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Definitions

• Y is an organic acid functional group, or an amide or ester thereof comprising up to 12 carbon atoms, or Y is hydroxymethyl or an ether thereof comprising up to 12 carbon atoms, or Y is a tetrazolyl functional group,
• A is -(CH 2 )6-, as or -CH 2 C ⁇ C-(CH 2 ) 3 -, wherein 1 or 2 carbon atoms may be substituted with S or O, or A is
• Ar is interarylene or heterointerarylene, the sum of m and o is from 1 to 4, and wherein one CH 2 may be substituted with S or O, U is O, S, NR 1 , wherein R 1 is H, Ci 6 alkyl, Ci 7 acyl, benzoyl, biphenylacyl, Ci ⁇ sulfonyl, phenylsulfonyl, biphenylsulfonyl, trifluoromethylacyl, or trifloyl, and
• B is aryl or heteroaryl
• Y is an organic acid functional group, or an amide or ester thereof comprising up to 12 carbon atoms, or Y is hydroxymethyl or an ether thereof comprising up to 12 carbon atoms, or Y is a tetrazolyl functional group
• An organic acid functional group is an acidic functional group on an organic molecule While not intending to be limiting, organic acid functional groups may comprise an oxide of carbon, sulfur, or phosphorous
• Y is a carboxylic acid, sulfonic acid, or phosphonic acid functional group, i e one of the structures shown below
• an amide or ester of one of the organic acids shown above comprising up to 12 carbon atoms is also contemplated.
• a hydrocarbyl moiety replaces a hydrogen atom of an acid such as in a carboxylic acid ester, e.g. CO 2 Me, CO 2 Et, etc.
• an amine group replaces an OH of the acid.
• amides include CON(R 2 ) 2 , CON(OR 2 )R 2 , CON(CH 2 CH 2 OH) 2 , and CONH(CH 2 CH 2 OH) where R 2 is independently H, Ci-C 6 alkyl, phenyl, or biphenyl.
• Moieties such as CONHSO 2 R 2 are also amides of the carboxylic acid notwithstanding the fact that they may also be considered to be amides of the sulfonic acid R 2 -SO 3 H.
• Y may also be hydroxymethyl or an ether thereof comprising up to 12 carbon atoms.
• Y may also be hydroxymethyl or an ether thereof comprising up to 12 carbon atoms.
• ethers of these compounds are also possible.
• An ether is a functional group wherein a hydrogen of an hydroxyl is replaced by carbon, e.g., Y is CH 2 OCHs, CH 2 OCH 2 CHs, etc.
• Y may be a tetrazolyl functional group, such as compounds having a structure according to the formula below.
• An unsubstituted tetrazolyl functional group has two tautomeric forms, which can rapidly interconvert in aqueous or biological media, and are thus equivalent to one another. These tautomers are shown below.
• R 2 is Ci-C 6 alkyl, phenyl, or biphenyl
• other isomeric forms of the tetrazolyl functional group such as the one shown below are also possible, unsubstituted and hydrocarbyl substituted tetrazolyl up to C12 are considered to be within the scope of the term "tetrazolyl.”
• Y is selected from the group consisting Of CO 2 (R 2 ), CON(R 2 ) 2 , CON(OR 2 )R 2 , CON(CH 2 CH 2 OH) 2 , CONH(CH 2 CH 2 OH), CH 2 OH, P(O)(OH) 2 , CONHSO 2 R 2 , SO 2 N(R 2 J 2 , SO 2 NHR 2 , and tetrazolyl-R 2 ; wherein R 2 is independently H, Ci-Ce alkyl, phenyl, or biphenyl.
• Y is not CONH-phenyl or CONH-cyclohexyl.
• A may be a group which is related to one of these three moieties in that any carbon is substituted with S and/or O.
• A may be an S substituted moiety such as one of the following or the like.
• A may be an O substituted moiety such as one of the following or the like.
• A may have both an O and an S substituted into the chain, such as one of the following or the like.
• A is -(CH 2 ) m -Ar- (CHb) 0 - wherein Ar is interarylene or heterointerarylene, the sum of m and o is from 1 to 4, and wherein one CH2 may be substituted with S or O.
• A comprises from 1 to 4 CH2 moieties and Ar, e.g.
• A comprises O, from O to 3 CH 2 moieties, and Ar, e.g., -0-Ar-, Ar-CH 2 -O-, -0-Ar-(CH 2 J 2 -, -0-CH 2 -Ar-, -O-CH 2 -Ar-(CH 2 ) 2 , and the like; or
• A comprises S, from O to 3 CH 2 moieties, and Ar, e.g., -S-Ar-, Ar-CH 2 -S-, -S-Ar-(CH 2 J 2 -, -S-CH 2 -Ar-, -S-CH 2 -Ar-(CH 2 J 2 , -(CH 2 ) 2 - S-Ar, and the like.
• Ar e.g., -S-Ar-, Ar-CH 2 -S-, -S-Ar-(CH 2 J 2 -, -S-CH 2 -Ar-, -S-CH 2 -Ar-(CH 2 J 2 , -(CH 2 ) 2 - S-Ar, and the like.
• the sum of m and 0 is from 2 to 4 wherein one CH 2 may be substituted with S or O.
• the sum of m and 0 is 3 wherein one CH 2 may be substituted with S or O.
• the sum of m and 0 is 2 wherein one CH 2 may be substituted with S or O.
• the sum of m and 0 is 4 wherein one CH 2 may be substituted with S or O.
• Interarylene or heterointerarylene refers to an aryl ring or ring system or a heteroaryl ring or ring system which connects two other parts of a molecule, i.e. the two parts are bonded to the ring in two distinct ring positions.
• Interarylene or heterointerarylene may be substituted or unsubstituted. Unsubstituted interarylene or heterointerarylene has no substituents other than the two parts of the molecule it connects. Substituted interarylene or heterointerarylene has one or more substitutuents in addition to the two parts of the molecule it connects.
• Ar is substituted or unsubstituted interphenylene, interthienylene, interfurylene, interpyridinylene, interoxazolylene, and interthiazolylene.
• Ar is interphenylene (Ph).
• A is -(CH 2 J 2 - Ph-. While not intending to limit scope of the invention in any way, substituents may have 4 or less heavy atoms, or in other words, non hydrogen atoms. Any number of hydrogen atoms required for a particular substituent will also be included. Thus, the substituent may be hydrocarbyl, i.e.
• a moiety consisting of only carbon and hydrogen such as alkyl, having up to 4 carbon atoms, including alkyl up to C4, alkenyl, alkynyl, and the like; hydrocarbyloxy up to C3; CF 3 ; halo, such as F, Cl, or Br; hvdroxyl; NH 2 and alkylamine functional groups up to C3; other N or S containing substituents; and the like.
• Substituted interarylene or interheteroarylene may have one or more substituents, up to as many as the ring or ring system will bear, and the substituents may be the same or different.
• an interarylene ring or interheteroarylene ring may be substituted with chloro and methyl; methyl, OH, and F; CN, NO 2 , and ethyl; and the like including any conceivable substituent or combination of substituent possible in light of this disclosure.
• A is -(CH 2 ) m -Ar-(CH 2 ) 0 - wherein Ar is interphenylene, the sum of m and 0 is from 1 to 3, and wherein one CH 2 may be substituted with S or O.
• A is -Chb-Ar-OChb-.
• A is -Chb-Ar-OChb- and Ar is interphenylene.
• Ar is 1 ,3 interaryl or interheteroaryl, where Ar attached at the 1 and 3 positions, such as when A has the structure shown below.
• A is not -(CHb)B-.
• A has one of the following structures, where Y is attached to the oxazolyl or thiazolyl ring.
• A is one of the structures shown below, where Y is attached to the phenyl or heteroaryl ring.
• A is -CH 2 OCH 2 Ar
• A is -CH 2 SCH 2 Ar
• A is -(Chb ⁇ Ar In another embodiment A is -CH 2 O(CH 2 )4
• A is -CH 2 S(CH 2 )4
• A is -S(CH 2 ) 3 S(CH 2 ) 2 -
• A is -(CH 2 )4 ⁇ CH 2 -
• A is -(CH 2 ) 2 S(CH 2 )3-
• A is -CH 2 -Ph-OCH 2 -, wherein Ph is interphenylene
• A is -CH 2 -mPh-OCH 2 -, wherein mPh is m-interphenylene
• A is -CH 2 -O-(CH 2 )4- In another embodiment A is -CH 2 -O-CH 2 -Ar-, wherein Ar is 2,5- ⁇ nterth ⁇ enylene
• A is -CH 2 -O-CH 2 -Ar-, wherein Ar is 2,5- ⁇ nterfurylene
• U is O, S, NR 1 , wherein R 1 is H, Ci 6 alkyl, Ci 7 acyl, benzoyl, biphenylacyl, Ci 6 sulfonyl, phenylsulfonyl, biphenylsulfonyl, trifluoromethylacyl, or trifloyl
• R 7 is H In another embodiment R 7 is methyl In another embodiment R 7 is ethyl In another embodiment R 7 a propyl isomer In another embodiment R 7 is H or Ci 3 alkyl
• Aryl is an unsubstituted or substituted aromatic ring or ring system such as phenyl, naphthyl, biphenyl, and the like
• Heteroaryl is aryl having one or more N, O, or S atoms in the ring, i e a ring carbon is substituted by N, O, or S While not intending to be limiting, examples of heteroaryl include unsubstituted or substituted thienyl, pyridinyl, furyl, benzothienyl, benzofuryl, imidizololyl, indolyl, and the like
• the substituents of aryl or heteroaryl may have up to 12 non-hydrogen atoms each and as many hydrogen atoms as necessary
• the substituents may be hydrocarbyl, i e a moiety consisting of only carbon and hydrogen such as alkyl, alkenyl, alkynyl, and the like, including linear, branched or cyclic hydrocarbyl, and combinations thereof, hydrocarbyloxy, meaning O-hydrocarbyl such as OCH 3 , OCH2CH 3 , O-cyclohexyl, etc, up to 11 carbon atoms, other ether substituents such as CH ⁇ OCHs, (CH2)2 ⁇ CH(CH 3 )2, and the like, thioether substituents including S-hydrocarbyl and other thioether substituents, hvdroxyhvdrocarbyl, meaning hydrocarbyl-OH such as CH2OH, C(CH 3 )2 ⁇ H
• the substituents contain only hydrogen, carbon, oxygen, halogen, nitrogen, and sulfur. In other embodiments, the substituents contain only hydrogen, carbon, oxygen, and halogen.
• references to aryl, heteroaryl, phenyl, thienyl, benzothienyl, and the like are intended to mean both the substituted and the unsubstituted moiety.
• Substituted aryl or heteroaryl may have one or more substituents, up to as many as the ring or ring system will bear, and the substituents may be the same or different.
• an aryl ring or a heteroaryl ring may be substituted with chloro and methyl; methyl, OH, and F; CN, NO2, and ethyl; and the like including any conceivable substituent or combination of substituent possible in light of this disclosure.
• B is phenyl.
• B is chlorophenyl, meaning phenyl with one or more chloro substituents.
• D is 3,5- dichlorophenyl.
• B is unsubstituted phenyl.
• B is alkylphenyl.
• B is t-butylphenyl.
• B is hydroxyalkylphenyl, meaning phenyl with a hydroxyalkyl substitutuent such as Ph- CH(OH)C(CHs) 3 .
• B can also be any of the groups shown below, where the remainder of the molecule attaches to the phenyl ring. The names of these moieties are shown to the right of the structure.
• B has one of the structures below, where the remainder of the molecule attaches to the phenyl ring, and wherein x is 5, 6, or 7, and y + z is 2x + 1.
• x is 5 and y + z is 11. In another embodiment, x is 6 and y + z is 13. In another embodiment, x is 7 and y + z is 15 Compounds have the formula
• R 3 , R 4 , and R 5 are independently H or Ci 6 alkyl
• R 4 and R 5 may be two separate moieties
• R 4 and R 5 is methyl, and no bond is present where indicated by the dashed line
• R 4 and R 5 may form a ring
• a compound such as the one shown below is possible, wherein x is from 1 to 6
• a pharmaceutically acceptable salt, prodrug, or a metabolite thereof is also contemplated.
• Another embodiment has the formula
• a pharmaceutically acceptable salt, prodrug, or a metabolite thereof is also contemplated.
• Other useful compounds have the formula
• a pharmaceutically acceptable salt, prodrug, or a metabolite thereof is also contemplated.
• Other useful examples of compounds have the formula
• Another useful compound is or a pharmaceutically acceptable salt or a prodrug thereof.
• Another useful compound is
• E is unsubstituted phenyl, chlorophenyl, fluorophenyl, or dimethylaminophenyl.
• Other compounds have the formula
• G is 1 ,3-interaryl or interheteroaryl, or -(CH2)3-.
• Other compounds have the formula or a pharmaceutically acceptable salt or a prodrug thereof; wherein a dashed line indicates the presence or absence of a bond; R is hydrocarbyl or hydroxyhydrocarbyl having from 1 to 12 carbon atoms; X iS CH 2 , O, or S; and
• G is 1 ,3-interaryl or interheteroaryl, or -(CH2)3-.
• A is -S(CH.2)3S(CH.2)2- and B is phenyl.
• A is -(CH ⁇ OChb- and B is phenyl.
• A is -ChhCH ⁇ CH-ChhOChh- and B is phenyl.
• A is -(CH.2)2S(CH.2)3- and B is phenyl.
• A is -CH.2-Ph-OCH.2-, wherein Ph is interphenylene, and B is phenyl.
• A is -CH2-mPh-OCH2-, wherein mPh is m-interphenylene, and B is phenyl.
• A is -CH2-O-(CH2)4- and B is phenyl.
• A is -CH2-O-CH2-Ar-, wherein Ar is 2,5-interthienylene, and B is phenyl.
• A is -CHk-O-CH--Ar-, wherein Ar is 2,5-interfurylene, and B is phenyl.
• phenyl in the above embodiments means substituted or unsubstituted phenyl unless indicated otherwise.
• A is -S(CH2)3S(CH2)2- and B is (1 -hydroxyhexyl)phenyl.
• A is -(Chb ⁇ OChb- and B is (i-hydroxyhexyl)phenyl.
• A is -ChbCH ⁇ CH-ChbOChb- and B is (i-hydroxyhexyl)phenyl.
• A is -(CH2)2S(CH2)3- and B is (1 -hydroxyhexyl)phenyl.
• A is -Chb-Ph-OChb-, wherein Ph is interphenylene, and B is (1 -hydroxyhexyl)phenyl.
• A is -Chb-mPh-OChb-, wherein mPh is m-interphenylene, and B is (i-hydroxyhexyl)phenyl.
• A is -CH2-O-(CH2)4- and B is (1 -hydroxyhexyl)phenyl.
• A is -Chb-O-Chb-Ar-, wherein Ar is 2,5-interthienylene, and B is (i-hydroxyhexyl)phenyl.
• A is -Chb-O-Chb-Ar-, wherein Ar is 2,5-interfurylene, and B is (i-hydroxyhexyl)phenyl.
• A is -S(CH2)3S(CH2)2- and B is (1-hydroxy-2,2-dimethylpropyl)phenyl.
• A is -(Chb ⁇ OChb- and B is (1-hydroxy-2,2-dimethylpropyl)phenyl.
• A is -ChbCH ⁇ CH-ChbOChb- and B is (1-hydroxy-2,2-dimethylpropyl)phenyl.
• A is -(CH2)2S(CH2)3- and B is (1 -hydroxy-2,2-dimethylpropyl)phenyl.
• A is -Chb-Ph-OChb-, wherein Ph is interphenylene, and B is (1 -hydroxy-2,2- dimethylpropyl)phenyl.
• A is -Chb-mPh-OChb-, wherein mPh is m-interphenylene, and B is (1-hydroxy-2,2- dimethylpropyl)phenyl.
• A is -CH2-O-(CH2)4- and B is (1 -hydroxy-2,2-dimethylpropyl)phenyl.
• A is -Chb-O-Chb-Ar-, wherein Ar is 2,5-interthienylene, and B is (1-hydroxy-2,2- dimethylpropyl)phenyl.
• A is -Chb-O-Chb-Ar-, wherein Ar is 2,5-interfurylene, and B is (1-hydroxy-2,2- dimethylpropyl)phenyl.
• A is -S(CH2)3S(CH2)2- and B is (1-hydroxy-2-methylpropyl)phenyl.
• A is -(Chb ⁇ OChb- and B is (1-hydroxy-2-methylpropyl)phenyl.
• A is -ChbCH ⁇ CH-ChbOChb- and B is (1-hydroxy-2-methylpropyl)phenyl.
• A is -(CH2)2S(CH2)3- and B is (1 -hydroxy-2-methylpropyl)phenyl.
• A is -Chb-Ph-OChb-, wherein Ph is interphenylene, and B is (1-hydroxy-2-methylpropyl)phenyl.
• A is -Chb-mPh-OChb-, wherein mPh is m-interphenylene, and B is (1-hydroxy-2- methylpropyl)phenyl.
• A is -CH2-O-(CH2)4- and B is (1 -hydroxy-2-methylpropyl)phenyl.
• A is -CHk-O-CH--Ar-, wherein Ar is 2,5-interthienylene, and B is (1-hydroxy-2- methylpropyl)phenyl.
• A is -Chb-O-Chb-Ar-, wherein Ar is 2,5-interfurylene, and B is (1-hydroxy-2- methylpropyl)phenyl.
• A is -S(CH2)3S(CH2)2- and B is (hydroxymethyl)phenyl.
• A is -(Chb ⁇ OChb- and B is (hydroxymethyl)phenyl.
• A is -ChbCH ⁇ CH-ChbOChb- and B is (hydroxymethyl)phenyl.
• A is -(CH2)2S(CH2)3- and B is (hydroxymethyl)phenyl.
• A is -Chb-Ph-OChb-, wherein Ph is interphenylene, and B is (hydroxymethyl)phenyl.
• A is -Chb-mPh-OChb-, wherein mPh is m-interphenylene, and B is (hydroxymethyl)phenyl.
• A is -CH2-O-(CH2)4- and B is (hydroxymethyl)phenyl.
• A is -Chb-O-Chb-Ar-, wherein Ar is 2,5-interthienylene, and B is (hydroxymethyl)phenyl.
• A is -Chb-O-Chb-Ar-, wherein Ar is 2,5-interfurylene, and B is (hydroxymethyl)phenyl.
• A is -S(CH2)3S(CH2)2- and B is [(i-propylcyclobutyljhydroxymethyllphenyl.
• A is -(Chb ⁇ OChb- and B is [(i-propylcyclobutyljhydroxymethyllphenyl.
• A is -ChbCH ⁇ CH-ChbOChb- and B is [(1 -propylcyclobutyl)hydroxymethyl]phenyl .
• A is -(CH2)2S(CH2)3- and B is [(1-propylcyclobutyl)hydroxymethyl]phenyl.
• A is -Chb-Ph-OChb-, wherein Ph is interphenylene, and B is [(1- propylcyclobutyl)hydroxymethyl]phenyl.
• A is -Chb-mPh-OChb-, wherein mPh is m-interphenylene, and B is [(1- propylcyclobutyl)hydroxymethyl]phenyl.
• A is -CH2-O-(CH2)4- and B is [(1 -propylcyclobutyljhydroxymethyllphenyl.
• A is -Chh-O-Chh-Ar-, wherein Ar is 2,5-interthienylene, and B is [(1- propylcyclobutyl)hydroxymethyl]phenyl.
• A is -Chh-O-Chh-Ar-, wherein Ar is 2,5-interfurylene, and B is [(1- propylcyclobutyl)hydroxymethyl]phenyl.
• A is -S(CH2)3S(CH2)2- and B is t-butylphenyl.
• A is -(Chb ⁇ OChb- and B is t-butylphenyl.
• A is -CH 2 CH ⁇ H-CH 2 OCH 2 - and B is t-butylphenyl.
• A is -(CH2)2S(CH2)3- and B is t-butylphenyl.
• A is -CH 2 -Ph-OCH 2 -, wherein Ph is interphenylene, and B is t-butylphenyl.
• A is -CH 2 -mPh-OCH 2 -, wherein mPh is m-interphenylene, and B is t-butylphenyl.
• A is -CH2-O-(CH2)4- and B is t-butylphenyl.
• A is -CH 2 -O-CH 2 -Ar-, wherein Ar is 2,5-interthienylene, and B is t-butylphenyl.
• A is -CHk-O-CH--Ar-, wherein Ar is 2,5-interfurylene, and B is t-butylphenyl.
• A is -S(CH2)3S(CH2)2- and B is (cyclohexylhydroxymethyljphenyl.
• A is -(Chb ⁇ OChb- and B is (cyclohexylhydroxymethyljphenyl.
• A is -ChbCH ⁇ CH-ChbOChb- and B is (cyclohexylhydroxymethyljphenyl.
• A is -(CH2)2S(CH2)3- and B is (cyclohexylhydroxymethyljphenyl.
• A is -Chb-Ph-OChb-, wherein Ph is interphenylene, and B is (cyclohexylhydroxymethyl)phenyl.
• A is -Chb-mPh-OChb-, wherein mPh is m-interphenylene, and B is (cyclohexylhydroxymethyl)phenyl .
• A is -CH2-O-(CH2)4- and B is (cyclohexylhydroxymethyljphenyl.
• A is -Chb-O-Chb-Ar-, wherein Ar is 2,5-interthienylene, and B is (cyclohexylhydroxymethyl)phenyl.
• A is -Chb-O-Chb-Ar-, wherein Ar is 2,5-interfurylene, and B is (cyclohexylhydroxymethyl)phenyl.
• A is -S(CH2)3S(CH2)2- and B is (cyclohexylmethyl)phenyl.
• A is -(Chb ⁇ OChb- and B is (cyclohexylmethyl)phenyl.
• A is -ChbCH ⁇ CH-ChbOChb- and B is (cyclohexylmethyl)phenyl.
• A is -(CH2)2S(CH2)3- and B is (cyclohexylmethyl)phenyl.
• A is -Chb-Ph-OChb-, wherein Ph is interphenylene, and B is (cyclohexylmethyl)phenyl.
• A is -Chb-mPh-OChb-, wherein mPh is m-interphenylene, and B is (cyclohexylmethyl)phenyl.
• A is -CH2-O-(CH2)4- and B is (cyclohexylmethyl)phenyl.
• A is -Chb-O-Chb-Ar-, wherein Ar is 2,5-interthienylene, and B is (cyclohexylmethyl)phenyl.
• A is -Chh-O-Chh-Ar-, wherein Ar is 2,5-interfurylene, and B is (cyclohexylmethyl)phenyl.
• A is -S(CH2)3S(CH2)2- and B is indanyl.
• A is -(Chb ⁇ OChb- and B is indanyl.
• A is cis -ChhCh ⁇ CH-ChhOChh- and B is indanyl.
• A is -CH 2 CH ⁇ H-CH 2 OCH 2 - and B is indanyl.
• A is -(CH2)2S(CH2)3- and B is indanyl.
• A is -CH 2 -Ph-OCH 2 -, wherein Ph is interphenylene, and B is indanyl.
• A is -CH 2 -mPh-OCH 2 -, wherein mPh is m-interphenylene, and B is indanyl.
• A is -CH2-O-(CH2)4- and B is indanyl.
• A is -CH 2 -O-CH 2 -Ar-, wherein Ar is 2,5-interthienylene, and B is indanyl.
• A is -CH 2 -O-CH 2 -Ar-, wherein Ar is 2,5-interfurylene, and B is indanyl.
• A is -S(CH2)3S(CH2)2- and B is indanolyl.
• A is -(CH 2 ⁇ OCH 2 - and B is indanolyl.
• A is -ChfcCH ⁇ CH-ChfcOChk- and B is indanolyl.
• A is -(CH2)2S(CH2)3- and B is indanolyl.
• A is -Chk-Ph-OChk-, wherein Ph is interphenylene, and B is indanolyl.
• A is -Chb-mPh-OChb-, wherein mPh is m-interphenylene, and B is indanolyl.
• A is -CH2-O-(CH2)4- and B is indanolyl.
• A is -CHk-O-CH--Ar-, wherein Ar is 2,5-interthienylene, and B is indanolyl.
• A is -Chb-O-Chb-Ar-, wherein Ar is 2,5-interfurylene, and B is indanolyl.
• A is -S(CH2)3S(CH2)2- and B is indanonyl.
• A is -(Chb ⁇ OChb- and B is indanonyl.
• A is -ChbCH ⁇ CH-ChbOChb- and B is indanonyl.
• A is -(CH2)2S(CH2)3- and B is indanonyl.
• A is -Chb-Ph-OChb-, wherein Ph is interphenylene, and B is indanonyl.
• A is -Chb-mPh-OChb-, wherein mPh is m-interphenylene, and B is indanonyl.
• A is -CH2-O-(CH2)4- and B is indanonyl.
• A is -Chb-O-Chb-Ar-, wherein Ar is 2,5-interthienylene, and B is indanonyl.
• A is -Chb-O-Chb-Ar-, wherein Ar is 2,5-interfurylene, and B is indanonyl.
• A is -S(CH2)3S(CH2)2- and B is (i-hydroxycyclobutyl)phenyl.
• A is -(Chb ⁇ OChb- and B is (1 -hydroxycyclobutyljphenyl.
• A is -ChbCH ⁇ CH-ChbOChb- and B is (i-hydroxycyclobutyl)phenyl.
• A is -(CH2)2S(CH2)3- and B is (1 -hydroxycyclobutyljphenyl.
• A is -Chh-Ph-OChh-, wherein Ph is interphenylene, and B is (i-hydroxycyclobutyl)phenyl.
• A is -Chb-mPh-OChb-, wherein mPh is m-interphenylene, and B is (i-hydroxycyclobutyl)phenyl.
• A is -CH2-O-(CH2)4- and B is (1 -hydroxycyclobutyljphenyl.
• A is -Chb-O-Chb-Ar-, wherein Ar is 2,5-interthienylene, and B is (i-hydroxycyclobutyl)phenyl.
• A is -Chh-O-Chh-Ar-, wherein Ar is 2,5-interfurylene, and B is (i-hydroxycyclobutyl)phenyl.
• A is -S(CH2)3S(CH2)2- and B is (2-methyl-3-hydroxypropyl)phenyl.
• A is -(Chb ⁇ OChb- and B is (2-methyl-3-hydroxypropyl)phenyl.
• A is -ChbCH ⁇ CH-ChbOChb- and B is (2-methyl-3-hydroxypropyl)phenyl.
• A is -(CH2)2S(CH2)3- and B is (2-methyl-3-hydroxypropyl)phenyl.
• A is -Chb-Ph-OChb-, wherein Ph is interphenylene, and B is (2-methyl-3-hydroxypropyl)phenyl.
• A is -Chb-mPh-OChb-, wherein mPh is m-interphenylene, and B is (2-methyl-3- hydroxypropyl)phenyl.
• A is -CH2-O-(CH2)4- and B is (2-methyl-3-hydroxypropyl)phenyl.
• A is -CHk-O-CH--Ar-, wherein Ar is 2,5- ⁇ nterth ⁇ enylene, and B is (2-methyl-3- hydroxypropyl)phenyl
• A is -Chb-O-Chb-Ar-, wherein Ar is 2,5- ⁇ nterfurylene, and B is (2-methyl-3- hydroxypropyl)phenyl
• A is -S(CH2)3S(CH2)2- and B is (1-hydroxy-2-phenylethyl)phenyl
• A is -(Chb ⁇ OChb- and B is (1-hydroxy-2-phenylethyl)phenyl
• A is -ChbCH ⁇ CH-ChbOChb- and B is (1-hydroxy-2-phenylethyl)phenyl
• A is -(CH2)2S(CH2)3- and B is (1 -hydroxy-2-phenylethyl)phenyl
• A is -Chb-Ph-OChb-, wherein Ph is interphenylene, and B is (1 -hydroxy-2-phenylethyl)phenyl
• A is -Chb-mPh-OChb-, wherein mPh is m-interphenylene, and B is (1-hydroxy-2- phenylethyl)phenyl
• A is -CH2-O-(CH2)4- and B is (1 -hydroxy-2-phenylethyl)phenyl
• A is -Chb-O-Chb-Ar-, wherein Ar is 2,5- ⁇ nterth ⁇ enylene, and B is (1-hydroxy-2- phenylethyl)phenyl
• A is -Chb-O-Chb-Ar-, wherein Ar is 2,5- ⁇ nterfurylene, and B is (1-hydroxy-2-phenylethyl)phenyl
• Y is an organic acid functional group, or an amide or ester thereof comprising up to 12 carbon atoms, or Y is hydroxymethyl or an ether thereof comprising up to 12 carbon atoms, or Y is a tetrazolyl functional group,
• U is O, S, NR 1 , wherein R 1 is H, Ci 6 alkyl, Ci 7 acyl, benzoyl, biphenylacyl, Ci ⁇ sulfonyl, phenylsulfonyl, biphenylsulfonyl, trifluoromethylacyl, or trifloyl, and
• B is aryl or heteroaryl
• Compound Example 4 The compound of compound example 2 wherein B is p-f-butylphenyl Compound Example 5.
• the compound of compound example 1 having the formula or a pharmaceutically acceptable salt, prodrug, or a metabolite thereof; wherein G is 1 ,3-interaryl or interheteroaryl, or -(CH2)3-.
• Compound Example 7 The compound of compound example 6 wherein B is hydroxyalkylphenyl.
• R is hydrocarbyl or hydroxyhydrocarbyl having from 1 to 12 carbon atoms
• G is 1 ,3-interaryl or interheteroaryl, or -(CH2)3-.
• Compound Example 11 The compound of compound example 1 having the formula or a pharmaceutically acceptable salt or a prodrug thereof.
• the compounds of disclosed herein are useful for the prevention or treatment of glaucoma or ocular hypertension in mammals, or for the manufacture of a medicament for the treatment of glaucoma or ocular hypertension. They are also useful for the treatment of those diseases disclosed in the art as being amenable to treatment by prostaglandin EP2 agonist, such treating or preventing inflammation and pain in joint and muscle (e.g., rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, juvenile arthritis, etc.), inflammatory skin condition (e.g., sunburn, burns, eczema, dermatitis, etc.), inflammatory eye condition (e.g., conjunctivitis, etc.), lung disorder in which inflammation is involved (e.g., asthma, bronchitis, pigeon fancier's disease, farmer's lung, etc.), condition of the gastrointestinal tract associated with inflammation (e.g., aphthous ulcer
• a "prodrug” is a compound which is converted to a therapeutically active compound after administration, and the term should be interpreted as broadly herein as is generally understood in the art While not intending to limit the scope of the invention, conversion may occur by hydrolysis of an ester group or some other biologically labile group Generally, but not necessarily, a prodrug is inactive or less active than the therapeutically active compound to which it is converted Ester prodrugs of the compounds disclosed herein are specifically contemplated An ester may be derived from a carboxylic acid of C1 ( ⁇ e the terminal carboxylic acid of a natural prostaglandin), or an ester may be derived from a carboxylic acid functional group on another part of the molecule, such as on a phenyl ring While not intending to be limiting, an ester may be an alkyl ester, an aryl ester, or a heteroaryl ester The term alkyl has the meaning generally understood by those skilled in the art and refers to linear, branched, or
• non-toxic solid carriers include, but are not limited to, pharmaceutical grades of manmtol, lactose, starch, magnesium stearate, sodium saccharin, the polyalkylene glycols, talcum, cellulose, glucose, sucrose and magnesium carbonate
• the solid dosage forms may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period
• a time delay material such as glyceryl monostearate or glyceryl distcarate may be employed. They may also be coated by the technique described in the U.S. Pat. Nos.
• Liquid pharmaceutically administrable dosage forms can, for example, comprise a solution or suspension of one or more of the presently useful compounds and optional pharmaceutical adjutants in a carrier, such as for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension.
• a carrier such as for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension.
• the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like.
• auxiliary agents are sodium acetate, sorbitan monolaurate, triethanolamine, sodium acetate, triethanolamine oleate, etc.
• Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 16th Edition, 1980.
• the composition of the formulation to be administered, in any event contains a quantity of one or more of the presently useful compounds in an amount effective to provide the desired therapeutic effect.
• Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously.
• Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol and the like.
• the injectable pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like.
• the amount of the presently useful compound or compounds administered is, of course, dependent on the therapeutic effect or effects desired, on the specific mammal being treated, on the severity and nature of the mammal's condition, on the manner of administration, on the potency and pharmacodynamics of the particular compound or compounds employed, and on the judgment of the prescribing physician.
• the therapeutically effective dosage of the presently useful compound or compounds is preferably in the range of about 0.5 or about 1 to about 100 mg/kg/day.
• a liquid which is ophthalmically acceptable is formulated such that it can be administered topically to the eye.
• the comfort should be maximized as much as possible, although sometimes formulation considerations (e.g. drug stability) may necessitate less than optimal comfort.
• the liquid should be formulated such that the liquid is tolerable to the patient for topical ophthalmic use.
• an ophthalmically acceptable liquid should either be packaged for single use, or contain a preservative to prevent contamination over multiple uses.
• solutions or medicaments are often prepared using a physiological saline solution as a major vehicle.
• Ophthalmic solutions should preferably be maintained at a comfortable pH with an appropriate buffer system.
• the formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
• Preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate.
• a useful surfactant is, for example, Tween 80.
• various useful vehicles may be used in the ophthalmic preparations of the present invention.
• Tonicity adjusters may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
• buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
• an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
• excipient components which may be included in the ophthalmic preparations are chelating agents.
• a useful chelating agent is edetate disodium, although other chelating agents may also be used in place or in conjunction with it.
• the ingredients are usually used in the following amounts:
• Inqredient Amount (% w/v) active ingredient about 0.001-5 preservative 0-0.10 vehicle 040 tonicity adjustor 1-10 buffer 0.01-10 pH adjustor q.s. pH 4.5-7.5 antioxidant as needed surfactant as needed purified water as needed to ma
• Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.
• the actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
• the compounds disclosed herein are also useful in combination with other drugs useful for the treatment of glaucoma or other conditions.
• combination treatment with the following classes of drugs are contemplated:
• 3-Blockers including carteolol, levobunolol, metiparanolol, timolol hemihydrate, timolol maleate, ⁇ 1- selective antagonists such as betaxolol, and the like, or pharmaceutically acceptable salts or prodrugs thereof;
• Adrenergic Agonists including non-selective adrenergic agonists such as epinephrine borate, epinephrine hydrochloride, and dipivefrin, and the like, or pharmaceutically acceptable salts or prodrugs thereof; and ⁇ 2-selective adrenergic agonists such as apraclonidine, brimonidine, and the like, or pharmaceutically acceptable salts or prodrugs thereof;
• Carbonic Anhydrase Inhibitors including acetazolamide, dichlorphenamide, methazolamide, brinzolamide, dorzolamide, and the like, or pharmaceutically acceptable salts or prodrugs thereof; Cholinergic Agonists including direct acting cholinergic agonists such as carbachol, pilocarpine hydrochloride, pilocarbine nitrate, pilocarpine, and the like, or pharmaceutically acceptable salts or prodrugs thereof; chlolinesterase inhibitors such as demecarium, echothiophate, physostigmine, and the like, or pharmaceutically acceptable salts or prodrugs thereof; Glutamate Antagonists and other neuroprotective agents such as Ca 2+ channel blockers such as memantine, amantadine, rimantadine, nitroglycerin, dextrophan, detromethorphan, CGS-19755, dihydropyridines, verapamil, emopamil, benzothiazepines,
• Prostamides such as bimatoprost, or pharmaceutically acceptable salts or prodrugs thereof; and Prostaglandins including travoprost, UFO-21 , chloprostenol, fluprostenol, 13,14-dihydro-chloprostenol , isopropyl unoprostone, latanoprost and the like.
• Cannabinoids including CB1 agonists such as WIN-55212-2 and CP-55940 and the like, or pharmaceutically acceptable salts or prodrugs thereof.
• these compounds can be administered topically, periocularly, intraocularly, or by any other effective means known in the art.
• Treatment of inflammatory bowel disease may be accomplished by the administration of the compounds described herein to the suffering mammal.
• Inflammatory bowel disease describes a variety of diseases characterized by inflammation of the bowels including, but not limited to, ulcerative colitis and Crohn's disease.
• Treatment may be accomplished by oral administration, by suppository, or parenteral administration, or some other suitable method.
• these methods include 1) administration of a prodrug, including an azo or a carbohydrate based prodrug; 2) coating the drug with, or encapsulating or impregnating the drug into a polymer designed for delivery to the colon, 3) time released delivery of the drug, 4) use of a bioadhesive system; and the like. While not intending to be bound in any way by theory, it is believed that intestinal microflora are capable of reductive cleavage of an azo bond leaving the two nitrogen atoms as amine functional groups.
• the azo prodrug approach has been used to deliver to 5-aminosalicylic acid to the colons of humans in clinical trials for the treatment of inflammatory bowel disease. It is also believed that bacteria of the lower Gl also have enzymes which can digest glycosides, glucuronides, cyclodextrins, dextrans, and other carbohydrates, and ester prodrugs formed from these carbohydrates have been shown to deliver the parent active drugs selectively to the colon.
• glycoside conjugates may be useful for the delivery of steroids to the human colon.
• Other in vivo studies have suggested that glucouronide, cyclodextrin, and dextran prodrugs of steroids or non-steroidal anti-inflammatory drugs are useful for delivery of these drugs to the lower Gl tract.
• An amide of salicylic acid and glutamic acid has been shown to be useful for the delivery of salicylic acid to the colon of rabbit and dog.
• carbohydrate polymers such as amylase, arabinogalactan, chitosan, chondroiton sulfate, dextran, guar gum, pectin, xylin, and the like, or azo-group containing polymers can be used to coat a drug compound, or a drug may be impregnated or encapsulated in the polymer. It is believed that after oral administration, the polymers remain stable in the upper Gl tract, but are digested by the microflora of the lower Gl thus releasing the drug for treatment.
• One embodiment is use of a compound in the manufacture of a medicament for the treatment of inflammatory bowel disease, said compound having the formula
• Y is an organic acid functional group, or an amide or ester thereof comprising up to 12 carbon atoms, or Y is hydroxymethyl or an ether thereof comprising up to 12 carbon atoms, or Y is a tetrazolyl functional group,
• U is O, S, NR 1 , wherein R 1 is H, Ci 6 alkyl, Ci 7 acyl, benzoyl, biphenylacyl, Ci ⁇ sulfonyl, phenylsulfonyl, biphenylsulfonyl, trifluoromethylacyl, or trifloyl, and
• B is aryl or heteroaryl
• Another embodiment is use of a compound in the manufacture of a medicament for the treatment of inflammatory bowel disease, said compound having the formula
• Y is an organic acid functional group, or an amide or ester thereof comprising up to 12 carbon atoms, or Y is hydroxymethyl or an ether thereof comprising up to 12 carbon atoms, or Y is a tetrazolyl functional group,
• Another embodiment is use of a compound in the manufacture of a medicament for the treatment of inflammatory bowel disease, said compound having the formula
• Y is an organic acid functional group, or an amide or ester thereof comprising up to 12 carbon atoms, or Y is hydroxymethyl or an ether thereof comprising up to 12 carbon atoms, or Y is a tetrazolyl functional group,
• U is O, S, NR 1 , wherein R 1 is H, Ci 6 alkyl, Ci i acyl, benzoyl, biphenylacyl, Ci ⁇ sulfonyl, phenylsulfonyl, biphenylsulfonyl, trifluoromethylacyl, or trifloyl, and
• B is alkylphenyl
• Another embodiment is use of a compound in the manufacture of a medicament for the treatment of inflammatory bowel disease, said compound having the formula
• Y is an organic acid functional group, or an amide or ester thereof comprising up to 12 carbon atoms, or Y is hydroxymethyl or an ether thereof comprising up to 12 carbon atoms, or Y is a tetrazolyl functional group,
• A is -(CH 2 )6-, as or -CH 2 C ⁇ C-(CH 2 ) 3 -, wherein 1 or 2 carbon atoms may be substituted with S or O, or A is -(CH 2 )m-Ar-(CH 2 )o- wherein Ar is interarylene or heterointerarylene, the sum of m and o is from 1 to 4, and wherein one CH 2 may be substituted with S or O,
• U is O, S, NR 1 , wherein R 1 is H, Ci 6 alkyl, Ci 7 acyl, benzoyl, biphenylacyl, Ci ⁇ sulfonyl, phenylsulfonyl, biphenylsulfonyl, trifluoromethylacyl, or trifloyl, and
• B is p-f-butylphenyl
• Another embodiment is use of a compound in the manufacture of a medicament for the treatment of inflammatory bowel disease, said compound comprising
• Y is an organic acid functional group, or an amide or ester thereof comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl functional group;
• G is 1 ,3-interaryl or interheteroaryl, or -(CH2)3-; and B is aryl or heteroaryl.
• Another embodiment is use of a compound in the manufacture of a medicament for the treatment of inflammatory bowel disease, said compound comprising
• Y is an organic acid functional group, or an amide or ester thereof comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl functional group;
• G is 1 ,3-interaryl or interheteroaryl, or -(CH2)3-;
• B is phenyl
• Another embodiment is use of a compound in the manufacture of a medicament for the treatment of inflammatory bowel disease, said compound comprising
• Y is an organic acid functional group, or an amide or ester thereof comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl functional group;
• G is 1 ,3-interaryl or interheteroaryl, or -(CH2)3-; and B is hydroxyalkylphenyl.
• Another embodiment is use of a compound in the manufacture of a medicament for the treatment of inflammatory bowel disease, said compound having the formula
• Y is an organic acid functional group, or an amide or ester thereof comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl functional group;
• R is hydrocarbyl or hydroxyhydrocarbyl having from 1 to 12 carbon atoms
• G is 1 ,3-interaryl or interheteroaryl, or -(CH2)3-.
• Another embodiment is use of a compound in the manufacture of a medicament for the treatment of inflammatory bowel disease, said compound having the formula
• Another embodiment is use of a compound in the manufacture of a medicament for the treatment of inflammatory bowel disease, said compound having the formula
• Another embodiment is use of a compound in the manufacture of a medicament for the treatment of inflammatory bowel disease, said compound having the formula or a pharmaceutically acceptable salt or a prodrug thereof, wherein A, Y, and R 1 are as disclosed herein
• Another embodiment is use of a compound in the manufacture of a medicament for the treatment of inflammatory bowel disease, said compound having the formula
• Another embodiment is use of a compound in the manufacture of a medicament for the treatment of inflammatory bowel disease, said compound having the formula
• Y is an organic acid functional group, or an amide or ester thereof comprising up to 12 carbon atoms, or Y is hydroxymethyl or an ether thereof comprising up to 12 carbon atoms, or Y is a tetrazolyl functional group,
• U is O, S, NR 1 , wherein R 1 is H, Ci 6 alkyl, Ci 7 acyl, benzoyl, biphenylacyl, Ci ⁇ sulfonyl, phenylsulfonyl, biphenylsulfonyl, trifluoromethylacyl, or trifloyl, and
• B is aryl or heteroaryl
• Another embodiment is a compound having the formula or a pharmaceutically acceptable salt or a prodrug thereof, wherein
• Y is an organic acid functional group, or an amide or ester thereof comprising up to 12 carbon atoms, or Y is hydroxymethyl or an ether thereof comprising up to 12 carbon atoms, or Y is a tetrazolyl functional group,
• A is -(CH 2 )6-, as or -CH 2 C ⁇ C-(CH 2 ) 3 -, wherein 1 or 2 carbon atoms may be substituted with S or O, or A is
• U is O, S, NR 1 , wherein R 1 is H, Ci 6 alkyl, Ci i acyl, benzoyl, biphenylacyl, Ci ⁇ sulfonyl, phenylsulfonyl, biphenylsulfonyl, trifluoromethylacyl, or trifloyl, and
• Y is an organic acid functional group, or an amide or ester thereof comprising up to 12 carbon atoms, or Y is hydroxymethyl or an ether thereof comprising up to 12 carbon atoms, or Y is a tetrazolyl functional group,
• U is O, S, NR 1 , wherein R 1 is H, Ci 6 alkyl, Ci i acyl, benzoyl, biphenylacyl, Ci ⁇ sulfonyl, phenylsulfonyl, biphenylsulfonyl, trifluoromethylacyl, or trifloyl, and
• B is alkylphenyl
• Y is an organic acid functional group, or an amide or ester thereof comprising up to 12 carbon atoms, or Y is hydroxymethyl or an ether thereof comprising up to 12 carbon atoms, or Y is a tetrazolyl functional group
• A is -(CH 2 )6-, as or -CH 2 C ⁇ C-(CH 2 ) 3 -, wherein 1 or 2 carbon atoms may be substituted with S or O, or A is -(CH 2 )m-Ar-(CH 2 )o- wherein Ar is interarylene or heterointerarylene, the sum of m and o is from 1 to 4, and wherein one CH 2 may be substituted with S or O,
• U is O, S, NR 1 , wherein R 1 is H, Ci 6 alkyl, Ci 7 acyl, benzoyl, biphenylacyl, Ci ⁇ sulfonyl, phenylsulfonyl, biphenylsulfonyl, trifluoromethylacyl, or trifloyl, and B is p-f-butylphenyl
• Y is an organic acid functional group, or an amide or ester thereof comprising up to 12 carbon atoms, or Y is hydroxymethyl or an ether thereof comprising up to 12 carbon atoms, or Y is a tetrazolyl functional group
• G is 1 ,3- ⁇ nteraryl or interheteroaryl, or -(CH 2 )3-
• B is aryl or heteroaryl
• Y is an organic acid functional group, or an amide or ester thereof comprising up to 12 carbon atoms, or Y is hydroxymethyl or an ether thereof comprising up to 12 carbon atoms, or Y is a tetrazolyl functional group
• G is 1 ,3- ⁇ nteraryl or interheteroaryl, or -(CH 2 )3-
• B is phenyl
• Another embodiment is a compound comprising or a pharmaceutically acceptable salt or a prodrug thereof; wherein
• Y is an organic acid functional group, or an amide or ester thereof comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl functional group;
• G is 1 ,3-interaryl or interheteroaryl, or -(CH2)3-;
• B is hydroxyalkylphenyl.
• Y is an organic acid functional group, or an amide or ester thereof comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl functional group;
• R is hydrocarbyl or hydroxyhydrocarbyl having from 1 to 12 carbon atoms
• G is 1 ,3-interaryl or interheteroaryl, or -(CH2)3-.
• Another embodiment is a compound having the formula or a pharmaceutically acceptable salt or a prodrug thereof.
• Another embodiment is a compound having the formula
• Another embodiment is a compound having the formula
• Embodiments contemplated for each compound disclosed herein are use of the compound in the manufacture of a medicament for the treatment of glaucoma or ocular hypertension.
• Embodiments contemplated for each compound disclosed herein are use of the compound in the manufacture of a medicament for the treatment of inflammatory bowel disease.
• Embodiments contemplated for each compound disclosed herein are methods comprising administering an effective amount of the compound to a mammal for the treatment of glaucoma or ocular hypertension.
• Embodiments contemplated for each compound disclosed herein are methods comprising administering an effective amount of the compound to a mammal for the treatment of inflammatory bowel disease.
• Embodiments contemplated for each compound disclosed herein are compositions comprising the compound, wherein said compositions are ophthalmically acceptable liquids.
• Step 3 Deprotection of 3 to give 4 and 5 HF-pyridine (0.25 mL) was added to a solution of silyl ether 3 (97 mg, 0.17 mmol) in MeCN (3.4 mL) at O 0 C in a plastic scintillation vial. After 1 h at 0 0 C, the reaction mixture was allowed to warm to room temperature. After 30 min at room temperature, the reaction was quenched with saturated aqueous NaHCCh and extracted with EtOAc (3x20 mL). The combined extracts were washed with brine (10 mL), then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the crude residue by flash column chromatography on 4 g of silica gel (hexane -> EtOAc, gradient) afforded 3 mg (3%) of 3, 6 mg (8%) of fluoride 5 and 62 mg (80%) of alcohol 4.
• Aqueous lithium hydroxide (1 N, 0.3 mL, 0.3 mmol) was added to a solution of ester 4 (26 mg, 0.058 mmol) in THF (0.6 mL).
• Example 2 ⁇ -ffSJ-S- ⁇ -fi-Fluoro-hexylJ-phenyll ⁇ -oxo-oxazolidin ⁇ -ylmethoxymethylJ-thiophene ⁇ -carboxylic acid (7)
• Aqueous lithium hydroxide (1 N, 0.075 mL, 0.075 mmol) was added to a solution of ester 5 (6 mg, 0.013 mmol) in THF (0.15 mL). After 18 h at room temperature, the solvent was removed under a stream of nitrogen, the residue was acidified with 1.0 M HCI (1 mL) and the mixture was extracted with EtOAc (3 x 5 mL).
• a compound such as 2 would serve as a precursor to analogs of compounds 6 and 7 which replace the alpha chain oxygen atom with a carbon atom. This might be accomplished using the procedures in United States Provisional Patent Application No. 60/777,506, filed February 28, 2006, which is expressly incorporated by reference herein. Other analogs wherein the alpha chain thiophene is replaced by a different aryl or heteroaryl group are also envisioned.
• (R)-2-Oxo-imidazolidine-1 ,4-dicarboxylic acid 1 -benzyl ester 4-methyl ester would be prepared from (R)-N- Cbz-asparagine (derived from D-asparagine) according to the procedures described by Saijo et al., Chem. Pharm. Bull. 1980, 28, 1459-1467. In the thiazolidinone case, the above procedures described for the oxazolidinone case would apply directly. Other arylation conditions, such as those catalyzed by palladium complexes are also envisioned.
• the methyl ester moiety would be selectively reduced to the hydroxymethyl derivative using NaBhU in EtOH.
• alkaline hydrolysis of the C-1 ester moiety should also remove the Cbz group from the core ring nitrogen atom. Re-esterification of the C-1 acid with diazomethane would then allow selective alkylation or acylation or sulfonylation of the core ring nitrogen atom. Re-hydrolysis (using esterase if necessary for selectivity) would then afford the desired C-1 acid.
• HEK-293 cells stably expressing the human or feline FP receptor, or EPi, EP2, or EP4 receptors are washed with TME buffer, scraped from the bottom of the flasks, and homogenized for 30 sec using a Brinkman PT 10/35 polytron.
• TME buffer is added to achieve a final 40 ml volume in the centrifuge tubes (the composition of TME is 100 mM TRIS base, 20 mM MgCb, 2M EDTA; 10N HCI is added to achieve a pH of 7.4).
• the cell homogenate is centrifuged at 19000 r.p.m. for 20 min at 4° C using a Beckman Ti-60 rotor.
• the resultant pellet is resuspended in TME buffer to give a final 1 mg/ml protein concentration, as determined by Biorad assay.
• Radioligand binding competition assays vs. [ 3 H-]17 -phenyl PGFa (5 nM) are performed in a 100 ⁇ l volume for 60 min. Binding reactions are started by adding plasma membrane fraction. The reaction is terminated by the addition of 4 ml ice-cold TRIS-HCI buffer and rapid filtration through glass fiber GF/B filters using a Brandel cell harvester. The filters are washed 3 times with ice-cold buffer and oven dried for one hour.
• [ 3 H-] PGE2 (specific activity 180 Ci mmol) is used as the radioligand for EP receptors
• [ 3 H] 17-phenyl PGFa is employed for FP receptor binding studies
• Binding studies employing EPi, EP2, EP4 and FP receptors are performed in duplicate in at least three separate experiments A 200 ⁇ l assay volume is used Incubations are for 60 mm at 25 0 C and are terminated by the addition of 4 ml of ice-cold 50 mM TRIS-HCI, followed by rapid filtration through Whatman GF/B filters and three additional 4 ml washes in a cell harvester (Brandel)
• Competition studies are performed using a final concentration of 5 nM [ 3 H]-PGE2, or 5 nM [ 3 H] 17-phenyl PGFa and non-specific binding determined with 10 5 M of unlabeled PGE2, or 17-phenyl PGF2 ⁇ , according to receptor subtype studied METHODS FOR FLIPRTM STUDIES (
• prostaglandin receptors expressed hDP/Gqs5, hEPi, hEP 2 /Gqs5, hEP3A/Gq ⁇ 5, hEP4/Gqs5, hFP, hlP, hTP are cultured in 100 mm culture dishes in high-glucose DMEM medium containing 10% fetal bovine serum, 2 mM l-glutamine, 250 ⁇ g/ml geneticin (G418) and 200 ⁇ g/ml hygromycin B as selection markers, and 100 units/ml penicillin G, 100 ⁇ g/ml streptomycin and 0 25 ⁇ g/ml amphotericin B (b) CALCIUM SIGNAL STUDIES ON THE FLIPRTM
• HTS high-throughput
• CoRe concentration-response
• IQP Intraocular Pressure
• Intraocular pressure studies in dogs involve pneumatonometry performed on conscious Beagle dogs of both sexes (10- 15 kg) The animals remain conscious throughout the study and are gently restrained by hand Drugs are administered topically to one eye as a 25 ⁇ L volume drop, the other eye receives 25 ⁇ L vehicle (0 1 % polysorbate 80 10 mM TRIS) as a control Proparacaine (0 1 %) is used for corneal anesthesia during tonometry
• Intraocular pressure is determined just before drug administration and at 2, 4 and 6 hr thereafter on each day of the 5 day study Drug is administered immediately after the first IOP reading

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