Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
  • C07F5/02—Boron compounds

Definitions

• R is a substituted aryl or an optionally- substituted heteroaryl, provided that the heteroaryl is not pyridyl or azaborine; and each of R 2 , R 5 , R 6 , R 7 and R 8 is individually H, halide, optionally- substituted alkyl, optionally-substituted cycloalkyl, optionally-substituted heteroalkyl, optionally- substituted arylalkyl, optionally- substituted alkoxy, optionally- substituted aryloxy, optionally- substituted amino, silyl, optionally- substituted alkenyl, optionally-substituted cycloalkenyl, optionally-substituted heteroalkenyl, optionally-substituted alkynyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted acyl, carbonyl, carboxylic acid, ester, nitrile
• Also disclosed herein is a method for making a 2-substituted-l,2-azaborine, comprising: reacting a 2-chloro-l,2-azaborine with an organotin reagent, wherein the organotin reagent has a structure of:
• R is an alkyl
• FG is a functional group selected from an aldehyde, a ketone, an ester, an amide, a nitrile, and/or an alcohol.
• Acyl refers to a group having the structure -C(0)R, where R may be, for example, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl.
• “Lower acyl” groups are those that contain one to six carbon atoms.
• Acyloxy refers to a group having the structure -OC(0)R-, where R may be, for example, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl.
• “Lower acyloxy” groups contain one to six carbon atoms.
• “Alkenyl” refers to a cyclic, branched or straight chain group containing only carbon and hydrogen, and unless otherwise mentioned typically contains one to twelve carbon atoms, and contains one or more double bonds that may or may not be conjugated. Alkenyl groups may be unsubstituted or substituted.
• “Lower alkenyl” groups contain one to six carbon atoms.
• alkoxy refers to a straight, branched or cyclic hydrocarbon configuration and combinations thereof, including from 1 to 20 carbon atoms, preferably from 1 to 8 carbon atoms (referred to as a "lower alkoxy”), more preferably from 1 to 4 carbon atoms, that include an oxygen atom at the point of attachment.
• An example of an “alkoxy group” is represented by the formula - OR, where R can be an alkyl group, optionally substituted with an alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, alkoxy or heterocycloalkyl group.
• Suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy cyclopropoxy, cyclohexyloxy, and the like.
• Alkoxycarbonyl refers to an alkoxy substituted carbonyl radical, -C(0)OR, wherein R represents an optionally substituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl or similar moiety.
• alkyl refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, w-propyl, isopropyl, w-butyl, isobutyl, i-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like.
• a "lower alkyl” group is a saturated branched or unbranched hydrocarbon having from 1 to 6 carbon atoms. Preferred alkyl groups have 1 to 4 carbon atoms.
• Alkyl groups may be "substituted alkyls" wherein one or more hydrogen atoms are substituted with a substituent such as halogen, cycloalkyl, alkoxy, amino, hydroxyl, aryl, alkenyl, or carboxyl.
• a lower alkyl or (Ci-C 6 )alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;
• (C 3 -C 6 )cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
• (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, or 2-cyclohexylethyl;
• (Ci-C 6 )alkoxy can be methoxy, ethoxy, propoxy,
• hydroxy(C 1 -C 6 )alkyl can be hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- hydroxybutyl, 4-hydroxybutyl, 1-hydroxypentyl, 5-hydroxypentyl, 1 -hydroxyhexyl, or 6- hydroxyhexyl;
• (C 1 -C 6 )alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, or hexyloxycarbonyl;
• C 1 -C 6 )alkylthio can be methylthi
• Alkynyl refers to a cyclic, branched or straight chain group containing only carbon and hydrogen, and unless otherwise mentioned typically contains one to twelve carbon atoms, and contains one or more triple bonds. Alkynyl groups may be unsubstituted or substituted. "Lower alkynyl” groups are those that contain one to six carbon atoms.
• amine refers to a group of the formula -NRR', where R and R' can be, independently, hydrogen or an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group.
• R and R' can be, independently, hydrogen or an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group.
• an “alkylamino” or “alkylated amino” refers to - NRR', wherein at least one of R or R' is an alkyl.
• aminocarbonyl alone or in combination, means an amino substituted carbonyl
• aminocarbonyl radical wherein the amino radical may optionally be mono- or di-substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, alkoxycarbonyl, aralkoxycarbonyl and the like.
• An aminocarbonyl group may be -N(R)-C(0)-R (wherein R is a substituted group or H).
• a suitable aminocarbonyl group is acetamido.
• amide or “amido” is represented by the formula -C(0)NRR', where R and R' independently can be a hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described above.
• Aryl refers to a monovalent unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl).
• a “heteroaryl group,” is defined as an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of hetero atoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorous.
• Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and the like.
• the aryl or heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, or alkoxy, or the aryl or heteroaryl group can be unsubstituted.
• aralkyl or "arylalkyl” refers to an alkyl group wherein an aryl group is substituted for a hydrogen of the alkyl group.
• An example of an aralkyl group is a benzyl group.
• Aryloxy or “heteroaryloxy” refers to a group of the formula -OAr, wherein Ar is an aryl group or a heteroaryl group, respectively.
• carboxylate or “carboxyl” refers to the group -COO " or -COOH.
• esters refers to a carboxyl group having the hydrogen replaced with, for example a Ci- 6 alkyl group (“carboxylCi-ealkyl” or “alkylester”), an aryl or aralkyl group (“arylester” or “aralkylester”) and so on.
• C0 2 C 1 _ 3 alkyl groups are preferred, such as for example, methylester (CO 2 Me), ethylester (C0 2 Et) and propylester (C0 2 Pr) and includes reverse esters thereof (e.g. - OCOMe, -OCOEt and -OCOPr).
• halogen or halide refers to fluoro, bromo, chloro and iodo substituents.
• hydroxyl is represented by the formula -OH.
• Neitro refers to an R-group having the structure -N0 2 .
• Phosphinyl refers to -PRR' wherein R and R' to substituted groups.
• Substituted or “substitution” refer to replacement of a hydrogen atom of a molecule or an R-group with one or more additional R-groups such as halogen, alkyl, alkoxy, alkylthio, trifluoromethyl, acyloxy, hydroxy, mercapto, carboxy, aryloxy, aryl, arylalkyl, heteroaryl, amino, alkylamino, dialkylamino, morpholino, piperidino, pyrrolidin-l-yl, piperazin-l-yl, nitro, sulfato or other R-groups.
• R-groups such as halogen, alkyl, alkoxy, alkylthio, trifluoromethyl, acyloxy, hydroxy, mercapto, carboxy, aryloxy, aryl, arylalkyl, heteroaryl, amino, alkylamino, dialkylamino, morpholino, piperidino, pyrrol
• Illustrative substituents include Ci-ealkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 3 _gcycloalkyl, hydroxyl, oxo, Ci ⁇ alkoxy, aryloxy, Ci ⁇ alkoxyaryl, halo, Ci ⁇ alkylhalo (such as CF 3 and CHF 2 ), Ci_ 6 alkoxyhalo (such as OCF 3 and OCHF 2 ), carboxyl, esters, cyano, nitro, amino, substituted amino, disubstituted amino, acyl, ketones, amides, aminoacyl, substituted amides, disubstituted amides, thiol, alkylthio, thioxo, sulfates, sulfonates, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfonylamides,
• substituted sulfinyl or “sulfoxide” refers to a sulfinyl group having the hydrogen replaced with, for example a Ci- 6 alkyl group ("Ci-ealkylsulfinyl” or “Ci-ealkylsulfoxide”), an aryl (“arylsulfinyl”), an aralkyl (“aralkyl sulfinyl”) and so on.
• C ⁇ alkylsulfinyl groups are preferred, such as for example, -SOmethyl, -SOethyl and -SOpropyl.
• sulfonyl refers to the group -S0 2 H.
• substituted sulfonyl refers to a sulfonyl group having the hydrogen replaced with, for example a Ci-ealkyl group ("sulfonylCi-ealkyl”), an aryl (“arylsulfonyl”), an aralkyl (“aralkylsulfonyl”) and so on.
• SulfonylC ⁇ alkyl groups are preferred, such as for example, - S0 2 Me, -S0 2 Et and -S0 2 Pr.
• sulfonylamido or "sulfonamide” refers to the group -S0 2 NH 2 .
• sulfate refers to the group -OS(0) 2 OH and includes groups having the hydrogen replaced with, for example a Ci-ealkyl group ("alkylsulfates”), an aryl (“arylsulfate”), an aralkyl (“aralkylsulfate”) and so on.
• alkylsulfates an aryl
• aralkyl an aralkyl
• C ⁇ sulfates are preferred, such as for example, OS(0) 2 OMe,
• sulfonate refers to the group -SO 3 H and includes groups having the hydrogen replaced with, for example a Ci-ealkyl group ("alkylsulfonate”), an aryl (“arylsulfonate”), an aralkyl (“aralkylsulfonate”) and so on.
• C ⁇ sulfonates are preferred, such as for example, S0 3 Me, S0 3 Et and S0 3 Pr.
• thioether refers to a -S-R group, wherein R may be, for example, alkyl
• thiol refers to -SH.
• substituted thiol refers to a -S-R group wherein R is not an aliphatic or aromatic group.
• a substituted thiol may be a halogenated thiol such as, for example, -SF 5 .
• salts or esters refers to salts or esters prepared by conventional means that include salts, e.g., of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like.
• inorganic and organic acids including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid,
• “Pharmaceutically acceptable salts” of the presently disclosed compounds also include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, ⁇ , ⁇ '-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.
• bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, ⁇ , ⁇ '-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethylamine, diethylamine, pipe
• any chemical compound recited in this specification may alternatively be administered as a pharmaceutically acceptable salt thereof.
• “Pharmaceutically acceptable salts” are also inclusive of the free acid, base, and zwitterionic forms. Descriptions of suitable pharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts, Properties, Selection and Use, Wiley VCH (2002). When compounds disclosed herein include an acidic function such as a carboxy group, then suitable pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art and include alkaline, alkaline earth, ammonium, quaternary ammonium cations and the like. Such salts are known to those of skill in the art. For additional examples of "pharmacologically acceptable salts,” see Berge et al., J. Pharm. Sci. 66: 1 (1977).
• “Pharmaceutically acceptable esters” includes those derived from compounds described herein that are modified to include a carboxyl group.
• An in vivo hydrolysable ester is an ester, which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
• esters thus include carboxylic acid esters in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, methyl, n-propyl, t-butyl, or n-butyl), cycloalkyl, alkoxyalkyl (for example,
• aralkyl for example benzyl
• aryloxyalkyl for example, phenoxymethyl
• aryl for example, phenyl, optionally substituted by, for example, halogen, C. sub.1-4 alkyl, or C. sub.1-4 alkoxy) or amino
• sulphonate esters such as alkyl- or aralkylsulphonyl (for example,
• amino acid esters for example, L-valyl or L-isoleucyl.
• esters also includes inorganic esters such as mono-, di-, or triphosphate esters. In such esters, unless otherwise specified, any alkyl moiety present
• esters advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms.
• Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms.
• Any aryl moiety present in such esters advantageously comprises a phenyl group, optionally substituted as shown in the definition of carbocycylyl above.
• Pharmaceutically acceptable esters thus include CrC 22 fatty acid esters, such as acetyl, t-butyl or long chain straight or branched unsaturated or omega-6 monounsaturated fatty acids such as palmoyl, stearoyl and the like.
• Alternative aryl or heteroaryl esters include benzoyl,
• esters include aliphatic L-amino acid esters such as leucyl, isoleucyl and especially valyl.
• salts of the compounds are those wherein the counter-ion is pharmaceutically acceptable.
• salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
• the pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds are able to form.
• the pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
• Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric, methanesulfonic,
• inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydro
• salt forms can be converted by treatment with an appropriate base into the free base form.
• the compounds containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.
• Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
• addition salt as used hereinabove also comprises the solvates which the compounds described herein are able to form.
• solvates are for example hydrates, alcoholates and the like.
• quaternary amine as used hereinbefore defines the quaternary ammonium salts which the compounds are able to form by reaction between a basic nitrogen of a compound and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide.
• an appropriate quaternizing agent such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide.
• Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates.
• a quaternary amine has a positively charged nitrogen.
• Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate.
• the counterion of choice can be introduced using ion exchange resins.
• Some of the compounds described herein may also exist in their tautomeric form.
• Prodrugs of the disclosed compounds also are contemplated herein.
• a prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into an active compound following administration of the prodrug to a subject.
• prodrug as used throughout this text means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds described herein.
• Prodrugs preferably have excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo.
• Prodrugs of a compounds described herein may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art. F or a general discussion of prodrugs involving esters see Svensson and Tunek, Drug Metabolism Reviews 165 (1988) and Bundgaard, Design of Prodrugs, Elsevier (1985).
• prodrug also is intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when the prodrug is administered to a subject. Since prodrugs often have enhanced properties relative to the active agent pharmaceutical, such as, solubility and bioavailability, the compounds disclosed herein can be delivered in prodrug form. Thus, also contemplated are prodrugs of the presently disclosed compounds, methods of delivering prodrugs and compositions containing such prodrugs. Prodrugs of the disclosed compounds typically are prepared by modifying one or more functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to yield the parent compound.
• Prodrugs include compounds having a phosphonate and/or amino group functionalized with any group that is cleaved in vivo to yield the corresponding amino and/or phosphonate group, respectively.
• Examples of prodrugs include, without limitation, compounds having an acylated amino group and/or a phosphonate ester or phosphonate amide group.
• a prodrug is a lower alkyl phosphonate ester, such as an isopropyl phosphonate ester.
• Protected derivatives of the disclosed compounds also are contemplated.
• a variety of suitable protecting groups for use with the disclosed compounds are disclosed in Greene and Wuts, Protective Groups in Organic Synthesis; 3rd Ed.; John Wiley & Sons, New York, 1999.
• protecting groups are removed under conditions that will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like.
• One preferred method involves the removal of an ester, such as cleavage of a phosphonate ester using Lewis acidic conditions, such as in TMS-Br mediated ester cleavage to yield the free phosphonate.
• a second preferred method involves removal of a protecting group, such as removal of a benzyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof.
• a t-butoxy-based group, including t-butoxy carbonyl protecting groups can be removed utilizing an inorganic or organic acid, such as HC1 or trifluoroacetic acid, in a suitable solvent system, such as water, dioxane and/or methylene chloride.
• a suitable solvent system such as water, dioxane and/or methylene chloride.
• Another exemplary protecting group, suitable for protecting amino and hydroxy functions amino is trityl.
• Other conventional protecting groups are known and suitable protecting groups can be selected by those of skill in the art in consultation with Greene and Wuts, Protective Groups in Organic Synthesis; 3rd Ed.; John Wiley & Sons, New York, 1999.
• an amine is deprotected, the resulting salt can readily be neutralized to yield the free amine.
• an acid moiety such as a phosphonic acid moiety is unveiled, the compound may be isolated as the acid compound or as a salt thereof.
• compounds and compositions may be provided as individual pure enantiomers or as stereoisomeric mixtures, including racemic mixtures.
• the compounds disclosed herein are synthesized in or are purified to be in substantially enantiopure form, such as in a 90%
• enantiomeric excess a 95% enantiomeric excess, a 97% enantiomeric excess or even in greater than a 99% enantiomeric excess, such as in enantiopure form.
• R is a substituted aryl or an optionally- substituted heteroaryl, provided that the heteroaryl is not pyridyl or azaborine; and each of R 2 , R 5 , R 6 , R 7 and R 8 is individually H, halide, optionally- substituted alkyl, optionally-substituted cycloalkyl, optionally-substituted heteroalkyl, optionally- substituted arylalkyl, optionally- substituted alkoxy, optionally- substituted aryloxy, optionally- substituted amino, silyl, optionally- substituted alkenyl, optionally-substituted cycloalkenyl, optionally-substituted heteroalkenyl, optionally- substituted alkynyl, optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted acyl, carbonyl, carboxylic acid, ester, nitrile, ison
• R 1 aryl or heteroaryl group can be substituted with one or more groups including, but not limited to, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted alkenyl, optionally substituted acyl, optionally substituted aryl, aryloxy, alkoxyaryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, cyano or optionally substituted alkoxy.
• R 1 is a para- substituted aryl meaning that the substitution is located at a para position relative to the aryl carbon that is bonded to the boron of the 1,2-azaborine.
• the R 1 substituent is a substituted alkyl or substituted acyl, particularly a carboxylic acid-substituted alkyl, a carboxylic acid- substituted acyl, or an amido-substituted alkyl.
• R 1 is a substituted phenyl or an optionally-substituted thiophenyl.
• Illustrative compounds include BN analogs of biaryl non-steroidal anti-inflammatory drugs (NSAIDs) such as, for example, difenpiramide, felbinac, fenbufen, and flurbiprofen. The BN analogs are shown below.
• NSAIDs biaryl non-steroidal anti-inflammatory drugs
• Angiotensin II receptor antagonists also known as angiotensin receptor blockers (ARBs) are used in the treatment of hypertension.
• ARBs angiotensin receptor blockers
• Valsartan, losartan, candesartan, olmesartan, and irbesartan all share the following biaryl motif:
• Illustrative BN-ARBs have a structure of:
• R is optionally- substituted alkyl, optionally- substituted cycloalkyl, optionally- substituted heteroalkyl, optionally- substituted arylalkyl, optionally-substituted alkoxy, optionally-substituted aryloxy, optionally- substituted aryl, optionally- substituted heteroaryl, optionally-substituted acyl, carbonyl, carboxylic acid, ester, nitrile, isonitrile, sulfanyl, sulfinyl, sulfonyl, optionally- substituted amido, optionally-substituted phosphoryl, optionally- substituted thiophosphoryl, optionally- substituted phosphinyl, optionally- substituted thiophosphinyl, thioester, nitro, azido, optionally- substituted hydrazinyl, optionally-substituted diazenyl, or thiocarbonyl
• One example is:
• the replacement of an arene motif with an azaborine (BN) motif in pharmaceuticals may provide further platforms for drug development. For example, toxic secondary metabolites of drugs may be avoided by creating the BN analog.
• organotin reagents that can contain functional groups (FG) that normally react with organometallic reagents
• organomagnesium, organolithium previously used in substituting 1,2-azaborine.
• organotin compatible functional groups include aldehydes, ketones, esters, amides, nitriles, and alcohols.
• An illustrative organotin reagent is shown below:
• R 4 is an alkyl, preferably a lower alkyl such as n-butyl or methyl.
• THF, diethyl ether and pentane were purified by passing through a neutral alumina column under argon. All other chemicals and solvents were purchased and used as received.
• U B NMR spectra were recorded on a Varian Unity/Inova 300 spectrometer at ambient temperature. 1H NMR spectra were recorded on a Varian Unity/Inova 300 or Unity/Inova 600 spectrometer. 13 C NMR spectra were recorded on a Unity/Inova 600 spectrometer.
• U B NMR chemical shifts are externally referenced to BF 3 Et 2 0 ( ⁇ 0).
• BN-fenbufen can also be synthesized by the method disclosed herein.
• the organotin corresponding to the fenbufen structure could be coupled to 1,2-azaborine.

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