US20070010489A1 - Cellular accumulation of phosphonate analogs of hiv protease inhibitor compounds - Google Patents

Cellular accumulation of phosphonate analogs of hiv protease inhibitor compounds

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Publication number
US20070010489A1
US20070010489A1 US10/511,998 US51199805A US2007010489A1 US 20070010489 A1 US20070010489 A1 US 20070010489A1 US 51199805 A US51199805 A US 51199805A US 2007010489 A1 US2007010489 A1 US 2007010489A1
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US
United States
Prior art keywords
compound
formula
independently
protease inhibitor
phosphonate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/511,998
Other languages
English (en)
Inventor
Murty Arimilli
Mark Becker
Clifford Bryant
James Chen
Xiaowu Chen
Azar Dastgah
Maria Fardis
Gong-Xin He
Haolun Jin
Choung Kim
William Lee
Christopher Lee
Kuei-Ying Lin
Hongtao Liu
Richard Mackman
Michael Mitchell
Peter Nelson
Hyung-Jung Pyun
Tanisha Rowe
Mark Sparacino
Sundaramoorthi Swaminathan
James Tario
Jianying Wang
Matthew Wiliams
Lianhong Xu
Zheng-Yu Yang
Richard Yu
Jiancun Zhang
Lijun Zhang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gilead Sciences Inc
Original Assignee
Gilead Sciences Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gilead Sciences Inc filed Critical Gilead Sciences Inc
Priority to US10/511,998 priority Critical patent/US20070010489A1/en
Assigned to GILEAD SCIENCES, INC. reassignment GILEAD SCIENCES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BECKER, MARK W., JIN, HAOLUN, KIM, CHOUNG U., LEE, WILLIAM A., MITCHELL, MICHAEL L., CHEN, JAMES M., CHEN, XIAOWU, FARDIS, MARIA, HE, GONG-XIN, LEE, CHRISTOPHER P., LIN, KUEI-YING, LIU, HONGTAO, MACKMAN, RICHARD L., ARIMILLI, MURTY N., BRYANT, CLIFFORD, DASTGAN, AZAR
Assigned to GILEAD SCIENCES, INC. reassignment GILEAD SCIENCES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BECKER, MARK W., JIN, HAOLUN, KIM, CHOUNG U., LEE, WILLIAM A., SPARACINO, MARK, YU, RICHARD H., MITCHELL, MICHAEL L., PYUN, HYUNG-JUNG, YANG, ZHENG-YU, CHEN, JAMES M., CHEN, XIAOWU, FARDIS, MARIA, HE, GONG-XIN, LEE, CHRISTOPHER P., LIN, KUEI-YING, LIU, HONGTAO, MACKMAN, RICHARD L., ROWE, TANISHA D., SWAMINATHAN, SUNDARAMOORTHI, TARIO, JAMES D., WANG, JIANYING, WILLIAMS, MATTHEW A., XU, LIANHONG, ZHANG, LIJUN, ARIMILLI, MURTY N., ZHANG, JIANCUN, BRYANT, CLIFFORD, DASTGAH, AZAR, NELSON, PETER H.
Publication of US20070010489A1 publication Critical patent/US20070010489A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
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    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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    • C07D239/72—Quinazolines; Hydrogenated quinazolines
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    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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    • G01N33/5038—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects involving detection of metabolites per se
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Definitions

  • the invention relates generally to compounds with antiviral activity and more specifically with anti-HIV protease properties.
  • AIDS is a major public health problem worldwide.
  • drugs targeting HIV viruses are in wide use and have shown effectiveness, toxicity and development of resistant strains have limited their usefulness.
  • Assay methods capable of determining the presence, absence or amounts of HIV viruses are of practical utility in the search for inhibitors as well as for diagnosing the presence of HIV.
  • HIV Human immunodeficiency virus infection and related disease is a major public health problem worldwide.
  • the retrovirus human immunodeficiency virus type 1 (HIV-1), a member of the primate lentivirus family (DeClercq E (1994) Annals of the New York Academy of Sciences, 724:438-456; Barre-Sinoussi F (1996) Lancet, 348:31-35), is generally accepted to be the causative agent of acquired immunodeficiency syndrome (AIDS) Tarrago etal FASEB Journal 1994, 8:497-503).
  • AIDS is the result of repeated replication of HIV-1 and a decrease in immune capacity, most prominently a fall in the number of CD4+ lymphocytes.
  • the mature virus has a single stranded RNA genome that encodes 15 proteins (Frankel et al (1998) Annual Review of Biochemistry, 67:1-25; Katz et al (1994) Annual Review of Biochemistry, 63:133-173), including three key enzymes: (i) protease (Prt) (von der Helm K (1996) Biological Chemistry, 377:765-774); (ii) reverse transcriptase (RT) (Hottiger etal (1996) Biological Chemistry Hoppe - Seyler, 377:97-120), an enzyme unique to retroviruses; and (iii) integrase (Asante etal (1999) Advances in Virus Research 52:351-369; Wlodawer A (1999) Advances in Virus Research 52:335-350; Esposito etal (1999) Advances in Virus Research 52:319-333).
  • Protease is responsible for processing the viral precursor polyproteins
  • integrase is responsible for the integration of the double stranded DNA form of the viral genome into host DNA
  • RT is the key enzyme in the replication of the viral genome.
  • RT acts as both an RNA- and a DNA-dependent DNA polymerase, to convert the single stranded RNA genome into double stranded DNA. Since virally encoded Reverse Transcriptase (RT) mediates specific reactions during the natural reproduction of the virus, inhibition of HIV RT is an important therapeutic target for treatment of HIV infection and related disease.
  • HIV protease is essential for the processing of the viral gag and gag-pol polypeptides into mature virion proteins. L. Ratner, et al., Nature, 313:277-284 (1985); L. H. Pearl and W. R. Taylor, Nature, 329:351 (1987). HIV exhibits the same gag/pol/env organization seen in other retroviruses. L. Ratner, et al., above; S. Wain-Hobson, et al., Cell, 40:9-17 (1985); R. Sanchez-Pescador, et al, Science, 227:484-492 (1985); and M. A. Muesing, et al., Nature, 313:450-458 (1985).
  • a therapeutic target in AIDS involves inhibition of the viral protease (or proteinase) that is essential for processing HIV-fusion polypeptide precursors.
  • the proteolytic maturation of the gag and gag/pol fusion polypeptides (a process indispensable for generation of infective viral particles) has been shown to be mediated by a protease that is, itself, encoded by the pol region of the viral genome.
  • Drugs approved in the United States for AIDS therapy include nucleoside inhibitors of RT (Smith et al (1994) Clinical Investigator, 17:226-243), protease inhibitors and non-nucleoside RT inhibitors (NNRTI), (Johnson et al (2000) Advances in Internal Medicine, 45 (1-40; Porche D J (1999) Nursing Clinics of North America, 34:95-112).
  • protease or proteinase
  • the protease consisting of only 99 amino acids, is among the smallest enzymes known, and its demonstrated homology to aspartyl proteases such as pepsin and renin (L. H. Pearl and W. R. Taylor, Nature, 329:351-354 (1987); and I. Katoh, et al., Nature, 329:654-656 (1987)), led to inferences regarding the three-dimensional structure and mechanism of the enzyme (L. H. Pearl and W. R. Taylor, above) that have since been borne out experimentally. Active HIV protease has been expressed in bacteria (see, e.g., P. L. Darke, et al., J. Biol.
  • Inhibitors of HIV protease are useful to limit the establishment and progression of infection by therapeutic administration as well as in diagnostic assays for HIV.
  • Protease inhibitor drugs approved by the FDA include:
  • Experimental protease inhibitor drugs include:
  • anti-HIV therapeutic agents i.e. drugs having improved antiviral and pharmacokinetic properties with enhanced activity against development of HIV resistance, improved oral bioavailability, greater potency and extended effective half-life in vivo.
  • New HIV protease inhibitors should be active against mutant HIV strains, have distinct resistance profiles, fewer side effects, less complicated dosing schedules, and orally active.
  • a less onerous dosage regimen such as one pill, once per day.
  • drugs targeting HIV protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have limited their usefulness (Palella, et al N. Engl. J. Med. (1998) 338:853-860; Richman, D. D. Nature (2001) 410:995-1001).
  • Combination therapy of PI and RT inhibitors has proven to be highly effective in suppressing viral replication to unquantifiable levels for a sustained period of time. Also, combination therapy with RT and protease inhibitors have shown synergistic effects in suppressing HIV replication. Unfortunately, many patients currently fail combination therapy due to the development of drug resistance, non-compliance with complicated dosing regimens, pharmacokinetic interactions, toxicity, and lack of potency. Therefore, there is a need for new HIV protease inhibitors that are synergistic in combination with other HIV inhibitors.
  • agents currently administered to a patient parenterally are not targeted, resulting in systemic delivery of the agent to cells and tissues of the body where it is unnecessary, and often undesirable. This may result in adverse drug side effects, and often limits the dose of a drug (e.g., cytotoxic agents and other anti-cancer or 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 novel compounds with HIV protease activity, i.e. novel human retroviral protease inhibitors. Therefore, the compounds of the invention may inhibit retroviral proteases and thus inhibit the replication of the virus. They are useful for treating human patients infected with a human retrovirus, such as human immunodeficiency virus (strains of HIV-1 or HIV-2) or human T-cell leukemia viruses (HTLV-I or HTLV-II) which results in acquired immunodeficiency syndrome (AIDS) and/or related diseases.
  • the present invention includes novel phosphonate HIV protease inhibitor (PI) compounds and phosphonate analogs of known approved and experimental protease inhibitors.
  • the compounds of the invention optionally provide cellular accumulation as set forth below.
  • the present invention relates generally to the accumulation or retention of therapeutic compounds inside cells.
  • the invention is more particularly related to attaining high concentrations of phosphonate-containing molecules in HIV infected cells.
  • Intracellular targeting may be achieved by methods and compositions which allow accumulation or retention of biologically active agents inside cells. Such effective targeting may be applicable to a variety of therapeutic formulations and procedures.
  • compositions of the invention include new PI compounds having at least one phosphonate group.
  • the invention includes all known approved and experimental protease inhibitors with at least one phosphonate group.
  • the invention includes compounds having Formulas I, II, III, IV, V, VI, VII and VIIIa-d: where a wavy line indicates the other structural moieties of the compounds.
  • Formulas I-VIII are substituted with one or more covalently attached groups, including at least one phosphonate group.
  • Formulas I-VIII are “scaffolds”, i.e. substructures which are common to the specific compounds encompassed therein.
  • Another aspect of the invention provides a pharmaceutical combination comprising an effective amount of a compound selected from Formulas I-VIII and a second compound having anti-HIV properties.
  • Another aspect of the invention provides a method for the treatment or prevention of the symptoms or effects of an HIV infection in an infected animal which comprises administering to, i.e. treating, said animal with a pharmaceutical combination comprising an effective amount of a compound selected from Formulas I-VIII and a second compound having anti-HIV properties.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound selected from Formulas I-VIII, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.
  • This invention pertains to a method of increasing cellular accumulation and retention of drug compounds, thus improving their therapeutic and diagnostic value.
  • the invention also provides a method of inhibiting HIV, comprising administering to a mammal infected with HIV (HIV positive) an amount of a compound of Formulas I-VIII, effective to inhibit the growth of said HIV infected cells.
  • the invention also provides a compound selected from Formulas I-VIII for use in medical therapy (preferably for use in treating cancer, e.g. solid tumors), as well as the use of a compound of Formulas I-VIII for the manufacture of a medicament useful for the treatment of cancer, e.g. solid tumors.
  • the invention also provides processes and novel intermediates disclosed herein which are useful for preparing compounds of the invention. Some of the compounds of Formulas I-VIII are useful to prepare other compounds of Formulas I-VIII.
  • the activity of HIV protease 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.
  • Another aspect of the invention provides a method for inhibiting the activity of HIV protease comprising the step of contacting a sample suspected of containing HIV virus with a composition of the invention.
  • novel methods for synthesis analysis, separation, isolation, purification, characterization, 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. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191).
  • Enzymes which are capable of an enzymatic activation mechanism with the phosphonate prodrug compounds of the invention include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphases.
  • Prodrug moieties can serve to enhance solubility, absorption and lipophilicity to optimize drug delivery, bioavailability and efficacy.
  • prodrug moieties include the hydrolytically sensitive or labile acyloxymethyl esters —CH 2 OC( ⁇ O)R 9 and acyloxymethyl carbonates —CH 2 OC( ⁇ O)OR 9 where R 9 is C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, C 6 -C 20 aryl or C 6 -C 20 substituted aryl.
  • the acyloxyalkyl ester was first used as a prodrug strategy for carboxylic acids and then applied to phosphates and phosphonates by Farquhar et al (1983) J. Pharm. Sci. 72: 324; also U.S. Pat. Nos.
  • 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.
  • An exemplary acyloxymethyl ester is pivaloyloxymethoxy, (POM) —CH 2 OC( ⁇ O)C(CH 3 ) 3 .
  • An exemplary acyloxymethyl carbonate prodrug moiety is pivaloyloxymethylcarbonate (POC) —CH 2 OC( ⁇ O)OC(CH 3 ) 3 .
  • the phosphonate group may be a phosphonate prodrug moiety.
  • the prodrug moiety may be sensitive to hydrolysis, such as, but not limited to a pivaloyloxymethyl carbonate (POC) or POM group.
  • the prodrug moiety may be sensitive to enzymatic potentiated cleavage, such as a lactate ester or a phosphonamidate-ester group.
  • Aryl esters of phosphorus groups are reported to enhance oral bioavailability (DeLambert et al (1994) J. Med. Chem. 37: 498). Phenyl esters containing a carboxylic ester ortho to the phosphate have also been described (Khamnei and Torrence, (1996) J. Med. Chem. 39:4109-4115). Benzyl esters are reported to generate the parent phosphonic acid. In some cases, substituents at the ortho-or para-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. Deesterification or reduction of the disulfide generates the free thio intermediate which subsequently breaks down to the phosphoric acid and episulfide (Puech et al (1993) Antiviral Res., 22: 155-174; Benzaria et al (1996) J. Med. Chem. 39: 4958). Cyclic phosphonate esters have also been described as prodrugs of phosphorus-containing compounds (Erion et al, U.S. Pat. No. 6,312,662).
  • 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. 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 4 + (wherein X is C 1 -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 4 + (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 1 -C 18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples are methyl (Me, —CH 3 ), ethyl (Et, —CH 2 CH 3 ), 1-propyl ( n -Pr, n -propyl, —CH 2 CH 2 CH 3 ), 2-propyl ( i -Pr, i -propyl, —CH(CH 3 ) 2 ), 1-butyl ( n -Bu, n -butyl, —CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl ( i -Bu, i -butyl, —CH 2 CH(CH 3 ) 2 ), 2-butyl ( s -Bu, s -butyl, —CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl ( t -Bu, t -butyl, —C(CH 3 ).
  • Alkenyl is C 2 -C 18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp 2 double bond. Examples include, but are not limited to: ethylene or vinyl (—CH ⁇ CH 2 ), allyl (—CH 2 CH ⁇ CH 2 ), cyclopentenyl (—C 5 H 7 ), and 5-hexenyl (—CH 2 CH 2 CH 2 CH 2 CH ⁇ CH 2 )
  • Alkynyl is C 2 -C 18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond. Examples include, but are not limited to: acetylenic (—C ⁇ CH) and propargyl (—CH 2 C ⁇ CH),
  • Alkylene refers to a saturated, branched or straight chain or cyclic hydrocarbon radical of 1-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane.
  • Typical alkylene radicals include, but are not limited to: methylene (—CH 2 —) 1,2-ethyl (—CH 2 CH 2 —), 1,3-propyl (—CH 2 CH 2 CH 2 —), 1,4butyl (—CH 2 CH 2 CH 2 CH 2 —), and the like.
  • Alkenylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene.
  • Typical alkenylene radicals include, but are not limited to: 1,2-ethylene (—CH ⁇ CH—).
  • Alkynylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene.
  • Typical alkynylene radicals include, but are not limited to: acetylene (—C ⁇ C—), propargyl (—CH 2 C ⁇ C—), and 4-pentynyl (—CH 2 CH 2 CH 2 C ⁇ CH—).
  • Aryl means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl and the like.
  • Arylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with an aryl radical.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like.
  • the arylalkyl group comprises 6 to 20 carbon atoms, e.g. the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms.
  • Substituted alkyl mean alkyl, aryl, and arylalkyl respectively, in which one or more hydrogen atoms are each independently replaced with a substituent.
  • Typical substituents include, but are not limited to, —X, —R, —O—, —OR, —SR, —S ⁇ , —NR 2 , —NR 3 , ⁇ NR, —CX 3 , —CN, —OCN, —SCN, —N ⁇ C ⁇ O, —NCS, —NO, —NO 2 , ⁇ N 2 , —N 3 , NC( ⁇ O)R, —C( ⁇ O)R, —C( ⁇ O)NRR —S( ⁇ O) 2 O ⁇ , —S( ⁇ O) 2 OH, —S( ⁇ O) 2 R, —OS( ⁇ O) 2 OR, —S( ⁇ O) 2 NR, —S( ⁇ O)R, —OP( ⁇ O)O 2 RR, —P( ⁇ O)O 2 RR —P( ⁇ O)(O ⁇ ) 2 , —P( ⁇ O)(OH) 2 ,
  • Heterocycle as used herein includes by way of example and not limitation these heterocycles described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566.
  • heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl pyrimidinyl, furanyl thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl 4-piperidonyl, pyrrolidinyl 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, bis-tetrahydrofuranyl, tetrahydropyranyl bis-tetrahydropyranyl, tetrahydroquinolin
  • carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.
  • carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
  • nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ -carboline.
  • nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
  • Carbocycle means a saturated, unsaturated or aromatic ring having 3 to 7 carbon atoms as a monocycle or 7 to 12 carbon atoms as a bicycle.
  • Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms.
  • Bicyclic carbocycles have 7 to 12 ring atoms, e.g. arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system.
  • Examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spiryl and naphthyl.
  • 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 portions of substituents A 1 and A 3 enumerated in Formula I, or substituents A 1 and A 3 enumerated in Formula II, which include moieties such as: repeating units of alkyloxy (e.g. polyethylenoxy, PEG, polymethyleneoxy) and alkylamino (e.g. polyethyleneamino, JeffamineTM); and diacid ester and amides including succinate, succinamide, diglycolate, malonate, and caproamide.
  • alkyloxy e.g. polyethylenoxy, PEG, polymethyleneoxy
  • alkylamino e.g. polyethyleneamino, JeffamineTM
  • diacid ester and amides including succinate, succinamide, diglycolate, malonate, and
  • 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.
  • d and 1, D and L, or (+) and ( ⁇ ) are employed to designate the sign of rotation of plane-polarized light by the compound, with ( ⁇ ) or 1 meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • these stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • the compounds of the invention include those with HIV protease inhibitory activity.
  • the compounds include HIV protease inhibitors.
  • the compounds of the inventions bear a phosphonate group, which may be a prodrug moiety.
  • ILPPI Intravir-like phosphonate protease inhibitors, Formula I
  • AMLPPI Anmprenavir-like phosphonate protease inhibitors, Formula II
  • KNILPPI KNI-like phosphonate protease inhibitors, Formula III
  • RLPPI Renid-like phosphonate protease inhibitors, Formula IV
  • LLPPI Lipinavir-like phosphonate protease inhibitors, Formula IV
  • NLPPI Nonelfinavir-like phosphonate protease inhibitors, Formula V
  • SLPPI Sequinavir-like phosphonate protease inhibitors, Formula V
  • ATLPPI Atanzavir-like phosphonate protease inhibitors, Formula VI
  • TLPPI Tipranavir-like phosphonate protease inhibitors, Formula VII
  • ILPPI Indinavir-like phosphonate protease inhibitors, Formula I
  • AMLPPI Anmprenavir-like phosphon
  • Formula I compounds have a 3-hydroxy-5-amino-pentamide core.
  • Formula II compounds have a 2-hydroxy-1, 3-amino-propylamide or 2-hydroxy-1,3-amino-propylaminosulfone core.
  • Formula III compounds have a 2-hydroxy-3-amino-propylamide core.
  • Formula IV compounds have a 2-hydroxy-4-amino-butylamine core.
  • Formula V compounds have a acylated 1,3-diaminopropane core.
  • Formula VI compounds have a 2-hydroxy-3-diaza-propylamide core.
  • Formula VII compounds have a sulfonamide 5,6-dihydro-4-hydroxy-2-pyrone core.
  • Formula VIIIa-d compounds have a six or seven-membered ring, and a cyclic carbonyl, sulfhydryl sulfoxide or sulfone core, where Y 1 is oxygen, sulfur, or substituted nitrogen and m2 is 0, 1 or 2.
  • Formulas I, II, III, IV, V, VI, VII and VIIIa-d are substituted with one or more covalently attached groups, including at least one phosphonate group.
  • Formulas I, II, III, IV, V, VI, VII and VIIIa-d are substituted with one or more covalently attached A 0 groups, including simultaneous substitutions at any or all A 0 .
  • a 0 is A 1 , A 2 or W 3 .
  • Compounds of Formulas I, II, III, IV, V, VI, VII and VIIIa-d include at least one A 1 .
  • Y 1 is independently O, S, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), or N(N(R x )(R x )).
  • Y 2 is independently a bond, O, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), N(N(R x )(R x )), —S(O) M2 ⁇ , or —S(O) M2 —S(O) M2 —.
  • R x is independently H, W 3 , a protecting group, or the formula: wherein:
  • M1a, M1c, and M1d are independently 0 or 1;
  • M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • R y is independently H, W 3 , R 2 or a protecting group.
  • R x is a group of the formula: wherein:
  • na, m1b, m1c, m1d and m1e are independently 0 or 1;
  • m12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • R y is H, W 3 , R 2 or a protecting group
  • m1a and m1d are 0 and m12c is not 0, then m1b and at least one of m1c and m1e are 0;
  • R 1 is independently H or alkyl of 1 to 18 carbon atoms.
  • R 2 is independently H, R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups.
  • R 4 is independently substituted with 0 to 3 R 3 groups.
  • two R 2 groups form a ring, i.e. a spiro carbon.
  • the ring may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • the ring may be substituted with 0 to 3 R 3 groups.
  • R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a heteroatom, then R 3 is R 3c or R 3d .
  • R 3a is F, Cl, Br, I, —CN, N 3 or —NO 2 .
  • R 3b is Y 1 .
  • R 3c is —R x , —N(R x )(R x ), —SR x , —S(O)R x , —S(O) 2 R x , —S(O)(OR x ), —S(O) 2 (OR x ), —OC(Y 1 )R x , —OC(Y 1 )OR x , —OC(Y 1 )(N(R x )(R x )), —SC(Y 1 )R x , —SC(Y 1 )OR x , —SC(Y 1 )(N(R x )(R x )), —N(R x )C(Y 1 )R x , —N(R x )C(Y 1 )OR x , or —N(R x )C(Y 1 )(N(R x )(R x )).
  • R 3d is —C(Y 1 )R x , —C(Y 1 )OR x or —C(Y 1 )(N(R x )(R x )).
  • R 4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms.
  • R 5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups.
  • R 5a is independently alkylene of 1 to 18 carbon atoms, alkenylene of 2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R 3 groups.
  • W 3 is W 4 or W 5 .
  • W 4 is R 5 , —C(Y 1 )R 5 , —C(Y 1 )W 5 , —SO 2 R 5 , or —SO 2 W 5 .
  • W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups.
  • W 3a is W 4a or W 5a .
  • W 4a is R 5a , —C(Y 1 )R 5a , —C(Y 1 )W 5a , —SO 2 R 5a , or SO 2 W 5a .
  • W 5a is a multivalent substituted carbocycle or heterocycle wherein W 5a is independently substituted with 0 to 3 R 2 groups.
  • W 6 is W 3 independently substituted with 1, 2, or 3 A 3 groups.
  • 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 or12.
  • W 5 and W 5a carbocycles and W 5 and W 5a a heterocycles may be independently substituted with 0 to 3 R 2 groups.
  • W 5 may be a saturated, unsaturated or aromatic ring comprising a mono- or bicyclic carbocycle or heterocycle.
  • W 5 may have 3 to 10 ring atoms, e.g., 3 to 7 ring atoms.
  • the W 5 rings are saturated when containing 3 ring atoms, saturated or mono-unsaturated when containing 4 ring atoms, saturated, or mono- or di-unsaturated when containing 5 ring atoms, and saturated, mono- or di-unsaturated, or aromatic when containing 6 ring atoms.
  • a W 5 or W 5a heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S).
  • W 5 and W 5a heterocyclic monocycles may have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S); or 5 or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selected from N and S).
  • W 5 and W 5a heterocyclic bicycles have 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S) arranged as a bicyclo [4,5], [5,5], [5,6], or [6,6] system; or 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2 hetero atoms selected from N and S) arranged as a bicyclo [5,6] or [6,6] system.
  • the W 5 heterocycle may be bonded to Y 2 through a carbon, nitrogen, sulfur or other atom by a stable covalent bond.
  • W 5 and W 5a heterocycles include for example, pyridyl, dihydropyridyl isomers, piperidine, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imindazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl thiofuranyl, thienyl, and pyrrolyl.
  • W 5 also includes, but is not limited to, examples such as:
  • W 5 and W 5a carbocycles and heterocycles may be independently substituted with 0 to 3 R 2 groups, as defined above.
  • substituted W 5 carbocycles include:
  • substituted phenyl carbocycles include:
  • Embodiments of A 1 include: and where one or more Y 2 are a bond, such as: where W 5a is a carbocycle or a heterocycle and W 5a is independently substituted with 0 or 1 R 2 groups.
  • Embodiments of A 1 also include: where n is an integer from 1 to 18.
  • Embodiments of A 3 include where M2 is 0, such as: and where M12b is 1, Y 1 is oxygen, and Y 2b is oxygen (O) or nitrogen (N(R x )) such as:
  • An embodiment of A 3 includes: where Y 2c is O, N(R y ) or S.
  • R 1 may be H and n may be 1.
  • a 3 includes: where W 5 is a carbocycle such as phenyl or substituted phenyl. Such embodiments include: where y 2b is O or N(R x ); M12d is 1, 2, 3, 4, 5, 6, 7 or 8; and the phenyl carbocycle is substituted with 0 to 3 R 2 groups. Such embodiments of A 3 include phenyl phosphonamidate amino acid, e.g. alanate esters and phenyl phosphonate-lactate esters:
  • the chiral carbon of the amino acid and lactate moieties may be either the R or S configuration or the racemic mixture.
  • Embodiments of R x include esters, carbamates, carbonates, thioesters, amides, thioamides, and urea groups:
  • Embodiments of A 2 include where W 3 is W 5 , such as:
  • a 2 is phenyl, substituted phenyl, benzyl, substituted benzyl, pyridyl or substituted pyridyl.
  • Exemplary embodiments of Formula I compounds include, but are not limited to, structures: where A 1 denotes a covalent attachment site of a phosphonate group.
  • Exemplary embodiments of Formula II compounds include, but are not limited to, structures: where A 1 denotes a covalent attachment site of a phosphonate group.
  • Exemplary embodiments of Formula III compounds include, but are not limited to, structures: where A 1 denotes a covalent attachment site of a phosphonate group.
  • Exemplary embodiments of Formula IV compounds include, but are not limited to, structures: where A 1 denotes a covalent attachment site of a phosphonate group.
  • Exemplary embodiments of Formula V compounds include, but are not limited to, structures: where A 1 denotes a covalent attachment site of a phosphonate group.
  • Exemplary embodiments of Formula VI compounds include, but are not limited to, structures: where A 1 denotes a covalent attachment site of a phosphonate group.
  • Exemplary embodiments of Formula VII compounds include, but are not limited to, structures: where A 1 denotes a covalent attachment site of a phosphonate group.
  • Exemplary embodiments of Formula VIIId compounds include structures: where A 1 denotes a covalent attachment site of a phosphonate group.
  • Another embodiment of the invention is directed toward an HIV protease inhibitor compound capable of accumulating in human PBMCs. Accumulation in human PBMCs is described in the examples herein.
  • the compounds of this embodiment further comprise a phosponate or phosphonate prodrug. More typically, the phosphonate or phosphonate prodrug has the structure A 3 as described herein.
  • Each of the preferred embodiments of A 3 described herein is a preferred embodiment of A 3 in the present embodiment.
  • the compounds of this embodiment demonstrate improved intracellular half-life of the compounds or intracellular metabolites of the compounds in human PBMCs 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 is typically generated intracellularly, more typically, it is generated within human PBMCs. Still more typically, the metabolite is a product of the cleavage of a phosphonate prodrug within human PBMCs. More typically yet, the phosphonate prodrug is cleaved to form a metabolite having at least one negative charge at physiological pH. Most typically, the phosphonate prodrug is enzymatically cleaved within human PBMCs to form a phosphonate having at least one active hydrogen atom of the form P—OH.
  • a 3 is A 3a which is of the formula: In this embodiment of the invention, any A 3 group may be A 3a .
  • a 3 is of the formula: M12a is other than 0 and at least one phosphonate group present in the compound is not bonded directly to W 3 . More typically, the phosphonate is not bonded directly to W 5 . In such an embodiment, the phosphorous atom of the phosphonate is not bonded directly to a carbon atom of a ring.
  • an Amprenavir like phosphonate protease inhibitor contains an A 3 group of the formula: M12a is other than 0 and at least one phosphonate group present in the compound is not bonded directly to W 3 . More typically, the phosphonate is not bonded directly to W 5 . In such an embodiment, the phosphorous atom of the phosphonate is not bonded directly to a carbon atom of a ring.
  • a 3 is of the formula: M12a is 0 and at least one phosphonate group present in the compound is bonded directly to W 3 . More typically, the phosphonate is bonded directly to W 5 . In such an embodiment, the phosphorous atom of the phosphonate is bonded directly to a carbon atom of a ring.
  • an Amprenavir like phosphonate protease inhibitor contains an A 3 group of the formula: M12a is 0 and at least one phosphonate group present in the compound is bonded directly to W 3 . More typically, the phosphonate is bonded directly to W 5 . In such an embodiment, the phosphorous atom of the phosphonate is bonded directly to a carbon atom of a ring.
  • Amprenavir like phosphonate protease inhibitors as described above in the description and below in the claims is directed to compounds of the formulas: Exemplary Enumerated Compounds.
  • MBF substituted nucleus
  • Sc substituted nucleus
  • Tables 1.1 to 1.5 are a schedule of nuclei used in forming the embodiments of Table 100.
  • Each nucleus (Sc) is given a number designation from Tables 1.1 to 1.5, and this designation appears first in each embodiment name.
  • Tables 10.1 to 10.19 and 20.1 to 20.36 list the selected linking groups (Lg) and prodrug (Pd 1 and Pd 2 ) substituents, again by letter or number designation, respectively.
  • each named embodiment of Table 100 is depicted by a number designating the nucleus from Table 1.1-1.5, followed by a letter designating the linking group (Lg) from Table 10.1-10.19, and two numbers designating the two prodrug groups (Pd 1 and Pd 2 ) from Table 20.1-20.36.
  • each embodiment of Table 100 appears as a name having the syntax: Sc.Lg.Pd 1 .Pd 2
  • structure 10, Scheme 2, Scheme Section A is represented by 12.AH.247.247.
  • Each Sc group is shown having a tilda (“[”).
  • the tilda is the point of covalent attachment of Sc to Lg.
  • Q 1 is the site of the covalent bond to the nucleus (Sc) and Q 2 is the site of the covalent bond to the phosphorous atom of formula MBF.
  • Each prodrug group (Pd 1 and Pd 2 ) are covalently bonded to the phosphorous atom of MBF at the tilda symbol (“ ⁇ ”).
  • Tables 10.1-10.19 and 20.1-20.36 may be designated as a combination of letters and numbers (Table 10.1-10.19) or number and letter (Table 20.1-20.36). For example there are Table 10 entries for BJ1 and BJ2. In any event, entries of Table 10.1-10.19 always begin with a letter and those of Table 20.1-20.36 always begin with a number.
  • a nucleus (Sc) is shown enclosed within square brackets (“[]”) and a covalent bond extends outside the brackets, the point of covalent attachment of Sc to Lg may be at any substitutable site on SC. Selection of the point of attachment is described herein. By way of example and not limitation, the point of attachment is selected from those depicted in the schemes and examples. TABLE 1.1
  • R x contains a R y substituent.
  • R y can be R 2 , which in turn can be R 3 . If R 3 is selected to be R 3c , then a second instance of R x can be selected.
  • R 3 is selected to be R 3c , then a second instance of R x can be selected.
  • properties include, by of example and not limitation, physical properties such as molecular weight, solubility or log P, application properties such as activity against the intended target, and practical properties such as ease of synthesis.
  • W 3 , R y and R 3 are all recursive substituents in certain embodiments. Typically, each of these may independently occur 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0, times in a given embodiment. More typically, each of these may independently occur 12 or fewer times in a given embodiment. More typically yet, W 3 will occur 0 to 8 times, R y will occur 0 to 6 times and R 3 will occur 0 to 10 times in a given embodiment. Even more typically, W 3 will occur 0 to 6 times, R y will occur 0 to 4 times and R 3 will occur 0 to 8 times in a given embodiment.
  • Recursive substituents are an intended aspect of the invention.
  • One of ordinary skill in the art of medicinal chemistry understands the versatility of such substituents.
  • protecting groups include prodrug moieties and chemical protecting groups.
  • Protecting groups are available, commonly known and used, and are optionally used to prevent side reactions with the protected group during synthetic procedures, i.e. routes or methods to prepare the compounds of the invention. For the most part the decision as to which groups to protect, when to do so, and the nature of the chemical protecting group “PRT” will be dependent upon the chemistry of the reaction to be protected against (e.g., acidic, basic, oxidative, reductive or other conditions) and the intended direction of the synthesis. The PRT groups do not need to be, and generally are not, the same if the compound is substituted with multiple PRT. In general, PRT will be used to protect functional groups such as carboxyl hydroxyl or amino groups and to thus prevent side reactions or to otherwise facilitate the synthetic efficiency. The order of deprotection to yield free, deprotected groups is dependent upon the intended direction of the synthesis and the reaction conditions to be encountered, and may occur in any order as determined by the artisan.
  • Various functional groups of the compounds of the invention may be protection.
  • protecting groups for —OH groups are embodiments of “ether- or ester-forming groups”.
  • Ether- or ester-forming groups are capable of functioning as chemical protecting groups in the synthetic schemes set forth herein.
  • some hydroxyl and thio protecting groups are neither ether- nor ester-forming groups, as will be understood by those skilled in the art, and are included with amides, discussed below.
  • Ester-forming groups include: (1) phosphonate ester-forming groups, such as phosphonamidate esters, phosphorothioate esters, phosphonate esters, and phosphon-bis-amidates; (2) carboxyl ester-forming groups, and (3) sulphur ester-forming groups, such as sulphonate, sulfate, and sulfinate.
  • phosphonate ester-forming groups such as phosphonamidate esters, phosphorothioate esters, phosphonate esters, and phosphon-bis-amidates
  • carboxyl ester-forming groups such as sulphonate, sulfate, and sulfinate.
  • the phosphonate moieties of the compounds of the invention may or may not be prodrug moieties, i.e. they may or may not be susceptible to hydrolytic or enzymatic cleavage or modification. Certain phosphonate moieties are stable under most or nearly all metabolic conditions. For example, a dialkylphosphonate, where the alkyl groups are two or more carbons, may have appreciable stability in vivo due to a slow rate of hydrolysis.
  • phosphonate prodrug moieties a large number of structurally-diverse prodrugs have been described for phosphonic acids (Freeman and Ross in Progress in Medicinal Chemistry 34: 112-147 (1997) and are included within the scope of the present invention.
  • An exemplary embodiment of a phosphonate ester-forming group is the phenyl carbocycle in substructure A 3 having the formula:
  • ml is 1, 2, 3, 4, 5, 6, 7 or 8, and the phenyl carbocycle is substituted with 0 to 3 R 2 groups.
  • Y 1 is 0, a lactate ester is formed.
  • R 1 may be H or C 1 -C 12 alkyl.
  • a protecting group typically is bound to any acidic group such as, by way of example and not limitation, a —CO 2 H or —C(S)OH group, thereby resulting in —CO 2 R x where R x is defined herein.
  • R x for example includes the enumerated ester groups of WO 95/07920.
  • protecting groups include:
  • aromatic groups optionally are polycyclic or monocyclic. Examples include phenyl, spiryl, 2- and 3-pyrrolyl, 2- and 3-thienyl, 2- and 4-imidazolyl, 2-, 4- and 5-oxazolyl, 3- and 4-isoxazolyl, 2-, 4- and 5-thiazolyl, 3-, 4- and 5-isothiazolyl, 3- and 4-pyrazolyl, 1-, 2-, 3- and 4-pyridinyl, and 1-, 2-, 4- and 5-pyrimidinyl,
  • C 3 -C 12 heterocycle or aryl substituted with halo R 1 , R 1 —O—C 1 -C 12 alkylene, C 1 -C 12 alkoxy, CN, NO 2 , OH, carboxy, carboxyester, thiol, thioester, C 1 -C 12 haloalkyl (1-6 halogen atoms), C 2 -C 12 alkenyl or C 2 -C 12 alkynyl.
  • Such groups include 2-, 3- and 4-alkoxyphenyl (C 1 -C 12 alkyl), 2-, 3- and 4-methoxyphenyl, 2-, 3- and 4-ethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-3,4- and 3,5-diethoxyphenyl, 2- and 3-carboethoxy-4-hydroxyphenyl, 2- and 3-ethoxy-4-hydroxyphenyl, 2- and 3-ethoxy-5-hydroxyphenyl, 2- and 3-ethoxy-6-hydroxyphenyl, 2-, 3- and 4-O-acetylphenyl, 2-, 3- and 4-dimethylaminophenyl, 2-, 3- and 4-methylmercaptophenyl, 2-, 3- and 4-halophenyl (including 2-, 3- and 4-fluorophenyl and 2-, 3- and 4-chlorophenyl), 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-
  • triglycerides such as ⁇ -D- ⁇ -diglycerides (wherein the fatty acids composing glyceride lipids generally are naturally occurring saturated or unsaturated C 6-26 , C 6-18 or C 6-10 fatty acids such as linoleic, lauric, myristic, palmitic, stearic, oleic, palmitoleic, linolenic and the like fatty acids) linked to acyl of the parental compounds herein through a glyceryl oxygen of the triglyceride;
  • cyclic carbonates such as (5-R d -2-oxo-1,3-dioxolen-4-yl)methyl esters (Sakamoto et al., Chem. Pharm. Bull (1984) 32(6)2241-2248) where R d is R 1 , R 4 or aryl; and
  • hydroxyl groups of the compounds of this invention optionally are substituted with one of groups III, IV or V disclosed in WO 94/21604, or with isopropyl.
  • Table A lists examples of protecting group ester moieties that for example can be bonded via oxygen to —C(O)O— and —P(O)(O—) 2 groups. Several amidates also are shown, which are bound directly to —C(O)— or —P(O) 2 .
  • Esters of structures 1-5, 8-10 and 16, 17, 19-22 are synthesized by reacting the compound herein having a free hydroxyl with the corresponding halide (chloride or acyl chloride and the like) and N,N-dicyclohexyl-N-morpholine carboxamidine (or another base such as DBU, triethylamine, CSCO 3 , N,N-dimethylamiline and the like) in DMF (or other solvent such as acetonitrile or N-methylpyrrolidone).
  • halide chloride or acyl chloride and the like
  • N,N-dicyclohexyl-N-morpholine carboxamidine or another base such as DBU, triethylamine, CSCO 3 , N,N-dimethylamiline and the like
  • DMF or other solvent such as acetonitrile or N-methylpyrrolidone
  • the esters of structures 5-7, 11, 12, 21, and 23-26 are synthesized by reaction of the alcohol or alkoxide salt (or the corresponding amines in the case of compounds such as 13, 14 and 15) with the monochlorophosphonate or dichlorophosphonate (or another activated phosphonate).
  • TABLE A 1. —CH 2 —C(O)—N(R 1 ) 2 * 2. —CH 2 —S(O)(R 1 ) 3. —CH 2 —S(O) 2(R 1 ) 4. —CH 2 —O—C(O)—CH 2 —C 6 H 5 5.
  • —CH 2 —O—C(O)—C 6 H 5 9. —CH 2 —O—C(O)—CH 2 CH 3 10. —CH 2 —O—C(O)—C(CH 3 ) 3 11. —CH 2 —CCl 3 12. —C 6 H 5 13. —NH—CH 2 —C(O)O—CH 2 CH 3 14. —N(CH 3 )—CH 2 —C(O)O—CH 2 CH 3 15. —NHR 1 16. —CH 2 —O—C(O)—C 10 H 15 17. —CH 2 —O—C(O)—CH(CH 3 ) 2 18.
  • Protecting groups also includes “double ester” forming profunctionalities such as —CH 2 OC(O)OCH 3 , —CH 2 SCOCH 3 , —CH 2 OCON(CH 3 ) 2 , or alkyl- or aryl-acyloxyalkyl groups of the structure —CH(R 1 or W 5 )O((CO)R 37 ) or —CH(R 1 or W 5 )((CO)OR 38 ) (linked to oxygen of the acidic group) wherein R 37 and R 38 are alkyl, aryl, or alkylaryl groups (see U.S. Pat. No. 4,968,788).
  • R 37 and R 38 are bulky groups such as branched alkyl ortho-substituted aryl, meta-substituted aryl, or combinations thereof, including normal, secondary, iso- and tertiary alkyls of 1-6 carbon atoms.
  • An example is the pivaloyloxymethyl group.
  • alkylacyloxymethyl esters and their derivatives including —CH(CH 2 CH 2 OCH 3 )OC(O)C(CH 3 ) 3 , —CH 2 OC(O)C 10 H 15 , —CH 2 OC(O)C(CH 3 ) 3 , —CH(CH 2 OCH 3 )OC(O)C(CH 3 ) 3 , —CH(CH(CH 3 ) 2 )OC(O)C(CH 3 ) 3 , —CH 2 OC(O)CH 2 CH(CH 3 ) 2 , —CH 2 OC(O)C 6 H 11 , —CH 2 OC(O)C 6 H 5 , —CH 2 OC(O)C 10 H 15 , —CH 2 OC(O)CH 2 CH 3 , —CH 2 )C(O)CH(CH 3 ) 2 , —CH 2 OC(O)C(CH 3 ) 3 and —CH 2 OC(O)C 10 H 15 ,
  • the ester typically chosen is one heretofore used for antibiotic drugs, in particular the cyclic carbonates, double esters, or the phthalidyl, aryl or alkyl esters.
  • the protected acidic group is an ester of the acidic group and is the residue of a hydroxyl-containing functionality.
  • an amino compound is used to protect the acid functionality.
  • the residues of suitable hydroxyl or amino-containing functionalities are set forth above or are found in WO 95/07920.
  • residues of amino acids, amino acid esters, polypeptides, or aryl alcohols are described on pages 11-18 and related text of WO 95/07920 as groups L1 or L2.
  • WO 95/07920 expressly teaches the amidates of phosphonic acids, but it will be understood that such amidates are formed with any of the acid groups set forth herein and the amino acid residues set forth in WO 95/07920.
  • Typical esters for protecting acidic functionalities are also described in WO 95/07920, again understanding that the same esters can be formed with the acidic groups herein as with the phosphonate of the '920 publication.
  • Typical ester groups are defined at least on WO 95/07920 pages 89-93 (under R 31 or R 35 ), the table on page 105, and pages 21-23 (as R).
  • esters of unsubstituted aryl such as phenyl or arylalkyl such benzyl or hydroxy-, halo-, alkoxy-, carboxy- and/or akylestercarboxy-substituted aryl or alkylaryl, especially phenyl, ortho-ethoxyphenyl or C 1 -C 4 alkylestercarboxyphenyl (salicylate C 1 -C 12 alkylesters).
  • the protected acidic groups are useful as prodrugs for oral administration. However, it is not essential that the acidic group be protected in order for the compounds of this invention to be effectively administered by the oral route.
  • the compounds of the invention having protected groups in particular amino acid amidates or substituted and unsubstituted aryl esters are administered systemically or orally they are capable of hydrolytic cleavage in vivo to yield the free acid.
  • One or more of the acidic hydroxyls are protected. If more than one acidic hydroxyl is protected then the same or a different protecting group is employed, e.g., the esters may be different or the same, or a mixed amidate and ester may be used.
  • Typical hydroxy protecting groups described in Greene include substituted methyl and alkyl ethers, substituted benzyl ethers, silyl ethers, esters including sulfonic acid esters, and carbonates.
  • substituted methyl and alkyl ethers include substituted methyl and alkyl ethers, substituted benzyl ethers, silyl ethers, esters including sulfonic acid esters, and carbonates.
  • Typical 1,2-diol protecting groups are described in Greene at pages 118-142 and include Cyclic Acetals and Ketals (Methylene, Ethylidene, 1-t-Butylethylidene, 1-Phenylethylidene, (4-Methoxyphenyl)ethylidene, 2,2,2-Trichloroethylidene, Acetonide (Isopropylidene), Cyclopentylidene, Cyclohexylidene, Cycloheptylidene, Benzylidene, p-Methoxybenzylidene, 2,4-Dimethoxybenzylidene, 3,4-Dimethoxybenzylidene, 2-Nitrobenzylidene); Cyclic Ortho Esters (Methoxymethylene, Ethoxymethylene, Dimethoxymethylene, 1-Methoxyethylidene, 1-Ethoxyethy
  • 1,2-diol protecting groups include those shown in Table B, still more typically, epoxides, acetonides, cyclic ketals and aryl acetals. TABLE B wherein R 9 is C 1 -C 6 alkyl. Amino Protecting Groups
  • Another set of protecting groups include any of the typical amino protecting groups described by Greene at pages 315-385. They include:
  • Protected amino groups include carbamates, amides and amidines, e.g. —NHC(O)OR 1 , —NHC(O)R 1 or —N ⁇ CR 1 N(R 1 ) 2 .
  • Another protecting group, also useful as a prodrug for amino or —NH(R 5 ), is: See for example Alexander, J. et al (1996) J. Med Chem. 39:480-486. Amino Acid and Polypeptide Protecting Group and Conjugates
  • An amino acid or polypeptide protecting group of a compound of the invention has the structure R 15 NHCH(R 16 )C(O)—, where R 15 is H, an amino acid or polypeptide residue, or R 5 , and R 16 is defined below.
  • R 16 is lower alkyl or lower alkyl (C 1 -C 6 ) substituted with amino, carboxyl, amide, carboxyl ester, hydroxyl, C 6 -C 7 aryl, guanidinyl, imidazolyl, indolyl, sulfhydryl, sulfoxide, and/or alkylphosphate.
  • R 16 also is taken together with the amino acid ⁇ -N to form a proline residue (R 16 ⁇ —CH 2 ) 3 —).
  • R 16 is generally the side group of a naturally-occurring amino acid such as H, —CH 3 , —CH(CH 3 ) 2 , —CH 2 —CH(CH 3 ) 2 , —CHCH 3 —CH 2 -CH 3 , —CH 2 -C 6 H 5 , —CH 2 CH 2 —S—CH 3 , —CH 2 OH, —CH(OH)—CH 3 , —CH 2 —SH, —CH 2 —C 6 H 4 OH, —CH 2 —CO—NH 2 , —CH 2 —CH 2 —CO—NH 2 , —CH 2 —COOH, —CH 2 —CH 2 —COOH, —(CH 2 ) 4 —NH 2 and —(CH 2 ) 3 —NH—C(NH 2 )—NH 2 .
  • R 16 also includes 1-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl, imidazol-4-y
  • Another set of protecting groups include the residue of an amino-containing compound, in particular an amino acid, a polypeptide, a protecting group, —NHSO 2 R, NHC(O)R, —N(R) 2 , NH 2 or —NH(R)(H), whereby for example a carboxylic acid is reacted, i.e. coupled, with the amine to form an amide, as in C(O)NR 2 .
  • a phosphonic acid may be reacted with the amine to form a phosphonamidate, as in —P(O)(OR)(NR 2 ).
  • Amino acids have the structure R 17 C(O)CH(R 16 )NH—, where R 17 is —OH, —OR, an amino acid or a polypeptide residue.
  • Amino acids are low molecular weight compounds, on the order of less than about 1000 MW and which contain at least one amino or imino group and at least one carboxyl group. Generally the amino acids will be found in nature, i.e., can be detected in biological material such as bacteria or other microbes, plants, animals or man.
  • Suitable amino acids typically are alpha amino acids, i.e. compounds characterized by one amino or imino nitrogen atom separated from the carbon atom of one carboxyl group by a single substituted or unsubstituted alpha carbon atom.
  • hydrophobic residues such as mono-or di-alkyl or aryl amino acids, cycloalkylamino acids and the like. These residues contribute to cell permeability by increasing the partition coefficient of the parental drug. Typically, the residue does not contain a sulfhydryl or guanidino substituent.
  • Naturally-occurring amino acid residues are those residues found naturally in plants, animals or microbes, especially proteins thereof. Polypeptides most typically will be substantially composed of such naturally-occurring amino acid residues. These amino acids are glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, glutamic acid, aspartic acid, lysine, hydroxylysine, arginine, histidine, phenylalanine, tyrosine, tryptophan, proline, asparagine, glutamine and hydroxyproline. Additionally, unnatural amino acids, for example, valanine, phenylglycine and homoarginine are also included.
  • amino acids that are not gene-encoded may also be used in the present invention. All of the amino acids used in the present invention may be either the D- or L-optical isomer. In addition, other peptidomimetics are also useful in the present invention. For a general review, see Spatola, A. F., in Chemistry and Biochemistry of Amino Acids, Peptides and Proteins, B. Weinstein, eds., Marcel Dekker, New York, p. 267 (1983).
  • protecting groups are single amino acid residues or polypeptides they optionally are substituted at R 3 of substituents A 1 , A 2 or A 3 in Formula I, or substituted at R 3 of substituents A 1 , A 2 or A 3 in Formula II.
  • These conjugates are generally produced by forming an amide bond between a carboxyl group of the amino acid (or C-terminal amino acid of a polypeptide for example).
  • conjugates are formed between R 3 (Formula I) or R 3 (Formula II) and an amino group of an amino acid or polypeptide.
  • R 3 Forma I
  • R 3 Forma II
  • only one of any-site in the scaffold drug-like compound is amidated with an amino acid as described herein, although it is within the scope of this invention to introduce amino acids at more than one permitted site.
  • a carboxyl group of R 3 is amidated with an amino acid.
  • the ⁇ -amino or ⁇ -carboxyl group of the amino acid or the terminal amino or carboxyl group of a polypeptide are bonded to the scaffold, parental functionalities.
  • Carboxyl or amino groups in the amino acid side chains generally may be used to form the amide bonds with the parental compound or these groups may need to be protected during synthesis of the conjugates as described further below.
  • carboxyl-containing side chains of amino acids or polypeptides it will be understood that the carboxyl group optionally will be blocked, e.g. by R 1 , esterified with R 5 or amidated. Similarly, the amino side chains R 16 optionally will be blocked with R 1 or substituted with R 5 .
  • esters or amide bonds with side chain amino or carboxyl groups like the esters or amides with the parental molecule, optionally are hydrolyzable in vivo or in vitro under acidic (pH ⁇ 3) or basic (pH>10) conditions. Alternatively, they are substantially stable in the gastrointestinal tract of humans but are hydrolyzed enzymatically in blood or in intracellular environments.
  • the esters or amino acid or polypeptide amidates also are useful as intermediates for the preparation of the parental molecule containing free amino or carboxyl groups.
  • the free acid or base of the parental compound for example, is readily formed from the esters or amino acid or polypeptide conjugates of this invention by conventional hydrolysis procedures.
  • any of the D, L, meso, threo or erythro (as appropriate) racemates, scalemates or mixtures thereof may be used.
  • D isomers are useful.
  • L isomers are more versatile since they can be susceptible to both non-enzymatic and enzymatic hydrolysis, and are more efficiently transported by amino acid or dipeptidyl transport systems in the gastrointestinal tract.
  • R x or R y examples include the following:
  • Aminopolycarboxylic acids e.g., aspartic acid, ⁇ -hydroxyaspartic acid, glutamic acid, ⁇ -hydroxyglutamic acid, ⁇ -methylaspartic acid, ⁇ -methylglutamic acid, ⁇ , ⁇ -dimethylaspartic acid, ⁇ -hydroxyglutamic acid, ⁇ , ⁇ -dihydroxyglutamic acid, ⁇ -phenylglutamic acid, ⁇ -methyleneglutamic acid, 3-aminoadipic acid, 2-aminopimelic acid, 2-aminosuberic acid and 2-aminosebacic acid;
  • Amino acid amides such as glutamine and asparagine
  • Polyamino- or polybasic-monocarboxylic acids such as arginine, lysine, ⁇ -aminoalanine, ⁇ -aminobutyrine, ornithine, citruline, homoarginine, homocitrulline, hydroxylysine, allohydroxylsine and diaminobutyric acid;
  • Diaminodicarboxylic acids such as ⁇ , ⁇ ′-diaminosuccinic acid, ⁇ , ⁇ ′-diaminoglutaric acid, ⁇ , ⁇ ′-diaminoadipic acid, ⁇ , ⁇ ′-diaminopimelic acid, ⁇ , ⁇ ′-diamino- ⁇ -hydroxypimelic acid, ⁇ , ⁇ ′-diaminosuberic acid, ⁇ , ⁇ ′-diaminoazelaic acid, and ⁇ , ⁇ ′-diaminosebacic acid;
  • Imino acids such as proline, hydroxyproline, allohydroxyproline, ⁇ -methylproline, pipecolic acid, 5-hydroxypipecolic acid, and azetidine-2-carboxylic acid;
  • a mono- or di-alkyl (typically C 1 -C 8 branched or normal) amino acid such as alanine, valine, leucine, allylglycine, butyrine, norvaline, norleucine, heptyline, ⁇ -methylserine, ⁇ -amino- ⁇ -methyl- ⁇ -hydroxyvaleric acid, ⁇ -amino- ⁇ -methyl- ⁇ -hydroxyvaleric acid, ⁇ -amino- ⁇ -methyl- ⁇ -hydroxycaproic acid, isovaline, ⁇ -methylglutamic acid, ⁇ -aminoisobutyric acid, ⁇ -aminodiethylacetic acid, ⁇ -aminodiisopropylacetic acid, ⁇ -aminodi-n-propylacetic acid, ⁇ -aminodiisobutylacetic acid, ⁇ -aminodi-n-butylacetic acid, ⁇ -aminoethylisopropylacetic acid,
  • Aliphatic ⁇ -amino- ⁇ -hydroxy acids such as serine, ⁇ -hydroxyleucine, ⁇ -hydroxynorleucine, ⁇ -hydroxynorvaline, and ⁇ -amino- ⁇ -hydroxystearic acid;
  • ⁇ -Amino, ⁇ -, ⁇ -, ⁇ - or ⁇ -hydroxy acids such as homoserine, ⁇ -hydroxynorvaline, ⁇ -hydroxynorvaline and ⁇ -hydroxynorleucine residues; canavine and canaline; ⁇ -hydroxyornithine;
  • 2-hexosaminic acids such as D-glucosaminic acid or D-galactosaminic acid
  • ⁇ -Amino- ⁇ -thiols such as penicillamine, ⁇ -thiolnorvaline or ⁇ -thiolbutyrine;
  • cysteine Other sulfur containing amino acid residues including cysteine; homocystine, ⁇ -phenylmethionine, methionine, S-allyl-L-cysteine sulfoxide, 2-thiolhistidine, cystathionine, and thiol ethers of cysteine or homocysteine;
  • Phenylalanine, tryptophan and ring-substituted ⁇ -amino acids such as the phenyl- or cyclohexylamino acids ⁇ -aminophenylacetic acid, ⁇ -aminocyclohexylacetic acid and ⁇ -amino- ⁇ -cyclohexylpropionic acid; phenylalanine analogues and derivatives comprising aryl, lower alkyl, hydroxy, guanidino, oxyalkylether, nitro, sulfur or halo-substituted phenyl (e.g., tyrosine, methyltyrosine and o-chloro-, p-chloro-, 3,4dichloro, o-, m- or p-methyl-, 2,4,6-trimethyl-, 2-ethoxy-5-nitro-, 2-hydroxy-5-nitro- and p-nitro-phenylalanine); furyl-, thienyl-,
  • ⁇ -Amino substituted amino acids including sarcosine (N-methylglycine), N-benzylglycine, N-methylalanine, N-benzylalanine, N-methylphenylalanine, N-benzylphenylalanine, N-methylvaline and N-benzylvaline; and
  • ⁇ -Hydroxy and substituted ⁇ -hydroxy amino acids including serine, threonine, allothreonine, phosphoserine and phosphothreonine.
  • Polypeptides are polymers of amino acids in which a carboxyl group of one amino acid monomer is bonded to an amino or imino group of the next amino acid monomer by an amide bond.
  • Polypeptides include dipeptides, low molecular weight polypeptides (about 1500-5000 MW) and proteins. Proteins optionally contain 3, 5, 10, 50, 75, 100 or more residues, and suitably are substantially sequence-homologous with human, animal, plant or microbial proteins. They include enzymes (e.g., hydrogen peroxidase) as well as immunogens such as KLH, or antibodies or proteins of any type against which one wishes to raise an immune response. The nature and identity of the polypeptide may vary widely.
  • polypeptide amidates are useful as immunogens in raising antibodies against either the polypeptide (if it is not immunogenic in the animal to which it is administered) or against the epitopes on the remainder of the compound of this invention.
  • Antibodies capable of binding to the parental non-peptidyl compound are used to separate the parental compound from mixtures, for example in diagnosis or manufacturing of the parental compound.
  • the conjugates of parental compound and polypeptide generally are more immunogenic than the polypeptides in closely homologous animals, and therefore make the polypeptide more immunogenic for facilitating raising antibodies against it.
  • the polypeptide or protein may be immunogenic in an animal typically used to raise antibodies, e.g., rabbit, mouse, horse, or rat.
  • the polypeptide optionally contains a peptidolytic enzyme cleavage site at the peptide bond between the first and second residues adjacent to the acidic heteroatom. Such cleavage sites are flanked by enzymatic recognition structures, e.g. a particular sequence of residues recognized by a peptidolytic enzyme.
  • Peptidolytic enzymes for cleaving the polypeptide conjugates of this invention are well known, and in particular include carboxypeptidases, which digest polypeptides by removing C-terminal residues, and are specific in many instances for particular C-terminal sequences.
  • carboxypeptidases which digest polypeptides by removing C-terminal residues, and are specific in many instances for particular C-terminal sequences.
  • Such enzymes and their substrate requirements in general are well known.
  • a dipeptide (having a given pair of residues and a free carboxyl terminus) is covalently bonded through its ⁇ -amino group to the phosphorus or carbon atoms of the compounds herein.
  • a phosphonate group substituted with an amino acid or peptide will be cleaved by the appropriate peptidolytic enzyme, leaving the carboxyl of the proximal amino acid residue to autocatalytically cleave the phosphonoamidate bond.
  • Suitable dipeptidyl groups are AA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK, AM, AF, AP, AS, AT, AW, AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, RM, RF, RP, RS, RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL, NK, NM, NF, NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG, DH, DI, DL, DK, DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, C
  • Tripeptide residues are also useful as protecting groups.
  • the sequence —X 4 -pro-X 5 — (where X 4 is any amino acid residue and X 5 is an amino acid residue, a carboxyl ester of proline, or hydrogen) will be cleaved by luminal carboxypeptidase to yield X 4 with a free carboxyl, which in turn is expected to autocatalytically cleave the phosphonoamidate bond.
  • the carboxy group of X 5 optionally is esterified with benzyl.
  • Dipeptide or tripeptide species can be selected on the basis of known transport properties and/or susceptibility to peptidases that can affect transport to intestinal mucosal or other cell types.
  • Dipeptides and tripeptides lacking an ⁇ -amino group are transport substrates for the peptide transporter found in brush border membrane of intestinal mucosal cells (Bai, J. P. F., (1992) Pharm Res. 9:969-978.
  • Transport competent peptides can thus be used to enhance bioavailability of the amidate compounds.
  • Di- or tripeptides having one or more amino acids in the D configuration may be compatible with peptide transport.
  • Amino acids in the D configuration can be used to reduce the susceptibility of a di- or tripeptide to hydrolysis by proteases common to the brush border such as aminopeptidase N.
  • di- or tripeptides alternatively are selected on the basis of their relative resistance to hydrolysis by proteases found in the lumen of the intestine.
  • tripeptides or polypeptides lacking asp and/or glu are poor substrates for aminopeptidase A
  • di- or tripeptides lacking amino acid residues on the N-terminal side of hydrophobic amino acids are poor substrates for endopeptidase
  • peptides lacking a pro residue at the penultimate position at a free carboxyl terminus are poor substrates for carboxypeptidase P.
  • Similar considerations can also be applied to the selection of peptides that are either relatively resistant or relatively susceptible to hydrolysis by cytosolic, renal, hepatic, serum or other peptidases.
  • Such poorly cleaved polypeptide amidates are immunogens or are useful for bonding to proteins in order to prepare immunogens.
  • the known experimental or approved protease inhibitor drugs which can be derivatized in accord with the present invention must contain at least one functional group capable of linking, i.e. bonding to the phosphorus atom in the phosphonate moiety.
  • the phosphonate derivatives of Formulas I-VIII may cleave in vivo in stages after they have reached the desired site of action, i.e. inside a cell.
  • One mechanism of action inside a cell may entail a first cleavage, e.g. by esterase, to provide a negatively-charged “locked-in” intermediate. Cleavage of a terminal ester grouping in Formulas I-VIII thus affords an unstable intermediate which releases a negatively charged “locked in” intermediate.
  • intracellular enzymatic cleavage or modification of the phosphonate prodrug compound may result in an intracellular accumulation of the cleaved or modified compound by a “trapping” mechanism.
  • the cleaved or modified compound may then be “locked-in” the cell i.e. accumulate in the cell by a significant change in charge, polarity, or other physical property change which decreases the rate at which the cleaved or modified compound can exit the cell, relative to the rate at which it entered as the phosphonate prodrug.
  • Other mechanisms by which a therapeutic effect is achieved may be operative as well.
  • Enzymes which are capable of an enzymatic activation mechanism with the phosphonate prodrug compounds of the invention include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphatases.
  • the drug is activated in vivo by phosphorylation.
  • activation may occur in the present system by enzymatic conversion of the “locked-in” intermediate with phosphokinase to the active phosphonate diphosphate and/or by phosphorylation of the drug itself after its release from the “locked-in” intermediate as described above.
  • the original nucleoside-type drug will be converted, via the derivatives of this invention, to the active phosphorylated species.
  • the selected drug contains multiple reactive hydroxyl functions
  • a mixture of intermediates and final products may again be obtained.
  • all hydroxy groups are approximately equally reactive, there is not expected to be a single, predominant product, as each mono-substituted product will be obtained in approximate by equal amounts, while a lesser amount of multiply-substituted product will also result.
  • one of the hydroxyl groups will be more susceptible to substitution than the other(s), e.g. a primary hydroxyl will be more reactive than a secondary hydroxyl, an unhindered hydroxyl will be more reactive than a hindered one. Consequently, the major product will be a mono-substituted one in which the most reactive hydroxyl has been derivatized while other mono-substituted and multiply-substituted products may be obtained as minor products.
  • Formula I compounds having a 3-hydroxy-5-amino-pentamide core include Indinavir-like phosphonate protease inhibitors (ILPPI).
  • Compounds of the invention include phosphonate analogs of other known PI compounds with a 3-hydroxy-5-amino-pentamide core which have been identified as CGP-49689, CGP-53437, CGP-57813 (Novartis); L-689502, L-693549, L-748496, L-754394, MK-944a, Iddb63, Iddb88 (Merck); Lasinavir (Bristol-Myers Squibb); U-81749 (PNU/Pfizer); SB-203386, SKF-108922 (SmithKline Beecham).
  • Formula II compounds having a 2-hydroxy-1,3-amino-propylamide or 2-hydroxy-1,3-amino-propylaminosulfone core include Amprenavir-like phosphonate protease inhibitors (AMLPPI).
  • AMLPPI Amprenavir-like phosphonate protease inhibitors
  • Compounds of the invention include phosphonate analogs of other known PI compounds with a 2-hydroxy-3-amido-propylamide or 2-hydroxy-3-amido-propylaminosulfone core which have been identified as Droxinavir, Telinavir, Iddb51 (Searle); Ph4556 (WO 95/29922; Ph5145 (WO 96/31527; DPC-681, DPC-684 (DuPont); VB-11328 (Vertex); TMC-114 (Tibotech/Johnson & Johnson).
  • Formula II compounds also include phosphonate analogs of fosamprenavir where the 2-hydroxy is phosphorylated, i.e. having a or 2-phosphate-1,3-amino-propylaminosulfone core (U.S. Pat. No. 6,436,989).
  • the embodiments of the invention also include the following phosphonate analogs of Formula II, represented as Formulas IIa-Ig: described as “(I)” in: WO 94/05639 (published 17 Mar. 1994) at page 4, line 15, to page 6, line 27, page 15, line 21, to page 17, line 33, and Claim 1; U.S. Pat. No. 5,585,397 (issued 17 Dec. 1996) at col. 2, line 45, to col. 3, line 53, and col. 8, line 1, to col. 9, line 12; U.S. Pat. No. 5,783,701 (issued 21 Jul. 1998) at col. 2, line 43, to col. 3, line 64, col. 8, line 13, to col. 9, line 33, and Claim 1; U.S. Pat. No.
  • Formula III compounds having a 2-hydroxy-3-amino-propylamide core include KNI-like phosphonate protease inhibitors (KNILPPI).
  • KNILPPI KNI-like phosphonate protease inhibitors
  • Compounds of the invention include phosphonate analogs of other known PI compounds with a 2-hydroxy-3-amido-propylamide or 2-hydroxy-3-amido-propylaminosulfone core which have been identified as KNI-764 (JE-2147, AG1776); KNI-102, KNI-227, KNI-241, KNI-272, KNI-413, KNI-549, KNI-577, KNI-727, JE-2178 (Japan Energy); Ph3939 (EP 587311); R-87366, Iddb134 (Sankyo); VLE-776 (Scripps Institute).
  • Formula IV compounds having a 2-hydroxy-4-amino-butylamine core include Ritonavir-like phosphonate protease inhibitors (RLPPI) and Lopinavir-like phosphonate protease inhibitors (LLPPI).
  • RLPPI Ritonavir-like phosphonate protease inhibitors
  • LLPPI Lopinavir-like phosphonate protease inhibitors
  • Compounds of the invention include phosphonate analogs of other known PI compounds with a 2-hydroxy-4-amino-butylamine core which have been identified as A-76928, A-80735, A-80987 (Abbott Laboratories).
  • Formula V compounds having an acylated 1,3-diaminopropane core include Saquinavir-like phosphonate protease inhibitors (SLPPI) and Nelfmavir-like phosphonate protease inhibitors (NLPPI).
  • SLPPI Saquinavir-like phosphonate protease inhibitors
  • NLPPI Nelfmavir-like phosphonate protease inhibitors
  • Compounds of the invention include phosphonate analogs of other known PI compounds with an acylated 1,3-diaminopropane core which have been identified as Ro-33-2910, Ro-33-4649 (Hofman La Roche); BMS-182193, BMS-186318, BMS-187071 (Bristol-Myers Squibb); JG-365 (Univ.
  • L-704325, L-738872, L-739594, L-743770 Merck & Co.
  • LB-71206 LG Chemical Ltd.
  • LY-296242, LY-314163, LY-316683, LY-326620 Eli Lilly Co.
  • Palinavir BioMega/B1
  • Ph5640, Ph6090 WO 97/21100.
  • Formula VI compounds having a 2-hydroxy-3-diaza-propylamide core include Atazanavir-like phosphonate protease inhibitors (ATLPPI).
  • ATLPPI Atazanavir-like phosphonate protease inhibitors
  • Compounds of the invention include phosphonate analogs of other known PI compounds with a 2-hydroxy-3-diaza-propylamide core which have been identified as CGP-56603, CGP-53820, CGP-70726 (Novartis), ABT-538 (Abbott Laboratories), and DG-35 (National Cancer Institute).
  • Formula VII compounds having sulfonamide 5,6-dihydro-4-hydroxy-2-pyrone core include Tipranavir-like phosphonate protease inhibitors (TLPPI).
  • Formula VIII compounds have a six or seven-membered ring, cyclic carbonyl, sulfone, or sulfonyl core, where Y 1 is oxygen, sulfur, or substituted nitrogen and M2 is 1 or 2.
  • the invention includes Cyclic carbonyl-like phosphonate protease inhibitor compounds
  • Cyclic carbonyl protease inhibitors without a phosphonate group are described in U.S. Pat. Nos. RE37781; 6,503,898; 5,880,295; 5,811,422; 5,610,294; 5,559,252; and 5,506,355, as well as patent applications and granted patents which are equivalents of, or related by priority claims thereto.
  • CCLPPI compounds also include phosphonate analogs of: described as “(I)” in WO 94/19329 (published 1 Sep. 1994) at page 4, line 23, to page 21, line 16 and Claim 1. Also contemplated are patent applications and granted patents which are equivalents of or related by priority claims to WO 94/19329. Stereoisomers
  • the compounds of the invention may have chiral centers, e.g. chiral carbon or phosphorus atoms.
  • the compounds of the invention thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers.
  • the compounds of the invention include enriched or resolved optical isomers at any or all asymmetric, chiral atoms. In other words, the chiral centers apparent from the depictions are provided as the chiral isomers or raceric mixtures.
  • racemic and diastereomeric mixtures are all within the scope of the invention.
  • the racemic mixtures are separated into their individual, substantially optically pure isomers through well-known techniques such as, for example, the separation of diastereomeric salts formed with optically active adjuncts, e.g., acids or bases followed by conversion back to the optically active substances.
  • optically active adjuncts e.g., acids or bases followed by conversion back to the optically active substances.
  • the desired optical isomer is synthesized by means of stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material.
  • the compounds of the invention can also exist as tautomeric isomers in certain cases. All though only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention.
  • ene-amine tautomers can exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and all their possible tautomeric forms are within the scope of the invention.
  • compositions of this invention optionally comprise salts of the compounds herein, especially pharmaceutically acceptable non-toxic salts containing, for example, Na + , Li + , K + , Ca °2 and Mg +2 .
  • Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid.
  • Monovalent salts are preferred if a water soluble salt is desired.
  • Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention.
  • metal salts which are prepared in this way are salts containing Li + , Na + , and K + .
  • a less soluble metal salt may be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
  • compositions herein comprise compounds of the invention in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
  • the salts of the parental compounds with one or more amino acids are suitable, especially the naturally-occurring amino acids found as protein components, although the amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
  • a basic or acidic group e.g., lysine, arginine or glutamic acid
  • a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
  • Another aspect of the invention relates to methods of inhibiting the activity of HV protease comprising the step of treating a sample suspected of containing HIV with a composition of the invention.
  • compositions of the invention may act as inhibitors of HIV protease, as intermediates for such inhibitors or have other utilities as described below.
  • the inhibitors will bind to locations on the surface or in a cavity of HIV protease having a geometry unique to HIV protease.
  • Compositions binding HIV protease may bind with varying degrees of reversibility. Those compounds binding substantially irreversibly are ideal candidates for use in this method of the invention. Once labeled, the substantially irreversibly binding compositions are useful as probes for the detection of HIV protease.
  • the invention relates to methods of detecting HIV protease in a sample suspected of containing HIV protease comprising the steps of: treating a sample suspected of containing HIV protease with a composition comprising a compound of the invention bound to a label; and observing the effect of the sample on the activity of the label.
  • Suitable labels are well known in the diagnostics field and include stable free radicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups and chromogens.
  • the compounds herein are labeled in conventional fashion using functional groups such as hydroxyl, carboxyl, sulfhydryl or amino.
  • samples suspected of containing HIV protease include natural or man-made materials such as living organisms; tissue or cell cultures; biological samples such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like); laboratory samples; food, water, or air samples; bioproduct samples such as extracts of cells, particularly recombinant cells synthesizing a desired glycoprotein; and the like.
  • biological material samples blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like
  • laboratory samples food, water, or air samples
  • bioproduct samples such as extracts of cells, particularly recombinant cells synthesizing a desired glycoprotein
  • samples can be contained in any medium including water and organic solvent ⁇ water mixtures. Samples include living organisms such as humans, and man made materials such as cell cultures.
  • the treating step of the invention comprises adding the composition of the invention to the sample or it comprises adding a precursor of the composition to the sample.
  • the addition step comprises any method of administration as described above.
  • the activity of HIV protease after application of the composition can be observed by any method including direct and indirect methods of detecting HIV protease activity. Quantitative, qualitative, and semiquantitative methods of determining HIV protease activity are all contemplated. Typically one of the screening methods described above are applied, however, any other method such as observation of the physiological properties of a living organism are also applicable.
  • Organisms that contain HIV protease include the HIV virus.
  • the compounds of this invention are useful in the treatment or prophylaxis of HIV infections in animals or in man.
  • compositions of the invention are screened for inhibitory activity against HIV protease by any of the conventional techniques for evaluating enzyme activity.
  • typically compositions are first screened for inhibition of HIV protease in vitro and compositions showing inhibitory activity are then screened for activity in vivo.
  • Compositions having in vitro Ki (inhibitory constants) of less then about 5 ⁇ 10 ⁇ 6 M, typically less than about 1 ⁇ 10 ⁇ 7 M and preferably less than about 5 ⁇ 10 ⁇ 8 M are preferred for in vivo use.
  • the compounds of this invention are formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice.
  • Tablets will contain excipients, glidants, fillers, binders and the like.
  • Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as those set forth in the “Handbook of Pharmaceutical Excipients” (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
  • the pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10.
  • the formulations both for veterinary and for human use, of the invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients.
  • the carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
  • the formulations include those suitable for the foregoing administration routes.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be administered as a bolus, electuary or paste.
  • a tablet is made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.
  • the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w.
  • the active ingredients may be employed with either a paraffmic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax
  • the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Emulgents and emulsion stabilizers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used.
  • compositions according to the present invention comprise a combination according to the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
  • Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration.
  • tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable.
  • excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example calcium phosphate or kaolin
  • an oil medium such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate).
  • a suspending agent
  • the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
  • Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives.
  • a dispersing or wetting agent e.g., sodium tartrate
  • suspending agent e.g., sodium EDTA
  • preservatives e.g., sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these.
  • Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
  • the emulsion may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, such as glycerol sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • sweetening agents such as glycerol sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight:weight).
  • the pharmaceutical composition can be prepared to provide easily measurable amounts for administration.
  • an aqueous solution intended for intravenous infusion may contain from about 3 to 500 ⁇ g of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • the active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%, and particularly about 1.5% w/w.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns, such as 0.5, 1, 30, 35 etc., which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.
  • Suitable formulations include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of HIV infections as described below.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
  • sterile liquid carrier for example water for injection
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.
  • controlled release formulations in which the release of the active ingredient are controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient.
  • Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses) or against an active viral infection, the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. It can be expected to be from about 0.0001 to about 100 mg/kg body weight per day. Typically, from about 0.01 to about 10 mg/kg body weight per day. More typically, from about 0.01 to about 5 mg/kg body weight per day. More typically, from about 0.05 to about 0.5 mg/kg body weight per day.
  • the daily candidate dose for an adult human of approximately 70 kg body weight will range from 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and may take the form of single or multiple doses.
  • One or more compounds of the invention are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the recipient.
  • An advantage of the compounds of this invention is that they are orally bioavailable and can be dosed orally.
  • compositions of the invention are also used in combination with other active ingredients. Such combinations are selected based on the condition to be treated, cross-reactivities of ingredients and pharmaco-properties of the combination. For example, when treating viral infections the compositions of the invention may be combined with other antivirals such as other protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors or HIV integrase inhibitors.
  • any compound of the invention with one or more other active ingredients in a unitary dosage form for simultaneous or sequential administration to an HIV infected patient.
  • the combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.
  • Second and third active ingredients in the combination may have anti-HIV activity.
  • Exemplary active ingredients to be administered in combination with compounds of the invention are protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and HIV integrase inhibitors.
  • the combination therapy may provide “synergy” and ⁇ synergistic”, i.e. the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.
  • a synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen.
  • a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g. in separate tablets, pins or capsules, or by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e. serially
  • effective dosages of two or more active ingredients are administered together.
  • a synergistic anti-viral effect denotes an antiviral effect which is greater than the predicted purely additive effects of the individual compounds of the combination.
  • the invention includes novel and unobvious compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.
  • Such products typically are identified by preparing a radiolabelled (e.g. 14 C or 3 H) compound of the invention, administering it parenterally in a detectable dose (e.g.
  • metabolite structures are determined in conventional fashion, e.g. by MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well-known to those skilled in the art.
  • the conversion products so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention even if they possess no HIV protease inhibitory activity of their own.
  • compositions of the invention are prepared by any of the applicable techniques of organic synthesis. Many such techniques are well known in the art, such as those elaborated in “Compendium of Organic Synthetic Methods” (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6, Michael B.
  • Dialkyl phosphonates may be prepared according to the methods of: Quast et al (1974) Synthesis 490; Stowell et al (1990) Tetrahedron Lett. 3261; U.S. Pat. No. 5,663,159.
  • phosphonate esters In general synthesis of phosphonate esters is achieved by coupling a nucleophile amine or alcohol with the corresponding activated phosphonate electrophilic precursor.
  • chlorophosphonate addition on to 5′-hydroxy of nucleoside is a well known method for preparation of nucleoside phosphate monoesters.
  • the activated precursor can be prepared by several well known methods.
  • Chlorophosphonates useful for synthesis of the prodrugs are prepared from the substituted-1,3-propanediol (Wissner, et al, (1992) J. Med Chem. 35:1650). Chlorophosphonates are made by oxidation of the corresponding chlorophospholanes (Anderson, et al, (1984) J. Org. Chem.
  • chlorophosphonate agent is made by treating substituted-1,3-diols with phosphorusoxychloride (Patois, et al, (1990) J. Chem. Soc. Perkin Trans. I, 1577). Chlorophosphonate species may also be generated in situ from corresponding cyclic phosphites (Silverburg, et al., (1996) Tetrahedron Lett., 37:771-774), which in turn can be either made from chlorophospholane or phosphoramidate intermediate.
  • Phosphoroflouridate intermediate prepared either from pyrophosphate or phosphoric acid may also act as precursor in preparation of cyclic prodrugs (Watanabe et al., (1988) Tetrahedron Lett., 29:5763-66). Caution: fluorophosphonate compounds may be highly toxic!
  • Phosphonate prodrugs of the present invention may also be prepared from the precursor free acid by Mitsunobu reactions (Mitsunobu, (1981) Synthesis, 1; Campbell, (1992) J. Org. Chem., 52:6331), and other acid coupling reagents including, but not limited to, carbodjimides (Alexander, et al, (1994) Collect. Czech. Chem. Commun. 59:1853; Casara, et al, (1992) Bioorg. Med. Chem. Lett., 2:145; Ohashi, et al.
  • Aryl halides undergo Ni +2 catalyzed reaction with phosphite derivatives to give aryl phosphonate containing compounds (Balthazar, et al (1980) J. Org. Chem. 45:5425).
  • Phosphonates may also be prepared from the chlorophosphonate in the presence of a palladium catalyst using aromatic triflates (Petrakis, et al, (1987) J. Am. Chem. Soc. 109:2831; Lu, et al, (1987) Synthesis, 726).
  • aryl phosphonate esters are prepared from aryl phosphates under anionic rearrangement conditions (Melvin (1981) Tetrahedron Lett.
  • N-Alkoxy aryl salts with alkali metal derivatives of cyclic alkyl phosphonate provide general synthesis for heteroaryl-2-phosphonate linkers (Redmore (1970) J. Org. Chem. 35:4114). These above mentioned methods can also be extended to compounds where the W 5 group is a heterocycle.
  • Cyclic-1,3-propanyl prodrugs of phosphonates are also synthesized from phosphonic diacids and substituted propane-1,3-diols using a coupling reagent such as 1,3-dicyclohexylcarbodiimide (DCC) in presence of a base (e.g., pyridine).
  • a coupling reagent such as 1,3-dicyclohexylcarbodiimide (DCC) in presence of a base (e.g., pyridine).
  • DCC 1,3-dicyclohexylcarbodiimide
  • EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • the carbamoyl group may be formed by reaction of a hydroxy group according to the methods known in the art, including the teachings of Ellis, US 2002/0103378 A1 and Hajima, U.S. Pat. No. 6,018,049.
  • compositions of the invention are provided below. These methods are intended to illustrate the nature of such preparations are not intended to limit the scope of applicable methods.
  • reaction conditions such as temperature, reaction time, solvents, work-up procedures, and the like, will be those common in the art for the particular reaction to be performed.
  • the cited reference material, together with material cited therein, contains detailed descriptions of such conditions.
  • temperatures will be ⁇ 100° C. to 200° C.
  • solvents will be aprotic or protic
  • reaction times will be 10 seconds to 10 days.
  • Work-up typically consists of quenching any unreacted reagents followed by partition between a water/organic layer system (extraction) and separating the layer containing the product.
  • Oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20° C.), although for metal hydride reductions frequently the temperature is reduced to 0° C. to ⁇ 100° C., solvents are typically aprotic for reductions and may be either protic or aprotic for oxidations. Reaction times are adjusted to achieve desired conversions.
  • Condensation reactions are typically carried out at temperatures near room temperature, although for non-equilibrating, kinetically controlled condensations reduced temperatures (0° C. to ⁇ 100° C.) are also common.
  • Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled reactions).
  • Standard synthetic techniques such as azeotropic removal of reaction by-products and use of anhydrous reaction conditions (e.g. inert gas environments) are common in the art and will be applied when applicable.
  • treated means contacting, mixing, reacting, allowing to react, bringing into contact, and other terms common in the art for indicating that one or more chemical entities is treated in such a manner as to convert it to one or more other chemical entities.
  • treating compound one with compound two is synonymous with “allowing compound one to react with compound two”, “contacting compound one with compound two”, “reacting compound one with compound two”, and other expressions common in the art of organic synthesis for reasonably indicating that compound one was “treated”, “reacted”, “allowed to react”, etc., with compound two.
  • “Treating” indicates the reasonable and usual manner in which organic chemicals are allowed to react. Normal concentrations (0.01M to 10M, typically 0.1M to 1M), temperatures ( ⁇ 100° C. to 250° C., typically ⁇ 78° C. to 150° C., more typically ⁇ 78° C. to 100° C., still more typically 0° C. to 100° C.), reaction vessels (typically glass, plastic, metal), solvents, pressures, atmospheres (typically air for oxygen and water insensitive reactions or nitrogen or argon for oxygen or water sensitive), etc., are intended unless otherwise indicated.
  • the knowledge of similar reactions known in the art of organic synthesis are used in selecting the conditions and apparatus for “treating” in a given process. In particular, one of ordinary skill in the art of organic synthesis selects conditions and apparatus reasonably expected to successfully carry out the chemical reactions of the described processes based on the knowledge in the art.
  • reaction products from one another and/or from starting materials.
  • the desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art.
  • separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.
  • Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium, and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
  • SMB simulated moving bed
  • reagents selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like.
  • reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like.
  • the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LIX), or the like.
  • a single stereoisomer, e.g. an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (“Stereochemistry of Carbon Compounds,” (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chronzatogr., 113:(3) 283-302).
  • Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions.
  • diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, ⁇ -methyl- ⁇ -phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid.
  • the diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography.
  • addition of chiral carboxylic or sulfonic acids such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.
  • the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair
  • Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched xanthene.
  • a method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g.
  • a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase ( Chiral Liquid Chromatography (1989) W. J. Lough, Ed Chapman and Hall, New York; Okamoto, (1990) J. of Chromatogr. 513:375-378).
  • Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.
  • the term “etc” appears as a substituent on chemical structures and as a term within the schemes. When used in the charts, the term is defined for each chart. When the term “etc” appears in a scheme and is not a substituent on a chemical structure, it means “and the like”.
  • SLPPI Saquinavir-Like Phosphonate Protease Inhibitors
  • the intermediate compounds 1 to 6 incorporate a phosphonate moiety (R 1 O) 2 P(O) connected to the nucleus by means of a variable linking group, designated as “link” in the attached structures.
  • Charts 4 and 5 illustrate examples of the lining groups present in the structures 1-5, and in which “etc” refers to the scaffold, e.g., saquinavir.
  • R 1 ⁇ H, alkyl, haloalkyl, alkenyl, aralkyl, aryl
  • R 7 ⁇ alkyl, CH 2 SO 2 CH 3 ,C(CH 3 ) 2 SO 2 CH 3 ,CH 2 CONH 2 , CH 2 SCH 3 , imidaz-4-ylmethyl,
  • R 7 alkyl, CH 2 SO 2 CH 3 ,C(CH 3 ) 2 SO 2 CH 3 ,CH 2 CONH 2 , CH 2 SCH 3 , imidaz-4-ylmethyl, CH 2 NHAc, CH 2 NHCOCF 3
  • R 7 alkyl, CH 2 SO 2 CH 3 ,C(CH 3 ) 2 SO 2 CH 3 ,CH 2 CONH 2 , CH 2 SCH 3 , imidaz-4-ylmethyl, CH 2 NHAc, CH 2 NHCOCF 3
  • Schemes 1-69 illustrate the syntheses of the intermediate phosphonate compounds of this invention, 1-4, and of the intermediate compounds necessary for their synthesis.
  • Scheme 1 illustrates one method for the preparation of the phosphonate esters 1.6 in which X is a direct bond.
  • an amine R 2 NHCH(R 3 )CONHR 4 1.2 is reacted with an epoxide 1.1 to afford the aminoalcohol 1.3.
  • the preparation of the epoxide 1.1 is described below, (Scheme 2)
  • the preparation of aminoalcohols by reaction between an amine and an epoxide is described, for example, in Advanced Organic Chemistry, by J. March, McGraw Hill, 1968, p 334.
  • the reaction can be effected by means of catalytic hydrogenation in the presence of hydrogen or a hydrogen donor, by reaction with a Lewis acid such as aluminum chloride or boron tribromide, or by basic hydrolysis, for example employing barium hydroxide in an aqueous organic solvent mixture.
  • a Lewis acid such as aluminum chloride or boron tribromide
  • basic hydrolysis for example employing barium hydroxide in an aqueous organic solvent mixture.
  • the protected amine 1.3 is converted into the free amine 1.4 by means of hydrogenation over 10% palladium on carbon catalyst in ethanol as described in U.S. Pat. No. 5196438.
  • the amine product 1.4 is then reacted with a carboxylic acid 1.5 to afford the amide 1.6.
  • the coupling reaction of amines 1.4 and a carboxylic acid 1.5 can be effected under a variety of conditions, for example as described in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 972ff.
  • the carboxylic acid can be activated by conversion to an imidazolide, mixed anhydride or active ester such as, for example, the ester with hydroxybenztriazole or N-hydroxysuccinimide.
  • the reactants can be combined in the presence of a carbodiimide, such as, for example, dicyclohexylcarbodiimide or diisopropylcarbodiimide, to afford the amide product 1.6.
  • equimolar amounts of the amine and the carboxylic acid are reacted in tetrahydrofuran at ca. ⁇ 10°, in the presence of dicyclohexylcarbodiimide, as described in U.S. Pat. No. 5,196,438, to afford the amide 1.6.
  • the carboxylic acid 1.5 employed in the above reaction is obtained by means of the reaction between the substituted quinoline-2-carboxylic acid 1.7, in which the substituent A is either the group link-P(O)(OR 1 ) 2 or a precursor group thereto, such as [OH], [SH], Br, as described below, and an aminoacid 1.8.
  • the reaction is performed under similar conditions to those described above for the preparation of the amide 1.6.
  • the quinoline carboxylic acid 1.7 is reacted with N-hydroxy succinimide and a carbodiimide to afford the hydroxysuccinimide ester, which is then reacted with the aminoacid 1.8 in dimethylformamide at ambient temperature for 2-4 days, as described in U.S. Pat. No. 5,196,438, to afford the amide product 1.5.
  • the preparation of the substituted quinoline carboxylic acids 1.7 is described below, Schemes 24-27.
  • Scheme 2 illustrates the preparation of the epoxides 1.1 used above in Scheme 1.
  • the preparation of the epoxide 1.1 in which R10 is H is described in J. Med. Chem., 1997, 40, 3979.
  • Analogs in which R10 is one of the substituents defined in Chart 2 are prepared as shown in Scheme 2.
  • a substituted phenylalanine 2.1 is first converted into the benzyloxycarbonyl derivative 2.2.
  • the preparation of benzyloxycarbonyl amines is described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Second Edition 1990, p. 335.
  • the aminoacid 2.1 is reacted with benzyl chloroformate or dibenzyl carbonate in the presence of a suitable base such as sodium carbonate or triethylamine, to afford the protected amine product 2.2.
  • a suitable base such as sodium carbonate or triethylamine
  • the carboxylic acid is first converted into an activated derivative such as the acid chloride 2.3, in which X is Cl, for example by treatment with oxalyl chloride, or into a mixed carbonate, for example by treatment with isobutyl chloroformate, and the activated derivative thus obtained is reacted with ethereal diazomethane, to afford the diazoketone 2.4.
  • the reaction is performed by the addition of a solution of the activated carboxylic acid derivative to an ethereal solution of three or more molar equivalents of diazomethane at 0° C.
  • the diazoketone is converted into the chloroketone 2.5 by reaction with anhydrous hydrogen chloride, in a suitable solvent such as diethyl ether, as described in J. Med.
  • Scheme 3 illustrates the preparation of the amine reactant R 2 NHCH(R 3 )CONHR 4 (1.2) employed above (Scheme 1).
  • the carboxylic acid R 2 NHCH( 3 )COOH 3.1 is first converted into the N-protected analog 3.2, for example by reaction with benzyloxychloroformate and triethylamine in tetrahydrofuran.
  • the carboxyl group is then activated, for example by conversion to the acid chloride or a mixed anhydride, or by reaction with isobutyl chloroformate, as described in Chimia, 50, 532, 1996 and in Synthesis, 1972, 453, and the activated derivative is then reacted with the amine R 4 NH 2 to produce the amide 3.4.
  • Deprotection for example as described above, then affords the free amine 1.2.
  • Scheme 4 depicts an alternative method for the preparation of the compounds 1 in which X is a direct bond.
  • a hydroxymethyl-substituted oxazolidinone 4.1 is converted into an activated derivative 4.2 which is then reacted with the amine R 2 NHCH( 3 )CONHR 4 (1.2) to afford the amide 4.3.
  • the preparation of the hydroxymethyl-substituted oxazolidinone 4.1 is described below, (Scheme 5)
  • the hydroxyl group can be converted into a bromo derivative, for example by reaction with triphenylphosphine and carbon tetrabromide, as described in J. An. Chem.
  • Equimolar amounts of the reactants are combined in an inert solvent such as dimethylformamide, acetonitrile or acetone, optionally in the presence of an organic or inorganic base such as triethylamine or sodium carbonate, at from about 0° C. to 100° C. to afford the amine product 4.3.
  • an organic or inorganic base such as triethylamine or sodium carbonate
  • the reaction is performed in methyl isobutyl ketone at 80° C., in the presence of sodium carbonate, as described in WO 9607642.
  • the oxazolidinone group present in the product 4.3 is then hydrolyzed to afford the hydroxyamine 4.4.
  • the hydrolysis reaction is effected in the presence of aqueous solution of a base such as an alkali metal hydroxide, optionally in the presence of an organic co-solvent.
  • a base such as an alkali metal hydroxide
  • an organic co-solvent Preferably, the oxazolidinone compound 4.3 is reacted with aqueous ethanolic sodium hydroxide at reflux temperature, as described in WO 9607642, to afford the amine 4.4.
  • This product is then reacted with the carboxylic acid or activated derivative thereof, 1.5, the preparation of which is described above, to afford the product 1.6.
  • the amide-forming reaction is conducted under the same conditions as described above, (Scheme 1)
  • Scheme 5 depicts the preparation of the hydroxymethyl oxazolidinones 4.1, which are utilized in the preparation of the phosphonate esters 1, as described above in Scheme 4.
  • phenylalanine, or a substituted derivative thereof, 2.1, in which R 10 is as defined in Chart 2 is converted into the phthalimido derivative 5.1.
  • the conversion of amines into phthalimido derivatives is described, for example, in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Second Edition 1990, p. 358.
  • the amine is reacted with phthalic anhydride, 2-carboethoxybenzoyl chloride or N-carboethoxyphthalimide, optionally in the presence of a base such as triethylamine or sodium carbonate, to afford the protected amine 5.1.
  • a base such as triethylamine or sodium carbonate
  • the aminoacid is reacted with phthalic anhydride in toluene at reflux, to yield the phthalimido product.
  • the carboxylic acid is then transformed into an activated derivative such as the acid chloride 5.2, in which X is Cl.
  • 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 a tertiary amide such as dimethylformamide.
  • a reagent such as, for example, thionyl chloride or oxalyl chloride in an inert organic solvent such as dichloromethane
  • a catalytic amount of a tertiary amide such as dimethylformamide.
  • the carboxylic acid is transformed into the acid chloride by reaction with oxalyl chloride and a catalytic amount of dimethylformamide, in toluene solution at ambient temperature, as described in WO 9607642.
  • the acid chloride 5.2, X ⁇ Cl is then converted into the aldehyde 5.3 by means of a reduction reaction.
  • This procedure is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 620.
  • the transformation can be effected by means of catalytic hydrogenation, a procedure which is referred to as the Rosenmund reaction, or by chemical reduction employing, for example, sodium borohydride, lithium aluminum tri-tertiarybutoxy hydride or triethylsilane.
  • the acid chloride 5.2 X ⁇ Cl is hydrogenated in toluene solution over a 5% palladium on carbon catalyst, in the presence of butylene oxide, as described in WO 9607642, to afford the aldehyde 5.3.
  • the aldehyde 5.3 is then transformed into the cyanohydrin derivative 5.4.
  • the conversion of aldehydes into cyanohydrins is described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Second Edition 1990, p. 211.
  • the aldehyde 5.3 is converted into the cyanohydrin 5.4 by reaction with trimethylsilyl cyanide in an inert solvent such as dichloromethane, followed by treatment with an organic acid such as citric acid, as described in WO 9607642, or by alternative methods described therein.
  • the cyanohydrin is then subjected to acidic hydrolysis, to effect conversion of the cyano group into the corresponding carboxy group, with concomitant hydrolysis of the phthalimido substituent to afford the aminoacid 5.5
  • the hydrolysis reactions are effected by the use of aqueous mineral acid.
  • the substrate 5.4 is reacted with aqueous hydrochloric acid at reflux, as described in WO 9607642, to afford the carboxylic acid product 5.5.
  • the aminoacid is then converted into a carbamate, for example the ethyl carbamate 5.6.
  • the conversion of amines into carbamates is described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Second Edition 1990, p. 317.
  • the amine is reacted with a chloroformate, for example ethyl chloroformate, in the presence of a base such as potassium carbonate, to afford the carbamate 5.6.
  • the aminoacid 5.5 is reacted, in aqueous solution, with ethyl chloroformate and sufficient aqueous sodium hydroxide to maintain a neutral pH, as described in WO 9607642, to afford the carbamate 5.6.
  • the latter compound is then transformed into the oxazolidinone 5.7, for example by treatment with aqueous sodium hydroxide at ambient temperature, as described in WP 9607642.
  • the resultant carboxylic acid is transformed into the methyl ester 5.8 by means of a conventional esterification reaction.
  • the conversion of carboxylic acids into esters is described for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 966.
  • the conversion can be effected by means of an acid-catalyzed reaction between the carboxylic acid and an alcohol, or by means of a base-catalyzed reaction between the carboxylic acid and an alkyl halide, for example an alkyl bromide.
  • carboxylic acid 5.7 is converted into the methyl ester 5.8 by treatment with methanol at reflux temperature, in the presence of a catalytic amount of sulfuric acid, as described in WO 9607642.
  • the carbomethoxyl group present in the compound 5.8 is then reduced to yield the corresponding carbinol 4.1.
  • the reduction of carboxylic esters to the carbinols is described in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p.
  • the transformation can be effected by the use of reducing agents such as borane-dimethylsulfide, lithium borohydride, diisobutyl aluminum hydride, lithium aluminum hydride and the like.
  • reducing agents such as borane-dimethylsulfide, lithium borohydride, diisobutyl aluminum hydride, lithium aluminum hydride and the like.
  • the ester 5.8 is reduced to the carbinol 4.1 by reaction with sodium borohydride in ethanol at ambient temperature, as described in WO 9607642.
  • Schemes 1 and 4 depict the preparation of the compounds 1.6 in which X is a direct bond, and in which the substituent A is either the group link-P(O)(OR 1 ) 2 or a precursor thereto, such as [OH], [SH] Br, as described below.
  • Scheme 6 illustrates the conversion of compounds 1.6 in which A is a precursor to the group link-P(O)(OR 1 ) 2 into the compounds 1. Procedures for the conversion of the substituent A into the group link-P(O)(OR 1 ) 2 are illustrated below, (Schemes 24-69).
  • Scheme 7 illustrates the preparation of the compounds 1 in which the substituent X is S, and in which the group A is either the group link-P(O)(OR 1 ) 2 or a precursor thereto, such as [OH], [SH] Br, as described below.
  • the reaction is conducted in a suitable solvent such as, for example, pyridine, DMF and the like, in the presence of an inorganic or organic base, at from 0° C. to 80° C., for from 1-12 hours, to afford the thioether 7.3.
  • a suitable solvent such as, for example, pyridine, DMF and the like
  • an inorganic or organic base at from 0° C. to 80° C., for from 1-12 hours, to afford the thioether 7.3.
  • the mesylate 7.1 is reacted with an equimolar amount of the thiol R 4 SH, in a mixture of a water-immiscible organic solvent such as toluene, and water, in the presence of a phase-transfer catalyst such as, for example, tetrabutyl ammonium bromide, and an inorganic base such as sodium hydroxide, at about 50° C., to give the product 7.3.
  • a phase-transfer catalyst such as, for
  • the 1,3-dioxolane protecting group present in the compound 7.3 is then removed by acid catalyzed hydrolysis or by exchange with a reactive carbonyl compound to afford the diol 7.4.
  • Methods for conversion of 1,3-dioxolanes to the corresponding diols are described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Second Edition 1990, p. 191.
  • the 1,3-dioxolane compound 7.3 is hydrolyzed by reaction with a catalytic amount of an acid in an aqueous organic solvent mixture.
  • the 1,3-dioxolane 7.3 is dissolved in aqueous methanol containing hydrochloric acid, and heated at ca. 50° C., to yield the product 7.4.
  • the primary hydroxyl group of the diol 7.4 is then selectively acylated by reaction with an electron-withdrawing acyl halide such as, for example, pentafluorobenzoyl chloride or mono- or di-nitrobenzoyl chlorides.
  • an electron-withdrawing acyl halide such as, for example, pentafluorobenzoyl chloride or mono- or di-nitrobenzoyl chlorides.
  • the reaction is conducted in an inert solvent such as dichloromethane and the like, in the presence of an inorganic or organic base.
  • equimolar amounts of the diol 7.4 and 4-nitrobenzoyl chloride are reacted in a solvent such as ethyl acetate, in the presence of a tertiary organic base such as 2-picoline, at ambient temperature, to afford the hydroxy ester 7.5.
  • the hydroxy ester is next reacted with a sulfonyl chloride such as methanesulfonyl chloride, 4-toluenesulfonyl chloride and the like, in the presence of a base, in an aprotic polar solvent at low temperature, to afford the corresponding sulfonyl ester 7.6.
  • equimolar amounts of the carbinol 7.5 and methanesulfonyl chloride are reacted together in ethyl acetate containing triethylamine, at about 10° C., to yield the mesylate 7.6.
  • the compound 7.6 is then subjected to a hydrolysis-cyclization reaction to afford the oxirane 7.7.
  • the mesylate or analogous leaving group present in 7.6 is displaced by hydroxide ion, and the carbinol thus produced, without isolation, spontaneously transforms into the oxirane 7.7 with elimination of 4-nitrobenzoate.
  • the sulfonyl ester 7.6 is reacted with an alkali metal hydroxide or tetraalkylammonium hydroxide in an aqueous organic solvent.
  • the mesylate 7.6 is reacted with potassium hydroxide in aqueous dioxan at ambient temperature for about 1 hour, to afford the oxirane 7.7.
  • the oxirane compound 7.7 is then subjected to regiospecific ring-opening reaction by treatment with a secondary amine 1.2, to give the aminoalcohol 7.8.
  • the amine and the oxirane are reacted in a protic organic solvent, optionally in the additional presence of water, at 0° C. to 100° C., and in the presence of an inorganic base, for 1 to 12 hours, to give the product 7.8.
  • equimolar amounts of the reactants 7.7 and 1.2 are reacted in aqueous methanol at about 60° C. in the presence of potassium carbonate, for about 6 hours, to afford the aminoalcohol 7.8.
  • the carbobenzyloxy (cbz) protecting group in the product 7.8 is removed to afford the free amine 7.9.
  • Methods for removal of cbz groups are described, for example, in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Second Edition, p. 335.
  • the methods include catalytic hydrogenation and acidic or basic hydrolysis.
  • the cbz-protected amine 7.8 is reacted with an alkali metal or alkaline earth hydroxide in an aqueous organic or alcoholic solvent, to yield the free amine 7.9.
  • the cbz group is removed by the reaction of 7.8 with potassium hydroxide in an alcohol such as isopropanol at ca. 60° C. to afford the amine 7.9.
  • the amine 7.9 so obtained is next acylated with a carboxylic acid or activated derivative 1.5, using the conditions described above for the conversion of the amine 1.4 into the amide 1.6 (Scheme 1), to yield the final amide product 7.10.
  • Scheme 7 depicts the preparation of the compounds 1 in which X is S, and in which the substituent A is either the group link-P(O)(OR 1 ) 2 or a precursor thereto, such as [OH], [SH] Br, as described below.
  • Scheme 8 illustrates the conversion of compounds 7.10 in which A is a precursor to the group link-P(O)(OR 1 ) 2 into the compounds 1. Procedures for the conversion of the substituent A into the group link-P(O)(OR 1 ) 2 are illustrated below, (Schemes 24-69).
  • Schemes 1-7 illustrate the preparation of the compounds 1 in which A is either the group link-P(O)(OR 1 ) 2 or a precursor thereto, such as, for example, optionally protected OH, SH, NH, as described below.
  • Scheme 8 depicts the conversion of the compounds 1 in which A is OH, SH, NH, as described below, into the compounds 1 in which A is the group link-P(O)(OR 1 ) 2 .
  • Procedures for the conversion of the group A into the group link-P(O))(OR 1 ) 2 are described below, (Schemes 24-69).
  • Scheme 9 depicts the one method for the preparation of the compounds 2 in which X is a direct bond, and in which the substituent A is either the group link-P(O)(OR 1 ) 2 or a precursor thereto, such as [OH], [SH] Br, as described below.
  • the hydroxymethyl oxazolidinone 9.1 the preparation of which is described below, is converted into an activated derivative, for example the 4-nitrobenzenesulfonate 9.2.
  • the conditions for this transformation are the same as those described above (Scheme 4) for the conversion of the carbinol 4.1 into the nosylate 4.2.
  • the activated ester 9.2 is then reacted with the amine 1.2, under the same conditions as described above for the preparation of the amine 4.3 to afford the oxazolidinone amine 9.3.
  • the oxazolidinone group is then hydrolyzed by treatment with aqueous alcoholic base, to produce the primary amine 4.4.
  • the oxazolidinone 9.3 is reacted with aqueous ethanolic sodium hydroxide at reflux temperature, as described in WO 9607642, to afford the amine product 9.4.
  • the latter compound is then coupled with the carboxylic acid 9.6, to afford the amide 9.5;
  • the conditions for the coupling reaction are the same as those described above for the preparation of the amide 1.6.
  • Scheme 10 illustrates an alternative method for the preparation of the compounds 2 in which X is a direct bond, and in which the substituent A is either the group link-P(O)(OR 1 ) 2 or a precursor thereto, such as [OH], [SH] Br, as described below.
  • the oxirane 10.1 the preparation of which is described below, is reacted with the amine 1.2 to afford the aminoalcohol 10.2.
  • the reaction is conducted under the same conditions as are described above for the preparation of the aminoalcohol 1.3.
  • the benzyloxycarbonyl protecting group is then removed from the product 10.2 to afford the free amine 10.3.
  • the conditions for the debenzylation reaction are the same as those described above for the debenzylation of the compound 1.3.
  • the amine 10.3 is then coupled with the carboxylic acid 9.6 to produce the amide 9.5, employing the same conditions as are described above (Scheme 9).
  • Schemes 9 and 10 depict the preparation of the compounds 9.5 in which the substituent A is either the group link-P(O)(OR 1 ) 2 or a precursor thereto, such as [OH], [SH] Br, as described below.
  • Scheme 11 illustrates the conversion of compounds 9.5 in which A is a precursor to the group link-P(O)(OR 1 ) 2 into the compounds 2.
  • Procedures for the conversion of the substituent A into the group link-P(O)(OR 1 ) 2 are illustrated below, (Schemes 24-69).
  • Schemes 12 and 13 depict the preparation of compounds 2 in which X is sulfur.
  • a substituted thiophenol 12.2 in which the substituent A is either the group link-P(O)(OR 1 ) 2 or a precursor thereto, such as [OH], [SH] Br, as described below, is reacted with methanesulfonic acid 2-benzyloxycarbonylamino-2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl ester 12.1, the preparation of which is described in J. Org. Chem, 2000, 65, 1623, to afford the displacement product 12.3.
  • the conditions for the reaction are the same as described above for the preparation of the thioether 7.3.
  • Scheme 12 depicts the preparation of the compounds 12.5 in which the substituent A is either the group link-P(O)(OR 1 ) 2 or a precursor thereto, such as [OH], [SH] Br, as described below.
  • Scheme 13 illustrates the conversion of compounds 12.5 in which A is a precursor to the group link-P(O)(OR 1 ) 2 into the compounds 2.
  • Procedures for the conversion of the substituent A into the group link-P(O)(OR 1 ) 2 are illustrated below, (Schemes 24-69). Preparation of the Phosphonate Intermediates 3.
  • Schemes 14-16 depict the preparation of the phosphonate esters 3 in which X is a direct bond.
  • the oxirane 1.1 the preparation of which is described above, is reacted with the amine 14.1 in which the substituent A is either the group link-P(O)(OR 1 ) 2 or a precursor thereto, such as [OH], [SH] Br, as described below, to yield the hydroxyamine 14.2.
  • the conditions for the reaction are the same as described above for the preparation of the amine 1.3.
  • Methods for the preparation of the amine 14.1 are described below, Schemes 45-48.
  • the hydroxyamine product 14.2 is then deprotected to afford the free amine 14.3.
  • the conditions for the debenzylation reaction are the same as those described above for the preparation of the amine 1.4. (Scheme 1).
  • the amine 14.3 is then coupled with the carboxylic acid or activated derivative thereof, 9.6, to afford the amide 14.4, using the conditions described above for the preparation of the amide 12.5.
  • Scheme 15 illustrates an alternative method for the preparation of the phosphonate esters 14.4.
  • the 4-nitrobenzenesulfonate 4.2 the preparation of which is described above, (Scheme 4)
  • the amine 14.1 in which the substituent A is either the group link-P(O)(OR 1 ) 2 or a precursor thereto, such as [OH], [SH] Br, as described below, to yield the amine 15.1.
  • the reaction is conducted under the same conditions as described above for the preparation of the amide 4.3.
  • the oxazolidine moiety present in the product is then removed, using the procedure described above for the conversion of the oxazolidine 4.3 into the hydroxyamine 4.4, to afford the hydroxyamine 15.2.
  • the latter compound is then coupled, as described above, with the carboxylic acid or activated derivative thereof, 9.6, to afford the amide 14.4.
  • Schemes 14 and 15 depict the preparation of the compounds 14.4 in which the substituent A is either the group link-P(O)(OR 1 ) 2 or a precursor thereto, such as [OH], [SH] Br, as described below.
  • Scheme 16 illustrates the conversion of compounds 14.4 in which A is a precursor to the group link-P(O)(OR 1 ) 2 into the compounds 3.
  • Procedures for the conversion of the substituent A into the group link-P(O)(OR 1 ) 2 are illustrated below, (Schemes 24-69).
  • Schemes 17 and 18 illustrates the preparation of the phosphonate esters 3 in which X is sulfur.
  • the oxirane 7.7 the preparation of which is described above, (Scheme 7) is reacted with the amine 14.1.
  • the conditions for the ring-opening reaction are the same as those described above for the preparation of the aminoalcohol 7.8, (Scheme 7).
  • the benzyloxycarbonyl protecting group is then removed to produce the free amine 17.2.
  • Scheme 17 depicts the preparation of the compound 17.3 in which the substituent A is either the group link-P(O)(OR 1 ) 2 or a precursor thereto, such as [OH], [SH] Br, as described below.
  • Scheme 18 illustrates the conversion of compounds 17.3 in which A is a precursor to the group link-P(O)(OR 1 ) 2 into the compounds 3.
  • Procedures for the conversion of the substituent A into the group link-P(O)(OR 1 ) 2 are illustrated below, (Schemes 24-69). Preparation of the Phosphonate Intermediates 4.
  • Scheme 19 illustrates one method for the preparation of the phosphonate esters 4 in which X is a direct bond.
  • the oxirane 1.1 the preparation of which is described above (Scheme 2) is reacted with the decahydroisoquinoline amine 19.1, in which the substituent A is either the group link-P(O)(OR 1 ) 2 or a precursor thereto, such as [OH], [SH] Br, as described below, to afford the aminoalcohol product 19.2.
  • the conditions for the ring-opening reaction are the same as those described above for the preparation of the aminoalcohol 1.3.
  • the preparation of the decahydroisoquinoline derivatives 19.1 is described below, (Schemes 48a -52).
  • the cbz protecting group is then removed to yield the free amine 19.3, using the same conditions as described above for the preparation of the amine 1.4, (Scheme 1).
  • the amine 19.3 is then coupled with the carboxylic acid or activated derivative thereof, 9.6, using the same conditions as described above, to afford the amide 19.4.
  • Scheme 20 illustrates an alternative method for the preparation of the phosphonate intermediates 19.4.
  • the 4-nitrobenzenesulfonyl ester 4.2 the preparation of which is described above, (Scheme 4) is reacted with the decahydroisoquinoline derivative 20.1, in which the substituent A is either the group link-P(O)(OR 1 ) 2 or a precursor thereto, such as [OH], [SH] Br, as described below.
  • the reaction conditions for the displacement reaction are the same as those described above for the preparation of the amine 4.3, (Scheme 4).
  • the oxazolidinone moiety present in the product 20.2 is then hydrolyzed, using the procedures described above (Scheme 4) to afford the free amine 20.3.
  • This compound is then coupled with the carboxylic acid or activated derivative thereof, 9.6, using the same conditions as are described above, to afford the amide product 19.4.
  • Schemes 19 and 20 depict the preparation of the compounds 19.4 in which the substituent A is either the group link-P(O)(OR 1 ) 2 or a precursor thereto, such as [OH], [SH] Br, as described below.
  • Scheme 21 illustrates the conversion of compounds 19.4 in which A is a precursor to the group link-P(O)(OR 1 ) 2 into the compounds 4.
  • Procedures for the conversion of the substituent A into the group link-P(O)(OR 1 ) 2 are illustrated below, (Schemes 24-69).
  • Schemes 22 and 23 depict the preparation of the phosphonate esters 4 in which X is sulfur.
  • the oxirane 7.7 prepared as described above (Scheme 7) is reacted with the decahydroisoquinoline derivative 19.1, in which the substituent A is either the group link-P(O)(OR 1 ) 2 or a precursor thereto, such as [OH], [SH] Br, as described below.
  • the reaction is conducted under the same conditions as described above for the preparation of the amine 7.8, (Scheme 7), to produce the hydroxyamine 22.1.
  • the cbz protecting group present in the product 22.1 is then removed, using the same procedures as described above (Scheme 7) to afford the free amine 22.2.
  • This material is then coupled with the carboxylic acid or activated derivative thereof, 9.6 to yield the amide 22.3.
  • the coupling reaction is preformed under the same conditions as previously described.
  • Scheme 22 depicts the preparation of the compounds 22.3 in which the substituent A is either the group hnk-P(O)(OR 1 ) 2 or a precursor thereto, such as [OH], [SH] Br, as described below.
  • Scheme 23 illustrates the conversion of compounds 22.3 in which A is a precursor to the group link-P(O)(OR 1 ) 2 into the compounds 4.
  • Procedures for the conversion of the substituent A into the group link-P(O)(OR 1 ) 2 are illustrated below, (Schemes 24-69). Preparation of Quinoline 2-Carboxylic Acids 1.7 Incorporating Phosphonate Moieties or Precursors Thereto.
  • quinoline-2-carboxylic acids A number of suitably substituted quinoline-2-carboxylic acids are available commercially or are described in the chemical literature. For example, the preparations of 6-hydroxy, 6-amino and 6-bromoquinoline-2-carboxylic acids are described respectively in DE 3004370, J. Het. Chem, 1989, 26, 929 and J. Labelled Comp. Radiopharm., 1998, 41, 1103, and the preparation of 7-aminoquinoline-2-carboxylic acid is described in J. Am Chem. Soc., 1987, 109, 620. Suitably substituted quinoline-2-carboxylic acids can also be prepared by procedures known to those skilled in the art.
  • Scheme 24 illustrates the preparation of quinoline-2-carboxylic acids by means of the Friedlander reaction, and further transformations of the products obtained.
  • a substituted 2-aminobenzaldehyde 24.1 is reacted with an alkyl pyruvate ester 24.2, in the presence of an organic or inorganic base, to afford the substituted quinoline-2-carboxylic ester 24.3.
  • Hydrolysis of the ester for example by the use of aqueous base, then afford the corresponding carboxylic acid 24.4.
  • the carboxylic acid product 24.4 in which X is NH 2 can be further transformed into the corresponding compounds 24.6 in which Z is OH, SH or Br.
  • the diazonium salt is reacted in aqueous solution with cuprous bromide and lithium bromide, as described in Organic Functional Group Preparations, by S. R. Sandler and W. Karo, Academic Press, 1968, p. 138, to yield the corresponding bromo compound, 24.6, Y ⁇ Br.
  • the diazonium tetrafluoborate is reacted in acetonitrile solution with a sulfhydryl ion exchange resin, as described in Sulfur Lett., 200, 24, 123, to afford the thiol 24.6, Y ⁇ SH.
  • the diazotization reactions described above can be performed on the carboxylic esters 24.3 instead of the carboxylic acids 24.5.
  • 2,4-diaminobenzaldehyde 24.7 (Apin Chemicals) is reacted with one molar equivalent of methyl pyruvate 24.2 in methanol, in the presence if abase such as piperidine, to afford methyl-7-aminoquinoline-2-carboxylate 24.8.
  • Basic hydrolysis of the product employing one molar equivalent of lithium hydroxide in aqueous methanol, then yields the carboxylic acid 24.9.
  • the amino-substituted carboxylic acid is then converted into the diazonium tetrafluoborate 24.10 by reaction with sodium nitrite and tetrafluoboric acid.
  • the diazonium tetrafluoborate is heated in aqueous organic solution with one molar equivalent of cuprous bromide and lithium bromide, to afford 7-bromoquinoline-2-carboxylic acid 24.11, X ⁇ Br.
  • Scheme 25 depicts the preparation of quinoline-2-carboxylic acids incorporating a phosphonate moiety attached to the quinoline ring by means of an oxygen or a sulfur atom.
  • an amino-substituted quinoline-2-carboxylate ester 25.1 is transformed, via a diazotization procedure as described above (Scheme 24) into the corresponding phenol or thiol 25.2.
  • the latter compound is then reacted with a dialkyl hydroxymethylphosphonate 25.3, under the conditions of the Mitsonobu reaction, to afford the phosphonate ester 25.4.
  • the preparation of aromatic ethers by means of the Mitsonobu reaction is described, for example, in Comprehensive Organic Transformations, by R. C.
  • methyl 6-amino-2-quinoline carboxylate 25.7 prepared as described in J. Het. Chem, 1989, 26, 929, is converted, by means of the diazotization procedure described above, into methyl 6-mercaptoquinoline-2-carboxylate 25.8.
  • This material is reacted with a dialkyl hydroxymethylphosphonate 25.9 (Aldrich) in the presence of diethyl azodicarboxylate and triphenylphosphine in tetrahydrofuran solution, to afford the thioether 25.10.
  • Basic hydrolysis then afford the carboxylic acid 25.11.
  • Scheme 26 illustrates the preparation of quinoline-2-carboxylic acids incorporating phosphonate esters attached to the quinoline ring by means of a saturated or unsaturated carbon chain.
  • a bromo-substituted quinoline carboxylic ester 26.1 is coupled, by means of a palladium-catalyzed Heck reaction, with a dialkyl alkenylphosphonate 26.2.
  • 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.
  • the aryl bromide and the olefin are coupled in a polar solvent such as dimethylformamide or dioxan, in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) or palladium(II) catalyst such as palladium(II) acetate, and optionally in the presence of a base such as triethylamine or potassium carbonate.
  • a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) or palladium(II) catalyst such as palladium(II) acetate
  • a base such as triethylamine or potassium carbonate.
  • the unsaturated carboxylic acid 26.4 can be reduced to afford the saturated analog 26.5.
  • the reduction reaction can be effected chemically, for example by the use of dimide or diborane, as described in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 5.
  • methyl 7-bromoquinoline-2-carboxylate, 26.6 prepared as described in J. Labelled Comp. Radiopharm, 1998, 41, 1103, is reacted in dimethylformamide at 60° C. with a dialkyl vinylphosphonate 26.7 (Aldrich) in the presence of 2 mol % of tetrakis(triphenylphosphine)palladium and triethylamine, to afford the coupled product 26.8.
  • the product is then reacted with lithium hydroxide in aqueous tetrahydrofuran to produce the carboxylic acid 26.9.
  • the latter compound is reacted with diimide, prepared by basic hydrolysis of diethyl azodicarboxylate, as described in Angew. Chem. Int. Ed., 4, 271, 1965, to yield the saturated product 26.10.
  • Scheme 27 depicts the preparation of quinoline-2-carboxylic acids 27.5 in which the phosphonate group is attached by means of a nitrogen atom and an alkylene chain.
  • a methyl aminoquinoline-2-carboxylate 27.1 is reacted with a phosphonate aldehyde 27.2 under reductive amination conditions, to afford the aminoalkyl product 27.3.
  • the preparation of amines by means of reductive amination procedures is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, p 421, and in Advanced Organic Chemistry, Part B, by F. A. Carey and R. J. Sundberg, Plenum, 2001, p. 269.
  • the amine component and the aldehyde or ketone component are reacted together in the presence of a reducing agent such as, for example, borane, sodium cyanoborohydride, sodium triacetoxyborohydride or diisobutylaluminum hydride, optionally in the presence of a Lewis acid, such as titanium tetraisopropoxide, as described in J. Org. Chem., 55, 2552, 1990.
  • a reducing agent such as, for example, borane, sodium cyanoborohydride, sodium triacetoxyborohydride or diisobutylaluminum hydride
  • a Lewis acid such as titanium tetraisopropoxide
  • methyl 7-aminoquinoline-2-carboxylate 27.6 prepared as described in J. Amer. Chem. Soc., 1987, 109, 620, is reacted with a dialkyl formylmethylphosphonate 27.7 (Aurora) in methanol solution in the presence of sodium borohydride, to afford the alkylated product 27.8.
  • the ester is then hydrolyzed, as described above, to yield the carboxylic acid 27.9.
  • the corresponding products 27.5 are obtained.
  • Scheme 28 illustrates the preparation of the hydroxymethyl oxazolidine derivative 9.1, in which the substituent A is either the group link-P(O)(OR 1 ) 2 or a precursor thereto, such as [OH], [SH] Br.
  • the substituted phenylalanine 28.1 in which A is as defined above, is transformed, via the intermediates 28.2-28.9, into the hydroxymethyl product 9.1.
  • the reaction conditions for each step in the sequence are the same as those described above for the corresponding step shown in Scheme 5.
  • the conversion of the substituent A into the group link-P(O)(OR 1 ) 2 may be effected at any convenient step in the reaction sequence, or after the reactant 9.1 has been incorporated into the intermediates 9.5 (Scheme 9). Specific examples of the preparation of the hydroxymethyl oxazolidinone reactant 9.1 are shown below, (Schemes 30-31).
  • Scheme 29 illustrates the preparation of the oxirane intermediate 10.1, in which the substituent A is either the group link-P(O)(OR 1 ) 2 or a precursor thereto, such as [OH], [SH] Br.
  • the substituted phenylalanine 29.1 in which A is as defined above, is transformed, via the intermediates 29.2-29.6, into the oxirane 10.1.
  • the reaction conditions for each step in the sequence are the same as those described above for the corresponding step shown in Scheme 2.
  • the conversion of the substituent A into the group ink-P(O)(OR 1 ) 2 may be effected at any convenient step in the reaction sequence, or after the reactant 10.1 has been incorporated into the intermediates 9.5 (Scheme 10). Specific examples of the preparation of the oxiranes reactant 10.1 are shown below, (Schemes 32-34).
  • Scheme 30 depicts the preparation of hydroxymethyloxazolidinones 30.9 in which the phosphonate ester moiety is attached directly to the phenyl ring.
  • a bromo-substituted phenylalanine 30.1 is converted, using the series of reactions illustrated in Scheme 28, into the bromophenyloxazolidinone 30.2.
  • the bromophenyl compound is then coupled, in the presence of a palladium (0) catalyst, with a dialkyl phosphite 30.3, to afford the phosphonate product 30.4.
  • the reaction between aryl bromide and dialkyl phosphites to yield aryl phosphonates is described in Synthesis, 56, 1981, and in J. Med. Chem., 1992, 35, 1371.
  • the reaction is conducted in an inert solvent such as toluene or xylene, at about 100° C., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium and a tertiary organic base such as triethylamine.
  • a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium
  • a tertiary organic base such as triethylamine.
  • the carbomethoxy substituent in the resultant phosphonate ester 30.4 is then reduced with sodium borohydride to the corresponding hydroxymethyl derivative 30.5, using the procedure described above (Scheme 28)
  • Scheme 31 illustrates the preparation of phosphonate-containing hydroxymethyl oxazolidinones 31.9 and 31.12 in which the phosphonate group is attached by means of a heteroatom and a carbon chain.
  • a hydroxy or thio-substituted phenylalanine 31.1 is converted into the benzyl ester 31.2 by means of a conventional acid catalyzed esterification reaction.
  • the hydroxyl or mercapto group is then protected.
  • the protection of phenyl hydroxyl and thiol groups are described, respectively, in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Second Edition 1990, p. 10, and p. 277.
  • trialkylsilyl groups are introduced by the reaction of the phenol or thiophenol 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. 10, p. 68-86.
  • thiol substituents can be protected by conversion to tert-butyl or adamantyl thioethers, or 4-methoxybenzyl thioethers, prepared by the reaction between the thiol and 4-methoxybenzyl chloride in the presence of ammonium hydroxide, as described in Bull. Chem. Soc. Jpn., 37, 433, 1974.
  • the protected ester 31.3 is then reacted with phthalic anhydride, as described above (Scheme 28) to afford the phthalimide 31.4.
  • the benzyl ester is then removed, for example by catalytic hydrogenation or by treatment with aqueous base, to afford the carboxylic acid 31.5.
  • Tert-butyl or adamantyl thioethers can be converted into the corresponding thiols by treatment with mercuric trifluoroacetate in aqueous acetic acid at ambient temperatures, as described in Chem. Pharm Bull., 26, 1576, 1978.
  • the resultant phenol or thiol 31.7 is then reacted with a hydroxyalkyl phosphonate 31.20 under the conditions of the Mitsonobu reaction, as described above (Scheme 25), to afford the ether or thioether 31.8.
  • the latter compound is then reduced with sodium borohydride, as described above (Scheme 28) to afford the hydroxymethyl analog 31.9.
  • the phenol or thiophenol 31.7 is reacted with a dialkyl bromoalkyl phosphonate 31.10 to afford the alkylation product 31.11.
  • the alkylation reaction is preformed in a polar organic solvent such as dimethylformamide, acetonitrile and the like, optionally in the presence of potassium iodide, and in the presence of an inorganic base such as potassium or cesium carbonate, or an organic base such as diazabicyclononene or dimethylaminopyridine.
  • the ether or thioether product is then reduced with sodium borohydride to afford the hydroxymethyl compound 31.12.
  • 3-hydroxyphenylalanine 31.13 (Fluka) is converted in to the benzyl ester 31.14 by means of a conventional acid-catalyzed esterification reaction.
  • the ester is then reacted with tert-butylchlorodimethylsilane and imidazole in dimethylformamide, to afford the silyl ether 31.15.
  • the protected ether is then reacted with phthalic anhydride, as described above (Scheme 28) to yield the phthalimido-protected compound 31.16.
  • Basic hydrolysis for example by reaction with lithium hydroxide in aqueous methanol, then affords the carboxylic acid 31.17.
  • This compound is then transformed, by means of the series of reactions shown in Scheme 28, into the carbomethoxy-substituted oxazolidinone 31.18.
  • the silyl protecting group is then removed by treatment with tetrabutylammonium fluoride in tetrahydrofuran at ambient temperature, to produce the phenol 31.19.
  • the latter compound is reacted with a dialkyl hydroxymethyl phosphonate 31.20 diethylazodicarboxylate and triphenylphosphine, by means of the Mitsonobu reaction, as described above (Scheme 25) to yield the phenolic ether 31.21.
  • the carbomethoxy group is then reduced by reaction with sodium borohydride, as described above, to afford the carbinol 31.22.
  • the mercapto group is then protected by conversion to the S-adamantyl group, by reaction with 1-adamantanol and trifluoroacetic acid at ambient temperature as described in Chem. Pharm Bull., 26, 1576, 1978.
  • the amino group is then converted into the phthalimido group as described above, and the ester moiety is hydrolyzed with aqueous base to afford the carboxylic acid 31.27.
  • the latter compound is then transformed, by means of the series of reactions shown in Scheme 28, into the carbomethoxy oxazolidinone 31.28.
  • the adamantyl protecting group is then removed by treatment of the thioether 31.28 with mercuric acetate in trifluoroacetic acid at 0° C., as described in Chem. Pharm. Bull., 26,. 1576, 1978, to produce the thiol 31.29.
  • the thiol is then reacted with one molar equivalent of a dialkyl bromoethylphosphonate 31.30, (Aldrich) and cesium carbonate in dimethylformamide at 70° C., to afford the thioether product 31.31.
  • the carbomethoxy group is then reduced with sodium borohydride, as described above, to prepare the carbinol 31.32.
  • Scheme 32 illustrates the preparation of phenylalanine derivatives 32.3 in which the phosphonate group is attached directly to the phenyl ring.
  • a bromo-substituted phenylalanine 32.1 is converted, by means of the series of reactions shown in Scheme 29 into the oxirane 32.2.
  • This compound is then coupled with a dialkyl phosphite 30.3, in the presence of a palladium(0) catalyst and an organic base, to afford the phosphonate oxirane 32.3.
  • the coupling reaction is performed under the same conditions previously described, (Scheme 30).
  • 3-bromophenylalanine 32.4 prepared as described in Pept. Res., 1990, 3, 176, is converted, as described above, into the oxirane 32.5.
  • This compound is reacted, in toluene solution at reflux temperature, with a dialkyl phosphonate 30.3, in the presence of tetrakis(triphenylphosphine)palladium(0) and triethylamine to afford the phosphonate ester 32.6.
  • Scheme 33 depicts the preparation of compounds 33.4 in which the phosphonate group is attached to the phenyl ring by means of a styrene moiety.
  • a vinyl-substituted phenylalanine 33.1 is converted, by means of the series of reactions shown in Scheme 29, into the oxirane 33.2.
  • This compound is then coupled with a dialkyl bromophenylphosphonate 33.3, employing the conditions of the Heck reaction, as described above (Scheme 26) to afford the coupled product 33.4.
  • 4-vinylphenylalanine 33.5 prepared as described in EP 206460, is converted, as described above, into the oxirane 33.6.
  • This compound is then coupled with a dialkyl 4-bromophenylphosphonate 33.7, prepared as described in J. Chem. Soc. Perkin Trans., 1977, 2, 789, using tetrakis(triphenylphosphine)palladium(0) as catalyst, to yield the phosphonate ester 33.8.
  • Scheme 34 depicts the preparation of phosphonate-substituted phenylalanine derivatives in which the phosphonate moiety is attached by means of an alkylene chain incorporating a heteroatom.
  • a hydroxymethyl-substituted phenylalanine 34.1 is converted into the cbz protected methyl ester 34.2, using the procedures described above (Scheme 29).
  • the product 34.2 is then converted into a halomethyl-substituted compound 34.3.
  • the carbinol 34.2 is treated with triphenylphosphine and carbon tetrabromide, as described in J. Amer. Chem. Soc., 108, 1035, 1986 to afford the product 34.3 in which Z is Br.
  • the bromo compound is then reacted with a dialkyl terminally hetero-substituted alkylphosphonate 34.4.
  • the reaction is accomplished in the presence of a base, the nature of which depends on the nature of the substituent X.
  • a base such as cesium carbonate, or an organic base such as diazabicyclononene or dimethylaminopyridine.
  • X is OH
  • a strong base such as lithium hexamethyldisilylazide or the like can be employed.
  • the condensation reaction affords the phosphonate-substituted ester 34.5, which is hydrolyzed to afford the carboxylic acid 34.6.
  • the latter compound is then, by means of the sequence of reactions shown in Scheme 29, is transformed into the epoxide 34.7.
  • the protected 4-hydroxymethyl-substituted phenylalanine derivative 34.9 obtained from the 4-hydroxymethyl phenylalanine 34.8, the preparation of which is described in Syn. Comm., 1998, 28, 4279, is converted into the bromo derivative 34.10, as described above.
  • the product is then reacted with a dialkyl 2-aminoethyl phosphonate 34.11, the preparation of which is described in J. Org. Chem, 2000, 65, 676, in the presence of cesium carbonate in dimethylformamide at ambient temperature, to afford the amine product 34.12.
  • the latter compound is then converted, using the sequence of reactions shown in Scheme 29, into the epoxide 34.14.
  • Scheme 35 illustrates the preparation of thiophenols in which a phosphonate moiety is attached directly to the aromatic ring.
  • a halo-substituted thiophenol 35.1 is subjected to a suitable protection procedure.
  • the protection of thiophenols is described, for example, in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Second Edition 1990, p 277ff.
  • the protected compound 35.2 is then coupled, under the influence of a transition metal catalyst, with a dialkyl phosphite 30.3, to afford the product 35.3.
  • the product is then deprotected to afford the free thiophenol 35.4.
  • Suitable protecting groups for this procedure include alkyl groups such as triphenylmethyl and the like. Palladium (0) catalysts are employed, and the reaction is conducted in an inert solvent such as benzene, toluene and the like, as described in J. Med. Chem, 35, 1371, 1992. Preferably, the 3-bromothiophenol 35.5 is protected by conversion to the 9-fluorenylmethyl derivative 35.6, as described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M. Wuts, Wiley, 1991, pp.
  • Scheme 36 illustrates an alternative method for obtaining thiophenols with a directly attached phosphonate group.
  • a suitably protected halo-substituted thiophenol 36.2 is metallated, for example by reaction with magnesium or by transmetallation with an alkyllithium reagent, to afford the metallated derivative 36.3.
  • the latter compound is reacted with a halodialkyl phosphate 36.4, followed by deprotection as described previously, to afford the product 36.5.
  • 4-bromothiophenol 36.7 is converted into the S-triphenylmethyl(trityl) derivative 36.8, as described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M. Wuts, Wiley, 1991, pp. 287.
  • the product is converted into the lithium derivative 36.9 by reaction with butyllithium in an ethereal solvent at low temperature, and the resulting lithio compound is reacted with a dialkyl chlorodiethyl phosphite 36.10 to afford the phosphonate 36.11.
  • Removal of the trityl group for example by treatment with dilute hydrochloric acid in acetic acid, as described in J. Org.
  • Scheme 37 illustrates the preparation of phosphonate-substituted thiophenols in which the phosphonate group is attached by means of a one-carbon link.
  • a suitably protected methyl-substituted thiophenol 37.1 is subjected to free-radical bromination to afford a bromomethyl product 37.1a.
  • This compound is reacted with a sodium dialkyl phosphite 37.2 or a trialkyl phosphite, to give the displacement or rearrangement product 37.3, which upon deprotection affords the thiophenols 37.4.
  • 2-methylthiophenol 37.5 is protected by conversion to the benzoyl derivative 37.6, as described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M. Wuts, Wiley, 1991, pp. 298.
  • the product is reacted with N-bromosuccinimide in ethyl acetate to yield the bromomethyl product 37.7.
  • This material is reacted with a sodium dialkyl phosphite 37.2, as described in J. Med. Chem., 35, 1371, 1992, to afford the product 37.8.
  • the bromomethyl compound 37.7 can be converted into the phosphonate 37.8 by means of the Arbuzov reaction, for example as described in Handb.
  • Scheme 38 illustrates the preparation of thiophenols bearing a phosphonate group linked to the phenyl nucleus by oxygen or sulfur.
  • a suitably protected hydroxy or thio-substituted thiophenol 38.1 is reacted with a dialkyl hydroxyalkylphosphonate 38.2 under the conditions of the Mitsonobu reaction, for example as described in Org. React., 1992, 42, 335, to afford the coupled product 38.3.
  • Deprotection then yields the O- or S-linked products 38.4.
  • the substrate 3-hydroxythiophenol, 38.5 is converted into the monotrityl ether 38.6, by reaction with one equivalent of trityl chloride, as described above.
  • This compound is reacted with diethyl azodicarboxylate, triphenyl phosphine and a dialkyl 1-hydroxymethyl phosphonate 38.7 in benzene, as described in Synthesis, 4, 327, 1998, to afford the ether compound 38.8.
  • Scheme 39 illustrates the preparation of thiophenols 39.4 bearing a phosphonate group linked to the phenyl nucleus by oxygen, sulfur or nitrogen.
  • a suitably protected O, S or N-substituted thiophenol 39.1 is reacted with an activated ester, for example the trifluoromethanesulfonate 39.2, of a dialkyl hydroxyalkyl phosphonate, to afford the coupled product 39.3.
  • an activated ester for example the trifluoromethanesulfonate 39.2, of a dialkyl hydroxyalkyl phosphonate
  • equimolar amounts of the phosphonate 39.7 and the amine 39.6 are reacted together in an aprotic solvent such as dichloromethane, in the presence of a base such as 2,6-lutidine, at ambient temperatures, to afford the phosphonate product 39.8.
  • aprotic solvent such as dichloromethane
  • a base such as 2,6-lutidine
  • Deprotection for example by treatment with dilute aqueous sodium hydroxide for two minutes, as described in J. Amer. Chem. Soc., 85, 1337, 1963, then affords the thiophenol 39.9.
  • Scheme 40 illustrates the preparation of phosphonate esters linked to a thiophenol nucleus by means of a heteroatom and a multiple-carbon chain, employing a nucleophilic displacement reaction on a dialkyl bromoalkyl phosphonate 40.2.
  • a suitably protected hydroxy, thio or amino substituted thiophenol 40.1 is reacted with a dialkyl bromoalkyl phosphonate 40.2 to afford the product 40.3.
  • Deprotection then affords the free thiophenol 40.4.
  • 3-hydroxythiophenol 40.5 is converted into the S-trityl compound 40.6, as described above.
  • This compound is then reacted with, for example, a dialkyl 4-bromobutyl phosphonate 40.7, the synthesis of which is described in Synthesis, 1994, 9, 909.
  • the reaction is conducted in a dipolar aprotic solvent, for example dimethylformamide, in the presence of a base such as potassium carbonate, and optionally in the presence of a catalytic amount of potassium iodide, at about 50° C. to yield the ether product 40.8.
  • a base such as potassium carbonate
  • a catalytic amount of potassium iodide at about 50° C.
  • Scheme 41 depicts the preparation of phosphonate esters linked to a thiophenol nucleus by means of unsaturated and saturated carbon chains.
  • the carbon chain linkage is formed by means of a palladium catalyzed Heck reaction, in which an olefinic phosphonate 41.2 is coupled with an aromatic bromo compound 41.1.
  • Deprotection, or hydrogenation of the double bond followed by deprotection affords respectively the unsaturated phosphonate 41.4, or the saturated analog 41.6.
  • 3-bromothiophenol is converted into the S—Fm derivative 41.7, as described above, and this compound is reacted with diethyl 1-butenyl phosphonate 41.8, the preparation of which is described in J. Med. Chem., 1996, 39, 949, in the presence of a palladium (II) catalyst, for example, bis(triphenylphosphine)palladium (II) chloride, as described in J. Med. Chem, 1992, 35, 1371.
  • the reaction is conducted in an aprotic dipolar solvent such as, for example, dimethylformamide, in the presence of triethylamine, at about 100° C. to afford the coupled product 41.9.
  • aprotic dipolar solvent such as, for example, dimethylformamide
  • the initially formed unsaturated phosphonate 41.9 can be subjected to catalytic hydrogenation, using, for example, palladium on carbon as catalyst, to yield the saturated product 41.11, which upon deprotection affords the thiol 41.12.
  • Scheme 42 illustrates the preparation of an aryl-linked phosphonate ester 42.4 by means of a palladium(0) or palladium(II) catalyzed coupling reaction between a bromobenzene and a phenylboronic acid, as described in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 57.
  • the sulfur-substituted phenylboronic acid 42.1 is obtained by means of a metallation-boronation sequence applied to a protected bromo-substituted thiophenol, for example as described in J. Org. Chem, 49, 5237, 1984.
  • a coupling reaction then affords the diaryl product 42.3 which is deprotected to yield the thiol 42.4.
  • Scheme 43 depicts the preparation of dialkyl phosphonates in which the phosphonate moiety is linked to the thiophenyl group by means of a chain which incorporates an aromatic or heteroaromatic ring.
  • a suitably protected O, S or N-substituted thiophenol 43.1 is reacted with a dialkyl bromomethyl-substituted aryl or heteroarylphosphonate 43.2, prepared, for example, by means of an Arbuzov reaction between equimolar amounts of a bis(bromo-methyl) substituted aromatic compound and a trialkyl phosphite.
  • the reaction product 43.3 is then deprotected to afford the thiol 43.4.
  • 1,4-dimercaptobenzene is converted into the monobenzoyl ester 43.5 by reaction with one molar equivalent of benzoyl chloride, in the presence of a base such as pyridine.
  • the monoprotected thiol 43.5 is then reacted with, for example diethyl 4-(bromomethyl)phenylphosphonate, 43.6, the preparation of which is described in Tetrahedron, 1998, 54, 9341.
  • the reaction is conducted in a solvent such as dimethylformamide, in the presence of a base such as potassium carbonate, at about 50° C.
  • the thioether product 43.7 thus obtained is deprotected, as described above, to afford the thiol 43.8.
  • Scheme 44 illustrates the preparation of phosphonate-containing thiophenols in which the attached phosphonate chain forms a ring with the thiophenol moiety.
  • a suitably protected thiophenol 44.1 for example an indoline (in which X—Y is (CH 2 ) 2 ), an indole (X—Y is CH ⁇ CH) or a tetrahydroquinoline (X—Y is (CH 2 ) 3 ) is reacted with a dialkyl trifluoromethanesulfonyloxymethyl phosphonate 44.2, in the presence of an organic or inorganic base, in a polar aprotic solvent such as, for example, dimethylformamide, to afford the phosphonate ester 44.3. Deprotection, as described above, then affords the thiol 44.4.
  • thio-substituted indolines The preparation of thio-substituted indolines is described in EP 209751.
  • Thio-substituted indoles, indolines and tetrahydroquinolines can also be obtained from the corresponding hydroxy-substituted compounds, for example by thermal rearrangement of the dimethylthiocarbamoyl esters, as described in J. Org. Chem, 31, 3980, 1966.
  • the preparation of hydroxy-substituted indoles is described in Syn., 1994, 10, 1018; preparation of hydroxy-substituted indolines is described in Tet. Lett., 1986, 27, 4565, and the preparation of hydroxy-substituted tetrahydroquinolines is described in J. Het.
  • 2,3-dihydro-1H-indole-5-thiol, 44.5 the preparation of which is described in EP 209751, is converted into the benzoyl ester 44.6, as described above, and the ester is then reacted with the triflate 44.7, using the conditions described above for the preparation of 39.8, (Scheme 39, to yield the phosphonate 44.8.
  • Deprotection for example by reaction with dilute aqueous ammonia, as described above, then affords the thiol 44.9.
  • Scheme 45 describes the preparation of tert-butylamines in which the phosphonate moiety is directly attached to the tert-butyl group.
  • a suitably protected 2.2-dimethyl-2-aminoethyl bromide 45.1 is reacted with a trialkyl phosphite 45.2, under the conditions of the Arbuzov reaction, as described above, to afford the phosphonate 45.3, which is then deprotected as described previously to give 45.4
  • the cbz derivative of 2,2-dimethyl-2-aminoethyl bromide 45.6 is heated with a trialkyl phosphite at ca 150° C. to afford the product 45.7. Deprotection, as previously described, then affords the free amine 45.8.
  • Scheme 46 illustrates the preparation of phosphonate esters attached to the tert butylamine by means of a heteroatom and a carbon chain.
  • An optionally protected alcohol or thiol 46.1 is reacted with a bromoalkylphosphonate 46.2, to afford the displacement product 46.3. Deprotection, if needed, then yields the amine 46.4.
  • the cbz derivative of 2-amino-2,2-dimethylethanol 46.5 is reacted with a dialkyl 4-bromobutyl phosphonate 46.6, prepared as described in Synthesis, 1994, 9, 909, in dimethylformamide containing potassium carbonate and potassium iodide, at ca 60° C. to afford the phosphonate 46.7 Deprotection then affords the free amine 46.8.
  • Scheme 47 describes the preparation of carbon-linked phosphonate tert butylamine derivatives, in which the carbon chain can be unsaturated or saturated.
  • 2-amino-2-methylprop-1-yne 47.7 is converted into the N-phthalimido derivative 47.8, by reaction with phthalic anhydride, as described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M. Wuts, Wiley, 1991, pp. 358.
  • This compound is reacted with lithium diisopropylamide in tetrahydrofuran at ⁇ 78° C.
  • the resultant anion is then reacted with a dialkyl chlorophosphite 47.2 to afford the phosphonate 47.9.
  • Deprotection for example by treatment with hydrazine, as described in J. Org.
  • Scheme 48 illustrates the preparation of a tert butylamine phosphonate in which the phosphonate moiety is attached by means of a cyclic amine.
  • an aminoethyl-substituted cyclic amine 48.1 is reacted with a limited amount of a bromoalkyl phosphonate 48.2, using, for example, the conditions described above for the preparation of 40.3, (Scheme 40) to afford the displacement product 48.3.
  • 3-(1-amino-1-methyl)ethylpyrrolidine 48.4 the preparation of which is described in Chem. Pharm. Bull., 1994, 42, 1442, is reacted with a dialkyl 4-bromobutyl phosphonate 48.5, prepared as described in Synthesis, 1994, 9, 909, to afford the displacement product 48.6.
  • Scheme 48a illustrates methods for the synthesis of intermediates for the preparation of decahydroquinolines with phosphonate moieties at the 6-position. Two methods for the preparation of the intermediate 48a.4 are shown.
  • the carboxylic acid is first transformed into the benzyl ester, and the product is reacted with acetic anhydride in the presence of an organic base such as, for example, pyridine, to afford the product 48a.2, in which R is benzyl.
  • This compound is reacted with a brominating agent, for example N-bromosuccinimide, to effect benzylic bromination and yield the product 48a.3.
  • the reaction is conducted in an aprotic solvent such as, for example, ethyl acetate or carbon tetrachloride, at reflux.
  • the brominated compound 48a.3 is then treated with acid, for example dilute hydrochloric acid, to effect hydrolysis and cyclization to afford the tetrahydroisoquinoline 48a.4, in which R is benzyl.
  • the tetrahydroisoquinoline 48a.4 can be obtained from 2-hydroxyphenylalanine 48a.5, the preparation of which is described in Can. J. Bioch., 1971, 49, 877. This compound is subjected to the conditions of the Pictet-Spengler reaction, for example as described in Chem. Rev., 1995, 95, 1797.
  • the substrate 48a.5 is reacted with aqueous formaldehyde, or an equivalent such as paraformaldehyde or dimethoxymethane, in the presence of hydrochloric acid, for example as described in J. Med. Chem., 1986, 29, 784, to afford the tetrahydroisoquinoline product 48a.4, in which R is H.
  • Catalytic hydrogenation of the latter compound using, for example, platinum as catalyst, as described in J. Amer. Chem. Soc., 69, 1250, 1947, or using rhodium on alumina as catalyst, as described in J. Med. Chem., 1995, 38, 4446, then gives the hydroxy-substituted decahydroisoquinoline 48a.6.
  • the reduction can also be performed electrochemically, as described in Trans SAEST 1984, 19, 189.
  • the tetrahydroisoquinoline 48a.4 is subjected to hydrogenation in an alcoholic solvent, in the presence of a dilute mineral acid such as hydrochloric acid, and 5% rhodium on alumina as catalyst.
  • the hydrogenation pressure is ca. 750 psi and the reaction is conducted at ca 50° C., to afford the decahydroisoquinoline 48a.6.
  • the ketone is reduced by treatment with sodium borohydride in an alcoholic solvent such as isopropanol, at ambient temperature, to afford the alcohol 48a.10.
  • the alcohol 48a.6 can be converted into the thiol 48a.13 and the amine 48a.14, by means of displacement reactions with suitable nucleophiles, with inversion of stereochemistry.
  • the alcohol 48a.6 can be converted into an activated ester such as the trifluoromethanesulfonyl ester or the methanesulfonate ester 48a.7, by treatment with methanesulfonyl chloride and a base.
  • the mesylate 48a.7 is then treated with a sulfur nucleophile, for example potassium thioacetate, as described in Tet. Lett., 1992, 4099, or sodium thiophosphate, as described in Acta Chem. Scand., 1960, 1980, to effect displacement of the mesylate, followed by mild basic hydrolysis, for example by treatment with aqueous ammonia, to afford the thiol 48a.13.
  • a sulfur nucleophile for example potassium thioacetate, as described in Tet. Lett., 1992, 4099, or sodium thiophosphate, as described in Acta Chem. Scand., 1960, 1980.
  • the mesylate 48a.7 is reacted with one molar equivalent of sodium thioacetate in a polar aprotic solvent such as, for example, dimethylformamide, at ambient temperature, to afford the thioacetate 48a.12, in which R is COCH 3 .
  • a mild base such as, for example, aqueous ammonia, in the presence of an organic co-solvent such as ethanol, at ambient temperature, to afford the thiol 48a.13.
  • the mesylate 48a.7 can be treated with a nitrogen nucleophile, for example sodium phthalimide or sodium bis(trimethylsilyl)amide, as described in Comprehensive Organic Transformations, by R. C. Larock, p. 399, followed by deprotection as described previously, to afford the amine 48a.14.
  • a nitrogen nucleophile for example sodium phthalimide or sodium bis(trimethylsilyl)amide, as described in Comprehensive Organic Transformations, by R. C. Larock, p. 399, followed by deprotection as described previously, to afford the amine 48a.14.
  • the mesylate 48a.7 is reacted, as described in Angew. Chem. Int. Ed., 7, 919, 1968, with one molar equivalent of potassium phthalimide, in a dipolar aprotic solvent, such as, for example, dimethylformamide, at ambient temperature, to afford the displacement product 48a.8, in which NR a R b is phthalimido.
  • a dipolar aprotic solvent such as, for example, dimethylformamide
  • NR a R b is phthalimido.
  • Removal of the phthalimido group for example by treatment with an alcoholic solution of hydrazine at ambient temperature, as described in J. Org. Chem., 38, 3034, 1973, then yields the amine 48a.14.
  • Scheme 49 illustrates the preparation of compounds in which the phosphonate moiety is attached to the decahydroisoquinoline by means of a heteroatom and a carbon chain.
  • the compound 49.5 in which the carboxylic acid group is protected as the trichloroethyl ester, as described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M. Wuts, Wiley, 1991, p. 240, and the amine is protected as the cbz group, is reacted with a dialkyl 3-bromopropylphosphonate, 49.6, the preparation of which is described in J. Amer. Chem. Soc., 2000, 122, 1554 to afford the displacement product 49.7.
  • Deprotection of the ester group, followed by conversion of the acid to the R 4 NH amide and N-deprotection, as described below, (Scheme 53) then yields the amine 49.8.
  • Scheme 50 illustrates the preparation of phosphonates linked to the decahydroisoquinoline moiety by means of a nitrogen atom and a carbon chain.
  • the compounds are prepared by means of a reductive amination procedure, for example as described in Comprehensive Organic Transformations, by R. C. Larock, p.421.
  • the protected amino compound 48a.14 is reacted with a dialkyl formylphosphonate 50.4, the preparation of which is described in U.S. Pat. No. 3,784,590, in the presence of sodium cyanoborohydride, and a polar organic solvent such as ethanolic acetic acid, as described in Org. Prep. Proc. Int., 11, 201, 1979, to give the amine phosphonate 50.5.
  • a polar organic solvent such as ethanolic acetic acid
  • Scheme 51 depicts the preparation of a decahydroisoquinoline phosphonate in which the phosphonate moiety is linked by means of a sulfur atom and a carbon chain.
  • a thiol phosphonate 51.2 is reacted with a mesylate 51.1, to effect displacement of the mesylate group with inversion of stereochemistry, to afford the thioether product 51.3.
  • Deprotection of the ester group, followed by conversion of the acid to the tert. butyl amide and N-deprotection, as described below, (Scheme 53) then yields the amine 51.4.
  • the protected mesylate 51.5 is reacted with an equimolar amount of a dialkyl 2-mercaptoethyl phosphonate 51.6, the preparation of which is described in Aust. J. Chem., 43, 1123, 1990.
  • the reaction is conducted in a polar organic solvent such as ethanol, in the presence of a base such as, for example, potassium carbonate, at ambient temperature, to afford the thio ether phosphonate 51.7.
  • a base such as, for example, potassium carbonate
  • Scheme 52 illustrates the preparation of decahydroisoquinoline phosphonates 52.4 in which the phosphonate group is linked by means of an aromatic or heteroaromatic ring.
  • the compounds are prepared by means of a displacement reaction between hydroxy, thio or amino substituted substrates 52.1 and a bromomethyl substituted phosphonate 52.2.
  • the reaction is performed in an aprotic solvent in the presence of a base of suitable strength, depending on the nature of the reactant 52.1.
  • a base of suitable strength, depending on the nature of the reactant 52.1.
  • X is S or NH
  • a weak organic or inorganic base such as triethylamine or potassium carbonate can be employed.
  • X is O
  • a strong base such as sodium hydride or lithium hexamethyldisilylazide is required.
  • the protected alcohol 52.5 is reacted at ambient temperature with a dialkyl 3-bromomethyl phenylmethylphosphonate 52.6, the preparation of which is described above, (Scheme 43).
  • the reaction is conducted in a dipolar aprotic solvent such as, for example, dioxan or dimethylformamide.
  • the solution of the carbinol is treated with one equivalent of a strong base, such as, for example, lithium hexamethyldisilylazide, and to the resultant mixture is added one molar equivalent of the bromomethyl phosphonate 52.6, to afford the product 52.7.
  • a strong base such as, for example, lithium hexamethyldisilylazide
  • Schemes 49-52 illustrate the preparation of decahydroisoquinoline esters incorporating a phosphonate group linked to the decahydroisoquinoline nucleus.
  • Scheme 53 illustrates the conversion of the latter group of compounds 53.1 (in which the group B is link-P(O)(OR 1 ) 2 or optionally protected precursor substituents thereto, such as, for example, OH, SH, NH 2 ) to the corresponding R 4 NH amides 53.5.
  • the ester compounds 53.1 are deprotected to form the corresponding carboxylic acids 53.2.
  • the methods employed for the deprotection are chosen based on the nature of the protecting group R, the nature of the N-protecting group R 2 , and the nature of the substituent at the 6-position. For example, if R is trichloroethyl, the ester group is removed by treatment with zinc in acetic acid, as described in J. Amer. Chem. Soc., 88, 852, 1966.
  • Conversion of the carboxylic acid 53.2 to the R 4 NH amide 53.4 is then accomplished by reaction of the carboxylic acid, or an activated derivative thereof, with the amine R 4 NH 2 53.3 to afford the amide 53.4, using the conditions described above for the preparation of the amide 1.6. Deprotection of the NR 2 group, as described above, then affords the free amine 53.5. Interconversions of the Phosphonates R-Link-P(O)(OR 1 ) 2 , R-Link-P(O)(OR 1 )(OH) and R-Link-P(O)(OH) 2 .
  • Schemes 1-69 described the preparations of phosphonate esters of the general structure R-link-P(O)(OR 1 ) 2 , in which the groups R 1 , the structures of which are defined in Chart 1, may be the same or different.
  • the R 1 groups attached to a phosphonate esters 1-6, or to precursors thereto, may be changed using established chemical transformations.
  • the interconversions reactions of phosphonates are illustrated in Scheme 54.
  • the group R in Scheme 54 represents the substructure to which the substituent link-P(O)(OR 1 ) 2 is attached, either in the compounds 1-6 or in precursors thereto.
  • the R 1 group may be changed, using the procedures described below, either in the precursor compounds, or in the esters 1-6.
  • the conversion of a phosphonate diester 54.1 into the corresponding phosphonate monoester 54.2 can be accomplished by a number of methods.
  • the ester 54.1 in which R 1 is an aralkyl group such as benzyl can be converted into the monoester compound 54.2 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 54.1 in which R 1 is an aryl group such as phenyl or an alkenyl group such as allyl, into the monoester 54.2 can be effected by treatment of the ester 54.1 with a base such as aqueous sodium hydroxide in acetonitrile or lithium hydroxide in aqueous tetrahydrofuran.
  • a base such as aqueous sodium hydroxide in acetonitrile or lithium hydroxide in aqueous tetrahydrofuran.
  • Phosphonate diesters 54.1 in which one of the groups R 1 is aralkyl, such as benzyl, and the other is alkyl can be converted into the monoesters 54.2 in which R 1 is alkyl by hydrogenation, for example using a palladium on carbon catalyst.
  • Phosphonate diesters in which both of the groups R 1 are alkenyl, such as allyl can be converted into the monoester 54.2 in which R 1 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.
  • the conversion of a phosphonate diester 54.1 or a phosphonate monoester 54.2 into the corresponding phosphonic acid 54.3 can effected by reaction of the diester or the monoester with trimethylsilyl bromide, as described in J. Chem. Soc., Chem. Comm., 739, 1979.
  • the reaction is conducted in an inert solvent such as, for example, dichloromethane, optionally in the presence of a silylating agent such as bis(trimethylsilyl)trifluoroacetamide, at ambient temperature.
  • a phosphonate monoester 54.2 in which R 1 is alkenyl such as, for example, allyl, can be converted into the phosphonic acid 54.3 by reaction with Wilkinson's catalyst in an aqueous organic solvent, for example in 15% aqueous acetonitrile, or in aqueous ethanol, for example using the procedure described in Helv. Chim. Acta., 68, 618, 1985.
  • the conversion of a phosphonate monoester 54.2 into a phosphonate diester 54.1 (Scheme 54, Reaction 4) in which the newly introduced R 1 group is alkyl, aralkyl haloalkyl such as chloroethyl, or aralkyl can be effected by a number of reactions in which the substrate 54.2 is reacted with a hydroxy compound R 1 OH, in the presence of a coupling agent.
  • Suitable coupling agents are those employed for the preparation of carboxylate esters, and include a carbodiimide such as dicyclohexylcarbodiimide, in which case the reaction is preferably conducted in a basic organic solvent such as pyridine, or (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PYBOP, Sigma), in which case the reaction is performed in a polar solvent such as dimethylformamide, in the presence of a tertiary organic base such as diisopropylethylamine, or Aldrithiol-2 (Aldrich) in which case the reaction is conducted in a basic solvent such as pyridine, in the presence of a triaryl phosphine such as triphenylphosphine.
  • a carbodiimide such as dicyclohexylcarbodiimide
  • PYBOP benzotriazol-1-yloxy)tripyrrolidinophosphonium
  • the conversion of the phosphonate monoester 54.2 to the diester 54.1 can be effected by the use of the Mitsonobu reaction, as described above (Scheme 25).
  • the substrate is reacted with the hydroxy compound R 1 OH, in the presence of diethyl azodicarboxylate and a triarylphosphine such as triphenyl phosphine.
  • the phosphonate monoester 54.2 can be transformed into the phosphonate diester 54.1, in which the introduced R 1 group is alkenyl or aralkyl, by reaction of the monoester with the halide R 1 Br, in which R 1 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.
  • a polar organic solvent such as dimethylformamide or acetonitrile
  • a base such as cesium carbonate.
  • the phosphonate monoester can be transformed into the phosphonate diester in a two step procedure.
  • the phosphonate monoester 54.2 is transformed into the chloro analog RP(O)(OR 1 )Cl by reaction with thionyl chloride or oxalyl chloride and the like, as described in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p.
  • a phosphonic acid R-link-P(O)(OH) 2 can be transformed into a phosphonate monoester RP(O)(OR 1 )(OH) (Scheme 54, Reaction 5) by means of the methods described above of for the preparation of the phosphonate diester R-link-P(O)(OR 1 ) 2 54.1, except that only one molar proportion of the component R 1 OH or R 1 Br is employed.
  • a phosphonic acid R-link-P(O)(OH) 2 54.3 can be transformed into a phosphonate diester R-link-P(O)(OR 1 ) 2 54.1 (Scheme 54, Reaction 6) by a coupling reaction with the hydroxy compound R 1 OH, in the presence of a coupling agent such as Aldrithiol-2 (Aldrich) and triphenylphosphine.
  • the reaction is conducted in a basic solvent such as pyridine.
  • phosphonic acids 54.3 can be transformed into phosphonic esters 54.1 in which R 1 is aryl, by means of a coupling reaction employing, for example, dicyclohexylcarbodiimide in pyridine at ca 70° C.
  • phosphonic acids 54.3 can be transformed into phosphonic esters 54.1 in which R 1 is alkenyl by means of an alkylation reaction.
  • the phosphonic acid is reacted with the alkenyl bromide R 1 Br in a polar organic solvent such as acetonitrile solution at reflux temperature, the presence of a base such as cesium carbonate, to afford the phosphonic ester 54.1.
  • the preparation of carbamates is described in Comprehensive Organic Functional Group Transformations, A. R. Katritzky, ed., Pergamon, 1995, Vol. 6, p. 416ff, and in Organic Functional Group Preparations, by S. R. Sandler and W. Karo, Academic Press, 1986, p. 260ff.
  • Scheme 55 illustrates various methods by which the carbamate linkage can be synthesized.
  • a carbinol 55.1 is converted into the activated derivative 55.2 in which Lv is a leaving group such as halo, imidazolyl, benztriazolyl and the like, as described below.
  • the activated derivative 55.2 is then reacted with an amine 55.3, to afford the carbamate product 55.4.
  • Examples 1-7 in Scheme 55 depict methods by which the general reaction can be effected.
  • Examples 8-10 illustrate alternative methods for the preparation of carbamates.
  • Example 1 illustrates the preparation of carbamates employing a chloroformyl derivative of the carbinol 55.5.
  • the carbinol 55.5 is reacted with phosgene, in an inert solvent such as toluene, at about 0° C., as described in Org. Syn. Coll. Vol. 3, 167, 1965, or with an equivalent reagent such as trichloromethoxy chloroformate, as described in Org. Syn. Coll. Vol. 6, 715, 1988, to afford the chloroformate 55.6.
  • the latter compound is then reacted with the amine component 55.3, in the presence of an organic or inorganic base, to afford the carbamate 55.7.
  • the chloroformyl compound 55.6 is reacted with the amine 55.3 in a water-miscible solvent such as tetrahydrofuran, in the presence of aqueous sodium hydroxide, as described in Org. Syn. Coll. Vol. 3, 167, 1965, to yield the carbamate 55.7.
  • a water-miscible solvent such as tetrahydrofuran
  • aqueous sodium hydroxide as described in Org. Syn. Coll. Vol. 3, 167, 1965
  • the reaction is preformed in dichloromethane in the presence of an organic base such as diisopropylethylamine or dimethylaminopyridine.
  • Example 2 depicts the reaction of the chloroformate compound 55.6 with imidazole, 55.7, to produce the imidazolide 55.8.
  • the imidazolide product is then reacted with the amine 55.3 to yield the carbamate 55.7.
  • the preparation of the imidazolide is performed in an aprotic solvent such as dichloromethane at 0° C., and the preparation of the carbamate is conducted in a similar solvent at ambient temperature, optionally in the presence of a base such as dimethylaminopyridine, as described in J. Med. Chem., 1989, 32, 357.
  • Example 3 depicts the reaction of the chloroformate 55.6 with an activated hydroxyl compound R′′OH, to yield the mixed carbonate ester 55.10.
  • the reaction is conducted in an inert organic solvent such as ether or dichloromethane, in the presence of a base such as dicyclohexylamine or triethylamine.
  • the hydroxyl component R′′OH is selected from the group of compounds 55.19-55.24 shown in Scheme 55, and similar compounds.
  • the mixed carbonate 55.10 is obtained by the reaction of the chloroformate with the hydroxyl compound in an ethereal solvent in the presence of dicyclohexylamine, as described in Can. J. Chem., 1982, 60, 976.
  • a similar reaction in which the component R′′OH is pentafluorophenol 55.22 or 2-hydroxypyridine 55.23 can be performed in an ethereal solvent in the presence of triethylamine, as described in Syn., 1986, 303, and Chem. Ber. 118, 468, 1985.
  • Example 4 illustrates the preparation of carbamates in which an alkyloxycarbonylimidazole 55.8 is employed.
  • a carbinol 55.5 is reacted with an equinolar amount of carbonyl diimidazole 55.11 to prepare the intermediate 55.8.
  • the reaction is conducted in an aprotic organic solvent such as dichloromethane or tetrahydrofuran.
  • the acyloxyimidazole 55.8 is then reacted with an equimolar amount of the amine R′NH 2 to afford the carbamate 55.7.
  • the reaction is performed in an aprotic organic solvent such as dichloromethane, as described in Tet. Lett., 42, 2001, 5227, to afford the carbamate 55.7.
  • Example 5 illustrates the preparation of carbamates by means of an intermediate alkoxycarbonylbenztriazole 55.13.
  • a carbinol ROH is reacted at ambient temperature with an equimolar amount of benztriazole carbonyl chloride 55.12, to afford the alkoxycarbonyl product 55.13.
  • the reaction is performed in an organic solvent such as benzene or toluene, in the presence of a tertiary organic amine such as triethylamine, as described in Syn., 1977, 704.
  • This product is then reacted with the amine RNH 2 to afford the carbamate 55.7.
  • the reaction is conducted in toluene or ethanol, at from ambient temperature to about 80° C. as described in Syn., 1977,704.
  • Example 6 illustrates the preparation of carbamates in which a carbonate (R′′O) 2 CO, 55.14, is reacted with a carbinol 55.5 to afford the intermediate alkyloxycarbonyl intermediate 55.15. The latter reagent is then reacted with the amine RNH 2 to afford the carbamate 55.7.
  • the procedure in which the reagent 55.15 is derived from hydroxybenztriazole 55.19 is described in Synthesis, 1993, 908; the procedure in which the reagent 55.15 is derived from N-hydroxysuccinimide 55.20 is described in Tet. Lett., 1992, 2781; the procedure in which the reagent 55.15 is derived from 2-hydroxypyridine 55.23 is described in Tet.
  • Example 7 illustrates the preparation of carbamates from alkoxycarbonyl azides 55.16.
  • an alkyl chloroformate 55.6 is reacted with an azide, for example sodium azide, to afford the alkoxycarbonyl azide 55.16.
  • the latter compound is then reacted with an equimolar amount of the amine RNH 2 to afford the carbamate 55.7.
  • the reaction is conducted at ambient temperature in a polar aprotic solvent such as dimethylsulfoxide, for example as described in Syn., 1982, 404.
  • Example 8 illustrates the preparation of carbamates by means of the reaction between a carbinol ROH and the chloroformyl derivative of an amine.
  • the reactants are combined at ambient temperature in an aprotic solvent such as acetonitrile, in the presence of a base such as triethylamine, to afford the carbamate 55.7.
  • Example 9 illustrates the preparation of carbamates by means of the reaction between a carbinol ROH and an isocyanate 55.18.
  • the reactants are combined at ambient temperature in an aprotic solvent such as ether or dichloromethane and the like, to afford the carbamate 55.7.
  • Example 10 illustrates the preparation of carbamates by means of the reaction between a carbinol ROH and an amine R′NH 2 .
  • the reactants are combined at ambient temperature in an aprotic organic solvent such as tetrahydrofuran, in the presence of a tertiary base such as triethylamine, and selenium.
  • a tertiary base such as triethylamine, and selenium.
  • Carbon monoxide is passed through the solution and the reaction proceeds to afford the carbamate 55.7.
  • Schemes 56-61 illustrate the preparation of phosphonate-containing analogs of the phenoxyacetic acid C8 (Chart 3a)
  • Schemes 62-65 illustrate the preparation of phosphonate-containing analogs of the carboxylic acid C4
  • Schemes 66-69 illustrate the preparation of phosphonate-containing analogs of the amine A12 (Chart 2)
  • Schemes 70-75 illustrate the preparation of phosphonate-containing analogs of the carboxylic acid C38.
  • the resultant phosphonate-containing analogs R 6a COOH and R 2e NHCH(R 3a )CONHR 4 can then, using the procedures described above, be employed in the preparation of the compounds 5 and 6.
  • Scheme 56 illustrates two alternative methods by means of which 2,6-dimethylphenoxyacetic acids bearing phosphonate moieties may be prepared.
  • the phosphonate group may be introduced into the 2,6-dimethylphenol moiety, followed by attachment of the acetic acid group, or the phosphonate group may be introduced into a preformed 2,6-dimethylphenoxyacetic acid intermediate.
  • a substituted 2,6-dimethylphenol 56.1 in which the substituent B is a precursor to the group link-P(O)(OR 1 ) 2 , and in which the phenolic hydroxyl may or may not be protected, depending on the reactions to be performed, is converted into a phosphonate-containing compound 56.2.
  • Methods for the conversion of the substituent B into the group link-P(O)(OR 1 ) 2 are described in Schemes 25-69.
  • the protected phenolic hydroxyl group present in the phosphonate-containing product 56.2 is then deprotected, using methods described below, to afford the phenol 56.3.
  • the phenolic product 56.3 is then transformed into the corresponding phenoxyacetic acid 56.4, in a two step procedure.
  • the phenol 56.3 is reacted with an ester of bromoacetic acid 56.5, in which R is an alkyl group or a protecting group.
  • R is an alkyl group or a protecting group.
  • Methods for the protection of carboxylic acids are described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Second Edition 1990, p. 224ff.
  • the alkylation of phenols to afford phenolic ethers is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 446ff.
  • the phenol and the alkylating agent are reacted together in the presence of an organic or inorganic base, such as, for example, diazabicyclononene, (DBN) or potassium carbonate, in a polar organic solvent such as, for example, dimethylformamide or acetonitrile.
  • an organic or inorganic base such as, for example, diazabicyclononene, (DBN) or potassium carbonate
  • a polar organic solvent such as, for example, dimethylformamide or acetonitrile.
  • equimolar amounts of the phenol 56.3 and ethyl bromoacetate are reacted together in the presence of cesium carbonate, in dioxan at reflux temperature, for example as described in U.S. Pat. No. 5,914,332, to afford the ester 56.6.
  • the thus-obtained ester 56.6 is then hydrolyzed to afford the carboxylic acid 56.4.
  • the methods used for this reaction depend on the nature of the group R. If R is an alkyl group such as methyl hydrolysis can be effected by treatment of the ester with aqueous or aqueous alcoholic base, or by use of an esterase enzyme such as porcine liver esterase. If R is a protecting group, methods for hydrolysis are described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Second Edition 1990, p. 224ff.
  • ester product 56.6 which R is ethyl is hydrolyzed to the carboxylic acid 56.4 by reaction with lithium hydroxide in aqueous methanol at ambient temperature, as described in U.S. Pat. No. 5,914,332.
  • an appropriately substituted 2,6-dimethylphenol 56.7 in which the substituent B is a precursor to the group link-P(O)(OR 1 ) 2 , is transformed into the corresponding phenoxyacetic ester 56.8.
  • the conditions employed for the alkylation reaction are similar to those described above for the conversion of the phenol 56.3 into the ester 56.6.
  • the phenolic ester 56.8 is then converted, by transformation of the group B into the group link-P(O)(OR 1 ) 2 followed by ester hydrolysis, into the carboxylic acid 56.4.
  • the group B which is present in the ester 56.4 may be transformed into the group link-P(O)(OR 1 ) 2 either before or after hydrolysis of the ester moiety into the carboxylic acid group, depending on the nature of the chemical transformations required.
  • Schemes 56-61 illustrate the preparation of 2,6-dimethylphenoxyacetic acids incorporating phosphonate ester groups. The procedures shown can also be applied to the preparation of phenoxyacetic esters acids 56.8, with, if appropriate, modifications made according to the knowledge of one skilled in the art.
  • Scheme 57 illustrates the preparation of 2,6-dimethylphenoxyacetic acids incorporating a phosphonate ester which is attached to the phenolic group by means of a carbon chain incorporating a nitrogen atom.
  • the compounds 57.4 are obtained by means of a reductive alkylation reaction between a 2,6-dimethylphenol aldehyde 57.1 and an aminoalkyl phosphonate ester 57.2.
  • the preparation of amines by means of reductive amination procedures is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, p. 421.
  • the amine component 57.2 and the aldehyde component 57.1 are reacted together in the presence of a reducing agent such as, for example, borane, sodium cyanoborohydride or diisobutylaluminum hydride, to yield the amine product 57.3.
  • a reducing agent such as, for example, borane, sodium cyanoborohydride or diisobutylaluminum hydride
  • the amination product 57.3 is then converted into the phenoxyacetic acid compound 57.4, using the alkylation and ester hydrolysis procedures described above, (Scheme 56)
  • Scheme 56 For example, equimolar amounts of 4-hydroxy-3,5-dimethylbenzaldehyde 57.5 (Aldrich) and a dialkyl aminoethyl phosphonate 57.6, the preparation of which is described in J. Org.
  • Scheme 58 depicts the preparation of 2,6-dimethylphenols incorporating a phosphonate group linked to the phenyl ring by means of a saturated or unsaturated alkylene chain.
  • an optionally protected bromo-substituted 2,6-dimethylphenol 58.1 is coupled, by means of a palladium-catalyzed Heck reaction, with a dialkyl alkenyl phosphonate 58.2.
  • the coupling of aryl bromides 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. 503.
  • the aryl bromide and the olefin are coupled in a polar solvent such as dimethylformamide or dioxan, in the presence of a palladium(0) or palladium (2) catalyst.
  • a polar solvent such as dimethylformamide or dioxan
  • the product 58.3 is converted, using the procedures described above, (Scheme 56) into the corresponding phenoxyacetic acid 58.4.
  • the olefinic product 58.3 is reduced to afford the saturated 2,6-dimethylphenol derivative 58.5.
  • Methods for the reduction of carbon-carbon double bonds are described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 6.
  • the methods include catalytic reduction, or chemical reduction employing, for example, diborane or diimide.
  • the product 58.5 is converted, as described above, (Scheme 56) into the corresponding phenoxyacetic acid 58.6.
  • 3-bromo-2,6-dimethylphenol 58.7 prepared as described in Can. J. Chem., 1983, 61, 1045, is converted into the tert-butyldimethylsilyl ether 58.8, by reaction with chloro-tert-butyldimethylsilane, and a base such as imidazole, as described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Second Edition 1990 p. 77.
  • the product 58.8 is reacted with an equimolar amount of a dialkyl allyl phosphonate 58.9, for example diethyl allylphosphonate (Aldrich) in the presence of ca. 3 mol % of bis(triphenylphosphine) palladium(II) chloride, in dimethylformamide at ca. 60° C., to produce the coupled product 58.10.
  • the silyl group is removed, for example by the treatment of the ether 58.10 with a solution of tetrabutylammonium fluoride in tetrahydrofuran, as described in J. Am. Chem., Soc., 94, 6190, 1972, to afford the phenol 58.11.
  • This compound is converted, employing the procedures described above, (Scheme 56) into the corresponding phenoxyacetic acid 58.12.
  • the unsaturated compound 58.11 is reduced, for example by catalytic hydrogenation employing 5% palladium on carbon as catalyst, in an alcoholic solvent such as methanol, as described, for example, in Hydrogenation Methods, by R. N. Rylander, Academic Press, 1985, Ch. 2, to afford the saturated analog 58.13.
  • This compound is converted, employing the procedures described above, (Scheme 56) into the corresponding phenoxyacetic acid 58.14.
  • Scheme 59 illustrates the preparation of phosphonate-containing 2,6-dimethylphenoxyacetic acids 59.1 in which the phosphonate group is attached to the 2,6-dimethylphenoxy moiety by means of a carbocyclic ring.
  • a bromo-substituted 2,6-dimethylphenol 59.2 is converted, using the procedures illustrated in Scheme 56, into the corresponding 2,6-dimethylphenoxyacetic ester 59.3.
  • the latter compound is then reacted, by means of a palladium-catalyzed Heck reaction, with a cycloalkenone 59.4, in which n is 1 or 2.
  • the coupling reaction is conducted under the same conditions as those described above for the preparation of 58.3 (Scheme 58).
  • the product 59.5 is then reduced catalytically, as described above for the reduction of 58.3, (Scheme 58), to afford the substituted cycloalkanone 59.6.
  • the ketone is then subjected to a reductive amination procedure, by reaction with a dialkyl 2-aminoethylphosphonate 59.7 and sodium triacetoxyborohydride, as described in J. Org. Chem., 61, 3849, 1996, to yield the amine phosphonate 59.8.
  • the reductive amination reaction is conducted under the same conditions as those described above for the preparation of the amine 57.3 (Scheme 57).
  • the resultant ester 59.8 is then hydrolyzed, as described above, to afford the phenoxyacetic acid 59.1.
  • the enone is then reduced to the saturated ketone 59.13, by means of catalytic hydrogenation employing 5% palladium on carbon as catalyst.
  • the saturated ketone is then reacted with an equimolar amount of a dialkyl aminoethylphosphonate 59.14, prepared as described in J. Org. Chem., 2000, 65, 676, in the presence of sodium cyanoborohydride, to yield the amine 59.15.
  • Hydrolysis employing lithium hydroxide in aqueous methanol at ambient temperature, then yields the acetic acid 59.16.
  • Scheme 60 illustrates the preparation of 2,6-dimethylphenoxyacetic acids incorporating a phosphonate group attached to the phenyl ring by means of a heteroatom and an alkylene chain.
  • the compounds are obtained by means of alkylation reactions in which an optionally protected hydroxy, thio or amino-substituted 2,6-dimethylphenol 60.1 is reacted, in the presence of a base such as, for example, potassium carbonate, and optionally in the presence of a catalytic amount of an iodide such as potassium iodide, with a dialkyl bromoalkyl phosphonate 60.2.
  • the reaction is conducted in a polar organic solvent such as dimethylformamide or acetonitrile at from ambient temperature to about 80° C.
  • a polar organic solvent such as dimethylformamide or acetonitrile
  • the product of the alkylation reaction, 60.3 is then converted, as described above (Scheme 56) into the phenoxyacetic acid 60.4.
  • 2,6-diimethyl-4-mercaptophenol 60.5 prepared as described in EP 482342, is reacted in dimethylformamide at ca. 60° C. with an equimolar amount of a dialkyl bromobutyl phosphonate 60.6, the preparation of which is described in Synthesis, 1994, 9, 909, in the presence of ca. 5 molar equivalents of potassium carbonate, to afford the thioether product 60.7.
  • This compound is converted, employing the procedures described above, (Scheme 56) into the corresponding phenoxyacetic acid 60.8.
  • Scheme 61 illustrates the preparation of 2,6-dimethylphenoxyacetic acids incorporating a phosphonate ester group attached by means of an aromatic or heteroaromatic group.
  • an optionally protected hydroxy, mercapto or amino-substituted 2.6-dimethylphenol 61.1 is reacted, under basic conditions, with a bis(halomethyl)aryl or heteroaryl compound 61.2.
  • Equimolar amounts of the phenol and the halomethyl compound are reacted in a polar organic solvent such as dimethylformamide or acetonitrile, in the presence of a base such as potassium or cesium carbonate, or dimethylaminopyridine, to afford the ether, thioether or amino product 61.3.
  • the product 61.3 is then converted, using the procedures described above, (Scheme 56) into the phenoxyacetic ester 61.4.
  • the latter compound is then subjected to an Arbuzov reaction by reaction with a trialkylphosphite 61.5 at ca. 100° C. to afford the phosphonate ester 61.6.
  • the preparation of phosphonates by means of the Arbuzov reaction is described, for example, in Handb. Organophosphorus Chem., 1992, 115.
  • the resultant product 61.6 is then converted into the acetic acid 61.7 by hydrolysis of the ester moiety, using the procedures described above, (Scheme 56).
  • Scheme 62 depicts the preparation of phosphonate-containing analogs of the benzyl carbamate aminoacid derivative C4 in which the phosphonate moiety is either directly attached to the phenyl ring or attached by means of an alkylene chain.
  • a dialkyl hydroxymethylphenyl alkylphosphonate 62.1 is converted into an activated derivative 62.2, in which Lv is a leaving group, as described above (Scheme 55).
  • the product is then reacted with a suitably protected aminoacid 62.3, to afford the carbamate product 62.4.
  • the reaction is conducted under the conditions described above for the preparation of carbamates (Scheme 55).
  • the protecting group on the carboxylic acid group in the product 62.4 is then removed to afford the free carboxylic acid 62.5.
  • Methods for the protection and deprotection of carboxylic acids are described, for example, in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Second Edition 1990, p. 224ff.
  • Example 1 a dialkyl 4-hydroxymethylphenyl phosphonate 62.6, prepared as described in U.S. Pat. No. 5,569,664, is reacted with phosgene, or an equivalent thereof, as described above (Scheme 55), to afford the chloroformyl product 62.7.
  • This compound is then reacted in an inert solvent such as dichloromethane or tetrahydrofuran, with the tert. butyl aminoacid ester 62.3, in the presence of a base such as triethylamine, to yield the carbamate product 62.8.
  • an inert solvent such as dichloromethane or tetrahydrofuran
  • a base such as triethylamine
  • the ester can be prepared by the reaction of the carboxylic acid with isobutylene and an acid catalyst, or by conventional esterification procedures employing tert. butanol.
  • the tert. butyl protecting group is then removed from the product 62.8, for example by reaction with trifluoroacetic acid at ambient temperature for about one hour, to afford the carboxylic acid 62.9.
  • Scheme 63 depicts the preparation of phosphonate-containing analogs of the benzyl carbamate aminoacid derivative C4 in which the phosphonate moiety is attached to the phenyl ring by means of a saturated or unsaturated alkylene chain.
  • a bromo-substituted benzyl alcohol 63.1 is subjected to a palladium catalyzed Heck reaction, as described above, (Scheme 26) with a dialkyl alkenyl phosphonate 63.2, to afford the olefinic product 63.3.
  • the product is then converted into the activated derivative 63.4, which is then reacted with aminoacid derivative 62.3, as described above, to afford, after deprotection of the carboxyl group, the carbamate product 63.5.
  • the olefinic coupling product can be reduced to the saturated analog 63.6.
  • the reduction reaction can be effected chemically, for example by the use of diimide or diborane, as described in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 5.
  • the product 63.6 is then converted, as described above, into the carbamate derivative 63.8.
  • 3-bromobenzyl alcohol 63.9 is coupled in acetonitrile solution, with a dialkyl allylphosphonate 63.10 (Aldrich), in the presence of palladium acetate, triethylamine and tri-o-tolylphosphine, as described in Synthesis, 1983, 556, to afford the product 63.11.
  • This material is then reacted with carbonyl diimidazole, as described above, (Scheme 55) to afford the imidazolide 63.12.
  • the product is then coupled with the aminoacid derivative 62.3, to afford after deprotection, the product 63.13.
  • the unsaturated phosphonate 63.11 is reduced, for example by reaction with diborane in tetrahydrofuran at ambient temperature, as described in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 5., to afford the saturated analog 63.14.
  • the latter compound is then transformed, as described above, into the carbamate aminoacid derivative 63.15.
  • Scheme 64 depicts the preparation of phosphonate-containing analogs of the benzyl carbamate aminoacid derivative C4 in which the phosphonate moiety is attached to the phenyl ring by means of an amino-containing alkylene chain.
  • a formyl-substituted benzyl alcohol 64.1 is converted, using the procedures described above is Schemes 55 and 63, into the aminoacid carbamate derivative 64.2.
  • the product is then subjected to a reductive amination reaction with a dialkyl aminoalkyl phosphonate 64.3, to afford the phosphonate product 64.4.
  • Reductive amination of carbonyl compounds is described above (Scheme 27).
  • 3-formyl benzyl alcohol 64.5 is converted into the carbamate derivative 64.6.
  • the product is then reacted in ethanol solution at ambient temperature with a dialkyl aminoethyl phosphonate 64.7, the preparation of which is described in J. Org. Chem., 2000, 65, 676, in the presence of sodium cyanoborohydride, to yield the phosphonate product 64.8.
  • a dialkyl aminoethyl phosphonate 64.7 the preparation of which is described in J. Org. Chem., 2000, 65, 676, in the presence of sodium cyanoborohydride, to yield the phosphonate product 64.8.
  • Scheme 65 depicts the preparation of phosphonate-containing analogs of the benzyl carbamate aminoacid derivative C4 in which the phosphonate moiety is attached to the phenyl ring by means of an O, S or N-alkyl-containing alkylene chain.
  • a chloromethyl-substituted benzyl alcohol 65.1 is reacted with a dialkyl hydroxy, mercapto or alkylaminoalkyl phosphonate 65.2.
  • the alkylation reaction is conducted between equimolar amounts of the reactants in a polar organic solvent such as dimethylformamide or acetonitrile, in the presence of an inorganic or organic base, such as diisopropylethylamine, dimethylaminopyridine, potassium carbonate and the like.
  • a polar organic solvent such as dimethylformamide or acetonitrile
  • an inorganic or organic base such as diisopropylethylamine, dimethylaminopyridine, potassium carbonate and the like.
  • the alkylated product 65.3 is then converted, as previously described, into the carbamate aminoacid derivative 65.4.
  • Scheme 66 illustrates the preparation of phosphonate-containing analogs of the amine A12 in which the phosphonate moiety is attached to the pyridine ring by means of a heteroatom and an alkylene chain.
  • 2-bromo-4-hydroxymethylpyridine the preparation of which is described in Chem. Pharm. Bull., 1990, 38, 2446, is subjected to a nucleophilic displacement reaction with a dialkyl hydroxy, thio or aminoalkyl-substituted alkyl phosphonate 66.2.
  • the displacement product 66.3 is then converted into the activated derivative 66.4, in which Lv is a leaving group such as halo, methanesulfonyloxy, p-toluenesulfonyloxy and the like.
  • Lv is a leaving group such as halo, methanesulfonyloxy, p-toluenesulfonyloxy and the like.
  • the conversion of alcohols into chlorides and bromides is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 354ff and p. 356ff.
  • benzyl alcohols can be transformed into the chloro compounds, in which Ha is chloro, by reaction with triphenylphosphine and N-chlorosuccinimide, as described in J. Am. Chem. Soc., 106, 3286, 1984.
  • Benzyl alcohols can be transformed into bromo compounds by reaction with carbon tetrabromide and triphenylphosphine, as described in J. Am. Chem. Soc., 92, 2139, 1970. Alcohols can be converted into sulfonate esters by treatment with the alkyl or aryl sulfonyl chloride and a base, in a solvent such as dichloromethane or pyridine.
  • the carbinol 66.3 is converted into the corresponding chloro compound, 66.4, in which Lv is Cl, as described above.
  • the product is then reacted with the piperidinol derivative 66.5.
  • the preparation of the compounds 66.5 is described in U.S. Pat. No. 5,614,533, and in J.
  • the deprotection can be effected by treatment of the BOC compound with anhydrous acids, for example, hydrogen chloride or trifluoroacetic acid, or by reaction with trimethylsilyl iodide or aluminum chloride.
  • anhydrous acids for example, hydrogen chloride or trifluoroacetic acid
  • the BOC group is removed by treatment of the substrate 66.6 with hydrochloric acid, as described in J. Org. Chem., 1997, 62, 3440.
  • 2-bromo-4-hydroxymethylpyridine 66.1 the preparation of which is described in Chem. Pharm Bull, 1990, 38, 2446, is reacted in dimethylformamide solution at ca 80° C. with an equimolar amount of a dialkyl mercaptoethyl phosphonate 66.8, prepared as described in Zh. Obschei. Khim, 1973, 43, 2364, and potassium carbonate, to yield the thioether product 66.9.
  • the product is then reacted with one molar equivalent of methanesulfonyl chloride in pyridine at 0° C., to produce the mesylate compound 66.10.
  • This material is reacted with the piperidinol reagent 66.5, using the conditions described above, to afford the ether 66.11.
  • the BOC protecting group is then removed as previously described, to afford the amine product 66.12.
  • Scheme 67 illustrates the preparation of phosphonate-containing analogs of the amine A12 in which the phosphonate moiety is directly attached to the pyridine ring.
  • a bromo-substituted 4-hydroxymethylpyridine 67.1 is coupled, in the presence of a palladium catalyst, with a dialkyl phosphite 67.2.
  • the reaction between aryl bromides and dialkyl phosphites to yield aryl phosphonates is described in Synthesis, 56, 1981, and in J. Med. Chem., 1992, 35, 1371.
  • the reaction is conducted in an inert solvent such as toluene or xylene, at about 100° C., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium and a tertiary organic base such as triethylamine.
  • a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium
  • a tertiary organic base such as triethylamine.
  • 3-bromo-4-hydroxymethylpyridine 67.5 prepared as described in Bioorg. Med. Chem. Lett., 1992, 2, 1619, is reacted with a dialkyl phosphite 67.2, as described above, to prepare the phosphonate 67.7.
  • the product is then transformed into the chloro derivative by reaction with triphenylphosphine and N-chlorosuccinimide, and the product is converted, as described above (Scheme 66) into the amine 67.9.
  • Scheme 68 illustrates the preparation of phosphonate-containing analogs of the amine A12 in which the phosphonate moiety is attached to the pyridine ring by means of an amine group and an alkyl chain.
  • an amino-substituted 4-hydroxymethylpyridine 68.1 is subjected to a reductive amination reaction with a dialkyl formylalkyl phosphonate 68.2.
  • the preparation of amines by means of reductive amination procedures is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, p. 421, and in Advanced Organic Chemistry, Part B, by F. A. Carey and R. J. Sundberg, Plenum, 2001, p. 269.
  • the amine component and the aldehyde or ketone component are reacted together in the presence of a reducing agent such as, for example, borane, sodium cyanoborohydride, sodium triacetoxyborohydride or diisobutylaluminum hydride, optionally in the presence of a Lewis acid, such as titanium tetraisopropoxide, as described in J. Org. Chem, 55, 2552, 1990.
  • a reducing agent such as, for example, borane, sodium cyanoborohydride, sodium triacetoxyborohydride or diisobutylaluminum hydride
  • a Lewis acid such as titanium tetraisopropoxide
  • 2-amino-4-hydroymethylpyridine 68.6 prepared as described in Aust. J. Chem., 1993, 46, 9897
  • a dialkyl formylmethylphosphonate 68.7 prepared as described in Zh. Obschei. Khim., 1987, 57, 2793
  • sodium cyanoborohydride sodium cyanoborohydride
  • Scheme 69 illustrates the preparation of phosphonate-containing analogs of the amine A12 in which the phosphonate moiety is attached to the pyridine ring by means of a saturated or unsaturated alkyl chain.
  • a bromo-substituted 4-hydroxymethylpyridine 69.1 is coupled, by means of a palladium-catalyzed Heck reaction, with a dialkyl alkenyl phosphonate 69.2.
  • the coupling of aryl bromides and olefins is described above (Scheme 26).
  • the product is then converted, as described above, into the piperidine derivative 69.5.
  • the latter compound can be reduced, for example as described above in Scheme 26, to afford the saturated analog 69.6.
  • 3-bromo-4-hydroxymethylpyridine 69.7 prepared as described in Bioorg. Med. Chem. Lett., 1992, 2, 1619, is coupled with a dialkyl vinylphosphonate 69.8, prepared as described in Synthesis, 1983, 556, to yield the olefinic product 69.9.
  • the product is reacted with one molar equivalent of p-toluenesulfonyl chloride in pyridine at ambient temperature to afford the tosylate 69.10.
  • the latter compound is then transformed, as previously described, into the piperidine derivative 69.11.
  • the latter compound is reduced, for example by reaction with diimide, to yield the saturated analog 69.12.
  • Scheme 70 illustrates two alternative methods by means of which (pyridin-3-yloxy)-acetic acids bearing phosphonate moieties may be prepared.
  • the phosphonate group may be introduced into the pyridyl moiety, followed by attachment of the acetic acid group, or the phosphonate group may be introduced into a preformed (Pyridin-3-yloxy)-acetic acid intermediate.
  • a substituted 3-hydroxypyridine 70.1 in which the substituent B is a precursor to the group link-P(O)(OR 1 ) 2 , and in which the aryl hydroxyl may or may not be protected, depending on the reactions to be performed, is converted into a phosphonate-containing compound 70.2.
  • Methods for the conversion of the substituent B into the group link-P(O)(OR 1 ) 2 are described in Schemes 25-75.
  • the protected aryl hydroxyl group present in the phosphonate-containing product 70.2 is then deprotected, using methods described below, to afford the phenol 70.3.
  • the product 70.3 is then transformed into the corresponding (pyridin-3-yloxy) acetic acid 70.4, in a two step procedure.
  • the phenol 70.3 is reacted with an ester of bromoacetic acid 70.9, in which R is an alkyl group or a protecting group.
  • R is an alkyl group or a protecting group.
  • Methods for the protection of carboxylic acids are described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Second Edition 1990, p. 224ff.
  • the alkylation of aryl hydroxyl groups to afford aryl ethers is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 446ff.
  • the aryl reagent and the alkylating agent are reacted together in the presence of an organic or inorganic base, such as, for example, diazabicyclononene, (DBN) or potassium carbonate, in a polar organic solvent such as, for example, dimethylformamide or acetonitrile.
  • an organic or inorganic base such as, for example, diazabicyclononene, (DBN) or potassium carbonate
  • a polar organic solvent such as, for example, dimethylformamide or acetonitrile.
  • equimolar amounts of the phenol 70.3 and ethyl bromoacetate are reacted together in the presence of cesium carbonate, in dioxan at reflux temperature, for example as described in U.S. Pat. No. 5,914,332, to afford the ester 70.4.
  • the thus-obtained ester 70.4 is then hydrolyzed to afford the carboxylic acid 70.5.
  • the methods used for this reaction depend on the nature of the group R. If R is an alkyl group such as methyl, hydrolysis can be effected by treatment of the ester with aqueous or aqueous alcoholic base, or by use of an esterase enzyme such as porcine liver esterase. If R is a protecting group, methods for hydrolysis are described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Second Edition 1990, p. 224ff.
  • ester product 70.4 which R is ethyl is hydrolyzed to the carboxylic acid 70.5 by reaction with lithium hydroxide in aqueous methanol at ambient temperature, as described in U.S. Pat. No. 5,914,332.
  • an appropriately substituted 3-hydroxypyridine 70.6 in which the substituent B is a precursor to the group link-P(O)(OR 1 ) 2 , is transformed into the corresponding acetic acid ester 70.7.
  • the conditions employed for the alkylation reaction are similar to those described above for the conversion of the phenol 70.3 into the ester 70.4.
  • the acetic acid ester 70.7 is then converted into the carboxylic acid 70.5 using the 2 step procedure shown above, involving transformation of the group B into the group link-P(O)(OR 1 ) 2 followed by ester hydrolysis of the acetic acid ester.
  • the group B which is present in the ester 70.7 may be transformed into the group link-P(O)(OR 1 ) 2 either before or after hydrolysis of the ester moiety into the carboxylic acid group, depending on the nature of the chemical transformations required.
  • Schemes 70-75 illustrate the preparation of (Pyridin-3-yloxy)-acetic acids incorporating phosphonate ester groups. The procedures shown can also be applied to the preparation of acetic esters acids 70.7, with, if appropriate, modifications made according to the knowledge of one skilled in the art.
  • Scheme 71 depicts the preparation of (pyridin-3-yloxy) acetic acids incorporating a phosphonate group linked to the pyridyl ring by means of a saturated or unsaturated alkylene chain.
  • an optionally protected halo-substituted 3-hydroxypyridine 71.1 is coupled, by means of a palladium-catalyzed Heck reaction, with a dialkyl alkenyl phosphonate 71.2.
  • the coupling of aryl bromides 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. 503.
  • the aryl halide and the olefin are coupled in a polar solvent such as dimethylformamide or dioxan, in the presence of a palladium(0) or palladium (2) catalyst.
  • the product 71.3 is converted, using the procedures described above, (Scheme 70) into the corresponding (pyridin-3-yloxy) acetic acid 71.4.
  • the olefinic product 71.3 is reduced to afford the saturated derivative 71.5.
  • Methods for the reduction of carbon-carbon double bonds are described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 6 .
  • the methods include catalytic reduction, or chemical reduction employing, for example, diborane or diimide.
  • the product 71.5 is converted, as described above, (Scheme 70) into the corresponding (pyridin-3-yloxy) acetic acid 71.6.
  • 2-iodo-5-hydroxy pyridine 71.7 prepared as described in J. Org. Chem, 1990, 55, 18, p. 5287, is converted into the tert-butyldimethylsilyl ether 71.8, by reaction with chloro-tert-butyldimethylsilane, and a base such as imidazole, as described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Second Edition 1990 p. 77.
  • the product 71.8 is reacted with an equimolar amount of a dialkyl allyl phosphonate 71.9, for example diethyl allylphosphonate (Aldrich) in the presence of ca.
  • This compound is converted, employing the procedures described above, (Scheme 70) into the corresponding (pyridin-3-yloxy) acetic acid 71.12.
  • the unsaturated compound 71.11 is reduced, for example by catalytic hydrogenation employing 5% palladium on carbon as catalyst, in an alcoholic solvent such as methanol, as described, for example, in Hydrogenation Methods, by R. N. Rylander, Academic Press, 1985, Ch 2, to afford the saturated analog 71.13.
  • This compound is converted, employing the procedures described above, (Scheme 70) into the corresponding (pyridin-3-yloxy) acetic acid 71.14.
  • the nature of the phosphonate ester group can be varied, either before or after incorporation into the scaffold, by means of chemical transformations.
  • the transformations, and the methods by which they are accomplished, are described above (Scheme 54).
  • Scheme 72 illustrates the preparation of phosphonate-containing analogs of (pyridin-3-yloxy) acetic acids in which the phosphonate moiety is attached to the pyridine ring by means of a heteroatom and an alkyl chain.
  • a suitably protected 2-halo-5-hydroxypyridine (see Scheme 71) is subjected to a nucleophilic displacement reaction with a dialkyl hydroxy, thio or aminoalkyl-substituted alkyl phosphonate 72.2.
  • 2-iodo-5-hydroxypyridine 71.7 (Scheme 71) is treated with benzyl bromide in the presence of base such as potassium carbonate as described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Third Edition 1999, p. 266 to give 72.6.
  • the benzyl ether 72.6 is reacted in dimethylformamide solution at ca 80° C. with an equimolar amount of a dialkyl mercaptoethyl phosphonate 72.7, prepared as described in Zh. Obschei Khim, 1973, 43, 2364, and potassium carbonate, to yield the thioether product 72.8.
  • the benzyl group is then removed by catalytic hydrogenation employing 5% palladium on carbon as catalyst, in an alcoholic solvent such as methanol, as described, for example, in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Third Edition 1999 p. 266ff., to afford the hydroxyl compound 72.9.
  • the product 72.9 is then converted into the (pyridin-3-yloxy) acetic acid phosphonate ester 72.10 using the procedures described above (Scheme 70).
  • Scheme 73 illustrates the preparation of phosphonate-containing analogs of (pyridin-3-yloxy) acetic acids in which the phosphonate moiety is directly attached to the pyridine ring.
  • a suitably protected 2-bromo-5-hydroxypyridine 73.1 is coupled, in the presence of a palladium catalyst, with a dialkyl phosphite 73.2.
  • the reaction between aryl bromides and dialkyl phosphites to yield aryl phosphonates is described in Synthesis, 70, 1981, and in J. Med. Chem., 1992, 35, 1371.
  • the reaction is conducted in an inert solvent such as toluene or xylene, at about 100° C., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium and a tertiary organic base such as triethylanine.
  • a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium
  • a tertiary organic base such as triethylanine.
  • 3-bromo-5-hydroxypyridine 73.6 (Synchem-OHG) is treated with benzyl bromide in the presence of base such as potassium carbonate as described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Third Edition 1999, p. 266 to give 73.7.
  • the product 73.7 is then treated with a dialkylphosphite 73.2 as described above to give the phosphonate 73.8.
  • Scheme 72 73.8 is converted in several steps to the (pyridin-3-yloxy) acetic acid phosphonate ester 73.10.
  • the corresponding products 73.5 are obtained.
  • Scheme 74 illustrates the preparation of (pyridin-3-yloxy) acetic acids incorporating a phosphonate group attached to the pyridyl ring by means of a heteroatom and an allylene chain.
  • the compounds are obtained by means of alkylation reactions in which an hydroxy, thio or amino-substituted 3-hydroxy pyridine 74.1, protected at the 3-hydroxyl position is reacted, in the presence of a base such as, for example, potassium carbonate, and optionally in the presence of a catalytic amount of an iodide such as potassium iodide, with a dialkyl bromoalkyl phosphonate 74.6.
  • the reaction is conducted in a polar organic solvent such as dimethylformamide or acetonitrile at from ambient temperature to about 80° C.
  • a polar organic solvent such as dimethylformamide or acetonitrile
  • the product of the alkylation reaction, 74.2 is then converted, as described above for converting 72.3 to 72.5 (Scheme 72) into the acid 74.5.
  • the protected pyridine 74.7 is converted to the acetic acid ester derivative 74.8 using the procedures described above in Scheme 70.
  • the acetic acid ester 74.8 is then deprotected following the procedures described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Third Edition 1999, ch 3,6,,and 7, and the product treated with a dialkyl bromoalkyl phosphonate 74.6 to give 74.4.
  • the ester 74.4 is converted to the acid 74.5 using the procedures described above (Scheme 70).
  • Scheme 75 illustrates the preparation of (Pyridin-3-yloxy)-acetic acids incorporating a phosphonate ester which is attached to the pyridyl group by means of a carbon chain incorporating a nitrogen atom.
  • the compounds 75.4 are obtained by means of a reductive alkylation reaction between hydroxyl protected 3-hydroxypyridyl aldehyde 75.1 and an aminoalkyl phosphonate ester 75.2.
  • the preparation of amines by means of reductive amination procedures is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, p. 421.
  • the amine component 75.2 and the aldehyde component 75.1 are reacted together in the presence of a reducing agent such as, for example, borane, sodium cyanoborohydride or diisobutylaluminum hydride, to yield the amine product 75.3.
  • a reducing agent such as, for example, borane, sodium cyanoborohydride or diisobutylaluminum hydride
  • the amination product 75.3 is then deprotected according to procedures described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Third Edition 1999, ch3, and subsequently converted into the (pyridin-3-yloxy) acetic acid compound 75.4, using the alkylation and ester hydrolysis procedures described above (Scheme 70).
  • ester 75.5 (TCI-US) is reacted with benzyl bromide in the presence of base such as potassium carbonate as described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Third Edition 1999, p. 266 to give 75.6.
  • base such as potassium carbonate
  • the benzyl ether 75.6 is then converted to the aldehyde 75.7 by reaction with DIBAL (see Comprehensive Organic Transformations, by R. C. Larock, 2 nd Edition, 1999, p. 1267. for examples).
  • the product 75.10 is then converted into the acetic acid 75.11, as described above (Scheme 70). Using the above procedures, but employing, in place of the aldehyde 75.7, different aldehydes 75.1, and/or different aminoalkyl phosphonates 75.2, the corresponding products 75.4 are obtained.
  • the structures of the intermediate phosphonate esters 1 to 7, and the structures for the component groups R 1 of this invention are shown in Chart 1.
  • the structures of the components R 2 COOH, R 3 COOH and R 4 are shown in Charts 2a, 2b and 2c. Specific stereoisomers of some of the structures are shown in Charts 1 and 2; however, all stereoisomers are utilized in the syntheses of the compounds 1 to 7. Subsequent chemical modifications to the compounds 1 to 7, as described herein, permit the synthesis of the final compounds of this invention.
  • the intermediate compounds 1 to 7 incorporate a phosphonate moiety connected to the nucleus by means of a variable linking group, designated as “link” in the attached structures.
  • Charts 3 and 4 illustrate examples of the linking groups present in the structures 1-7, and in which “etc” refers to the scaffold, e.g., ritonavir.
  • Schemes 1-28 illustrate the syntheses of the intermediate phosphonate compounds of this invention, 1-5, and of the intermediate compounds necessary for their synthesis.
  • the preparation of the compounds 6 and 7, in which the phosphonate moiety is attached to the R 2 COOH or R 3 COOH group, is also described below.
  • R 4 alkyl, CH 2 SO 2 CH 3 ,C(CH 3 ) 2 SO 2 CH 3 ,CH 2 CONH 2 , CH 2 SCH 3 , imidaz-4-ylmethyl, CH 2 NHAc, CH 2 NHCOCF 3
  • R 4 alkyl, CH 2 SO 2 CH 3 ,C(CH 3 ) 2 SO 2 CH 3 ,CH 2 CONH 2 , CH 2 SCH 3 , imidaz-4-ylmethyl, CH 2 NHAc, CH 2 NHCOCF 3 CHART 3
  • link examples direct bond 63 64 65 66 67 single carbon 68 69 70 multiple carbon 71 72 73 hetero atoms 74 75 76
  • Chart 4 Examples of the linking group between the scaffold and the phosphonate moiety. link examples aryl, heteroaryl cycloalkyl cyclized
  • 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 hydroxybenztriazole, in a non-protic solvent such as, for example, pyridine, dimethylformamide 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, dimethylformamide or dichloromethane
  • the carboxylic acid may first be converted into an activated derivative such as the acid chloride, 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 activated derivative such as the acid chloride, anhydride, imidazolide and the like
  • 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.
  • a reagent such as, for example, thionyl chloride or oxalyl chloride in an inert organic solvent such as dichloromethane.
  • the carboxylic acid 1.2 is converted into the acid chloride, and the latter compound is reacted with an equimolar amount of the amine 1.1, in an aprotic solvent such as, for example, tetrahydrofuran, at ambient temperature.
  • the reaction is conducted in the presence of an organic base such as triethylamine, so as to afford the amide 1.3.
  • the N,N-dibenzylamino amide product 1.3 is then transformed into the free amine compound 1.4 by means of a debenzylation procedure.
  • the deprotection of N-benzyl amines is described, for example, in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Second Edition 1990, p 365.
  • the transformation can be effected under reductive conditions, for example by the use of hydrogen or a hydrogen donor, in the presence of a palladium catalyst, or by treatment of the N-benzyl amine with sodium in liquid ammonia, or under oxidative conditions, for example by treatment with 3-chloroperoxybenzoic acid and ferrous chloride.
  • the N,N-dibenzyl compound 1.3 is converted into the amine 1.4 by means of hydrogen transfer catalytic hydrogenolysis, for example by treatment with methanolic ammonium formate and 5% palladium on carbon catalyst, at ca. 75° C. for ca. 6 hours, for example as described in U.S. Pat. No. 5,914,332.
  • the thus-obtained amine 1.4 is then transformed into the amide 1.6 by reaction with the carboxylic acid 1.5, or an activated derivative thereof, in which the substituent A is either the group link-P(O)(OR 1 ) 2 or a precursor thereto.
  • the carboxylic acids 1.5 are described below, Schemes 13-15.
  • the amide-forming reaction is conducted under similar conditions to those described above for the preparation of the amide 1.3.
  • the carboxylic acid is converted into the acid chloride, and the acid chloride is reacted with the amine 1.4 in a solvent mixture composed of an organic solvent such as ethyl acetate, and water, in the presence of a base such as sodium bicarbonate, for example as described in Org. Process Res. Dev., 2000, 4, 264, to afford the amide product 1.6.
  • a solvent mixture composed of an organic solvent such as ethyl acetate, and water, in the presence of a base such as sodium bicarbonate, for example as described in Org. Process Res. Dev., 2000, 4, 264, to afford the amide product 1.6.
  • Scheme 2 illustrates an alternative method for the preparation of the phosphonate-containing diamides 1.
  • 2-phenyl-1-[4-phenyl-2-(1-vinyl-propenyl)-[1,3,2]oxazaborinan-6-yl]-ethylamine 2.1 the preparation of which is described in WO 9414436, is reacted with the carboxylic acid R 2 COOH 1.2, or an activated derivative thereof, to afford the amide product 2.2.
  • the reaction is effected employing the same conditions as were described above for the preparation of the amide 1.3.
  • equimolar amounts of the acid chloride derived from the carboxylic acid 1.2 is reacted with the amine 2.1 in a polar aprotic solvent such as tetrahydrofuran or dimethylformamide, at from ambient temperature to about ⁇ 60° C., in the presence of an organic or inorganic base, to produce the amide 2.2.
  • the product is then reacted with the carboxylic acid 1.5, or an activated derivative thereof, to afford the amide 1.6.
  • the amide-forming reaction is conducted under similar conditions to those described above for the preparation of the amide 1.3.
  • the acid 1.5 and the amine 2.2 are reacted in the presence of hydroxybenztriazole, and N-ethyl-N′-diethylaminopropyl carbodiimide, in tetrahydrofuran at ambient temperature, as described in U.S. Pat. No. 5,484,801, to yield the amide 1.6.
  • Schemes 1 and 2 illustrate the preparation of the compounds 1.6 in which A is either the group link-P(O)(OR 1 ) 2 or a precursor thereto, such as, for example, optionally protected OH, SH, NH, as described below.
  • Scheme 3 depicts the conversion of the compounds 1.6 in which A is OH, SH, NH, as described below, into the compounds 1 in which A is the group link-P(O)(OR 1 ) 2 .
  • Procedures for the conversion of the group A into the group link-P(O))(OR 1 ) 2 are described below, (Schemes 16-26).
  • the tribenzylated phenylalanine derivative 4.1 in which the substituent A is either the group link-P(O)(OR 1 ) 2 or a precursor thereto, as described below, is reacted with the anion 4.2 derived from acetonitrile, to afford the ketonitrile 4.3.
  • the tribenzylated phenylalanine derivatives 4.1 are described below, Schemes 16-18.
  • the anion of acetonitrile is prepared by the treatment of acetonitrile with a strong base, such as, for example, lithium hexamethyldisilylazide or sodium hydride, in an inert organic solvent such as tetrahydrofuran or dimethoxyethane, as described, for example, in U.S. Pat. No. 5,491,253.
  • a strong base such as, for example, lithium hexamethyldisilylazide or sodium hydride
  • an inert organic solvent such as tetrahydrofuran or dimethoxyethane, as described, for example, in U.S. Pat. No. 5,491,253.
  • the solution of the acetonitrile anion 4.2, in an aprotic solvent such as tetrahydrofuran, dimethoxyethane and the like, is then added to a solution of the ester 4.1 at low temperature, to afford the coupled product 4.3.
  • a solution of ca. two molar equivalent of acetonitrile prepared by the addition of ca. two molar equivalent of sodium amide to a solution of acetonitrile in tetrahydrofuran at ⁇ 40° C., is added to a solution of one molar equivalent of the ester 4.1 in tetrahydrofuran at ⁇ 40° C., as described in J. Org. Chem., 1994, 59, 4040, to produce the ketonitrile 4.3.
  • ketonitrile compound 4.3 is then reacted with an organometallic benzyl reagent 4.4, such as a benzyl Grignard reagent or benzyllithium, to afford the ketoenamine 4.5.
  • organometallic benzyl reagent 4.4 such as a benzyl Grignard reagent or benzyllithium
  • the reaction is conducted in an inert aprotic organic solvent such as diethyl ether, tetrahydrofuran or the like, at from -80° C. to ambient temperature.
  • aprotic organic solvent such as diethyl ether, tetrahydrofuran or the like
  • the ketonitrile 4.3 is reacted with three molar equivalents of benzylnagnesium chloride in tetrahydrofuran at ambient temperature, to produce, after quenching by treatment with an organic carboxylic acid such as citric acid, as described in J. Org. Chem., 1994, 59, 4040, the ketoenamine 4.5.
  • an organic carboxylic acid such as citric acid
  • the ketoenamine 4.5 is then reduced, in two stages, via the ketoamine 4.6, to produce the amino alcohol 4.7.
  • the transformation of the ketoenamine 4.5 to the aminoalcohol 4.7 can be effected in one step, or in two steps, with or without isolation of the intermediate ketoamine 4.6, as described in U.S. Pat. No. 5,491,253.
  • the ketoenamine 4.5 is reduced with a boron-containing reducing agent such as sodium borohydride, sodium cyanoborohydride and the like, in the presence of an acid such as methanesulfonic acid, as described in J. Org. Chem., 1994, 59, 4040, to afford the ketoamine 4.6.
  • a boron-containing reducing agent such as sodium borohydride, sodium cyanoborohydride and the like
  • an acid such as methanesulfonic acid, as described in J. Org. Chem., 1994, 59, 4040
  • the reaction is performed in an ethereal solvent such as, for example, tetrahydrofuran or methyl tert-butyl ether.
  • the latter compound is then reduced with sodium borohydride-trifluoroacetic acid, as described in U.S. Pat. No. 5,491,253, to afford the aminoalcohol 4.7.
  • the ketoenamine 4.5 can be reduced to the aminoalcohol 4.7 without isolation of the intermediate ketoamine 4.6.
  • the ketoenamine 4.5 is reacted with sodium borohydride-methanesulfonic acid, in an ethereal solvent such as dimethoxyethane and the like.
  • the reaction mixture is then treated with a quenching agent such as triethanolamine, and the procedure is continued by the addition of sodium borohydride and a solvent such as dimethyl formamide or dimethylacetamide or the like, to afford the aminoalcohol 4.7.
  • the aminoalcohol 4.7 is converted into the amide 4.9 by reaction with the acid R 3 COOH 4.8, or an activated derivative thereof, to produce the amide 4.9.
  • This reaction is conducted under similar conditions to those described above for the preparation of the amides 1.3 and 1.6.
  • the dibenzylated amide product 4.9 is deprotected to afford the free amine 4.10.
  • the conditions for the debenzylation reaction are the same as those described above for the deprotection of the dibenzyl amine 1.3 to yield the amine 1.4, (Scheme 1).
  • the amine 4.10 is then reacted with the carboxylic acid R 2 COOH 1.2, or an activated derivative thereof, to produce the amide 4.11.
  • This reaction is conducted under similar conditions to those described above for the preparation of the amides 1.3 and 1.6.
  • the amide 4.11 can be prepared by means of the sequence of reactions illustrated in Scheme 5.
  • the tribenzylated amino acid derivative 4.1 is converted, by means of the reaction sequence shown in Scheme 4 into the dibenzylated amine 4.7.
  • This compound is then converted into a protected derivative, for example the tert-butoxycarbonyl (BOC) derivative 5.1.
  • BOC tert-butoxycarbonyl
  • the amine can be reacted with di-tert-butoxycarbonylanhydride (BOC anhydride) and a base, or with 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (BOC-ON), and the like.
  • BOC anhydride di-tert-butoxycarbonylanhydride
  • BOC-ON 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile
  • the amine is reacted with ca. 1.5 molar equivalents of BOC anhydride and excess potassium carbonate, in methyl tert-butyl ether, at ambient temperature, for example as described in U.S. Pat. No. 5,914,3332, to yield the BOC-protected product 5.1.
  • N-benzyl protecting groups are then removed from the amide product 5.1 to afford the free amine 5.2.
  • the conditions for this transformation are similar to those described above for the preparation of the amine 1.4, (Scheme 1).
  • the N,N-dibenzyl compound 5.1 is converted into the amine 5.2 by means of hydrogen transfer catalytic hydrogenolysis, for example by treatment with methanolic ammonium formate and 5% palladium on carbon catalyst, at ca. 75° C. for ca. 6 hours, for example as described in U.S. Pat. No. 5,914,332.
  • the amine compound 5.2 is then reacted with the carboxylic acid R 2 COOH 1.2, or an activated derivative thereof, to produce the amide 5.3.
  • This reaction is conducted under similar conditions to those described above for the preparation of the amides 1.3 and 1.6, to afford the amide product 5.3.
  • the latter compound is then converted into the amine 5.4 by removal of the BOC protecting group.
  • the removal of BOC protecting groups is described, for example, in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Second Edition 1990, p. 328.
  • the deprotection can be effected by treatment of the BOC compound with anhydrous acids, for example, hydrogen chloride or trifluoroacetic acid, or by reaction with trimethylsilyl iodide or aluminum chloride.
  • the BOC group is removed by treatment of the substrate 5.3 with trifluoroacetic acid in dichloromethane at ambient temperature, for example as described in U.S. Pat. No. 5,914,232, to afford the free amine product 5.4.
  • Schemes 4 and 5 illustrate the preparation of the compounds 4.11 in which A is either the group link-P(O)(OR 1 ) 2 or a precursor thereto, such as, for example, optionally protected OH, SH, NH, as described below.
  • Scheme 6 depicts the conversion of the compounds 4.11 in which A is OH, SH, NH, as described below, into the compounds 2. Procedures for the conversion of the group A into the group link-P(O))(OR 1 ) 2 are described below, (Schemes 16-26).
  • the phosphonate ester intermediate compounds 3 can be prepared by two alternative methods, illustrated in Schemes 7 and 8. The selection of the route to be employed for a given compound is made after consideration of the substituents which are present, and their stability under the reaction conditions required.
  • the ketonitrile 7.1 is reacted with three molar equivalents of the substituted benzylmagnesium chloride 7.2 in tetrahydrofuran at ambient temperature, to produce, after quenching by treatment with an organic carboxylic acid such as citric acid, as described in J. Org. Chem., 1994, 59,-4040, the ketoenamine 7.3.
  • an organic carboxylic acid such as citric acid
  • the thus-obtained ketoenamine 7.3 is then transformed, via the intermediate compounds 7.4, 7.5, 7.6, and 7.7 into the diacylated carbinol 7.8.
  • the conditions for each step in the conversion of the ketoenamine 7.3 to the diacylated carbinol 7.8 are the same as those described above (Scheme 4) for the transformation of the ketoenamine 4.5 into the diacylated carbinol 4.11.
  • the diacylated carbinol 7.8 is then converted into the phosphonate ester 3, using procedures illustrated below in Schemes 16-26.
  • the phosphonate esters 3 can be obtained by means of the reactions illustrated in Scheme 8.
  • the amine 7.5 the preparation of which is described above, (Scheme 7) is converted into the BOC derivative 8.1.
  • the conditions for the introduction of the BOC group are similar to those described above for the protection of the amine 5.1, (Scheme 5).
  • the amine is reacted with ca. 1.5 molar equivalents of BOC anhydride and excess potassium carbonate, in methyl tert-butyl ether, at ambient temperature, for example as described in U.S. Pat. No. 5,914,332, to yield the BOC-protected product 8.1.
  • the BOC-protected amine 8.1 is then converted, via the intermediates 8.2, 8.3 and 8.4 into the diacylated carbinol 8.5.
  • the reaction conditions for this sequence of reactions are similar to those described above for the transformation of the BOC-protected amine 5.1 into the diacylated carbinol 5.4 (Scheme 5).
  • the diacylated carbinol 8.5 is then converted into the phosphonate ester 3, using procedures illustrated below in Schemes 16-26.
  • Scheme 9 illustrates the preparation of the intermediate phosphonate esters 9.2 in which the substituent A, which is the phosphonate ester moiety or a precursor group thereto, is attached to one of the urea nitrogen atoms in the carboxylic acid reactant 9.1.
  • the preparation of the carboxylic acid reactant 9.1 is described below, Schemes 24-25.
  • the amine 1.4 prepared as described in Scheme 1, is reacted with the carboxylic acid 9.1, to afford the amide 9.2.
  • the reaction between the amine 1.4 and the carboxylic acid 9.1, or an activated derivative thereof, is conducted under the same general conditions as those described above for the preparation of the amide 1.6 (Scheme 1).
  • the reactants are combined in the presence of hydroxybenztriazole and a carbodiimide, as described in U.S. Patent 5,484,801, to yield the amide product 9.2.
  • Scheme 9 describes the preparation of the compounds 9.2 in which the substituent A is either the group link-P(O)(OR 1 ) 2 or a precursor group thereto, such as [OH], [SH, [NH], as described below.
  • Scheme 10 depicts the conversion of compounds 9.2 in which A is [OH], [SH, [NH], into the compounds 4, in which the group A has been transformed into the group link-P(O)(OR 1 ) 2 . The methods for accomplishing this transformation are described below, Schemes 16-26.
  • Scheme 11 illustrates the preparation of the intermediate phosphonate esters 11.2 in which the substituent A, which is the phosphonate ester moiety or a precursor group thereto, is attached to the valine moiety in the carboxylic acid reactant 11.1.
  • the preparation of the carboxylic acid reactant 11.1 is described below, Scheme 26.
  • the reaction between the amine 1.4 and the carboxylic acid 11.1, or an activated derivative thereof, is conducted under the same general conditions as those described above for the preparation of the amide 1.3 (Scheme 1).
  • the reactants are combined in the presence of hydroxybenztriazole and a carbodiimide, as described in U.S. Pat. No. 5,484,801, to yield the amide product 11.2.
  • Scheme 11 describes the preparation of the compounds 11.2 in which the substituent A is either the group link-P(O)(OR 1 ) 2 or a precursor group thereto, such as [OH], [SH, [NH] Ha, as described below.
  • Scheme 12 depicts the conversion of compounds 11.2 in which A is [OH], [SH, [NH] Br, into the compounds 5, in which the group A has been transformed into the group link-P(O)(OR 1 ) 2 .
  • the methods for accomplishing this transformation are described below, Schemes 16-26.
  • Scheme 13 illustrates the preparation of carboxylic acid reactants 1.5, in which a substituent A, attached to the isopropyl group, is either the group link-P(O)(OR 1 ) 2 or a precursor group thereto, such as [OH], [SH, AH] Br.
  • the group A may, at an appropriate stage, be converted into the group link-P(O)(OR 1 ) 2 , according to the knowledge of one skilled in the art.
  • the carboxylic acid 1.5 in which A is link-P(O)(OR 1 ) 2 , may be incorporated into the diamide compounds 1.6, as described above, (Schemes 1 and 2) before effecting the transformation of the group A into the group link-P(O)(OR 1 ) 2 .
  • a substituted derivative of isobutyramide 13.1 is converted into the corresponding thioamide 13.2.
  • the conversion of amides into thioamides is described in Synthetic Organic Chemistry, by R. B. Wagner and H. D. Zook, Wiley, 1953, p. 827.
  • the amide is reacted with a sulfur-containing reagent such as phosphorus pentasulfide or Lawessson's reagent, as described in Reagents for Organic Synthesis, by L. F. Fieser and M. Fieser, Wiley, Vol. 13, p. 38, to yield the thioamide 13.2.
  • the amide 13.1 is reacted with phosphorus pentasulfide in ether solution, at ambient temperature, as described in U.S. Pat. No. 5,484,801, to afford the amide 13.2.
  • the latter compound is then reacted with 1,3-dichloroacetone 13.3 to produce the substituted thiazole 13.4.
  • the preparation of thiazoles by the reaction between a thioamide and a chloroketone is described, for example, in Heterocyclic Chemistry, by T. A. Gilchrist, Longman, 1997, p. 321.
  • equimolar amounts of the reactants are combined in acetone solution at reflux temperature, in the presence of magnesium sulfate, as described in U.S. Pat. No.
  • the chloromethyl thiazole 13.4 is then reacted with methylamine to afford the substituted methylamine 13.6.
  • the preparation of amines by the reaction of amines with alkyl halides is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 397.
  • the components are reacted together in a polar solvent such as an alkanol or dimethylformamide and the like.
  • the chloro compound 13.4 is reacted with excess aqueous methylamine at ambient temperature, as described in U.S. Pat. No. 5,484,801, to afford the amine product 13.6.
  • the amine is then converted into the urea derivative 13.8 by reaction with an activated derivative of the valine carbamic acid 13.7, in which X is a leaving group such as alkanoyloxy or 4-nitrophenoxy.
  • X is a leaving group such as alkanoyloxy or 4-nitrophenoxy.
  • Suitable carbamic acid derivatives are prepared by the reaction between an amine and an alkyl or aryl chloroformate, for example as described in WO 9312326.
  • the reaction is performed using carbamic acid derivative 13.7, in which X is 4-nitrophenoxy, and the amine 13.8; the reaction is conducted at about 0° C.
  • the ester group present in the urea product 13.8 is then hydrolyzed to afford the corresponding carboxylic acid 1.5.
  • Hydrolysis methods for converting esters into carboxylic acids are described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 981.
  • the methods include the use of enzymes such as pig liver esterase, and chemical methods such as the use of alkali metal hydroxides in aqueous organic solvent mixtures.
  • the methyl ester is hydrolyzed by treatment with lithium hydroxide in aqueous dioxan, as described in U.S. Pat. No. 5,848,801, to yield the carboxylic acid 1.5.
  • Scheme 14 illustrates the preparation of the carboxylic acids 9.1 in which the group A, attached to the amine moiety, is either the group link-P(O)(OR 1 ) 2 or a precursor group thereto, such as [OH], [SH, [NH] Br.
  • the group A may, at an appropriate stage, be converted into the group link-P(O)(OR 1 ) 2 , according to the knowledge of one skilled in the art.
  • the carboxylic acid 9.1, in which A is link-P(O)(OR 1 ) 2 may be incorporated into the diamide compounds 9.2, as described above, (Scheme 9) before effecting the transformation of the group A into the group link-P(O)(OR 1 ) 2 .
  • Scheme 15 illustrates the preparation of the carboxylic acids 11.1 in which the group A, attached to the valine moiety, is either the group link-P(O)(OR 1 ) 2 or a precursor group thereto, such as [OH), [SH, [NH] Br.
  • the group A may, at an appropriate stage, be converted into the group link-P(O)(OR 1 ) 2 , according to the knowledge of one skilled in the art.
  • the carboxylic acid 11.1, in which A is link-P(O)(OR 1 ) 2 may be incorporated into the diamide compounds 11.2, as described above, (Scheme 11) before effecting the transformation of the group A into the group link-P(O)(OR 1 ) 2 .
  • Scheme 16 illustrates the preparation of phenylalanine derivatives incorporating phosphonate moieties attached to the phenyl ring by means of a heteroatom and an alkylene chain.
  • the compounds are obtained by means of alkylation or condensation reactions of hydroxy or mercapto-substituted phenylalanine derivatives 16.1.
  • a hydroxy or mercapto-substituted phenylalanine is converted into the benzyl ester 16.2.
  • the conversion of carboxylic acids into esters is described for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 966.
  • the conversion can be effected by means of an acid-catalyzed reaction between the carboxylic acid and benzyl alcohol, or by means of a base-catalyzed reaction between the carboxylic acid and a benzyl halide, for example benzyl chloride.
  • the hydroxyl or mercapto substituent present in the benzyl ester 16.2 is then protected.
  • protecting groups for phenols and thiophenols include tert-butyldimethylsilyl or tert-butyldiphenylsilyl.
  • Thiophenols may also be protected as S-adamantyl groups, as described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Second Edition 1990, p. 289.
  • the protected hydroxy- or mercapto ester 16.3 is then reacted with a benzyl or substituted benzyl halide and a base, for example as described in U.S. Pat. No. 5,491,253, to afford the N,N-dibenzyl product 16.4.
  • the amine 16.3 is reacted at ca 90° C. with two molar equivalents of benzyl chloride in aqueous ethanol containing potassium carbonate, to afford the tribenzylated product 16.4, as described in U.S. Pat. No. 5,491,253.
  • the protecting group present on the 0 or S substituent is then removed. Removal of 0 or S protecting groups is described in Protective Groups in Organic Synthesis, by T. W. Greene and P.
  • silyl protecting groups are removed by treatment with tetrabutylammonium fluoride and the like, in a solvent such as tetrahydrofuran at ambient temperature, as described in J. Am. Chem. Soc., 94, 6190, 1972.
  • S-Adamantyl groups can be removed by treatment with mercuric trifluoroacetate in acetic acid, as described in Chem. Pharm Bull., 26, 1576, 1978.
  • the resultant phenol or thiophenol 16.5 is then reacted under various conditions to provide protected phenylalanine derivatives 16.9, 16.10 or 16.11, incorporating phosphonate moieties attached by means of a heteroatom and an alkylene chain
  • the phenol or thiophenol 16.5 is reacted with a dialkyl bromoalkyl phosphonate 16.6 to afford the product 16.9.
  • the alkylation reaction between 16.5 and 16.6 is effected in the presence of an organic or inorganic base, such as, for example, diazabicyclononene, cesium carbonate or potassium carbonate.
  • the reaction is performed at from ambient temperature to ca. 80° C., in a polar organic solvent such as dimethylformamide or acetonitrile, to afford the ether or thioether product 16.9.
  • Example 1 a hydroxy-substituted phenylalanine derivative such as tyrosine, 16.12 is converted, as described above, into the benzyl ester 16.13.
  • the latter compound is then reacted with one molar equivalent of chloro tert-butyldimethylsilane, in the presence of a base such as imidazole, as described in J. Am. Chem Soc., 94, 6190, 1972, to afford the silyl ether 16.14.
  • This compound is then converted, as described above, into the tribenzylated derivative 16.15.
  • the silyl protecting group is removed by treatment of 16.15 with a tetrahydrofuran solution of tetrabutyl ammonium fluoride at ambient temperature, as described in J. Am. Chem. Soc., 94, 6190, 1972, to afford the phenol 16.16.
  • the latter compound is then reacted in dimethylformamide at ca. 60° C., with one molar equivalent of a dialkyl 3-bromopropyl phosphonate 16.17 (Aldrich), in the presence of cesium carbonate, to afford the alkylated product 16.18.
  • the hydroxy or mercapto-substituted tribenzylated phenylalanine derivative 16.5 is reacted with a dialkyl hydroxymethyl phosphonate 16.7 under the conditions of the Mitsonobu reaction, to afford the ether or thioether compounds 16.10.
  • the preparation of aromatic ethers by means of the Mitsonobu reaction is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 448, and in Advanced Organic Chemistry, Part B, by F. A. Carey and R. J. Sundberg, Plenum, 2001, p. 1534.
  • phenol or thiophenol and the alcohol component are reacted together in an aprotic solvent such as, for example, tetrahydrofuran, in the presence of a dialkyl azodicarboxylate and a triarylphosphine, to afford the ether or thioether products 16.10.
  • an aprotic solvent such as, for example, tetrahydrofuran
  • the 4-methoxybenzyl group is then removed by the reaction of the thioether 16.22 with mercuric trifluoroacetate and anisole in trifluoroacetic acid, as described in J. Org. Chem., 52, 4420, 1987, to afford the thiol 16.23.
  • the latter compound is reacted, under the conditions of the Mitsonobu reaction, with diethyl hydroxymethyl phosphonate 16.7, diethylazodicarboxylate and triphenylphosphine, for example as described in Synthesis, 4, 327, 1998, to yield the thioether product 16.24.
  • the hydroxy or mercapto-substituted tribenzylated phenylalanine derivative 16.5 is reacted with an activated derivative of a dialkyl hydroxymethylphosphonate 16.8 in which Lv is a leaving group.
  • the components are reacted together in a polar aprotic solvent such as, for example, dimethylformamide or dioxan, in the presence of an organic or inorganic base such as triethylamine or cesium carbonate, to afford the ether or thioether products 16.11.
  • Scheme 17 illustrates the preparation of phenylalanine derivatives incorporating phosphonate moieties attached to the phenyl ring by means of an alkylene chain incorporating a nitrogen atom
  • the compounds are obtained by means of a reductive alkylation reaction between a formyl-substituted tribenzylated phenylalanine derivative 17.3 and a dialkyl aminoalkylphosphonate 17.4.
  • a hydroxymethyl-substituted phenylalanine 17.1 is converted into the tribenzylated derivative 17.2 by reaction with three equivalents of a benzyl halide, for example, benzyl chloride, in the presence of an organic or inorganic base such as diazabicyclononene or potassium carbonate.
  • the reaction is conducted in a polar solvent optionally in the additional presence of water.
  • the aminoacid 17.1 is reacted with three equivalents of benzyl chloride in aqueous ethanol containing potassium carbonate, as described in U.S. Pat. No. 5,491,253, to afford the product 17.2.
  • the latter compound is then oxidized to afford the corresponding aldehyde 17.3.
  • the conversion of alcohols to aldehydes is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 604ff.
  • the alcohol is reacted with an oxidizing agent such as pyridinium chlorochromate, silver carbonate, or dimethyl sulfoxide/acetic anhydride, to afford the aldehyde product 17.3.
  • an oxidizing agent such as pyridinium chlorochromate, silver carbonate, or dimethyl sulfoxide/acetic anhydride
  • the carbinol 17.2 is reacted with phosgene, dimethyl sulfoxide and triethylamine, as described in J. Org. Chem., 43, 2480, 1978, to yield the aldehyde 17.3.
  • This compound is reacted with a dialkyl aminoalkylphosphonate 17.4 in the presence of a suitable reducing agent to afford the amine product 17.5.
  • the preparation of amines by means of reductive amination procedures is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, p. 421, and in Advanced Organic Chemistry, Part B, by F.A. Carey and R. J. Sundberg, Plenum, 2001, p. 269.
  • the amine component and the aldehyde or ketone component are reacted together in the presence of a reducing agent such as, for example, borane, sodium cyanoborohydride, sodium triacetoxyborohydride or diisobutylaluminum hydride, optionally in the presence of a Lewis acid, such as titanium tetraisopropoxide, as described in J. Org. Chem., 55, 2552, 1990.
  • a reducing agent such as, for example, borane, sodium cyanoborohydride, sodium triacetoxyborohydride or diisobutylaluminum hydride
  • a Lewis acid such as titanium tetraisopropoxide
  • 3-(hydroxymethyl)-phenylalanine 17.6 prepared as described in Acta Chen-Scand. Ser. B, 1977, B31, 109, is converted, as described above, into the formylated derivative 17.7.
  • This compound is then reacted with a dialkyl aminoethylphosphonate 17.8, prepared as described in J. Org. Chem., 200, 65, 676, in the presence of sodium cyanoborohydride, to produce the alkylated product 17.9.
  • Scheme 18 depicts the preparation of phenylalanine derivatives in which a phosphonate moiety is attached directly to the phenyl ring.
  • a bromo-substituted phenylalanine 18.1 is converted, as described above, (Scheme 17) into the tribenzylated derivative 18.2.
  • the product is then coupled, in the presence of a palladium(0) catalyst, with a dialkyl phosphite 18.3 to produce the phosphonate ester 18.4.
  • 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.
  • This compound is then reacted, in toluene solution at reflux, with diethyl phosphite 18.7, triethylamine and tetrakis(triphenylphosphine)palladium(0), as described in J. Med. Chem., 35, 1371, 1992, to afford the phosphonate product 18.8.
  • Scheme 19 illustrates the preparation of compounds 3 in which the phosphonate ester moiety is attached directly to the phenyl ring.
  • the ketonitrile 7.1 prepared as described in J. Org. Chef, 1994, 59, 4080, is reacted with a bromobenzylmagnesium halide reagent 19.1.
  • the resultant ketoenamine 19.2 is then converted into the diacylated bromophenyl carbinol 19.3.
  • the conditions required for the conversion of the ketoenamine 19.2 into the carbinol 19.3 are similar to those described above (Scheme 4) for the conversion of the ketoenamine 4.5 into the carbinol 4.12.
  • the product 19.3 is then reacted with a dialkyl phosphite 18.3, in the presence of a palladium (0) catalyst, to yield the phosphonate ester 19.4.
  • the conditions for the coupling reaction are the same as those described above (Scheme 18) for the preparation of the phosphonate ester 18.4.
  • ketonitrile 7.1 is reacted, in tetrahydrofuran solution at ⁇ 40° C., with three molar equivalents of 4-bromobenzylmagnesium bromide 19.5, the preparation of which is described in Tetrahedron, 2000, 56, 10067, to afford the ketoenamine 19.6.
  • the latter compound is then converted into the bromophenyl carbinol 19.7, using the sequence of reactions described above (Scheme 4) for the conversion of the ketoenamine 4.5 into the carbinol 4.12.
  • the resultant bromo compound 19.7 is then reacted with diethyl phosphite 18.3 and triethylamine, in toluene solution at reflux, in the presence of tetrakis(triphenylphosphine)palladium(0), as described in J. Med. Chem., 35, 1371, 1992, to afford the phosphonate product 19.8.
  • Scheme 20 illustrates the preparation of compounds 3 in which the phosphonate ester moiety is attached to the nucleus by means of a phenyl ring.
  • a bromophenyl-substituted benzylmagnesium bromide 20.1 prepared from the corresponding bromomethyl compound by reaction with magnesium, is reacted with the ketonitrile 7.1.
  • the conditions for this transformation are the same as those described above (Scheme 4).
  • the product of the Grignard addition reaction is then transformed, using the sequence of reactions described above, (Scheme 4) into the diacylated carbinol 20.2.
  • 4-(4-bromophenyl)benzyl bromide prepared as described in DE 2262340, is reacted with magnesium to afford 4-(4-bromophenyl)benzylmagnesium bromine 20.4.
  • This product is then reacted with the ketonitrile 7.1, as described above, to yield, after the sequence of reactions shown in Scheme 4, the diacylated carbinol 20.5.
  • the latter compounds then reacted, as described above, (Scheme 18) with a dialkyl phosphite 18.3, to afford the phenylphosphonate 20.6.
  • Scheme 21 depicts the preparation of phosphonate esters 3 in which the phosphonate group is attached by means of a heteroatom and a methylene group.
  • a hetero-substituted benzyl alcohol 21.1 is protected, affording the derivative 21.2.
  • the protection of phenyl hydroxyl, thiol and amino groups are described, respectively, in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Second Edition 1990, p. 10, p. 277, 309.
  • hydroxyl and thiol substituents can be protected as trialkylsilyloxy groups.
  • Trialkylsilyl groups are introduced by the reaction of the phenol or thiophenol with a chlorotrialkylsilane, for example as described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Second Edition 1990, p. 10, p. 68-86.
  • thiol substituents can be protected by conversion to tert-butyl or adamantyl thioethers, as described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Second Edition 1990, p. 289.
  • Amino groups can be protected, for example by dibenzylation.
  • benzyl alcohols 21.2 can be transformed into the chloro compounds 21.3, in which Ha is chloro, by reaction with triphenylphosphine and N-chlorosuccinimide, as described in J. Am Chem. Soc., 106, 3286, 1984.
  • Benzyl alcohols can be transformed into bromo compounds by reaction with carbon tetrabromide and triphenylphosphine, as described in J. Am. Chem Soc., 92, 2139, 1970.
  • the resultant protected benzyl halide 21.3 is then converted into the corresponding benzylmagnesium halide 21.4 by reaction with magnesium metal in an ethereal solvent, or by a Grignard exchange reaction treatment with an alkyl magnesium halide.
  • the resultant substituted benzylmagnesium halide 21.4 is then converted, using the sequence of reactions described above (Scheme 4) for the preparation of the diacylated carbinol 4.11, into the carbinol 21.5 in which the substituent XH is suitably protected.
  • the protecting group is then removed to afford the phenol, thiophenol or amine 21.6.
  • Deprotection of phenols, thiophenols and amines is described respectively in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, Second Edition 1990.
  • trialkylsilyl ethers or thioethers can be deprotected by treatment with a tetraalkylammonium fluoride in an inert solvent such as tetrahydrofuran, as described in J. Am Chem. Soc., 94, 6190, 1972.
  • Tert-butyl or adamantyl thioethers can be converted into the corresponding thiols by treatment with mercuric trifluoroacetate in aqueous acetic acid at ambient temperatures, as described in Chem. Pharm Bull., 26, 1576, 1978.
  • N,N-dibenzyl amines can be converted into the unprotected amines by catalytic reduction in the presence of a palladium catalyst, as described above (Scheme 1).
  • the resultant phenol, thiophenol or amine 21.6 is then converted into the phosphonate ester 21.7 by reaction with an activated derivative of a dialkyl hydroxymethyl phosphonate 16.27, in which Lv is a leaving group.
  • the reaction is conducted under the same conditions as described above for the conversion of 16.5 to 16.11 (Scheme 16).
  • 3-hydroxybenzyl alcohol 21.8 (Aldrich) is reacted with chlorotriisopropylsilane and imidazole in dimethylformamide, as described in Tet. Lett., 2865, 1964, to afford the silyl ether 21.9.
  • This compound is reacted with carbon tetrabromide and triphenylphosphine in dichloromethane, as described in J. Am Chem Soc., 109, 2738, 1987, to afford the brominated product 21.10.
  • This material is reacted with magnesium in ether to afford the Grignard reagent 21.11, which is then subjected to the series of reaction shown in Scheme 4 to afford the carbinol 21.12.
  • the triisopropylsilyl protecting group is then removed by treatment of the ether 21.12 with tetrabutylammonium fluoride in tetrahydrofuran, as described in J. Org. Chem., 51, 4941, 1986.
  • the resultant phenol 21.13 is then reacted with a dialkyl trifluoromethanesulfonyloxymethylphosphonate 16.27, prepared as described in Tet. Lett., 1986, 27, 1477, in dimethylformamide solution at 60° C. in the presence of cesium carbonate, to afford the phosphonate product 21.14.
  • Scheme 22 illustrates methods for the preparation of carboxylic acids 1.5, in which A is Br, and methods for the conversion of the bromo substituent into various phosphonate-containing substituents.
  • the ester 22.2 is reacted with a trialkyl phosphate 22.3 in an Arbuzov reaction, to afford the phosphonate ester 22.4.
  • the preparation of phosphonates by means of the Arbuzov reaction is described, for example, in Handb. Organophosphorus Chem., 1992, 115.
  • the reaction is performed by heating the substrate at 100° C. to 150° C. with an excess of the trialkyl phosphite.
  • the methyl ester group in the phosphonate product 22.4 is then hydrolyzed, using the procedures described above, (Scheme 13) to prepare the carboxylic acid 22.5.
  • Example 1 the bromo compound 22.2 is heated at 120° C. with a ten molar excess of tribenzyl phosphite 22.6 to afford the benzylphosphonate 22.7. Hydrolysis of the methyl ester, as described above, then yields 2-(3- ⁇ 2-[2-(bis-benzyloxy-phosphoryl)-1-methyl-ethyl]-thiazol-4-ylmethyl ⁇ -3-methyl-ureido)-3-methyl-butyric acid 22.8.
  • the bromoester 22.2 is oxidized to the corresponding aldehyde 22.9.
  • Methods for the oxidation of bromo compounds to the corresponding aldehyde are described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989 p. 599.
  • the transformation can be effected by reaction of the aldehyde with dimethyl sulfoxide, optionally in the presence of a silver salt, as described in Chem Rev., 67, 247, 1967.
  • the bromo compound is reacted with trimethylamine oxide, as described in Ber., 94, 1360, 1961, to prepare 3-methyl-2- ⁇ 3-methyl-3-[2-(1-methyl-2-oxo-ethyl)-thiazol-4-ylmethyl]-ureido ⁇ -butyric-acid methyl ester 22.9.
  • the aldehyde is then reacted with a dialkyl aminoalkyl phosphonate 22.10 in a reductive amination reaction to afford the aminophosphonate 22.11.
  • the conditions for the reductive amination reaction are the same as those described above for the preparation of the aminophosphonate 17.5, (Scheme 17).
  • the methyl ester group present in the product 22.11 is then hydrolyzed, as described above, to yield the carboxylic acid 22.12.
  • the bromo compound 22.2 is heated at 80° C in dimethylsulfoxide solution, in the presence of one molar equivalent of silver tetrafluoborate and triethylamine, as described in J. Chem. Soc., Chem. Comm., 1338, 1970, to afford the aldehyde 22.9.
  • Reductive amination of the product in the presence of a dialkyl aminoethyl phosphonate 22.13, the preparation of which is described in J. Org. Chem., 2000, 65, 676 and sodium triacetoxy borohydride, then affords the amino phosphonate 22.14.
  • Hydrolysis of the methyl ester as described above, then afford the carboxylic acid 22.15.
  • the bromo compound 22.2 is reacted with a dialkyl thioalkyl phosphonate 22.16 to effect displacement of the bromo substituent to afford the thioether 22.17.
  • the preparation of thioethers by the reaction of bromo compounds with thiols is described, for example, in Synthetic Organic Chemistry, R. B. Wagner, H. D. Zook, Wiley, 1953, p. 787.
  • the reactants are combined in the presence of a suitable base, such as sodium hydroxide, dimethylaminopyridine, potassium carbonate and the like, in a polar organic solvent such as dimethylformamide or ethanol, to afford the thioether 22.17.
  • the product is then subjected to hydrolysis, as described above, to afford the carboxylic acid 22.18.
  • Example 3 the bromo compound 22.2 is reacted with a dialkyl thioethylphosphonate 22.19, the preparation of which is described in Aust. J. Chen., 43, 1123, 1990, and dimethylaminopyridine, in dimethylformamide solution at ambient temperature, to yield the thioether 22.20. Hydrolysis of the methyl ester group, as described above, then afford the carboxylic acid 22.21.
  • Scheme 23 mustrates the preparation of carboxylic acids 23.7 in which the phosphonate moiety is attached to the isopropyl group by means of a phenyl ring and a heteroatom.
  • the hydroxy or mercapto substituent on a phenylbutanamide 23.1 is protected.
  • Methods for the protection of hydroxyl and thiol groups are described above (Scheme 21).
  • the protected amide 23.2 is then subjected to the series of reactions illustrated in Scheme 13, so as to afford the O- or S-protected ester 23.3.
  • the protecting group is then removed.
  • Methods for the deprotection of phenols and thiophenols are described above (Scheme 16).
  • the resultant phenol or thiophenol 23.4 is then reacted with a dialkyl bromoalkyl phosphonate 23.5, to afford the ether or thioether compounds 23.6.
  • Conditions for the alkylation of phenols and thiophenols are described above (Scheme 16).
  • the ester groups present in the product 23.6 is then hydrolyzed, as described above, to afford the corresponding carboxylic acid 23.7.
  • 3-(4hydroxyphenyl)butyric acid 23.8 prepared as described in J. Med. Chem, 1992, 35, 548, is converted into the acid chloride by reaction with thionyl chloride. The acid chloride is then reacted with excess aqueous ethanolic ammonia to afford the amide 23.9.
  • This compound is converted into the tert. butyldimethylsilyl derivative 23.10 by treatment with tert-butylchlorodimethylsilane and imidazole in dichloromethane.
  • the resultant amide 23.10 is then subjected to the series of reactions shown in Scheme 13, so as to yield the ester 23.11.
  • Scheme 24 and 25 describes the preparation of carboxylic acids 9.1 in which the phosphonate moiety is attached to the amine component.
  • the chloromethylthiazole 14.1 is reacted with a dialkyl aminoalkyl phosphonate 24.1 to produce the substituted amine 24.2.
  • the preparation of amines by reacting amines with alkyl halides is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 397.
  • the components are reacted together in a polar solvent such as an alkanol or dimethylformamide and the like, to yield the substituted amine 24.2.
  • the latter compound is then converted into the carboxylic acid 24.3, by means of the series of reactions shown in Scheme 14.
  • the chloromethyl thiazole 14.1 is reacted at 50° C. in acetonitrile solution containing potassium carbonate, with one molar equivalent of a dialkyl aminomethyl phosphonate 24.4, prepared as described in Bioorg. Chem., 2001, 29, 77, to afford the substituted amine 24.5.
  • the product is then converted, using the reactions shown in Scheme 14, into the carboxylic acid 24.6.
  • Scheme 25 illustrates the preparation of carboxylic acids 9.1 in which the phosphonate moiety is attached to the amine component by means of a saturated or unsaturated alkyl chain and a phenyl ring.
  • the chloromethylthiazole 14.1 is reacted with allylamine 25.1, using the procedures described above (Scheme 24) to afford allyl-(2-isopropyl-thiazol-4-ylmethyl)-amine 25.2.
  • the ester amine is then converted, by means of the series of reactions shown in Scheme 14, into 2-[3-allyl-3-(2-isopropyl-thiazol-4-ylmethyl)-ureido]-3-methyl-butyric acid methyl ester 25.3.
  • This material is coupled with a dialkyl bromo-substituted phenylphosphonate 25.4, under the conditions of the palladium-catalyzed Heck reaction, to afford the coupled product 25.5.
  • 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.
  • the aryl bromide and the olefin are coupled in a polar solvent such as dimethylformamide or dioxan, in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) or palladium(II) catalyst such as palladium(II) acetate, and optionally in the presence of a base such as triethylamine or potassium carbonate.
  • a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) or palladium(II) catalyst such as palladium(II) acetate
  • a base such as triethylamine or potassium carbonate.
  • Hydrolysis of the methyl ester as described above, then yields the carboxylic acid 25.6.
  • the double bond present in the product 25.6 is reduced to afford the dihydro analog 25.7.
  • the double bond is reduced in the presence of a palladium catalyst, such as, for example,
  • the allyl-substituted urea 25.3 is reacted with a dialkyl 4-bromophenyl phosphonate 25.8, prepared as described in J. Chem. Soc., Perkin Trans.,1977, 2, 789 in the presence of tetrakis(triphenylphosphine)palladium (0) and triethylamine, to afford the phosphonate ester 25.9.
  • Scheme 26 illustrates the preparation of carboxylic acids 11.1 in which the phosphonate moiety is attached to the valine substructure.
  • 2-amino-4-bromo-3-methyl-butyric acid methyl ester 26.1 prepared as described in U.S. Pat. No. 5,346,898, is reacted with a chloroformate, for example 4-nitrophenyl chloroformate, to prepare the activated derivative 26.2 in which X is a leaving group.
  • a chloroformate for example 4-nitrophenyl chloroformate
  • the aminoester 26.1 is reacted with 4-nitrophenylchloroformate in dichloromethane at 0° C., as described in U.S. Pat. No. 5,484,801, to afford the product 26.2 in which X is 4-nitrophenoxy.
  • the aldehyde is then subjected to a reductive amination procedure, in the presence of a dialkyl aminoalkyl phosphonate 26.6, to afford the amine product 26.7.
  • a dialkyl aminoalkyl phosphonate 26.6 to afford the amine product 26.7.
  • the preparation of amines by means of reductive alkylation reactions is described above (Scheme 22).
  • Equimolar amounts of the aldehyde 26.5 and the amine 26.6 are reacted in the presence of a boron-containing reducing agent such as, for example, sodium triacetoxyborohydride, to yield the amine 26.7.
  • the methyl ester is then hydrolyzed, as described above, to yield the carboxylic acid 26.8.
  • the reactants are combined in the presence of a suitable base, such as sodium hydroxide, dimethylamino pyridine, potassium or cesium carbonate and the like, in a polar organic solvent such as dimethylformamide or ethanol, to afford the thioether 26.13.
  • a suitable base such as sodium hydroxide, dimethylamino pyridine, potassium or cesium carbonate and the like
  • a polar organic solvent such as dimethylformamide or ethanol
  • the bromo compound 26.4 is reacted with a dialkyl mercaptoethyl phosphonate 26.15, the preparation of which is described in Aust. J. Chem, 43, 1123, 1990, in dimethylformamide solution, in the presence of cesium carbonate, to produce the thio ether product 26.16.
  • the methyl ester is then hydrolyzed, as described above, to yield the carboxylic acid 26.17.
  • Schemes 1-26 described the preparations of phosphonate esters of the general structure R-link-P(O)(OR 1 ) 2 , in which the groups R 1 , the structures of which are defined in Chart 1, may be the same or different.
  • the R 1 groups attached to a phosphonate esters 1-7, or to precursors thereto, may be changed using established chemical transformations.
  • the interconversions reactions of phosphonates are illustrated in Scheme 27.
  • the group R in Scheme 27 represents the substructure to which the substituent link-P(O)(OR 1 ) 2 is attached, either in the compounds 1-7 or in precursors thereto.
  • the R 1 group may be changed, using the procedures described below, either in the precursor compounds, or in the esters 1-7.
  • the conversion of a phosphonate diester 27.1 into the corresponding phosphonate monoester 27.2 can be accomplished by a number of methods.
  • the ester 27.1 in which R 1 is an aralkyl group such as benzyl can be converted into the monoester compound 27.2 by reaction with a tertiary organic base such as diazabicyclooctane (DABCO) or quinuclidine, as described in J. Org. Chem, 1995, 60, 2946.
  • DABCO diazabicyclooctane
  • the reaction is performed in an inert hydrocarbon solvent such as toluene or xylene, at about 110° C.
  • the conversion of the diester 27.1 in which R 1 is an aryl group such as phenyl, or an alkenyl group such as allyl, into the monoester 27.2 can be effected by treatment of the ester 27.1 with a base such as aqueous sodium hydroxide in acetonitrile or lithium hydroxide in aqueous tetrahydrofuran.
  • a base such as aqueous sodium hydroxide in acetonitrile or lithium hydroxide in aqueous tetrahydrofuran.
  • Phosphonate diesters 27.1 in which one of the groups R 1 is aralkyl, such as benzyl and the other is alkyl can be converted into the monoesters 27.2 in which R 1 is alkyl by hydrogenation, for example using a palladium on carbon catalyst.
  • Phosphonate diesters in which both of the groups R 1 are alkenyl, such as allyl can be converted into the monoester 27.2 in which R 1 is alkenyl, by treatment with chlorotris(triphenylphosphine)rhodium (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.
  • the conversion of a phosphonate diester 27.1 or a phosphonate monoester 27.2 into the corresponding phosphonic acid 27.3 can effected by reaction of the diester or the monoester with trimethylsilyl bromide, as described in J. Chem. Soc., Chem. Comm., 739, 1979.
  • the reaction is conducted in an inert solvent such as, for example, dichloromethane, optionally in the presence of a silylating agent such as bis(trimethylsilyl)trifluoroacetamide, at ambient temperature.
  • a phosphonate monoester 27.2 in which R 1 is alkenyl such as, for example, allyl, can be converted into the phosphonic acid 27.3 by reaction with Wilkinson's catalyst in an aqueous organic solvent, for example in 15% aqueous acetonitrile, or in aqueous ethanol, for example using the procedure described in Helv. Chime Acta., 68, 618, 1985.
  • the conversion of a phosphonate monoester 27.2 into a phosphonate diester 27.1 (Scheme 27, Reaction 4) in which the newly introduced R 1 group is alkyl aralkyl, haloalkyl such as chloroethyl, or aralkyl can be effected by a number of reactions in which the substrate 27.2 is reacted with a hydroxy compound R 1 OH, in the presence of a coupling agent.
  • Suitable coupling agents are those employed for the preparation of carboxylate esters, and include a carbodiimide such as dicyclohexylcarbodiimide, in which case the reaction is preferably conducted in a basic organic solvent such as pyridine, or (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PYBOP, Sigma), in which case the reaction is performed in a polar solvent such as dimethylformamide, in the presence of a tertiary organic base such as diisopropylethylamine, or Aldrithiol-2 (Aldrich) in which case the reaction is conducted in a basic solvent such as pyridine, in the presence of a triaryl phosphine such as triphenylphosphine.
  • a carbodiimide such as dicyclohexylcarbodiimide
  • PYBOP benzotriazol-1-yloxy)tripyrrolidinophosphonium
  • the conversion of the phosphonate monoester 27.2 to the diester 27.1 can be effected by the use of the Mitsonobu reaction, as described above (Scheme 16).
  • the substrate is reacted with the hydroxy compound R 1 OH, in the presence of diethyl azodicarboxylate and a triarylphosphine such as triphenyl phosphine.
  • the phosphonate monoester 27.2 can be transformed into the phosphonate diester 27.1, in which the introduced R 1 group is alkenyl or aralkyl, by reaction of the monoester with the halide R 1 Br, in which R 1 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.
  • a polar organic solvent such as dimethylformamide or acetonitrile
  • a base such as cesium carbonate.
  • the phosphonate monoester can be transformed into the phosphonate diester in a two step procedure.
  • the phosphonate monoester 27.2 is transformed into the chloro analog RP(O)(OR 1 )Cl by reaction with thionyl chloride or oxalyl chloride and the like, as described in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p.
  • a phosphonic acid R-link-P(O)(OH) 2 can be transformed into a phosphonate monoester RP(O)(OR 1 )(OH) (Scheme 27, Reaction 5) by means of the methods described above of for the preparation of the phosphonate diester R-link-P(O)(OR 1 ) 2 27.1, except that only one molar proportion of the component R 1 OH or R 1 Br is employed.
  • a phosphonic acid R-link-P(O)(OH) 2 27.3 can be transformed into a phosphonate diester R-link-P(O)(OR 1 ) 2 27.1 (Scheme 27, Reaction 6) by a coupling reaction with the hydroxy compound R 1 OH, in the presence of a coupling agent such as Aldrithiol-2 (Aldrich) and triphenylphosphine.
  • the reaction is conducted in a basic solvent such as pyridine.
  • phosphonic acids 27.3 can be transformed into phosphonic esters 27.1 in which R 1 is aryl, by means of a coupling reaction employing, for example, dicyclohexylcarbodiimide in pyridine at ca 70° C.
  • phosphonic acids 27.3 can be transformed into phosphonic esters 27.1 in which R 1 is alkenyl, by means of an alkylation reaction.
  • the phosphonic acid is reacted with the alkenyl bromide R 1 Br in a polar organic solvent such as acetonitrile solution at reflux temperature, the presence of a base such as cesium carbonate, to afford the phosphonic ester 27.1.
  • the preparation of carbamates is described in Comprehensive Organic Functional Group Transformations, A. R. Katritzky, ed., Pergamon, 1995, Vol. 6, p. 416ff, and in Organic Functional Group Preparations, by S. R. Sandler and W. Karo, Academic Press, 1986, p. 260ff.
  • Scheme 28 illustrates various methods by which the carbamate linkage can be synthesized.
  • a carbinol 28.1 is converted into the activated derivative 28.2 in which Lv is a leaving group such as halo, imidazolyl, benztriazolyl and the like, as described below.
  • the activated derivative 28.2 is then reacted with an amine 28.3, to afford the carbamate product 28.4.
  • Examples 1-7 in Scheme 28 depict methods by which the general reaction can be effected.
  • Examples 8-10 illustrate alternative methods for the preparation of carbamates.
  • Example 1 illustrates the preparation of carbamates employing a chloroformyl derivative of the carbinol 28.5.
  • the carbinol 28.5 is reacted with phosgene, in an inert solvent such as toluene, at about 0° C., as described in Org. Syn. Coll. Vol. 3, 167, 1965, or with an equivalent reagent such as trichloromethoxy chloroformate, as described in Org. Syn. Coll. Vol. 6, 715, 1988, to afford the chloroformate 28.6.
  • the latter compound is then reacted with the amine component 28.3, in the presence of an organic or inorganic base, to afford the carbamate 28.7.
  • the chloroformyl compound 28.6 is reacted with the amine 28.3 in a water-miscible solvent such as tetrahydrofuran, in the presence of aqueous sodium hydroxide, as described in Org. Syn. Coll. Vol. 3, 167, 1965, to yield the carbamate 28.7.
  • aqueous sodium hydroxide as described in Org. Syn. Coll. Vol. 3, 167, 1965, to yield the carbamate 28.7.
  • the reaction is preformed in dichloromethane in the presence of an organic base such as diisopropylethylamine or dimethylaminopyridine.
  • Example 2 depicts the reaction of the chloroformate compound 28.6 with imidazole, 28.7, to produce the imidazolide 28.8.
  • the imidazolide product is then reacted with the amine 28.3 to yield the carbamate 28.7.
  • the preparation of the imidazolide is performed in an aprotic solvent such as dichloromethane at 0° C., and the preparation of the carbamate is conducted in a similar solvent at ambient temperature, optionally in the presence of a base such as dimethylaminopyridine, as described in J. Med. Chem., 1989, 32, 357.
  • Example 3 depicts the reaction of the chloroformate 28.6 with an activated hydroxyl compound R′′OH, to yield the mixed carbonate ester 28.10.
  • the reaction is conducted in an inert organic solvent such as ether or dichloromethane, in the presence of a base such as dicyclohexylamine or triethylamine.
  • the hydroxyl component R′′OH is selected from the group of compounds 28.19-28.24 shown in Scheme 28, and similar compounds.
  • the mixed carbonate 28.10 is obtained by the reaction of the chloroformate with the hydroxyl compound in an ethereal solvent in the presence of dicyclohexylamine, as described in Can. J. Chem., 1982, 60, 976.
  • a similar reaction in which the component R′′OH is pentafluorophenol 28.22 or 2-hydroxypyridine 28.23 can be performed in an ethereal solvent in the presence of triethylamine, as described in Syn., 1986, 303, and Chem. Ber. 118, 468, 1985.
  • Example 4 illustrates the preparation of carbamates in which an alkyloxycarbonylimidazole 28.8 is employed.
  • a carbinol 28.5 is reacted with an equimolar amount of carbonyl diimidazole 28.11 to prepare the intermediate 28.8.
  • the reaction is conducted in an aprotic organic solvent such as dichloromethane or tetrahydrofuran.
  • the acyloxyimidazole 28.8 is then reacted with an equimolar amount of the amine RNH 2 to afford the carbamate 28.7.
  • the reaction is performed in an aprotic organic solvent such as dichloromethane, as described in Tet. Lett., 42, 2001, 5227, to afford the carbamate 28.7.
  • Example 5 illustrates the preparation of carbamates by means of an intermediate alkoxycarbonylbenztriazole 28.13.
  • a carbinol ROH is reacted at ambient temperature with an equimolar amount of benztriazole carbonyl chloride 28.12, to afford the alkoxycarbonyl product 28.13.
  • the reaction is performed in an organic solvent such as benzene or toluene, in the presence of a tertiary organic amine such as triethylamine, as described in Syn., 1977, 704.
  • This product is then reacted with the amine R 1 NH 2 to afford the carbamate 28.7.
  • the reaction is conducted in toluene or ethanol, at from ambient temperature to about 80° C. as described in Syn., 1977, 704.
  • Example 6 illustrates the preparation of carbamates in which a carbonate (R′′O) 2 CO, 28.14, is reacted with a carbinol 28.5 to afford the intermediate alkyloxycarbonyl intermediate 28.15. The latter reagent is then reacted with the amine R′NH 2 to afford the carbamate 28.7.
  • the procedure in which the reagent 28.15 is derived from hydroxybenztriazole 28.19 is described in Synthesis, 1993, 908; the procedure in which the reagent 28.15 is derived from N-hydroxysuccinimide 28.20 is described in Tet. Lett., 1992, 2781; the procedure in which the reagent 28.15 is derived from 2-hydroxypyridine 28.23 is described in Tet.
  • Example 7 illustrates the preparation of carbamates from alkoxycarbonyl azides 28.16.
  • an alkyl chloroformate 28.6 is reacted with an azide, for example sodium azide, to afford the alkoxycarbonyl azide 28.16.
  • the latter compound is then reacted with an equimolar amount of the amine R′NH 2 to afford the carbamate 28.7.
  • the reaction is conducted at ambient temperature in a polar aprotic solvent such as dimethylsulfoxide, for example as described in Syn., 1982, 404.
  • Example 8 illustrates the preparation of carbamates by means of the reaction between a carbinol ROH and the chloroformyl derivative of an amine.
  • the reactants are combined at ambient temperature in an aprotic solvent such as acetonitrile, in the presence of a base such as triethylamine, to afford the carbamate 28.7.
  • aprotic solvent such as acetonitrile
  • a base such as triethylamine
  • Example 9 illustrates the preparation of carbamates by means of the reaction between a carbinol ROH and an isocyanate 28.18.
  • the reactants are combined at ambient temperature in an aprotic solvent such as ether or dichloromethane and the like, to afford the carbamate 28.7.
  • Example 10 illustrates the preparation of carbamates by means of the reaction between a carbinol ROH and an amine RNH 2 .
  • the reactants are combined at ambient temperature in an aprotic organic solvent such as tetrahydrofuran, in the presence of a tertiary base such as triethylamine, and selenium.
  • a tertiary base such as triethylamine, and selenium.
  • Carbon monoxide is passed through the solution and the reaction proceeds to afford the carbamate 28.7.
  • the structures of the intermediate phosphonate esters 1 to 22 and the structures of the component groups R 1 , R 4 , R 8 , R 9, , R 11 , X and X′ of this invention are shown in Charts 1-3.
  • the structures of the R 2 R 3 NH components are shown in Chart 4; the structures of the amines components R 7 NHCH(R 6 )CONHR 4 are shown as the structures A1-A16 in Chart 4.
  • the structures of the R 5 XCH 2 groups are shown in Chart 5, and those of the R 10 CO components are illustrated in Chart 6.
  • the structures of the R 7 NHCH(R 6 )COOH components are shown in Chart 10.
  • the intermediate compounds 1 to 24 incorporate a phosphonate moiety (R 1 O) 2 P(O) connected to the nucleus by means of a variable linking group, designated as “link” in the attached structures.
  • Charts 7, 8 and 9 illustrate examples of the linking groups present in the structures 1-24.
  • Schemes 1-207 illustrate the syntheses of the intermediate phosphonate compounds of this invention, 1-22, and of the intermediate compounds necessary for their synthesis.
  • the preparation of the phosphonate esters 23 and 24, in which a phosphonate moiety is incorporated into one of the groups R 2 , R 3 , R 5 , R 10 or R 11 is also described below.
  • compounds 2, 6, 23 and 24 where two groups are the same Chart 4 it is noted that these groups may be independent or identical.
  • R 1 H, alkyl, haloalkyl, alkenyl, aralkyl, aryl
  • R 4 CH(CH 3 ) 3 ; CH 2 CF 3 ; CH 2 C 6 H 4 (CH 3 )-2; CH 2 C 6 H 3 (CH 3 ) 2 2,6
  • R 11 phenyl, alkyl
  • R 1 H, alkyl, haloalkyl, alkenyl, aralkyl, aryl
  • R 4 C(CH 3 ) 3 ; CH 2 CF 3 ; CH 2 C 6 H 4 (CH 3 )-2; CH 2 C 6 H 3 (CH 3l ) 2 2,6
  • R 9 morpholino or methoxy
  • R 1 H, alkyl, haloalkyl, alkenyl, aralkyl, aryl
  • R 4 C(CH 3 ) 3 ; CH 2 CH 3 ; CH 2 C 6 H 4 (CH 3 )-2; CH 2 C 6 H 3 (CH 3 ) 2 2,6
  • R 8 alkyl, CH 2 SO 2 CH 3 ,C(CH 3 ) 2 SO 2 CH 3 ,CH 2 CONH 2 , CH 2 SCH 3 , imidaz-4-ylmethyl, CH 2 NHAc, CH 2 NHCOCF 3
  • R 9 morpholino; alkoxy.
  • R 11 phenyl, alkyl
  • Y H, OC 2 H 5 , OCH 2 C 6 H 5 , MeO, (MeO) 2 , (MeO) 3 , CH 2 CH 2 OH, OH, Ha, CN, Ph, OCH 2 O, OCH 2 Ph

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KR20060022647A (ko) 2003-04-25 2006-03-10 길리애드 사이언시즈, 인코포레이티드 키나아제 억제 포스포네이트 유사체

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US8389571B2 (en) 2007-03-16 2013-03-05 Sequoia Pharmaceuticals, Inc. Benzofuran derived HIV protease inhibitors
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US9012462B2 (en) 2008-05-21 2015-04-21 Ariad Pharmaceuticals, Inc. Phosphorous derivatives as kinase inhibitors
US9273077B2 (en) 2008-05-21 2016-03-01 Ariad Pharmaceuticals, Inc. Phosphorus derivatives as kinase inhibitors
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