05-16 Intermune Inc Therapeutic antiviral peptides
JP2013509433A (ja) * 2009-10-30 2013-03-14 キメリクス，インコーポレイテッド ウイルス関連疾患を処置する方法
US9006218B2 (en) 2010-02-12 2015-04-14 Chimerix Inc. Nucleoside phosphonate salts
UY33312A (es) 2010-03-31 2011-10-31 Pharmasset Inc Fosforamidato de nucleosido de purina
US8563530B2 (en) 2010-03-31 2013-10-22 Gilead Pharmassel LLC Purine nucleoside phosphoramidate
PT3290428T (pt) 2010-03-31 2021-12-27 Gilead Pharmasset Llc Comprimido compreendendo 2-(((s)-(((2r,3r,4r,5r)-5-(2,4-dioxo-3,4-dihidropirimidin-1-(2h)-il)¿4¿fluoro¿3¿hidroxi¿4¿metiltetrahidrofuran¿2¿il)metoxi) (fenoxi)fosforil)amino)propanoato de (s)- isopropil cristalino
CA2797601A1 (en) 2010-04-26 2011-11-10 Chimerix, Inc. Methods of treating retroviral infections and related dosage regimes
US8884027B2 (en) 2010-10-22 2014-11-11 University Of Rochester Melampomagnolide B derivatives as antileukemic and cytotoxic agents
PT3042910T (pt) 2010-11-30 2019-04-16 Gilead Pharmasset Llc 2'-espiro-nucleósidos para utilização na terapia da hepatite c
CN102127030B (zh) * 2011-01-21 2013-05-22 天津大学 4-(取代-1,3-二炔基)-4-(三氟甲基)苯并-1,4-二氢噁嗪-2-酮类化合物及其制备方法和应用
TWI635093B (zh) * 2011-05-19 2018-09-11 基利科學股份有限公司 用於製備抗ｈｉｖ藥劑的方法與中間物
JP2014524121A (ja) 2011-07-14 2014-09-18 ザ・ジョージ・ワシントン・ユニバーシティ レーザアブレーション・エレクトロスプレイイオン化質量分析用のプルームコリメーション
EP2548991B1 (en) * 2011-07-18 2014-03-05 ESSILOR INTERNATIONAL (Compagnie Générale d'Optique) Machine for coating an optical article with an anti-soiling coating composition and method for using the machine
AU2012345732B2 (en) 2011-11-30 2016-07-14 Emory University Antiviral JAK inhibitors useful in treating or preventing retroviral and other viral infections
CN103665043B (zh) 2012-08-30 2017-11-10 江苏豪森药业集团有限公司 一种替诺福韦前药及其在医药上的应用
ES2687958T3 (es) 2013-03-15 2018-10-30 The Regents Of The University Of California Fosfonato diésteres de nucleósido acíclico
DK3116511T3 (da) 2014-03-14 2020-11-23 Alltech Inc Sammensætninger af selenoorganiske forbindelser og fremgangsmåder til anvendelse deraf
JPWO2016039403A1 (ja) * 2014-09-11 2017-06-29 塩野義製薬株式会社 持続性ｈｉｖプロテアーゼ阻害剤
JP6708329B2 (ja) 2014-09-15 2020-06-10 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア ヌクレオチド類似体
WO2016069955A1 (en) * 2014-10-29 2016-05-06 Wisconsin Alumni Research Foundation Boronic acid inhibitors of hiv protease
CN107427529A (zh) 2014-12-26 2017-12-01 埃莫里大学 N4‑羟基胞苷和衍生物及与其相关的抗病毒用途
WO2016187788A1 (en) 2015-05-25 2016-12-01 Merck Sharp & Dohme Corp. Fused tricyclic heterocyclic compounds useful for treating hiv infection
EP3350191B9 (en) 2015-09-15 2021-12-22 The Regents of the University of California Nucleotide analogs
WO2017048252A1 (en) 2015-09-15 2017-03-23 Alltech, Inc. Compositions of selenoorganic compounds and methods of use thereof
EP3368574A1 (en) 2015-10-30 2018-09-05 NBE-Therapeutics AG Anti-ror1 antibodies
EP3377066B1 (en) 2015-11-17 2021-04-07 Merck Sharp & Dohme Corp. Amido-substituted pyridotriazine derivatives useful as hiv integrase inhibitors
CA3011815A1 (en) 2016-01-20 2017-07-27 The Scripps Research Institute Ror1 antibody compositions and related methods
CN107709288A (zh) * 2016-02-03 2018-02-16 四川海思科制药有限公司 一种磷酰胺衍生物及制备方法和用途
CN106045874B (zh) * 2016-05-20 2017-12-05 大连医科大学 二苯甲酮‐二酮酸类化合物，组合物及用途
JOP20190130A1 (ar) 2016-12-02 2019-06-02 Merck Sharp & Dohme مركبات حلقية غير متجانسة رباعية الحلقات مفيدة كمثبطات إنزيم مدمج لفيروس نقص المناعة البشرية (hiv)
KR20190086017A (ko) 2016-12-02 2019-07-19 머크 샤프 앤드 돔 코포레이션 Hiv 인테그라제 억제제로서 유용한 트리시클릭 헤테로사이클 화합물
US11427613B2 (en) 2017-03-16 2022-08-30 Evolve Biologics Inc. Method for purification of albumin
CN109305989B (zh) * 2017-07-28 2021-02-26 四川海思科制药有限公司 一种磷酰胺衍生物及制备方法和用途
CN109305990B (zh) * 2017-07-28 2021-02-26 四川海思科制药有限公司 一种磷酸衍生物及制备方法和用途
PL3661937T3 (pl) 2017-08-01 2021-12-20 Gilead Sciences, Inc. Formy krystaliczne ((s)-((((2r,5r)-5-(6-amino-9h-puryn-9-ylo)-4-fluoro-2,5-dihydrofuran-2-ylo)oksy)metylo)(fenoksy)fosforylo)-l-alaninianu etylu (gs-9131) do leczenia zakażeń wirusowych
KR102486090B1 (ko) 2017-08-07 2023-01-10 엔비이-테라퓨틱스 아게 생체 내 내성이 높은 항체 약물 결합체
KR102626210B1 (ko) 2017-12-07 2024-01-18 에모리 유니버시티 N4-하이드록시사이티딘 및 유도체 및 이와 관련된 항-바이러스 용도
US11542288B2 (en) * 2020-06-01 2023-01-03 University Of Massachusetts Antiviral compounds

Family Cites Families (61)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IE63869B1 (en) 1986-11-06 1995-06-14 Res Dev Foundation Aerosols containing liposomes and method for their preparation
FR2611203B1 (fr) 1987-02-20 1989-06-09 Sturtz Georges Analogues gem-diphosphoniques d'amethopterine (methotrexate) et de derives deaza-n-10 amethopterine. leur preparation et les compositions pharmaceutiques qui les contiennent
US5631370A (en) 1988-01-20 1997-05-20 Regents Of The University Of Minnesota Optically-active isomers of dideoxycarbocyclic nucleosides
DE4003574A1 (de) * 1990-02-07 1991-08-08 Bayer Ag Neue dipeptide, verfahren zu ihrer herstellung und ihre verwendung als renininhibitoren in arzneimitteln
DE69115694T2 (de) 1990-06-13 1996-10-17 Arnold Newton Mass. Glazier Phosphorylierte prodrugs
ES2085446T3 (es) 1990-07-04 1996-06-01 Merrell Pharma Inc Derivados de acido 9-purinil fosfonico.
US5177064A (en) 1990-07-13 1993-01-05 University Of Florida Targeted drug delivery via phosphonate derivatives
DE4111730A1 (de) 1991-04-10 1992-10-15 Knoll Ag Neue cytarabin-derivate, ihre herstellung und verwendung
EP0531597A1 (en) 1991-09-12 1993-03-17 Merrell Dow Pharmaceuticals Inc. Novel unsaturated acyclic phosphonate derivatives of purine and pyrimidine
US5610294A (en) 1991-10-11 1997-03-11 The Du Pont Merck Pharmaceutical Company Substituted cyclic carbonyls and derivatives thereof useful as retroviral protease inhibitors
GB9126144D0 (en) 1991-12-10 1992-02-12 British Bio Technology Compounds
FR2692265B1 (fr) 1992-05-25 1996-11-08 Centre Nat Rech Scient Composes biologiquement actifs de type phosphotriesters.
IS2334B (is) 1992-09-08 2008-02-15 Vertex Pharmaceuticals Inc., (A Massachusetts Corporation) Aspartyl próteasi hemjari af nýjum flokki súlfonamíða
ATE199906T1 (de) 1993-06-29 2001-04-15 Mitsubishi Chem Corp Phosphonat-nukleotid ester-derivate
EP0708760A1 (en) * 1993-07-14 1996-05-01 Novartis AG Cyclic hydrazine compounds
US5446137B1 (en) 1993-12-09 1998-10-06 Behringwerke Ag Oligonucleotides containing 4'-substituted nucleotides
US5854227A (en) 1994-03-04 1998-12-29 Hartmann; John F. Therapeutic derivatives of diphosphonates
WO1997011092A1 (fr) 1994-04-07 1997-03-27 Nippon Shinyaku Co., Ltd. Derives de phosphates de cyclosporine et composition medicinale
RU2157368C2 (ru) * 1994-09-26 2000-10-10 Сионоги Энд Ко., Лтд. Производные имидазола и фармацевтическая композиция на их основе
US5705524A (en) * 1994-11-04 1998-01-06 Gilead Sciences, Inc. Thiepane compounds
CA2203570A1 (en) * 1994-11-04 1996-05-17 Lawrence R. Mcgee Thiepane compounds inhibiting and detecting hiv protease
US5750493A (en) 1995-08-30 1998-05-12 Raymond F. Schinazi Method to improve the biological and antiviral activity of protease inhibitors
US5914332A (en) * 1995-12-13 1999-06-22 Abbott Laboratories Retroviral protease inhibiting compounds
US5874577A (en) 1996-04-03 1999-02-23 Medichem Research, Inc. Method for the preparing 9-12-(Diethoxyphosphonomethoxy)ethyl!adenine and analogues thereof
JP4033494B2 (ja) 1996-07-26 2008-01-16 ギリヤド サイエンシーズ， インコーポレイテッド ヌクレオチドアナログ
EP0919562B1 (en) 1996-08-13 2002-11-06 Mitsubishi Chemical Corporation Phosphonate nucleotide compounds
JP2002514183A (ja) * 1996-09-17 2002-05-14 スーパージェン・インコーポレーテッド リン脂質薬剤誘導体
US6436989B1 (en) * 1997-12-24 2002-08-20 Vertex Pharmaceuticals, Incorporated Prodrugs of aspartyl protease inhibitors
CN1110492C (zh) * 1997-12-24 2003-06-04 沃泰克斯药物股份有限公司 天冬氨酰蛋白酶抑制剂的前药
US6312662B1 (en) * 1998-03-06 2001-11-06 Metabasis Therapeutics, Inc. Prodrugs phosphorus-containing compounds
AU4125099A (en) 1998-06-01 1999-12-20 S & T Science And Technology Inc. Antiviral phosphorus derivatives of 4'-thio-5-ethyl-2'-deoxyuridine
GB9815567D0 (en) * 1998-07-18 1998-09-16 Glaxo Group Ltd Antiviral compound
TWI260322B (en) * 1999-02-12 2006-08-21 Vertex Pharma Inhibitors of aspartyl protease
US6258831B1 (en) 1999-03-31 2001-07-10 The Procter & Gamble Company Viral treatment
AR031520A1 (es) * 1999-06-11 2003-09-24 Vertex Pharma Un compuesto inhibidor de aspartilo proteasa, una composicion que lo comprende y un metodo para tratar un paciente con dicha composicion
MXPA02001857A (es) 1999-08-24 2003-07-14 Cellgate Inc Composiciones y metodos para incrementar la entrega de drogas a traves y dentro de tejidos epiteliales.
GB9920872D0 (en) 1999-09-04 1999-11-10 Glaxo Group Ltd Benzophenones as inhibitors of reverse transcriptase
IL131887A0 (en) 1999-09-14 2001-03-19 Dpharm Ltd Phospholipid prodrugs of anti-proliferative drugs
BR0016058A (pt) * 1999-12-03 2003-07-15 Univ California San Diego Compostos de fosfonato
EP1242431A1 (en) 1999-12-22 2002-09-25 Merck Frosst Canada & Co. Aromatic phosphonates as protein tyrosine phosphatase 1b (ptp-1b) inhibitors
CN1426418A (zh) 2000-02-29 2003-06-25 三菱制药株式会社 膦酸酯核苷酸化合物
EP1295879A4 (en) 2000-06-13 2004-04-14 Shionogi & Co MEDICINAL COMPOSITIONS CONTAINING PROPENONE DERIVATIVES
FR2810322B1 (fr) * 2000-06-14 2006-11-10 Pasteur Institut PRODUCTION COMBINATOIRE D'ANALOGUES DE NUCLEOTIDES ET NUCLEOTIDES (XiTP)
UA72612C2 (en) 2000-07-06 2005-03-15 Pyrido[2.3-d]pyrimidine and pyrimido[4.5-d]pyrimidine nucleoside analogues, prodrugs and method for inhibiting growth of neoplastic cells
US6617310B2 (en) * 2000-07-19 2003-09-09 Bristol-Myers Squibb Pharma Company Phosphate esters of bis-amino acid sulfonamides containing substituted benzyl amines
KR100749160B1 (ko) 2000-07-21 2007-08-14 길리애드 사이언시즈, 인코포레이티드 포스포네이트 뉴클레오티드 유사체의 전구 약물의 제조방법
US6420586B1 (en) * 2000-08-15 2002-07-16 University Of Kansas Amino acid-derived cyclic phosphonamides and methods of synthesizing the same
KR100828453B1 (ko) 2001-01-22 2008-05-13 머크 앤드 캄파니 인코포레이티드 Ｒｎａ 의존성 ｒｎａ 바이러스 폴리머라제의억제제로서의 뉴클레오시드 유도체
GB0114286D0 (en) 2001-06-12 2001-08-01 Hoffmann La Roche Nucleoside Derivatives
KR20020097384A (ko) 2001-06-20 2002-12-31 미쯔비시 도꾜 세이야꾸 가부시끼가이샤 기존의 약제에 내성변이를 가지는 바이러스에 유효한 약제
WO2002103008A2 (en) * 2001-06-20 2002-12-27 Nuevolution A/S Templated molecules and methods for using such molecules
WO2003028737A1 (en) 2001-08-30 2003-04-10 Mitsubishi Pharma Corporation Anti-viral agents and in-vitro method for the identification of candidates able to inhibit binding of polymerase to epsilon
WO2003050129A1 (en) 2001-12-07 2003-06-19 Eli Lilly And Company Use of phosphonate nucleotide analogue for treating hepatitis b virus infections
JP4369237B2 (ja) 2001-12-21 2009-11-18 エーザイ コーポレーション オブ ノース アメリカ アルコールおよびフェノールの水溶性ホスホノオキシメチル誘導体の調製法
ES2485841T3 (es) 2002-02-01 2014-08-14 Ariad Pharmaceuticals, Inc Compuestos que contienen fósforo y usos de los mismos
CA2474508A1 (en) 2002-02-08 2003-08-14 Conforma Therapeutics Corporation Ansamycins having improved pharmacological and biological properties
AU2003216523A1 (en) 2002-03-18 2003-10-08 Mitsubishi Pharma Corporation Treatment of pre-core hepatitis b virus mutant infections
US20050239054A1 (en) * 2002-04-26 2005-10-27 Arimilli Murty N Method and compositions for identifying anti-HIV therapeutic compounds
PL211979B1 (pl) * 2002-04-26 2012-07-31 Gilead Sciences Pochodne fosfonianowe, ich zastosowanie w leczeniu zakażenia wirusem HIV i chorób wpływających na białe krwinki, oraz kompozycje farmaceutyczne zawierające te związki
EP2298783B1 (en) 2003-02-19 2017-12-06 Yale University Anti-viral nucleoside analogs and methods for treating viral infections, especially hiv infections
MXPA05011296A (es) 2003-04-25 2006-01-24 Gilead Sciences Inc Conjugados de fosfonato inhibidores de la cinasa.

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9012462B2 (en) 2008-05-21 2015-04-21 Ariad Pharmaceuticals, Inc. Phosphorous derivatives as kinase inhibitors
US9273077B2 (en) 2008-05-21 2016-03-01 Ariad Pharmaceuticals, Inc. Phosphorus derivatives as kinase inhibitors
WO2011002523A1 (en) * 2009-07-02 2011-01-06 Kanionusa Inc. Phosphorus containing quinazoline compounds and methods of use
US8987284B2 (en) 2009-07-02 2015-03-24 Newgen Therapeutics, Inc. Phosphorus containing quinazoline compounds and methods of use
US9834518B2 (en) 2011-05-04 2017-12-05 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in EGFR-driven cancers
US9919939B2 (en) 2011-12-06 2018-03-20 Delta Faucet Company Ozone distribution in a faucet
US10947138B2 (en) 2011-12-06 2021-03-16 Delta Faucet Company Ozone distribution in a faucet
US9834571B2 (en) 2012-05-05 2017-12-05 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in EGFR-driven cancers
US9611283B1 (en) 2013-04-10 2017-04-04 Ariad Pharmaceuticals, Inc. Methods for inhibiting cell proliferation in ALK-driven cancers
US11458214B2 (en) 2015-12-21 2022-10-04 Delta Faucet Company Fluid delivery system including a disinfectant device

Also Published As

Publication number Publication date
MXPA04010527A (es) 2004-12-13
WO2003090690A2 (en) 2003-11-06
US7462608B2 (en) 2008-12-09
DE60315023T2 (de) 2008-04-03
WO2003090691A2 (en) 2003-11-06
WO2004096818A3 (en) 2005-04-07
CA2481261C (en) 2011-11-01
AU2003231765A1 (en) 2003-11-10
BR0309573A (pt) 2005-02-01
HRP20041113B1 (en) 2008-09-30
SI1509537T1 (sl) 2008-02-29
CN1656109A (zh) 2005-08-17
KR100987815B1 (ko) 2010-10-18
MXPA04010528A (es) 2005-05-27
EA200401437A1 (ru) 2005-04-28
AU2003291998A1 (en) 2004-11-23
US20050209197A1 (en) 2005-09-22
US20070190523A1 (en) 2007-08-16
IL164490A0 (en) 2005-12-18
ES2290485T3 (es) 2008-02-16
CA2481449A1 (en) 2003-11-06
KR20040108756A (ko) 2004-12-24
PL374968A1 (en) 2005-11-14
CN1649885A (zh) 2005-08-03
DK1509537T3 (da) 2007-11-12
JP2005523912A (ja) 2005-08-11
CN101074242A (zh) 2007-11-21
TWI332956B (en) 2010-11-11
JP2005523922A (ja) 2005-08-11
IS2714B (is) 2011-01-15
IS7555A (is) 2004-11-25
CA2481285A1 (en) 2003-11-06
EP1509537B1 (en) 2007-07-18
US20070010489A1 (en) 2007-01-11
EP1575486A2 (en) 2005-09-21
WO2003090691A3 (en) 2006-02-09
CN101041669A (zh) 2007-09-26
HK1073467A1 (en) 2005-10-07
CA2481261A1 (en) 2003-11-06
ZA200409376B (en) 2005-11-30
JP2006524487A (ja) 2006-11-02
UA80819C2 (en) 2007-11-12
JP4942915B2 (ja) 2012-05-30
US20050197320A1 (en) 2005-09-08
PT1509537E (pt) 2007-11-02
EP1501841A2 (en) 2005-02-02
US7649015B2 (en) 2010-01-19
PL374522A1 (en) 2005-10-31
NO20045150L (no) 2005-01-26
AU2003228707A1 (en) 2003-11-10
AU2003231766A1 (en) 2003-11-10
AU2003231765B9 (en) 2010-01-28
EP1509537A2 (en) 2005-03-02
ZA200409377B (en) 2006-03-29
CY1108036T1 (el) 2013-09-04
WO2003090690A3 (en) 2004-06-24
WO2004096818A2 (en) 2004-11-11
HRP20041114A2 (en) 2005-08-31
EP1509537B9 (en) 2007-11-14
JP2009112319A (ja) 2009-05-28
NZ535828A (en) 2007-10-26
IL164491A0 (en) 2005-12-18
PL211979B1 (pl) 2012-07-31
AU2003231765B2 (en) 2009-12-10
NO20045152L (no) 2005-01-24
ATE367394T1 (de) 2007-08-15
TW200404075A (en) 2004-03-16
EA008775B1 (ru) 2007-08-31
CN1313472C (zh) 2007-05-02
WO2003091264A3 (en) 2004-03-11
JP2006508634A (ja) 2006-03-16
US20040121316A1 (en) 2004-06-24
EP1575486A4 (en) 2007-02-28
HRP20041113A2 (en) 2005-08-31
AU2003291998A8 (en) 2004-11-23
IL164490A (en) 2010-11-30
DE60315023D1 (de) 2007-08-30
WO2003091264A2 (en) 2003-11-06
KR20040108757A (ko) 2004-12-24
EA200401436A1 (ru) 2005-04-28
NO336469B1 (no) 2015-08-31
EP1620445A2 (en) 2006-02-01
IS7556A (is) 2004-11-25
TW200408645A (en) 2004-06-01
BR0309557A (pt) 2005-03-01
US20060128692A1 (en) 2006-06-15

Similar Documents

Publication Publication Date Title
US20060115815A1 (en) Method and compositions for identifying anti-hiv therapeutic compounds
US8329926B2 (en) Antiviral compounds
US20050239054A1 (en) Method and compositions for identifying anti-HIV therapeutic compounds
US7579332B2 (en) Nucleobase phosphonate analogs for antiviral treatment
US7427636B2 (en) Inosine monophosphate dehydrogenase inhibitory phosphonate compounds
US20080171724A1 (en) Phosphonate Derivatives of Mycophenolic Acid
US7427624B2 (en) Purine nucleoside phosphorylase inhibitory phosphonate compounds
AU2011218664A1 (en) Antiviral compounds

Legal Events

Date Code Title Description
AS Assignment

Owner name: GILEAD SCIENCES, INC., CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BIRKUS, GABRIEL;CHEN, JAMES M.;CHEN, XIAOWU;AND OTHERS;REEL/FRAME:016468/0413;SIGNING DATES FROM 20041109 TO 20041111

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION