WO98/34915
`
`PCT/1B98/00101
`
`-3-
`
`(CH),
`
`(CHa)
`
`X
`
`wherein the carbon atom bearing the asterisk is the carbon to which R® and R*are atttached, “n”
`and “m”are independently selected from the integers one and two, and X is CF, O, SO, or NR®,
`wherein R® is hydrogen,
`(C,-Ce)alkyl, (Ce-Ci)aryl, (C2-C,)heteroaryl, (Ce-C,)aryl(C,-C,)alkyl,
`(C2-Cg)heteroaryl(C,-Ce)aikyl,
`(C,-C,)alkylsulfonyl,
`(C.-C,)arylsulfonyl,
`(C,-C,)alkyl(C=O)-,
`(Cy-Ce)alkoxy(C=O)-, (Ce-Cro)aryl(C=O)-, (Ce-Cy)aryloxy(C=O)-, (Cg-Cyo)aryl(C-C,)alkyl(C=O)-
`or
`(C,-C,,)aryl(C,-C,g)alkoxy(C=O)-, wherein each of said (C,-C,,)aryl,
`(C2-Co)heteroary! or
`(C3-Cg)cycloalkyl moieties of
`said (C.-C,g)aryl,
`(C2-Cyg)heteroaryl,
`(Cg-Cy9)aryl(Cy-C,)alkyl,
`(Cz-Cg)heteroaryl(C,-Ce)alkyl,—§(Ce-Ci)aryl(Cg-Cyp)aryl,—(Cg-Cyo)aryi(C™-C jo)aryl(C,-Cg)alkyl,
`
`(C,_-Cy)aryl(C=O)O-(C,-C,)aikyl,
`
`(C,-Ci)aryl(C,-C,)alkyl(C=O)O-(C,-Ce)alkyl,
`
`(C5-C,,)aryl(C,-C,)alkoxy(C=O)0-(C,-Ce)alkyl,
`
`(C,-C, ,)aryloxy(C,-C,)aikyl,
`
`(C.-C, ,)aryl(C,-C,)alkoxy(C,-Ce)alkyl,
`
`(C2-C,)heteroaryl(C,-C,)alkoxy(C,-C,)aikyl,
`
`(C,-C,.)aryl(C=O)NH(C,-Ce)alkyl,
`
`(C,-C,.)aryl(C,-C,)alkyl(C=O)NH(C,-Ce,)alkyl,
`
`(C.-C ,,)aryl(C,-C,)alkoxy(C=O)NH(C,-C,)aikyl,
`
`(C,-C,,)arylsulfonyl,
`
`20
`
`(C.-C,.)aryisulfonyl(C,-Ce)alkyl,
`
`(C.-C,,.)aryl(C=O)-,
`
`(C.-C, )aryl(C,-C,)alkyl(C=O)-,
`
`(C,4-C,))aryl(C,-C,)alkoxy(C=O0)-, (C3-C,)cycloalkyl, or benzo-fused(C3-C,)cycloalkyl ring may be
`
`optionally substituted on any ring atom capable of forming an additional bond by a substituent
`(preferably one to three substituents per ring) independently selected from the group consisting
`of fluoro, chloro, bromo, (C,-C,)alkyl, (C;-C,)alkoxy, perfluoro(C ,-C3)alkyl, perfluoro(C ,-C,)alkoxy
`
`25
`
`and (C.-C, ))aryloxy;
`or when R® and R* are taken together with the carbon atom to which they are attached
`
`to form a group of the formula
`
`(CH2),—(CHa)m
`
`Xx
`
`30
`
`then any of the carbon atoms of said ring, capable of forming an additional bond, may be
`optionally substituted by a substituent (preferably zero to three substituents) independently
`selected from the group corsisting of
`fluoro, chloro, bromo,
`(C,-Ce,)alkyl,
`(C,-Ce)alkoxy,
`perfluoro(C,-C,)alkyl, perfluoro(C,-C,)alkoxy and (C,g-C,)aryloxy;
`
`AQUESTIVE EXHIBIT 1004
`
`AQUESTIVE EXHIBIT 1004 page 1051
`
`page 1051
`
`

`

`WO98/34915
`
`PCT/IB98/00101
`
`-4-
`
`R® is R°O or R°R’N wherein R® and R’ are each independently selected from the group
`consisting of hydrogen,
`(C,-Ce)alkyl,
`(Cg-Cio)aryl(C,-Cg)alkyl or (C2-Cg)heteroaryl(C,-C,)alkyl;
`wherein each of said (Cg-C)ary! and (C,-C,)heteroary! moieties of said (Cg-C,9)aryl(C,-C,)alkyl
`or
`(C,-Cy)heteroaryl(C,-C,)alkyl groups may be optionally substituted by one or more
`substituents independently selected from fluoro, chloro, bromo,
`(C4-Ce)alkyl,
`(C,-C,)alkoxy,
`perfluoro(C,-C3)alkyl, perfluoro(C,-C3)alkoxy and (C.-C, ,)aryloxy;
`or R® and R’ taken together with the nitrogen atom to which they are attached form an
`optionally
`substituted
`heterocycle
`selected
`from piperazinyl,
`(C,-C,)alkylpiperaziny!,
`
`(C,-C,)arylpiperazinyl,
`
`(C2-Cg)heteroarylpiperazinyl,
`
`(Ce-Cy,)aryl(C,-C,)alkylpiperazinyl,
`
`(C2-Cy)heteroaryi(C,-C,)
`
`alkylpiperazinyl,
`
`(C,-C,)alkyl(C=O)-piperazinyl,
`
`(C,-Cg)alkoxy(C=O)-
`
`10
`
`15
`
`piperazinyl,
`
`(C.-C, ,)aryl(C=O)-piperazinyl,
`
`(Ceg-Cip)aryl(C,-C,)alkyl(C=O)-piperazinyl,
`
`20
`
`25
`
`30
`
`35
`
`(C,-C ,p)aryl(C,-Cg)alkoxy(C=O)-piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl or azetidiny!:
`
`wherein
`
`each
`
`of
`
`said
`
`piperazinyl,
`
`(C,-C,)alky!piperazinyl,
`
`(C,-C,,)arylpiperaziny|,
`
`(Cz-Cy)heteroaryi({C,-C,)
`(C.-C p)aryl(C,-Ce)alkylpiperazinyl,
`(C.-C,)heteroaryipiperazinyl,
`alkylpiperazinyl,
`(C,-C,)alkyl{(C=O)-piperazinyi,
`(C,-C,)alkoxy(C=O)-piperazinyl,
`(Cy-C,9)aryl(C=O)-piperazinyl,
`(C.-C,)aryl(C,-C,)alkyl(C=O)-piperazinyi,
`(Cy-C,9)aryl(C,-C,)alkoxy(C=O)-piperaziny!, morpholinyl, piperidinyl, pyrrolidiny! or azetidinyl may
`be optionally substituted on any ring carbon atom capabie of forming an additional bond with a
`substituent (preferably one to three substituents per ring) independently selected from fluoro,
`chloro, bromo, (C,-C,)alkyl, (C,-Cg)alkoxy, perfluoro(C,-C,)alkyl, or perfluoro(C,-Cz)alkoxy and
`
`(Cg-Cyo)aryloxy;
`(C,-C,,)arylpiperazinyl,
`(C,-C,)alkylpiperazinyl,
`piperaziny!,
`is
`R®
`(Co-C,)heteroaryl(C,-Cg)
`(C.-Cg)heteroarylpiperaziny|,
`(C.-C,,)aryl(C,-C,)alkylpiperaziny|,
`alkylpiperaziny|,
`(C4-C,)alkyl(C=O)-piperazinyl,
`(C,-C,)alkoxy(C=0)-piperazinyl,
`(C.-C, ,)aryl(C=O)-piperazinyl,
`(Cg-Cy9)aryl(C,-Cg)alkyl(C=O)-piperazinyl,
`(Cg-Cyo)ary\(C,-Cg)alkoxy(C=O)-piperazinyl, morpholinyl,
`piperidinyl,
`pyrrolidinyl,
`azetidinyl,
`piperidyl,
`(C,-C,)alkylpiperidy!,
`(Cg-C,))arylpiperidyl,
`(C»-Cg)heteroaryipiperidy|,
`(Cg-C,o)aryKC,-Ce)alkylpiperidyl,
`(C,-C,}heteroaryi(C,-C,)alkylpiperidyl,
`(C,-Cg)alkyl(C=O)-
`piperidyl,
`(C,-C,)alkoxy(C=O)-piperidyl,
`(C,-C,,.)aryi(C=0)-piperidyl,
`(Cg-Cyp)aryl(C,-Cg)alkyl(C=O)-piperidyl,
`or
`(Cg-C,9)aryl(C,-C,)alkoxy(C=O)-piperidyl; wherein
`each
`of
`said
`piperazinyl,
`(C,-C,)alkylpiperaziny|,
`(C,-C,,)arylpiperazinyl,
`(C,-C,)heteroarylpiperazinyl,
`(Cg-C,.)aryl(C,-C,)alkylpiperazinyl,
`(C,-C,)heteroaryl(C ,-Cg)
`alkylpiperazinyl,
`(C,-C,)alkyl(C=O)-piperazinyl,
`(C,-C,)alkoxy(C=O0)-piperazinyl,
`(C,-C,,)atyl(C=O)-piperazinyl,
`(C,-C,9)aryl(C,-C,)alky!(C=O)-piperazinyl,
`(Cg-C,p)aryl(C,-C,)alkoxy(C=O)-piperazinyl, morpholinyl,
`piperidinyl,
`pyrrolidinyl,
`azetidinyl,
`
`AQUESTIVE EXHIBIT 1004=page 1052
`
`AQUESTIVE EXHIBIT 1004 page 1052
`
`

`

`WO 98/34915
`
`PCT/1B98/00101
`
`-5-
`
`(C2-Cg)heteroarylpiperidyl,
`(C,-C,)arylpiperidy|,
`(C,-C,)alkylpiperidyl,
`piperidyl,
`(C,-C,)heteroaryl(C,-C,)alkylpiperidy|
`(C,-Ce)alkyl(C=0)-
`(C_-C,,)aryl(C,-C,)alkylpiperidy!,
`piperidyl,
`(C,-C,)alkoxy(C=O)-piperidyl,
`
`(Cg-C19)aryl(C=O)-piperidyl,
`(Cg-Cp)aryl(C;-Ce)aikyl(C=O)-piperidyl, and (Cg-C,p)aryi(C,-C,g)alkoxy(C=O)-piperidyl may be
`optionally substituted on any ring carbon atom capable of forming an additional bond with a
`
`10
`
`substituent (preferably one to three substituents per ring) independently selected from fluoro,
`
`chloro, bromo, (C,-Ce)alky!, (C,-C,)alkoxy, perfiuoro(C,-C,)alkyl, or perfluoro(C,-C3)alkoxy and
`
`(C_-C,o)aryloxy;
`
`Q is (C,-Ce)alkyl, (Ce-Cyo)aryl, (Ce-Cio)aryloxy(Cg-Cyo)aryl, (Ce-Cyo)aryl(Cg-Cyo)aryl, (Ce-
`
`Cyrp)aryl(C™-C jp)aryl(C,-Ce)alkyi,
`
`(C.-C,)aryloxy(C2-Cy)heteroaryl,
`
`(Cz-C,)heteroaryl,
`
`15
`
`C,)heteroaryl(C.-C,)heteroaryl,
`
`(C,-Ce)alkyl(Ce-C jo)aryl,
`
`(C,-Cg)alkoxy(C,-C,9)aryl,
`
`Cyp)aryl(C,-Ce)alkoxy(Ce-C,o)aryl,
`
`(Co-Cyp)aryl(C y-Ce)alkoxy(C,-Ce)alkyl,
`
` (Cz-
`
`(Ce-
`
`(C2-
`
`Cy)heteroaryloxy(C,-Ci,)aryl, (C.-C,)alkyl(C2-C,)heteroaryl, (C,-C,)alkoxy(Cz-Cg)heteroaryl,
`
`(Ce™-
`
`20
`
`(Ce-
`(C,-C,)heteroaryloxy(C2-Cy)heteroaryl,
`Cig)aryl(C,-C,)aikoxy(C2-C,)heteroaryl,
`Cig)arytoxy(C,-C,)alkyl,
`(C,-Cyg)heteroaryloxy(C,-C,)alkyl,
`(C,-Cg)alkyl(C,-Cy,)aryloxy(Ce-
`Cio)aryl,
`(C,-C,)alkyl(Cz-Cg)heteroaryloxy(C,-C,,)aryl,
`(C,-C,)alkyi(C,-C,,)aryloxy(C2-
`C,)heteroaryl,
`(C,-Ce)alkoxy(C,g-C,o)aryloxy(Cg-Cio)aryl,
`(C,-C,)alkoxy(C2-Ce)heteroaryloxy(C.-
`Cig)aryl or (Cy-C,)alkoxy(C,-C,o)aryloxy(C2-C,)heteroary! wherein each (Cg-Cyo)ary! or
`(C2-
`C,)heteroary! moieties of said (Ce-Cyo)aryl, (Ce-Cyo)aryloxy(Ce-Cyo)aryl, (Ce-Cro)aryl(C™e-Cio)aryl,
`(Cg-C,9)aryl(Ce-C,,)aryl(C,-Ce)alkyl,
`(C™-Cyo)aryloxy(C2-C,)heteroaryl,
`(C.-Cy)heteroaryl,
`(C,-
`
`Ca)alkyl(Cg-Cyp)aryl, (Cy-Cg)alkoxy(Cg-Cio)aryl,—(Cg-Crp)ary'(Cy-Ce)alkoxy(Ce-Cyo)aryl,9(Cer
`25
`Cip)aryl(C,-Ce)alkoxy(C,-Ce)alky!,
`(C>-Cy)heteroaryloxy(C,-C i)aryl,
`(C,-Ce)alky(C2-
`C,)heteroaryl,
`(C,-Cg)alkoxy(C.-Cy)heteroaryl,
`(C,4-Cig)aryl(C,-C,)alkoxy(C2-Ce)heteroary!,
`(C2-
`C,)heteroaryloxy(C2-C,)heteroaryl, (Ce-Cyo)aryloxy(C,-Cg)alkyl, (C,-C,)heteroaryloxy(C,-C,)alkyl,
`(C,-C,)alkyl(C,-C,,)aryloxy(C™-Ci)aryl,
`(C,-C,)aikyl(C,-Cy)heteroaryloxy(C,-Cyo)aryl,
`(Cy-
`C,)alkyl(C5-Cy9)aryloxy(C2-Cg)heteroaryl,
`(C,-C,)alkoxy(Cg-C,p)aryloxy(C,-C,)aryl,
`(C,-
`C,)alkoxy(C2-Cy)heteroaryloxy(Cg-Cyo)ary! or
`(C,-C,)alkoxy(C,-C ;9)aryloxy(C-C)heteroaryl
`is
`optionally substituted on any of the ring carbon atoms capable of forming an additional bond by
`one or more substituents (preferably one to three substituents) independently selected from
`fluoro, chloro, bromo, (C,-Ce)alky!, (C,-C,)alkoxy, perfluoro(C,-C3)alkyl, perfluoro(C,-Cz)alkoxy
`
`30
`
`35
`
`and (C,-C,,)aryloxy;
`with the proviso thatif either R° or R* is hydrogen, orif both R® and R" are hydrogen,
`then R' and R? can not both be hydrogen or R' must be hydroxy,
`(C,-C,)alkoxy,
`(Cg-Cy9)aryl(C,-C,)alkoxy,
`(C,-Cg)alkyl(C=O)O-(C,-Ce)alkyl,
`(C,-C,)alkoxy(C=O)O-(C,-C,)alkyl,
`
`AQUESTIVE EXHIBIT 1004=page 1053
`
`AQUESTIVE EXHIBIT 1004 page 1053
`
`

`

`WO 98/34915
`
`PCT/3B98/00101
`
`(C.-C, ,)aryl(C=O)O-(C,-Ce)alkyl,
`
`(Ce-Cip)aryloxy(C=O)O-
`
`(C,-Cyg)arylalkyl(C=O)O-(C,-C,)alkyl
`
`or (C6-C,,)arylalkoxy(C=O)O-(C,-Ce)alkyl:
`
`or a pharmaceutically acceptable salt thereof.
`
`The presentinvention also relates to the pharmaceutically acceptable acid addition salts
`
`of compounds of the formula |. The acids which are used to prepare the pharmaceutically
`
`10
`
`acceptable acid addition salts of the aforementioned base compounds of this invention are those
`
`which form non-toxic acid addition salts, ie., salts containing pharmacologically acceptable
`
`anions,
`
`such as the hydrochloride, hydrobromide, hydroiodide, nitrate,
`
`sulfate, bisulfate,
`
`phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate,
`
`maleate,
`
`fumarate, gluconate,
`
`saccharate, benzoate, methanesuifonate, ethanesulfonate,
`
`15
`
`benzenesulfonate, p-toluenesulfonate
`
`and pamoate
`
`[ie.,
`
`1,1'-methylene-bis-(2-hydroxy-3-
`
`naphthoate)]salts.
`
`The invention also relates to base addition salts of formula |. The chemical bases that
`
`20
`
`those
`may be used as reagents to prepare pharmaceutically acceptable base salts of
`compoundsof formula | that are acidic in nature are those that form non-toxic base salts with
`such compounds. Such non-toxic base salts include, but are notlimited to those derived from
`such pharmacologically accepiable cations such as alkali metal cations (e.g., potassium and
`sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-
`soluble amine addition salts such as N-methyiglucamine-(meglumine), trimethyl-ammonium or
`
`
`diethylammonium, alkanolammonium_salts such_tris-(hydroxymethyl)-and the flower
`
`
`
`methylammonium and other base salts of pharmaceutically acceptable organic amines.
`The term “alkyl", as used herein, unless otherwise indicated,
`includes saturated
`monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations
`thereof.
`
`The term "alkoxy", as used herein, includes O-alkyi groups wherein "alkyl" is defined
`
`30
`
`above.
`
`The term "aryl", as used herein, unless otherwise indicated, includes an organic radical
`derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyi.
`The term "heteroaryl", as used herein, unless otherwise indicated, includes an organic
`radical derived from an aromatic heterocyclic compound by removal of one hydrogen, such as
`pyridyl,
`furyl, pyroy!,
`thienyl,
`isothiazoly!,
`imidazolyl, benzimidazolyl,
`tetrazolyl, pyrazinyl,
`pyrimidyl, quinolyl,
`isoquinoly:, benzofuryl,
`isobenzofury!, benzothieny!, pyrazolyl,
`indoiyl,
`isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazoly!, oxazolyl, benzthiazoly! or benzoxazolyl.
`
`35
`
`AQUESTIVE EXHIBIT 1004=page 1054
`
`AQUESTIVE EXHIBIT 1004 page 1054
`
`

`

`WO 98/34915
`
`PCT/1B98/00101
`
`-7-
`
`general formula RCO whereinRis alkyl, alkoxy, aryl, arylalkyl or arylalkoxy and the terms "alkyl"
`
`The term "acyl", as used herein, unless otherwise indicated, includes a radical of the
`
`or “aryl" are as defined above.
`
`The term "acyloxy", as used herein,
`
`includes O-acyl groups wherein “acyl” is defined
`
`above.
`
`10
`
`The compound of formula | may have chiral centers and therefore exist in different
`
`diasteriomeric or enantiomeric forms.
`
`This invention relates to all optical
`
`isomers and
`
`stereoisomers of the compoundsof formula I and mixtures thereof.
`Preferred compoundsof formulaI include those wherein R' is OH and R? is hydrogen.
`Other preferred compounds of formula !
`include those wherein both R® and R* are
`(C,-Cg)alky! or R® and R’‘ are taken together to form an optionally substituted (C3-C,)cycloalky|
`ring or a benzo-fused(C3-C,)cycloalkyl ring or a group of the formula
`
`15
`
`(CHa),
`
`(CHa)
`
`X
`wherein the carbon atom bearing the asterisk is the carbon to which R® and R* are
`atttached,
`“n” and “m” are independently selected from the integers one and two, and X is CFz,
`O, SO, or NR°, wherein R® is hydrogen,
`(Cy-Ce)alkyl,
`(Ce-Cyo)aryl,
`(C2-Co)heteroalkyl, (Ce
`C,)aryl(C,-C,)alkyl,
`(C-Cg)heteroaryl(C,-Cg)alky!,
`(C,-Cg)alkylsulfonyl,
`(C,_-C,9)ary!sulfonyl,
`(C,-C,)alky(C=O)-, (C1-Cg)alkoxy(C=0)-, (Ce-Cyo)aryl(C=O)-, (Cg-Cio)aryl(C,-Ce)alkyl(C=O)-, or
`(Cg-Cip)aryl(C,-Cg)alkoxy(C=O)-; wherein each of said (C,-C,)aryl and (C,-C)heteroary|
`moieties of said (C,_-C,)aryl, (C2-C,)heteroalkyl, (Cg-C,p)aryl(C;-C,)alky!, (C2-C,)heteroaryi(C,-
`Cejalky!,
` (Cg-Cio)arylsulfonyl!,
`(Cg-Cip)ary\(C=O)-,
`(C_-Ci)aryl(C,-C,)alky(C=O)-,
`and
`(Cg-C)aryl(C,-C,)alkoxy(C=O)- groups may be optionally independently substituted with one or
`more substituents (preferably one to three substituents) independently selected from the group
`consisting
`of
`fluoro,
`chloro,
`bromo,
`(C,-C,)alky!,
`(C,-C,)alkoxy,
`perfluoro(C,-C,)alkyl,
`perfluoro(C,-C3)alkoxy and (C.-C, ,)aryloxy.
`More preferred compounds of formula | include those wherein R° and R* are taken
`together to form an optionally substituted (C,-C,)cycioalkyl ring.
`Other preferred compoundsof formula| include those wherein R' is hydroxy.
`Other preferred compoundsofformula ! include those wherein Q is (Cg-Cyo)aryl or (Ce-
`Cyp)aryloxy(C,-C,o)aryl, wherein each (C,-C,,)aryl moieties of said is (C.-Cyo)aryl or
`(Cep-
`C,,)aryloxy(C,-C,,)aryl groups may be optionally substituted with one or more substituents
`
`20
`
`25
`
`30
`
`35
`
`AQUESTIVE EXHIBIT 1004=page 1055
`
`AQUESTIVE EXHIBIT 1004 page 1055
`
`

`

`WO 98/34915
`
`PCT/1B98/00101
`
`independently selected from fluoro, chloro, bromo, (C,-C,)alkyl, (C,-Cg)alkoxy or perfluoro(C,-
`C3)aikyl.
`
`include those wherein @ is phenyl or
`formula I
`More preferred compounds of
`phenoxypheny! optionally substituted with one or more substituents independently selected from
`
`fluoro, chloro, bromo, (C,-Ce,)alkyl, (C,-Cg)alkoxy or perfluoro(C,-C,)alkyl, more preferably the
`
`10
`
`substituents are selected from fluoro, chloro, (C,-Cg)alkoxy or (C,-C,)alkyl, most preferably the
`
`substituentis in the 4-position.
`
`Specific preferred compounds of formula | include the following:
`
`(2S)-2,N-dihydroxy-3-(4-methoxybenzenesulfony!l)propionamide,
`
`3-[4-(4-fluorophenoxy)phenyisulfony!]-2,N-dihydroxypropionamide,
`
`15
`
`2,N-dihydroxy-2-[1-(4-methoxy benzenesulfonyl)cyclobutyljacetamide.
`
`20
`
`2,N-dihydroxy-2-[1-(4-methoxybenzenesulfonyl)cyclopenty ljacetamide,
`
`2-[1-(4-cyclobutoxybenzenesulfony|)cyclobuty!]-2,N-dihydroxyacetamide,
`
`2-[1-(4-butoxybenzenesulfonyl)cyclobutyl]-2,N-dihydroxyacetamide,
`
`2-{1-[4-(4-fluorophenoxy )benzenesulfony I|cyclobuty!}-2,N-dihydroxyacetamide, or
`2-{1-[4-(4-fluorophenoxy)benzenesulfony||cyciopenty|}-2,N-dihydroxyacetamide.
`Other specific compoundsof formula | include the following:
`2,N-dihydroxy-2-[1-(4-phenoxybenzenesulfonyl)cyciopentyljacetamide,
`2,N-dihydroxy-2-[1-(4-phenoxybenzenesulfonyl)cyclobutyllacetamide,
`acetic
`acid
`{1-[4-(4-fluorophenoxy)benzenesulfonyl]cyclopentyl}hydroxycarbamoy!
`
`25
`
`methyl ester,
`acetic
`
`acid
`
`{1-[4-(4-fluorophenoxy)benzenesulfonyl]cyclobutyl}hydroxycarbamoy|
`
`methyl ester,
`2-{1 -[4-(4-fluorophenoxy)benzenesuifonyl]cyclopentyl}-N-hydroxy-2-methoxy-
`
`30
`
`35
`
`acetamide,
`2-{1 -[4-(4-fluorophenoxy)benzenesulfonyljcyclobuty|}-N-hydroxy-2-
`methoxyacetamide,
`2-[1 -(4-butoxybenzenesulfonyl)cyclohexy!]-2,N-dihydroxyacetamide,
`2-(1 -(4-butoxybenzenesulfonyl)cyclopenty!]-2,N-dihydroxyacetamide, or
`2-[1-(4-butoxybenzenesulfony!)cyclobutyl]-2,N-dihydroxyacetamide.
`The presentinvention also relates to a pharmaceutical composition for (a) the treatment
`of a condition selected from the group consisting ofarthritis, osteoporosis, cancer, synergy with
`cytotoxic anticancer agents,
`tissue ulceration, macular degeneration, restenosis, periodontal
`disease, epidermolysis bullosa, scleritis,
`in combination with standard NSAID'S and analgesics
`and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic
`
`AQUESTIVE EXHIBIT 1004=page 1056
`
`AQUESTIVE EXHIBIT 1004 page 1056
`
`

`

`WO 98/34915
`
`PCT/1B98/00101
`
`-9-
`
`shock and other diseases involving the production of tumor necrosis factor (TNF) or (b) the
`inhibition of matrix metalloproteinases or the production of tumor necrosis factor (TNF) in a
`mammal,
`including a human, comprising an amount of a compound of formula f or a
`pharmaceutically acceptable salt thereof effective in such treatments and a pharmaceutically
`acceptable carrier.
`
`10
`
`(a) matrix
`the inhibition of
`invention also relates to a method for
`The present
`metalloproteinasesor (b) the production of tumor necrosis factor (TNF) in a mammal, including a
`human, comprising administering to said mammal an effective amount of a compound of formula
`
`tor a pharmaceutically acceptable salt thereof.
`
`The present invention also relates to a method for treating a condition selected from the
`
`15
`
`group consisting of arthritis, osteoporosis, cancer,
`
`tissue ulceration, macular degeneration,
`
`restenosis, periodontal disease, epidermolysis bullosa, scleritis, compounds of formula | may be
`
`used in combination with standard NSAID'S and analgesics and in combination with cytotoxic
`
`anticancer agents, and other diseases characterized by matrix metalloproteinase activity, AIDS,
`
`sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF)
`
`20
`
`in a mammal,
`
`including a human, comprising administering to said mammal an amount of a
`
`compound of formula f or a pharmaceutically acceptable salt thereof effective in treating such a
`
`condition.
`
`AQUESTIVE EXHIBIT 1004=page 1057
`
`AQUESTIVE EXHIBIT 1004 page 1057
`
`

`

`WO 98/34915
`
`.
`
`PCT/IB98/00101
`
`-10-
`
`Detailed Description of the Invention
`
`The following reaction Schemes illustrate the preparation of the compounds of the
`present invention. Unless otherwiseindicated n, m, R', R?, R°, R*, R®, R®, R”, R®, Q and X in the
`reaction Schemes and the discussion that follow are defined as above.
`
`AQUESTIVE EXHIBIT 1004=page 1058
`
`AQUESTIVE EXHIBIT 1004 page 1058
`
`

`

`WO98/34915
`
`PCT/1B98/00101
`
`-11-
`
`SCHEME1
`
`O
`
`R?
`
`CO,CH.Ph
`
`Vi
`
`O R2
`
`ae)
`
`Wl
`
`|
`
`
`
`°
`
`PhCH,O—N
`
`O R2
`
`R1
`
`©
`;, °
`O
`
`O R
`
`RI
`
`Vv
`
`OR
`
`Ri
`
`Oo
`do
`O
`
`IV
`
`Oo R
`
`rr HO—N
`Hy ‘R
`
`R*
`
`SO,-Q
`
`AQUESTIVE EXHIBIT 1004=page 1059
`
`AQUESTIVE EXHIBIT 1004 page 1059
`
`

`

`WO 98/34915
`
`PCT/1B98/00101
`
`-12-
`
`SCHEME2
`
`
`
`R3
`
`R4
`
`»—x
`XIV
`
`ys S—aQ
`Xi
`
`R3
`
`RA
`
`R3
`
`R4
`
`/>
`
`Rs
`
`O
`
`I
`
`—
`
`.
`
`
`
`HO
`
`R4 O
`
`xl
`
`n
`
`O x
`
`S—aQ
`|
`
`l
`
`Oo
`
`ro
`
`i
`
`RS
`
`1]
`F_ 8
`e
`Rt ©
`
`Ix
`
`|
`
`R3
`
`O
`l
`I
`R4 O
`
`\
`
`/j
`
`Oo
`
`P
`
`Q
`
`
`
`ne
`
`x
`
`BnO —N
`
`Oo
`HO
`
`Rs
`
`4
`
`R
`Vu
`
`9
`Ss—a
`I
`
`.
`
`—_
`
`BnoO —N
`H
`
`O
`
`po
`
`i
`R3
`S—aQ
`|
`R# ©
`vil
`
`AQUESTIVE EXHIBIT 1004
`
`AQUESTIVE EXHIBIT 1004 page 1060
`
`page 1060
`
`

`

`WO 98/34915
`
`PCT/IB98/00101
`
`-13-
`
`SCHEME 3
`
`\
`
`/
`
`Oo
`
`HO
`
`Rs
`
`O
`i
`i Q
`Ro O
`x!
`
`oN
`
`f\ RF
`oO
`i Q
`
`Rt
`
`R4 O
`
`HO- .
`
`R'
`
`RS
`
`° a
`:— Q
`™ oN
`
`R4 O
`
`BnO —N
`
`O
`
`R'
`
`XV
`
`R3
`
`9
`i Q
`
`pe O
`XVII
`
`O RF
`
`ps
`
`pore0.9R'
`
`R2
`
`AQUESTIVE EXHIBIT 1004
`
`AQUESTIVE EXHIBIT 1004 page 1061
`
`page 1061
`
`

`

`WO 98/34915
`
`PCT/1B98/00101
`
`-14-
`
`SCHEME 4
`
`OT
`
`XXI
`
`o R
`
`R4
`
`P'O
`
`HO
`
`R2
`
`so,—Q
`
`R4
`
`oO, —-Q
`
`XXIl
`
`3
`
`Qo Rp,
`
`XXIV
`
`P'O
`
`So,—Q
`
`1
`
`R2
`
`Qo
`
`RS
`
`BnONH HO
`
`XXIill
`
`R4
`So,
`
`—
`
`Q
`
`Oo R:
`
`HO
`
`R4
`SO,—Q
`
`XXV
`
`
`
`BnONH
`
`R4
`
`XXVI
`so,——Q
`
`AQUESTIVE EXHIBIT 1004
`
`AQUESTIVE EXHIBIT 1004 page 1062
`
`page 1062
`
`

`

`WO 98/34915
`
`PCT/1B98/00101
`
`-15-
`
`Scheme 1 refers to the preparation of compoundsof the formula f, wherein R3 and R4
`
`are hydrogen. Referring to Scheme !, a compound of the formula {i
`
`is prepared from a
`
`compound of the formula I! by hydrogenolysis under an atmosphere of hydrogen in the
`
`presence of a catalyst in a reaction inert solvent. Suitable catalysts include 5% palladium on
`
`barium sulfate or 5% palladium on carbon, preferably 5% palladium on barium sulfate.
`
`10
`
`Suitable solvents include an aicohol such as ethanol, methanoi or isopropanol, preferably
`
`methanol. The aforesaid reaction may be performed at a pressure from about 1 to about 5
`
`atmospheres, preferably about 3 atmospheres.
`
`Suitable temperatures for the aforesaid
`
`reaction range from about 20°C (room temperature) to about 60°C, preferably the temperature
`
`may range from about 20°C to about 25°C (i.e. room temperature). The reaction is complete
`within about 0.5 hours to about 5 hours, preferably about 3 hours.
`
`15
`
`The compound of formula {I
`
`is prepared from a compound of formula II! by reaction
`
`with O-benzyihydroxylamine hydrochtoride, an activating agent, and a basein a reaction inert
`solvent.
`Suitable
`activating
`agents
`include
`(benzotriazol-1-yloxy)tris(dimethylamino)
`
`20
`
`25
`
`4 -(3-(dimethylaminopropyl)-3-ethyicarbodiimide
`phosphonium hexafiuorophosphate—or
`(benzotriazol-1-yloxy)tris(dimethylamino)
`phosphonium
`hydrochloride,
`preferably
`hexafluorophosphate.
`Suitable bases include tertiary amines
`such as triethylamine,
`diisopropylethylamine
`or 4-N,N-dimethylaminopyridine,
`preferably
`triethylamine.
`The
`temperature of the aforesaid reaction may range from about 0°C to about 60°C, preferably
`about 20°C (room temperature). Suitable solvents include halogenated solvents such as
`methylene chloride or chloroform, or ethers such as THF or diethyl ether, preferably the
`solvent is methylene chloride. The reaction is complete in about 4 hours to about 48 hours,
`preferably about 16 hours.
`is prepared from a compound of formula IV by
`The compound of formula Il!
`hydrogenolysis under an atmosphere of hydrogen in the presence of a catalyst in a reaction
`inert solvent. Suitable catalysts include palladium or 5-10% pailadium on activated charcoal,
`preferably 10% palladium on activated charcoal.
`Suitable solvents include acetic acid,
`alcohols such as ethanol, methanol, or isopropanol, preferably ethanol.
`The aforesaid
`reaction may be performed at a pressure from about 1
`to about 5 atmospheres, preferably
`about 3 atmospheres. Suitable temperatures for the aforesaid reaction range from about 20°C
`(room temperature) to about 60°C,preferably the temperature may range from about 20°C to
`about 25°C (i.e. room temperature). The reaction is complete within about 0.5 hours to about
`24 hours, preferably about 3 hours.
`Compoundsof the formula !V can be prepared from compoundsof the formula V by
`reaction with an oxidant
`in a reaction inert solvent.
`Suitable oxidants include meta-
`
`30
`
`35
`
`AQUESTIVE EXHIBIT 1004=page 1063
`
`AQUESTIVE EXHIBIT 1004 page 1063
`
`

`

`WO 98/34915
`
`PCT/IB98/00101
`
`-16-
`
`preferably meta-
`sodium perborate,
`or
`peroxide
`hydrogen
`acid,
`chloroperbenzoic
`chloroperbenzoic acid. Suitable solvents include halogenated solvents such as methylene
`chloride or chloroform, preferably methylene chloride. Suitable temperatures for the aforesaid
`reaction range from about 0°C to about 60°C, preferably the temperature may range from
`about 20°C to about 25°C (i.e. room temperature). The reaction is complete within about 0.5
`hours to about 24 hours, preferably about 3 hours.
`is hydroxy, can be prepared from
`Compounds of
`the formula V, wherein R'
`compounds of the formula VI by reaction with a Grignard reagent and a thiol of the formula
`
`QSH in a reaction inert solvent. Suitable Grignard reagents include ethyl magnesium bromide
`
`or phenyl magnesium bromide, preferably ethyl magnesium bromide.
`
`Suitable solvents
`
`10
`
`15
`
`include ethers such as diethy' ether, tetrahydrofuran or 1,2-dimethoxyethane, preferably the
`
`20
`
`25
`
`30
`
`35
`
`solvent
`
`is a mixture of tetrahydrofuran and diethyl ether.
`
`Suitable temperatures for the
`
`aforesaid reaction are from about -78°C to about 50°C , preferably from about 0°C to about
`
`25°C (i.e.
`
`room temperature). The reaction is complete in about
`
`1
`
`to about 24 hours,
`
`preferably about 3 hours.
`is (C.-C,g)aryi(C,-C,)alkoxy or (C,-C,)alkoxy,
`Compoundsof the formula V, wherein R'
`can be prepared from compoundsof the formula V, wherein R'
`is hydroxy, by reaction with a
`compoundof the formula R"@L, wherein L is a leaving group and R"is (Cg-C,)aryi(C,-C,)alky!
`or (C,-C,)alkyl,
`in the presence of a strong base in an aprotic polar solvent. Suitable leaving
`groupsinclude chloro, fluoro, bromo, mesylate,triflate or tosylate. Preferably, the leaving group
`is iodo. Suitable bases include sodium hydride,
`lithium dialkyl amides such aslithium N-
`isopropyl-N-cyclohexylamide or
`lithium diisopropy! amide, potassium t-butoxide,
`sodium
`amide, or potassium hydride, preferably sodium hydride. Suitable solvents include ethers
`(such as THF,diethyl ether or 1,2-dimethoxyethane), preferably THF. The aforesaid reaction
`is conducted at about -78°C to about 0°C, preferably at about 0°C.
`(C,-Ce)alkoxy-
`Compounds of the formula V, wherein R'
`is
`(C,-Cg)alky(C=O)O-,
`(C=O)O-,
`(Ce-Cyp)ary(C=O)O-,
`(Ce-Ci)aryloxy(C=O)O-,
`(C,-Cy)aryl(C,-Ce)alkyi(C=O)O- or
`(Cg-Ci9)aryl(C,-C,)alkoxy(C=O)O-, can be prepared from compounds of the formula V, wherein
`R'
`is hydroxy, by reaction with a compound of the formula R"L, wherein L is a leaving group
`and R" is (C,-C,)alkyl(C=O)-, (C,-Cg)alkoxy(C=O0)-, (Ce-C,o)aryl(C=0)-, (Cg-Cy)aryloxy(C=0)-,
`(Cg-C,p)aryl(C,-Cg)alkyl(C=O)}- or (Cg-C4)aryl(C ,-Cg)alkoxy(C=0)-, in the presence of a basein
`a reaction inert solvent. Suitable leaving groups include chloro, fluoro, bromo, or RO (i.e. an
`anhydride). Preferably, the leaving group is chloro. Suitable bases include tertiary amine
`bases such astriethylamine, pyridine or 4-dimethylaminopyridine, preferably triethylamine.
`The temperature of the aforesaid reaction is from about 0°C to about 30°C, preferably from
`
`AQUESTIVE EXHIBIT 1004
`
`AQUESTIVE EXHIBIT 1004 page 1064
`
`page 1064
`
`

`

`WO 98/34915
`
`PCT/1B98/00101
`
`-17-
`
`about 20°C to about 25°C (i.e. room temperature). Suitable solvents include halogenated
`
`solvents such as methylene chloride or chloroform, preferably methylene chloride. The
`
`reaction is conducted from about 1 hour to about 24 hours, preferably for about 2 hours.
`Compounds of the formula VI can be prepared by methods well known to those of
`
`ordinary skill in the art. Compounds of the formula VI can also be prepared by peracid oxidation
`
`10
`
`(e.g., meta-chloroperbenzoic acid) of the corresponding o,f-unsaturated benzyl esters as
`
`15
`
`20
`
`25
`
`30
`
`35
`
`described in Jerry March, Advanced Organic Chemistry, 735 (3rd ed., 1985). The corresponding
`
`a,B-unsaturated benzyl esters may be prepared by Knovenagel condensation between a
`
`malonate monobenzyl ester and paraformaldehyde in the presenceof piperidine as described in
`
`H.O. House, Modern Synthetic Reactions, 649-651 (2nd ed., W.A. Benjamin, Menlo Park,
`
`California, 1972).
`Compoundsof the formula VI, wherein R? is hydrogen, can also be prepared in racemic
`or enantiomerically pure form by conversion of L-, D-, or D,L-serine as reported by W. Roush
`
`and B. Brown, J. Org. Chem., 47, 3387 (1992).
`Scheme 2 refers to the preparation of compounds of the formula |, wherein R? is
`hydrogen and R' is OH. Referring to Scheme 2, compoundsof formula | can be prepared from
`compounds of the formula Vil by hydrogenolysis under an atmosphere of hydrogen in the
`presenceof a catalyst in a reaction inert solvent. Suitable catalysts include 5% palladium on
`barium sulfate or 5% palladium on carbon, preferably 5% palladium on barium sulfate.
`Suitable solvents include an alcohol such as ethanol, methanol or isopropanol, preferably
`methano!. The aforesaid reaction may be performed at a pressure from about 1 to about 5
`atmospheres, preferably about 3 atmospheres.
`Suitable temperatures for the aforesaid
`reaction range from about 20°C (room temperature) to about 60°C, preferably the temperature
`may range from about 20°C to about 25°C (i.e. room temperature). The reaction is complete
`within about 0.5 hours to about 5 hours, preferably about 3 hours.
`Compoundsof the formula VII can be prepared from compoundsof the formula VIII by
`reaction with an alkali metal hydroxide in a polar solvent. Suitable alkali metal hydroxides
`include lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably lithium
`hydroxide, most preferably about 5 equivalents of the alkali metal hydroxide. The aforesaid
`reaction may conducted at a temperature from about 0°C to about 60°C, preferably from about
`20°C to about 25°C (i.e. room temperature). Suitable solvents include a mixture of water and
`an alcohol such as methanol or ethanol and, optionally an water miscible ether such as
`tetrahydrofuran
`or
`1,2-dimethoxyethane.
`Preferably,
`the
`solvent
`system is
`methanol/water/tetrahydrofuran. The reaction is conducted from about 1
`to about 72 hours,
`
`preferably about 24 hours.
`
`AQUESTIVE EXHIBIT 1004=page 1065
`
`AQUESTIVE EXHIBIT 1004 page 1065
`
`

`

`WO 98/34915
`
`PCT/1B98/00101
`
`-18-
`
`The compound of formula VIil
`
`is prepared from a compound of the formula IX by
`
`reaction with O-benzylhydroxylamine hydrochloride in the presence of a catalyst and a base in
`
`a
`
`reaction
`
`inert
`
`solvent.
`
`Suitable
`
`catalysts
`
`include
`
`(benzotriazol-1-
`
`yloxy)tris(dimethylamino)phosphonium hexafluorophosphate or 1-(3-(dimethylaminopropy|)-3-
`ethylicarbodiimide
`hydrochloride,
`preferably
`(benzotriazol-1-yloxy)tris(dimethylamino)
`Suitable bases include tertiary amines
`such as
`phosphonium hexafiuorophosphate.
`triethylamine. diisopropylethylamine or dimethyiaminopyridine, preferably triethylamine. The
`aforesaid reaction temperature is from about 0° C to about 60°C, preferably from about 20° C
`to about 25°C (i.e. room temperature). Suitable solvents include halogenated solvents such
`as methylene chloride or cnloroform, preferably methylene chloride.
`The reaction is
`conducted from about 4 hours to about 48 hours, preferably about 16 hours.
`The compound of formula IX is prepared from a compound of the formula X by reaction
`with an excess of sodium periodate in the presence of catalytic ruthenium trichloride hydrate.
`The aforesaid reaction is conducted at a temperature from about 0°C to about 35°C,
`preferably from about 20°C to about 25°C (i.e. room temperature). Suitable solvents include
`acetone or a mixture of acetonitrile, carbon tetrachloride and water, preferably a 1:1:2 mixture
`of acetonitile, carbon tetrachloride and water. The reaction is conducted from about 0.5 to
`about 2 hours, preferably about 1.25 hours.
`The compound of the formula X, wherein “P” is pivaloyl, acetyl or benzoyl, is prepared
`by reaction of a compoundofthe formula XI with a protecting group reagentin the presence of a
`base in a reaction inert solvent. Suitable protecting group reagents include pivaloyl chloride,
`pivatoic anhydride, acety! chloride, acetic anhydride, benzoyl cloride or benzoic anhydride,
`preferably acetic anhydride. Suitable bases include tertiary amine bases such as pyridine or
`4-N,N-dimethylaminopyridine, preferably 4-N, N-dimethylaminopyridine. The temperature of
`the aforesaid reaction is from about 0°C to about 30°C, preferably from about 20°C to about
`25°C (i.e.
`room temperature).
`Suitable solvents include halogenated solvents such as
`methylene chloride or chioroform, preferably methylene chloride. The reaction is conducted
`from about 1 hour to about 24 hours, preferably for about 2 hours.
`The compoundof formula XI is prepared from a compoundof the formula XII by reaction
`with 2-furaldehyde and a strong base in a polar aprotic solvent. Suitable bases include
`potassium-tert.-butoxide,
`lithium diisopropylamide, and butyl
`lithium, preferably 2.5 M n-
`butyllithium in hexane. The temperature of the aforesaid reaction is from about -78°C to about
`0°C, preferably about -78°C. Suitable solvents include diethy! ether, tetrahydrofuran, or 1,2-
`dimethoxyethane, preferably the solvent is tetrahydrofuran. The reaction is conducted from
`about 0.25 hours to about 6 hours, preferably about 0.33 hours.
`
`15
`
`20
`
`25
`
`30
`
`35
`
`AQUESTIVE EXHIBIT 1004
`
`AQUESTIVE EXHIBIT 1004 page 1066
`
`page 1066
`
`

`

`WO 98/34915
`
`PCT/1TB98/00101
`
`-19-
`
`is prepared from a compound of the formula XIll by
`The compound of formula XII
`reaction with an oxidant
`in a reaction inert solvent.
`Suitable oxidants include meta-
`
`preferably meta-
`sodium perborate,
`or
`peroxide
`hydrogen
`acid,
`chloroperbenzoic
`chloroperbenzoic acid. Suitable solvents include halogenated solvents such as methylene
`chloride or chloroform, preferably methylene chloride. Suitable temperatures for the aforesaid
`
`10
`
`reaction range from about O°C to about 60°C, preferably the temperature may range from
`
`about 20°C to about 25°C (i.e. room temperature). The reaction is complete within about 0.5
`
`hours to about 24 hours, preferably abou