Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/36—Oxygen or sulfur atoms
  • C07D207/40—2,5-Pyrrolidine-diones
  • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
• • 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
• • 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
  • 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
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
  • C07D498/20—Spiro-condensed systems

Definitions

• the invention relates generally to compounds with antiviral activity and more specifically with HIN-integrase inhibitory properties.
• HIN infection and related diseases are a major public health problem worldwide.
• a virally encoded integrase protein mediates specific incorporation and integration of viral D ⁇ A into the host genome. Integration is necessary for viral replication. Accordingly, inhibition of HUN integrase is an important therapeutic pursuit for treatment of HIN infection of the related diseases.
• Human immunodeficiency virus type 1 (HIN-1) encodes three enzymes which are required for viral replication: reverse transcriptase, protease, and integrase.
• integrase The function of integrase is to catalyze integration of proviral D ⁇ A, resulting from the reverse transcription of viral R ⁇ A, into the host genome, by a stepwise fashion of endonucleolytic processing of proviral D ⁇ A within a cytoplasmic preintegration complex (termed 3'-processing or "3'-P") with specific D ⁇ A sequences at the end of the HIN-1 long terminal repeat (LTR) regions, followed by
• HIN integrase inhibitors which block integration in extracellular assays and exhibit good antiviral effects against HIN-infected cells
• etal WO 02/30426 Anthony, etal WO 02/30930; Anthony, etal WO 02/30931; WO 02/055079; Zhuang, etal WO 02/36734; US 6395743; US 6245806; US 6271402; Fujishita, etal WO 00/039086; Uenaka etal WO 00/075122; Selnick, etal WO 99/62513; Young, etal WO 99/62520; Payne, etal WO 01/00578; Jing, etal Biochemistry (2002) 41:5397-5403; Pais, etal Jour.
• HIN 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 ( ⁇ air, N. "HEN integrase as a target for antiviral chemotherapy” Reviews in Medical Virology (2002) 12(3): 179-193).
• agents currently administered parenterally to a patient 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 anti-viral drugs) that can be administered.
• a drug e.g., cytotoxic agents and other anti-cancer or anti-viral drugs
• 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.
• 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 which allow accumulation or retention of biologically active agents inside
• the present invention provides compositions and methods for inhibition of HIN integrase.
• the invention includes tricyclic compounds represented by the following structure:
• the compounds of the invention have binding functionality, e.g. nitrogen, hydroxyl, and X-carbonyl, in a pre-organized configuration which may confer optimized inhibitory properties against HIV integrase.
• a 1 and A 2 are each and independently a moiety forming a five, six, or seven membered ring.
• Q is N, substituted nitrogen (NR), CH, or substituted carbon.
• L is a bond or a linker connecting a ring atom of Ar to N.
• X is O, S, NH, or substituted nitrogen (NR).
• Ar is a carbocycle, aryl or heteroaryl group.
• R is a substituent including H, alkyl, aryl, heteroaryl and substituted forms thereof, as well as polyethyleneoxy, phosphonate, phosphate, or a prodrug moiety.
• the 5 and 6 positions are represented in the structure above by Y and Z respectively.
• the chemical bond between Y and Z may be a single bond, a double bond, or a bond with enolic, tautomeric character, depending on the substituent on Z, i.e. R 1 or X.
• the Y and Z substructure is represented wherein:
• the compounds of the invention may include prodrug moieties covalently attached at any site.
• the prodrug moiety may be a phosphonate group.
• the invention also includes a pharmaceutical composition
• a pharmaceutical composition comprising a therapeutic ally effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.
• the invention also includes a pharmaceutical composition
• a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of an AIDS treatment agent selected from an HIV inhibitor agent, an anti-infective agent, and an immunomodulator.
• the HIV inhibitor agent may include an HIV-protease inhibitor, a nucleoside reverse transcriptase inhibitor, or a non-nucleoside reverse transcriptase inhibitor.
• the invention also includes methods of preventing the proliferation of HIV virus, treating AIDS, delaying the onset of AIDS or ARC symptoms, and generally inhibiting HIV integrase.
• the methods comprise administering to a mammal infected with HIV (HIV positive) an amount of a compound of the invention, in a therapeutically effective dose or administration to inhibit the growth of HTV infected cells of the mammal.
• the activity of HIV integrase is inhibited by a method comprising the step of treating a sample suspected of containing HIV virus with a compound or composition of the invention.
• the invention also includes processes and novel intermediates disclosed herein which are useful for preparing compounds of the invention. Some of the compounds of the invention are useful to prepare other compounds of the invention.
• This invention also includes methods of increasing cellular accumulation, bioavailability, or retention of drug compounds, thus improving their therapeutic and diagnostic value, by administering a phosphonate prodrug form of a compound of the invention.
• Another aspect of the invention provides a method for inhibiting the activity of HIV integrase comprising the step of contacting a sample suspected of containing HIV virus with the composition embodiments of the invention.
• novel methods for the synthesis, analysis, separation, isolation, crystallization, purification, characterization, resolution of isomers including enantiomers and diastereomers, and testing of the compounds of this invention are provided.
• 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, and nitrogen substituents. These substituents may be part of a prodrug moiety.
• phosphonate and “phosphonate group” include molecules with phosphonic acid, phosphonic monoester, phosphonic diester, phosphonamidate, phosphondiamidate, 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, deesterified, 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.
• 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.
• a "prodrug” is thus a covalently modified analog of a therapeutically-active compound.
• the acyloxyalkyl ester was first used as a prodrug strategy for carboxylic acids and then applied to phosphates and phosphonates by Farquhar etal (1983) 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 etal (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 ⁇ rt/-oor/7 ⁇ r ⁇ -position 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.
• proesters contain an ethylthio group in which the thiol group is either esterified with an acyl group or combined with another thiol group to form a disulfide. Deesterifi cation or reduction of the disulfide generates the free thio intermediate which subsequently breaks down to the phosphoric acid and episulfide (Puech etal (1993) Antiviral Res., 22: 155-174; Benzaria etal (1996) J. Med. Chem. 39: 4958). Cyclic phosphonate esters have also been described as prodrugs of phosphorus-containing compounds (Erion etal, US Patent No. 6312662).
• 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. Greene (John Wiley & Sons, Inc., New York, 1991, which is incorporated herein by reference.
• 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 metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX + (wherein X is C ⁇ -C 4 alkyl).
• Physiologically acceptable salts of an hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p- toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
• organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids
• organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p- toluenesulfonic acids
• Physiologically acceptable salts of a compound of an hydroxy group include the anion of said compound in combination with a suitable cation such as Na + and NX + (wherein X is independently selected from H or a C 1 -C 4 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 C ⁇ -Ci8 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 Q-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-pentyl (n- pentyl, -CH2CH2CH2CH3), 2-pentyl (n-
• alkylene and alkyldiyl each refer to a saturated, branched or straight chain or cyclic hydrocarbon radical of 1-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane.
• Typical alkylene radicals include, but are not limited to: methylene (-CH 2 -) 1,2-ethyl (-CH 2 CH 2 -), 1,3-propyl (-CH 2 CH 2 CH 2 -), 1,4-butyl (-CH 2 CH 2 CH 2 CH 2 -), and the like.
• alkenylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene, i.e. double carbon-carbon bond moiety.
• 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, i.e. triple carbon-carbon bond moiety.
• Typical alkynylene radicals include, but are not limited to: acetylene (-C ⁇ C-), propargyl (-CH 2 C ⁇ C-), and 4-pentynyl (-CH 2 CH 2 CH 2 C ⁇ CH-).
• Aryl means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
• Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl, and the like.
• Heteroaryl means a monovalent aromatic radical of one or more carbon atoms and one or more atoms selected from N, O, S, or P, derived by the removal of one hydrogen atom from a single atom of a parent aromatic ring system.
• Heteroaryl groups 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).
• Heteroaryl bicycles have 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S) arranged as a bicyclo [4,5], [5,5], [5,6], or [6,6] system; or 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2 hetero atoms selected from N and S) arranged as a bicyclo [5,6] or [6,6] system.
• the heteroaryl group may be bonded to the drug scaffold through a carbon, nitrogen, sulfur, phosphorus or other atom by a stable covalent bond.
• Heteroaryl groups include, for example: pyridyl, dihydropyridyl isomers, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, and pyrrolyl.
• Arylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 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-l-yl, naphthobenzyl, 2-naphthophenylethan-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
• the arylalkyl group is 1 to 6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms.
• Substituted substituents such as "substituted alkyl”, “substituted aryl”, “substituted heteroaryl” and “substituted arylalkyl” mean alkyl, aryl, and arylalkyl respectively, in which one or more hydrogen atoms are each independently replaced with a substituent.
• Heterocycle means a saturated, unsaturated or aromatic ring system including at least one N, O, S, or P. Heterocycle thus include heteroaryl groups. Heterocycle as used herein includes by way of example and not limitation these heterocycles described in Paquette, Leo A. "Principles of Modern Heterocyclic Chemistry” (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic
• 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, tetra
• carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.
• carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3- pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5- pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
• nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, lH-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ -carboline.
• nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
• Carbocycle means a saturated, unsaturated or aromatic ring system 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-l-enyl, l-cyclopent-2-enyl, 1- cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, phenyl, spiryl and naphthyl.
• Carbocycle thus includes some aryl groups.
• 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.
• Linkers include L interposed between Ar and the nitrogen of the tricyclic compounds of the invention.
• the structures herein may refer to linkers as "link” or “L”.
• Linkers may also be interposed between a phosphorus-containing A 3 group and the R 1 , R 2 , R 3 , or R 4 position of the compounds of the invention.
• Linkers include, but are not limited to moieties such as O, S, NR, N-OR, C !
• Linkers also include 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.
• 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.
• stereoisomers are identical except that they are mirror images of one another.
• a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
• a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
• racemic mixture and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
• Novel tricyclic compounds with inhibitory activity against HTV integrase are described, including any pharmaceutically acceptable salts thereof.
• the compounds are pre-organized with constrained conformations that include an active form for inhibition of nuclear integration of reverse-transcribed HIV DNA.
• the invention includes tricyclic compounds represented by the following structure:
• a 1 and A 2 are each and independently any moiety forming a five, six, or seven membered ring.
• Q is N, + NR, or CR 4 .
• 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 (-NH2).
• X may be O, S, NH, NR, N-OR, N-NR 2 , N-CR 2 OR or N-CR 2 NR 2 .
• 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 ⁇ 2 carbocycle, C -C 12 substituted carbocycle, C 6 -C 2 o aryl, C 6 -C 2 o substituted aryl, C 2 -C 2 o heteroaryl, or C 2 -C 2 o substituted heteroaryl.
• C 6 -C 2 o 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:
• R 1 , R 2 , R 3 , and R 4 , and substituents of Ar may independently be H, F, Cl, Br, I, OH, amino (-NH 2 ), ammonium (-NH 3 + ), alkylamino, dialkylamino, trialkylammonium, -Cs alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, -Cs alkylsulfonate, C]-C 8 alkylamino, 4-dialkylaminopyridinium, C]-C 8 alkylhydroxyl, C]-C 8 alkylthiol, alkylsulfone (-SO 2 R), arylsulfone (-SO 2 Ar), arylsulfoxide (-SOAr), arylthio (-SAr), sulfonamide (-SO 2 NR 2 ), alkylsulfoxide (-S
• R 1 , R 2 , R 3 , and R 4 include the structures:
• R may be independently selected from H, Q- alkyl, Q- substituted alkyl, C-.-C 20 aryl, C 6 -C 20 substituted aryl, C2 ⁇ C 2 o heteroaryl, C2-C20 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.
• a 1 and A 2 in the compounds of the invention include but are not limited to the following structures.
• Various embodiments of A 1 form 5- membered rings in the exemplary 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:
• One aspect of the invention includes compounds with a cyclic imide group, e.g. 5,9- dihydroxy-pyrrolo[3,4-g]quinoline-6,8-dione (Myers, etal U.S. Patent No. 5,252,560;
• 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-naphthyri dines as novel HIN-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:
• R 1 , R 2 , R 3 , or R 4 may independently comprise a phosphonate group or phosphonate prodrug moiety.
• a tricyclic integrase inhibitor compound of the invention may include one or more phosphonate group or phosphonate prodrug moiety.
• R 1 , R 2 , R 3 , or R 4 may comprise the structure A , where A is:
• Y 1 is independently O, S, ⁇ (R X ), N(O)(R x ), N(OR x ), N(O)(OR x ), or N(N(R X ) 2 .
• M2 is 0, 1 or 2.
• M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.
• M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.
• R y is independently H, C ⁇ -C 6 alkyl, C ⁇ -C 6 substituted alkyl, aryl, substituted aryl, or a protecting group. 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, C ⁇ -C 6 alkyl, Ci-C ⁇ substituted alkyl, C 6 -C 2 o aryl, C 6 -C 2 o substituted aryl, or a protecting group, or the formula:
• Mia, Mlc, and Mid are independently 0 or 1.
• M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
• a linker may be interposed between positions R 1 , R 2 , R 3 or R 4 and substituent A 3 .
• Linkers may also be repeating units of alkyloxy (e.g.
• linker may comprise propargyl, urea, or alkoxy groups in the exemplary structures:
• Embodiments of A include where M2 is 0, such as:
• Y 1 is oxygen
• Y 2b is independently oxygen (O) or nitrogen (N(R X )) such as:
• W 5 is a carbocycle such as phenyl or substituted phenyl
• Y 2c is independently O, N(R y ) or S.
• R 1 may be H and n may be 1.
• W 5 also includes, but is not limited to, aryl and heteroaryl groups such as:
• Y 2b is O or N(R X ); M12d is 1, 2, 3, A, 5, 6, 7 or 8; R 1 is H or Q- alkyl; and the phenyl carbocycle is substituted with 0 to 3 R groups where R is Cj-C ⁇ alkyl or substituted alkyl.
• a 3 include phenyl phosphonamidate amino acid, e.g. alanate esters and phenyl phosphonate-lactate esters:
• Embodiments of R X include esters, carbamates, carbonates, thioesters, amides, thioamides, and urea groups:
• the compounds of the invention may also include one or more prodrug moieties located as a covalently-attached substituent at any location or site, e.g. Ar, L, X, A, R 1 , R 2 , R 3 , R 4 , or the 9-hydroxyl.
• One substituent which may be modified as a prodrug moiety is a phosphonate, phosphate, phosphinate or other phosphorus functionality (Oliyai etal
• Prodrug moieties of phosphorus functionality serve to mask anionic charges and decrease polarity.
• the phosphonate prodrug moiety may be an ester (Oliyai, etal Intl. Jour. Pharmaceutics (1999) 179:257-265), e.g. POC and POM (pivaloyloxymethyl, Yuan, etal Pharmaceutical Res.
• 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 prodrug moieties 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).
• 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.
• R 5 is -CR2CO2R 7 where R 6 and R 7 are independently H or C]-C 8 alkyl.
• 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:
• R is the amino acid side-chain, e.g. H, CH 3 , CH(CH 3 ) 2 , etc.
• 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 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.
• 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.
• 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, or it is 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 pre-organized binding modes which optimize the binding affinity of other, known HIN integrase inhibitors.
• the inhibitor may attain a low energy conformation (also called bound conformation) in order to interact within an active site.
• a low energy conformation also called bound conformation
• ligands of molecules with multiple rotational bonds exist in many potential conformational states, most of which are not able to bind to the active site. The greater the number of possible ligand conformations typically results in a greater decrease in efficiency of the entropy contribution to the free energy of binding, and will result in less favorable binding affinities.
• One aspect of designing pre-organized binding features in an integrase inhibitor compound is incorporating conformational constraints that reduces the total number of conformational states and places the inhibitor into a correct binding conformation (Lam , P.Y.S. et al. J. Med. Chem, (1996) 39:3514-3525; Chen, J.M. et al. Biochemistry (1998) 37:17735-17744; Chen, J.M. et al. Jour. Amer. Chem. Soc. (2000) 122:9648-9654; Chen, J.M. et al US 6187907; Chen, et al Bio. Org. Med. Chem. Letters (2002) 12:1195-1198). Knowledge of one or more preferred, i.e.
• 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.
• the compounds of this invention optionally comprise salts of the compounds herein, especially pharmaceutically acceptable non-toxic salts containing, for example, Na , Li , K > Ca and Mg .
• Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid.
• the compounds of the invention may bear multiple positive or negative charges. The net charge of the compounds of the invention may be either positive or negative. Any associated counter ions are typically dictated by the synthesis and/or isolation methods by which the compounds are obtained.
• Typical counter ions include, but are not limited to ammonium, sodium, potassium, lithium, halides, acetate, trifluoroacetate, etc., and mixtures thereof. It will be understood that the identity of any associated counter ion is not a critical feature of the invention, and that the invention encompasses the compounds in association with any type of counter ion. Moreover, as the compounds can exists in a variety of different forms, the invention is intended to encompass not only forms of the compounds that are in association with counter ions (e.g., dry salts), but also forms that are not in association with counter ions (e.g., aqueous or organic solutions).
• counter ions e.g., dry salts
• counter ions e.g., aqueous or organic solutions
• Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention.
• metal salts which are prepared in this way are salts containing Li + , Na + , and K + .
• a less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
• salts may be formed from acid addition of certain organic and inorganic acids, e.g., HC1, HBr, H2SO4, H3PO4 or organic sulfonic acids, to basic centers, typically amines, or to acidic groups.
• the compositions herein comprise compounds of the invention in their unionized, 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 included within the scope of this invention.
• the amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
• the compounds of the invention can also exist as tautomeric, resonance isomers in certain cases.
• the structures shown herein exemplify only one tautomeric or resonance form of the compounds.
• hydrazine, oxime, hydrazone groups may be shown in either the syn or anti configurations. The corresponding alternative configuration is contemplated as well. All possible tautomeric and resonance forms are within the scope of the invention.
• One enantiomer of a compound of the invention can be separated substantially free of its opposing enantiomer by 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).
• Separation of diastereomers formed from the racemic mixture can be accomplished 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 enantiomers. Alternatively, enantiomers can be separated directly under chiral conditions, method (3).
• 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 may be reacted with one enantiomer of a chiral compound to form a diastereomeric pair
• a diastereomeric pair Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds. John Wiley & Sons, Inc., p. 322).
• Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched xanthene.
• a method of determining optical purity involves making chiral esters, such as a menthyl ester or Mosher ester, ⁇ -methoxy- ⁇ -(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers.
• Stable diastereomers can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO 96/15111).
• a racemic mixture of two asymmetric enantiomers can be separated by chromatography using a chiral stationary phase (Chiral Liquid Chromatography (1989) W. J. Lough, Ed. Chapman and Hall, New York; Okamoto, (1990) "Optical resolution of dihydropyridine enantiomers by High-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase", J. of Chromatogr. 513:375-378).
• Enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.
• 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.
• 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. Zn, or hydride reagents, e.g. NaBHj, to form a lactam.
• dissolving metal reducing agents e.g. Zn
• hydride reagents e.g. NaBHj
• Exemplary regioselective conversions shown in Scheme 3 include:
• 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 7. 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 where MOM is methoxymethyl and
• 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 HI compounds may be prepared by the following methods in Schemes 11-
• the acid 1 (WO02/30930, p.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.
• COR 3 are generated by reaction with acid chlorides or activated carboxylic acids.
• 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 7 -X) or an alcohol under Mitsunobu condition, an ether 18 is formed.
• 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
• 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 PtO 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 structures of the intermediate phosphonate esters Iaa to IVcc are shown in Chart 1, in which the substituents R 1 , R 2 , R 3 , R 4 , A 1 and A 2 are as previously defined.
• the groups A la and A 2a are the same as the groups A 1 and A 2 , except that a substituent link- P(O)(OR 5 ) 2 is appended.
• the substituent R 5 is hydrogen, alkyl, alkenyl, aralkyl, or aryl. Subsequent chemical modifications to the compounds Iaa to Vcc, as described herein, permit the synthesis of the final compounds of this invention.
• the intermediate compounds Iaa to IVcc incorporate a phosphonate moiety (R 5 O) 2 P(O) 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.
• Schemes Al - A5 illustrate methods for the preparation of the intermediate phosphonate esters Iaa.
• the phenolic hydroxyl substituent present in the tricyclic compound Al.l is protected to afford the derivative A1.2.
• the protection of hydroxyl groups is described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 10.
• hydroxyl substituents are protected as trialkylsilyloxy, methoxymethyl, benzyl or tert-butyl ethers.
• Trialkylsilyl groups are introduced by the reaction of the phenol with a chlorotrialkylsilane and a base such as imidazole, for example as described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. lOff.
• 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°C, to yield the alkylated product A1.4.
• a base such as sodium hydride, an alkali metal alkoxide, lithium hexamethyldisilazide, and the like
• the product is then reacted in dimethylformamide solution at about 60°C with one molar equivalent of a dialkyl 2-bromoethyl phosphonate A1.8 (Aldrich) and lithium hexamethyldisilazide, to yield the alkylated product A1.9.
• the silyl protecting group is then removed by reaction with tetrabutylammonium fluoride in tetrahydrofuran, as described in J. Org. Chem., 51, 4941, 1986, to give the phenolic product A1.10.
• 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, tetrahydrofuran and the like, at from -40°C to ambient temperature, to give the carbinol 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°C, in the presence of a palladium (0) catalyst such as tetrakis(triphenylphosphine)palladium(0), and a tertiary base such as triethylamine or diisopropylethylamine.
• a palladium (0) catalyst such as tetrakis(triphenylphosphine)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-triisopropylsilanyloxy-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°C to produce the carbinol A2.ll.
• 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 amination conditions, with a dialkyl formylalkyl phosphonate A3.2.
• the preparation of amines by means of reductive amination procedures is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, NCH, 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 tetrahydrofuran, 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 arylmethylene 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 product is then reductively aminated, as described in Scheme A3, with a phosphonate aldehyde A5.3, in which the group R is an alkyl group or an aryl group, to give the amine product A5.4.
• This material is then coupled with the glycine derivative A5.5 to yield the amide A5.6.
• 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, ⁇ -hydroxysuccinimide or ⁇ -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.
• the product is then coupled in dimethylformamide solution, in the presence of dicyclohexyl carbodiimide, with (4-fluoro-benzylamino)-acetic acid A5.10, to give the amide A5.ll.
• This material is converted, by reaction with trimethylaluminum in dichloromethane, as described above, into the diazepin derivative A5.12. Removal of the MOM protecting groups, as previously described, then affords the phenolic product A5.13.
• 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.
• 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, NCH, 1989, p. 448, and in Advanced Organic Chemistry, Part B, by F.A. Carey and R. J. Sundberg, Plenum, 2001, p.
• 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°C 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. This material is then reacted, as described in
• Scheme A8 illustrates the preparation of phosphonate esters of structure Ibb in which the phosphonate group is linked by means of a 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 carbinols, 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°C, 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°C with one molar equivalent of a dialkyl methylaminomethyl phosphonate
• Scheme A9 depicts the preparation of phosphonate esters of structure Ibb in which the phosphonate group is attached by means of a 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 A10.1 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, NCH, 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.
• 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.
• benzyl alcohols can be transformed into the bromo compounds by reaction with bromine and tri phenyl 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°C-130°C to produce the phosphonate product, which upon deprotection affords the phenolic phosphonate A11.4.
• 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°C with an excess of a trialkyl phosphite A11.3.
• 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 carbinol 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.
• 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 olefin 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 palladium(II) catalyst such as palladium(II) acetate, and optionally in the presence of a base such as triethylamine or potassium carbonate.
• a palladium(O) catalyst such as tetrakis(triphenylphosphine)palladium(0) or a palladium(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 e
• 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, NCH, 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.
• Scheme A14 depicts the preparation of phosphonate esters of structure Ibb in which the phosphonate group is attached by means of an alkoxy chain incorporating an amide linkage.
• 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, NCH, 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.
• 5-hydroxy-9-methoxymethoxy-7-(4-methyl-benzyl)-pyrrolo[3,4- g]quinoline-6,8-dione A14.8 prepared, for example, by the method shown in Example 6 is reacted in dimethylformamide solution with methyl bromoacetate A14.9 and cesium carbonate, to give the ether A14.10.
• the ester group is then hydrolyzed by reaction with one molar equivalent of lithium hydroxide in aqueous glyme, to produce the carboxylic acid A14.ll.
• the carboxylic acid is then coupled in dimethylformamide solution in the presence of diisopropyl carbodiimide with a dialkyl 2-aminoethyl phosphonate A14.12, (J. Org. Chem., 2000, 65, 676) to form the amide A14.13.
• Deprotection for example by the use of 50% aqueous acetic acid containing a catalytic amount of sulfuric acid, as described in J. Am. Chem. Soc, 55, 3040, 1933, then affords the phenol A14.14.
• Scheme A15 depicts the preparation of phosphonate esters of structure Ibb in which the phosphonate group is attached by means of an alkylene chain incorporating an amide linkage.
• the malonic ester derivative of a protected phenol A15.1 prepared, for example, by the methods shown in Example 86, is hydrolyzed and decarboxylated to give the corresponding acetic acid derivative A15.2.
• Hydrolysis and decarboxylation of malonic esters is described, for example, in Advanced Organic Chemistry, Part B, by F.A. Carey and R. J. Sundberg, Plenum, 2001, p. 15.
• the ester hydrolysis is effected under conventional basic conditions, and decarboxylation occurs after acidification either spontaneously or under mild heating.
• the resultant acetic acid derivative is then coupled, as described previously, with a dialkyl amino-substituted phosphonate A15.3, to give the amide product which upon deprotection affords the phenol A15.4.
• the carboxylic acid is then coupled in acetonitrile solution in the presence of a water-soluble carbodiimide with a dialkyl 4-aminophenyl phosphonate A15.7 (Epsilon) to yield after deprotection the phenolic amide A15.8.
• a water-soluble carbodiimide with a dialkyl 4-aminophenyl phosphonate A15.7 (Epsilon) to yield after deprotection the phenolic amide A15.8.
• Scheme A16 depicts the preparation of phosphonate esters of structure Ibb in which the phosphonate group is attached by means of an alkoxy chain and the nucleus incorporates a benzazepin moiety.
• a quinoline monoester A16.1 is decarboxylated to afford the ester A16.2.
• Decarboxylation of carboxylic acids is described in Advanced Organic Chemistry, Part B, by F.A. Carey and R. J. Sundberg, Plenum, 2001, p. 676 and in Advanced Organic Chemistry, By J. Marsh, McGraw Hill, 1968, p. 435.
• the carboxylic acid is decarboxylated thermally in the presence of copper powder and quinoline, or by conversion to an ester with N-hydroxyphthalimide or N-hydroxythiopyridine, followed by photolysis in the presence of a hydrogen donor.
• the decarboxylated product A16.2 is then converted into the allyl ether A16.3 by reaction with allyl bromide in a polar solvent such as dimethylformamide in the presence of a base such h as triethylamine or potassium carbonate.
• the allyl ester is then subjected to a thermal Claisen rearrangement to afford the allyl-substituted phenol A16.4.
• the olefin is reacted with diborane or a substituted borane such as 9-BBN or catechyl borane, and the resulting borane is oxidized, for example with hydrogen peroxide, oxygen, sodium peroxycarbonate or a tertiary amine oxide.
• the resultant carbinol A16.6 is then converted into the substituted amine A16.7. The conversion is effected in two stages.
• the carbinol is converted into a leaving group such as mesylate, tosylate or bromide by reaction with, for example, methanesulfonyl chloride, p-toluenesulfonyl chloride or triphenylphosphine/carbon tetrabromide.
• the activated intermediate is reacted in a polar solvent such as N-methylpyrrolidinone or acetonitrile with the amine ArBNH 2 to give the product A16.7.
• the aminoester is then cyclized to yield the azepin derivative A16.8.
• the cyclization reaction is performed under similar conditions to those described above (Scheme A5).
• the aminoester is heated in xylene at reflux temperature in the presence of a catalytic amount of sodium isopropoxide.
• the doubly protected azepin derivative A16.8 is then selectively deprotected to give the phenol A16.9.
• the procedure for the selective deprotection is dependent on the nature of the protecting groups. For example, if the phenol A16.1 is protected as the benzhydryl derivative, the phenol A16.4 is protected as, for example, the TIPS derivative.
• Deprotection of the azepin A16.8 is then effected by treatment with tetrabutylammonium fluoride in tetrahydrofuran.
• the phenol A16.9 is then reacted with a dialkyl hydroxy-substituted phosphonate A16.10, in which the group R is an alkylene or alkenyl chain, optionally incorporating an aryl or heteroaryl group.
• the reaction is performed under the conditions of the Mitsonobu reaction, as described in Scheme A6.
• the resultant ether is then deprotected to afford the phenol A16.ll.
• 8-benzhydryloxy-7-methyl-quinolin-5-ol A16.12 prepared as described above from the corresponding carboxyester is converted, via allylation, rearrangement and hydroboration/oxidation, as described above, into 3-(8-benzhydryloxy-7- methyl-5-triisopropylsilanyloxy-quinolin-6-yl)-propan-l-ol A16.13.
• Cyclization of the product for example by reaction with trimethylaluminum, employing the conditions described above, affords ll-benzhydryloxy-9-(3-chloro-4-fluoro-benzyl)-5- triisopropylsilanyloxy-6,7,8,9-tetrahydro-l,9-diaza-cyclohepta[b]naphthalen-10-one A16.16.
• the compound is deprotected by reaction with tetrabutylammonium fluoride, to produce 1 l-benzhydryloxy-9-(3-chloro-4-fluoro-benzyl)-5-hydroxy-6,7,8,9-tetrahydro-l ,9- diaza-cyclohepta[b]naphthalen-10-one A16.17.
• the product is then reacted with a dialkyl hydroxyethyl phosphonate A16.18, diethyl azodicarboxylate and triphenylphosphine in tetrahydrofuran to give after deprotection the phenolic ether A16.19.
• Scheme A17 illustrates methods for the preparation of phosphonate esters of structure Ice in which the phosphonate group is attached by means of a one-carbon link, or by saturated or unsaturated multicarbon chains optionally incorporating a heteroatom.
• a 4-methyl-substituted quinoline A17.3 is prepared by means of a Doebner- von Miller condensation between an enone A17.2 and a substituted aniline A17.1.
• the preparation of quinolines by means of the Doebner-von Miller reaction is described in Heterocyclic Chemistry, by T. L. Gilchrist, Longman, 1992, p. 158.
• the reaction is performed by heating equimolar amounts of the reactants in an inert solvent such as dimethylacetamide.
• the bromohydroxyquinoline A17.3 is then transformed, by means of reaction sequence such as that illustrated in Scheme 8 into the protected tricyclic compound A17.4. Benzylic bromination of the latter compound, for example by reaction with N- bromosuccinimide or N-bromoacetamide in an inert solvent such as ethyl acetate at ca.
• the bromomethyl derivative A17.5 is reacted, using the conditions described in Scheme A12, with a dialkyl hydroxy, mercapto or amino-substituted phosphonate A17.6, in which the group R is an acyclic or cyclic saturated or unsaturated alkylene, or aryl, aralkyl or heteroaryl moiety, to give after deprotection the ether, thioether or amino product A17.7.
• the methyl-substituted tricyclic compound A17.4 is condensed, under basic conditions, with a dialkyl formyl -substituted phosphonate A17.9.
• the reaction is conducted between equimolar amounts of the reactants in a polar solvent such as dioxan or dimethylformamide, in the presence of a strong base such as sodium hydride or lithium tetramethyl piperidide.
• a polar solvent such as dioxan or dimethylformamide
• a strong base such as sodium hydride or lithium tetramethyl piperidide.
• benzoic acid 7-cyclopent-3-enylmethyl-4-methyl-8-oxo-7,8-dihydro- 6H-pyrrolo[3,4-g]quinolin-9-yl ester A17.12 is reacted with N-bromosuccinimide in refluxing ethyl acetate to afford benzoic acid 4-bromomethyl-7-cyclopent-3-enylmethyl-8- oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-9-yl ester A17.13.
• This compound is heated to 120°C with an excess of a trialkyl phosphite to give after deprotection the phenolic phosphonate ester A17.14.
• Schemes A18 and A19 illustrate the preparation of phosphonate esters of structure Ilaa.
• Scheme A18 depicts the preparation of phosphonate esters of structure Ilaa in which the phosphonate group is attached by means of an alkoxy, alkylthio or alkylamino group.
• an alkoxyethene triester A18.1 JP 61289089
• a 3-aminopyridine A18.2 are reacted together, as described in JP 61289089 and GB 1509695, to produce the pyridylamino triester A18.3.
• the reaction is performed using equimolar amounts of the reactants at a temperature of about 150°C.
• the product is then cyclized to afford the 1,5- naphthyridine derivative A18.4.
• the reaction is performed in a high-boiling solvent such as diphenyl ether at a temperature of about 250°C.
• the diester is then converted to the anhydride, and the latter compound is transformed by reaction with the amine ArBNH 2 , and protection of the phenolic hydroxyl group, into the cyclic imide A18.5.
• This material is then reduced, as described in Example 20, for example by the use of sodium borohydride, to afford the hydroxylactam A18.6.
• the triester A18.1 is reacted with 3-aminopyridine A18.9 to afford the pyridylamino triester A18.10.
• the product is heated in diphenyl ether at 250°C to form the 1,5-naphthyridine A18.ll.
• the latter compound is then transformed, as described above, into 7-(4-fluoro-benzyl)-6-hydroxy-9-triisopropylsilanyloxy-6,7-dihydro-pyrrolo[3,4- b][l,5]naphthyridin-8-one A18.12.
• the hydroxylactam is then reacted in dichloromethane solution with a dialkyl 4-hydroxybutyl phosphonate A18.13 (J. Med. Chem., 1996, 39, 949) and trifluoroacetic acid, by a similar reaction as Example 23, to generate the phosphonate product A18.14.
• Scheme A19 depicts the preparation of phosphonate esters of structure Ilaa in which the phosphonate group is attached by means of variable carbon linkage, and the nucleus is a 1,3,5,9-tetraazaanthracene.
• the 1,5-naphthyridine A18.4 is converted into the phenol-protected analog A19.1.
• the product is then subjected to a selective partial hydrolysis, for example by reaction with one molar equivalent of a base such as lithium hydroxide in an aqueous organic solvent mixture, to produce the carboxy ester A19.2.
• the product is then subjected to a Curtius rearrangement, as described in Scheme A3, to afford the amine A19.3.
• the product is then reductively aminated, as described in Scheme A3, by reaction with a dialkyl formyl-substituted phosphonate A19.4, in which the group R is an acyclic or cyclic saturated or unsaturated alkylene, or aryl, aralkyl or heteroaryl moiety, to give the amine A19.5.
• the ester group is then transformed, as described previously (Scheme A3), into the amide A19.6, by reaction with the amine ArBNH 2 .
• the product is then cyclized to afford, after deprotection of the phenolic hydroxyl, the tricyclic product, A19.7, in which A is, for example, CO or CH 2 , by reaction respectively with phosgene or an equivalent thereof, or with diiodomethane or a similar reagent.
• Scheme A20 illustrates the preparation of phosphonate esters of structure lice, in which the phosphonate group is attached by means of a one-carbon or multicarbon link, or by means of a heteroatom and a variable carbon linkage.
• the triester A18.1 is reacted, as described in Scheme A 18, with a 3-amino-4-methylpyridine A20.1 to give the substituted pyridine product A20.2.
• the latter compound is then transformed, as described previously, into the methyl-substituted tricyclic compound A20.3.
• This compound is then subjected to benzylic bromination, for example by reaction with N- bromosuccinimide, to form the bromomethyl product A20.4.
• the methyl compound A20.3 is subjected, as described in Scheme A17, to a base-catalyzed condensation reaction with a dialkyl formyl-substituted phosphonate A20.8, in which R is an acyclic or cyclic saturated or unsaturated alkylene, or aryl, aralkyl or heteroaryl moiety, to generate after deprotection of the phenolic hydroxyl, the unsaturated product A20.9.
• the double bond is then reduced, as described in Scheme A17, to afford the saturated analog A20.10.
• condensation between the triester A18.1 and 3-amino-4- methylpyridine A20.ll gives the pyridine product A20.12.
• the compound is then transformed, as described above, into 7-[l-(4-fluoro-phenyl)-l-methyl-ethyl]-4-methyl-9- triisopropylsilanyloxy-pyrrolo[3,4-b][l,5]naphthyridine-6,8-dione A20.13.
• the latter compound is then reacted with a dialkyl formylethyl phosphonate A20.14 (Zh. Obschei.
• Scheme A21 illustrates methods for the preparation of phosphonates of structure Illaa in which the phosphonate group is attached by means of a heteroatom and a variable carbon link.
• a carbomethoxymethyl derivative of the amine ArBNH 2 , A21.1 is coupled with the 1,6-naphthyridine carboxylic acid A21.2, prepared as described in WO 0230930, using the methods described previously, to prepare the amide A21.3.
• Bromination for example using N-bromosuccinimide, yields the 5-bromo derivative A21.4.
• the latter compound is reacted with a dialkyl hydroxy, mercapto, or amino-substituted phosphonate A21.9, in which the group R is an acyclic or cyclic saturated or unsaturated alkylene, or aryl, aralkyl or heteroaryl moiety, in the presence of an acid such as trifluoroacetic acid, as described in Scheme A4, to yield the ether, thioether or amine product A21.10. Deprotection then gives the phenol A21.ll.
• (4-fluoro-benzylamino)-acetic acid methyl ester A21.12 is coupled in tetrahydrofuran solution with one molar equivalent of 8-hydroxy-[l,6]naphthyridine-7- carboxylic acid A21.13, (WO 0230930) in the presence of diisopropyl carbodiimide, to form [(4-fluoro-benzyl)-(8-hydroxy-[l,6]naphthyridine-7-carbonyl)-amino]-acetic acid methyl ester A21.14.
• Schemes A22 - A24 illustrate methods for the preparation of phosphonate esters of structure Illbb.
• Scheme A22 illustrates methods for the preparation of phosphonates of structure Illbb in which the phosphonate group is attached by means of a variable carbon linkage.
• the naphthyridine carboxylic acid A21.2 is coupled, as described previously, with the amine derivative A22.1, following a procedure similar to Example 28, to form the amide A22.2.
• Displacement of the bromine by reaction with a dialkyl amino-substituted phosphonate A22.5, in which the group R is an acyclic or cyclic saturated or unsaturated alkylene, or aryl, aralkyl or heteroaryl moiety, affords the amine A22.6.
• the reaction is performed in a polar organic solvent such as dimethylformamide in the presence of a base such as potassium carbonate.
• Deprotection of the alcoholic hydroxyl group affords the carbinol A22.7, which upon activation and cyclization, for example as described in Scheme 11 then gives the tricyclic product A22.8, which upon deprotection affords the phenol A22.9.
• acetic acid 5-bromo-7-[(4-fluoro-benzyl)-propyl-carbamoyl]- [l,6]naphthyridin-8-yl ester A22.10 is reacted with one molar equivalent of a dialkyl aminopropyl phosphonate A22.ll, (Acros) to yield the amine A22.12.
• a dialkyl aminopropyl phosphonate A22.ll (Acros)
• Deprotection and activation of the alcoholic hydroxyl group for example by conversion to the mesylate, followed by cyclization under basic conditions, and deprotection of the phenolic hydroxyl group, then affords the enol A22.13.
• Scheme A23 illustrates methods for the preparation of phosphonates of structure Illbb in which the phosphonate group is attached by means of a nitrogen and a variable carbon linkage.
• a tricyclic imine A23.1 (Scheme 12) is reacted with a dialkyl bromoalkyl phosphonate A23.2 to give the alkylated product A23.3.
• the reaction is performed in a polar organic solvent such as acetonitrile or dimethylsulfoxide, in the presence of a base such as diisopropylethylamine or 2,6-lutidine.
• the imine A23.1 is converted into a hydrazone A23.5 by reaction with a dialkyl formyl-substituted phosphonate A23.4 in which the group R is an acyclic or cyclic saturated or unsaturated alkylene, or aryl, aralkyl or heteroaryl moiety.
• the hydrazone is prepared by the reaction of equimolar amounts of the reactants in a polar organic solvent such as ethanol, optionally in the presence of a catalytic amount of an acid such as acetic acid.
• the hydrazone product A23.5 is reduced, for example by treatment with sodium borohydride, to give the dihydro derivative A23.6.
• acetic acid 7-(4-fluoro-benzyl)-10-hydrazono-8-oxo-6,7,8,10- tetrahydro-5H-l,7,10a-triaza-anthracen-9-yl ester A23.7 (Scheme 12) is reacted at 60°C in dimethylformamide solution containing potassium carbonate with one molar equivalent of a dialkyl 2-bromoethyl phosphonate A23.8 (Aldrich), to prepare the alkylated product which upon deprotection yields the enol A23.9.
• the hydrazone A23.7 is reacted in ethanol solution at ambient temperature with one molar equivalent of a dialkyl 2-formylphenyl phosphonate A23.10 (Epsilon) to give the hydrazone product A23.ll.
• Scheme A24 illustrates methods for the preparation of phosphonates of structure Illbb in which the phosphonate group is attached by means of a hydroxyimino linkage.
• a tricyclic oxime A24.1 (Scheme 14) is reacted with a dialkyl bromo- substituted phosphonate A24.2 in which the group R is an acyclic or cyclic saturated or unsaturated alkylene, or aryl, aralkyl or heteroaryl moiety.
• the reaction is performed in a polar organic solvent in the presence of a base such as sodium hydride or lithium hexamethyldisilazide. Deprotection then yields the enol A24.4.
• acetic acid 7-(4-fluoro-benzyl)-10-hydroxyimino-8-oxo-6,7,8,10- tetrahydro-5H-l,7,10a-triaza-anthracen-9-yl ester A24.5 (Scheme 14) is reacted in dimethylformamide solution with one molar equivalent of sodium hydride, followed by the addition of one molar equivalent of a dialkyl 4-(bromomethyl)phenyl phosphonate A24.6 (Tet., 1998, 54, 9341) to afford after deprotection the iminoether A24.7.
• Scheme A25 illustrates methods for the preparation of phosphonates of structure IIIcc.
• This compound is then transformed, as described in Scheme 12, into the imine A25.3. Protection of the hydroxyl and amino groups then furnishes the derivative A25.4.
• the product is then condensed under basic conditions, as described in Scheme A20, with a dialkyl formyl-substituted phosphonate A25.5, in which the group R is an acyclic or cyclic saturated or unsaturated alkylene, or aryl, aralkyl or heteroaryl moiety.
• the product A25.6 is optionally reduced, as described in Scheme A20, to give the saturated analog A25.17.
• the methyl-substituted tricycle A25.4 is brominated, for example by reaction with N-bromosuccinimide, to give the bromomethyl product A25.7.
• the compound is then subjected to a Arbuzov reaction with a trialkyl phosphite, to yield after deprotection the phosphonate A25.8.
• the bromomethyl compound A25.7 is reacted, as described previously (Scheme A20) with a dialkyl hydroxy, mercapto or amino-substituted phosphonate A25.18, in which the group R is an acyclic or cyclic saturated or unsaturated alkylene, or aryl,
• acetic acid 7-[2-(4-fluoro-phenyl)-ethyl]-10-hydrazono-4-methyl-8- oxo-6,7,8,10-tetrahydro-5H-l,7,10a-triaza-anthracen-9-yl ester A25.10 prepared according to the procedures described above, is converted into the phthalimido derivative by reaction with one molar equivalent of phthalic anhydride, as described in J. Org. Chem., 43, 2320, 1978. The protected product is then reacted with N-bromosuccinimide in hexachloroethane to give the bromomethyl derivative A25.12.
• This compound is heated to 120°C with an excess of a trialkyl phosphite to produce the phosphonate A25.13.
• Deprotection for example by reaction with ethanolic hydrazine, as described in J. Org. Chem., 43, 2320, 1978, then affords the phosphonate A25.14.
• the phthalimi do-protected methyl-substituted tricycle A25.ll is reacted in dioxan solution with a dialkyl formylphosphonate A25.12 (Tet., 1994, 50, 10277) and lithium tetramethyl piperidide, to yield, after removal of the protecting groups, the unsaturated phosphonate A25.13. Reduction of the double bond then gives the saturated analog A25.14.
• the bromomethyl derivative A25.12 is reacted in acetonitrile solution with one molar equivalent of a dialkyl 2-mercaptopropyl phosphonate A25.15(WO 007101) and diisopropylethylamine, to produce after deprotection the phosphonate A25.16.
• a dialkyl 2-mercaptopropyl phosphonate A25.15(WO 007101) and diisopropylethylamine to produce after deprotection the phosphonate A25.16.
• Scheme A29 illustrates the preparation of compounds in which phosphonate is attached by means of an ether, thioether of amine linkage.
• a substituted succinimide A29.1 is condensed, as described in Scheme 1 and Example 2, with a heterocyclic diester A29.2 to afford after protection the tricyclic product A29.3.
• Scheme A30 illustrates the preparation of phosphonate esters of structure IVaa in which the phosphonate is attached by means of a variable carbon linkage.
• dimethyl succinate A30.1 is condensed, under base catalysis, for example using the procedure described on Scheme 1 and Example 2 with a heterocyclic diester A30.2, to yield after protection of the phenolic hydroxyl groups, the diester A30.3.
• Partial basic hydrolysis for example by reaction with one molar equivalent of lithium hydroxide in aqueous dimethoxyethane, then affords the monoacid A30.4.
• the carboxylic acid is homologated to produce the corresponding acetic acid A30.5.
• the transformation is effected by means of the Arndt Eistert reaction. In this procedure, which is described in Advanced Organic Chemistry, Part B, by F.A. Carey and R. J. Sundberg, Plenum, 2001, p. 641, and in
• the carboxylic acid is coupled, in the presence of dicyclohexyl carbodiimide, with cyclohexylmethylamine A30.15 to give the amide A30.16.
• Cyclization is effected as described above to prepare 6- cyclohexylmethyl-4,9-bis-methoxymethoxy-l-methyl-l,5,6,8-tetrahydro-l,3,6-triaza- cyclopenta[b]naphthalen-7-one A30.17.
• Schemes A31 and A32 illustrates the preparation of phosphonate esters of structure IVbb.
• Scheme A31 illustrates the preparation of phosphonate esters in which the phosphonate is attached by means of a variable carbon linkage linkage. In this procedure, the doubly protected phenol A29.3 is selectively deprotected to give the phenol A31.1.
• the product is converted into the triflate A31.2 and this material is reacted with a dialkyl hydroxy, mercapto or amino-substituted phosphonate A31.3, in which the group R is an acyclic or cyclic saturated or unsaturated alkylene, or aryl, aralkyl or heteroaryl moiety, in the presence of a base, as described in Scheme A8, to afford the displacement product A31.4, which upon deprotection gives the phenol A31.5.
• 2-naphthylmethylsuccinimide A31.6 is reacted with dimethyl pyrimidine 4,5-dicarboxylate A31.7 (Chem.
• Scheme A32 depicts the preparation of phosphonate esters of structure Vbb in which the phosphonate is attached by means of an ether linkage.
• dimethyl succinate A32.1 is condensed under basic conditions, with a heterocyclic dicarboxylic ester A32.2 to afford the bicyclic product A32.3.
• the anhydride is then reacted, as described with the substituted hydrazine A32.5, to yield the tricyclic product A32.6.
• condensation between dimethyl succinate and dimethyl 1,3,4-triazine- 5,6-dicarboxylate A32.10 affords after selective silylation, following a procedure similar to Example 12, 6-(4-fluoro-benzyl)-9-hydroxy-10- triisopropylsilanyloxy-6,7-dihydro-l,2,4,6,7-pentaaza-anthracene-5,8-dione A32.ll.
• the group R in Scheme A34 represents the substructure to which the substituent link-P(O)(OR 5 ) 2 is attached, either in the compounds Iaa - IVcc or in precursors thereto.
• the R group may be changed, using the procedures described below, either in the precursor compounds, or in the esters Iaa - IVcc.
• the methods employed for a given phosphonate transformation depend on the nature of the substituent R 5 .
• the preparation and hydrolysis of phosphonate esters is described in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p. 9ff.
• the conversion of a phosphonate diester A34.1 into the corresponding phosphonate monoester A34.2 can be accomplished by a number of methods.
• the ester A34.1 in which R 5 is an aralkyl group such as benzyl can be converted into the monoester compound A34.2 by reaction with a tertiary organic base such as diazabicyclooctane (DABCO) or quinuclidine, as described in J. Org. Chem., 1995, 60, 2946.
• DABCO diazabicyclooctane
• the reaction is performed in an inert hydrocarbon solvent such as toluene or xylene, at about 110°C.
• the conversion of the diester A34.1 in which R 5 is an aryl group such as phenyl, or an alkenyl group such as allyl, into the monoester A34.2 can be effected by treatment of the ester A34.1 with a base such as aqueous sodium hydroxide in acetonitrile or lithium hydroxide in aqueous tetrahydrofuran.
• Phosphonate diesters A34.1 in which one of the groups R 5 is aralkyl, such as benzyl, and the other is alkyl can be converted into the monoesters A34.2 in which R is alkyl by hydrogenation, for example using a palladium on carbon catalyst.
• Phosphonate diesters in which both of the groups R 5 are alkenyl, such as allyl can be converted into the monoester A34.2 in which R is alkenyl, by treatment with chlorotris(triphenylphosphine)rhodium (Wilkinson's catalyst) in aqueous ethanol at reflux, optionally in the presence of diazabicyclooctane, for example by using the procedure described in J. Org. Chem., 38, 3224, 1973 for the cleavage of allyl carboxylates.
• R is aralkyl such as benzyl
• the conversion of a phosphonate monoester A34.2 into a phosphonate diester A34.1 (Scheme A34, Reaction 4) in which the newly introduced R 5 group is alkyl, aralkyl, haloalkyl such as chloroethyl, or aralkyl can be effected by a number of reactions in which the substrate A34.2 is reacted with a hydroxy compound R 5 OH, in the presence of a coupling agent.
• Suitable coupling agents are those employed for the preparation of carboxylate esters, and include a carbodiimide such as dicyclohexylcarbodiimide, in which case the reaction is preferably conducted in a basic organic solvent such as pyridine, or (benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PYBOP, Sigma), in which case the reaction is performed in a polar solvent such as dimethylformamide, in the presence of a tertiary organic base such as diisopropylethylamine, or Aldrithiol-2 (Aldrich) in which case the reaction is conducted in a basic solvent such as pyridine, in the presence of a triaryl phosphine such as triphenylphosphine.
• a carbodiimide such as dicyclohexylcarbodiimide
• PYBOP benzotriazol-l-yloxy)tripyrrolidinophospho
• the substrate is reacted with the hydroxy compound R 5 OH, in the presence of diethyl azodicarboxylate and a triarylphosphine such as triphenyl phosphine.
• the phosphonate monoester A34.2 can be transformed into the phosphonate diester A34.1, in which the introduced R 5 group is alkenyl or aralkyl, by reaction of the monoester with the halide R 5 Br, in which R 5 is as alkenyl or aralkyl.
• the alkylation reaction is conducted in a polar organic solvent such as dimethylformamide or acetonitrile, in the presence of a base such as cesium carbonate.
• the phosphonate monoester can be transformed into the phosphonate diester in a two step procedure.
• the phosphonate monoester A34.2 is transformed into the chloro analog RP(O)(OR 5 )Cl by reaction with thionyl chloride or oxalyl chloride and the like, as described in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p.
• a phosphonic acid R-link-P(O)(OH) 2 can be transformed into a phosphonate monoester RP(O)(OR 5 )(OH) (Scheme A34, Reaction 5) by means of the methods described above of for the preparation of the phosphonate diester R-link-P(O)(OR 5 ) A34.1, except that only one molar proportion of the component R 5 OH or R 5 Br is employed.
• a phosphonic acid R-link-P(O)(OH) 2 A34.3 can be transformed into a phosphonate diester R-link-P(O)(OR 5 ) 2 A34.1 (Scheme A34, Reaction 6) by a coupling reaction with the hydroxy compound R 5 OH, in the presence of a coupling agent such as Aldrithiol-2 (Aldrich) and triphenylphosphine.
• the reaction is conducted in a basic solvent such as pyridine.
• phosphonic acids A34.3 can be transformed into phosphonic esters A34.1 in which R 5 is aryl, by means of a coupling reaction employing, for example, dicyclohexylcarbodiimide in pyridine at ca 70°C.
• phosphonic acids A34.3 can be transformed into phosphonic esters A34.1 in which R 5 is alkenyl, by means of an alkylation reaction.
• the phosphonic acid is reacted with the alkenyl bromide R 5 Br in a polar organic solvent such as acetonitrile solution at reflux temperature, the presence of a base such as cesium carbonate, to afford the phosphonic ester A34.1.
• the conversion of phosphonic acids into phosphoryl chlorides is accomplished by reaction with thionyl chloride, for example as described in J. Gen. Chem. USSR, 1983, 53, 480, Zh. Obschei Khim., 1958, 28, 1063, or J. Org. Chem., 1994, 59, 6144, or by reaction with oxalyl chloride, as described in J. Am. Chem. Soc, 1994, 116, 3251, or J. Org. Chem., 1994, 59, 6144, or by reaction with phosphorus pentachloride, as described in J. Org. Chem., 2001, 66, 329, or in J. Med. Chem., 1995, 38, 1372.
• the resultant phosphoryl chlorides are then reacted with amines or hydroxy compounds in the presence of a base to afford the amidate or ester products.
• Phosphonic acids are converted into activated imidazolyl derivatives by reaction with carbonyl diimidazole, as described in J. Chem. Soc, Chem. Comm., 1991, 312, or
• Activated sulfonyloxy derivatives are obtained by the reaction of phosphonic acids with trichloromethylsulfonyl chloride, as described in J. Med. Chem. 1995, 38, 4958, or with triisopropylbenzenesulfonyl chloride, as described in Tet. Lett., 1996, 7857, or Bioorg. Med. Chem. Lett., 1998, 8, 663.
• the activated sulfonyloxy derivatives are then reacted with amines or hydroxy compounds to afford amidates or esters.
• the phosphonic acid and the amine or hydroxy reactant are combined in the presence of a diimide coupling agent.
• a diimide coupling agent The preparation of phosphonic amidates and esters by means of coupling reactions in the presence of dicyclohexyl carbodiimide is described, for example, in J. Chem. Soc, Chem. Comm., 1991, 312, or J. Med. Chem., 1980, 23, 1299 or Coll. Czech. Chem. Comm., 1987, 52, 2792.
• the use of ethyl dimethylaminopropyl carbodiimide for activation and coupling of phosphonic acids is described in Tet. Lett., 2001, 42, 8841, or Nucleosides Nucleotides, 2000, 19, 1885.
• the agents include Aldrithiol-2, and PYBOP and BOP, as described in J. Org. Chem., 1995, 60, 5214, and J. Med. Chem., 1997, 40, 3842, mesitylene-2-sulfonyl-3-nitro-l,2,4-triazole (MSNT), as described in J. Med. Chem., 1996, 39, 4958, diphenylphosphoryl azide, as described in J. Org.
• Phosphonic acids are converted into amidates and esters by means of the Mitsonobu reaction, in which the phosphonic acid and the amine or hydroxy reactant are combined in the presence of a triaryl phosphine and a dialkyl azodicarboxylate.
• the procedure is described in Org. Lett., 2001, 3, 643, or J. Med. Chem., 1997, 40, 3842.
• Phosphonic esters are also obtained by the reaction between phosphonic acids and halo compounds, in the presence of a suitable base. The method is described, for example, in Anal. Chem., 1987, 59, 1056, or J. Chem. Soc. Perkin Trans., I, 1993, 19, 2303, or J. Med.
• Schemes 1 - 5 illustrate the conversion of phosphonate esters and phosphonic acids into carboalkoxy-substituted phosphorobisamidates (Scheme 1), phosphoroamidates (Scheme 2), phosphonate monoesters (Scheme 3) and phosphonate diesters, (Scheme 4)
• Scheme 1 illustrates various methods for the conversion of phosphonate diesters 1.1 into phosphorobisamidates 1.5.
• the diester 1.1 prepared as described previously, is hydrolyzed, either to the monoester 1.2 or to the phosphonic acid 1.6. The methods employed for these transformations are described above.
• the monoester 1.2 is converted into the monoamidate 1.3 by reaction with an aminoester 1.9, in which the group R 2 is H or alkyl, the group R 4 is an alkylene moiety such as, for example, CHCH 3 , CHPr 1 , CH(CH 2 Ph), CH 2 CH(CH 3 ) and the like, or a group present in natural or modified aminoacids, and the group R 5 is alkyl.
• the reactants are combined in the presence of a coupling agent such as a carbodiimide, for example dicyclohexyl carbodiimide, as described in J. Am. Chem. Soc, 1957, 79, 3575, optionally in the presence of an activating agent such as hydroxybenztriazole, to yield the amidate product 1.3.
• a coupling agent such as a carbodiimide, for example dicyclohexyl carbodiimide, as described in J. Am. Chem. Soc, 1957, 79, 3575
• an activating agent such as hydroxybenztriazole
• the amidate-forming reaction is also effected in the presence of coupling agents such as BOP, as described in J. Org. Chem., 1995, 60, 5214, Aldrithiol, PYBOP and similar coupling agents used for the preparation of amides and esters.
• the reactants 1.2 and 1.9 are transformed into the monoamidate 1.3 by means of a Mitsonobu
• the phosphonic acid 1.6 is converted into the bisamidate 1.5 by use of the coupling reactions described above.
• the reaction is performed in one step, in which case the nitrogen-related substituents present in the product 1.5 are the same, or in two steps, in which case the nitrogen-related substituents can be different.
• the phosphonic acid 1.6 is converted into the mono or bis- activated derivative 1.7, in which Lv is a leaving group such as chloro, imidazolyl, triisopropylbenzenesulfonyloxy etc.
• Lv is a leaving group such as chloro, imidazolyl, triisopropylbenzenesulfonyloxy etc.
• the phosphonic acid is activated by reaction with triisopropylbenzenesulfonyl chloride, as described in Nucleosides and Nucleotides, 2000, 10, 1885.
• the activated product is then reacted with the aminoester 1.9, in the presence of a base, to give the bisamidate 1.5.
• the reaction is performed in one step, in which case the nitrogen substituents present in the product 1.5 are the same, or in two steps, via the intermediate 1.11, in which case the nitrogen substituents can be different.
• N-methylalaninate 1.33a different aminoesters 1.9, the corresponding products 1.5 are obtained.
• the intermediate monoamidate 1.3 is also prepared from the monoester 1.2 by first converting the monoester into the activated derivative 1.8 in which Lv is a leaving group such as halo, imidazolyl etc, using the procedures described above.
• the product 1.8 is then reacted with an aminoester 1.9 in the presence of a base such as pyridine, to give an intermediate monoamidate product 1.3.
• the latter compound is then converted, by removal of the R 1 group and coupling of the product with the aminoester 1.9, as described above, into the bisamidate 1.5.
• An example of this procedure, in which the phosphonic acid is activated by conversion to the chloro derivative 1.26, is shown in Scheme 1, Example 4.
• the phosphonic monobenzyl ester 1.15 is reacted, in dichloromethane, with thionyl chloride, as described in Tet. Let., 1994, 35, 4097, to afford the phosphoryl chloride 1.26.
• the product is then reacted in acetonitrile solution at ambient temperature with one molar equivalent of ethyl 3-amino-2-methylpropionate 1.27 to yield the monoamidate product 1.28.
• the latter compound is hydrogenated in ethylacetate over a 5% palladium on carbon catalyst to produce the monoacid product 1.29.
• the product is subjected to a Mitsonobu coupling procedure, with equimolar amounts of butyl alaninate 1.30, triphenyl phosphine, diethylazodicarboxylate and triethylamine in tetrahydrofuran, to give the bisamidate product 1.31.
• the activated phosphonic acid derivative 1.7 is also converted into the bisamidate 1.5 via the diamino compound 1.10.
• the conversion of activated phosphonic acid derivatives such as phosphoryl chlorides into the corresponding amino analogs 1.10, by reaction with ammonia, is described in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976.
• the diamino compound 1.10 is then reacted at elevated temperature with a haloester 1.12, in a polar organic solvent such as dimethylformamide, in the presence of a base such as dimethylaminopyridine or potassium carbonate, to yield the bisamidate 1.5.
• Scheme 1 illustrates the preparation of bisamidates derived from tyrosine.
• the monoimidazolide 1.32 is reacted with propyl tyrosinate 1.40, as described in Example 5, to yield the monoamidate 1.41.
• the product is reacted with carbonyl diimidazole to give the imidazolide 1.42, and this material is reacted with a further molar equivalent of propyl tyrosinate to produce the bisamidate product 1.43.
• a phosphonate monoester 1.1 is converted, as described in Scheme 1, into the activated derivative 1.8.
• This compound is then reacted, as described above, with an aminoester 1.9, in the presence of a base, to afford the monoamidate product 2.1.
• the procedure is illustrated in Scheme 2, Example 1.
• a monophenyl phosphonate 2.7 is reacted with, for example, thionyl chloride, as described in J. Gen. Chem. USSR., 1983, 32, 367, to give the chloro product 2.8.
• the product is then reacted, as described in Scheme 1, with ethyl alaninate 2.9, to yield the amidate 2.10.
• the phosphonate monoester 1.1 is coupled, as described in Scheme 1, with an aminoester 1.9 to produce the amidate 2.1. If necessary, the R 1 substituent is then altered, by initial cleavage to afford the phosphonic acid 2.2. The procedures for this transformation depend on the nature of the R 1 group, and are described above.
• the phosphonic acid is then transformed into the ester amidate product 2.3, by reaction with the hydroxy compound R OH, in which the group R is aryl, heteroaryl, alkyl, cycloalkyl, haloalkyl etc, using the same coupling procedures (carbodiimide, Aldrithiol-2, PYBOP, Mitsonobu reaction etc) described in Scheme 1 for the coupling of amines and phosphonic acids.
• Example 3 the monoamidate 2.13 is coupled, in tetrahydrofuran solution at ambient temperature, with equimolar amounts of dicyclohexyl carbodiimide and 4-hydroxy-N-methylpiperidine 2.16, to produce the amidate ester product 2.17.
• ethyl alaninate product is coupled, in tetrahydrofuran solution at ambient temperature, with equimolar amounts of dicyclohexyl carbodiimide and 4-hydroxy-N-methylpiperidine 2.16, to produce the amidate ester product 2.17.
• the monoamidate products 2.3 are also prepared from the doubly activated phosphonate derivatives 1.7.
• the intermediate 1.7 is reacted with a limited amount of the aminoester 1.9 to give the mono-displacement product 1.11.
• the latter compound is then reacted with the hydroxy compound R 3 OH in a polar organic solvent such as dimethylformamide, in the presence of a base such as diisopropylethylamine, to yield the monoamidate ester 2.3.
• Scheme 3 illustrates methods for the preparation of carboalkoxy-substituted phosphonate diesters in which one of the ester groups incorporates a carboalkoxy substituent.
• a phosphonate monoester 1.1 is coupled, using one of the methods described above, with a hydroxyester 3.1, in which the groups R 4 and R 5 are as described in Scheme 1.
• equimolar amounts of the reactants are coupled in the presence of a carbodiimide such as dicyclohexyl carbodiimide, as described in Aust. J. Chem., 1963, 609, optionally in the presence of dimethylaminopyridine, as described in Tet., 1999, 55, 12997.
• the reaction is conducted in an inert solvent at ambient temperature. The procedure is illustrated in Scheme 3, Example 1.
• the conversion of a phosphonate monoester 1.1 into a mixed diester 3.2 is also accomplished by means of a Mitsonobu coupling reaction with the hydroxyester 3.1, as described in Org. Lett., 2001, 643.
• the reactants 1.1 and 3.1 are combined in a polar solvent such as tetrahydrofuran, in the presence of a triarylphosphine and a dialkyl azodicarboxylate, to give the mixed diester 3.2.
• the R 1 substituent is varied by cleavage, using the methods described previously, to afford the monoacid product 3.3.
• the product is then coupled, for example using methods described above, with the hydroxy compound R 3 OH, to give the diester product 3.4.
• the mixed diesters 3.2 are also obtained from the monoesters 1.1 via the intermediacy of the activated monoesters 3.5.
• the mixed phosphonate diesters are also obtained by an alternative route for incorporation of the R O group into intermediates 3.3 in which the hydroxyester moiety is already incorporated.
• the monoacid intermediate 3.3 is converted into the activated derivative 3.6 in which Lv is a leaving group such as chloro, imidazole, and the like, as previously described.
• the activated intermediate is then reacted with the hydroxy compound R 3 OH, in the presence of a base, to yield the mixed diester product 3.4.
• the phosphonate esters 3.4 are also obtained by means of alkylation reactions performed on the monoesters 1.1.
• the reaction between the monoacid 1.1 and the haloester 3.7 is performed in a polar solvent in the presence of a base such as diisopropylethylamine, as described in Anal. Chem., 1987, 59, 1056, or triethylamine, as described in J. Med. Chem., 1995, 38, 1372, or in a non-polar solvent such as benzene, in the presence of 18- crown-6, as described in Syn. Comm., 1995, 25, 3565.
• the method is illustrated in Scheme 3, Example 5.
• the monoacid 3.26 is reacted with ethyl 2-bromo-3-phenylpropionate 3.27 and diisopropylethylamine in dimethylformamide at 80°C to afford the mixed diester product 3.28.
• Scheme 4 illustrates methods for the preparation of phosphonate diesters in which both the ester substituents incorporate carboalkoxy groups.
• the compounds are prepared directly or indirectly from the phosphonic acids 1.6.
• the phosphonic acid is coupled with the hydroxyester 4.2, using the conditions described previously in Schemes 1 - 3, such as coupling reactions using dicyclohexyl carbodiimide or similar reagents, or under the conditions of the Mitsonobu reaction, to afford the diester product 4.3 in which the ester substituents are identical.
• the diesters 4.3 are obtained by alkylation of the phosphonic acid 1.6 with a haloester 4.1.
• the alkylation reaction is performed as described in Scheme 3 for the preparation of the esters 3.4.
• Example 4 depicts the displacement reaction between equimolar amounts of the phosphoryl dichloride 2.22 and ethyl 2-methyl-3-hydroxypropionate 4.11, to yield the monoester product 4.12.
• the reaction is conducted in acetonitrile at 70°C in the presence of diisopropylethylamine.
• the product 4.12 is then reacted, under the same conditions, with one molar equivalent of ethyl lactate 4.13, to give the diester product 4.14.
• Representative compounds of the invention were tested for biological activity by methods including anti-HIN assay, measuring inhibition of HIN-integrase strand transfer catalysis, and cytotoxicity. See: Wolfe, etal J. Virol. (1996) 70:1424-1432; Hazuda, etal Nucleic Acids Res. (1994) 22:1121-22; Hazuda, etal J. Virol. (1997) 71:7005-7011; Hazuda, etal Drug Design and Discovery (1997) 15: 17-24; and Hazuda, etal Science (2000) 287:646- 650.
• the antiviral activity of a compound of the invention can be determined using pharmacological models which are well known in the art.
• the compounds of the invention may be active via inhibition of HIN-integrase or other enzymes associated with HIN infection, ADDS, or ARC.
• the compounds of the invention may have significant activity against other viral diseases.
• the specific assays embodied in Examples x-y are not meant to limit the present invention to a specific mechanism of action.
• the compounds of the invention may be 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. Formulations optionally contain excipients such as those set forth in the "Handbook of Pharmaceutical Excipients" (1986) and include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
• Compounds of the invention and their physiologically acceptable salts may be administered by any route appropriate to the condition to be treated, suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural).
• suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural).
• the preferred route of administration may vary with for example the condition of the recipient.
• the formulations both for veterinary and for human use, of the present invention comprise at least one active ingredient, as above defined, together with one or more pharmaceutically 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 not deleterious to the recipient thereof.
• the formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration.
• 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.
• 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 solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
• the active ingredient may also be presented as a bolus, electuary or paste.
• a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, 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 compound moistened with an inert liquid diluent.
• the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
• For infections of the eye or other external tissues e.g.
• 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
• 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
• 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 dimethylsulfoxide 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.
• 14T 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. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and 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 present invention include TweenTM 60, SpanTM 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, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low.
• 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 can be used.
• 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 nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc), which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
• Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops include aqueous or oily solutions of the active ingredient.
• Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as pentamidine for treatment of pneumocystis pneumonia.
• 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 may be 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 injections, immediately prior to use.
• Extemporaneous injection solutions and suspensions may be 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 an 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 present invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor.
• Neterinary 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 adapted for oral administration in which discrete units comprising one or more compounds of the invention can be prepared according to conventional methods.
• Controlled release formulations may be employed for the treatment or prophylaxis of various microbial infections particularly human bacterial, human parasitic protozoan or human viral infections caused by microbial species including Plasmodium, Pneumocystis, herpes viruses (CMN, HSN 1, HSN 2, NZN, and the like), retroviruses, adenoviruses and the like.
• the controlled release formulations can be used to treat HIN infections and related conditions such as tuberculosis, malaria, pneumocystis pneumonia, CMN retinitis, AIDS, AIDS-related complex (ARC) and progressive generalized lymphadeopathy (PGL), and AIDS-related neurological conditions such as multiple sclerosis, and tropical spastic paraparesis.
• HTLN Human T-cell Lymphotropic virus
• IV Human T-cell Lymphotropic virus
• HIN-2 infections Other human retroviral infections that may be treated with the controlled release formulations according to the invention.
• the invention accordingly provides pharmaceutical formulations for use in the treatment or prophylaxis of the above-mentioned human or veterinary conditions and microbial infections.
• the compounds of the invention may be employed in combination with other therapeutic agents for the treatment or prophylaxis of the infections or conditions indicated above.
• further therapeutic agents include agents that are effective for the treatment or prophylaxis of viral, parasitic or bacterial infections or associated conditions or for treatment of tumors or related conditions include 3'-azido-3'-deoxythymidine (zidovudine, AZT), 2'-deoxy-3'-thiacytidine (3TC), 2',3'-dideoxy-2',3'-didehydroadenosine (D4A), 2',3'-dideoxy-2',3'-didehydrothymidine (D4T), carbovir (carbocyclic 2',3'-dideoxy- 2',3'-didehydroguanosine), 3'-azido-2',3'-dideoxyuridine, 5-fluorothymidine, (E)-5-(2- bromovinyl)-2'-deoxyuridine (
• Freshly ground potassium carbonate, K 2 CO 3 (31 g, 225 mmol) was added to dry acetone (200ml) in a 3-necked flask equipped with drying tube, condenser, and mechanical stirrer. Succinimide (7.43 g, 75mmol) and 4-fluorobenzylbromide (11.21 mL, 90 mmol) were added. The mixture was refluxed for 19 hours and filtered through Celite. Acetone was removed under vacuum, diluted with EtO Ac, washed with saturated aqueous sodium bicarbonate and also with brine, dried (MgSO ), filtered and concentrated to give crude.
• N-4-fluorobenzyl-succinimide 1 (8 g, 38.6 mmol) and 2,3-pyridine carboxylic acid dimethyl ester (7.9 g, 40.6 mmol) were dissolved in dry tetrahydrofuran (THF, 78 mL) and dry methanol (MeOH, 1.17 mL) in a 3-necked flask with mechanical stirrer and condenser. Sodium hydride (NaH, 60% in mineral oil, 3.4g, 85 mmol) was added slowly in four portions. The mixture was stirred until bubbling ceased, then refluxed for 24 hours. HC1 (30 mL 6 M) was then added to the mixture while in an ice bath, with stirring for 15 minutes.
• THF dry tetrahydrofuran
• MeOH dry methanol
• HC1 30 mL 6 M
• N,N-diisopropylethylamine (0.019 mL, 0.1 mmol) and trifluoromethanesulfonic anhydride (0.012 mL, 0.054 mmol) successively.
• the solution was stirred at the same temperature for 30 minutes and diluted with dichloromethane, washed with water and brine, dried (MgSO 4 ) and concentrated.
• Methoxymethyl ether 6 (0.02g, 0.052mmol) was dissolved in 2 mL dry dichloromethane at 0°C. An excess of a diazomethane solution in diethylether was added. After about 20 minutes, all starting 6 was consumed. The mixture was concentrated in vacuo to give crude 7-(4-fluoro-benzyl)-5-methoxy-9-methoxymethoxy-pyrrolo[3,4- g]quinoline-6,8-dione 8 (0.0223g, 0.0527mmol).
• Methoxymethyl ether 6 (0.0172g, 0.045mmol) was dissolved in 1.5 mL dry dimethylformamide (DMF). Ground K 2 CO 3 (0.0186g, 0.135 mmol) was added, followed by allyl bromide (0.0077 mL, 0.09 mmol). The mixture was stirred at room temperature overnight, then diluted with 100 mL of ethylacetate, washed with saturated NH-jCl solution, dried (MgSO 4 ), and concentrated to give crude 10. The crude product 10 was chromatographed on silica gel, eluting with ethylacetate and hexanes to give white solid allyl, methoxymethyl diether 10: (0.0063g, 33%).
• Example 13 7-(4-Fluoro-benzyl)-5-methoxy-9-triisopropylsilanyloxy-pyrrolo[3,4- g]quinoline-6,8-dione 13
• a mixture of 12 from the monosilylation reaction was heated at 40°C in anhydrous acetonitrile with K 2 CO 3 (1.64 g, 11.8 mmol) and methyl iodide (4.2 g, 29.6 mmol) for 5 hours.
• the reaction mixture was worked up by addition of H O and EtO Ac.
• the organic layer was washed with H 2 O and the solvent was removed in vacuo.
• Example 16 7-(4-Fluoro-benzyl)-6-hydroxy-5-methoxy-6-methyl-9- triisopropylsilanyloxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one l6 Under a nitrogen atmosphere, a solution of 13 (90 mg, 0.18 mmol) was dissolved in
• the exocyclic olefin in 17 can be utilized toward a cycloaddition reaction.
• a TIPS protected analog 17a (17 mg, 0.033 mmol) was suspended in 0.17 mL of dry CH 2 C1 2 .
• 4-chlorophenylglyoxyl-O-hydroxamyl chloride (7.3 mg, 0.034 mmol) and TEA (4.7 ⁇ L, 0.034 mmol).
• the solution was stirred at room temperature for 12 hours.
• the reaction was worked up by diluting the solution with EtOAc and washing the organic layer with water. The organic layer was removed under reduced pressure. The residue was dissolved in EtOAc and diluted with hexanes.
• Example 26 ( ⁇ 3-[7-(4-Fluoro-benzyl)-9-hydroxy-5-methoxy-8-oxo-7,8-dihydro-6H- pyrrolo[3,4-g]quinolin-6-ylsulfanyl]-propionylamino ⁇ -methyl)-phosphonic acid diethyl ester 26
• diethyl(aminomethyl)phosphonate oxalate 27 mg, 0.105 mmol
• EDC 20 mg, 0.105 mmol
• TEA 15 ⁇ L, 0.105 mmol
• the solution was stirred at room temperature for 1 day when the same amount of the aminomethyl phosphonate, EDC and TEA were added.
• the reaction was stirred for another day when complete conversion of starting materials to the desired product was observed by LCMS.
• the product 26 was purified by reverse phase HPLC using 5- 95% A.
• Buffer A contained CH 3 CN-1% HOAc and buffer B was H 2 O-l% HOAc.
• Example 31 3-[4-(4-Fluoro-benzyl)-3,5-dioxo-piperazine-l-carbonyl]-pyridine-2- carboxylic acid isopropyl ester 31
• Example 32 7-(4-Fluoro-ben ⁇ yl)-9-hydroxy-l,7,10a-tria ⁇ a-anthracene-6,8,10-trione 32
• a solution of 31 (5 mg, 0.01 mmol) in 0.3 mL of dry 0.5 M NaOMe was stirred at ambient temperature for 15 minutes when a yellow precipitate formed.
• the solvent was removed in vacuo and the solid was dissolved in a mixture of CH 2 C1 2 - IN HCl.
• the layers were separated and the aqueous layer was washed with CH 2 C1 2 .
• the organic solvent was removed to provide an off-white solid.
• the product 32 was purified by trituration using CH 2 C1 2 and hexane.
• Example 33 3-Oxo-piperazine-l -carboxylic acid tert-butyl ester 33
• piperazine-2-one 1.037 g, 10.4 mmol
• BOC 2 O 2.5 g, 11.4 mmol
• the reaction became homogeneous after 3 hours when the starting material was completely consumed.
• the reaction was diluted with CH 2 C1 2 and the organic layer was washed with water. The solvent was removed in vacuo to yield quantitative amount of product 33 as a white solid.
• Example 34 4-(4-Fluoro-benzyl)-3-oxo-piperazine-l-carboxylic acid tert-butyl ester 34 To a heterogeneous solution of 33 (1.6 g, 8.1 mmol) in 16.2 mL of dry THF under a
• Example 36 3-[4-(4-Fluoro-benzyl)-3-oxo-piperazine-l-carbonyl]-pyridine-2-carboxylic acid isopropyl ester 36
• a solution of 35 (1.46 g, 4.55 mmol) was dissolved in 20 mL of a 1:1 solution of
• Mono carbonate 4 (8.9 g, 21.7 mmol) was dissolved in 1,2-dichloroethane (400 mL).

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