WO 98/34915
`
`PCT/IB98/00101
`
`(CH2)n
`
`(CH2)m
`
`\/
`
`10
`
`15
`
`20
`
`wherein the carbon atom bearing the asterisk is the carbon to which R3 and R4 are atttached, “n"
`
`and “m" are independently selected from the integers one and two, and X is CF2, O, 802 or NR9,
`wherein R9 is hydrogen,
`(C1-Ce)alkyl,
`(Cs—C1o)aryl,
`(CZ-C9)heteroaryl,
`(C5-C10)aryl(C1—C5)alkyl,
`
`(C2-C9)heteroaryl(C1—C6)alkyl,
`
`(C1-C5)alkylsultony|,
`
`(Ce-C1o)arylsulfonyl,
`
`(C1-Ce)alkyl(C=O)-,
`
`(Ci-Cs)alk0XY(C=O)-, (Ce-Cm)ary|(C=0)-. (Ce-Clo)ary|0Xy(C=O)-. (Ce-Clo)ary|(C1-Ce)a|ky|(C=O)-
`
`or
`
`(Ce-C1o)aryl(C1-Ce)alkoxy(C=O)-; wherein each of said (C5-C10)aryl,
`
`(C2-C9)heteroaryl or
`
`(Ca-Ce)cycloalkyl moieties of
`
`said (Ce-C10)aryl,
`
`(CZ-C9)heteroaryl,
`
`(C6-C1O)aryl(C1—C6)alkyl,
`
`(C2-C9)heteroaryl(C1-C6)alkyl,
`
`(Cs‘C1o)aryl(Ce'C1o)a’-YL
`
`(Ce—C10)aryl(ce'c1o)aryl(C1‘Ce)alkyly
`
`(C5—C1o)aryl(C=O)O~(C1—C5)alkyl.
`
`(C6-C10)aryl(C1—C6)alkyl(C=O)O—(C1-C6)alkyl,
`
`(Ce-C1o)aryl(C1—C5)alkoxy(C=O)O—(C1-Ce)alky|,
`
`(CG-C1o)aryloxy(C1—C6)alkyl,
`
`(Ce—Cm)aryl(C1—C6)alkoxy(C1-Ce)alkyl.
`
`(C2—C9)heteroaryl(C1—C5)alkoxy(C1—C6)alkyl,
`
`(Ce-C1o)aryl(C=O)NH(C1—Cs)alkyl.
`
`(Ce-C1o)aryl(C1—C6)alkyl(C=O)NH(C1-C6)alky|.
`
`(CG—C10)aryl(C1-Cs)alkoxy(C=O)NH(C1-C6)alkyl,
`
`(Ce-C1o)arylsulfony|.
`
`(Ce-C1o)arylsulfonyl(C1—Cs)alkyl,
`
`(C5—C,o)aryl(C=O)-,
`
`(C6—C1o)aryl(C1—Ce)alkyl(C=O)-.
`
`(C6—C1o)aryl(C1-Ce)alkoxy(C=O)-, (Cs-C6)cycloalkyl, or benzo-fused(C3-C6)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, (C1-Ce)alkyl, (C1-Ce)alkoxy, perfluoro(C1-Ca)alkyl, perfluoro(C1-Cs)alkoxy
`
`25
`
`and (C6—C1o)aryloxy;
`
`or when R3 and R4 are taken together with the carbon atom to which they are attached
`
`to form a group of the formula
`
`/’\
`(CH2)n
`(CH2)m
`\X/
`
`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 consisting of
`
`fluoro, chloro, bromo,
`
`(C1-C6)alkyl,
`
`(C1-Ce)alkoxy.
`
`perfluoro(C1-Ca)a|kyl, perfluoro(C1-C3)aikoxy and (Ce-C10)aryloxy;
`
`AQUESTIVE EXHIBIT 1004
`
`AQUESTIVE EXHIBIT 1004 page 1051
`
`page 1051
`
`

`

`WO 98/34915
`
`PCT/IB98/00101
`
`R5 is R50 or R6R7N wherein R6 and R7 are each independently selected from the group
`
`consisting of hydrogen,
`
`(C1—Ce)alky|,
`
`(C6—C1o)aryl(C1—Cs)alkyl or (CZ-Cg)heteroaryl(C1-Ce)alkyl;
`
`wherein each of said (Cs—C1o)aryl and (CZ-Cg)heteroaryl moieties of said (Ce—C1o)aryl(C1—Cs)alkyl
`
`or
`
`(CZ-Cg)heteroaryl(C1-Cs)alky| groups may be optionally substituted by one or more
`
`substituents independently selected from fluoro, chloro, bromo,
`
`(C1—Ce)alkyl,
`
`(C1-C6)alkoxy,
`
`perfluoro(C1—C3)alkyl, perfluoro(C1-C3)alkoxy and (C6—C1o)aryloxy;
`
`or R6 and R7 taken together with the nitrogen atom to which they are attached form an
`
`optionally
`
`substituted
`
`heterocycle
`
`selected
`
`from piperazinyl,
`
`(C1-Ce)alkylpiperazinyl,
`
`(Ce-C,o)arylpiperazinyl,
`
`(Cg—C9)heteroarylpiperazinyl.
`
`(CG-C1o)aryl(C1-C6)alky|piperazinyl,
`
`(CZ—Cg)heteroaryl(C1-CB)
`
`alkylpiperazinyl,
`
`(C1-Ce)alkyI(C=O)—piperazinyl,
`
`(C1-Ce)alkoxy(C=O)-
`
`piperazinyl,
`
`(C6-C1o)aryl(C=O)~piperazinyl,
`
`(C6-C1O)aryl(C1-C6)alkyl(C=O)-piperazinyI,
`
`(CG—C1o)aryl(C1—Ce)alkoxy(C=O)-piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl or azetidinyl;
`
`wherein
`
`each
`
`of
`
`said
`
`piperazinyl,
`
`(C1-Ca)alkylpiperazinyl,
`
`(C6-C1o)arylpiperazinyl,
`
`10
`
`15
`
`(CZ-Cg)heteroarylpiperazinyl,
`
`(Ce—C1o)aryl(C1—Ce)alkylpiperazinyl,
`
`(CZ—Cg)heteroaryl(C1-C5)
`
`alkylpiperazinyl,
`
`(C1-Ce)alkyl(C=O)-piperazinyl,
`
`(C1-C6)alkoxy(C=O)—piperazinyl,
`
`20
`
`(Ce-C1o)aryl(C=O)—piperazinyl,
`
`(CS-C1o)aryl(C1-Ce)alkyl(C=O)—piperazinyl,
`
`(Ce-C1o)aryl(C1—C6)alkoxy(C=O)-piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl or azetidinyl may
`
`be optionally substituted on any ring carbon atom capable of forming an additional bond with a
`
`substituent (preferably one to three substituents per ring) independently selected from fluoro.
`
`chloro, bromo,
`
`(C1—Ce)alkyl, (C1-C6)alkoxy, perfluoro(C1-C3)alkyl, or perfluoro(C1-Ca)alkoxy and
`
`25
`
`(Cs-Cio)ary|oxy;
`
`R8
`
`is
`
`piperazinyl,
`
`(C1-Ce)alkylpiperazinyl,
`
`(Ce—C1o)arylpiperazinyl,
`
`(Cz-CQ)heteroarylpiperazinyl,
`
`(Ce-C1o)aryl(C1-Ce)alkylpiperazinyl,
`
`(CZ—Cg)heteroaryl(C1-C6)
`
`alkylpiperazinyl,
`
`(C1—Ce)alkyl(C=O)-piperazinyl,
`
`(C1—Ce)alkoxy(C=O)—piperazinyl,
`
`(Ce—C10)aryl(C=O)-piperazinyl,
`
`(CG-C1o)ary|(C1—C6)alkyl(C=O)-piperazinyl.
`
`30
`
`35
`
`azetidinyl,
`pyrrolidinyl,
`piperidinyl,
`(CG-C10)aryl(C1-Ce)alkoxy(C=O)—piperazinyl, morpholinyl,
`piperidyl,
`(C1—C5)alkylpiperidyl,
`(Ce-C1o)arylpiperidyl,
`(Oz—Cg)heteroarylpiperidyl,
`(Ce-C1o)aryI(C1—Cs)alkylpiperidyl,
`(CZ-Cg)heteroaryl(c1—Ce)alkylpiperidyl,
`(C1-C6)alkyl(C=O)—
`piperidyl.
`(C1—Cs)a|koxy(C=O)-piperidyl,
`(C6-C1o)aryl(C=O)-piperidyl.
`(CG—C10)aryl(C1-Ce)alkyl(C=O)-piperidyl,
`or
`(C6—C1o)aryl(C1-CB)alkoxy(C=O)-piperidyl; wherein
`each
`of
`said
`piperazinyl,
`(C1—Ce)alkylpiperazinyl,
`(C6-C1o)arylpiperazinyl,
`
`(C2—C9)heteroaryl(C1-C6)
`(CG—C10)ary|(C1-Ce)alkylpiperazinyl,
`(CZ-Cg)heteroarylpiperazinyl.
`alkylpiperazinyl,
`(C1-C6)alkyl(C=O)-piperazinyl,
`(C1—Ce)alkoxy(C=O)—piperazinyl,
`(Ca-C10)aryI(C=O)—piperazinyl,
`(CG—C10)aryl(C1-Ce)alkyl(C=O)—piperazinyl,
`(Cs—Cm)aryl(C1-Ce)alkoxy(C=O)—piperazinyl, morpholinyl,
`piperidinyl,
`pyrrolidinyl,
`azetidinyl,
`
`AQUESTIVE EXHIBIT 1004
`
`AQUESTIVE EXHIBIT 1004 page 1052
`
`page 1052
`
`

`

`WO 98/34915
`
`PCT/IB98/00101
`
`-5-
`
`piperidyl,
`
`(C1—Cs)alkylpiperidyl,
`
`(C6-C10)arylpiperidyl,
`
`(C2-CQ)heteroarylpiperidyl,
`
`(Ce-C10)aryl(C1-Ce)alkylpiperidyi,
`
`(C2-Cg)heteroaryl(C1-C6)alkylpiperidy|
`
`(C1-Cs)alkyl(C=O)-
`
`piperidyl,
`
`(C1-C6)alkoxy(C=O)-piperidyl,
`
`(C6-Cm)aryl(C=O)—piperidyl,
`
`(Ce-C1o)aryl(C1—Ce)alky|(C=O)—piperidyl, and (C6—C10)aryl(C1-Ce)alkoxy(C=O)—piperidyl may be
`
`optionally substituted on any ring carbon atom capable of forming an additional bond with a
`
`substituent (preferably one to three substituents per ring) independently selected from fluoro,
`
`chloro, bromo, (C1-Ce)alky|, (C1-Ce)alkoxy, perfluoro(C1-Cg)alky|, or perfluoro(C1-Ca)alkoxy and
`
`(Ce—C1o)ary|°XY§
`
`Q is (C1'Ce)a|kyly (CG'C10)arylv (CS'C10)aWIOXY(Cs‘C1o)aryl- (Ce'C1o)aW|(Ce'C1o)aryls (CG'
`
`C1o)aryl(Ce-C1o)aryl(C1-Ce)alkyl,
`
`(Ce-C1o)aryloxy(C2-Cg)heteroaryl,
`
`(CZ-C9)heteroaryl,
`
`Cg)heteroaryl(Cz—C9)heteroaryl,
`
`(C1-C6)alkyl(CS-C1o)aryl,
`
`(C1-C6)a|koxy(Cs—C1o)aryil
`
`C1o)aryl(C1—Ce)alkoxy(Ce-C1o)aryl,
`
`(Cs-C1o)aryl(C1-Ce)a|koxy(C1-Cs)alkyl,
`
`(Cz-
`
`(Ce-
`
`(02‘
`
`Cg)heteroaryloxy(Cs—C,o)aryI. (C1—Ce)alkyl(C2-Cg)heteroaryl, (C1-Ce)alkoxy(Cz-C9)heteroaryl, (Cs-
`
`C1o)aryl(C1—Ce)alkoxy(Cz-Cg)heteroaryl,
`
`(Cg-Cg)heteroaryloxy(Cz-CQ)heteroaryl.
`
`(C6-
`
`C1o)aryloxy(C1-Ce)alkyl,
`
`(CZ-Cg)heteroaryloxy(C1-Ce)alkyl,
`
`(C1—CG)alkyl(CG-C1o)aryloxy(Cs—
`
`C10)aryl.
`
`(C1-Cs)alkyl(CZ-Cg)heteroaryloxy(C6~C1o)aryl,
`
`(C1—Ce)alkyl(C5-C1o)aryloxy(Cz-
`
`C9)heteroaryl,
`
`(C1-Ce)alkoxy(C5-C1O)aryloxy(Ce-C10)aryl,
`
`(C1~Ce)alkoxy(Cz-Cg)heteroaryloxy(Ce-
`
`C1o)aryl or (C1—C6)alkoxy(Cs-C1o)aryloxy(Cz—C9)heteroaryl wherein each (Cs-C1o)aryl or
`
`(CZ—
`
`Cg)heteroaryl moieties of said (C6—C10)aryl, (C6~C1o)aryloxy(Ce-C10)aryl. (Cs-C10)aryl(C6—C1o)aryl,
`
`10
`
`15
`
`20
`
`(Cs-C10)aryl(Ce-C10)aryl(C1-Ce)alkyl,
`
`(Ce-C1o)aryloxy(C2-C9)heteroaryl,
`
`(CZ-C9)heteroaryl,
`
`(C1~
`
`25
`
`Ce)alky|(Cs-Cm)ary|.
`
`(Ci-Ce)alkoxy(Cs-Cio)ary|,
`
`(Cs-Cm)ary!(Ci-Ce)alkoxy(Ce-Cio)aryi,
`
`(Ce-
`
`C10)aryl(C1—Ce)alkoxy(C1-Ce)alkyl,
`
`(Cg-C9)heteroaryloxy(Ce—C1o)aryl,
`
`(C1—Ce)alkyl(Cz-
`
`C9)heteroaryl,
`
`(C1—Ce)alkoxy(C2-Cg)heteroaryI,
`
`(Ce—C1o)aryl(C1—Ce)alkoxy(C2—C9)heteroaryl,
`
`(C2-
`
`C9)heteroaryloxy(Cz-Cg)heteroaryl. (CG—Cw)aryloxy(C1-Ce)alkyl, (Cg—Cg)heteroaryloxy(C1-C6)alkyl,
`
`(C1-Cs)alkyl(Ce-Cm)aryloxy(C5-C1o)aryl,
`
`(C1-Ce)alkyl(CZ-Cs)heteroaryloxy(Ce-C1o)aryl.
`
`30
`
`C5)alkyl(CG-C1o)aryloxy(Cz—Cg)heteroaryl,
`
`(C1—05)alkoxy(CG-C10)aryloxy(Ce-C1o)ary|,
`
`(C1-
`
`(C1-
`
`Ce)alkoxy(CZ-C9)heteroaryloxy(C6-C1o)aryl or
`
`(C1—Ce)alkoxy(Ce-C1o)aryloxy(Cz—C9)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,
`
`(C1—Cs)alkyl, (C1-Ce)alkoxy. perfluoro(C1—Ca)alkyl, perfluoro(C1—Ca)alkoxy
`
`35
`
`and (CG-C1o)aryloxy;
`with the proviso that if either R3 or R4 is hydrogen, or if both R3 and R4 are hydrogen,
`then R1 and R2 can not both be hydrogen or R1 must be hydroxy,
`(C1-Cs)alkoxy,
`
`(C6—C1o)aryl(C1-Cs)alkoxy,
`
`(C1-C6)alkyl(C=O)O—(C1—C5)alkyl,
`
`(C1-C6)alkoxy(C=O)O-(C1-Ce)a|kyl,
`
`AQUESTIVE EXHIBIT 1004
`
`AQUESTIVE EXHIBIT 1004 page 1053
`
`page 1053
`
`

`

`WO 98/34915
`
`PCT/IB98/00101
`
`(C6-C,o)aryl(C=O)O-(C1-Cs)all<yl,
`
`(Ce-C10)aryloxy(C=O)O— (C5-C,o)arylalkyl(C=O)O—(C1—C6)alkyl
`
`or (C6-C1o)arylalkoxy(C=O)O-(C,~Ce)alkyl;
`
`or a pharmaceutically acceptable salt thereof.
`
`The present invention also relates to the pharmaceutically acceptable acid addition salts
`
`of compounds of the formula I. 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,
`
`i._e,, salts containing pharmacologically acceptable
`
`anions,
`
`such as the hydrochloride, hydrobromide, hydroiodide, nitrate,
`
`sulfate, bisuifate,
`
`phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate,
`
`maleate,
`
`fumarate, gluconate,
`
`saccharate, benzoate, methanesulfonate, ethanesulfonate,
`
`15
`
`benzenesulfonate,
`
`p—toluenesulfonate
`
`and pamoate Hi,
`
`1,1‘—methylene—bis-(Z-hydroxy-3—
`
`naphthoate)]salts.
`
`The invention also relates to base addition salts of formula I. The chemical bases that
`
`may be used as reagents to prepare pharmaceutically acceptable base salts of
`
`those
`
`compounds of formula I that are acidic in nature are those that form non-toxic base salts with
`
`20
`
`such compounds. Such non—toxic base salts include, but are not limited to those derived from
`
`such pharmacologically acceptable cations such as alkali metal cations (egg potassium and
`
`sodium) and alkaline earth metal cations (fl, calcium and magnesium), ammonium or water—
`
`soluble amine addition salts such as N-methylglucamine-(meglumine), trimethyl-ammonium or
`
`diethylammonium,
`
`and
`
`the
`
`lower
`
`alkanolammonium salts
`
`such
`
`tris-(hydroxymethyl)-
`
`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-alkyl 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
`
`35
`
`tetrazolyl, pyrazinyl,
`imidazolyl, benzimidazolyl,
`isothiazolyl,
`thienyl,
`furyl, pyroyl,
`pyridyl,
`isobenzofuryl, benzothienyl, pyrazolyl,
`indolyl,
`pyrimidyl, quinolyl,
`isoquinoly., benzofuryl,
`isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl or benzoxazolyl.
`
`AQUESTIVE EXHIBIT 1004
`
`AQUESTIVE EXHIBIT 1004 page 1054
`
`page 1054
`
`

`

`WO 98/34915
`
`PCT/H398/00101
`
`The term "acyl", as used herein, unless otherwise indicated. includes a radical of the
`
`general formula RCO wherein R is alkyl, alkoxy, aryl, arylalkyl or arylalkoxy and the terms "alkyl"
`
`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 I may have chiral centers and therefore exist in different
`
`diasteriomeric or enantiomeric forms.
`
`This invention relates to all optical
`
`isomers and
`
`stereoisomers of the compounds of formula I and mixtures thereof.
`
`Preferred compounds of formula I include those wherein R1 is OH and R2 is hydrogen.
`
`Other preferred compounds of formula I
`
`include those wherein both R3 and R‘4 are
`
`15
`
`(C1-Ce)alkyl or R3 and R4 are taken together to form an optionally substituted (C3-Ce)cycloalkyl
`
`ring or a benzo-fused(C3—Ce)cycloalkyl ring or a group of the formula
`/\
`(CH2)n
`(CH2)m
`\X/
`
`20
`
`25
`
`wherein the carbon atom bearing the asterisk is the carbon to which R3 and R4 are
`
`atttached,
`
`“n" and "m” are independently selected from the integers one and two, and X is CF2,
`
`(Ce-
`(CZ-C9)heteroalkyl.
`(Ce-C1o)aryl,
`(C1-C6)alkyl,
`O, 802 or NR9, wherein R9 is hydrogen,
`C1o)aryl(C1—Cs)alkyl,
`(C2—Cg)heteroaryl(C1-Cs)alkyl,
`(C1-C6)alkylsulfonyl,
`(C5-C1o)arylsulfonyl,
`(C‘-C6)alkyl(C=O)-, (C1-C6)alkoxy(C=O)-,
`(Ce-C1o)aryl(C=O)—, (C6-C1o)aryl(C1-Ce)alkyl(C=O)-, or
`(Ca—C1o)aryl(C1—Cs)alkoxy(C=O)-; wherein each of said (CB-C1o)aryl and (CZ—Cg)heteroaryl
`moieties of said (Ce-C1o)aryl,
`(CZ—C9)heteroalkyl,
`(Ce—C10)aryl(C1—Cs)alkyl,
`(CZ—Cs)heteroaryl(C1—
`Cg)alkyl,
`(Os-C1O)arylsulfonyl,
`(C6-C1o)aryl(C=O)—,
`(Ce—C1o)aryl(C1—Cs)alkyl(C=O)-,
`and
`(C5-C1o)aryl(C1-C6)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,
`(C1-Ce)alkyl,
`(C1-Cs)alkoxy_
`perfluoro(C1—Cg)alkyl.
`
`perfluoro(C1-C3)alkoxy and (Ce-C10)aryloxy.
`More preferred compounds of formula I include those wherein R3 and R4 are taken
`
`30
`
`together to form an optionally substituted (Ca-Cs)cycloalkyl ring.
`Other preferred compounds of formula I include those wherein R1 is hydroxy.
`Other preferred compounds of formula I include those wherein Q is (C6—C1o)aryl or (Cs—
`C1o)aryloxy(CG-C1o)aryl, wherein each (Ce-Cw)aryl moieties of said is (Cs-C1o)aryl or
`(CB-
`C1o)aryloxy(Cs-C1o)aryl groups may be optionally substituted with one or more substituents
`
`35
`
`AQUESTIVE EXHIBIT 1004
`
`AQUESTIVE EXHIBIT 1004 page 1055
`
`page 1055
`
`

`

`WO 98/34915
`
`PCT/IB98/00101
`
`5
`
`independently selected from fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy or perfluoro(C1-
`
`Ca)alkyl.
`
`More preferred compounds of
`
`formula I
`
`include those wherein Q is phenyl or
`
`phenoxyphenyl optionally substituted with one or more substituents independently selected from
`
`fluoro, chioro, bromo, (C1-C5)alky|, (C1-Ce)alkoxy or perfluoro(C1—C3)alkyl, more preferably the
`
`10
`
`substituents are selected from fluoro, chloro, (C1—Ce)alkoxy or (C1—Cs)alkyi, most preferably the
`
`substituent is in the 4-position.
`
`Specific preferred compounds of formula I include the following:
`
`(28)—2,N—dihydroxy-3-(4-methoxybenzenesulfonyl)propionamide,
`
`3-[4-(4—fluorophenoxy)phenylsulfonyl]-2,N-dihydroxypropionamide,
`
`1 5
`
`2,N-dihydroxy—2—[1-(4-methoxybenzenesuifonyl)cyclobutyl}acetamide.
`
`2,N-dihydroxy—2-[1-(4-methoxybenzenesulfonyl)cyclopentyi]acetamide,
`
`2-[1-(4-cyclobutoxybenzenesulfonyl)cyclobutyl]-2,N-dihydroxyacetamide,
`
`2-[1-(4—butoxybenzenesulfonyl)cyclobutyl]—2,N-dihydroxyacetamide,
`
`2—{1—[4-(4-fluorophenoxy)benzenesulfonyI]cyclobutyl}-2,N-dihydroxyacetamide, or
`
`20
`
`2—{1-[4-(4-fluorophenoxy)benzenesulfony|]cyclopentyl}-2,N-dihydroxyacetamide.
`
`Other specific compounds of formula I include the following:
`
`2,N-dihydroxy-2—[1—(4—phenoxybenzenesulfonyI)cyclopenty|]acetamide,
`
`2,N-dihydroxy-2-[1-(4-phenoxybenzenesulfonyl)cyclobutyl]acetamide,
`
`acetic
`
`acid
`
`{1-[4-(4-fluorophenoxy)benzenesulfonyI]cyclopentyl}hydroxycarbamoyl
`
`25
`
`methyl ester,
`
`acetic
`
`acid
`
`{1-[4-(4-fluorophencxy)benzenesulfonyl]cyclobutyl}hydroxycarbamoyl
`
`methyl ester,
`
`2-{1-[4-(4—fluorophenoxy)benzenesuifonyl]cyclopentyI}-N—hydroxy—2—methoxy-
`
`acetamide,
`
`30
`
`2-{1-[4-(4-fluorophenoxy)benzenesulfonyl]cyclobutyl}-N-hydroxy-2-
`
`methoxyacetamide,
`
`2-[1-(4-butoxybenzenesulfonyl)cyclohexyl]-2,N-dihydroxyacetamide,
`
`2-[1-(4—butoxybenzenesulfonyl)cyclopentyl]—2,N-dihydroxyacetamide, or
`
`35
`
`2-[1—(4-butoxybenzenesulfonyi)cyclobutyl]-2,N-dihydroxyacetamide.
`The present invention also relates to a pharmaceutical composition for (a) the treatment
`of a condition selected from the group consisting of arthritis, osteoporosis, cancer, synergy with
`
`tissue ulceration, macuiar degeneration, restenosis, periodontal
`cytotoxic anticancer agents,
`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
`
`AQUESTIVE EXHIBIT 1004 page 1056
`
`page 1056
`
`

`

`WO 98/34915
`
`PCT/I398/00101
`
`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 I or a
`
`pharmaceutically acceptable salt thereof effective in such treatments and a pharmaceutically
`
`acceptable carrier.
`
`The present
`
`invention also relates to a method for
`
`the inhibition of
`
`(a) matrix
`
`metalloproteinases or (b) the production of tumor necrosis factor (TN F) in a mammal, including a
`
`human, comprising administering to said mammal an effective amount of a compound of formula
`
`l or a pharmaceutically acceptable salt thereof.
`
`The present invention also relates to a method for treating a condition selected from the
`
`group consisting of arthritis, osteoporosis, cancer,
`
`tissue ulceration, macular degeneration,
`
`restenosis, periodontal disease, epidermolysis bullosa, scleritis, compounds of formula I may be
`
`used in combination with standard NSAlD‘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)
`
`in a mammal,
`
`including a human, comprising administering to said mammal an amount of a
`
`compound of formula I or a pharmaceutically acceptable salt thereof effective in treating such a
`
`condition.
`
`10
`
`15
`
`20
`
`AQUESTIVE EXHIBIT 1004
`
`AQUESTIVE EXHIBIT 1004 page 1057
`
`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 otherwise indicated n, m, R‘, R2, R3, R4, R5, R6, R7, R8, Q and X in the
`reaction Schemes and the discussion that follow are defined as above.
`
`AQUESTIVE EXHIBIT 1004
`
`AQUESTIVE EXHIBIT 1004 page 1058
`
`page 1058
`
`

`

`WO 98/34915
`
`PCT/I898/00101
`
`-11-
`
`5mg;
`
`0'
`
`R2
`
`COZCHZPh
`
`VI
`
`o R2
`
`
`
`5’
`
`R1
`
`O
`
`III
`
`l
`
`0 R2
`
`R1
`
`1
`
`V
`
`0 R2
`
`0
`S” Q
`
`R1
`
`0
`
`'V
`
`5)
`0 R2
`PhCHZO—‘u/ufiA/IS O
`
`
`
`0
`
`R3
`
`WWHo—N
`H
`R1
`R2
`
`802-0
`
`AQUESTIVE EXHIBIT 1004
`
`AQUESTIVE EXHIBIT 1004 page 1059
`
`page 1059
`
`

`

`WO 98/34915
`
`PCT/1398/00 101
`
`-12-
`
`SCHEME2
`
`
`
`R3
`
`>——X
`XIV
`
`R4
`
`R3
`
`>— S— Q
`XIII
`
`R4
`
`\
`
`/
`
`O
`
`HO
`
`R3
`
`(I)!
`8—— 0
`II
`R4 O
`
`
`
`XI
`
`l
`
`/
`
`\
`
`0
`
`P
`
`R3
`
`O
`H
`fi— Q
`R4 0
`
`X
`
`
`
`AQUESTIVE EXHIBIT 1004
`
`AQUESTIVE EXHIBIT 1004 page 1060
`
`page 1060
`
`E?
`R3
`>7 8—— Q
`H
`
`R4
`
`O X
`
`II
`
`O
`
`IX
`
`

`

`WO 98/34915
`
`>
`
`PCT/IB98/00101
`
`-13-
`
`SCHEME 3
`
`O
`
`Ho
`
`~—Q
`
`I;
`R4
`XI \
`
`/
`
`\
`
`0
`
`R3
`
`ff
`fi—Q
`
`R1
`
`R4 O
`
`XV
`
`O /
`R3
`?
`HO’J>P_+__Q_Q
`R1
`R4 g
`XVI \
`
`BnO —~H
`
`fi_Q
`
`R1
`
`R4 O
`XVII
`
`R4
`
`HOHN/%>€><:soy0
`
`R
`
`R2
`
`AQUESTIVE EXHIBIT 1004
`
`AQUESTIVE EXHIBIT 1004 page 1061
`
`page 1061
`
`

`

`WO 98/34915
`
`’
`
`PCT/IB98/00101
`
`-14-
`
`SCHEME 4
`
`R3
`
`4
`
`(I?
`fi—Q
`o
`
`XII
`
`
`
`0 R3
`
`R4
`
`P'O
`
`802*0
`
`HO
`
`R2
`
`XXI
`
`0 R3
`
`R4
`
`Ho/U>%<so2 — —Q
`
`HO
`
`R2
`
`XXII
`
`0 R3
`
`R4
`
`XXIV
`
`P0
`
`802—0
`
`1
`
`R2
`
`O
`BnONH HO
`
`R3
`
`R4
`R2802
`
`__
`
`Q
`
`XX!“
`
`O R3
`
`HO
`
`1
`
`R2
`
`R4
`SOZ—Q
`
`XXV
`
`I
`
`
`
`BnONH
`
`0 R3
`
`R4
`
`XXVI
`802—0
`
`1
`
`R2
`
`AQUESTIVE EXHIBIT 1004
`
`AQUESTIVE EXHIBIT 1004 page 1062
`
`page 1062
`
`

`

`WO 98/34915
`
`PCT/IB98/00101
`
`-15-
`
`5
`
`Scheme 1 refers to the preparation of compounds of the formula I, wherein R3 and R4
`
`are hydrogen. Referring to Scheme l, a compound of the formula i
`
`is prepared from a
`
`compound of the formula II 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 alcohol such as ethanol, methanol 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 (is. room temperature). The reaction is complete
`
`15
`
`within about 0.5 hours to about 5 hours, preferably about 3 hours.
`
`The compound of formula ii
`
`is prepared from a compound of formula III by reaction
`
`with O—benzylhydroxylamine hydrochloride, an activating agent, and a base in a reaction inert
`
`solvent.
`
`Suitable
`
`activating
`
`agents
`
`include
`
`(benzotriazol-1—yloxy)tris(dimethylamino)
`
`phosphonium hexafluorophosphate
`
`or
`
`1-(3—(dimethylaminopropyl)-3-ethylcarbodiimide
`
`20
`
`hydrochloride,
`
`preferably
`
`(benzotriazoI—1-yloxy)tris(dimethylamino)
`
`phosphonium
`
`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
`
`25
`
`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.
`The compound of formula III
`
`is prepared from a compound of formula IV by
`
`hydrogenolysis under an atmosphere of hydrogen in the presence of a catalyst in a reaction
`inert solvent. Suitable catalysts include palladium or 5-10% palladium on activated charcoal,
`
`30
`
`Suitable solvents include acetic acid,
`preferably 10% palladium on activated charcoal.
`alcohols such as ethanol, methanol, or isopropanol, preferably ethanol.
`The aforesaid
`
`to about 5 atmospheres, preferably
`reaction may be performed at a pressure from about 1
`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
`
`35
`
`24 hours, preferably about 3 hours.
`Compounds of the formula N can be prepared from compounds of the formula V by
`reaction with an oxidant
`in a reaction inert solvent.
`Suitable oxidants include meta-
`
`AQUESTIVE EXHIBIT 1004
`
`AQUESTIVE EXHIBIT 1004 page 1063
`
`page 1063
`
`

`

`WO 98/34915
`
`PCT/[B98/00101
`
`~16-
`
`chloroperbenzoic
`
`acid,
`
`hydrogen
`
`peroxide
`
`or
`
`sodium perborate,
`
`preferably meta-
`
`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.
`
`Compounds of
`
`the formula V, wherein R1
`
`is hydroxy, can be prepared from
`
`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
`
`include ethers such as diethy' ether, tetrahydrofuran or 1,2-dimethoxyethane, preferably the
`
`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.
`
`Compounds of the formula V, wherein R1 is (C6~C1o)aryl(C1—C5)alkoxy or (C1-C6)alkoxy,
`
`can be prepared from compounds of the formula V, wherein R1 is hydroxy, by reaction with a
`
`compound of the formula R13L, wherein L is a leaving group and R1&1 is (Cs-C1o)aryl(C1-C6)alkyl
`
`or (C1-Ce)alkyl,
`
`in the presence of a strong base in an aprotic polar solvent. Suitable leaving
`
`groups include chloro, fluoro, bromo, mesylate, triflate or tosylate. Preferably, the leaving group
`
`is iodo. Suitable bases include sodium hydride,
`
`lithium dialkyl amides such as lithium N-
`
`isopropyl-N-cyclohexylamide or
`
`lithium diisopropyl 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.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Compounds of the formula V. wherein R1
`
`is
`
`(C1-C6)alkyl(C=O)O-,
`
`(C1-C6)alkoxy-
`
`(C=O)O-,
`
`(C5-C,o)aryl(C=O)O-,
`
`(Ce-C1o)aryloxy(C=O)O-,
`
`(C6-C1o)aryl(C1-Ce)alkyl(C=O)O- or
`
`(Ce-C1o)aryl(C1-Cs)alkoxy(C=O)O—, can be prepared from compounds of the formula V, wherein
`R1 is hydroxy, by reaction with a compound of the formula R‘bL, wherein L is a leaving group
`
`and R1b is (C1-C6)alkyl(C=O)-, (C1-C6)alkoxy(C=O)-, (C6-C1o)aryl(C=O)-, (Ce-C,o)aryloxy(C=0)—.
`
`35
`
`in the presence of a base in
`(Ce-C10)aryl(C1-C6)alkyl(C=O)— or (Ce-C1o)aryl(C1—C6)a|koxy(C=O)-,
`a reaction inert solvent. Suitable leaving groups include chloro, fluoro, bromo, or R‘bO (i.e. an
`
`anhydride). Preferably, the leaving group is chloro. Suitable bases include tertiary amine
`
`bases such as triethylamine. 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/IB98/00101
`
`-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 a,l3—unsaturated benzyl esters as
`
`described in Jerry March, Advanced Organic Chemistm, 735 (3rd ed., 1985). The corresponding
`
`oc,[3-unsaturated benzyl esters may be prepared by Knovenagel condensation between a
`
`malonate monobenzyl ester and paraformaldehyde in the presence of piperidine as described in
`
`H0. House, Modern Synthetic Reactions, 649-651 (2nd ed., W.A. Benjamin, Menlo Park,
`
`15
`
`California, 1972).
`
`Compounds of the formula VI. wherein R2 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, 511, 3387 (1992).
`
`Scheme 2 refers to the preparation of compounds of the formula l, wherein R2 is
`
`20
`
`hydrogen and R1 is OH. Referring to Scheme 2, compounds of formula I can be prepared from
`
`compounds of the formula Vll 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.
`
`Suitable solvents include an alcohol such as ethanol, methanol or isopropanol, preferably
`
`25
`
`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.
`
`30
`
`Compounds of the formula Vll can be prepared from compounds of the formula Vlll 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
`
`35
`
`an alcohol such as methanol or ethanol and. optionally an water miscible ether such as
`
`system is
`solvent
`the
`Preferably,
`1,2-dimethoxyethane.
`or
`tetrahydrofuran
`methanol/water/tetrahydrofuran. The reaction is conducted from about 1
`to about 72 hours,
`
`preferably about 24 hours.
`
`AQUESTIVE EXHIBIT 1004
`
`AQUESTIVE EXHIBIT 1004 page 1065
`
`page 1065
`
`

`

`WO 98/34915
`
`PCT/IB98/00101
`
`-1 8-
`
`The compound of formula VIII
`
`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
`
`(benzotriazoI-1 —
`
`yloxy)tris(dimethy|amino)phosphonium hexafluorophosphate or 1-(3—(dimethylaminopropyl)—3—
`
`ethylcarbodiimide
`
`hydrochloride,
`
`preferably
`
`(benzotriazol—1~yloxy)tris(dimethylamino)
`
`IO
`
`phosphonium hexafluorophosphate.
`
`Suitable bases include tertiary amines
`
`such as
`
`triethylamine. diisopropylethylamine or dimethylaminopyridine, 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 chloroform, preferably methylene chloride.
`
`The reaction is
`
`15
`
`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 (ie. room temperature). Suitable solvents include
`acetone or a mixture of acetonitrile, carbon tetrachloride and water, preferably a 1:1:2 mixture
`
`20
`
`25
`
`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 compound of the formula XI with a protecting group reagent in the presence of a
`base in a reaction inert solvent. Suitable protecting group reagents include pivaloyl chloride,
`pivaloic anhydride. acetyl 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
`
`30
`
`Suitable solvents include halogenated solvents such as
`room temperature).
`25°C (i.e.
`methylene chloride or chloroform, preferably methylene chloride. The reaction is conducted
`
`35
`
`from about 1 hour to about 24 hours, preferably for about 2 hours.
`The compound of formula XI is prepared from a compound of the formula XII by reaction
`with 2-furaldehyde and a strong base in a polar aprotic solvent. Suitable bases include
`potassium—ted.-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 diethyl 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.
`
`AQUESTIVE EXHIBIT 1004
`
`AQUESTIVE EXHIBIT 1004 page 1066
`
`page 1066
`
`

`

`WO 98/34915
`
`PCT/IB98/00 101
`
`-19-
`
`The compound of formula Xll
`
`is prepared from a compound of the formula XIII by
`
`reaction with an oxidant
`
`in a reaction inert solvent.
`
`Suitable oxidants include meta-
`
`chloroperbenzoic
`
`acid,
`
`hydrogen
`
`peroxide
`
`or
`
`sodium perborate,
`
`preferably meta—
`
`chloroperbenzoic acid. Suitable solvents include halogenated solvents such as methylene
`
`chloride or ch