Classifications

• • 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
  • A61K31/66—Phosphorus compounds
  • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
• • 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
  • A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/548—Phosphates or phosphonates, e.g. bone-seeking
• • 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
• • 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
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
  • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
• • 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
  • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
  • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• • 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
  • C07D471/02—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 two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—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
  • C07F9/547—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

Definitions

• the invention relates generally to phosphonate compounds with antiviral activity and more specifically with anti-HIV integrase properties.
• BACKGROUND OF THE INVENTION AIDS is a major public health problem worldwide.
• ALDS remains a major world health problem being the first cause of death in Africa and the fourth leading cause of death worldwide. Rapid emergence of drug-resistant HIV variants and severe side effects limit the efficacy of existing therapies.
• drugs targeting HIV viruses are in wide use and have shown effectiveness, toxicity and development of resistant strains have limited their usefulness.
• Assay methods capable of determining the presence, absence or amounts of HIV viruses are of practical utility in the search for inhibitors as well as for diagnosing the presence of HIV.
• HIV Human immunodeficiency virus infection and related disease is a major public health problem worldwide.
• the retrovirus human immunodeficiency virus type 1 (HIV-1), a member of the primate lentivirus family (De Clercq E (1994) Annals of the New York Academy of Sciences, 724:438-456; Barre-Sinoussi F (1996) Lancet, 348:31-35), is generally accepted to be the causative agent of acquired immunodeficiency syndrome (ALDS) Tarrago et al FASEB Journal 1994, 8:497-503).
• AIDS is the result of repeated replication of HIV-1 and a decrease in immune capacity, most prominently a fall in the number of CD4+ lymphocytes.
• the mature virus has a single stranded RNA genome that encodes 15 proteins (Frankel et al (1998) Annual Review of Biochemistry, 67:1-25; Katz et al (1994) Annual Review of Biochemistry, 63:133-173), including three key enzymes: (i) protease (Prt) (von der Helm K (1996) Biological Chemistry, 377:765-774); (ii) reverse transcriptase (RT) (Hottiger et al (1996) Biological Chemistry Hoppe-Seyler, 377:97-120), an enzyme unique to retroviruses; and (iii) integrase (Asante et al (1999) Advances in Virus Research 52:351-369; Wlodawer A (1999) A dvances in Virus Research 52:335-350; Esposito et al (1999) Advances in Virus Research 52:319-333).
• RT is the key enzyme in the replication of the viral genome
• integrase a viral encoded protein
• integrase a viral encoded protein
• HIV infectious virus
• PIC nucleoprotein pre-integration complex
• HIV integrase inhibitors which block integration in extracellular assays and exhibit antiviral effects against HIV-infected cells (Anthony, et al WO 02/30426; Anthony, et al WO 02/30930; Anthony, et al WO 02/30931; WO 02/055079 A2 A3; Zhuang, et al WO 02/36734; US 6395743; US 6245806; US 6271402; Fujishita, et al WO 00/039086; Uenaka et al WO 00/075122; Selnick, et al WO 99/62513; Young, et al WO 99/62520; Payne, et al WO 01/00578; Parrill, A.L.
• HIV integrase inhibitory compounds with improved antiviral and pharmacokinetic properties are desirable, including enhanced activity against development of HIV resistance, improved oral bioavailability, greater potency and extended effective half-life in vivo (Nair, V. "HIV integrase as a target for antiviral chemotherapy” Reviews in Medical Virology (2002) 12(3): 179- 193).
• Three- dimensional quantitative structure-activity relationship studies and docking simulations (Buolamwini, et al Jour. Med. Chem. (2002) 45:841-852) of conformationally-restrained cinnamoyl-type integrase inhibitors (Artico, et al Jour. Med. Chem. (1998) 41 :3948-3960) have correlated hydrogen-bonding interactions to the inhibitory activity differences among the compounds.
• anti-HiV therapeutic agents i.e. drugs having improved antiviral and pharmacokinetic properties with enhanced activity against development of HIV resistance, improved oral bioavailability, greater potency and extended effective half-life in vivo.
• New HIV inhibitors should be active against mutant HIV strains, have distinct resistance profiles, fewer side effects, less complicated dosing schedules, and orally active.
• a less onerous dosage regimen such as one pill, once per day.
• drugs targeting HIV protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have limited their usefulness (Palella, et al N. Engl. J. Med. (1998) 338:853-860; Richman, D. D. Nature (2001) 410:995- 1001).
• Combination therapy with HIV inhibitors has proven to be highly effective in suppressing viral replication to unquantifiable levels for a sustained period of time. Also, combination therapy with RT and protease inhibitors have shown synergistic effects in suppressing HIV replication. Unfortunately, many patients currently fail combination therapy due to the development of drug resistance, non-compliance with complicated dosing regimens, pharmacokinetic interactions, toxicity, and lack of potency. Therefore, there is a need for HIV integrase inhibitors that are synergistic in combination with other HIV inhibitors, or show chemical stability in combination formulations.
• agents currently administered to a patient parenterally are not targeted, resulting in systemic delivery of the agent to cells and tissues of the body where it is unnecessary, and often undesirable. This may result in adverse drug side effects, and often limits the dose of a drug (e.g., cytotoxic agents and other anti-cancer or antiviral drugs) that can be administered.
• a drug e.g., cytotoxic agents and other anti-cancer or antiviral drugs
• oral administration of drugs is generally recognized as a convenient and economical method of administration
• oral administration can result in either (a) uptake of the drug through the cellular and tissue barriers, e.g. blood/brain, epithelial, cell membrane, resulting in undesirable systemic distribution, or (b) temporary residence of the drug within the gastrointestinal tract. Accordingly, a major goal has been to develop methods for specifically targeting agents to cells and tissues.
• Benefits of such treatment includes avoiding the general physiological effects of inappropriate delivery of such agents to other cells and tissues, such as uninfected cells.
• Intracellular targeting may be achieved by methods and compositions, including prodrugs (Krise et al (1996) Advanced Drug Delivery Reviews 19:287-310), which allow accumulation or retention of biologically active agents inside cells.
• the present invention provides novel compounds with HIV integrase activity, i.e. novel human retroviral integrase inhibitors. Therefore, the compounds of the invention may inhibit retroviral integrases and thus inhibit the replication of the virus. They are useful for treating human patients infected with a human retrovirus, such as human immunodeficiency virus (strains of HIV-1 or HIV-2) or human T-cell leukemia viruses (HTLV-I or HTLV-II) which results in acquired immunodeficiency syndrome (AIDS) and/or related diseases.
• the present invention includes novel phosphonate HIV integrase inhibitor compounds and phosphonate analogs of known experimental integrase inhibitors.
• the compounds of the invention optionally provide cellular accumulation as set forth below.
• the present invention relates generally to the accumulation or retention of therapeutic compounds inside cells.
• the invention is more particularly related to attaining high concentrations of phosphonate-containing molecules in HIV infected cells.
• Intracellular targeting may be achieved by methods and compositions which allow accumulation or retention of biologically active agents inside cells. Such effective targeting may be applicable to a variety of therapeutic formulations and procedures.
• compositions of the invention include new HTV integrase inhibitor compounds having at least one phosphonate group.
• the compositions of the invention thus include all known approved, experimental, and proposed HIV integrase inhibitors, that do not already comprise a phosphonate group, with at least one phosphonate group covalently attached.
• Experimental HIV integrase inhibitors include those reviewed in: Dayam et al (2003) Current Pharmaceutical Design 9:1789-1802; De Clercq E. (2002) Biochimica etBiophysica Ada 1587(2-3):258-275; Nair, V. (2002) Reviews in Medical Virology 12(3):179-193; Neamati, N.
• the invention includes novel phosphonate analogs of the following experimental HIV integrase inhibitors in Groups I to XXXLX.
• the invention includes tricyclic phosphonate compounds represented by the following structure, Formula I:
• the invention includes phosphonate analogs of aza-quinolinol compounds represented by the Formula II:
• the invention includes phosphonate analogs of quinoline compounds represented by the Formula III:
• the invention includes phosphonate analogs of 4,5- dihydroxypyrimidine, 6-carboxamide compounds having Formula TV:
• the invention includes phosphonate analogs of 3-N-substituted
• the invention includes phosphonate analogs of 1 ,3 diketo compounds having Formula VI:
• the invention includes phosphonate analogs of 2,5 diarylsubstituted, furan compounds having Formula VII:
• the invention includes phosphonate analogs of 2,5 substituted, diketo-furan compounds having Formula VIII:
• the invention includes phosphonate analogs of catechol compounds including caffeic acid phenylethyl ester (CAPE) compounds having Formula IX:
• CAE caffeic acid phenylethyl ester
• Catechol compounds LX include phosphonate analogs of styryl catechol compounds and analogs of chicoric acid.
• Phosphonate analogs of styryl catechol compounds generally have Formula X:
• the invention includes phosphonate analogs of benzimidazole compounds and bis-benzimidazole compounds having Formula XI:
• the invention includes phosphonate analogs of indoloquinoxaline compounds having Formula XII:
• the invention includes phosphonate analogs of acridine compounds including phosphonate analogs of bis-acridine compounds having Formula XIII:
• the invention includes phosphonate analogs of polyamide, DNA binding compounds, such as polypyrrole amide phosphonate oligomers having Formula XIV:
• the invention includes phosphonate analogs of [6,6] bicyclic compounds, including integramycins and fungal metabolites having Formula XV:
• the invention includes phosphonate analogs of [6,6] bicyclic terpenoid compounds having Formula XVI:
• the invention includes phosphonate analogs of aurintricarboxylic acid compounds having Formula XVII:
• the invention includes phosphonate analogs of integrastatin compounds having Formula XVIII:
• the invention includes phosphonate analogs of 6- (arylazo)pyridoxal-5-phosphate compounds having Formula XIX:
• the invention includes phosphonate analogs of 1 ,3-oxazine-, 1,3-thiazine-, pyran-, 1,4-oxazepine-, and 1,4-thiazepine-fused naphthalene compounds having Formula XX:
• the invention includes phosphonate analogs of chaetochromin compounds derived from chaetochromin fermentation products and their chemically modified derivatives including naphtho- ⁇ -pyrones having Formula
• the invention includes phosphonate analogs of hydroxyphenylundecane compounds derived from fermentation products and their chemically modified derivatives including integracins having Formula XXII:
• the invention includes phosphonate analogs of: (i) tetracyclic steroidal compounds derived from fermentation products and their chemically modified derivatives; and (ii) tetracyclic triterpenoid compounds having Formula XXIII: XXIII
• the invention includes phosphonate analogs of plant natural products including: (i) glycerrhenitic and betulonic acids; (ii) compounds from Coleus parvifolius Benth.; (iii) eudesmane-type sesquiterpenes and aporphine alkaloid lindechunines from Lindera chunii roots including hernandonine, laurolistine, 7-oxohernangerine and lindechunine A; and (iv) lithospermic acid.
• the invention includes phosphonate analogs of tetracyclic aromatic ketone compounds and derived from fungal cultures and fungus, and their chemically modified derivatives.
• the invention includes phosphonate analogs of aromatic compounds derived from lichen extracts, and their chemically modified derivatives.
• the invention includes phosphonate analogs of salicylhydrazide and mercaptosalicylhydrazide compounds.
• the invention includes phosphonate analogs of thiazolothiazepine compounds.
• the invention includes phosphonate analogs of benzodiazepine hydrazide compounds.
• the invention includes phosphonate analogs of coumarin compounds, including Larnellarin-type marine natural products.
• the invention includes phosphonate analogs of brominated polyacetylene marine natural products from sponges such as Diplastrella sp.
• the invention includes phosphonate analogs of cobalamin compounds.
• the invention includes phosphonate analogs of hydroxylated aromatic compounds, including: tetracycline compounds; anthraquinones and naphthoquinones; and flavones, flavanones, flavanols, and flavanoids including thalassiolins and benzopyrano- oxopyrimidotefr ahydrothiazines .
• the invention includes phosphonate analogs of various sulfur-containing compounds including phosphonate analogs of: polyanionic sulfonate suramin and dextran sulfate; diaryl sulfones; sulfonamides; aromatic disulfides; and 2-mercaptobenzenesulfonamides.
• the invention includes phosphonate analogs of symmetrical pentamidine compounds derived from serine protease inhibitors.
• the invention includes phosphonate analogs of nucleic acid compounds.
• Nucleic acid phosphonate compounds include: (a) nucleosides and nucleotides; dinucleotides, including 5H-pyrano[2,3-d:-6,5- d'jdipyrimidines; (b) oligonucleotides; and (c) analogs thereof, with one or more phosphonate groups.
• Nucleic acid analogs include nucleobase, sugar, and internucleotide phosphate analogs.
• the invention includes phosphonate analogs of amino acids and peptides.
• the invention includes phosphonate analogs of polyketide natural products including Xanthoviridicatins isolated from a fermentation broth of an endophytic strain of Penicillium chrysogenum.
• the invention includes phosphonate analogs of polyketide natural products including cytosporic acid, australifungin and australifunginol isolated from a fermentation broth of the filamentous fungus.
• Formulas I-XXXIX are substituted with one or more covalently attached phosphonate groups.
• Formulas I- XXXIX are "scaffolds", i.e. substructures which are common to the specific compounds encompassed therein.
• the scope of the invention includes compounds in which hydrogen atoms at any of the various positions in Formulas I-XXXIX are independently substituted with non-hydrogen substituents.
• the variable positions on the scaffolds of Formulas I-XXXIX and experimental HIV integrase inhibitors of Groups I-XXXIX are independently substituted with the non-hydrogen substituents described herein.
• the invention includes pharmaceutically acceptable salts of Formulas I-
• the invention provides a pharmaceutical composition comprising an effective amount of a compound selected from Formulas I-XXXLX, or a pharmaceutically acceptable salt thereof, in a formulation, i.e. in combination with a pharmaceutically acceptable excipient, diluent or carrier.
• the invention includes combination formulations including the compounds of the invention, with other active ingredients that treat or prevent HIV infections.
• Such combination formulations may be a fixed dose of two or more active ingredients, including at least one compound of the invention.
• This invention also pertains to a method of increasing cellular accumulation and retention of drug compounds, thus improving their therapeutic and diagnostic value.
• the use of the compounds of the invention in an HIV infected patient, or in a sample suspected of containing HIV anticipates all metabolites of the compounds so administered which occur by solvolysis, hydrolysis, photolysis, or by enzymatic action which converts or degrades the administered compound into, e.g. an activated form, an incorporated form, a cleaved form, or a metabolite for excretion.
• the invention also provides a method of inhibiting HIV, comprising administering to a mammal infected with HIV (HIV positive) an amount of a compound of Formulas I-XXXLX, effective to inhibit the growth of said HIV infected cells.
• the invention also provides a compound selected from Formulas I-XXXLX for use in medical therapy, as well as the use of a compound of Formulas I-XXXIX for the manufacture of a medicament useful for: (1) the treatment of AIDS or ARC (AIDs related complex); or (2) the prophylaxis of infection by HIV.
• the invention also provides processes and novel intermediates disclosed herein which are useful for preparing compounds of the invention.
• Other aspects of the invention are novel methods for synthesis, i.e. preparation, of the compounds of the invention.
• One aspect of the invention is the inhibition of the activity of HIV integrase by a method comprising the step of treating a sample suspected of containing HIV virus with a compound or composition of the invention.
• compositions of the compounds of the invention are formulation compositions of the compounds of the invention, as well as methods of formulating the compositions.
• phosphonate and phosphonate group mean a functional group or moiety within a molecule that comprises at least one phosphorus-carbon bond, and at least one phosphorus-oxygen double bond.
• the phosphorus atom is further substituted with oxygen, sulfur, or nitrogen substituents. These substituents may be part of a prodrug moiety.
• phosphonate and “phosphonate group” include moieties with phosphonic acid, phosphonic monoester, phosphonic diester, phosphonamidate, and phosphonthioate functional groups.
• prodrug refers to any compound that when administered to a biological system generates the drug substance, i.e. active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, and/or metabolic chemical reaction(s).
• a prodrug is thus a covalently modified analog or latent form of a therapeutically-active compound.
• “Pharmaceutically acceptable prodrug” refers to a compound that is metabolized in the host, for example hydrolyzed or oxidized, by either enzymatic action or by general acid or base solvolysis, to form an active ingredient.
• Typical examples of prodrugs of the compounds of the invention have biologically labile protecting groups on a functional moiety of the compound.
• Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, esterified, deesterif ⁇ ed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated, photolyzed, hydrolyzed, or other functional group change or conversion involving forming or breaking chemical bonds on the prodrug.
• Prodrug moiety means a labile functional group which separates from the active inhibitory compound during metabolism, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, “Design and Application of Prodrugs” in Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 113- 191).
• Enzymes which are capable of an enzymatic activation mechanism with the phosphonate prodrug compounds of the invention include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphases.
• Prodrug moieties can serve to enhance solubility, absorption and lipophilicity to optimize drug delivery, bioavailability and efficacy.
• the acyloxyalkyl ester was first used as a prodrug strategy for carboxylic acids and then applied to phosphates and phosphonates by Farquhar et al (19S3) J. Pharm. Sci. 72: 324; also US Patent Nos. 4816570, 4968788, 5663159 and 5792756.
• a prodrug moiety is part of a phosphonate group.
• the acyloxyalkyl ester was used to deliver phosphonic acids across cell membranes and to enhance oral bioavailability.
• a close variant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester (carbonate), may also enhance oral bioavailability as a prodrug moiety in the compounds of the combinations of the invention.
• the phosphonate group may be a phosphonate prodrug moiety.
• the prodrug moiety may be sensitive to hydrolysis, such as, but not limited to a pivaloyloxymethyl carbonate (POC) or POM group.
• the prodrug moiety may be sensitive to enzymatic potentiated cleavage, such as a lactate ester or a phosphonamidate-ester group.
• Aryl esters of phosphorus groups are reported to enhance oral bioavailability (DeLambert et al (1994) J. Med. Chem. 37: 498). Phenyl esters containing a carboxylic ester ortho to the phosphate have also been described (Khamnei and Torrence, (1996) J. Med. Chem. 39:4109-4115). Benzyl esters are reported to generate the parent phosphonic acid. In some cases, substituents at the ortho-o ⁇ para-iposition may accelerate the hydrolysis. Benzyl analogs with an acylated phenol or an alkylated phenol may generate the phenolic compound through the action of enzymes, e.g.
• Protecting group refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole.
• 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.
• Protecting groups are often utilized 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 a compound alters other physical properties besides the reactivity of the protected functional 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 with intended therapeutic effects may be referred to as prodrugs.
• Another function of a protecting group is to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo. Because active prodrugs may be absorbed more effectively than the parental drug, prodrugs may possess greater potency in vivo than the parental drug.
• Protecting groups are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting products after deprotection, e.g. alcohols, be physiologically acceptable, although in general it is more desirable if the products are pharmacologically innocuous.
• 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 met al (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX (wherein X is C 1 -C alkyl).
• Physiologically acceptable salts of an hydrogen atom or an arnino 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 X (wherein X is independently selected from H or a -C alkyl group).
• salts of active ingredients of the compounds of the invention 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.
• Alkyl is C1-C18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples are methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1- propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1 -butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-l-propyl (i-Bu, i-butyl, - CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t- Bu, t-butyl, -C(CH3)3), 1- ⁇ entyl (n-pentyl, -CH2CH2CH2CH3, 2-p
• C(CH3)2CH2CH3) 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3 -methyl- 1 -butyl (- CH2CH2CH(CH3)2), 2-methyl-l -butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (- CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH3), 3-hexyl (- CH(CH2CH3)(CH2CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 )2CH2CH CH3), 3- methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-
• CH(CH3)CH2CH(CH3)2) 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3- pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3- dimethyl-2-butyl (-CH(CH3)C(CH3)3.
• Alkynyl is C2-C18 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 ⁇ CH),
• 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-buryl (-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.
• 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. Some aryl groups are represented in the exemplary structures as "Ar”. 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-l-yl, 2-phenylethen-l-yl, naphthylmethyl, 2-naphthylethan-l-yl, 2- naphthylethen-1-yl, naphthobenzyl, 2-na ⁇ hthophenylethan-l-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.
• Heteroarylalkyl 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 a heteroaryl radical.
• Typical heteroarylalkyl groups include, but are not limited to, 2-benzimidazolylmethyl, 2-furylethyl, and the like.
• the heteroarylalkyl group comprises 6 to 20 carbon atoms, e.g.
• the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the heteroarylalkyl group is 1 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S.
• the heteroaryl moiety of the heteroarylalkyl group may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms 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), for example: abicyclo [4,5], [5,5], [5,6], or [6,6] system.
• Substituted alkyl mean alkyl, aryl, and arylalkyl respectively, in which one or more hydrogen atoms are each independently replaced with a substituent.
• Heteroaryl and Heterocycle refer to a ring system in which one or more ring atoms is a heteroatom, e.g. nitrogen, oxygen, and sulfur.
• the heterocycle radical comprises 5 to 14 carbon atoms and 1 to 3 heteroatoms selected from , O, P, and S.
• a 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), for example: abicyclo [4,5], [5,5], [5,6], or [6,6] system.
• 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, bis- tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, te
• 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- ⁇ yridyl, 3-pyridazinyl, 4-pyridazinyl, 5- pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrirnidinyl, 5 -pyrimidinyl, 6- pyrimidinyl, 2-pyrazinyl, 3 -pyrazinyl, 5- ⁇ yrazinyl, 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, irnidazolidine, 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 orpholine, 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, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l- enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, phenyl, spiryl and naphthyl.
• Nucleobase means any nitrogen-containing heterocyclic moiety capable of forming Watson-Crick hydrogen bonds in pairing with a complementary nucleobase or nucleobase analog, e.g.
• nucleobases are the naturally occurring nucleobases: adenine, guanine, cytosine, uracil, thymine, and analogs of the naturally occurring nucleobases, e.g.
• Nucleobases include the f ⁇ ve- membered heterocyclic nucleobase analogs disclosed in WO 03/073989 A2 such as substituted triazoles:
• Nucleobases also include any of the above nitrogen-containing heterocyclic moieties which have one or more protecting groups (PG) covalently attached to reactive functionality, such as theN-2 orN-6 exocyclic amino of purines, the -3 or -4 nitrogen of pyrimidines, or the 0-6 oxygen of guanine type nucleobases.
• Suitable nucleobase protecting groups include amide-forming groups such as benzoyl or isobutyramide, acetaniidme-forming groups, and formamidine-forming groups such as dimethylformamidyl (dmf).
• Reactive functionality of nucleobases can also be protected with transient groups such as 6-chloro of purines.
• Nucleobases are typically attached in the configurations of naturally-occurring nucleic acids to the sugar moiety through a covalent bond between the 1 ' carbon of the sugar moiety and the -9 of purines, e.g. adenin-9-yl and guanin-9-yl, or N-l of pyrimidines, e.g. thymin-1-yl and cytosin-1-yl (Blackburn, G. and Gait, M. Eds. "DNA and RNA structure” in Nucleic Acids in Chemistry and Biology, 2 nd Edition, (1996) Oxford University Press, pp. 15-81).
• purines e.g. adenin-9-yl and guanin-9-yl
• N-l of pyrimidines e.g. thymin-1-yl and cytosin-1-yl
• Linker or “link” means a chemical moiety comprising a covalent bond or a chain of atoms that covalently attaches a phosphonate group to a drug.
• a linker is specified as L.
• Linkers include a divalent radical such as an alkyldiyl, an aryldiyl, or a heteroaryldiyl; or portions of substituent A 1 enumerated in Formulas I-XXXIX, which include moieties such as: -(CR 2 ) n O(CR 2 ) n -, repeating units of alkyloxy (e.g. polyethylenoxy, PEG, polymethyleneoxy) and alkylamino (e.g. polyethyleneamino, JeffamineTM); and diacid ester and amides including succinate, succinamide, diglycolate, malonate, and caproamide.
• alkyloxy e.g. polyethylenoxy, PEG, poly
• 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.
• 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.
• the compounds of the invention include those with HIV integrase inhibitory activity.
• the compounds include HIV integrase inhibitors.
• the compounds of the inventions bear at least one phosphonate group, selected from: phosphonic acid, phosphonate monoester, phosphonate diester, phosphonamidate, phosphonthioate, phosphondithioate, phosphonamidate-ester prodrug, or a phosphonbisamidate-ester (Jiang et al, US 2002/0173490 Al), any of which may be a prodrug moiety.
• compositions of the invention include all known approved, experimental, and proposed HIV integrase inhibitors, that do not already comprise a phosphonate group, with at least one phosphonate group covalently attached.
• the invention includes novel phosphonate analogs of the following experimental HJV integrase inhibitors in Groups I to XXXIX that do not already comprise a phosphonate group.
• Embodiments of the invention include phosphonate analogs of compounds that fall within the generic scope of the documents cited in Groups I to XXXIX.
• the invention includes pharmaceutically acceptable salts of Formulas I- XXXIX, and all enol and tautomeric resonance isomers thereof.
• Formulas I-XXXIX are substituted with one or more covalently attached groups, including at least one phosphonate group, i.e. A or A .
• Formulas I-XXXIX are "scaffolds", i.e. substructures which are common to the specific compounds encompassed therein.
• Formulas I-XXXIX are substituted with one or more covalently attached A 0 groups, including simultaneous substitutions at any or all A 0 .
• a 0 is A 1 , A 2 or W 3 .
• Compounds of Formulas I-XXXLX include at least one A 1 and thus include at least one A 3 .
• a 1 is:
• a 2 is:
• a 3 is:
• Y 1 is independently O, S, NR X , N(0)(R x ), N(OR x ), N(0)(OR x ), or N(N(R X ) 2 );
• Y 2 is independently a bond, O, NR X , N(0)(R ), N(OR x ), N(0)(OR x ), N(N(R X ) 2 ), -S(O)- (sulfoxide), -S(0) 2 - (sulfone), -S- (sulfide), or -S-S- (disulfide); M2 is 0, 1 or 2;
• M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.
• R y is independently H, C ⁇ -C 18 alkyl, C ⁇ -C 18 substituted alkyl, C 2 -C ⁇ 8 alkenyl, C 2 -C 18 substituted alkenyl, C 2 -C 18 alkynyl, C 2 -C 18 substituted alkynyl, C 6 -C 20 aryl, C 6 -C 2 o substituted aryl, or a protecting group, or where taken together at a carbon atom, two vicinal R y groups form a carbocycle or a heterocycle. Alternatively, taken together at a carbon atom, two vicinal R y groups form a ring, i.e. a spiro carbon.
• the ring may be all carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or alternatively, the ring may contain one or more heteroatoms, for example, piperazinyl, piperidinyl, pyranyl, or tetrahydrofuryl; R x is independently H, -Cig alkyl, C ⁇ -C 18 substituted alkyl, C 2 -C 18 alkenyl,
• W 3 is W 4 orW 5 ;
• W 4 is R 5 , -C ⁇ R 5 , -CCY ⁇ W 5 , -S0 2 R 5 , or -S0 2 W 5 ;
• W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;
• W 3a is W 4a or W 5a ;
• W 4a is R 5a , -CCY ⁇ R 51 , -CfY ⁇ W 53 , -S0 2 R 5a , or -S0 2 W ⁇ 5 5 a.
• W 5a is a multivalent substituted carbocycle or heterocycle wherein W 5a is independently substituted with 0 to 3 R 2 groups;
• W 6 is W 3a independently substituted with 1, 2, or 3 A 3 groups;
• 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 groups.
• the ring may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
• the ring may be substituted with 0 to 3 R 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 -N0 2 ;
• R ⁇ is Y 1 ;
• R 3c is -R x , -N(R X ) 2 , -SR X , -S(0)R x , -S(0) 2 R x , -S(0)(OR x ), -S(0) 2 (OR x ), -SC(Y 1 )R X , -SC(Y 1 )OR x , -SC(Y 1 )N(R X ) 2 , -N(R X )C(Y 1 )R X , -N ⁇ CO ⁇ CR 31 , or -N(R X )C(Y 1 )N(R X ) 2 ;
• R 3d is -C(Y 1 )R X , -C ⁇ OR" or -C(Y 1 )N(R X ) 2 ;
• 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; and
• 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 groups.
• R is independently selected from H, Cr-C 18 alkyl, Cr-C 18 substituted alkyl,
• Substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, and substituted heterocycle are independently substituted with one or more substituents selected from F, Cl, Br, I, OH, amino (-NH 2 ), ammonium (-NH 3 + ), alkylamino (-NHR), dialkylamino (-NR 2 ), trialkylammonium (-NR 3 + ), -Cg alkyl, Ci-C 8 alkylhalide, carboxylate, thiol (-SH), sulfate (-OS0 3 R), sulfamate, sulfonate (-S0 3 R), 5-7 membered ring sultam, Ci-C 8 alkylsulfonate, Ci-Cg alkylamino, 4- dialkylaminopyridinium, -Cg alkylhydroxyl, - alkylthiol, alkylsulfone (-S0 2 R), ary
• L is a bond or any linker which covalently attaches a phosphonate group to a drug scaffold.
• Carbocycles and heterocycles may be independently substituted with 0 to 3 R 2 groups.
• Carbocycles and heterocycles may be a saturated, unsaturated or aromatic ring comprising a mono- or bicyclic carbocycle or heterocycle.
• Carbocycles and heterocycles 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.
• Carbocycles and heterocycles include, but are not limited to, examples such as:
• Carbocycles and heterocycles may be independently substituted with 0 to 3 groups, as defined above.
• substituted carbocycles (Ar) include:
• C 6 -C 20 substituted aryl groups include halo- substituted phenyl such as 4-fluorophenyl, 4-chlorophenyl, 3,5-dichlorophenyl, and 3,5-difluorophenyl.
• halo- substituted phenyl such as 4-fluorophenyl, 4-chlorophenyl, 3,5-dichlorophenyl, and 3,5-difluorophenyl.
• substituted phenyl carbocycles include:
• Embodiments of A 1 include:
• W 5a is a carbocycle or a heterocycle and W 5a is independently substituted with 0 or 1 R 2 groups.
• Embodiments of A 1 also include:
• n is an integer from 1 to 18.
• Embodiments of A 2 include where W 3 is W 5 , such as:
• a 2 is phenyl, substituted phenyl, benzyl, substituted benzyl, pyridyl or substituted pyridyl.
• Embodiments of A include where M2 is 0, such as:
• Y is oxygen, and Y is independently oxygen (O) or nitrogen (N(R X )) such as:
• M12a where W is a carbocycle such as phenyl or substituted phenyl, and Y • 2c . is independently O, N(R y ) or S.
• R 2 may be H and M12a may be 1.
• An embodiment of A includes:
• a 3 includes:
• W 5 is a carbocycle such as phenyl or substituted phenyl.
• Embodiments of R x include esters, carbamates, carbonates, thioesters, amides, thioamides, and urea groups:
• 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.
• a 3 include phenyl phosphonamidate amino acid, e.g. alanate esters and phenyl phosphonate-lactate esters:
• the chiral carbon of the amino acid and lactate moieties may be either the R or S configuration, such as:
• the compounds including amino acid and lactate moieties may alternatively exist as enantiomerically-enriched mixtures or as racemic mixtures.
• Formula I-XXXLX compounds include all pharmaceutically acceptable salts thereof.
• Formula I-XXXIX compounds also include all enol, tautomeric, and resonance isomers, enantiomers, diastereomers, and racemic mixtures thereof.
• Phosphonate groups of the compounds of the invention may comprise the substituent structure A .
• the compounds of the invention include one or more phosphonate groups located as a covalently-attached substituent at any location of Formulas I-XXXIX.
• Prodrug moieties of phosphorus functionality may serve to mask anionic charges and decrease polarity.
• the phosphonate prodrug moiety may be an ester (Oliyai etal Pharmaceutical Res. (1999) 16:1687-1693; Krise, J. and Stella, V. Adv. Drug Del. Reviews (1996) 19:287-310; Bischofberger etal, U.S. Patent No. 5,798,340; Oliyai, etal Intl. Jour. Pharmaceutics (1999) 179:257-265), e.g.
• POC and POM (pivaloyloxymethyl, Yuan, etal Pharmaceutical Res. (2000) 17:1098-1103), or amidate which separates from the integrase inhibitor compound in vivo or by exposure in vitro to biological conditions, e.g. cells, tissue isolates.
• biological conditions e.g. cells, tissue isolates.
• the separation may be mediated by general hydrolytic conditions, oxidation, enzymatic action or a combination of steps.
• Compounds of the invention bearing one or more phosphonate groups may increase or optimize the bioavailability of the compounds as therapeutic agents. For example, bioavailability after oral administration may be preferred and depend on resistance to metabolic degradation in the gastrointestinal tract or circulatory system, and eventual uptake inside cells. Prodrug moieties are considered to confer said resistance by slowing certain hydrolytic or enzymatic metabolic processes. Lipophilic prodrug moieties may also increase active or passive transport of the compounds of the invention across cellular membranes (Darby, G. Antiviral Chem. & Chemotherapy (1995) Supp. 1, 6:54-63).
• the compounds of the invention include an active form for inhibition of nuclear integration of reverse-transcribed HIV DNA.
• Exemplary embodiments of the invention includes phosphonamidate and phosphoramidate (collectively "amidate”) prodrug compounds.
• General formulas for phosphonamidate and phosphoramidate prodrug moieties include:
• the phosphorus atom of the phosphonamidate group is bonded to a carbon atom.
• the nitrogen substituent R may include an ester, an amide, or a carbamate functional group.
• the nitrogen atom may comprise an amino acid residue within the prodrug moiety, such as a glycine, alanine, or valine ester (e.g.
• valacyclovir see: Beauchamp, etal Antiviral Chem. Chemotherapy (1992) 3:157-164), such as the general structure: where R is the amino acid side-chain, e.g. H, CH 3 , CH(CH 3 ) 2 , etc.
• the compounds of the invention may exist in many different protonation states, depending on, among other things, the pH of their environment. While the structural formulae provided herein depict the compounds in only one of several possible protonation states, it will be understood that these structures are illustrative only, and that the invention is not limited to any particular protonation state—any and all protonated forms of the compounds are intended to fall within the scope of the invention.
• R x contains a R y substituent.
• R y can be R 2 , which in turn can be R 3 . If R 3 is selected to be R 3c , then a second instance of R x can be selected.
• R 3 is selected to be R 3c , then a second instance of R x can be selected.
• W 3 , R y and R 3 are all recursive substituents in certain embodiments. Typically, each of these may independently occur 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0, times in a given embodiment. More typically, each of these may independently occur 12 or fewer times in a given embodiment. More typically yet, W will occur 0 to 8 times, R y will occur 0 to 6 times and R 3 will occur 0 to 10 times in a given embodiment. Even more typically, W 3 will occur 0 to 6 times, R y will occur 0 to 4 times and R 3 will occur 0 to 8 times in a given embodiment.
• Recursive substituents are an intended aspect of the invention.
• One of ordinary skill in the art of medicinal chemistry understands the versatility of such substituents.
• the invention includes tricyclic phosphonate Group I compounds represented by the following structure, Formula I:
• a 4 and A 5 are each and independently any moiety forming a five, six, or seven membered ring.
• Q is N, ⁇ R, or CR 4 .
• X may be O, S, NH, NR, N-OR, N-NR 2 , N-CR 2 OR or N-CR 2 NR 2 .
• R may be independently selected from H, -Cs alkyl, -Cg substituted alkyl, C 2 -C 18 alkenyl, C 2 -C ⁇ 8 substituted alkenyl, C 2 -C 18 alkynyl, C 2 -C 18 substituted alkynyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety.
• Two R groups may form a ring, such as when the two R groups are bonded to a nitrogen atom and form a ring such as aziridinyl, azetidinyl, pyrrolidinyl, pyrazinyl, imidazolyl, piperidyl, piperazinyl, pyridinium, or morpholino.
• R 1 , R 2 , R 3 , and R 4 include the structures:
• R, R 1 , R l , R or R * may independently comprise A 1 1 , A A 3 or
• L is a bond or any linker which covalently attaches the Ar group to the tricyclic scaffold.
• Substituted alkylene, substituted alkyenylene, substituted alkynylene, substituted aryl, and substituted heteroaryl are independently substituted with one or more substituents selected from F, Cl, Br, I, OH, amino (-NH 2 ), ammonium (-NH 3 + ), alkylamino, dialkylamino, trialkylammonium, -Cg alkyl, -Cg alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, Q-Cg alkylsulfonate, Ci-Cg alkylamino, 4-dialkylan ⁇ inopyridinium, -Cg alkylhydroxyl, Ci-Cg alkylthiol, alkylsulfone (-S0 2 R), arylsulfone (-S0 2 Ar), arylsulfoxide (-SOAr), arylthio
• Ar groups may be any saturated, unsaturated or aromatic ring or ring system comprising a mono- or bicyclic carbocycle or heterocycle, e.g. 3 to 12 ring atoms.
• the 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.
• Ar may be C 3 -C 12 carbocycle, C 3 -C 12 substituted carbocycle, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, or C 2 -C 20 substituted heteroaryl.
• C6-C 20 substituted aryl groups include halo- substituted phenyl such as 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethyl, 2-amide phenyl, 3,5-dichlorophenyl, and 3,5-difluorophenyl.
• Ar groups include substituted phenyl groups such as, but not limited to:
• substituted phenyl groups include:
• Ar groups also include disubstituted phenyl groups such as, but not limited to:
• n 1 to 6.
• Ar groups also include carbocycles such as, but not limited to:
• Ar groups also include phenyl and substituted phenyl fused to a carbocycle to form groups including:
• Substituents of Ar may independently be H, F, Cl, Br, I, OH, amino (-NH 2 ), ammomum (-NH3 ), alkylamino, dialkylamino, trialkylammonium, -Cg alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, Ci-Cg alkylsulfonate, Ci-Cg alkylamino, 4-dialkylaminopyridinium, Ci-Cg alkylhydroxyl, Ci-Cg alkylthiol, alkylsulfone (-S0 2 R), arylsulfone (-S0 2 Ar), arylsulfoxide (-SOAr), arylthio (-SAr), sulfonamide (-S0 2 NR 2 ), alkylsulfoxide (-SOR), ester (-C0 2 R), amido (
• Formula I compounds of the invention include the following structures:
• Embodiments of Formula I also include Ia-c where A is CH 2 , CH 2 CH 2 , and CH 2 CH 2 CH 2 , respectively:
• the 7 membered ring may be comprised of a second amide group, as shown by exemplary Formula Id:
• the cyclic imide group of Formula le provides functionality which may be in a pre-organized state for optimized HIV integrase inhibition relative to compounds without the cyclic imide group (Anthony, etal WO 02/30931; Zhuang, etal "Design and synthesis of 8-hydroxy-l,6- naphthyridines as novel HIV-1 integrase inhibitors" Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, Sept. 27-30, 2002).
• Formula la compounds include the following amide structure:
• the invention includes phosphonate analogs of aza-quinolinol compounds (Zhuang et al (2003) J. Med. Chem. 46(4):453-456; Zouhiri et al (2000) J.
• X 2 is CR 2 , NR, or N;
• X 3 is CR 3 , NR, orN;
• X 4 is CR 4 , NR, orN;
• X 5 is CR 5 , NR, orN; at least one of X 1 , X 2 , X 3 , X 4 , and X 5 is NR or N;
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are independently selected from H, F, Cl, Br, I, OH, amino (-NH 2 ), ammomum (-NH 3 + ), alkylamino, dialkylamino, trialkylammonium, Ci-C 8 alkyl, Ci-Cg alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, Ci ⁇ C 8 alkylsulfonate, Ci-Cg alkylamino, 4- dialkylaminopyridinium, Ci-Cg alkylhydroxyl, -Cg alkylthiol, alkylsulfone (-S0 2 R), arylsulfone (-S0 2 Ar), arylsulfoxide (-SOAr), arylthio (-SAr), sulfonamide (-S0 2
• R is independently selected from H, Ci-C 8 alkyl, Ci-Cg substituted alkyl, C 2 -Cig alkenyl, C 2 -C 18 substituted alkenyl, C - g alkynyl, C 2 -Cig substituted alkynyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl.
• R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , or R 7 may independently comprise A 1 , A 3 or L-A 3 .
• At least one of R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 comprises a phosphonate group.
• the phosphonate group may be a prodrug moiety.
• the phosphonate group maybe directly attached to a ring carbon (CR 1 , CR 2 , CR 3 , CR 4 or CR 5 ) of Formula II.
• L is a bond or any linker which covalently attaches the Ar group to the tricyclic scaffold.
• Ar groups may be any saturated, unsaturated or aromatic ring or ring system comprising a mono- or bicyclic carbocycle or heterocycle, e.g. 3 to 10 ring atoms.
• the 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.
• Ar is covalently attached to L and to one or more R .
• Exemplary structures within Formula II include the following:
• CR 1 and CR 2 together may form a ring.
• X 3 is CR 3 and when X 4 is CR 4 , then CR 3 and CR 4 together may form a ring.
• X 4 is CR 4 and X 5 is CR 5 , then CR 4 and CR 5 together may form a ring.
• the ring may be 5, 6, or 7-membered.
• the ring may be all carbon atoms or it may have one or more heteroatoms selected from nitrogen, oxygen, and sulfur.
• Exemplary structures when CR 4 and CR 5 form a ring include the following:
• Y is CR 5 , NR or N.
• Z is a moiety forming a five, six, or seven membered ring.
• R 2 may include a ring, e.g. 4-7 membered ring lactam or sultam, or piperazinyl sulfamate:
• any aryl or sultam ring carbon atom may be substituted with an A 2 group, including the exemplary structures:
• the invention includes phosphonate analogs of quinoline compounds (WO 03/031413 Al) represented by the Formula III:
• X is L and Z is R 6 -Ar as defined in Formula II.
• the aryl carbons and amide nitrogen may be further substituted as defined in the following embodiments of Formula III.
• Embodiments of Formula III include the structures:
• the invention includes phosphonate analogs of 4,5- dihydroxypyrimidine, 6-carboxamide compounds (WO 03/035076 Al) having Formula IV:
• R is independently selected from H, Ci-Cg alkyl, Ci-Cg substituted alkyl, C 2 -C ⁇ g alkenyl, C 2 -C 18 substituted alkenyl, C 2 -C 18 alkynyl, C 2 -Cig substituted alkynyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C -C 20 heteroaryl, and C -C 20 substituted heteroaryl.
• R, R 1 , R 2a , R 3 , R 4 , or R 5 may independently comprise A 1 , A 3 or L-A 3 .
• At least one of R, R 1 , R 2a , R 3 , R 4 , and R 5 comprises a phosphonate group.
• the phosphonate group may be a prodrug moiety.
• Embodiments of R 1 , R 2a , R 2b , R 3 , R 4 , and R 5 may also individually or in combination form a ring, e.g. 4-7 membered ring lactam, carbonate, or sultam, or piperazinyl sulfamate:
• a linker may be interposed between positions R 1 , R 2a , R 3 , R 4 , or R 5 and substituent A 3 , as exemplified in some structures herein as "L-A 3 ".
• Linkers may also be repeating units of alkyloxy (e.g. polyethylenoxy, PEG, polymethyleneoxy) and alkylamino (e.g. polyethyleneamino, JeffamineTM); and diacid ester and amides including succinate, succinamide, diglycolate, malonate, and caproamide.
• the linker may comprise propargyl, urea, or alkoxy groups.
• Exemplary structures within Formula IV include IVa, IVb, IVc, IVd:
• the invention includes phosphonate analogs of 3-N-substituted
• R .1 , r R>2b , 1 R,3 , R ⁇ ,4 , and R are as defined for Formula IV.
• R, R , 1 1 , ⁇ R2b , D R3 J , r R ⁇ 4 4 , osmith_r ⁇ R, 5 5 may independently comprise A 1 1 , A ⁇ ?3 or L-A J .
• At least one of R, R 1 , R 2 , R 3 , R 4 , and R 5 comprises a phosphonate group.
• the phosphonate group may be a prodrug moiety.
• Embodiments of R 1 , R 2a , R 2b , R 3 , R 4 , and R 5 may also individually or in combination form a ring, e.g. 4-7 membered ring lactam, carbonate, or sultam, or piperazinyl sulfamate:
• a linker may be interposed between positions R 1 , R 2 , R 3 , R 4 , or R 5 and substituent A 3 , as exemplified in some structures herein as "L-A 3 ".
• Linkers may also be repeating units of alkyloxy (e.g. polyethylenoxy, PEG, polymethyleneoxy) and alkylamino (e.g. polyethyleneamino, JeffamineTM); and diacid ester and amides including succinate, succinamide, diglycolate, malonate, and caproamide.
• the linker may comprise propargyl, urea, or alkoxy groups.
• Exemplary structures within Formula V include Va, Vb, Vc, Vd:
• the invention includes phosphonate analogs of 1,3 diketo compounds having Formula VI:
• R is Ci-C 8 alkyl, d-C 8 substituted alkyl, C 2 -C 18 alkenyl, C 2 -C 18 substituted alkenyl, C 2 -C 18 alkynyl, C 2 -C 18 substituted alkynyl, C 6 -C 20 aryl, C ⁇ -C 2 o substituted aryl, C 2 -C 20 heteroaryl, or C 2 -C 20 substituted heteroaryl (Pais et al (2002) Drugs of the Future 27(11):1101-1111).
• R may be Ci-Cg alkylamino, Ci-Cg substituted alkylamino, C 2 -Cig alkenylamino, C 2 -Cig substituted alkenylamino, C 2 -C 18 alkynylamino, C 2 -C 18 substituted alkynylamino, C 6 -C 20 arylamino, C 6 -C 2 o substituted arylamino, C 6 -C 20 arylalkylamino, C 6 -C 20 substituted arylalkylamino, C 2 -C 20 heteroarylamino, or C 2 -C 2 o substituted heteroarylamino, whereby the amide is formed (WO 04/004657; WO 01/96283; WO 01/98248).
• Exemplary Formula VI compounds include where R is benzylamino, thiophenyl, thioimidazolyl, benzothiophenyl, napthothiophenyl, pyrrolidinyl, pyrazolyl, indanyl, indolyl, sesamyl, and benzoxazolyl.
• X is: (Via) a carboxylic acid or ester group (Zhang et al (2003) Bioorganic & Medicinal Chemistry Letters 13(6):1215-1219; Pais et al (2002) Jour. Med. Chem. 45(15):3184-3194; Reinke et al (2002) Antimicrob. Agents and Chemo. 46(10):3301- 3303; Marchand et al (2002) Jour. Biological Chem. 277(15):12596-112603; Hazuda et al (2000) Science 287(5453):646-650; Espeseth et al (2000) Proc. Natl. Acad. Sci.
• Embodiments of Formula VI compounds also include: Embodiments of Formula VI compounds also include:
• n may be 1, 2, 3, 4, 5, or 6.
• Embodiments of Formula VI compounds also include:
• the invention includes phosphonate analogs of 2,5 diarylsubstituted, furan compounds having Formula VII:
• Embodiments of Fo ⁇ nula VII compounds also include:
• the invention includes phosphonate analogs of 2,5 substituted, diketo-furan compounds (WO 03/016275 Al) having Formula VIII:
• the invention includes phosphonate analogs of catechol compounds (Dupont et al (2001) Bioorganic & Medicinal Chemistry Letters 11(24):3175-3178; Neamati et al (1997) Drug Discovery Today 2:487-498; Neamati et al (2000) Adv. Pharmacol. 49:147-165; Fesen et al (1993) Proc. Natl. Acad. Sci USA 90:2399-2403; Lafemina et al (1995) Antimicrob. Agents Chemother. 39:320- 324; Eich et al (1996) J. Med. Chem. 39(l):86-95; Pommier et al (1997) Antiviral Chem. Chemother.
• Neamati et al (1997) Antimicrob. Agents Chemother. 41 :385-393; Neamati et al
• R is a variety of scaffolds that is covalently attached to the catechol moiety through a single bond or a fused ring system.
• R aa is an amino acid side chain, including proline.
• Embodiments of Formula IX also include the bis catechol, ⁇ -conidendrol phosphonate structures:
• Catechol compounds IX include phosphonate analogs of styryl catechol compounds (Di Santo et al (2003) Pure and Applied Chemistry 75(2-3): 195-206; Xu et al (2003) Bioorganic & Medicinal Chemistry 11(17):3589-3593); Lamidey et al (2002) Helv. Chim. Acta 85(8):2328-2334; Zouhiri et al (2000) J. Med. Chem. 43(8):1533-1540; Zouhiri et al (2001) Tetrahedron Letters 42(46):8189-8192; Ouali et al (2000) J Med. Chem. 43(10)1949-1957; Mazumder et al (1997) J Med.
• Phosphonate analogs of styryl catechol compounds generally have Formula X:
• R x is a variety of scaffolds that is covalently attached to the catechol moiety through a single bond or a fused ring system.
• Embodiments of Formula X compounds include:
• X 1 is -NH(CH2)nNH- where n is 1-6, alkylarylene, or arylene, and X 2 is CN, Br, or OH, and any carbon or hydroxyl oxygen atom may be independently substituted with A 2 .
• Embodiments of Formula X compounds also include:
• Embodiments of Formula X compounds also include: where Q is CH 2 , O, S, NH, or NR.
• the invention includes phosphonate analogs of benzimidazole compounds (WO 02/070491 Al) and bis-benzimidazole compounds (WO 95/08540; WO 95/19772; WO 98/38170; Pluymers et al (2000) Mol. Pharmacol. 58:641-648) having Formula XI:
• Formula XI compounds may be further subsituted with fused ring systems, and L is a linker.
• the invention includes phosphonate analogs of indoloquinoxaline compounds (WO 96/00067) having Formula XII:
• the invention includes phosphonate analogs of acridine compounds (Thale et al (2002) J. Org. Chem. 67:9384-9391) including phosphonate analogs of bis-acridine compounds (Turpin et al (1998) Antimicrob. Agents Chemother. 42:487-494; WO 97/38999) having Formula XIII:
• the invention includes phosphonate analogs of polyamide, DNA binding compounds (Fesen et al (1993) Proc. Natl. Acad. Sci. USA 90:2399-2403; Carteau et al (1993) Biochem. Biophys. Res. Commun. 192:1409-1414; Carteau et al (1994) Biochem. Pharmacol. 47:1821-1826; Mazumder et al (1995) AIDS Res. Hum. Retroviruses 11:115-125; Bouziane et al (1996) J. Biol. Chem. 271:10359-10364; Billich et al (1992) Antiviral Chem. Chemother.
• the invention includes phosphonate analogs of [6,6] bicyclic compounds (Hazuda et al (1999) Antiviral. Chem. Chemother. 10:63; US 6541515; Singh et al (1998) Tetrahedron Lett. 39:2243-2246; GB 2306476; US5759842), including integramycins (Singh et al (2002) Organic Letters 4(7): 1123-1126) and fungal metabolites having Formula XV:
• Embodiments of Formula XV compounds include: Embodiments of integramycin phosphonate Formula XV compounds also include:
• the invention includes phosphonate analogs of [6,6] bicyclic terpenoid compounds (GB 2319026) having Formula XVI:
• Embodiments of Formula XVI compounds include phosphonate [6,6] bicyclic terpenoid compounds having the structures:
• the invention includes phosphonate analogs of aurintricarboxylic acid compounds (Cushman et al (1992) Biochem. Biophys. Res. Commun. 185:85-90; Cushman et al (1995) J. Med. Chem. 38:443-452; Cushman et al (1991) J. Med. Chem. 34(l):337-342) having Formula XVII:
• the invention includes phosphonate analogs of integrastatin compounds (Foot et al (2003) Organic Letters 5(23):4441-444; Singh et al (2002) Tetrahedron Lett. 43:2351-2354; WO 01/09114) having Formula XVIII:
• Embodiments of Formula XVIII compounds include phosphonate integrastatin compounds having the structures:
• the invention includes phosphonate analogs of 6- (arylazo)pyridoxal-5-phosphate compounds (WO 03/082881 A2) having Formula XIX:
• Embodiments of Formula XIX compounds include phosphonate 6- (arylazo)pyridoxal-5-phosphate compounds having the structures:
• the invention includes phosphonate analogs of 1,3-oxazine-, 1,3-thiazine-, pyran-, 1,4-oxazepine-, and 1,4-thiazepine-fused naphthalene compounds (WO 03/024941 Al) having Formula XX structures.
• R 1 is H, (un)substituted Cl-6 alkyl, halo, N0 2 , NH 2 , C0 2 H, (un)substituted aryl, optionally benzene-fused 5- or 6-membered aromatic or saturated, heterocyclyl containing 1-3 heteroatoms selected from N, S, and O, (un)substituted aryl- carbonylamino;
• R 2 and R 3 are independently H, C 1-6 alkyl or alkoxy, halo, NH 2 , C 1-6 alkylamino, di(Cl-6 alkyl)amino, N0 2 , CN, CONH 2 , C0 2 H, C 2-7 alkylcarbonylamino, C 3 - 13 alkoxycarbonylaminoalkoxy, C 1-6 aminoalkoxy, C 3 _ 13 alkylcarbonylaminoalkoxy;
• Embodiments of Formula XX compounds include phosphonate 1 ,3-oxazine-
• the invention includes phosphonate analogs of chaetochromin compounds derived from chaetochromin fermentation products and their chemically modified derivatives (WO 98/34932) including naphtho- ⁇ -pyrones (Singh et al (2003) Bioorganic &Med. Chemistry Letters 13 (4) :713 -717 having Formula XXI.
• Formula XXI compounds further include phosphonate unsaturated (isochaetochromin D ⁇ and further oxidized lactone (oxychaeotochromin B) analogs of isochaetochromin Bi and B 2 according to following structures:
• the invention includes all rotational isomers, i.e. atropisomers, which may exist as stable enantiomers due to slow rotation around the single bond connecting the aryl rings of Formula XXI compounds.
• the invention includes phosphonate analogs of hydroxyphenylundecane compounds derived from fermentation products and their chemically modified derivatives (GB 2327674) including integracins (Singh et al (2002) Tetrahedron Lett. 43(9):1617-1620) having Formula XXII structures:
• the invention includes phosphonate analogs of: (i) tetracyclic steroidal compounds derived from fermentation products and their chemically modified derivatives (Singh et al (2003) Jour, of Natural Products 66(10):1338-1344; WO 00/36132); and (ii) tetracyclic triterpenoid compounds, such as integracides (Singh et al (2003) Bioorganic & Med. Chemistry 11(7):1577-1582).
• the invention includes phosphonate analogs of plant natural products including: (i) glycerrhenitic and betulonic acids (Semenova et al (2003) Doklady Biochemistry and Biophysics 391:218-220); (ii) compounds from Coleus parvifolius Benth.
• Embodiments of Formula XXLV glycerrhenitic and betulonic acid phosphonate compounds include the structures:
• Embodiments of laurolistine phosphonate Formula XXIV compounds include the structures:
• the invention includes phosphonate analogs of spiro ketal compounds derived from fungal cultures and fungus, and their chemically modified derivatives (Neamati, N. (2002) Expert Opinion Therapeutic Patents 12(5):709-724, compound 47, Table 2, p. 714) with the Formula XXV structure:
• the invention includes phosphonate analogs of aromatic lactone compounds derived from lichen extracts, and their chemically modified derivatives (Neamati et al (1997) J. Med. Chem. 40:942-951; Neamati et al (1997) Antimicrob. Agents Chemother. 41:385-393).
• Phosphonate aromatic lactone Formula XXVI compounds include the structures:
• the invention includes phosphonate analogs of salicylhydrazide and mercaptosalicylhydrazide compounds (Neamati et al (2002) J. Med. Chem. 45(26): 5661-5670; Neamati et al (1998) J. Med. Chem. 41:3202-3209; Zhao et al (1997) J. Med. Chem. 40:937-941; WO 00/53577) which have Formula XXVII structures:
• the invention includes phosphonate analogs of thiazolothiazepine compounds (Neamati et al (1999) J. Med. Chem. 42:3334-3341; WO 00/68235).
• the invention includes phosphonate analogs of benzodiazepine hydrazide compounds (WO 98/18473).
• Embodiments of Formula XXIX benzodiazepine hydrazide phosphonate compounds include the structures:
• the invention includes phosphonate analogs of coumarin compounds (Mao et al (2002) Chemical & Pharmaceutical Bulletin 50(12):1634- 1637; Chavda et al (2002) Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry 41B(10):2197-2199; Zhao et al (1997) J. Med. Chem. 40:242-249; Mazumder et al (1996) J. Med. Chem. 39:2472-2481; Hong et al (1997) J. Med. Chem. 40-930-936; JP 12178267).
• Coumarin phosphonate compounds include Lamellarin-type marine natural products (Reddy et al (1999) J. Med. Chem.
• Exemplary phosphonate coumarin Formula XXX compounds include the structures:
• R is H, Ci-C 8 alkyl, - substituted alkyl, C 2 -C 18 alkenyl, C 2 -C 18 substituted alkenyl, C 2 ⁇ C 18 alkynyl, C 2 -C 18 substituted alkynyl, C 6 -C 20 aryl, C 6 -C 2 o substituted aryl, C 2 -C 20 heteroaryl, or C -C 20 substituted heteroaryl.
• Exemplary phosphonate coumarin dimer Formula XXX compounds include the structures:
• Z is -C(0)Ar or -S0 2 R.
• Exemplary phosphonate Lamellarin Formula XXX compounds include the structures:
• the invention includes phosphonate analogs of brominated polyacetylene marine natural products from sponges such as Diplastrella sp. (Lerch et al (2003) Journal of Natural Products 66(5):667-670).
• Brominated polyacetylene phosphonate Formula XXXI compounds including sulfated and sufonated analogs, have the structure:
• Exemplary phosphonate brominated polyacetylene Formula XXXI compounds include the structures:
• the invention includes phosphonate analogs of cobalamin
• Exemplary phosphonate cobalamin Formula XXXI compounds include the structures:
• the invention includes phosphonate analogs of hydroxylated aromatic compounds (Burke et al (1995) J. Med. Chem. 38:4171-4178), including: tetracycline compounds (Neamati et al (1997) Mol. Pharmacol. 52:1041-1055); anthraquinones and naphthoquinones (Fesen et al (1993) Proc. Natl. Acad. Sci. USA 90:2399-2403; Farnet et al (1996) Proc. Nat. Acad. Sci.
• Exemplary embodiments of Formula XXXIII flavanol phosphonate compounds include phosphonate analogs of quercetin 3-0-(2"-galloyl)- ⁇ -L- arabinopyranoside such as the structures:
• Disaccharide catechol phosphonate Formula XXXIII compounds include the structures:
• Exemplary flavonoid glucuronide phosphonate Formula XXXIII compounds include the structures:
• the invention includes phosphonate analogs of various sulfur- containing compounds including phosphonate analogs of: polyanionic sulfonate suramin and dextran sulfate (Billich et al (1992) Antivir. Chem. Chemother. 3:113- 119; Carteau et al (1993) Arch. Biochem. Biophys. 305:606-610); diaryl sulfones (Gervay-Hague et al (2003) Abstracts of Papers, 225th ACS National Meeting, New La, LA, United States, March 23-27, 2003; Abstract No. 2003:184008; Neamati et al (1991) Antimicrob. Agents Chemother.
• Exemplary phosphonate sulfonamide Formula XXXLV compounds include:
• Exemplary diaryl sulfone phosphonate Formula XXXIV compounds include:
• Exemplary distyryl disulfone phosphonate Formula XXXIV compounds include:
• Exemplary 2-merca ⁇ tobenzenesulfonamide phosphonate Formula XXXIV compounds include the structures:
• the invention includes phosphonate analogs of symmetrical pentamidine compounds derived from serine protease inhibitors (WO 02/02516).
• exemplary embodiments of pentamidine phosphonate Formula XXXV compounds include the structures:
• the invention includes phosphonate analogs of nucleic acid compounds.
• Nucleic acid phosphonate compounds include: (a) nucleosides and nucleotides (Zhao et al (1997) Heterocycles 45:2277-2282; Drake et al (1998) Proc. Natl. Acad. S.ci. USA 95:4170-4175; Mazumder et al (1994) Proc. Natl. Acad. Sci. USA 91:5771-5775), dinucleotides (Taktakishvili et al (2000) J. Am. Chem. Soc. 122(24):5671-5677; Mazumder et al (1997) Mol. Pharmacol.
• Nucleic acid analogs include L and D stereoisomers (Mazumder et al (1996) Mol. Pharmacol.
• nucleobase analogs Brodin et al (2002) Biochemistry 41(5):1529-1538; Brodin et al (2001) Nucleosides, Nucleotides & Nucleic Acids 20(4-7):481-486); sugar analogs and; internucleotide phosphate analogs (Tramontano et al (1998) Biochemistry 37:7237-7243; Zhang et al (1998) Bioorg. Med. Chem. Lett. 8:1887- 1890; 8).
• Formula XXXVI compounds may be substituted at any location on the 5' terminus, 3' terminus, internucleotide phosphate linkage, sugar, or nucleobase moieties with a phosphonate group, as described for A 1 .
• Formula XXXVI compounds also include any oligonucleotide analog with a modified internucleotide linkage, a modified sugar, or a modified nucleobase.
• the invention includes phosphonate analogs of amino acids (WO
• Formula XXXVII compounds may be substituted at any location on the amino terminus, carboxyl terminus, side chain, or amide backbone with a phosphonate group, as described for A .
• Exemplary phosphonate peptide and protein Formula XXXVII compounds include the substructures:
• the invention includes phosphonate analogs of polyketide natural products including Xanthoviridicatins isolated from a fermentation broth of an endophytic strain of Penicillium chrysogenum (Singh, et al (2003) Helvetica Chimica Acta, 86(10):3380-3385) having the Formula XXXVIII structure:
• Exemplary phosphonate polyketide Formula XXXVIII compounds include:
• the invention includes phosphonate analogs of polyketide natural products including cytosporic acid, australifungin and australifunginol isolated from a fermentation broth of the filamentous fungus Cytospora sp. (Jayasuriya et al (2003) Journal of Natural Products 66(4):551-553).
• Exemplary phosphonate cytosporic australifungin and australifunginol analog Formula XXXIX compounds include:
• 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 "PG" 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 PG groups do not need to be, and generally are not, the same if the compound is substituted with multiple PG. In general, PG 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.
• 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.
• 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.
• a protecting group typically is bound to any acidic group such as, by way of example and not limitation, a -CO2H or -C(S)OH group, thereby resulting in -C ⁇ 2 x where R x is defined herein.
• R x for example includes the enumerated ester groups of WO 95/07920. Examples of protecting groups include:
• C3-C12 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,
• Such groups include 2-, 3- and 4-alkoxyphenyl (C1-C12 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, 2- and 3- carboethoxy-4-hydroxyphenyl, 2- and 3-ethoxy-4-hydroxyphenyl, 2- and 3-ethoxy-5- hydroxyphenyl, 2- and 3-ethoxy-6-hydroxyphenyl, 2-, 3- and 4-O-acetylphenyl, 2-, 3- and 4-dimethylaminophenyl, 2-, 3- and 4-methylmercaptophenyl, 2-, 3- and 4- halophenyl (including 2-, 3- and 4-fluorophenyl and 2-, 3- and 4-chlorophenyl), 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,
• Table A lists examples of protecting group ester moieties that for example can be bonded via oxygen to -C(0)0- and -P(0)(0-)2 groups. Several amidates also are shown, which are bound directly to -C(O)- or -
• P(0)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, CSCO3, N,N-dimethylaniline and the like) in 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).
• # - chiral center is (R), (S) or racemate.
• Protecting groups also includes "double ester” forming profunctionalities such as -CH2 ⁇ C(0)OCH3,
• alkyl- or aryl- acyloxyalkyl groups of the structure -CH(R 1 or W 5 )0((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. patent 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.
• Such useful protecting groups are alkylacyloxymethyl esters and their derivatives, including -CH(CH 2 CH2 ⁇ CH 3 )OC(0)C(CH3)3,
• -CH 2 OC(O)C 10 Hi 5 , -CH 2 OC(0)C(CH 3 ) 3 , -CH(CH 2 OCH 3 )OC(0)C(CH 3 ) 3 , - CH(CH(CH 3 ) 2 )OC(0)C(CH 3 )3, -CH 2 OC(0)CH 2 CH(CH 3 )2, -CH 2 OC(0)C 6 Hn, - CH 2 OC(0)C 6 H 5 , -CH 2 OC(O)C 10 Hi5, -CH 2 OC(0)CH 2 CH 3 , -CH 2 OC(0)CH(CH 3 ) , -CH 2 OC(0)C(CH 3 )3 and -CH 2 OC(0)CH2C 6 H5.
• 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 LI 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 C1-C4 alkylestercarboxyphenyl (salicylate C1-C12 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.
• Exemplary hydroxy protecting groups include:
• Methoxybenzyloxymethyl (4-Methoxyphenoxy)methyl, Guaiacolmethyl, t- Butoxymethyl, 4-Pentenyloxymethyl, Siloxymethyl, 2-Methoxyethoxymethyl, 2,2,2-Trichloroethoxymethyl, Bis(2-chloroethoxy)methyl, 2- (Trimethylsilyl)ethoxymethyl, Tetrahydropyranyl, 3 -Bromotetrahydropyranyl, Tetrahydropthiopyranyl, 1-Methoxycyclohexyl, 4-Methoxytetrahydropyranyl, 4-
• esters (Formate, Benzoylformate, Acetate, Choroacetate, Dichloroacetate, Trichloroacetate, Trifluoroacetate, Methoxyacetate, Triphenylmethoxyacetate, 3 -
• Phenylpropionate 4-Oxopentanoate (Levulinate), 4,4-(Ethylenedithio)pentanoate, Pivaloate, Adamantoate, Crotonate, 4-Methoxycrotonate, Benzoate, - Phenylbenzoate, 2,4,6-Trimethylbenzoate (Mesitoate));
• Dimethylphosphinothioyl, 2,4-Dinitrophenylsulfenate Dimethylphosphinothioyl, 2,4-Dinitrophenylsulfenate); and • Sulfonates (Sulfate, Methanesulfonate (Mesylate), Benzylsulfonate, Tosylate).
• Typical 1,2-diol protecting groups are described in Greene at pages 118- 142 and include Cyclic Acet als and Ket als (Methyl ene, Ethylidene, 1-t- Butylethylidene, 1-Phenylethylidene, (4-Methoxyphenyl)ethylidene, 2,2,2- Trichloroethylidene, Acetonide (Isopropylidene), Cyclopentylidene, Cyclohexylidene, Cycloheptylidene, Benzylidene, >-Methoxybenzylidene, 2,4-Dimethoxybenzylidene, 3,4-Dimethoxybenzylidene, 2-Nitrobenzylidene); Cyclic Ortho Esters (Methoxymethylene, Ethoxymethylene, Dimethoxymethylene, 1-Methoxyethylidene, 1-E
• 1,2-diol protecting groups include those shown in Table B, still more typically, epoxides, acetonides, cyclic ket als and aryl acet als.
• R ⁇ is C ⁇ -C alkyl.
• Another set of protecting groups include any of the typical amino protecting groups described by Greene at pages 315-385.
• Exemplary amino protecting groups include:
• Ethyl (2,2,2-trichoroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1-(1- adamantyl)-l-methylethyl, l,l-dimethyl-2-haloethyl, l,l-dimethyl-2,2- dibromoethyl, 1 , 1 -dimethyl-2,2,2-trichloroethyl, 1 -methyl- 1 -(4-biphenylyl)ethyl, l-(3,5-di-t-butylphenyl)-l-methylethyl, 2-(2'- and 4'-pyridyl)ethyl, 2-(N,N- dicyclohexylcarboxamido)ethyl, t-butyl, 1-adamantyl, vinyl, allyl, 1- isopropylallyl, cinnamyl, 4-nitrocin
• N-Met al Derivatives N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentacarbonylchromium- or -tungsten)] carbenyl, N-copper or N-zinc chelate;
• N-p-toluenesulfonyl N-benzenesulfonyl, N-2,3, 6-trimethyl-4- methoxybenzenesulfonyl, N-2,4,6-trimethoxybenzenesulfonyl, N-2,6-dimethyl-4- methoxybenzenesulfonyl, N-pentamethylbenzenesulfonyl, N-2,3 ,5,6,-tetramethyl- 4-methoxybenzenesulfonyl, N-4-methoxybenzenesulfonyl, N-2,4,6- trimethylbenzenesulfonyl, N-2,6-dimethoxy-4-methylbenzenesulfonyl, N-
• An amino acid or polypeptide protecting group of a compound of the invention has the structure R 15 NHCH(R 16 )C(0)-, where R 15 is H, an amino acid or polypeptide residue, or R 5 , and R 16 is defined below.
• R 16 is lo,wer alkyl or lower alkyl (C ⁇ -C6) substituted with amino, carboxyl, amide, carboxyl ester, hydroxyl, C 6 -C aryl, guanidinyl, imidazolyl, indolyl, sulfhydryl, sulfoxide, and/or alkylphosphate.
• R 10 is generally the side group of a naturally-occurring amino acid such as H, -CH 3 , -CH(CH3) 2 , - CH 2 -CH(CH 3 ) 2 , -CHCH3-CH2-CH3, -CH 2 -C 6 H 5 , -CH 2 CH 2 -S-CH 3 , -CH 2 OH, - CH(OH)-CH 3 , -CH2-SH, -CH 2 -C 6 H 4 OH, -CH 2 -CO-NH 2 , -CH 2 -CH 2 -CO-NH 2 , - CH2-COOH, -CH2-CH2-COOH, -(CH 2 ) 4 -NH 2 and -(CH 2 ) 3 -NH-C(NH 2 )-NH 2 .
• a naturally-occurring amino acid such as H, -CH 3 , -CH(CH3) 2 , - CH 2 -CH(CH 3 ) 2 , -CHCH3
• R 10 also includes l-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl, imidazol-4-yl, indol-3- yl, methoxyphenyl and ethoxyphenyl.
• Another set of protecting groups include the residue of an amino-containing compound, in particular an amino acid, a polypeptide, a protecting group, -NHS02R, NHC(0)R, -N(R)2, NH2 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(0)NR 2 .
• a phosphonic acid may be reacted with the amine to form a phosphonamidate, as in - P(0)(OR)(NR 2 ).
• amino acids have the structure R 17 C(0)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). When protecting groups are single amino acid residues or polypeptides, these conjugates may be produced by forming an amide bond between a carboxyl group of the amino acid (or C-terminal amino acid of a polypeptide for example).
• 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.
• 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 .
• Such ester 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.
• 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.
• D isomers are useful.
• L isomers 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. Examples of suitable amino acids whose residues are represented by R x or R y 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, omithine, citruline, homoarginine, homocitruUine, hydroxylysine, allohydroxylsine and diaminobutyric acid;
• Diaminodicarboxylic acids such as ⁇ , ⁇ '-diaminosuccinic acid, ⁇ , ⁇ '- diaminoglutaric acid, ⁇ , ⁇ '-diaminoadipic acid, ⁇ , ⁇ '-diaminopimelic 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 Ci-Cs 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, ⁇ -aminoisobutyric acid, ⁇ -aminodiethylacetic acid, ⁇ - aminodiisopropylacetic acid, ⁇ -aminodi-n-prop
• 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 peptido lytic 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 ⁇ - amino group to the phosphorus or carbon atoms of the compounds herein.
• the known experimental or approved HIV integrase inhibitor drugs which can be derivatized in accord with the present invention must contain at least one functional group capable of bonding to the phosphorus atom in the phosphonate moiety.
• the phosphonate derivatives of Formulas I-XXXIX may cleave in vivo in stages after they have reached the desired site of action, i.e. inside a cell.
• One mechanism of action inside a cell may entail a first cleavage, e.g. by esterase, to provide a negatively-charged "locked-in" intermediate. Cleavage of a terminal ester grouping in Formulas I-XXXIX thus affords an unstable intermediate which releases a negatively charged "locked in” intermediate.
• intracellular enzymatic cleavage or modification of the phosphonate prodrug compound may result in an intracellular accumulation of the cleaved or modified compound by a "trapping" mechanism.
• the cleaved or modified compound may then be "locked-in” the cell by a significant change in charge, polarity, or other physical property change which decreases the rate at which the cleaved or modified compound can exit the cell, relative to the rate at which it entered as the phosphonate prodrug.
• Other mechanisms by which a therapeutic effect are achieved may be operative as well.
• Enzymes which are capable of an enzymatic activation mechanism with the phosphonate prodrug compounds of the invention include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphatases.
• the drug is of the nucleoside type, such as is the case of zidovudine and numerous other antiretroviral agents, it is known that the drug is activated in vivo by phosphorylation. Such activation may occur in the present system by enzymatic conversion of the "locked-in” intermediate with phosphokinase to the active phosphonate diphosphate and/or by phosphorylation of the drug itself after its release from the "locked-in” intermediate as described above.
• nucleoside-type drug will be convened, via the derivatives of this invention, to the active phosphorylated species.
• the selected drug contains multiple reactive hydroxyl functions
• a mixture of intermediates and final products may again 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 approximate by equal amounts, while a lesser amount of multiply-substituted product 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.
• PBMC peripheral blood mononuclear cells
• PBMC peripheral blood mononuclear cells
• PBMC peripheral blood mononuclear cells
• PBMC peripheral blood mononuclear cells
• PBMC peripheral blood mononuclear cells
• PBMC are critical components of the mechanism against infection.
• PBMC may be isolated from heparinized whole blood of normal healthy donors or buffy coats, by standard density gradient centrifugation and harvested from the interface, washed (e.g. phosphate- buffered saline) and stored in freezing medium.
• PBMC may be cultured in multi-well plates. At various times of culture, supernatant may be either removed for assessment, or cells may be harvested and analyzed (Smith R.
• the compounds of this embodiment may further comprise a phosphonate or phosphonate prodrug. More typically, the phosphonate or phosphonate prodrug has the structure A 3 as described herein.
• the compounds of this embodiment demonstrate improved intracellular half-life of the compounds or intracellular metabolites of the compounds in human PBMC when compared to analogs of the compounds not having the phosphonate or phosphonate prodrug. Typically, the half-life is improved by at least about 50%, more typically at least in the range 50-100%, still more typically at least about 100%, more typically yet greater than about 100%.
• the intracellular half-life of a metabolite of the compound in human PBMCs is improved when compared to an analog of the compound not having the phosphonate or phosphonate prodrug.
• the metabolite may be generated intracellularly, e.g. generated within human PBMC.
• the metabolite may be a product of the cleavage of a phosphonate prodrug within human PBMCs.
• the phosphonate prodrug may be cleaved to form a metabolite having at least one negative charge at physiological pH.
• the phosphonate prodrug may be enzymatically cleaved within human PBMC to form a phosphonate having at least one active hydrogen atom of the form P-OH.
• the compounds of the invention may have chiral centers, e.g. chiral carbon, sulfur, or phosphorus atoms.
• the compounds of the invention thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers.
• the compounds of the invention include enriched or resolved optical isomers at any or all asymmetric, chiral atoms. In other words, the chiral centers apparent from the depictions are provided as the chiral isomers or racemic mixtures.
• racemic and diastereomeric mixtures are all within the scope of the invention.
• the 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 followed by conversion back to the optically active substances.
• the desired optical isomer is synthesized by means of stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material.
• the compounds of the invention 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 tefrazole systems and all their possible tautomeric forms are within the scope of the invention.
• compositions of this invention optionally comprise salts of the compounds herein, especially pharmaceutically acceptable non-toxic salts containing, for example, Na + , Li + , K + > Ca + 2 and Mg + 2.
• Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth met al 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.
• Met al salts typically are prepared by reacting the met al hydroxide with a compound of this invention. Examples of met al salts which are prepared in this way are salts containing Li + , Na + , and K + . A less soluble met al salt can be precipitated from the solution of a more soluble salt by addition of the suitable met al 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.
• the salts of the parental compounds with one or more amino acids 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.
• a basic or acidic group e.g., lysine, arginine or glutamic acid
• a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
• HIV integrase comprising the step of treating a sample suspected of containing HIV with a composition of the invention.
• compositions of the invention may act as inhibitors of HIV integrase, as intermediates for such inhibitors or have other utilities as described below.
• the inhibitors will bind to locations on the surface or in a cavity of HIV integrase having a geometry unique to HIV integrase.
• Compositions binding HIV integrase may bind with varying degrees of reversibility. Those compounds binding substantially irreversibly are ideal candidates for use in this method of the invention. Once labeled, the substantially irreversibly binding compositions are useful as probes for the detection of HIV integrase.
• the invention relates to methods of detecting HIV integrase in a sample suspected of containing HIV integrase comprising the steps of: treating a sample suspected of containing HIV integrase with a composition comprising a compound of the invention bound to a label; and observing the effect of the sample on the activity of the label.
• Suitable labels are well known in the diagnostics field and include stable free radicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups and chromogens.
• the compounds herein are labeled in conventional fashion using functional groups such as hydroxyl or amino.
• samples suspected of containing HIV integrase include natural or man-made materials such as living organisms; tissue or cell cultures; biological samples such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like); laboratory samples; food, water, or air samples; bioproduct samples such as extracts of cells, particularly recombinant cells synthesizing a desired glycoprotein; and the like.
• biological material samples blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like
• laboratory samples food, water, or air samples
• bioproduct samples such as extracts of cells, particularly recombinant cells synthesizing a desired glycoprotein
• samples can be contained in any medium including water and organic solvent ⁇ water mixtures. Samples include living organisms such as humans, and man made materials such as cell cultures.
• the treating step of the invention comprises adding the composition of the invention to the sample or it comprises adding a precursor of the composition to the sample.
• the addition step comprises any method of administration as described above.
• the activity of HIV integrase after application of the composition can be observed by any method including direct and indirect methods of detecting HIV integrase activity. Quantitative, qualitative, and semiquantitative methods of determining HIV integrase activity are all contemplated. Typically one of the screening methods described above are applied, however, any other method such as observation of the physiological properties of a living organism are also applicable.
• Organisms that contain HIV integrase include the HIV virus.
• the compounds of this invention are useful in the treatment or prophylaxis of HIV infections in animals or in man.
• screening compounds capable of inhibiting human immunodeficiency viruses it should be kept in mind that the results of enzyme assays may not correlate with cell culture assays.
• a cell based assay should be the primary screening tool.
• compositions of the invention are screened for inhibitory activity against HIV integrase by any of the conventional techniques for evaluating enzyme activity. Within the context of the invention, typically compositions are first screened for inhibition of HIV integrase in vitro and compositions showing inhibitory activity are then screened for activity in vivo. Compositions having in vitro Ki (inhibitory constants) of less then about 5 X 10 ⁇ 6 M, typically less than about 1 X 10 ⁇ 7 M and preferably less than about 5 X 10 ⁇ 8 M are preferred for in vivo use.
• Ki inhibitory constants
• compositions 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
• 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 Remington'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.
• 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 the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
• the active ingredient may also be administered as a bolus, electuary or paste.
• a tablet 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 emulsifying 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.
• compositions containing the active ingredient may be in any form suitable for the intended method of administration.
• tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
• Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
• Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable.
• excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
• inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate
• granulating and disintegrating agents such as maize starch, or alginic acid
• binding agents such as starch, ge
• Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
• Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
• Such excipients include a suspending agent, such as sodium carboxymethylcellulose, croscarmellose, povidone, 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 such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose,
• the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
• Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
• the oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
• Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
• These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
• Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
• the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
• the oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these.
• Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
• the emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
• compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
• a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
• This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1 ,3-butane-diol or prepared as a lyophilized powder.
• 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 maybe 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 (weigh 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 this invention 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.
• Effective dose of active ingredient 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 viral 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 .01 to about 5 mg/kg body weight per day. More typically, from about .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.
• Active ingredients of the invention 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-properties of the combination. For example, when treating viral infections the compositions of the invention are combined with other antivirals such as other protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors or HIV integrase inhibitors.
• One or more compounds of the invention 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.
• Combination Therapy 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.
• Exemplary active ingredients to be administered in combination with compounds of the invention are protease inhibitors, nucleoside reverse transcriptase inhibitors, non- nucleoside reverse transcriptase inhibitors, and HIV integrase inhibitors.
• the combination therapy may provide "synergy” and "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, unit dosage 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 invention provides an HIV integrase inhibitor compound provided that the compound is not 4-(3-benzyl-phenyl)-2-hydroxy-4-oxo- but-2-enoic acid, 1 -[5-(4-fluoro-benzyl)-furan-2-yl]-3-hydroxy-3-(l H-[l ,2,4]triazol- 3-yl)-pro ⁇ enone, or 5-(l,l-dioxo-116-[l,2]thiazinan-2-yl)-8-hydroxy-quinoline-7- carboxylic acid 4-fluoro-benzylamide.
• X 74 (-X 75 , -X 76 ) is not phenyl substituted with benzyl and X 77 is not hydrogen; or the compound is not:
• X 74 (-X 75 , -X 76 , -X 79 ) is not furan substituted with p-fluorobenzyl, when X 78 is hydroxy, and X 80 (-X 81 ) is 2H-[l,2,4]triazole.
• a compound of the invention with a second or third active ingredient in a unitary dosage form for simultaneous or sequential administration.
• the combination may be administered in two or three administrations.
• the second or third active ingredient may have anti-HIV activity and include protease inhibitors (PI), nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), and integrase inhibitors.
• PI protease inhibitors
• NRTI nucleoside reverse transcriptase inhibitors
• NRTI non-nucleoside reverse transcriptase inhibitors
• integrase inhibitors Exemplary second or third active ingredients to be administered in combination with a compound of the invention are shown in Table C. Table C
• CDG carbocyclic 2'-deoxyguanosine Cidofovir, HPMPC; (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine
• Combivir® (lamivudine/zidovudine) Cytallene; [ 1 -(4'-hydroxy- 1 ',2'-butadienyl)cytosine] d4C; 3 '-deoxy-2',3 '-didehydrocytidine
• DAPD DAPD
• Enfuvirtide Fuzeon®
• F-ara-A F-ara-A
• fluoroarabinosyladenosine Fludarabine
• FIAU 1 -(2-deoxy-2-fluoro- ⁇ -D-arabinofuranosyl)-5-iodouridine FLG; 2',3'-dideoxy-3'-fluoroguanosine
• FMAU 2'-Fluoro-5-methyl-b-L-arabino-furanosyluracil
• Oxetanocin A 9-(2-deoxy-2-hydroxymethyl-beta-D-erythro- oxetanosyl)adenine
• Ribavirin 1 - ⁇ -D-ribofuranosyl- 1 ,2,4-triazole-3 -carboxamide Ritonavir, Norvir®
• TFT Tenofovir disoproxil fumarate
• TFT Trifluorothymidine
• Trizivir® (abacavir sulfate/lamivudine/zidovudine)
• the invention includes novel and unobvious 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 4 or H ⁇ ) 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 compounds of the invention even if they possess no HIV integrase inhibitory activity of their own.
• the compounds of the invention may be prepared by a variety of synthetic routes and methods known to those skilled in the art.
• the invention also relates to methods of making the compounds of the invention.
• the 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.
• 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 met al 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 byproducts 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.
• This means that "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 IM), 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, met al), 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. Modifications of each of the exemplary schemes above and in the examples
• each of the exemplary schemes it maybe advantageous to separate 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.
• 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
• 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 pure or enriched enantiomer.
• a method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g.
• protecting groups to mask reactive functionality and direct reactions regioselectively (Greene, etal (1991) "Protective Groups in Organic Synthesis", 2nd Ed., John Wiley & Sons).
• useful protecting groups for the 8-hydroxyl group and other hydroxyl substituents include methyl, MOM (methoxymethyl), trialkylsilyl, benzyl, benzoyl, trityl, and tetrahydropyranyl. Certain aryl positions may be blocked from substitution, such as the 2-position as fluorine.
• a succinimide with a labile protecting group (P) on the nitrogen may be reacted with a pyridine dicarboxylate compound.
• P may be an acid-labile protecting group, such as trialkylsilyl.
• Trialkylsilyl groups may also be removed with fluoride reagents. After P is removed, a variety of Ar-L groups may be covalently attached, according to Scheme 2.
• Imide compounds can be reduced with dissolving metal reducing agents, e.g.
• Imide compounds may also be reduced to the hydroxylactam under mild conditions. Reductions with sodium borohydride and cerium or samarium salts have been shown to proceed with regioselectivity on asymmetric imides (Mase, etal J Chem. Soc. Perkin Communication 1 (2002) 707-709), as in Scheme 4, upper. Grignard reagents and acetylenic anions (Chihab-Eddine, etal Tetrahedron Lett. (2001) 42:573-576) may also add with regioselectivity to an imide carbonyl to form alkyl-hydroxylactam compounds, as in Scheme 4, lower). The phenolic oxygen groups may be protected and deprotected as necessary to furnish yield reactions.
• cyclic anhydride may be regioselectively esterified to give the compounds of the invention, for example via the route in Scheme 6
• a cyclic imide may be conveniently alkylated, acylated, or otherwise reacted to form a broad array of compounds with Ar-L groups:
• the Ar-L group may be attached by a multi step process.
• Annulation of the third, 5-7 membered ring can be conducted by appropriate selection of aryl substituents on the quinoline ring system, utilizing known synthetic transformations to give compounds of Formula I.
• methods for coupling carboxylic acids and other activated acyl groups with amines to form carboxamides are well known in the art (March, J. Advanced Organic Chemistry, 3rd Edition, John Wiley & Sons, 1985, pp. 370-376).
• An exemplary cyclization includes the following:
• Scheme 8 below shows another synthetic route to compounds of the invention, i.e. Formula I.
• This route proceeds by cyclization of a 2-O-protected, 3 halo-aniline compound with an ⁇ , ⁇ -unsaturated carbonyl compound to give a functionalized quinoline.
• Carbonylation via palladium catalysis can give an ester which may be elaborated to the amide functionality and cyclization to form a 5, 6, or 7 membered ring.
• the R group of phenolic oxygen may be a labile protecting group, e.g. trialkylsilyl or tetrahydropyranyl, which may be removed at a step in the synthetic route, or it may be a substituent which is retained in the putative integrase inhibitor compound.
• a labile protecting group e.g. trialkylsilyl or tetrahydropyranyl
• Halo quinoline intermediates may undergo a flexible array of nucleophilic aromatic substitutions and Suzuki-type reactions, as shown in Scheme 9 below.
• Suzuki coupling of aryl halide compounds with acetylenic and vinylic palladium complexes are carbon-carbon bond forming reactions under relatively mild conditions. In some instances it may be necessary to block the 2 position to direct reaction at the desired aryl position.
• Formula I compounds with a 5,9-dihydroxy-pyrrolo[3,4-g]quinoline-6,8-dione were prepared by selective protection of the C9 phenol in 5,9-dihydroxy-pyrrolo[3,4- g]quinoline-6,8-dione.
• the C9 phenol was protected with a TIPS group and the C5 phenol could then be alkylated or acylated (Scheme 10).
• Formula III compounds may be prepared by the following methods in
• the acid 1 (WO02/30930, ⁇ .173) may be reacted with amine 2 (prepared according to the methods described by T. Morie, et al, Chem. Pharm. Bull., 42 , 1994, 877-882; D. Wenninger, et al, Nucleosides Nucleotides, 16 , 1997, 977-982) by the method of peptide coupling such as described in WO02/30930, p. 173 to form amide 3. Bromination with NBS generates compound 4. The phenol is protected with a bulky acyl group such as pivaloyl. Displacement of bromine at C5 of naphthyridine by Bis-boc protected hydrazine is achieved using the method reported by J.B.
• the simple sulfonamides are produced when 8 reacts with sulfonyl chlorides.
• the ester group in compounds 9 is removed upon saponification to give compound 10.
• R 6 in 14 is OR a , or where R a can be removed, oxime 16 is obtained and can be functionalized with many reagents to yield compound 17. Hydrolysis of ester group affords 18.
• 16 is treated with an alkyl halide (R -X) or an alcohol under Mitsunobu condition, an ether 18 is formed.
• R -X alkyl halide
• R -X isocyanate or thioisocyanate
• Scheme 15 depicts one of the methods to prepare a spiro-cyclopropane- containing lactam fused to quinoline, an embodiment of Formula I.
• a differentially protected phenol 19 is used where R 8 can be a removable ether group such as trimethylsilyethyl ether and R 9 can be a bulky group such as diphenylmethyl or t- butyl ether.
• the carbonyl of C6 is converted to an olefin regioselectively by treating 19 with methylmagnesium bromide followed by dehydration of aminal to give 20.
• Carbene insertion by Simmons-Smith reaction (for example, Y. Biggs et al, JOC, 57, 1992, 5568-5573) produces cyclopropane 21.
• Selective removal of R 8 by TBAF followed by fuctionalization using the methods described in many examples leads to compound 24.
• a dimethyl substituted lactam can be prepared by reacting 19 with a Grignard reagent followed by converting aminal 25 to acetate 26 and treating 26 with Me 3 Al/TMSOTf, a method reported by C.U. Kim, et al, Tetrahedron Letters, 35, 1994, 3017-3020, to afford 27.
• An alternative method can be used by reducing cyclopropane 21 with Pt0 2 /H 2 as reported by C.K. Cheung et al, JOC, 54, 1989, 570- 573, to give 27.
• Another version of modified lactam can be obtained according to Scheme 17. Treating 19 with an allyl Grignard reagent gives 30. Activating aminal 30 by forming acetate 31 followed by treating 31 with allyl trimethylsilane mediated by a Lewis acid such as TMSOTf affords 32. Cyclization can be achieved by using Grubb's RCM (ring closure metathesis) method (P. Schwab et al, Angew. Chem. Intl. 34, 1995, 2039). Alternatively, the terminal olefins in 32 can be converted to aldehydes and reductive amination leads to a spiro-piperidine.
• Grubb's RCM ring closure metathesis
• the intermediate compounds Iaa to IVcc incorporate a phosphonate moiety (R 5 0) 2 P(0) connected to the nucleus by means of a variable linking group, designated as "link” in the attached structures.
• Chart 2 illustrates examples of the linking groups present in the structures Iaa - IVcc.
• Schemes Al - A33 illustrate the syntheses of the intermediate phosphonate compounds of this invention, Iaa - IVcc, and of the intermediate compounds necessary for their synthesis.
• reaction sequences which produce the phosphonates Iaa are, with appropriate modifications, applicable to the preparation of the phosphonates Ilaa, Illaa, or IVaa.
• Methods described below for the attachment of phosphonate groups to reactive substituents such as OH, NH 2 , CH 2 Br, COOH, CHO etc are applicable to each of the scaffolds I - V.
• Scheme A34 illustrates methods for the interconversion of phosphonate diesters, monoesters and acids.
• the protected product A1.2 is then reacted, in the presence of a strong base, with a bromoalkyl phosphonate A1.3, to give the alkylation product A1.4.
• the reaction is effected in a polar organic solvent such as dimethylformamide, dimethylacetamide, diglyme, tetrahydrofuran and the like, in the presence of a base such as sodium hydride, an alkali metal alkoxide, lithium hexamethyldisilazide, and the like, at from ambient temperature to about 100°, to yield the alkylated product A1.4.
• phenolic hydroxyl group is then deprotected to afford the phenol A1.5.
• Methods for the deprotection of hydroxyl groups are described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. lOff.
• 7-(4-fluoro-benzyl)-9-hydroxy-5H-l,7-diaza-anthracene-6,8- dione A1.6 is reacted with one molar equivalent of chlorotriisopropylsilane and imidazole in dimethylformamide at ambient temperature, as described in Tet.
• Scheme A2 illustrates the preparation of phosphonate esters of structure Iaa in which the phosphonate group is attached by means of an aryl of heteroaryl ring.
• the reaction is performed between approximately equimolar amounts of the reactants in an ethereal solvent such as diethyl ether, tefrahydrofuran and the like, at from -40 °C to ambient temperature, to give the alcohol product A2.4.
• This material is then reacted with a dialkyl phosphite A2.5 and a palladium catalyst, to give the phosphonate A2.6.
• the preparation of arylphosphonates by means of a coupling reaction between aryl bromides and dialkyl phosphites is described in J. Med. Chem., 35, 1371, 1992.
• the reaction is conducted in a hydrocarbon solvent such as benzene, toluene or xylene, at about 100°, in the presence of a palladium (0) catalyst such as tetrakis(tri ⁇ henylphosphine)palladium(0), and a tertiary base such as triethylamine or diisopropylethylamine.
• a palladium (0) catalyst such as tetrakis(tri ⁇ henylphosphine)palladium(0)
• a tertiary base such as triethylamine or diisopropylethylamine.
• the benzylic hydroxyl substituent in the product A2.7 is removed by means of a reductive procedure, as shown on Scheme 4.
• Benzylic hydroxyl groups are removed by catalytic hydrogenation, for example by the use of 10% palladium on carbon in the presence of hydrogen or a hydrogen donor, or by means of chemical reduction, for example employing triethylsilane and boron trifluoride etherate.
• catalytic hydrogenation for example by the use of 10% palladium on carbon in the presence of hydrogen or a hydrogen donor, or by means of chemical reduction, for example employing triethylsilane and boron trifluoride etherate.
• 7-(3,5-dichloro-benzyl)-5,9-bis-triisopro ⁇ ylsilanyloxy- pyrrolo[3,4-g]quinoline-6,8-dione A2.9 prepared by silylation of the corresponding diol, which is reacted with one molar equivalent of 4-bromophenyl magnesium bromide A2.10 in ether at 0° to produce the alcohol A2.ll.
• Scheme A3 illustrates the preparation of phosphonate esters of structure Iaa in which the phosphonate group is attached by means of an alkylene chain.
• a 6-aminoquinoline ester A3.1 prepared, for example, from the corresponding carboxylic acid by means of a Curtius rearrangement, (Advanced Organic Chemistry, Part B, by F.A. Carey and R. J. Sundberg, Plenum, 2001, p.646) is reacted, under reductive animation conditions, with a dialkyl formylalkyl phosphonate A3.2.
• the preparation of amines by means of reductive animation procedures is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, p 421, and in Advanced Organic Chemistry, Part B, by F.A. Carey and R. J. Sundberg, Plenum, 2001, p 269.
• the amine component and the aldehyde or ketone component are reacted together in the presence of a reducing agent such as, for example, borane, sodium cyanoborohydride, sodium triacetoxyborohydride or diisobutylaluminum hydride, optionally in the presence of a Lewis acid, such as titanium tetraisopropoxide, as described in J. Org. Chem., 55, 2552, 1990.
• a Lewis acid such as titanium tetraisopropoxide, as described in J. Org. Chem., 55, 2552, 1990.
• the product A3.3 is then converted, by reaction with the amine ArBNH 2 A3.4, or a derivative thereof, into the amide A3.5.
• the conversion of esters into amides is described in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 987.
• the reactants are combined in the presence of a base such as sodium methoxide under azeotropic conditions, or of a dialkyl aluminum or trialkyl tin derivative of the amine.
• a base such as sodium methoxide under azeotropic conditions
• a dialkyl aluminum or trialkyl tin derivative of the amine is described in J. Med. Chem. Chim. Ther., 34, 1999, 1995, and Syn. Comm., 25, 1401, 1995.
• the reaction is conducted in an inert solvent such as dichloromethane or toluene.
• the amide product A3.5 is then cyclized by reaction with a reagent such as phosgene or a functional equivalent thereof, such as triphosgene or a dialkyl carbonate, or a reagent such as diiodomethane, to give the cyclized product A3.6 in which D is CO or CH 2 .
• a reagent such as phosgene or a functional equivalent thereof, such as triphosgene or a dialkyl carbonate, or a reagent such as diiodomethane, to give the cyclized product A3.6 in which D is CO or CH 2 .
• the reaction is conducted in an aprotic solvent such as tefrahydrofuran, in the presence of an inorganic or organic base such as potassium carbonate or diisopropylethylamine.
• the amine A3.7 prepared by means of a Curtius rearrangement of the corresponding MOM-protected carboxylic acid, is reacted in isopropanol solution with a dialkyl formylmethyl phosphonate A3.8, prepared as described in Zh. Obschei. Khim., 1987, 57, 2793, sodium cyanoborohydride and acetic acid, to give the reductive amination product A3.9.
• the product is then reacted with an excess of 3,4-dichlorobenzylamine and sodium methoxide in toluene at reflux, to yield the amide A3.10.
• Scheme A4 illustrates the preparation of phosphonate esters of structure Iaa in which the phosphonate group is attached by means of an alkylene chain or an aryl, heteroaryl or aralkyl group and a heteroatom O, S or N.
• a tricyclic aminal A4.1 is reacted in the presence of an acid catalyst with a hydroxy, mercapto or amino-substituted dialkyl phosphonate A4.2 in which X is O, S, NH or N-alkyl, and R is alkyl, alkenyl, aryl, heteroaryl or aralkyl.
• the reaction is effected at ambient temperature in an inert solvent such as dichloromethane, in the presence of an acid such as p-toluenesulfonic acid or trifluoroacetic acid and an excess of the reagent A4.2.
• an acid such as p-toluenesulfonic acid or trifluoroacetic acid and an excess of the reagent A4.2.
• the hydroxyl group is then deprotected to yield the phenolic product A4.4.
• 6-hydroxy-5-methoxy-7-(4-trifluoromethyl-benzyl)-9- triisopropylsilanyloxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one A4.9 prepared analogously to the 4-fluoro analog A4.5, is reacted, under the same conditions, with a dialkyl 3-mercaptophenyl phosphonate A4.10 to give the thioether A4.ll which upon deprotection affords the phenol A4.12.
• the phosphonate reagent A4.10 is obtained by palladium (0) catalyzed coupling reaction, as described in Scheme A2, between a dialkyl phosphite and an S-protected derivative of 3-bromothiophenol, for example the S-trityl derivative, followed by removal of the sulfur protecting group. Protection and deprotection of thiols is described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 277.
• Scheme A5 illustrates the preparation of phosphonate esters of structure Iaa in which the phosphonate group is attached to a 7-membered ring by means of an alkylene or arylmetliylene chain.
• a suitable protected quinoline acid ester A5.1 is subjected to a Curtius rearrangement, as described in Scheme A3 to yield the amine A5.2.
• the carboxylic acid is reacted with the amine in the presence of an activating agent, such as, for example, dicyclohexylcarbodiimide or diisopropylcarbodiimide, optionally in the presence of, for example, hydroxybenztriazole, N-hydroxysuccinimide or N- hydroxypyridone, in a non-protic solvent such as, for example, pyridine, DMF or dichloromethane, to afford the amide.
• an activating agent such as, for example, dicyclohexylcarbodiimide or diisopropylcarbodiimide
• a non-protic solvent such as, for example, pyridine, DMF or dichloromethane
• the carboxylic acid may first be converted into an activated derivative such as the acid chloride, anhydride, mixed anhydride, imidazolide and the like, and then reacted with the amine, in the presence of an organic base such as, for example, pyridine, to afford the amide.
• an organic base such as, for example, pyridine
• the conversion of a carboxylic acid into the corresponding acid chloride can be effected by treatment of the carboxylic acid with a reagent such as, for example, thionyl chloride or oxalyl chloride in an inert organic solvent such as dichloromethane, optionally in the presence of a catalytic amount of dimethylformamide.
• the product A5.6 is then cyclized, for example by heating at reflux temperature in toluene in the presence of a basic catalyst such as sodium methoxide, or by reaction with trimethylaluminum, as described in Syn. Comm., 25, 1401, 1995, to afford after deprotection of the hydroxyl groups, the diazepindione derivative A5.7.
• a basic catalyst such as sodium methoxide
• trimethylaluminum as described in Syn. Comm., 25, 1401, 1995
• the MOM-protected amine A3.7 is reductively aminated by reaction with a dialkyl phosphonoacetaldehyde A5.8 (Aurora) and sodium triacetoxyborohydride, to produce the amine A5.9.
• Schemes A6 - A16 illustrate methods for the preparation of the phosphonate esters of general structure Ibb.
• Scheme A6 depicts two methods for the preparation of phosphonate esters in which the phosphonate group is linked by means of a saturated or unsaturated alkylene chain, or alkylene chains incorporating carbocyclic, aryl or heteroaryl rings, hi this procedure, a mono-protected phenol A6.1, for example, is reacted either with a bromo-substituted alkyl phosphonate A6.2, in which the group R is alkylene, cycloalkyl, alkenyl, aralkyl, heterarylalkyl and the like, or with an analogous hydroxyl-substituted dialkyl phosphonate A6.3.
• the reaction between the phenol and the bromo compound A6.2 is conducted in a polar organic solvent such as dimethylformamide, 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 ether product A6.4.
• the ether compounds A6.4 are obtained by means of a Mitsonobu reaction between the phenol A6.1 and the hydroxy compound A6.3.
• the preparation of aromatic ethers by means of the Mitsonobu reaction is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 448, and in Advanced Organic Chemistry, Part B, by F.A. Carey and R. J. Sundberg, Plenum, 2001, p.
• Scheme A7 illustrates the preparation of phosphonate esters of structure Ibb in which the phosphonate is linked by means of an aryl or a heteroaryl group.
• a mono-protected phenol A7.1 (Formula I) is converted into the triflate A7.2 by reaction, in an inert solvent such as dichloromethane, with trifluoromethanesulfonyl chloride or anhydride, or with trimethylsilyl triflate and triethylsilane, in each case in the presence of a tertiary base such as triethylamine.
• the triflate is then coupled with a bromo-substituted arylboronate A7.3, in which the group Ar 1 is an aromatic or heteroaromatic moiety, to afford the coupled product A7.4.
• trifluoro-methanesulfonic acid 9-benzhydryloxy-7-(4-fluoro- benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester A7.8 (Example 46) is reacted in dioxan solution at 70° with one molar equivalent of 3-bromophenyl boronic acid A7.9 (Maybridge), sodium bicarbonate and a catalytic amount of tri-(o- tolyl)phosphine, to produce the coupled compound A7.10.
• Scheme A8 illustrates the preparation of phosphonate esters of structure Ibb in which the phosphonate group is linked by means of an oxygen, sulfur or nitrogen and an aliphatic or aromatic moiety.
• a monoprotected phenol A8.1 (Formula I) is converted into the corresponding triflate A8.2, as described above (Scheme A7).
• the product is then subjected to a nucleophilic displacement reaction with various alcohols, thiols or amines A8.3, in which the group R is an acyclic or cyclic saturated or unsaturated alkylene, or aryl, aralkyl or heteroaryl moiety, to afford after deprotection the ether, thioether or amine products A8.4.
• the displacement reaction is performed in an inert solvent such as dichloroethane or dioxan, at from ambient temperature to about 80°, in the presence of a tertiary organic base such as N-methyl morpholine and the like.
• trifluoro-methanesulfonic acid 9-benzhydryloxy-7-(4-fluoro- benzyl)-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester A8.5 (Example 56) is reacted in dioxan at 50° with one molar equivalent of a dialkyl methylaminomethyl phosphonate A8.6 and diisopropylethylamine, to give the amine product A8.7. Deprotection then affords the phenol A8.8.
• Scheme A9 depicts the preparation of phosphonate esters of structure Ibb in which the phosphonate group is attached by means of an methylamino group and a carbon link R, in which the group R is an acyclic or cyclic saturated or unsaturated alkylene, or aryl, aralkyl or heteroaryl moiety.
• the compounds are obtained by means of a reductive alkylation reaction, as described above (Scheme A3) between the aldehyde A9.1, prepared by the method shown in Example 49, and a dialkyl aminoalkyl or aryl phosphonate A9.2.
• the amination product A9.3 is then deprotected to give the phenol A9.3.
• Scheme A10 depicts the preparation of phosphonate esters of structure Ibb in which the phosphonate group is attached by means of an amide linkage and a carbon link R, in which the group R is an acyclic or cyclic saturated or unsaturated alkylene, or aryl, aralkyl or heteroaryl moiety.
• the aldehyde AlO.l prepared, for example, as shown in Example 49 is oxidized to the corresponding carboxylic acid A10.2.
• the conversion of an aldehyde to the corresponding carboxylic acid is described in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 838.
• the reaction is effected by the use of various oxidizing agents such as, for example, potassium permanganate, ruthenium tetroxide, silver oxide or sodium chlorite.
• oxidizing agents such as, for example, potassium permanganate, ruthenium tetroxide, silver oxide or sodium chlorite.
• the carboxylic acid is then coupled, as described in Scheme A5, with an amine A10.3 to afford the amide, which upon deprotection gives the phenolic amide A10.4.
• 9-benzhydryloxy-7-(4-chloro-benzyl)-6,8-dioxo-7,8-dihydro- 6H-pyrrolo[3,4-g]quinoline-5-carbaldehyde A10.5 prepared using the methods described in Example 49, is treated with silver oxide in acetonitrile, as described in Tet. Lett., 5685, 1968, to produce the corresponding carboxylic acid 9- benzhydryloxy-7-(4-chloro-benzyl)-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4- g]quinoline-5-carboxylic acid A10.6.
• benzyl alcohols can be transformed into the bromo compounds by reaction with bromine and triphenyl phosphite, or by reaction with trimethylsilyl chloride and lithium bromide, or with carbon tetrabromide and triphenylphosphine, as described in J. Am. Chem. Soc, 92, 2139, 1970.
• the resultant bromomethyl compound A11.2 is treated with a trialkyl phosphite A11.3 in an Arbuzov reaction.
• the preparation of phosphonates by means of the Arbuzov reaction is described in Handb. Organophosphorus Chem., 1992, 115-72.
• the bromo compound is heated with an excess of the phosphite at from about 80°-130° to produce the phosphonate product, which upon deprotection affords the phenolic phosphonate All.4.
• 9-benzhydryloxy-5-hydroxymethyl-7-(4-methoxy-benzyl)-6,7- dihydro-pyrrolo[3,4-g]quinolin-8-one A11.5 prepared by the method shown in Example 50, is reacted in dichloromethane with one molar equivalent of carbon tetrabromide and triphenylphosphine to produce 9-benzhydryloxy-5-bromomethyl-7- (4-methoxy-benzyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one A11.6.
• the product is then heated at 120° with an excess of a trialkyl phosphite A11.3.
• Scheme A12 depicts the preparation of phosphonate esters of structure Ibb in which the phosphonate group is attached by means of a methyleneoxy and a variable alkyl moiety.
• a protected hydroxymethyl-substituted tricyclic phenol A12.1 prepared according to the procedure of Example 50, is alkylated with a dialkyl bromo-substituted phosphonate A12.2, in which the group R is an acyclic or cyclic saturated or unsaturated alkylene, or aryl, aralkyl or heteroaryl moiety.
• the alcohol is reacted with one molar equivalent of the bromo compound in a polar aprotic organic solvent such as dimethylacetamide, dioxan and the like, in the presence of a strong base such as sodium hydride, lithium hexamethyldisilazide, or potassium tert.-butoxide.
• a strong base such as sodium hydride, lithium hexamethyldisilazide, or potassium tert.-butoxide.
• the thus-obtained ether A12.3 is then deprotected to give the phenol A12.4.
• a vinyl-substituted OH-protected phenol A13.1 prepared by the method shown in Example 59, is coupled in a palladium-catalyzed Heck reaction with a dibromo-substituted aromatic or heteroaromatic reagent A13.2, in which the group Ar 1 is an aromatic or heteroaromatic ring.
• the coupling of aryl halides with olefins by means of the Heck reaction is described, for example, in Advanced Organic Chemistry, by F. A. Carey and R. J. Sundberg, Plenum, 2001, p. 503ff and in Ace. Chem. Res., 12, 146, 1979.
• the aryl bromide and the olef ⁇ n are coupled in a polar solvent such as dimethylformamide or dioxan, in the presence of a palladium(O) catalyst such as tetrakis(triphenylphosphine)palladium(0) or a ⁇ alladium(II) catalyst such as palladium(II) acetate, and optionally in the presence of a base such as triethylamine or potassium carbonate.
• a polar solvent such as dimethylformamide or dioxan
• a palladium(O) catalyst such as tetrakis(triphenylphosphine)palladium(0) or a ⁇ alladium(II) catalyst such as palladium(II) acetate
• a base such as triethylamine or potassium carbonate.
• the coupled product A13.3 is then reacted, as described in Scheme A7, with a dialkyl phosphite A13.4 and a palladium catalyst, to afford, after deprotection of the phenolic hydroxyl, the ethenyl phosphonate ester A13.5. Catalytic or chemical reduction of the product then yields the saturated analog A13.6.
• the reduction reaction is effected chemically, for example by the use of diimide or diborane, as described in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 5, or catalytically, for example by the use of a palladium on carbon catalyst in the presence of hydrogen or a hydrogen donor.
• a mono-protected phenol A14.1 (Example 6) is alkylated with a methyl bromoalkyl carboxylate A14.2.
• the alkylation reaction is conducted under similar conditions to those described in Scheme A6, to afford the ester ether A14.3.
• Hydrolysis of the ester group then gives the carboxylic acid A14.4.
• Hydrolysis methods for converting esters into carboxylic acids are described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p 981.
• the methods include the use of enzymes such as pig liver esterase, and chemical methods such as the use of alkali metal hydroxides in aqueous organic solvent mixtures, for example lithium hydroxide in an aqueous organic solvent.
• the resultant carboxylic acid is then coupled, as described in Scheme A10, with a dialkyl amino-substituted phosphonate A14.5, in which the group R is an acyclic or cyclic saturated or unsaturated alkylene, or aryl, aralkyl or heteroaryl moiety, to produce the amide A14.6.
• Deprotection then yields the phenol A14.7.

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