WO2002018321A2 - Inhibiteurs de proteine tyrosine phosphatase d'acide amino(oxo)acetique - Google Patents

Inhibiteurs de proteine tyrosine phosphatase d'acide amino(oxo)acetique Download PDF

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Publication number
WO2002018321A2
WO2002018321A2 PCT/US2001/026133 US0126133W WO0218321A2 WO 2002018321 A2 WO2002018321 A2 WO 2002018321A2 US 0126133 W US0126133 W US 0126133W WO 0218321 A2 WO0218321 A2 WO 0218321A2
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Prior art keywords
amino
oxo
acetic acid
benzyl
phenyl
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PCT/US2001/026133
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English (en)
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WO2002018321A3 (fr
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Gang Liu
Yihong Li
David A. Janowick
Zhonghua Pei
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Abbott Laboratories
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    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
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Definitions

  • the instant invention is directed to compounds useful for inhibiting protein tyrosine phosphatase PTPIB, preparation of the compounds, compositions containing the compounds, and treatment of diseases using the compounds.
  • PTPIB belongs to a family of protein tyrosine phosphatases involved in the regulation of the cellular signalling mechanisms which are involved in metabolism, growth, proliferation and differentiation (Science 253:401-6 (1991)). Overexpression or altered activity of tyrosine phosphatase PTPIB can also contribute to the progression of various diseases (Ann. Rev. Biochem., 54:897-930 (1985)); and there is evidence which suggests inhibition of protein tyrosine phosphatase PTPIB is therapeutically beneficial for the treatment of diseases such as type I and II diabetes, obesity, autoimmune disease, acute and chronic inflammation, osteoporosis and various forms of cancer (J. Natl. cancer Inst. 86:372- 8 (1994); Mol. Cell. Biol. 14: 6674-6682 (1994); The EMBO J. 12:1937-46 (1993); j. Biol.
  • L 2 is selected from CH(R 6 ) and CH 2 CH(R 6 );
  • R is selected from hydrogen and a carboxy protecting group
  • R is selected from hydrogen, aminoalkyl, loweralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, (heterocycle)alkyl, hydroxyalkyl, and haloalkyl; each R is independently selected from hydrogen, loweralkoxy, alkoxyalkyl, alkoxyalkenyl, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkoxy, aryl, arylalkyl, arylalkenyl, arylalkoxy, carboxamido, carboxamidoalkyl, carboxamidoalkenyl, carboxamidoalkoxy, carboxy, carboxyalkyl, carboxyalkenyl, carboxyalk
  • R is selected from hydrogen, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle, and (heterocycle)alkyl;
  • R is selected from aryl and heteroaryl
  • T is selected from C(O)N(R 8 ), N(R 8 )C(O), N(R 8 ), OC(O)N(R 8 ), N(R 8 )C(O)O, C(O), OC(O), (O)CO, O, S, S(O), SO 2 , C(O), OC(O)O, N(R 8 )C(O)N(R 8 ), and C(O)OC(O); wherein the asymmetric groups defining T are drawn with their left ends attached to
  • R is selected from hydrogen and loweralkyl.
  • R and R are defined previously, and R is selected from hydrogen and halo
  • R is arylalkyl, and R is aryl.
  • R and R are defined previously; R is selected from hydrogen, loweralkoxy, alkoxycarbonylalkenyl, alkoxycarbonylalkoxy, aryl, carboxamidoalkenyl, carboxamidoalkoxy, carboxyalkenyl, carboxyalkoxy, halo, and heteroarylalkoxy; and R is selected from hydrogen and halo.
  • R is hydrogen, arylalkyl, cycloalkyl, or (heterocycle)alkyl; and R is aryl or heteroarylalkoxy.
  • R and R are defined previously;
  • R is selected from hydrogen and aryl;
  • X is selected from CH 2 and ⁇ (R x ); and
  • R x is selected from alkanoyl, alkylsulfonyl, arylsulfonyl, aryloyl, arylsulfonyl, carboxamidoalkyl, and (heterocycle)alkyl.
  • R is hydrogen, arylalkyl, arylalkyl, (heterocycle)alkyl, or aminoalkyl; and R is hydrogen, halo, aryl, alkoxycarbonylalkenyl, carboxyalkenyl, heteroaryl, or carboxamidoalkenyl.
  • R selected from hydrogen and heteroaryl.
  • L is a covalent bond or O; R is hydrogen; and R is hydrogen, halo, aryl, or heteroarylalkoxy.
  • R is hydroxyalkyl or arylalkyl and R is loweralkoxy, alkoxy, or aryl.
  • R is coupling promoter group selected from the group consisting of chloride, bromide, trifluoromethanesulfonate, iodide, and hydroxy, with a coupling partner, a base, and, optionally, a palladium catalyst; and (b) optionally hydrolyzing the product of step (a).
  • the coupling partner is selected from a substituted alkene, an optionally substituted arylboronic acid, an optionally substituted heteroarylboronic acid, an optionally substituted aryl trialkylstannane, an optionally substituted heteroaryl trialkylstannane, and an optionally substituted alkyl halide; and the palladium catalyst is selected from tetrakistriphenyl-phosphinepalladium(O), palladium(II) bis(triphenyl-phosphine)dichloride, and dipalladium tris(dibenzylidine-acetone).
  • a method for inhibiting protein tyrosine phosphatase comprising administering a therapeutically effective amount of a compound of formula (II).
  • a method for inhibiting protein tyrosine phosphatase comprising administering a therapeutically effective amount of a compound of formula (III).
  • a method for inhibiting protein tyrosine phosphatase comprising administering a therapeutically effective amount of a compound of formula (N).
  • a method for inhibiting protein tyrosine phosphatase comprising administering a therapeutically effective amount of a compound of formula (NI).
  • a method for treating diseases in a patient in recognized need of such treatment comprising administering to the patient a therapeutically effective amount of a compound of formula (II).
  • a method for treating diseases in a patient in recognized need of such treatment comprising administering to the patient a therapeutically effective amount of a compound of formula (III).
  • a method for treating diseases in a patient in recognized need of such treatment comprising administering to the patient a therapeutically effective amount of a compound of formula (IN).
  • composition comprising a compound of formula (I) in combination with a therapeutically acceptable excipient.
  • composition comprising a compound of formula (II) in combination with a therapeutically acceptable excipient.
  • composition comprising a compound of formula (III) in combination with a therapeutically acceptable excipient.
  • composition comprising a compound of formula (IV) in combination with a therapeutically acceptable excipient.
  • composition comprising a compound of formula (V) in combination with a therapeutically acceptable excipient.
  • composition comprising a compound of formula (VI) in combination with a therapeutically acceptable excipient.
  • the instant invention provides a series of compounds which inhibit protein tyrosine phosphatase PTPIB.
  • the compounds comprise a proximal, optionally substituted aryl or heteroaryl ring tethered through an optionally substituted linker to the nitrogen of an amino(oxo)acetic acid group.
  • the proximal ring is optionally substituted phenyl, naphthyl, furanyl, thienyl, pyrrolyl, pyridyl, oxazolyl, or thiazolyl and has attached thereto at least one distal substituent other than hydrogen.
  • the linker group connecting the proximal ring to the amino(oxo)acetic acid group is optionally substituted methylene or ethylene which can be optionally interrupted at the carbon-nitrogen juncture by an oxygen atom.
  • the preferred substituents on the linker group are cycloalkyl, especially cyclohexyl, and heterocycle, preferably optionally N-substituted piperidiny-4-yl.
  • alkanoyl refers to a loweralkyl group attached to the parent molecular group through a carbonyl.
  • alkanoyloxy refers to an alkanoyl group attached to the parent molecular group through an oxygen atom.
  • alkoxy refers to an alkyl group attached to the parent molecular group through an oxygen atom.
  • alkoxyalkenyl refers to a loweralkoxy group attached to the parent molecular group through an alkenyl group.
  • alkoxyalkoxy refers to a loweralkoxy group attached to the parent molecular group through a loweralkoxy group.
  • alkoxyalkyl refers to a loweralkoxy group attached to the parent molecular group through a loweralkyl group.
  • alkoxycarbonyl refers to an ester group; e.g., an alkoxy group attached to the parent molecular group through a carbonyl.
  • alkoxycarbonylalkyl refers to an alkoxycarbonyl group attached to the parent molecular group through a loweralkyl group.
  • alkoxycarbonylalkenyl refers to an alkoxycarbonyl group attached to the parent molecular group through an alkenyl group.
  • alkoxycarbonylalkoxy refers to an alkoxycarbonyl group attached to the parent molecular group through a loweralkoxy group.
  • alkenyl refers to a monovalent straight or branched chain hydrocarbon radical having from two to six carbons and at least one carbon-carbon double bond.
  • alkyl refers to a saturated, monovalent straight or branched chain hydrocarbon having from one to twenty carbons.
  • alkylsulfonyl refers to a loweralkyl group attached to the parent molecular group through a sulfonyl.
  • alkynyl refers to a monovalent straight or branched chain hydrocarbon group having from two to six carbons and at least one carbon-carbon triple bond.
  • amino refers to -NR R , wherein R and R are independently selected from hydrogen, loweralkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycle, (heterocycle)alkyl, carboxycarbonyl, and an amino protecting group.
  • aminoalkyl refers to an amino group attached to the parent molecular group through a loweralkyl group.
  • aminonosulfonyl refers to an amino group attached to the parent molecular group through a sulfonyl.
  • amino protecting group refers to selectively introducible and removable groups which protect amino groups against undesirable side reactions during synthetic procedures.
  • amino protecting groups include methoxycarbonyl, ethoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl
  • Cbz chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert- butoxycarbonyl (Boc), para-methoxybenzyloxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, benzyl, diphenylmethyl, triphenylmethyl (trityl), methylsulfonyl, phenylsulfonyl, para-toluene-sulfonyl, trimethylsilyl, triethylsilyl, triphenylsilyl, and the like.
  • Preferred nitrogen protecting groups of the invention are benzyloxycarbonyl (Cbz), formyl, acetyl, methylsulfonyl, benzoyl, and phenylsulfonyl.
  • aryl refers to an aromatic, carbocyclic ring or two fused aromatic, carbocyclic rings. These groups are exemplified by phenyl and naphthyl.
  • the aryl groups of the invention can be optionally substituted with one, two, three, four, or five substituents independently selected from loweralkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonyl, amino, aminosulfonyl, azido, carboxamido, carboxy, cyano, halo, hydroxy, nitro, perfluoroalkyl, perfluoroalkoxy, oxo, thioalkoxy, phenyl, heteroaryl selected from furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl,
  • the phenyl, the heteroaryl, and the heterocycle groups optionally substituting the aryl groups of the invention are attached to the parent aryl groups through either a covelent bond, a loweralkyl, an oxygen atom, or a carbonyl.
  • the phenyl, the heteroaryl, and the heterocycle groups optionally substituting the aryl groups of the invention can also be further substituted with one, two, or three substituents independently selected from loweralkyl, loweralkoxy, carboxyl, azido, carboxaldehyde, halo, hydroxy, perfluoroalkyl, and perfluoroalkoxy.
  • arylboronic acid refers to an aryl group to which is attached -B(OH) 2 .
  • aryl trialkylstannane refers to an aryl group to which is attached -
  • each R is independently selected from loweralkyl.
  • arylalkenyl refers to an aryl group, attached to the parent molecular group through an alkenyl group.
  • arylalkyl refers to an aryl group attached to the parent molecular group through a loweralkyl group.
  • the loweralkylene part of the arylalkyl group can be optionally substituted with a substituent selected from alkoxycarbonyl, hydroxy, carboxy, and alkanoyloxy.
  • arylalkoxy refers to an aryl group attached to the parent molecular group through a loweralkoxy group.
  • zido refers to -N 3 .
  • carbonyl refers to -C(O)-.
  • carboxylate refers to an amide; e.g., an amino group attached to the parent molecular group through a carbonyl.
  • carboxamidoalkenyl refers to a carboxamido group attached to the parent molecular group through an alkenyl group.
  • carboxyalkyl refers to a carboxamido group attached to the parent molecular group through a loweralkyl group.
  • carboxy refers to -CO 2 H.
  • the carboxy groups of the invention can be optionally protected by the replacement of the hydrogen atom thereof by a carboxy protecting group.
  • carboxy refers to -CO 2 H.
  • the carboxy groups of the invention can be optionally protected by the replacement of the hydrogen atom thereof by a carboxy protecting group.
  • carboxyalkoxy refers to a carboxy group attached to the parent molecular group through an alkoxy group.
  • carboxycarbonyl refers to a carboxy group connected to the parent molecular group through a carbonyl.
  • carboxy protecting group refers to selectively introducible and removable groups which protect carboxyl groups against undesirable side reactions during synthetic procedures and includes all conventional carboxyl protecting groups.
  • carboxyl groups include loweralkyl, phenyl, naphthyl, benzyl, diphenylmethyl, friphenylmethyl (trityl), para-nitrobenzyl, para-methoxybenzyl, acetylmethyl, benzoylmethyl, para- nitrobenzoylmethyl, para-bromobenzoylmethyl, 2-tetrahydropyranyl 2-tetrahydrofuranyl, 2,2,2-trichloroethyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl, arylalkoxy alkyl benzyloxymethyl l,l-dimethyl-2-propenyl, 3-methyl- 3-butenyl, allyl, and the
  • cyano refers to -CN.
  • cycloalkenyl refers to a monovalent cyclic or bicyclic hydrocarbon of four to twelve carbons having at least one carbon-carbon double bond.
  • cycloalkenylalkyl refers to a cycloalkenyl group attached to the parent molecular group through a loweralkyl group.
  • cycloalkyl refers to a monovalent saturated cyclic or bicyclic hydrocarbon group of three to twelve carbons.
  • the cycloalkyl groups of the invention can be optionally substituted with one, two, three, or four substituents independently selected from loweralkyl, amino, alkoxy, alkoxycarbonyl, carboxaldehyde, carboxyl, halo, hydroxy, phenyl, heteroaryl, heterocycle, and oxo.
  • cycloalkylalkyl refers to a cycloalkyl group attached to the parent molecular group through a loweralkyl group.
  • halo refers to F, CI, Br, or I.
  • haloalkyl refers to a halo group attached to the parent molecular group through a loweralkyl group.
  • heteroaryl refers to cyclic, aromatic groups having five or six atoms, wherein at least one atom is selected from nitrogen, oxygen, and sulfur, and the remaining atoms are carbon.
  • the five-membered rings have two double bonds, and the six-membered rings have three double bonds.
  • Heteroaryls of the invention are exemplified by furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazinyl, and the like.
  • the heteroaryl groups of the invention are connected to the parent molecular group through a carbon atom in the ring or, as exemplified by imidazole and pyrazolyl, through either a carbon atom or nitrogen atom in the ring.
  • the heteroaryl groups of the invention can be optionally substituted with one, two, or three radicals independently selected from loweralkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonyl, amino, aminosulfonyl, azido, carboxamido, carboxy, cyano, halo, hydroxy, nitro, perfluoroalkyl, perfluoroalkoxy, oxo, thioalkoxy, a nitrogen protecting group, phenyl, and a heterocycle selected from tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, and
  • the phenyl and the heterocycle groups optionally substituting the heteroaryl groups of the invention are attached to the heteroaryl through either a covelent bond, a loweralkyl group, an oxygen, or a carbonyl group.
  • the phenyl and the heterocycle groups optionally substituting the heteroaryl groups of the invention can also be further substituted with one, two, or three substituents independently selected from loweralkyl, loweralkoxy, carboxyl, azido, carboxaldehyde, halo, hydroxy, perfluoroalkyl, and perfluoroalkoxy.
  • heteroaryl groups of the invention can also be fused to one or two phenyl rings, in which case the heteroaryl group can be connected to the parent molecular group through either the heteroaryl part or the phenyl part of the fused ring system.
  • Heteroaryl groups of this type are exemplified by quinolinyl, isoquinolinyl, benzodioxolyl, benzodioxinyl, dibenzo( ⁇ , ⁇ i)furan, indolyl, and the like.
  • heteroarylalkoxy refers to a heteroaryl attached to the parent molecular group through an alkoxy group.
  • heteroarylalkyl refers to a heteroaryl group attached to the parent molecular group through a loweralkyl group.
  • heteroarylalkenyl refers to a heteroaryl group attached to the parent molecular group through an alkenyl group.
  • heteroarylboronic acid refers to a heteroaryl group to which is attached - B(OH) 2 .
  • heteroaryl trialkylstannane refers to a heteroaryl group to which is
  • heteroarylthioxy refers to a heteroaryl attached to the parent molecular group through a sulfur atom.
  • heteroarylthioxyalkyl refers to a heteroarylthioxy group attached to the parent molecular group through a loweralkyl group.
  • heterocycle refers to cyclic, non-aromatic, four-, five-, or six-membered groups containing at least one atom selected from oxygen, nitrogen, and sulfur.
  • the four- membered rings have zero double bonds, the five-membered rings have zero or one double bonds, and the six-membered rings have zero, one, or two double bonds.
  • Heterocycle groups of the invention are exemplified by dihydropyridinyl, imidazolinyl, morpholinyl, piperazinyl, pyrrolidinyl, pyrazolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,3-dioxanyl, and the like.
  • the heterocycles of the invention are attached to the parent molecular group through a carbon atom or nitrogen atom in the ring.
  • heterocycles of the invention can be optionally substituted one, two, or three substituents independently selected from loweralkyl, loweralkoxy, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonyl, amino, aminosulfonyl, azido, carboxamido, carboxy, cyano, halo, hydroxy, a nitrogen protecting group, perfluoroalkyl, perfluoroalkoxy, oxo, phenyl, and heteroaryl selected from furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, and triaziny
  • the phenyl and the heteroaryl groups optionally substituting the heterocycles of the invention are attached through a covelent bond, a loweralkyl group, an oxygen atom, or a carbonyl.
  • the phenyl and the heteroaryl groups optionally substituting the heterocycles of the invention can also be further substituted with one, two, or three substituents independently selected from loweralkyl, loweralkoxy, carboxyl, azido, carboxaldehyde, halo, hydroxy, perfluoroalkyl, and perfluoroalkoxy.
  • heterocycles of the invention can also be optionally fused to one or two phenyl rings, in which case the heterocycle can be connected to the parent molecular group through either the heterocycle part or the phenyl part of the fused ring system.
  • Heterocycle groups of this type are exemplified by 1,3-benzodioxanyl, 1,3-benzodioxolyl, 2,4-dihydro-2H-l,4-benzoxazinyl, 1,3-benzothiazole, isoindoline, and the like.
  • (heterocycle)alkyl refers to a heterocycle attached to the parent molecular group through a loweralkyl group.
  • hydroxy refers to -OH.
  • the hydroxy groups of the invention can be optionally protected by replacement of the hydrogen atom thereof with a hydroxy protecting group.
  • hydroxy alkyl refers to a hydroxyl group attached to the parent molecular group through a loweralkyl group.
  • hydroxy protecting group refers to selectively introducible and removable groups which protect hydroxy groups against undesirable side reactions during synthetic procedures.
  • hydroxy protecting groups include benzyloxycarbonyl, 4- nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl,
  • 2,2,2-trichloroethoxycarbonyl 2-(trimethylsilyl)ethoxy carbonyl, 2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, l,l-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl, para- methoxybenzyldiphenylmethyl, friphenylmethyl (trityl), tefrahydrofuryl methoxymethyl, methylthiomethyl, benzyloxymethyl, 2,2,2-trichloroethoxymethyl, 2- (trimethylsilyl)efhoxymethyl, methanesulfonyl, para-toluen
  • loweralkoxy refers to a loweralkyl group attached to the parent molecular group through an oxygen atom.
  • loweralkyl refers to a saturated, monovalent straight or branched chain hydrocarbon having from one to six carbons.
  • loweralkylene refers to a divalent straight or branched chain saturated hydrocarbon diradical having from one to six carbons.
  • nitro refers to -NO 2 .
  • oxo refers to a group formed by the replacement of two hydrogen atoms on the same carbon atom with a single oxygen atom.
  • perfluoroalkoxy refers to a perfluoroalkyl group attached to the parent group through an oxygen atom.
  • perfluoroalkyl refers to a loweralkyl group in which all of the hydrogen atoms have been replaced with fluoride atoms.
  • the instant compounds can exist as therapeutically acceptable salts.
  • “therapeutically acceptable salt” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of diseases without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
  • the salts can be prepared during the final isolation and purification of the compounds or separately by reacting the amino group of the compounds with a suitable acid.
  • Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalic, maleic, pivalate, propionate, succinate, tartrate, trichloroacetic, trifluoroacetic, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulphuric, phosphoric, and the like.
  • the amino groups of the compounds can also be quaternized with alkyl chlorides, bromides, and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, and the like.
  • Basic addition salts can be prepared during the final isolation and purification of the instant compounds by reaction the carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine.
  • Quaternary amine salts derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributlyamine, pyridine, N,N-dimethylaniline, N-methylpiperidine,
  • N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N- dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like, are contemplated as being within the scope of the instant invention.
  • the instant compounds can also exist as therapeutically acceptable prodrugs.
  • the term "therapeutically acceptable prodrug,” refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • prodrug refers to compounds which are rapidly transformed in vivo to parent compounds of formulas (I)-(VI) for example, by hydrolysis in blood.
  • sulfonyl refers to -SO 2 -.
  • thioalkoxy refers to a loweralkyl group attached to the parent molecular group through a sulfur atom.
  • Asymmetric centers can exist in the instant compounds.
  • Individual stereoisomers of the compounds are prepared by synthesis from chiral starting materials or by preparation of racemic mixtures and separation by conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of the enantiomers on chiral chromatographic columns.
  • Starting materials of particular stereochemistry are either commercially available or are made by the methods described hereinbelow and resolved by techniques well-known in the art.
  • Geometric isomers can exist in the instant compounds The invention contemplates the various geometric isomers and mixtures thereof resulting from the disposal of substituents around a carbon-carbon double bond, a cycloalkyl, or a heterocycle.
  • compositions of the instant compounds comprise an effective amount of the same formulated with one or more therapeutically acceptable excipients.
  • therapeutically acceptable excipient refers to a non-toxic, solid, semi-solid or liquid filler, diluent, encapsulating material, or formulation auxiliary of any type.
  • therapeutically acceptable excipients include sugars; cellulose and derivatives thereof; oils; glycols; solutions; buffering, coloring, releasing, coating, sweetening, flavoring, and perfuming agents; and the like.
  • Liquid dosage forms for oral administration of the instant compounds comprise formulations of the same as emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms can contain diluents and/or solubilizing or emulsifying agents.
  • the oral compositions can include wetting, emulsifying, sweetening, flavoring, and perfuming agents.
  • Injectable preparations of the instant compounds comprise sterile, injectable, aqueous and oleaginous solutions, suspensions or emulsions, any of which can be optionally formulated with parenterally acceptable diluents, dispersing, wetting, or suspending agents.
  • injectable preparations can be sterilized by filtration through a bacterial-retaining filter or formulated with sterilizing agents which dissolve or disperse in the injectable media.
  • PTP inhibition by the instant compounds can be delayed by using a liquid suspension of crystalline or amorphous material with poor water solubility.
  • the rate of absorption of the compounds depends upon their rate of dissolution which, in turn, depends on their crystallinity. Delayed absorption of a parenterally administered compound can be accomplished by dissolving or suspending the compound in oil.
  • injectable depot forms of the compounds can also be prepared by microencapsulating the same in biodegradable polymers. Depending upon the ratio of compound to polymer and the nature of the polymer employed, the rate of release can be controlled. Depot injectable formulations are also prepared by entrapping the compounds in liposomes or microemulsions which are compatible with body tissues.
  • Solid dosage forms for oral administration of the instant compounds include capsules, tablets, pills, powders, and granules.
  • the compound is mixed with at least one inert, therapeutically acceptable excipient such as a carrier, filler, extender, disintegrating agent, solution retarding agent, wetting agent, absorbent, or lubricant.
  • the excipient can also contain buffering agents.
  • Suppositories for rectal administration can be prepared by mixing the compounds with a suitable nonirritating excipient which is solid at ordinary temperature but fluid in the rectum.
  • the instant compounds can be micro-encapsulated with one or more of the excipients discussed previously.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric and release-controlling.
  • the compounds can be mixed with at least one inert diluent and can optionally comprise tableting lubricants and aids.
  • Capsules can also optionally contain opacifying agents which delay release of the compounds in a desired part of the intestinal tract.
  • Transdermal patches have the added advantage of providing controlled delivery of the instant compounds to the body.
  • dosage forms are prepared by dissolving or dispensing the compounds in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compounds across the skin, and the rate of absorption can be controlled by providing a rate controlling membrane or by dispersing the compounds in a polymer matrix or gel.
  • Diseases caused or exacerbated by protein tyrosine phosphatase PTPIB activity are treated or prevented in a patient by administering to the same a therapeutically effective amount of the instant compounds in such an amount and for such time as is necessary to achieve the desired result.
  • terapéuticaally effective amount refers to a sufficient amount of the compound to treat protein tyrosine phosphatase PTPIB activity at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the compound employed; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, rate of excretion; the duration of the treatment; and drugs used in combination or coincidental therapy.
  • the total daily dose of the instant compounds in single or divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight.
  • Single dose compositions can contain such amounts or submultiples thereof of the compounds to make up the daily dose.
  • treatment regimens comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compounds per day in single or multiple doses.
  • Specific compounds of the invention include, but are not limited to,
  • the cell paste was resuspended in 4 cell paste volumes of lysis buffer containing 100 mM MES (pH 6.5), 100 mM NaCl, 1 mM EDTA, 1 mM DTT, 1 mM PMSF, 20 U/mL Benzonase, 0.5 mg/mL lysozyme, and 1 mM MgCl 2 and incubated for 35 minutes at room temperature.
  • the cells were lysed at 11,000 psi using a Rannie homogenizer, and the homogenate was clarified in a Beckman GSA rotor at 10,000 x g for 30 minutes at 4 °C.
  • Protein tyrosine phosphatase PTPIB activity was determined by measuring the phosphate release from triphosphorylated peptide which corresponds to residues 1135-1156 of the b-subunit of the human insulin receptor (blRK substrate) as described in Nature, 313, 756-761 (1985). Protein tyrosine phosphatase PTPIB activity was determined in a final assay volume of 50 ⁇ L containing 50 mM Tris HC1, 50 mM Tris Base, 150 mM NaCl, 3 mM DTT, 0.1 mg/mL bovine serum albumin (Sigma), 2 nM protein tyrosine phosphatase PTP1B(1-321), and 16 ⁇ M blRK substrate.
  • test compounds in 5 ⁇ L of 10% DMSO were incubated for 5 minutes at room temperature with 20 ⁇ L of protein tyrosine phosphatase PTPIB enzyme in a flat-bottom microtiter plate (Costar).
  • the phosphatase reaction was initiated by the addition of blRK substrate (25 ⁇ L) and proceeded for 10 minutes at room temperature.
  • the reaction was terminated by the addition of 100 ⁇ L of malachite green (Upstate Biotechnology Inc.) containing 0.01% Tween-20.
  • quantitation of free phosphate released from the blRK substrate was determined in a Beckman Biomek Plate Reader by measuring the absorbence of the malachite green at 650 nm.
  • the instant compounds were found to inhibit protein tyrosine phosphatase PTPIB with inhibitory potencies in a range of about of about 3 ⁇ M to about 100 ⁇ M. In a preferred range, the compounds inhibited protein tyrosine phosphatase PTPIB with inhibitory potencies in a range of about of about 29 ⁇ M to about 60 ⁇ M; and in a more preferred range, the compounds inhibited protein tyrosine phosphatase PTPIB with inhibitory potencies in a range of about of about 3 ⁇ M to about 21 ⁇ M.
  • the instant compounds are useful for treating diseases caused by overexpressed or altered protein tyrosine phosphatase PTPIB activity.
  • diseases include autoimmune diseases, acute and chronic inflammatory diseases, osteoporosis, obesity, cancer, malignant diseases, type I and type II diabetes.
  • compounds of formula (1) wherein R is an R precursor such as hydroxy, triflate, bromo, or iodo can be converted to compounds of formula (2) by treatment of the former with coupling partners.
  • the compounds of formula (1) are commercially available or can be prepared by means well-known in the art, such as, for example, deprotonation of the corresponding aryl or heteroaryl group with a base such as lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, n-butyllithium, sec- butyllithium, tert-butyllithium, or lithium diisopropylamide and treatment of the resulting anion with a reagent which introduces the desired functionality.
  • a base such as lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, n-butyllithium, sec- butyllithium, tert-buty
  • treatment of the anion with DMF will introduce a carboxaldehyde group at the first deprotonation site; treatment of the anion with electrophilic halogenating reagents such as bromine, N- bromosuccinimide, iodine, or N-iodosuccinimide will introduce the corresponding halide that site; treatment of the anion with an oxidizing agent such as MoOs-py-HMPA will introduce a hydroxy group at that site; and treatment of the anion with electrophilic nitrogen reagents such as C1NH 2 , (C 6 H 5 ) 2 P(O)NH 2 , Br 2 /NaN 3 , and TsN 3 .
  • electrophilic halogenating reagents such as bromine, N- bromosuccinimide, iodine, or N-iodosuccinimide will introduce the corresponding halide that site
  • treatment of the anion with an oxidizing agent such as MoOs-p
  • 4P carboxaldehyde and R on what will become the proximal ring of the instant compounds can be predetermined by the different acidities of the protons on the aryl or heteroaryl ring starting materials and the strength of the base used for the deprotination. Subsequent deprotonation and derivitization reactions can be accomplished by treatment of the starting material with a second equivalent of base followed by treatment of the anion with the appropriate electrophile.
  • the coupling partners comprise substituted alkenes, optionally substituted arylboronic acids, optionally substituted heteroarylboronic acids, optionally substituted aryl trialkylstannanes, and optionally substituted heteroaryl trialkylstannanes.
  • the reactions are conducted with a base such as cesium fluoride, sodium carbonate, or potassium carbonate and palladium catalysts such as Pd(PPh 3 ) 4 , Pd(PPli 3 ) 2 Cl 2 , or Pd 2 (dba) 3 in solvents such as acetonitrile, THF, DME, DMF, benzene, toluene, or mixtures thereof at temperatures of about 25 °C to about 120 °C.
  • a base such as cesium fluoride, sodium carbonate, or potassium carbonate
  • palladium catalysts such as Pd(PPh 3 ) 4 , Pd(PPli 3 ) 2 Cl 2 , or Pd 2 (dba) 3
  • solvents such as acetonitrile, THF, DME, DMF, benzene, toluene, or mixtures thereof at temperatures of about 25 °C to about 120 °C.
  • the reagents and reaction conditions selected depend on the nature of the coup
  • the coupling partners comprise optionally substituted alkyl halides in the presence of a base such as sodium hydride or potassium hydride at reaction temperatures are about O °C to about 50 °C.
  • the reaction times are typically about 1 to about 18 hours.
  • compounds of formula (2) can be converted to compounds of formula (3) by treatment of the former with amines in the presence of reducing agents.
  • Representative reducing agents include sodium triacetoxyborohydride, sodium borohydride, and sodium cyanoborohydride.
  • the reactions are conducted in solvents such as methanol, ethanol, isopropanol, or mixtures thereof at temperatures of about 0 °C to about 30 °C. Reaction times are typically about 1 to about 24 hours.
  • compounds of formula (4) can be converted to compounds of formula (5) by treatment of the former with base and compounds of formula R -X , wherein X represents a leaving group such as halide, sulfonate, or triflate.
  • Representative bases include sodium hydride, potassium hydride, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and LDA.
  • Solvents used in these reactions include THF, DMF, DMSO, MTBE, diethyl ether, or mixtures thereof.
  • the reaction temperatures are about 0 °C to 30 °C and depend on the method chosen. Reaction times are typically about 1 to about 12 hours.
  • Compounds of formula (6) can be converted to compounds of formula (7) by treatment of the former with reducing agents followed by hydrolysis with aqueous acid.
  • Representative reducing agents include SnCl 2 /HCl lithium aluminum hydride, and DIBAL-H.
  • Representative acids include HCl, HBr, TFA, or mixtures thereof. Examples of solvents used in these reactions include toluene, THF, and hexanes.
  • the reaction temperatures are about - 78 °C to about 0 °C and depend on the method chosen.
  • Representative trialkylphosphines include tributylphosphine and trimethylphosphine; representative triarylphosphines include triphenylphosphine and tri-o-tolylphosphine; and representative diazo compounds include DEAD and DIAD.
  • solvents used in this reaction include THF, MTBE, diethyl ether, benzene, toluene, or mixtures thereof.
  • the reaction temperatures are about 25 °C to about 35 °C. Reaction times are typically about 4 to about 18 hours.
  • the conversion of compounds of formula (10) to compounds of formula (11) can be accomplished by treatment of the former with hydrazine.
  • solvents used in this reaction include ethanol, methanol, water, dioxane, and mixtures thereof.
  • the reaction temperatures are about 60 °C to about 120 °C. Reaction times are typically about 15 mmutes to about 1 hour.
  • compounds of formula (12) can be converted to compounds of formula (I) by treatment of the former with an alkyl oxalyl chloride and base.
  • Representative bases include diisopropylethylamine, triethylamine, and pyridine.
  • solvents include DME, dioxane, and DMF.
  • the reaction temperatures are about -5 °C to about 25 °C, and the reaction times are typically about 30 minutes to about 12 hours.
  • Intraconversion of compounds of formula (I) can be accomplished by hydrolysis with aqueous base followed by treatment with acid.
  • Representative bases include sodium hydroxide, potassium hydroxide, and lithium hydroxide.
  • Examples of acids include hydrochloric acid, sulfuric acid, and nitric acid.
  • the reaction temperatures are about 25 °C to about 100 °C and the reaction times are typically about 1 to about 4 hours.
  • compounds of formula (13) can be converted to compounds of formula (la) by the chemistry described for the conversion of compounds of formula (12) to compounds of formula (I) in Scheme 5.
  • the conversion of the compounds of formula (la) to compounds of formula (I) can be accomplished by the chemistry described for the conversion of compounds of formula (1) to compounds of formula (2) in Scheme 1.
  • Example 1C ethyl ((2-(4-bromophenyl)-2-cyclohexylethyl)amino)-(oxo)acetate
  • the desired product was prepared by substituting Example IB for Example 16B in Example 16C.
  • Example 16C ((2-(4-bromophenyl)-2-cyclohexylethyl)amino)(oxo)acetic acid
  • Example 2 (benzyl(2-(4-bromophenyl)-2-cyclohexylethyl)amino)-(oxo)acetic acid
  • the desired product was prepared by substituting Example 1 A for Example 16A in Examples 16B-16D.
  • Example 3A l-((amino)oxy)(cyclohexyl)methyl)-4-bromobenzene
  • the desired product was prepared by substituting 4-bromobenzaldehyde for 4-(2- quinolinyl)benzaldehyde in the procedure described in Tetrahedron: Asymmetry 1996, 7, 2645.
  • Example 3B (((4-bromophenyl)(cyclohexyl)methoxy)amino)(oxo)acetic acid
  • the desired product was prepared by substituting Example 3 A for 2-(4- ((amino)oxy)(cyclohexyl)methyl)phenyl)-quinoline in Example 4.
  • MS (ESI(-)) m/z 354 (M- H) " ; ! H NMR (300 MHz, DMSO-d 6 ) ⁇ 7.52 (d, 2H), 7.26 (d, 2H), 4.65 (d, IH), 1.98 (m, IH),
  • Example 4A ethyl ((cyclohexyl(3-(2-quinolinyl)phenyl)methoxy)amino)-(oxo)acetate
  • 2-(4-((amino)oxy)(cyclohexyl)methyl)-phenyl)quinoline 119 mg, 0.32 mmol
  • diisopropylethylamine 0.112 mL, 0.64 mmol
  • dichloromethane 2.0 mL
  • ethyl oxalyl chloride 72 ⁇ L, 0.65 mmol
  • Example 4 A A solution of Example 4 A (70 mg, 0.162 mmol) in ethanol (2 mL) at room temperature was treated with 2M NaOH (1 mL), stirred for 2 hours, adjusted to pH 1 with IM HCl, and extracted with ethyl acetate. The extract was dried (Na 2 SO 4 ), filtered, and concentrated to provide the desired product.
  • Example 5C N-benzyl(2,3 -dichloro-4-( 1 -naphthyl)phenyl)methanamine
  • a solution of Example 5B (65 mg, 0.22 mmol) and benzylamine (0.024 mL, 0.22 mmol) in 1,2-dichloroethane (3 mL) at room temperature was treated with acetic acid (0.05 mL, 0.84 mmol), stirred for 2 hours, treated with sodium triacetoxyborohydride (64 mg, 0.31 mmol), stirred for 16 hours, and treated with saturated NaHCO 3 .
  • the organic layer was dried (MgSO 4 ), filtered, and concentrated.
  • the concentrate was purified by flash column chromatography on silica gel with 2:1 hexanes/ethyl acetate to ethyl acetate to provide the ddeessiirreedd pprroodduucctt..
  • MMSS ((EESSII((++)))) mm//zz 339933 ((MM++HH)) ++ ;; 1H1H NNMMRR ((CCDDCC1 3 , 300 MHz) ⁇ 7.92 (d, 2H), 7.56-7.46 (m, 3H), 7.45-7.26 (m, 9H), 4.05 (s, 2H), 3.93 (s, 2H)
  • Example 5C A solution of Example 5C (0.035 mg, 0.089 mmol) and triethylamine (0.042 mL, 0.3 mmol) in dichloromethane (2 mL) at 0 °C was treated dropwise with ethyl oxalyl chloride, warmed to room temperature, stirred for 1 hour, and treated with water. The organic phase was dried (MgSO 4 ), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5:1 hexanes/ethyl acetate to provide the desired product. MS (ESI(+)) 493 (M+H) + .
  • Example 5D The desired product was prepared by substituting Example 5D for Example 16C in Example 16D.
  • Example 6 N-benzyl-2-hydroxy-N-((4, 1 '-binaphth- 1 -yl)methyl)amino)-(oxo)acetic acid
  • the desired product was prepared by substituting 4-hydroxy-l-naphthaldehyde for 2,3-dichloro-4-hydroxybenzaldehyde in Example 5.
  • MS (ESI(+)) m/z 446 (M+H) + ; *H NMR
  • Example 8 (benzyl((4-bromo-5 -( 1 -naphthyl)-2-thienyl)methyl)amino)-(oxo)acetic acid
  • the desired product was prepared by substituting 4,5-dibromo-2- thiophenecarbaldehyde for Example 5 A in Examples 5B-5E.
  • MS (ESI(+)) m/z 481 (M+H) + ; 1H NMR (300 MHz, CDC1 3 ) ⁇ 7.84-7.78 (m, 2H), 7.62 (t, IH), 7.45-7.32 (m, 4H), 7.25-7.05
  • Example 9 (benzyl((5 -(1 -naphthyl)-2-thienyl)methyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting 5-bromo-2-thiophenecarbaldehyde for Example 5A in Examples 5B-5E.
  • MS (ESI(+)) m/z 402 (M+H) + ; *H NMR (300 MHz, CDCI 3 ) ⁇ 8.07 (t, IH), 7.77 (d, IH), 7.69 (d, IH), 7.40-7.00 (m, 9H), 6.87 (dd, IH), 6.78 (dd, IH), 4.55 (d, 2H), 4.40 (s, 2H).
  • the desired product was prepared by substituting 4-(2-quinolinylmethoxy)- benzaldehyde, prepared as described in J Med. Chem. 2000, 43, 690, for Example 5B in Examples 5C-5E.
  • MS (ESI(+)) m/z 427 (M+H) + ; 1H NMR (300 MHz, CDC1 3 ) ⁇ 8.42-8.30 (m, 2H), 7.94-7.78 (m, 3H), 7.66 (dd, IH), 7.40-7.26 (m, 3H), 7.28-7.10 (m, 4H), 6.98 (dd, 2H), 5.52 (s, 2H), 4.65 (d, 2H), 4.46 (d, 2H).
  • Example 11 oxo((2-phenylethyl)(4-(2-quinolinylmethoxy)benzyl)amino)-acetic acid
  • the desired product was prepared by substituting 4-(2- quinolinylmethoxy)benzaldehyde (prepared as described inJ Med. Chem. 2000, 43, 690) and phenylethanamine for Example 5B and benzylamine, respectively, in Examples 5C-5E.
  • Example 12 (cyclohexyl(4-(2-quinolinylmethoxy)benzyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting 4-(2- quinolinylmethoxy)benzaldehyde (prepared according to the procedure described in J. Med. Chem. 2000, 43, 690) and cyclohexylamine for Example 5B and benzylamine, respectively, in Examples 5C-5E.
  • Example 13 (benzyl(2-methoxy-4-(l -naphthyl)benzyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting 4-hydroxy-2-methoxybenzaldehyde for 2,3-dichloro-4-hydroxybenzaldehyde in Example 5.
  • MS (ESI(+)) m/z 426 (M+H) + ;
  • H NMR 300 MHz, DMSO-d 6 ) ⁇ 7.98 (dd, IH), 7.83 (dd, IH), 7.66-7.17 (m, 10H), 7.04 (d,
  • Example 14 ((2-hydroxyethyP)((4, 1 '-binaphth- 1 -yl)methyl)amino)-(oxo)acetic acid
  • the desired product was prepared by substituting 2-aminoethanol and 4-hydroxy-l- naphthaldehyde for benzylamine and 2,3-dichloro-4-hydroxybenzaldehyde in Example 5.
  • the desired product was prepared by substituting 2-(4-morpholinyl)ethanamine for benzylamine in Example 16.
  • Example 1 A A mixture of Example 1 A (3.0 g, 10.8 mmol), 1-naphthylboronic acid (2.04 g, 11.9 mmol), Pd(PPh 3 ) 4 (249 mg, 0.22 mmol), and 3M Na 2 CO 3 (9.0 mL, 27 mmol) in toluene (18 mL) was heated to 100 °C in a sealed tube, stirred for 14 hours, cooled to room temperature, and partitioned between water and diethyl ether. The organic phase was washed with brine, dried (Na 2 SO 4 ), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20:1 to 10:1 hexanes/ethyl acetate to provide the desired product.
  • Example 16A A solution of Example 16A (1.0 g, 3.07 mmol) in toluene at room temperature was treated dropwise with 1.5M DIBAL-H in toluene (2.25 L, 3.41 mmol), stirred for 30 minutes, quenched slowly with 3M HCl, and extracted with diethyl ether. The extract was washed with brine, dried (Na 2 SO 4 ), filtered, and concentrated to provide cyclohexyl(4-(l- naphthyl)phenyl)acetaldehyde.
  • the concentrate was dissolved in 2:1 methanol/THF, treated with benzylamine (0.37 mL, 3.40 mmol), stirred for 4 hours, treated withNaBH 4 (0.12 g, 3.40 mmol), stirred for 1 hour, poured into saturated NaHCO 3 , and extracted with dichloromethane. The extract was washed with brine, dried (Na SO 4 ), filtered, and concentrate to provide the desired product of sufficient purity for subsequent use.
  • Example 16C ethyl (benzyl(2-cyclohexyl-2-(4-( 1 -naphthyl)phenyl)ethyl)-amino)(oxo)acetate
  • a mixture of Example 16B (75.0 mg, 0.18 mmol) and diisopropylamine (100 ⁇ L, 0.36 mmol) in dichloromethane (2 mL) at 0 °C was treated with ethyl oxalyl chloride (36 mL, 0.32 mmol), stirred for 1 hour, treated with water, and extracted with ethyl acetate. The extract was dried (Na SO 4 ), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5:1 hexanes/ethyl acetate to provide the desired product.
  • Example 16D (benzyl(2-cyclohexyl-2-(4-( 1 -naphthy l)phenyl)ethyl)amino)-(oxo)acetic acid
  • Example 16C A solution of Example 16C (50.0 mg, 0.096 mmol) in ethanol (2 mL) at room temperature was treated with 2M NaOH (0.2 mL), stirred for 2 hours, adjusted to pH 1 with IM HCl, and extracted with ethyl acetate. The extract was dried (Na 2 SO 4 ), filtered, and concentrated to provide the desired product.
  • MS (ESI(+)) m/z 492 (M+H) + ; 1H NMR (300 MHz, DMSO-d 6 ) ⁇ 8.04-7.83 (m, 2H), 7.67-7.00 (m, 14H), 4.54-4.33 (m, IH), 3.93-3.62 (m,
  • Example 17 ((2-cyclohexyl-2-(4-( 1 -naphthy l)phenyl)ethyl)(2-phenylethyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting phenylethanamine for benzylamine in Example 16.
  • Example 18 ((2-cyclohexyl-2-(4-(l-naphthyl)phenyl)ethyl)(2-(3,4- dimethoxyphenyl)ethyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting 2-(3,4-dimethoxy- phenyl)ethanamine for benzylamine in Example 16.
  • MS (ESI(+)) m/z 566 (M+H) + ; 1H NMR
  • N-benzyl(2-methoxy-4-( 1 -naphthy l)phenyl)methanamine The desired product was prepared by substituting 4-hydroxy-2-methoxybenzaldehyde for 2,3-dichloro-4-hydroxybenzaldehyde in Examples 5A-5C.
  • Example 20A 2-((benzylamino)methyl)-5-(l-naphthyl)phenol
  • IM BBr 3 in dichloromethane (15.0 mL, 15.0 mmol)
  • the extract was washed with saturated NaHCO 3 and brine, dried (Na 2 SO 4 ), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use.
  • Example 20C ethyl (benzyl(2-hydroxy-4-(l -naphthyl)benzyl)amino)-(oxo)acetate
  • the desired product was prepared by substituting Example 20B for Example 5C in
  • Example 20D ethyl (ber2yl(2-(2-tert-butoxy-2-oxoethoxy)-4-(l-naphmyl)benzyl)amino)(oxo)acetate
  • DMF 5.0 mL
  • Example 21 (2-((benzyl( ' ethoxy(oxo)acetyl)amino)methyl)-5-(l-naphthyl)phenoxy)acetic acid
  • Example 20D 300 mg, 0.54 mmol
  • TFA/dichloromethane 1:1 TFA/dichloromethane
  • Example 2 IB methyl 3-(((2-((benzyl(ethoxy(oxo)acetyl)amino)methyl)-5-(l - naphthyl)phenoxy)acetyl)amino)benzoate
  • ethyl 3-aminobenzoate (20 ⁇ L, 0.13 mmol)
  • HOBT 23 mg, 0.14 mmol
  • EDCI 29 mg, 0.15 mmol
  • Et 3 N 21 ⁇ L, 0.15 mmol
  • the organic phase was washed with brine, dried (Na 2 SO 4 ), filtered, and concentrated.
  • the concentrate was purified by flash column cliromatography on silica gel with 2:5 hexanes/ethyl acetate to provide the desired product.
  • Example 22 (benzyl(2-(2-(((4-(methoxycarbonyl)cyclohexyl)methyl)amino)-2-oxoethoxy)-4-(l- naphthyl)benzyl)ammo)(oxo)acetic acid
  • the desired product was prepared by substituting methyl trans-4- (aminomethyl)cyclohexanecarboxylate for ethyl 3-aminobenzoate in Example 21.
  • MS (ESI(+)) m/z 623 (M+H) + ;
  • Example 23 (benzyl(4-(l-naphthyl)-2-(2-oxo-2-((3-(2-oxo-l- pyrrolidinyl)propyl)amino)ethoxy)benzyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting l-(3-aminopropyl)-2-pyrrolidinone for ethyl 3-aminobenzoate in Example 21.
  • Example 24 5-((2-((benzyl(carboxycarbonyl)amino)methyl)-5-(l-naphthyl)phenoxy)methyl)-2-furoic acid
  • the desired product was prepared by substituting ethyl 5-(chloromethyl)-2-furoate for tert-butyl bromoacetate in Example 20.
  • Example 25A cyclohexyl(4-(2-quinolinylmethoxy)phenyl)methanamine
  • the desired product was prepared by substituting 4-(2- quinolinylmethoxy)benzaldehyde (prepared according to the procedure described in J Med.
  • Example 26 ((2-methoxy-4-( 1 -naphthyl)benzyl)(2 -phenyl ethyl)amino)-(oxo)acetic acid
  • the desired product was prepared by substituting 4-hydroxy-2-methoxybenzaldehyde and phenylethanamine for 2,3-dichloro-4-hydroxybenzaldehyde and benzylamine, respectively, in Example 5.
  • Example 27 ((2,3-dichloro-4-(l-naphthyl)benzyl)(2-phenylethyl)amino)-(oxo)acetic acid
  • the desired product was prepared by substituting phenylethanamine for benzylamine in Example 5.
  • the desired product was prepared by substituting 4-(2- aminoethyl)benzenesulfonamide for benzylamine in Example 16.
  • Example 29 ((2-cyclohexyl-2-(4-(l-naphthyl)phenyl)ethyl)(3-(2-oxo-l- pyrrolidinyl)propyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting 1 -(3-aminopropyl)-2-pyrrolidinone for benzylamine in Example 16.
  • Example 30A 2-((benzylamino)methyl)-5-(l-naphthyl)phenyl trifluoromethanesulfonate
  • the desired product was prepared by substituting Example 20B for 2,3-dichloro-4- hydroxybenzaldehyde in Example 5A.
  • Example 3 OB N-benzyl(5-( 1 -naphthyl)( 1 , 1 '-biphenyl)-2-yl)methanamine
  • the desired product was prepared by substituting Example 30A and phenylboronic acid for Example 5 A and 1 -naphthy lboronic acid in Example 5B.
  • Example 3 PC (benzyl((5-(l-naphthyl)(l,r-biphenyl)-2-yl)methyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting Example 30B for Example 16B in
  • Example 31 (benzyl((4'-formyl-5-( 1 -naphthy 1)( 1 , 1 '-biphenyl)-2-yl)methyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting 4-formylphenylboronic acid for phenylboronic acid in Example 30.
  • MS (DCI/NH 3 ) m/z 500 (M+H) + ; 1H NMR (300 MHz, DMSO-d 6 ) ⁇ 10.03 (d, IH), 8.05-7.84 (m, 3H), 7.63-7.46 (m, 4H), 7.32 (dd, IH), 7.20-7.09
  • Example 32A tert-butyl (2E)-3-(2-((benzylamino)methyl)-5-(l-naphthyl)phenyl)-2-propenoate
  • the desired product was prepared by substituting Example 30A for Example 34A in Example 34B.
  • Example 32B tert-butyl (2E)-3-(2-((benzyl(ethoxy(oxo)-acetyl)amino)methyl)-5-(l-naphthyl)phenyl)-2- propenoate
  • the desired product was prepared by substituting Example 32A for Example 16B in Example 16C.
  • Example 32C (benzyl(2-(( 1 E)-3 -tert-butoxy-3 -oxo- 1 -propenyl)-4-( 1 -naphthy l)benzyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting Example 32B for Example 16C in Example 16D.
  • Example 34A ethyl (benzyl(2-(4-bromophenyl)-2-cyclohexylethyl)amino)-(oxo)acetate
  • the desired product was prepared by substituting Example 1 A for Example 16A in Examples 16B and 16C.
  • Example 34B tert-butyl (2E)-3-(4-(2-(benzyl(ethoxy(oxo)acetyl)amino)-l-cyclohexylethyl)phenyl)-2- propenoate
  • the organic phase was washed with brine, dried (Na 2 SO 4 ), filtered, and concentrated.
  • the concentrate was purified by flash column chromatography on silica gel with 3 : 1 hexanes/ethyl acetate to provide the desired product.
  • Example 34C (benzyl(2-(4-(( 1 E)-3 -tert-butoxy-3 -oxo- 1 -propenyl)phenyl)-2- cyclohexylethyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting Example 34B for Example 20D in Example 20E.
  • Example 35 ((2,3-dichloro-4-(l -naphthy l)benzyl)(2-(l ,3-dioxo-l ,3-dihydro-2H-isoindol-2- yl)ethyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting 2-(2-aminoethyl)-lH-isoindole- l,3(2H)-dione for benzylamine in Example 5.
  • MS (ESI(+)) m/z 548 (M+H) + ; !
  • Example 36A 4-((amino)oxy)(cyclohexyl)methyl)- 1 , 1 '-biphenyl
  • the desired product was prepared by substituting (1,1 '-biphenyl)-4-carbaldehyde for
  • Example 36B (((1,1 '-biphenyl)-4-yl(cyclohexyl)methoxy)amino)(oxo)acetic acid
  • the desired product was prepared by substituting Example 36A for 2-(4-
  • Example 37 (2E)-3-(2-((benzyl(ethoxy(oxo)acetyl)amino)methyl)-5-(l-naphthyl)phenyl)-2-propenoic acid
  • the desired product was prepared by substituting Example 32B for Example 20D in Example 21 A.
  • Example 37B ethyl (benzyl(4-(l-naphthyl)-2-((lE)-3-oxo-3-((3-(2-oxo-l-pyrrolidinyl)propyl)amino)-l- propenyl)benzyl)amino)-(oxo)acetate
  • the desired product was prepared by substituting Example 37A and l-(3- aminopropyl)-2-pyrrolidinone for Example 21 A and ethyl 3-aminobenzoate in Example 2 IB.
  • Example 37C (benzyl(4-( 1 -naphthy l)-2-(( 1 E)-3-oxo-3 -((3-(2-oxo- 1 -pyrrolidinyl)propyl)amino)- 1 - propenyl)benzyl)amino)-(oxo)acetic acid
  • the desired product was prepared by substituting Example 37B for Example 16C in Example 16D.
  • Example 39 (benzyl(2-cy clohexyl-2-(4-(( 1 E)-3 -(4-hydroxy-3 , 5 -diphenylanilino)-3 -oxo- 1 - propenyl)phenyl)ethyl)amino)-(oxo)acetic acid
  • the desired product was prepared by substituting Example 34B and 3,5-diphenyl-4- hydroxyaniline for Example 20D and ethyl 3-aminobenzoate, respectively, in Example 21.
  • Example 40 (benzyl(2-cyclohexyl-2-(4-(3-(4-hydroxy-3,5-diphenylanilino)-3- oxopropyl)phenyl
  • Example 42 (benzyl(2-cyclohexyl-2-(3 '-phenyl( 1 , 1 '-biphenyl)-4-yl)ethyl)amino)(oxo)acetic acid
  • Example 43 (benzyl(2-cyclohexyl-2-(4-dibenzo(b,d)furan-2-ylphenyl)ethyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting dibenzo(b,d)furan-2-yl-boronic acid for 1-naphthylboronic acid in Example 16.
  • MS (ESI(+)) m/z 532 (M+H) + ; !
  • Example 44 (benzyl(2-cyclohexyl-2-(4-(8-quinolinyl)phenyl)ethyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting 8-quinolinylboronic acid for 1- naphthylboronic acid in Example 16.
  • Example 45 (benzyl(2-cyclohexyl-2-(4-(2,3-dihydro-l,4-benzodioxin-6- yl)phenyl)ethyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting 2,3-dihydro-l,4-benzodioxin-6- ylboronic acid for 1-naphthylboronic acid in Example 16.
  • MS (ESI(+)) m/z 500 (M+H) + ; 1H
  • Example 47A ethyl ((2-(4-( 1 -naphthyl)phenyl)-2-(4-piperidinyl)ethyl)(2-phenylethyl)amino)(oxo)acetate
  • the desired product was prepared by substituting Example 41 for Example 20D in Example 21 A.
  • Example 47B ethyU(2-(l-acetyl-4-piperidinyl)-2-(4-(l-naphthyl)phenyl)ethyl)(2- phenylethyl)amino)(oxo)acetate
  • a room temperature solution of Example 47A (50.0 mg, 0.094 mmol) in dichloromethane (2 mL) was treated with triethylamine (26.2 ⁇ L, 0.19 mmol) and acetyl chloride (10.0 ⁇ L, 0.14 mmol), stirred for 1 hour, and concentrated.
  • the concentrate was purified by flash column cliromatography on silica gel with 4: 1 hexanes/ethyl acetate to provide the desired product.
  • Example 47B The desired product was prepared by substituting Example 47B for Example 16C in Example 16D.
  • Example 48 ((2-( 1 -(methylsulfonyl)-4-piperidinyl)-2-(4-( 1 -naphthyl)phenyl)ethyl)(2- phenylethyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting methanesulfonyl chloride for acetyl chloride in Example 47.
  • Example 50 ((2-(4-( 1 -naphthyl)phenyl)-2-( 1 -(phenylsulfonyl)-4-piperidinyl)ethyl)(2- phenylethyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting benzenesulfonyl chloride for acetyl chloride in Example 47.
  • Example 53 ((2-cyclohexyl-2-(4-(l-naphthyl)phenyl)ethyl)(2-((5-nitro-2- pyridinyl)amino)ethyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting N -(6-nitro-2-pyridinyl)-l,2- ethanediamine for benzylamine in Example 16.
  • Example 54 ((2-cyclohexyl-2-(4-( 1 -naphthyl)phenyl)ethyl)(2-( 1 -pyrrolidinyl)ethyl)amino)(oxo)acetic acid
  • Example 56 ((2-cyclohexyl-2-(4-(l-naphthyl)phenyl)ethyl)(2-hydroxy-2-phenylethyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting 2-amino-l-phenylethanol for benzylamine in Example 16.
  • Example 57 ((( 1 S)- 1 -benzyl-2-hydroxyethyl)(2-cyclohexyl-2-(4-( 1 - naphthyl)phenyl)ethyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting (2S)-2-amino-3-phenyl-l -propanol for benzylamine in Example 16.
  • Example 59 (benzyl(2-(4-((lE)-3-((l , 1 '-biphenyl)-4-ylamino)-3-oxo-l -propenyl)phenyl)-2- cyclohexylethyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting (1,1 '-biphenyl)-4-amine for 3 ,5- diphenyl-4-hydroxyaniline in Example 39.
  • Example 60 (benzyl(2-cyclohexyl-2-(4-(( 1 E)-3 -(3 , 5 -ditert-butylanilino)-3 -oxo- 1 - propenyl)phenyl)ethyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting 3,5-ditert-butylaniline for 3,5- diphenyl-4-hydroxyaniline in Example 39.
  • Example 61 (benzyl(2-cyclohexyl-2-(4-(( 1 E)-3 -oxo-3 -(4-phenoxyanilino)- 1 - propenyl)phenyl)ethyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting 4-phenoxyaniline for 3,5-diphenyl-
  • Example 62 (benzyl(2-cyclohexyl-2-(4-(( 1 E)-3 -(4-(2,3 -dimethylphenyl)- 1 -piperazinyl)-3-oxo- 1 - propenyl)phenyl)ethyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting l-(2,3-dimethylphenyl)piperazine for 3,5-diphenyl-4-hydroxyaniline in Example 39.
  • Example 63 ((2-(4-(( 1 E)-3 -(4-benzhydryl- 1 -piperazinyl)-3 -oxo- 1 -propenyl)phenyl)-2- cyclohexylethyl)(benzyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting 1-benzhydrylpiperazine for 3,5- diphenyl-4-hydroxyaniline in Example 39.
  • Example 64 oxo((2-phenylethyl)((4, 1 '-binaphth- 1 -yl)methyl)amino)acetic acid
  • the desired product was prepared by substituting 4-hydroxy-l-naphthaldehyde and phenylethanamine for 2,3-dichloro-4-hydroxybenzaldehyde and benzylamine, respectively, in Example 5.
  • MS (ESI(+)) m/z 460 (M+H) + ;
  • Example 65B (((4-(( 1 ,3 -benzothiazol-2-ylsulfanyl)methyl)phenyl)-(cyclohexyl)methoxy amino)-
  • Example 66A 6-(4-((amino)oxy)(cyclohexyl)methyl)phenyl)-2,3 -dihydro- 1 ,4-benzodioxine
  • the desired product was prepared by substituting Example 3 A and 2,3 -dihydro- 1 ,4- benzodioxin-6-ylboronic acid for Example 1A and 1-naphthylboronic acid, respectively, in Example 16A.
  • Example 66B ((cyclohexyl(4-(2,3 -dihydro- 1 ,4-benzodioxin-6-yl)phenyl)methoxy)amino)(oxo)acetic acid
  • Example 67A 4-(decyloxy)- 1 -naphthaldehyde
  • the desired product was prepared by substituting 4-hydroxy-l -naphthaldehyde and 1- chlorodecane for Example 20C and tert-butyl bromoacetate, respectively, in Example 20D.
  • Example 67B (((4-(decyloxy)- 1 -naphthyl)methyl)(2-phenylethyl)amino)-(oxo)acetic acid
  • the desired product was prepared by substituting Example 67A and phenylethanamine for Example 5B and benzylamine, respectively, in Examples 5C-5E.
  • MS (ESI(+)) m/z 490 (M+H) + ; 1H NMR (300 MHz, CDC1 3 ) ⁇ 8.35 (d, IH), 7.84 (d, IH), 7.60-
  • Example 68 (((4-(octadecyloxy)- 1 -naphthyl)methyl)(2-phenylethyl)amino)-(oxo)acetic acid
  • Example 69A (3-bromophenyl)(cyclohexyl)acetonitrile
  • the desired product was prepared by substituting 3-bromophenylacetonitrile for 4- bromophenylacetonitrile in Example 1 A.
  • Example 69B ((2-(l , 1 '-biphenyl)-3-yl-2-cyclohexylethyl)(2-phenylethyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting Example 69A, phenylboronic acid, and phenylethanamine for Example 1A, 1-naphthylboronic acid, and benzylamine, respectively, in Example 16.
  • H NMR 300 MHz, CDC1 3
  • Example 70 (((4-butoxy- 1 -naphthyl)methyl)(2-phenylethyl)amino)-(oxo)acetic acid
  • Example 71 oxo((2-phenylethyl)((4-(tetradecyloxy)- 1 -naphthyl)methyl)amino)acetic acid
  • the desired product was prepared by substituting 1-bromotetradecane for 1- chlorodecane in Example 67.
  • Example 72 ((2-cyclohexyl-2-(3-(l-naphthyl)phenyl)ethyl)(2-phenylethyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting 1-naphthylboronic acid for phenylboronic acid in Example 69.
  • Example 73 ((2-cyclohexyl-2-(3-(2-naphthyl)phenyl)ethyl)(2-phenylethyl)amino)(oxo)acetic acid
  • the desired product was prepared by substituting 2-naphthylboronic acid for phenylboronic acid in Example 69.
  • MS (APCI(-)) m/z 504 (M-H) " ; 1H NMR (300 MHz, CDC1 3 ) ⁇ 7.99 (br s, IH), 7.93-7.84 (m,

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Abstract

L'invention concerne des composés de formule (I), y compris les sels thérapeutiquement acceptables correspondants, qui sont des inhibiteurs de protéine tyrosine kinase PTP1B. L'invention concerne également l'élaboration des composés considérés, différentes compositions renfermant ce type de composé, et le traitement de maladies par le biais de tels composés.
PCT/US2001/026133 2000-08-29 2001-08-21 Inhibiteurs de proteine tyrosine phosphatase d'acide amino(oxo)acetique WO2002018321A2 (fr)

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Cited By (21)

* Cited by examiner, † Cited by third party
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WO2003064376A1 (fr) * 2002-01-29 2003-08-07 Applied Research Systems Ars Holding N.V. Derives amides substitues methylene en tant que modulateurs de proteine tyrosine phosphatases (ptp)
WO2004009533A1 (fr) * 2002-07-24 2004-01-29 Ptc Therapeutics, Inc. Composes d'acide acetylamino benzoique et leur utilisation pour la suppression de non-sens et le traitement de maladie
WO2004087671A1 (fr) * 2003-03-31 2004-10-14 Warner-Lambert Company Llc Preparation d'hydrochlorure de quinapril
WO2005012280A1 (fr) * 2003-07-21 2005-02-10 Applied Research Systems Ars Holding N.V. Alkynylaryl-carboxamides
US7141596B2 (en) 2003-10-08 2006-11-28 Incyte Corporation Inhibitors of proteins that bind phosphorylated molecules
US7247741B2 (en) 2005-01-21 2007-07-24 Ptc Therapeutics, Inc. Acetylamino benzoic acid compounds and their use for nonsense suppression and the treatment of disease
US7521473B2 (en) 2004-02-25 2009-04-21 Wyeth Inhibitors of protein tyrosine phosphatase 1B
US7601725B2 (en) 2004-07-16 2009-10-13 Sunesis Pharmaceuticals, Inc. Thienopyrimidines useful as Aurora kinase inhibitors
JP2010520240A (ja) * 2007-03-06 2010-06-10 中国科学院上海薬物研究所 プロティンチロシンホスファターゼ１ｂ阻害剤及びその調製方法と用途
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CN104761540A (zh) * 2015-03-12 2015-07-08 佛山市赛维斯医药科技有限公司 一种含烟酸酰胺和哌啶结构的化合物及其用途
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US7592477B2 (en) 2002-01-29 2009-09-22 Laboratoires Serono Sa Substituted methylene amide derivatives as modulators of protein tyrosine phosphatases (PTPs)
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