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  • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
  • C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
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Definitions

• the present invention relates to diverse libraries of peptidomimetic aminothioether acid compounds and derivatives thereof, methods of making such libraries, and an apparatus for storing and providing a readily accessible source of diverse peptidomimetic compounds.
• the apparatus harboring the present combinatorial libraries is a useful component of assay systems for identifying compounds for drug development.
• Synthesis of compounds is an expensive and time consuming phase of research and development. Historically, research chemists individually synthesized and analyzed high purity compounds for biological screening to develop pharmaceutical leads. Although such methods were successful in bringing new drugs to the market, the limitations of individual synthesis and complete compound characterization considerably slowed the discovery of new pharmaceutically active compounds. The need for more rapid and less expensive drug discovery methodology is increasingly important in today's competitive pharmaceutical industry. Recently, modern drug discovery has utilized combinatorial chemistry to generate large numbers (10 2 - l ⁇ 6) of compounds generically referred to as "libraries”. An important objective of combinatory chemistry is to generate a large number of novel compounds that can be screened to identify lead compounds for pharmaceutical research.
• the total number of compounds which may be produced for a given library is limited only by the number of reagents available to form substituents on the variable positions on the library's molecular scaffold.
• the combinatorial process lends itself to automation, both in the generation of compounds and in their biological screening, thereby greatly enhancing the opportunity and efficiency of drug discovery.
• Combinatorial chemistry may be performed in a manner where libraries of compounds are generated as mixtures with complete identification of the individual compounds postponed until after positive screening results are obtained.
• a preferred form of combinatorial chemistry is "parallel array synthesis", where individual reaction products are simultaneously synthesized, but are retained in separate vessels.
• the individual library compounds can be prepared, stored, and assayed in separate wells of a microtiter plate, each well containing one member of the parallel array.
• the use of standardized microtiter plates or equivalent apparatus is advantageous because such an apparatus is readily accessed by programmed robotic machinery, both during library synthesis and during library sampling or assaying.
• Combinatorial chemistry can be carried out in solution phase where both reactants are dissolved in solution or in solid phase where one of the reactants is covalently bound to a solid support.
• completion of the solution phase reactions in combinatorial chemistry schemes are ensured by selecting high yielding chemical reactions and/or by using one reagent in considerable excess.
• one reagent is used in excess, completion of the reaction produces a mixture of a soluble product with at least one soluble unreacted reagent.
• Solid phase synthesis offers the advantage that the solid support bound-products are easily washed free of excess reagent.
• Solution phase synthesis typically requires use of one or more reaction mixture work up procedures to separate reaction product from unreacted excess reagent.
• Combinatorial chemistry may be used at two distinct phases of drug development.
• discovery phase diverse libraries are created to find lead compounds.
• second optimization phase strong lead compounds are more narrowly modified to find optimal molecular configurations .
• the present invention is directed to the use of a combinatorial chemistry approach to prepare novel peptidomimetics, and the use of those compounds to identify lead compounds.
• Small peptides as a class of compounds possess rich diversity and potent bioactivity and thus remain a vital starting point for drug discovery.
• peptidomimetics are frequently used to redeploy important peptide mainchain and sidechain pharmacophores onto less peptide- like scaffolds.
• Peptidomimetics vary greatly in their resemblance to peptides. Success has been achieved with peptides containing hydrolytically stable amide surrogates, mixed organo-peptide frameworks, and with non-peptide scaffolds alike.
• benzodiazepines, penicillins and cephalosporins are well- established peptidomimetic drugs and it is easy to see that organo-peptide chimeras are essential to both rational design and combinatorial chemistry approaches to drug discovery.
• ATAs novel a ino thioether acid compounds and their corresponding sulfoxides and sulfones
• ATAs are dipeptides where a thioether bridge (or oxidized derivatives thereof) replaces the central amide linkage.
• the diverse library of ATAs in accordance with one embodiment of this invention generally represent a continuum of related structures ranging from analogs of known dipeptides, through organo-peptide hybrids, to bona fide organic compounds.
• the present ATA libraries can be prepared using combinatorial chemistry protocols and tested for biological activity.
• the ATAs can be prepared in quantity using classical organic synthesis techniques and used as starting materials for preparation of diverse ATA derivative libraries, or they can be used as building blocks to construct ATA polymer libraries for biological testing.
• the ATAs can be used alone or in combination with amino acids encoded by the genetic code, or with other amino acids, to prepare predetermined peptide mixtures analogous to those described in, for example, U.S. Patent No 5,266,684, the disclosure of which is incorporated herein by reference.
• the general method used to prepare the diverse libraries of ATA library compounds in accordance with this invention utilizes commercially available or readily synthesized amino acids or amino alcohols and mercapto acids.
• One embodiment of the method is illustrated using a subset of available amino acids/amino alcohols in the reaction scheme (Scheme I) shown below:
• An amino-protected amino alcohol (optionally derived by reduction of an amino acid) is converted to its corresponding mesylate and reacted with a dibasic salt of a mercapto acid (or a mercaptide salt of an ester or amide derivative thereof) to form ATA and ATA derivative library compounds of the present invention.
• R and W are selected from non-interfering substituents and P is an amino-protecting group stable under conditions of thioether formation, e.g., t- butyloxycarbonyl (Boc) or allyloxycarbonyl (Alloc) .
• Thioether formation is preferably conducted in solution phase.
• reaction can be carried out using solid phase synthesis techniques wherein the mercapto acid is bound through its acid moiety to a solid support having acid reactive groups, and the covalently bound mercapto compound is reacted as its mercaptide salt with the amino alcohol derived esylates to provide support bound amino thioether library compounds of this invention which can optionally be further reacted and either cleaved from the solid support or retained as a solid phase source of library compounds .
• the resulting diverse library is useful in the identification of new lead compounds.
• ATA library compounds can be selected for preparation of diverse ATA libraries derived, for example, by oxidation to the corresponding sulfoxide and/or sulfone, by removal of the amino protecting group and reacting the resulting amine functionality with electrophilic reagents, and/or by reacting the ATA acid functionality, either with bases to prepare the corresponding salts, or in activated form, with ester forming alcohols or amide-forming amines.
• the libraries are created, stored, and used as an apparatus comprising a two-dimensional array of reservoirs, each reservoir containing a predetermined library reaction product differing from those in adjacent reservoirs.
• the diverse ATA library also serves as a convenient source of ATAs useful for the preparation of protein/peptide mimetic polymers useful for identifying lead compounds.
• kits for the identification of pharmaceutical lead ATA and ATA derivative compounds comprising assay materials and a well plate apparatus or equivalent apparatus providing a two-dimensional array of defined reservoirs.
• the well plate apparatus provides a diverse combinatorial library, wherein each well (reservoir) contains a unique library compound.
• the well plate apparatus is used to provide multiple reaction zones for making the library, to store the library and to provide a readily accessible source of library compounds.
• Fig. 1 is a top view of a well plate in accordance with this invention.
• Fig. 2 is a side view of a well plate apparatus for use in the process of this invention.
• test kit refers to an assemblage of two cooperative elements, namely (1) a well plate apparatus and (2) biological assay materials.
• Biological assay materials are materials necessary to conduct a biological evaluation of the efficacy of any library compound in a screen relevant to a selected disease state.
• a “library” is a collection of compounds created by a combinatorial chemical process, said compounds having a common scaffold with one or more variable substituents.
• the scaffold of the present invention comprises peptidomimetic aminothioether acids and derivatives thereof .
• a “library compound” is an individual reaction product, a single compound or a mixture of iso ers, in a combinatorial library.
• a "Lead compound” is a library compound in a selected combinatorial library for which the assay kit has revealed significant activity relevant to a selected disease state.
• a “diverse library” means a library where the substituents on the combinatorial library scaffold or core structure, are highly variable in constituent atoms, molecular weight, and structure, and the library, considered in its entirety, is not a collection of closely related homologues or analogues (compare to "directed library”).
• a “directed library” is a collection of compounds created by a combinatorial chemical process, for the purpose of optimization of the activity of a lead compound, wherein each library compound has a common scaffold, and the library, considered in its entirety, is a collection of closely related homologues or analogues to the lead compound (compare with “diverse library”).
• the term "scaffold” as used in accordance with the present invention refers to the invariable region (a thioether core in the present invention) of the compounds which are members of the combinatorial library.
• Substituents are chemical radicals which are bonded to or incorporated onto or into the thioether scaffold through the combinatorial synthesis process.
• the different functional groups account for the diversity of the molecules throughout the library and are selected to impart diversity of biological activity to the scaffold in the case of diverse libraries, and optimization of a particular biological activity in the case of directed libraries .
• Reagent means a reactant, any chemical compound used in the combinatorial synthesis to place substituents on the scaffold of a library.
• Parallel array synthesis refers to the method of conducting combinatorial chemical synthesis of libraries wherein the individual combinatorial library compounds are separately prepared and stored without prior and subsequent intentional mixing.
• Simultaneous synthesis means making of library compounds within one production cycle of a combinatorial method (not making all library compounds at the same instant in time) .
• reaction zone refers to the individual vessel location where the combinatorial chemical library compound preparation process of the invention is carried out and where the individual library compounds are synthesized. Suitable reaction zones include, but are not intended to be limited to, the individual wells of a well plate apparatus.
• Well plate apparatus refers to a structure comprising a plurality of reservoirs capable of holding a library of compounds in dimensionally fixed and defined positions .
• Non-interfering substituents are those groups that do not significantly impede the process of the invention and yield stable aminothioether acid library compounds.
• Aryl means one or more aromatic rings, each of 5 or 6 ring carbon atoms and includes substituted aryl having one or more non-interfering substituents . Multiple aryl rings may be fused, as in naphthyl , or unfused, as in biphenyl .
• Alkyl means straight or branched chain or cyclic hydrocarbon having 1 to 20 carbon atoms.
• Substituted alkyl is alkyl having one or more non- interfering substituents.
• Halo means chloro, fluoro, iodo or bromo .
• Heterocycle or “heterocyclic radical” means one or more rings of 5, 6 or 7 atoms with or without unsaturation or aromatic character, optionally substituted with one or more non-interfering substituents, and at least one ring atom which is not carbon.
• Preferred heteroatoms include sulfur, oxygen, and nitrogen. Multiple rings may be fused, as in quinoline or benzofuran, or unfused as in 4- phenylpyridine.
• Suitable substituents on the heterocyclic ring structure include, but are not limited to halo, Ci-Cio alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C7-C12 aralkyl, C7-C12 alkaryl, C1-C10 alkylthio, arylthio, aryloxy, arylamino, C3-C10 cycloalkyl, C3-C10 cycloalkenyl , di (C1-C10 ) -alkylamino, C2-C12 alkoxyalkyl, C1-C6 alkylsulfinyl , C1-C10 alkylsulfonyl, arylsulfonyl , aryl, hydroxy, hydroxy (C ⁇ C10) alkyl, aryloxy (C1-C10 ) alkyl , C ⁇ _-C ⁇ o alkoxycarbonyl
• Heteroaryl is heterocycle or heterocyclic radical having aromatic character.
• Organic moiety means a substituent comprising a non-interfering substituent covalently bonded through at least one carbon atom.
• Suitable radicals for substitution onto a connecting carbon atom include, but are not limited to hydrogen, halo, optionally substituted Ci-Cio alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C7-C12 aralkyl, C7-C12 alkaryl, C1-C10 alkylthio, arylthio, aryloxy, arylamino, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, di (C1-C10 ) -alkylamino, C2-C12 alkoxyalkyl, C1-C6 alkylsulfinyl, C1-C10 alkylsulfonyl , arylsulfonyl, aryl, hydroxy, hydroxy (
• amino acid as used in accordance with the present invention includes the 20 proteiogenic amino acids encoded by the genetic code, as well as hydroxyproline, alpha-aminoisobutyric acid, sarcosine, citrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, beta-alanine, 4- aminobutyric acid and other compounds of the general formula:
• R n is hydrogen or an organic moiety
• Q is an organic group comprising 1 to 12 carbon atoms and 0 to 4 heteroatoms selected from 0, N and S; or R n taken together with Q and the nitrogen atom to which they are bound form a 5 or 6-membered ring.
• Proteiogenic amino acids are those amino acids of the formula
• Ri is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, hydroxymethyl , 1-hydroxyethyl , sulfhydrylmethyl , 2 (methylthio) ethyl, benzyl, 4-hydroxybenzyl, 3-indolylmethyl , carboxymethyl, 2 -carboxyethy1 , carbamidomethyl, 2-carbamidoethyl, 4-aminobutyl ,
• Rn is hydrogen, or R n and Ri taken together with the common bonded nitrogen atom form a pyrrolidine ring.
• Activated acid or “activated acid group” refers to a carboxylic acid that has been reacted to form a group -C(0)X wherein X is a leaving group subject to nucleophilic displacement by nucleophiles .
• group X are acid halides, such as acid chlorides, acid fluorides, and the like, acid anhydrides, active esters, and the like. Preparation of such activated acid derivatives and their use in preparation of other acid derivatives are well known in the art
• Acid reactive groups refer to those nucleophilic groups capable of reacting with activated acids to form a covalent bond. Exemplary of acid reactive groups are -
• R r is hydrogen or an organic moiety and stabilized carbon anions.
• Solid support refers to a solvent insoluble substrate having acid reactive groups for forming cleavable covalent bonds with acid reagents, such as S- -Unprotected mercapto acids for use in preparing the present library compounds in accordance with one embodiment of this invention.
• the present invention provides a diverse combinatorial library of peptidomimetic aminothioether acids and derivatives thereof of the general formula:
• P is hydrogen, a substituent derived from an electrophilic reagent, or an amino-protecting group
• Q is an organic group comprising 1 to 12 carbon atoms and 0 to 4 heteroatoms selected from 0, N and S;
• Rs is hydrogen or an organic moiety;
• R n is hydrogen or an organic moiety, or P in combination with R n is an amino-protecting group; or R n and Rs taken together with -Q- and the atoms to which they are bonded form a 4- to 7-membered ring or a bicyclic or tricyclic ring comprising 6 to 12 carbon atoms; or R n or R s taken together with -Q- and the atoms to which they are commonly bonded form a 4- to 7- membered ring; m is 0, 1 or 2;
• W is a divalent organic group comprising 1 to 12 carbon atoms and 0 to 4 heteroatoms selected from 0, N and S; and A is OH, NH2 , an ester-forming substituent derived from an alcohol, or an amide-forming substituent derived from a primary or secondary amine, said substituents optionally covalently bound to a solid support, and when A is OH, salts of the acid represented thereby.
• a diverse library of ATA compounds of Formula I wherein A is OH and P is hydrogen can be prepared using combinatorial synthesis protocols or the individual ATA library compounds and their amino-protected derivatives can be prepared by standard chemical synthesis techniques and used as core structures for preparation of directed libraries; or they can be used in preparation of peptidomimetic polymers of ATAs and other amino acid compounds using conventional peptide coupling protocols.
• amino-protected ATAs are converted to an activated acid form and reacted with either an amino acid or another ATA, optionally covalently bound to a solid support, to provide peptide-linked oligomers or polymers.
• Such procedures can be used to prepare combinatorial libraries of peptidomimetic compounds, such as those described and claimed in US Patent No. 5,266,684, wherein ATAs are substituted for one or more conventional amino acid compounds in preparation of the described combinatorial libraries.
• Amino-protected ATAs and amino-protected ATA derivative compounds in accordance with this invention are those compounds of Formula I above wherein R n is hydrogen or a substituent derived from an electrophilc agent and P is an amino-protecting group or wherein P and R n taken together form a divalent amino-protecting group, such as phthaloyl or diphenylmethylene .
• Exemplary of monovalent amino-protecting groups include, but are not intended to be limited to, 9-fluorenylmethyloxycarbonyl (Fmoc) , tert-butyloxycarbony1 (Boc) , allyloxycarbonyl (Alloc) , 2-trimethylsilylethoxycarbonyl (Teoc) , biphenylisopropyloxycarbonyl (Bpoc) , nitroveratryloxycarbonyl (Nvoc) , (4-methoxyphenyl) diphenylmethyl (MMTr) , (4,4' -dimethoxyphenyl ) phenylmethy1 (DMT) , benzyloxycarbonyl (Cbz or Z), and the like.
• Fmoc 9-fluorenylmethyloxycarbonyl
• Boc tert-butyloxycarbony1
• Alloc 2-trimethylsilylethoxycarbonyl
• Teoc 2-trimethyls
• the nature/structure of the amine or alcohol is not critical; primary or secondary alcohols and primary or secondary amines having a molecular weight of about 30 to about 500 are preferred.
• the amine or alcohol functionality can be covalently bound to a solid support.
• W is a divalent organic moiety selected from the group consisting of a divalent organic group comprising a 5- or 6-membered aromatic ring containing 0 to 4 heteroatoms selected from 0, N and S, -CHRs- , and -
• CR4R5CR6R7- wherein Rs is hydrogen or a noninterfering substituent; R4 , R5 , and R6 are independently hydrogen or alkyl; and R7 is hydrogen, hydroxy, protected hydroxy, amino or protected amino or substituted amino wherein the substituent is derived from an electrophilic reagent.
• Such groups are derived generally from mercapto acids of the formula
• HS-W-COOH having a molecular weight of about 90 to about 400.
• W is a divalent moiety selected from the group consisting of
• Ri is hydrogen or a non-interfering substituent
• R2 is hydrogen or a non-interfering substituent; or Ri taken together with R n forms a 5- or 6-membered ring; or Ri taken together with R s forms a 5- or 6- membered ring; or Ri taken together with R2 forms a 3- to 6-membered ring.
• Other embodiments of this invention within that embodiment, but having more restricted diversity in the group Q, are libraries wherein:
• Rl taken together with R s forms a 5- or 6-membered ring; or wherein Ri taken together with R2 forms a 3- to 6-membered ring.
• Ri is selected from the group consisting of hydrogen, phenyl, substituted phenyl, C1-C4 alkyl, substituted C1-C4 alkyl, C5-C6 cycloalkyl, C1-C4 alkoxyl, substituted C1-C4 alkoxyl, hydroxy, protected hydroxy, carboxy, protected carboxy, alkylthio, protected alkylthio, carbamido, amidino; and R2 is hydrogen, C1-C4 alkyl, or substituted C1-C4 alkyl.
• Such library compounds are derived from amino alcohols of the formula
• the process comprises the step of reacting a compound of the formula
• P is an amino-protecting group
• X is an electrophilic group subject to nucleophilic displacement from its bonded carbon atom
• R n , Q, s are as defined above with a salt of a mercapto compound of the formula
• W and A are as defined above; and when A is OH in Formula I, optionally reacting the aminothioether acid represented thereby with an ester- forming alcohol or an amide-forming primary or secondary amine; optionally oxidizing the aminothioether to provide a library compound wherein m is 1 or 2; removing the protecting group P to provide a library compound of the formula;
• Each of the reaction steps, whether conducted on solid phase (A is covalently bound to a solid support) or in solution phase, is typically carried out using a dry, inert, polar, aprotic solvent at a temperature of about 0° to about 30°C, using stoichiometrically equivalent amounts or near stoichiometrically equivalent amounts of reactants, and standard work up procedures.
• Suitable solvents include dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dioxane, ethyl acetate, diethyl ether and the like.
• reaction steps can be carried out using standard combinatorial chemistry protocols to produce arrays of library compounds, or they can be carried out on a larger scale using standard chemical synthesis, work-up, and product isolation and purification procedures.
• reaction is carried out in solution phase, and a solution of the compound of Formula II is added slowly to a solution of the mercaptide salt.
• reaction is carried out on solid phase (wherein A is a covalently bound solid support) .
• the mercaptide salt is most typically generated by reacting the corresponding mercaptan in solution with about one stoichiometric equivalent amount of an alkali metal alkoxide base, for example sodium methoxide.
• alkali metal alkoxide base for example sodium methoxide.
• Other mercaptide forming bases can be used (e.g. alkali metal dimsylates or hydrides) , but without advantage.
• a in the above formula is OH (representative of a mercapto acid)
• base represents 2 stoichiometric equivalents of base
• suitable mercapto acids for use in preparing the library compounds of this invention include, but are not intended to be limited to:
• aminothioether compounds of this invention the mercaptide salt is reacted with a compound of the Formula II.
• the substituent X is a suitable leaving group subject to nucleophilic displacement by the mercaptide salt.
• suitable X groups are mesylate, tosylate, and halo.
• Such compounds are typically derived from an amino alcohol or protected-amino alcohol of the formula
• the amino alcohol is selected to have a molecular weight of about 60 to about 450, most typically about 60 to about 300.
• the amino alcohol starting material is reacted with methane sulfonyl chloride to provide the corresponding mesylate in high yield using the mesylation protocol of Crossland and Servis [JOC 35, 31952-6 (1970)].
• Suitable amino alcohols for use in preparing the present library compounds include, but are not intended to be limited to:
• TRANS-2-AMINOMETHYL-1-CYCLOHEXANOL TRANS-2-HYDROXYMETHYL-1-CYCLOHEXYLAMINE HYDROCHLORIDE DL-3-PHENYLSERINE HYDRATE N-(2-HYDROXYETHYL)CARBAMIC ACID BENZYL ESTER
• Amino alcohol starting materials can also be prepared in high yield from available amino acids and protected amino acids of the formula -N Q ⁇ COOH
• R s is hydrogen
• these compounds can be obtained from sodium borohydride reduction of the mixed carbonate formed, for example, between the starting acid and isobutyryl chloroformate .
• Amino acids available for conversion to the corresponding amino alcohols for use in preparing library compounds of this invention include, but are not intended to be limited to, the following listed amino acids:
• L-THIAZOLIDINE-4-CARBOXYLIC ACID 3 4-DEHYDRO-DL-PROLINE 3-AMINOPYRAZOLE-4-CARBOXYLIC ACID DL-PROLINE
• the excess reagent frequently migrates with the thioether acid product on a flash silica column and cannot be removed by simple extraction.
• the excess acid can be separated from the product by dissolving the reaction mixture in ethyl acetate and adding a 2-fold molar excess of solid mercuric acetate to the solution.
• the defined acid can optionally be converted into its corresponding carboxylate salt by addition of a suitable salt-forming base, such as ammonium or alkali metal hydroxides or primary or secondary amines.
• a suitable salt-forming base such as ammonium or alkali metal hydroxides or primary or secondary amines.
• the acid group can be converted to an activated acid group and reacted with an ester-forming alcohol or an amide-forming primary or secondary amine to form the corresponding ester or amide derivatives respectively.
• Suitable amines and alcohols have a molecular weight of about 30 to about 500.
• Exemplary of primary and secondary amines for use in preparing library compounds of this invention include, but are not intended to be limited to, the following:
• the oxidation can be accomplished in high yields using stoichiometric amounts of any one of several oxidizing agents including m- chloroperbenzoic acid, periodate, and oxone (a mixture of potassium hydrogen persulfate, potassium bisulfate and potassium sulfate) .
• the oxidation reaction is carried out in any one of a wide variety of solvents at a temperature of about -10_C to about 30_C.
• the preparation of sulfoxides and sulfones by oxidation of thioethers are well known in the art.
• the next step in the process of the present invention includes removing the protecting group P to produce compounds of the formula
• reaction conditions used to accomplish removal of the amino-protecting group are dependent on the nature of the protecting group and are well known to skilled practitioners in the art.
• the tert- butyloxycarbonyl groups can be removed with trifluoracetic acid while the allyloxycarbonyl group is removed by reaction with triphenylphosphine and tetrakis (triphenylphosphine) palladium.
• electrophilic agent having a molecular weight of about 30 to about 600.
• electrophilic agents include organic halides, acyl halides, sulfonic acid esters, organohaloformates, organosulfonyl halides, organic isocyanates, organic isothiocyanates, aldehydes and ketones .
• electrophilic agents include, but are not intended to be limited to: 3 , 5-bis (trifluoromethyl ) benzoyl chloride benzoyl chloride
• 11-eicosenoyl chloride behenoyl chloride petroselinoyl chloride palmitoleoyl chloride tridecanoyl chloride

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  • 1998-04-08 WO PCT/US1998/007151 patent/WO1998046786A1/en not_active Application Discontinuation
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  • 1998-04-08 CA CA002286862A patent/CA2286862A1/en not_active Abandoned
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