WO2007095383A2 - Prodrugs - Google Patents

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Publication number
WO2007095383A2
WO2007095383A2 PCT/US2007/004189 US2007004189W WO2007095383A2 WO 2007095383 A2 WO2007095383 A2 WO 2007095383A2 US 2007004189 W US2007004189 W US 2007004189W WO 2007095383 A2 WO2007095383 A2 WO 2007095383A2
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WO
WIPO (PCT)
Prior art keywords
fluoro
phenyl
biphenyl
acid
chosen
Prior art date
Application number
PCT/US2007/004189
Other languages
French (fr)
Other versions
WO2007095383A3 (en
Inventor
Ruth J. Walton
Rachel M. Slade
J. Adam Willardsen
Warren S. Weiner
Mark B. Anderson
Original Assignee
Myriad Genetics, Inc.
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Application filed by Myriad Genetics, Inc. filed Critical Myriad Genetics, Inc.
Publication of WO2007095383A2 publication Critical patent/WO2007095383A2/en
Publication of WO2007095383A3 publication Critical patent/WO2007095383A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/08—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/32—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings and esterified hydroxy groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C233/07—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/11—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • C07C233/15—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/22—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/40—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/44—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a carbon atom of an unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C307/04—Diamides of sulfuric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/51—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/62—Halogen-containing esters
    • C07C69/65—Halogen-containing esters of unsaturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/61—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C07D257/06—Five-membered rings with nitrogen atoms directly attached to the ring carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the invention relates to compounds and pharmaceutical compositions.
  • AD Alzheimer's disease
  • Dementia is a brain disorder that seriously affects a person's ability to carry out normal daily activities.
  • AD Alzheimer's disease
  • the causes of AD are still unknown and there is no cure.
  • AD most commonly begins after the age of 60, with the risk of acquiring the disease increasing with age. Younger people can also get AD, but it is much less common. It is estimated that 3 percent of men and women ages 65 to 74 have AD. Almost half of those ages 85 and older may have the disease.
  • AD Alzheimer's disease is a complex disease that can be caused by genetic and environmental factors.
  • Plaques and tangles are found in the same brain regions that are affected by neuronal and synaptic loss. Neuronal and synaptic loss is universally recognized as the primary cause of decline in cognitive function in AD patients. The number of tangles is more highly correlated with cognitive decline than amyloid load in patients with AD (Albert PNAS 93: 13547-13551 (1996)). The cellular, biochemical, and molecular events responsible for neuronal and synaptic loss in AD are not known. A number of studies have demonstrated that amyloid can be directly toxic to neurons resulting in behavioral impairment (see, e.g., Iversen et al. Biockem. J. 311 : 1 -16 (1995); Weiss et al. J.
  • A/?) deposition causes some forms of AD was provided by genetic and molecular studies of some familial forms of AD (FAD). ⁇ See, e.g. , Ii Drugs Aging 7(2):97-109 (1995); Hardy PNAS 94(6):2095-7 (1997); and Selkoe J. Biol. Chem. 271(31): 18295-8 (1996)).
  • the amyloid plaque buildup in AD patients suggests that abnormal processing of A ⁇ may be a cause of AD.
  • a ⁇ is a peptide of 39 to 42 amino acids and is the core of senile plaques observed in all Alzheimer's disease cases.
  • FAD familial Alzheimer's disease
  • the first of the FAD genes codes for the A ⁇ precursor, amyloid precursor protein (APP) (Selkoe J. Biol. Chem. 271 (31 ): 18295-8 (1996)). Mutations in the APP gene are very rare, but all of them cause AD with 100% penetrance and result in elevated production of either total A/3 or A/? 4 2, both in model transfected cells and transgenic animals.
  • Two other FAD genes code for presenilin 1 and 2 (PSl , PS2) (Hardy PNAS 94(6):2095-7 (1997)).
  • PSl presenilin 1 and 2
  • PS2 Kondy PNAS 94(6):2095-7 (1997).
  • the presenilins contain 8 transmembrane domains and several lines of evidence suggest that they are involved in intracellular protein trafficking. Other studies suggest that the presenilins function as proteases.
  • AD Alzheimer's disease
  • memantine is a NMDA receptor antagonist.
  • the drugs currently used for treating AD including memantine and the acetylcholine esterase inhibitors, are marginally efficacious and have undesirable side- effects. Thus, there is a large unmet need for better and safer drugs.
  • the invention provides prodrugs of phenyl alkanoic acids and analogs thereof.
  • the compounds of the invention are comprised of a phenyl alkanoic acid moiety and a prodrug moiety.
  • the invention provides prodrugs of 2-halo-4-biphenyl alkanoic acids.
  • the prodrugs of the invention can enhance and/or improve delivery of the phenyl alkanoic acid moiety to a desired target tissue.
  • the invention provides a compound which is a phenyl alkanoic acid (e.g., 2-halo-4-biphenyl alkanoic acid) prodrug where the prodrug moiety is covalently linked to the active moiety through the alkanoic acid moiety.
  • the prodrug moiety enhances delivery of the phenyl alkanoic acid moiety (e.g., 2-halo-4-biphenyl alkanoic acid) to a desired target tissue, organ, and/or cell-type.
  • the prodrug can facilitate delivery of the 2-halo- 4-biphenyl alkanoic acid across the blood-brain-barrier.
  • the prodrug moiety enhances delivery of the phenyl alkanoic acid moiety e.g., (2-halo-4-biphenyl alkanoic acid) to a tumor or cancer cell.
  • the invention provides a pharmaceutical composition having a phenyl alkanoic acid prodrug and a pharmaceutically acceptable carrier.
  • the phenyl alkanoic acid moiety is a 2-halo-4-biphenyl alkanoic acid.
  • the pharmaceutical composition is suitable for oral administration.
  • the pharmaceutical composition is formulated in a capsule or tablet unit dosage form.
  • the invention provides a pharmaceutically acceptable salt of a phenyl alkanoic acid prodrug (e.g., 2-halo-4-biphenyl alkanoic acid prodrug).
  • a phenyl alkanoic acid prodrug e.g., 2-halo-4-biphenyl alkanoic acid prodrug.
  • the invention provides a compound which is a phenyl alkanoic acid (e.g., 2-halo-4-biphenyl alkanoic acid) prodrug where the prodrug moiety is covalently linked to the active moiety through the alkanoic acid.
  • the prodrug enhances the efficacy and/or improves the safety profile of the parent phenyl alkanoic acid.
  • An enhancement of efficacy and/or improvement is safety profiles can be accomplished e.g., by improving bioavailability, improving up-take in a target tissue, and/or improving patient adherence to dosing regimens.
  • the prodrug moiety enhances delivery of the 2-halo-4-biphenyl alkanoic acid to a desired target tissue, organ, and/or cell-type.
  • the prodrug can facilitate delivery of the 2-halo-4-biphenyl alkanoic acid across the blood-brain-barrier.
  • the prodrug moiety enhances delivery of the 2-halo-4-biphenyl alkanoic acid to a tumor or cancer cell.
  • the invention provides a method of treating a patient in need of such treatment by administering to the patient a therapeutically effective amount of a pharmaceutical composition having one or more prodrugs of the invention.
  • the invention provides a method of treating a disease characterized by abnormal amyloid precursor protein processing by (1) identifying a patient in need of such treatment, and (2) administering to the patient a therapeutically effective amount of a pharmaceutical composition having one or more phenyl alkanoic acid prodrugs of the invention (e.g., 2-halo-4-biphenyl alkanoic acid prodrug).
  • a pharmaceutical composition having one or more phenyl alkanoic acid prodrugs of the invention e.g., 2-halo-4-biphenyl alkanoic acid prodrug.
  • biochemical disease markers include, for example, amyloid beta peptide (A/3), AjS 42 , and tau.
  • the invention general relates to compounds of Formula I and analogs thereof:
  • Rl is chosen from -H and C1-C6 alkyl
  • R2 is chosen from -H and C1 -C6 alkyl
  • Rl and R2 can be taken together to form a C3-C7 carbocyclic ring
  • R3 is a moiety chosen from a central nervous system penetration enhancer, a blood-brain-barrier penetration enhancer, a bioavailability enhancer, and a tumor targeting agent;
  • X is chosen from chloro, fluoro, bromo, and iodo
  • L is a covalent bond in the compounds of Formulae I-III.
  • X is fluoro in the compounds of Formulae I-III.
  • Rl is -CH 3 in the compounds of Formulae I-III.
  • R2 is hydro.
  • the carbon attached to Rl and R2 is chiral and has the (R) stereochemical configuration.
  • Rl and R2 are independently chosen from -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , - CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , and -CH 2 CH(CH 3 )CH 3 .
  • the stereochemical configuration at the carbon attached to Rl and R2 is (R) in the compounds of Formulae I-III. In some embodiments and aspects of the invention, the stereochemical configuration at the carbon attached to Rl and R2 is (S) in the compounds of Formulae I-III. In some embodiments and aspects of the invention, the stereochemical configuration at the carbon attached to Rl and R2 is (+) in the compounds of Formulae I-III. In some embodiments and aspects of the invention, the stereochemical configuration at the carbon attached to Rl and R2 is (-) in the compounds of Formulae I-III.
  • the carbon attached to Rl and R2 is chiral, and the compound is in a racemic form. In some embodiments and aspects of the invention, in the compounds of Formula I, the carbon attached to Rl and R2 is chiral, and the composition has a ratio of more than 50:50, 60:40, 75:25; 90:10, 95:5, 98:2 or 99: 1 (R) to (S) enantiomer.
  • R3 is chosen from -NH 2 , -
  • -L-R3, taken together is chosen from - NHCH 2 CH 2 CH 2 CH 2 NH 2 , -NHCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 NH 25 -NHCH 2 - ⁇ yridinyl, - NH-cyclopentyl, -NHCH 2 (4-methoxy-phenyl), -NH-cyclopropyl, ⁇ NHCH 2 (phenyl)CH 2 - imadozolyl, -NHCH 2 CH 2 (2,4-dimethyl-phenyl) > -NHCH 2 (phenyl), -NHCH 2 (3,5- dimethoxy-phenyl), -NHC(CH 3 ) 2 , -NHCH 2 CH 2 (I -methyl-pyrrolidinyl), -NHCH 2 (4- trifluoromethoxy-phenyl), -NHCH 2 CH 2 CH 3 , -NHCH 2 (4-trifluoromethyl- ⁇ henyl),
  • -L-R3 is chosen from -NCH 2 S(O) 2 OH, -NCH 2 CH 2 S(O) 2 OH, -NCH 2 CH 2 CH 2 S(O) 2 OH, -NCH 2 CH 2 CH 2 CH 2 S(O) 2 OH, - NCH 2 CH 2 CH 2 CH 2 CH 2 S(O) 2 OH, -NCH 2 CH 2 CH 2 CH 2 CH 2 S(O) 2 OH, -NCH 2 CH 2 CH 2 CH 2 CH 2 CH 2 S(O) 2 OH 1 -NCH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 S(O) 2 OH 1 -N CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 S(O) 2 OH, -
  • one or more carbons of — L-R3 can be substituted with one or more substituents.
  • R3 is chosen from cis-inositol, epi-inositol, allo- inositol, neo-inositol, myo-inositol, muco-inositol, scyllo-inositol, L-(-)-chiro-inositol, and R-(+)-chiro-inositol.
  • the —OH groups of the inositol moiety can be substituted with 6, 5, 4, 3, 2 or 1 compounds of Formulae I-III.
  • the phenyl alkanoic acid moiety of the prodrug is a 2-halo-4-biphenyl alkanoic acid. In one aspect, the phenyl alkanoic acid moiety of the prodrug is 2-(2-fluoro- biphenyl-4-yl)-propionic acid.
  • R3 is chosen from, -CH 3 , -dehydroascorbate, - CH 2 CH 2 (4-trifluoromethyl-phenyl), -CH 2 CH 2 O(4-trifluoromethyl-phenyl), -CH 2 (4- fluoro-phenyl), -CH 2 CH 2 OCH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , -CH 2 CH 2 (3- methoxy-phenyl), -CH 2 CH 2 (morpholino), -CH2CH 2 (phenyl), -CH 2 CH 2 (cyclopro ⁇ yl), - CH 2 CH 2 (imidazolyl), -CH 2 CH 2 (piperidinyl), -CH 2 CH 2 O(4-chloro-phenyl), -CH 2 (4- dimethylamino-phenyl), -phenyl, -(4-chloro-phenyl), -(4
  • L is a bond. In some aspects of this embodiment, L is -(CH 2 ) n O(CH 2 ) n -. In some aspects of this embodiment, L is -O-. In some aspects of this embodiment, X is fluoro. In some aspects of this embodiment, Rl is -CH 3 . In one aspect of this embodiment, R2 is hydro. In another aspect of this embodiment, the carbon attached to Rl and R2 is chiral and has the (R) configuration. In some aspects of this embodiment, Rl is -CH 3 .
  • Rl and R2 are independently chosen from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , - C(CH 3 ) 3 , -CH(CH 3 )CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , and -CH 2 CH(CH 3 )CH 3 .
  • R3 is chosen from, -OCH 3 , dehydroascorbate, - OCH 2 CH 2 (4-trifIuoromethyl-phenyl), -OCH 2 CH 2 O(4-trifluoromethyl-phenyl), -OCH 2 (4- fluoro-phenyl), -OCH 2 CH 2 OCH 2 CH 2 N(CH 3 ) 2 , -OCH 2 CH 2 OCH 2 CH 2 OCH 3 , - OCH 2 CH 2 (3-methoxy-phenyl), -OCH 2 CH 2 (morpholino), -OCH 2 CH 2 (phenyl), - OCH 2 CH 2 (cyclopropyl), -OCH 2 CH 2 (imidazolyl), -OCH 2 CH 2 (piperidinyl), - OCH 2 CH 2 O(4-chloro-phenyl), -OCH 2 (4-dimethylamino-phenyl), -O( ⁇ henyl),
  • R3 is chosen from -
  • -R3 is capable of enhancing CNS penetration and/or penetration of the blood-brain barrier.
  • -R3 is chosen from ascorbic acid analogs, choline, choline analogs, taurine, taurine analogs, amino acids, glycine, tris, and GABA.
  • -R3 is chosen from Vitamin B3 and Vitamin B3 analogs.
  • -R3 is chosen from vitamin D and vitamin D3 analogs.
  • -R3 is chosen from sulfonates and phosphates.
  • -R3 is chosen from morpholine and morpholine salts.
  • -R3 is chosen from phenethylamines, dihydropyridine, and azomethines. [0048] In one embodiment, -R3 is chosen from esters, amino acid, peptide, carbamate, polyethylene glycol, vitamins, phosphates, neuroactive amines, amidines, and imines.
  • -R3 is a glyceride or glyceride analog.
  • R3 is a moiety chosen from ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 1-propanesulfonic acid, 1 ,3-propanedisulfonic acid, 1 ,4- butanedisulfonic acid, 1,5-pentanedisulfonic acid, 2-aminoethanesulfonic acid, 4- hydroxybutane-1-sulfonic acid.
  • -R3 is a moiety chosen from 1-butanesulfonic acid, 1-decanesulfonic acid, 2-propanesulfonic acid, 3-pentanesulfonic acid, and 4-heptanesulfonic acid.
  • -R3 is a moiety chosen from l ,7-dihydroxy-4-heptanesulfonic acid and 3-amino-l-propanesulfonic acid.
  • -R3 is
  • Ra-Rg and Ra-Rg can be optionally substituted, and are independently chosen from -H, halo, -OH, alkyl, aryl, amine, ether, amide, ester, urea, carbamate, imine, nitro, sulfide, sulfoxide, and sulfone.
  • -R3 is
  • R is a phenyl alkanoic acid moiety and the other R- groups are independently chosen from a phenyl alkanoic acid moiety, -H, or an optionally substituted alkyl or acyl group.
  • the compounds of the invention are of Formula II below, wherein the substituents are defined as in any of the other embodiments (and/or aspects) of the invention and Z is chosen from N or S.
  • the invention provides prodrugs of a compound of Formula III below
  • the prodrugs of the invention Ce. g., those of Formula I-III) can improve a number of therapeutically important properties of the parent drug, such as improved blood-brain barrier penetration, improved bioavailability, improved delivery to cancerous tissue, improved tableting properties, improved metabolic stability, improved, improved pharmacokinetic properties, and the such.
  • the phenyl alkanoic acid moiety of the prodrug, or analog thereof is an abeta42 (AjS 42 ) lowering agent.
  • the AjS 42 lowering agents for use in the invention can be a known Aj3 42 lowering agents such as (R)-2-(2-fluoro-4- biphenylyl)propionic acid, 5 [ 1 -(2-Fluoro-biphenyl-4-yl)- 1 -methyl-ethyl]-2H-tetrazole, 2-(4-isobutyl-phenyl)-2-methyl propionic acid, or 2-(2-fluoro-l,l '-biphenyl-4-yl)-2- methylpropionic acid.
  • Aj3 42 lowering agents such as (R)-2-(2-fluoro-4- biphenylyl)propionic acid, 5 [ 1 -(2-Fluoro-biphenyl-4-yl)- 1 -methyl-ethyl]-2H-tetrazole, 2-(4-isobutyl-phenyl)-2-methyl propionic acid, or 2-(2-fluoro
  • AjS 42 lowering agents for use in the combination formulations and treatments of the invention are given in, e.g., WO 01/78721, WO 2004/073705, WO 2004/064771, and WO 2004/074232, and PCT/US2005/009595 (each of which is herein incorporated by reference).
  • the phenyl alkanoic acid moiety is replaced with an A/3 42 lowering agent, and the — L-R3 moiety can be as in any of the other embodiments or aspects of the invention.
  • AjS 42 lowering agents include, but are not limited to, those having the following Formulae (the R-groups in these compounds below are to be taken as independent of the R-groups identified elsewhere in the specification):
  • R is chosen from -H 5 -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , and CH 2 CH 2 CH 2 CH 3 (or can be taken together with R 2 to give a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or a cyclohexyl ring);
  • R 2 is chosen from -H, -CH 3 , -CH 2 CH 3 . -CH 2 CH 2 CH 3 , and - CH 2 CH 2 CH 2 CH 3 , (or can be taken together with Ri to give a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or a cyclohexyl ring);
  • R 3 is chosen from -COOH 5 -COOR 6 , -CONH 2 , -CONHR 6 , -CONR 6 R 7 , -CONHSO 2 R 6 , tetrazolyl, and a -COOH bioisostere;
  • R 6 is chosen from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , and - CH 2 CH 2 CH 2 CH 3 .
  • R 7 is chosen from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , and - CH 2 CH 2 CH 2 CH 3 .
  • m is an integer chosen from 0, 1, 2, and 3.
  • n is an integer chosen from 0, 1, 2, and 3.
  • Examples of the phenyl alkanoic acid moiety of the prodrug compounds for use in the invention include those as shown above (and below), including enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts thereof.
  • the compounds described in this invention disclosure can be made by an ordinary artisan skilled in the art of organic chemistry synthesis.
  • Additional phenyl alkanoic acid moieties (or analogs thereof) of A/3 42 lowering agents that can be used in the prodrugs of the invention include: 2-methyl-2- (2-fluoro-4'-trifluoromethylbiphen-4-yl) propionic acid; 2-methyl-2-(2-fluoro- 4'cyclohexyl biphen-4-yl) propionic acid;l- (2-fluoro-4'-trifluoromethylbiphenyl-4-yl) cyclopropanecarboxylic acid;l-(4'-cyclohexyl-2-fluorobiphenyl-4-yl) cyclopropanecarboxylic acid;l-(4'-benzyloxy-2-fluorobiphenyl-4-yl) cyclopropanecarboxylic acid;l-(2-fluoro-4' ⁇ isopropyloxybiphenyl-4-yl) cyclopropanecarboxylic acid;l-(2-fluoro
  • acylamino (or “acylamido”) groups are any C 1-6 acyl (alkanoyl) as defined herein, attached to an amino nitrogen, e.g., acetamido, chloroacetamido, propionamido, butanoylamido, pentanoylamido and hexanoylamido, as well as aryl-substituted Cl-6 acylamino groups, e.g., benzoylamido, and pentafluorobenzoylamido.
  • acyloxy groups are any Cl -6 acyl (alkanoyl) as definided herein, attached to an oxy (— O— ) group, e.g., formyloxy, acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy, and hexanoyloxy.
  • alkenyl refers to, by itself or as part of another group, a straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, including at least one double bond between two of the carbon atoms in the chain.
  • alkenyl groups include ethenyl, 1 -propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl and 2-butenyl.
  • alkoxy refers to both an -O-alkyl and an -O- cycloalkyl group, as defined herein.
  • Lower alkoxy refers to -O-lower alkyl groups.
  • Non-limiting alkoxy groups include oxygen substituted by one of the Cl -10 alkyl groups mentioned above, which may be optionally substituted.
  • Alkoxy substituents include, without limitation, halo, morpholino, amino including alkylamino and dialkylamino, and carboxy including esters thereof.
  • alkyl refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups.
  • the alkyl group has 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “ 1 to 20” refers to each integer in the given range; e.g., "1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms). In another aspect, it is a medium size alkyl having 1 to 10 carbon atoms.
  • the alkyl group may be substituted or unsubstituted.
  • the substituent group(s) is preferably one or more individually selected from cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C- amido, N-amido, C-carboxy, O-carboxy, cyanato, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, and amino.
  • Cl-10 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec butyl, tert butyl, 3 pentyl, hexyl and octyl groups, which may be optionally substituted.
  • alkylthio refers to both an S-alkyl and an -S-cycloalkyl group, as defined herein.
  • Non-limiting alkylthio groups include sulfur substituted by one of the Cl-10 alkyl groups mentioned above, which may be optionally substituted. Also included are the sulfoxides and sulfones of such alkylthio groups.
  • alkynyl refers to a straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, wherein there is at least one triple bond between two of the carbon atoms in the chain.
  • Typical alkynyl groups include ethynyl, 1-propynyl, l-methyl-2-propynyl, 2-propynyl, 1- butynyl and 2-butynyl.
  • amino refers to an — NR 1 7R18 group, with Ri7 and Rig being hydro to give an -NH 2 group.
  • R ] 7 and Ris may also be hydro, C l-10 alkyl or cycloalkyl groups, or Rj 7 and R) 7 are combined with the N to form a ring structure, such as a piperidine, or Ri 7 and Rig are combined with the N to form a ring, such as a piperazine.
  • One of Ri 7 and Ri 8 can be hydro and the other alkyl or cycloalkyl.
  • the alkyl or cycloalkyl group may be optionally substituted.
  • aryl refers to, by itself or as part, of another group a monocyclic, bicyclic or tricyclic aromatic groups containing from 6 to 14 carbons in the ring portion.
  • Non-limiting aryl groups include C6-14 aryl, preferably C6-10 aryl.
  • Typical C6-14 aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups.
  • arylalkyl refers to any of the Cl-10 alkyl groups substituted by any of the above-mentioned C6-14 aryl groups as defined herein.
  • the arylalkyl group is benzyl, phenethyl or naphthylmethyl.
  • arylalkenyl is used herein to mean any of the above-mentioned C2-10 alkenyl groups substituted by any of the above-mentioned C6-14 aryl groups.
  • arylalkynyl refers to any of C2-10 alkynyl groups substituted by any of the above-mentioned C6-14 aryl groups as defined herein.
  • arylalkoxy refers to any of the Cl-IO alkoxy groups substituted by any of the aryl groups as defined herein, which may be optionally substituted. Examples of arylalkoxy groups include benzyloxy and phenethyloxy.
  • aryloxy refers to oxygen substituted by any of the C6-14 aryl groups defined herein, which may be optionally substituted.
  • aryloxy groups include phenoxy and 4-methylphenoxy.
  • arylthio refers to both an -S-aryl and an -S-heteroaryl group, as defined herein.
  • carbocycle or “carbocyclic” refers to cycloalkyl and partially saturated carbocyclic groups.
  • Non-limiting carbocyclic groups are C3-8 cycloalkyl and cycloalkenyl.
  • Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, and cycloheptyl.
  • cyano refers to a -C ⁇ N group.
  • cyanato refers to a -CNO group.
  • halo or halogen group refers to a fluoro, chloro, bromo and iodo group.
  • haloalkyl refers to Cl-10 alkyl groups substituted by one or more fluoro, chloro, bromo or iodo groups, e.g., fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1 ,1-difluoroethyl, chloromethyl, chlorofluoromethyl and trichloromethyl groups.
  • the halo groups can be independently selected.
  • halophenyl refers to a phenyl group ' substituted with one or more fluoro, chloro, bromo or iodo groups.
  • the halo groups can be independently chosen, e.g., a di halo substituted phenyl can have a fluoro and a chloro substituent.
  • hydro refers to an — H group.
  • hydroxyl refers to an -OH group.
  • heteroaryl refers to groups having 5 to 14 ring atoms; 6, 10 or 14 ⁇ electrons shared in a cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms.
  • Non-limiting heteroaryl groups include thienyl (thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (furanyl), isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, including without limitation 2H-pyrrolyl ?
  • heteroaryl group contains a nitrogen atom in a ring
  • nitrogen atom may be in the form of an N-oxide, e.g., a pyridyl N oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide.
  • heteroaryl groups can be monocyclic, bicyclic, tricyclic, and/or polycyclic.
  • heteroaryloxy refers to oxygen substituted by a heteroaryl group as defined herein, which may be optionally substituted.
  • Non- limiting heteroaryloxy groups include pyridyloxy, pyrazinyloxy, pyrrol yloxy, pyrazolyloxy, imidazolyloxy and thiophenyloxy.
  • heterocycle refers to a saturated or partially saturated 3-7 membered monocyclic, 7-10 membered bicyclic ring system, or 7-14 membered polycyclic ring system, which consists of carbon atoms and from one to five heteroatoms independently selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, the nitrogen can be optionally quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, and wherein the heterocyclic ring can be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
  • Non-limiting saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetronoyl and tetramoyl groups.
  • heteroarylalkoxy refes to a Cl-IO alkoxy groups substituted by a heteroaryl group as defined herein, which may be optionally substituted.
  • isocyanato refers to a -NCO group.
  • isothiocyanato refers to a -NCS group.
  • nitro refers to a -NO 2 group.
  • R can be a cycloalkyl or alkyl group. The alkyl or cycloalkyl group may be optionally substituted.
  • R can be a cycloalkyl or alkyl group. The alkyl or cycloalkyl group may be optionally substituted.
  • sulfonamido refers to a 7 Ri 8 .
  • Rj 7 and Rj 8 may be hydro, Cl-10 alkyl or cycloalkyl groups, or Ri 7 and Ri 8 are combined with the N to form a ring structure, such as a piperidine, or R] 7 and Rig are combined with the N and to form a ring, such as a piperazine.
  • One Of Ri 7 . and Ri 8 can be hydro and the other alkyl or cycloalkyl.
  • the alkyl or cycloalkyl group may be optionally substituted.
  • R can be a cycloalkyl or alkyl group. The alkyl or cycloalkyl group may be optionally substituted.
  • thiocyanato refers to a -CNS group.
  • trihalomethanesulfonamido refers to a -group with X being independently selected halo groups and Ri 7 as defined herein.
  • Ri 7 and Ris may be hydro, Cl -10 alkyl or cycloalkyl groups, or Ri 7 and Rig are combined with the N to form a ring structure, such as a piperidine, or Ri 7 and Rj g are combined with the N and to form a ring, such as a piperazine.
  • R] 7 and Ri s can be hydro and the other alkyl or cycloalkyl.
  • the alkyl or cycloalkyl group may be optionally substituted.
  • Ri 8 may be hydro; Ri 7 and Rig may be Cl -I O alkyl or cycloalkyl groups, or R ]7 and Ri 8 are combined with the N to form a ring structure, such as a piperidine, or Rj 7 and Rig are combined with the N and to form a ring, such as a piperazine.
  • R 17 and Ri 8 can be hydro and the other alkyl or cycloalkyl.
  • the alkyl or cycloalkyl group may be optionally substituted.
  • Ri 7 and R ⁇ may be hydro, Cl- 10 alkyl or cycloalkyl groups, or Ri 7 and Ris are combined with the N to form a ring structure, such as a piperidine, or R] 7 and Ri $ are combined with the N and to form a ring, such as a piperazine.
  • One of Ri 7 and Ri 8 can be hydro and the other alkyl or cycloalkyl.
  • the alkyl or cycloalkyl group may be optionally substituted.
  • Ri 7 may be hydro;
  • Ri 7 and Ris may be Cl-10 alkyl or cycloalkyl groups. The alkyl or cycloalkyl group may be optionally substituted.
  • Ri 7 and R ] 8 may be hydro, C l-10 alkyl or cycloalkyl groups, or R) 7 and Rig are combined with the N to form a ring structure, such as a piperidine, or Ri 7 and Ri 8 are combined with the N and to form a ring, such as a piperazine.
  • Rj 7 and Ri 8 can be hydro and the other alkyl or cycloalkyl.
  • the alkyl or cycloalkyl group may be optionally substituted.
  • optional substituents include one or more halo, hydroxy, carboxyl, amino, nitro, cyano, C1 -C6 acylamino, C1-C6 acyloxy, C 1 -C6 alkoxy, aryloxy, alkylthio, C6-C10 aryl, C4-C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl(C2-C6)alkenyl, C6-C10 aryl(C2-C6)alkynyl, saturated and unsaturated heterocyclic or heteroaryl unless otherwise specified.
  • optional substituents include one or more halo, C1 -C6 haloalkyl, C6-C 10 aryl, C4-C7 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl(Cl-C6)alkyl, C6-C10 aryl(C2-C6)alkenyl, C6-C10 aryl(C2- C6)alkynyl, C1 -C6 hydroxyalkyl, nitro, amino, ureido, cyano, C1 -C6 acylamino, hydroxy, thiol, C1 -C6 acyloxy, azido, C1-C6 alkoxy, carboxy or Cl -2 alkylenedioxy (e.g., methylenedioxy) unless otherwise specified.
  • C1 -C6 haloalkyl C6-C 10 aryl, C4
  • the term "ascorbic acid analog” refers to compounds such as ⁇ -Bromo- ⁇ -deoxy-L-ascorbic acid, dehydroascorbic acid (dehydroascorbate), 6- halo-ascorbates, 6-bromo-6-deoxy dehydroascorbic acid, 6-halo-dehydroascorbic acids, and the such (see e.g., Corpe et al. JBC 280:5211-20 (2005)).
  • choline analogs refers to compounds such as CDP-choline (cytidine 5'-diphosphocholine) and N-cyclohexylcholine, see e.g., Buccafusco et al. J Alzheimers Dis. 2004 Dec;6(6 Suppl):S85-92; Geldenhuys et al. J Drug Target. 2005 May;13(4):259-66; and US patent publication no. 2005/0227993, pubished Oct. 13, 2005, each of which is herein incorporated by reference in its entirety.
  • glyceride refers to a compound of Formula I wherein -R3 or -L-R3 has a glyceride moiety, e.g., CH 2 OR 3Ct CHORgCH 2 OR g , CH 2 OgRCHORa C tCH 2 ORg, or CH 2 ORgCHOR g CH 2 OR ac where R act is the active agent and each R g is independently chosen from — H, acyl, alkyl, acyloxy, and cycloalkyl, and optionally substituted versions thereof. See e.g., Kahn et al. Eur J Med Chem. 2005 Apr;40(4):371-6 and Kahn et al. Pharmazie 2005 Feb;60(2): 1 10-4, each of which is herein incorporated by reference in its entirety.
  • taurine analog refers to a compound of Formula I wherein -R3 or — L-R3 is a taurine analog or derivative such as taltrimide, tramiprosate, acamprosate, tauromustine, N-pivaloyltaurine, 2- aminocycloalkanesulfonic acids, See e.g., Gupta et al. Curr Med Chem. 2005;12(17):2021-39 and Machetti et al. Adv Exp Med Biol. 2000;483:399-401 , each of which is herein incorporated by reference in its entirety.
  • prodrug refers to a derivative of a parent drug molecule that requires transformation within the body in order to release the active drug, and that has improved physical and/or delivery properties over the parent drug molecule.
  • Prodrugs are designed to enhance pharmaceutically and/or pharmacokinetically based properties associated with the parent drug molecule.
  • the advantage of a prodrug lies in its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent drug, or it enhances absorption from the digestive tract, or it may enhance drug stability for long- term storage.
  • compositions having one or more compounds of Formulae I-III are given in the Examples.
  • the invention also includes pharmaceutical compositions having one or more compounds of Formulae I-III and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable salt of the compound of the present invention is exemplified by a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like, and a salt with an organic acid such as acetic acid, propionic acid, succinic acid, maleic acid, fumaric acid, benzoic acid, citric acid, malic acid, methanesulfonic acid, benzenesulfonic acid and the like.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like
  • an organic acid such as acetic acid, propionic acid, succinic acid, maleic acid, fumaric acid, benzoic acid, citric acid, malic acid, methanesulfonic acid, benzenesulfonic acid and the like.
  • pharmaceutically acceptable salts include acid salt of inorganic bases, such as salts containing alkaline cations (e.g., Li+, Na+ or K+), alkaline earth cations (e.g., Mg++, Ca++ or Ba++), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations, such as those arising from protonation of peralkylation of thriethylamine, N,N-diethylamine, N,N-dicyclohexylamine, pyridine, N 5 N- dimethylaminopyridine (DMAP), l,4-diazabiclo[2.2.2]octane (DABCO), 1,5- diazavicyclo[4.3.0]non-5-ene (DBN) and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
  • alkaline cations
  • the compounds of Formulae I-III can contain asymmetric carbon atoms and can therefore exist in racemic and optically active forms.
  • optical isomers or enantiomers, racemates, and diastereomers are also encompassed in the compounds of Formula I-III.
  • the methods of present invention include the use of all such isomers and mixtures thereof. Methods of separation of enantiomeric and diastereomeric mixtures are well known to one skilled in the art.
  • the present invention encompasses any isolated racemic or optically active form of compounds described in Formulae I-III, or any mixture thereof.
  • the compounds of this invention are typically administered in combination with a pharmaceutically acceptable carrier through any appropriate route, e.g., parenteral, oral, or topical administration, in a therapeutically acceptable amount.
  • the phenyl alkanoic acid prodrug tablets can be manufactured using e.g., a high shear wet granulation method incorporating pre-blending and pre-milling to reduce the size of the large particles in the drug substance. Once granulated, the material can be dried, milled and blended again. The final powder blend can be compressed into tablets on a high-speed rotary press and the resulting tablets coated in a perforated pan.
  • Soft gelatin capsules can be prepared in which capsules contain a mixture of the active pharmaceutical ingredient and vegetable oil or non-aqueous, water miscible materials such as, for example, polyethylene glycol and the like.
  • Hard gelatin capsules may contain granules of the active pharmaceutical ingredient in combination with a solid, pulverulent carrier, such as, for example, lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin.
  • Tablets are typically made by molding, by compression or by generally accepted tablet forming methods. Accordingly, compressed tablets are usually prepared by large-scale production methods while molded tablets often involve small- scale operations.
  • Tablets for oral use are typically prepared in the following manner, although other techniques may be employed.
  • the solid substances are ground or sieved to a desired particle size, and the binding agent is homogenized and suspended in a suitable solvent.
  • the active pharmaceutical ingredient and auxiliary agents are mixed with the binding agent solution.
  • the resulting mixture is moistened to form a uniform suspension.
  • the moistening typically causes the particles to aggregate slightly, and the resulting mass is gently pressed through a stainless steel sieve having a desired size.
  • the layers of the mixture are then dried in controlled drying units for determined length of time to achieve a desired particle size and consistency.
  • the granules of the dried mixture are gently sieved to remove any powder.
  • disintegrating, antifriction, and anti-adhesive agents are added.
  • the mixture is pressed into tablets using a machine with the appropriate punches and dies to obtain the desired tablet size.
  • the operating parameters of the machine may be selected by the skilled artisan.
  • Various tablet formulations may be made in accordance with the present invention. These include tablet dosage forms such as sugar-coated tablets, film- coated tablets, enteric-coated tablets, multiple-compressed tablets, prolonged action tablets and the like.
  • Sugar-coated tablets SCT are compressed tablets containing a sugar coating. Such coatings may be colored and are beneficial in covering up drug substances possessing objectionable tastes or odors and in protecting materials sensitive to oxidation.
  • Film-coated tablets (FCT) are compressed tablets that are covered with a thin layer or film of a water-soluble material. A number of polymeric substances with film-forming properties may be used. The film coating imparts the same general characteristics as sugar coating with the added advantage of a greatly reduced time period required for the coating operation.
  • Enteric-coated tablets are also suitable for use in the present invention.
  • Enteric-coated tablets are compressed tablets coated with substances that resist dissolution in gastric fluid but disintegrate in the intestine.
  • Enteric coating can be used for tablets containing drug substances that are inactivated or destroyed in the stomach, for those which irritate the mucosa or as a means of delayed release of the medication.
  • MCT Multiple compressed tablets
  • layered tablets are prepared by compressing additional tablet granulation on a previously compressed granulation. The operation may be repeated to produce multilayered tablets of two, three or more layers.
  • special tablet presses are required to make layered tablets. See, for example, U.S. Pat. No. 5,213,738, incorporated herein in its entirety by reference thereto.
  • Press coated tablets are another form of multiple compressed tablets. Such tablets, also referred to as dry-coated tablets, are prepared by feeding previously compressed tablets into a tableting machine and compressing another granulation layer around the preformed tablets. These tablets have all the advantages of compressed tablets, i.e. , slotting, monogramming, speed of disintegration, etc., while retaining the attributes of sugar coated tablets in masking the taste of the drug substance in the core tablet. Press-coated tablets can also be used to separate incompatible drug substances. Further, they can be used to provide an enteric coating to the core tablets. Both types of tablets (i.e., layered tablets and press-coated tablets) may be used, for example, in the design of prolonged-action dosage forms of the present invention.
  • compositions or unit dosage forms of the present invention in the form of prolonged-action tablets may comprise compressed tablets formulated to release the drug substance in a manner to provide medication over a period of time.
  • tablet types that include delayed-action tablets in which the release of the drug substance is prevented for an interval of time after administration or until certain physiological conditions exist.
  • Repeat action tablets may be formed that periodically release a complete dose of the drug substance to the gastrointestinal fluids.
  • extended release tablets that continuously release increments of the contained drug substance to the gastrointestinal fluids may be formed.
  • the phenyl alkanoic acid prodrug can be combined as the active pharmaceutical ingredient in intimate admixture with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques.
  • the pharmaceutically acceptable carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral, parenteral (including intravenous, subcutaneous, intrathecal, and intramuscular), transdermal, and topical.
  • parenteral including intravenous, subcutaneous, intrathecal, and intramuscular
  • transdermal and topical.
  • any of the usual pharmaceutical media or excipients may be employed.
  • oral liquid preparations such as suspensions, elixirs and solutions; or aerosols; or excipients such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, capsules, caplets, and tablets.
  • Solid oral preparations are generally preferred over liquid ones. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical pharmaceutically acceptable excipients are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Preferred solid oral preparations are tablets and capsules.
  • compositions comprising the phenyl alkanoic acid prodrug, or pharmaceutically acceptable salts, solvates, or clathrates thereof.
  • Acceptable stabilizers include, but are not limited to, L- cysteine hydrochloride, glycine hydrochloride, malic acid, sodium metabisulfite, citric acid, tartaric acid, and L-cystine dihydrochloride. See, e.g. , U.S. Patent Nos.: 5,731 ,000; 5, 763,493;'5, 541 ,231 ; and 5,358,970, all o ' f which are incorporated herein by reference.
  • the active pharmaceutical ingredient i.e., phenyl alkanoic acid prodrug
  • controlled release means and/or delivery devices capable of releasing the active pharmaceutical ingredient at a rate required to maintain constant pharmacological activity for a desirable period of time.
  • Such dosage forms provide a supply of a drug to the body during a predetermined period of time and thus maintain drug levels in the therapeutic range for longer periods of time than conventional non-controlled formulations. Examples of controlled release pharmaceutical compositions and delivery devices which may be adapted for the administration of the active pharmaceutical ingredient of the invention are described in U.S.
  • compositions of the invention suitable for oral administration may be presented as discrete units such as capsules, cachets, caplets, or tablets or aerosol sprays, each containing a predetermined amount of the active pharmaceutical ingredient as a powder, as granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.
  • Such compositions may be prepared by any of the methods of pharmacy which include the step of bringing into association the active pharmaceutical ingredient with a pharmaceutically acceptable carrier which constitutes one or more necessary ingredients.
  • compositions are prepared by uniformly and intimately admixing the active pharmaceutical ingredient with a liquid pharmaceutically acceptable carrier or a finely divided solid pharmaceutically acceptable carrier, or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active pharmaceutical ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, disintegrating .agent, and/or surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert, liquid diluent.
  • the formulations and unit dosage forms of the invention can have a number of different ingredients. Depending on the dosage strength, a unit dosage form has an amount of active pharmaceutical ingredient (API) sufficient for achieving a therapeutic effect in a target population. Additionally "inactive pharmaceutical ingredients” need to be present to achieve a therapeutically effect release of the API. Thus the amount and type of inactive ingredients help achieve a therapeutically effective release of the therapeutic agent.
  • API active pharmaceutical ingredient
  • a tablet unit dosage form having the following inactive ingredients: one or more disintegrants in an amount sufficient to facilitate break-up (disintegration) of the tablet after administration (e.g., provide an immediate release dissolution profile), one or more binders in an amount sufficient to impart adequate cohesiveness to the tablet and/or provide adequate free flowing qualities by formulation of granules of desired size/hardness, one or more diluents in an amount sufficient to impart satisfactory compression characteristics, one or more lubricants in an amount sufficient to provide an adequate flow rate of the granulation and/or prevent adhesion of the material to the die/punch, reduce interparticle friction, and/or facilitate ejection from the die, and if desired, optional ingredients.
  • one or more disintegrants in an amount sufficient to facilitate break-up (disintegration) of the tablet after administration (e.g., provide an immediate release dissolution profile)
  • one or more binders in an amount sufficient to impart adequate cohesiveness to the tablet and/or provide adequate free flowing qualities by formulation of granule
  • the disintegration rate, and often the dissolution rate of a compacted solid pharmaceutical formulation in an aqueous environment may be increased by the addition of a disintegrant to the formulation.
  • Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac-Di-Sol® Primellose®.), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab®) and starch.
  • alginic acid include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac-Di-Sol® Primellose®.), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.
  • Solid pharmaceutical formulations that are compacted into a dosage form may include excipients whose functions include helping to bind the active pharmaceutical ingredient and other excipients together after compression.
  • Binders for solid pharmaceutical formulations include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methylcellulose (e.g.
  • Methocel® lactose
  • liquid glucose e.g., glycerol
  • magnesium aluminum silicate e.g., glycerol
  • maltodextrin methylcellulose
  • polymethacrylates e.g., polymethacrylates
  • povidone e.g. Kollidon®, Plasdone®
  • pregelatinized starch sodium alginate and starch.
  • Glidants can be added to improve the flowability of a non-compacted solid formulation and to improve the accuracy of dosing.
  • Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
  • a dosage form such as a tablet is made by the compaction of a powdered formulation
  • the formulation is subjected to pressure from a punch and dye.
  • Some excipients and active pharmaceutical ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
  • a lubricant can be added to the formulation to reduce adhesion and ease the release of the product from the dye.
  • Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
  • diluents include, but are not limited to, calcium carbonate, calcium phosphate, calcium sulfate, cellulose, cellulose acetate, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, ethyl cellulose, fructose, fumaric acid, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, medium chaim glyceride, microcrystalline cellulose, polydextrose, polymefhylacrylates, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelantized starch, sterilizabfe maize, sucrose, sugar spheres, talc, tfagacanth, trehalose, and xylitol. , :
  • disintegrants include, but are not limited to, alginic acid, calcium phosphate, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, powdered cellulose, chitosan, crospovidone, docusate sodium, guar gum, hydroxylpropyl cellulose, magnesium aluminum silicate, methylcellulose, poidone, sodium alginate, sodium starch glycolate, starch, and pregelantinized starch.
  • binders include, but are not limited to, acacia, alginic acid, carbomers, carboxymethyl cellulose sodium, carrageenan, cellulose acetate phthalate, ceratonia, chitosan, confectioners sugar, cottonseed oil, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glucose, glyceryl behenate, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxylpropyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, maltodextrin, maltose, methylcellulose, microcrystalline cellulose, poloxamer, polydextrose, polyethylene oxide, polymethyl acrylates, povidone, sodium alginate, starch, pregelantized starch, stearic acid, sucrose, sunflower oil, and zein.
  • lubricants include, but are not limited to, calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium lauryl sulfate, magnesium stearate, medium chain triglycerides, mineral oil, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
  • glidants include, but are not limited to, calcium phosphate, calcium silicate, cellulose powdered, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, silicon dioxide, starch, and talc.
  • Optional ingredients in the formulations of the invention include, but are not limited to, flavors, coloring agents, and stabilizers.
  • Flavoring agents and flavor enhancers make the dosage form more palatable to the patient.
  • Common flavoring agents and flavor enhancers for pharmaceutical products include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid.
  • Solid and liquid formulations may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
  • phenyl alkanoic acid prodrugs of the invention i.e., those of Formulae I-III
  • various phenyl alkanoic acids can be substituted for the 2-(2-fluoro-biphenyl-4-yl)-propionic acid starting material used in the example below to give the corresponding phenyl alkanoic acid prodrug.
  • Example 2 Compounds having the structures given in the table below were synthesized using general synthetic scheme A or B as described above.
  • Example 3 Assay for testing ability to cross the blood brain barrier.
  • a high throughput screen for membrane permeability can be used to assay for blood-brain barrier permeability.
  • the method disclosed in Di et al. Eur. J. Med. Chem. 38:223-32 (2003) can be used to assess the ability of a compound of the invention to cross the blood-brain barrier.
  • the tablets are prepared using art known procedures.
  • coated tablets are produced using art known procedures.
  • the capsules are produced using art known procedures.
  • Example 5 Treatment of Alzheimer's disease with a compound of Formulae I-III
  • the compounds of Formulae I-III can be administered twice daily as tablets containing 400 mg of active ingredient or as a capsule containing 400 mg of the active ingredient.
  • a higher dose can be administered to the patient in need of such treatment which can involve the patient talcing e.g., a 800 mg dose of a compound of Formulae I- III in the morning and a 800 mg dose of a compound of Formulae I-III in the evening.
  • a 800 mg dose of a compound of Formulae I-III in the morning and a 800 mg dose of a compound of Formulae I-III in the evening.
  • an individual is diagnosed by a doctor as having the disease using a suitable combination of observations.
  • One criterion indicating a likelihood of mild-to-moderate Alzheimer's disease is a score of about 15 to about 26 on the MMSE test.
  • Compounds of Formulae I-III can also be administered in liquid dosage forms.
  • the dosages can also be divided or modified, and taken with or without food.
  • the 400 mg dose can be divided into two 200 mg tablets or capsules.
  • the compound ⁇ i.e., Formulae I-III can also be administered twice daily in liquid, capsule, or tablet dosage forms where the dose has various amounts (i.e., 850 mg, 750 mg, 700 mg, 650 mg, 600 mg, 550 mg, 500 mg, 450 mg, 350 mg, 300 mg, 250 mg, 200 mg, 150 mg, and 100 mg).
  • the dosages can also be divided or modified, and taken with or without food. The doses can be taken during treatment with other medications for treating Alzheimer's disease or symptoms thereof.
  • the compound can be administered in the morning as a tablet containing 400 mg of active ingredient (i.e., a compound of Formulae I-III) and an acetylcholine esterase inhibitor (i.e., tacrine (Cognex®), donepezil (Aricept®), rivastigmine (Exelon®), and galantamine (Reminyl®)), and/or an NMDA antagonist (i.e., memantine). It may be desirable to lower the amount of acetylcholine esterase inhibitor (and/or NMDA antagonist) to avoid adverse side effects associated with higher doses of these compounds.
  • the acetylcholine esterase inhibitor (and/or NMDA antagonist) and prodrug of the invention can be co-formulated into a single dosage form, i.e., liquid, tablet, capsule, etc.
  • Patients having mild-to-moderate Alzheimer's disease undergoing the treatment regimen of this example with a compound of Formulae I-III in doses of about 20 mg to 1600 mg per day can experience a lessening in decline of cognitive function (as measured by the ADAS-cog or CDR sum of boxes), plaque pathology, and/or biochemical disease marker progression.

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Abstract

The invention relates prodrugs of phenyl alkanoic acids. The prodrugs of the invention can enhance and/or improve delivery of the phenyl alkanoic acid moiety to a desired target tissue.

Description

PRODRUGS
Inventor(s):
Ruth J. Walton
Rachel M. Slade
J. Adam Willardsen
Warren S. Weiner
Mark B. Anderson
Jonathan A. Baker Registration No. 49,022 Intellectual Property Department Myriad Genetics, Inc. (Customer No. 26698) 320 Wakara Way Salt Lake City, UT 84108 Telephone: 801 -584-3600 Fax: 801-883-3871 PRODRUGS
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S. C. § 119(e) to United States provisional application number 60/773,952, filed February 15, 2006, which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The invention relates to compounds and pharmaceutical compositions.
BACKGROUND OF THE INVENTION
[0003] Dementia is a brain disorder that seriously affects a person's ability to carry out normal daily activities. Among older people, Alzheimer's disease (AD) is the most common form of dementia and involves parts of the brain that control thought, memory, and language. Despite intensive research throughout the world, the causes of AD are still unknown and there is no cure. AD most commonly begins after the age of 60, with the risk of acquiring the disease increasing with age. Younger people can also get AD, but it is much less common. It is estimated that 3 percent of men and women ages 65 to 74 have AD. Almost half of those ages 85 and older may have the disease. A recent study indicated that in newly diagnosed AD patients over 60 years old that the survival period was about half that as compared to the control population (Larson et al. Ann. Int. Med. 140:501 -509 (2004)). AD is not a normal part of aging. Alzheimer's disease is a complex disease that can be caused by genetic and environmental factors.
[0004] In 1906, Dr. Alois Alzheimer noticed changes in the brain tissue of a woman who had died of an unusual mental illness. In her brain tissue, he found abnormal clumps (now known as amyloid plaques) and tangled bundles of fibers (now known as neurofibrillary tangles) which, today, are considered the pathological hallmarks of AD. Other brain changes in people with AD have been discovered. For example, with AD, there is a loss of nerve cells in areas of the brain that are vital to memory and other mental abilities. Scientists have found that there are lower levels of chemicals in the brain that carry complex messages back and forth between nerve cells. AD may disrupt normal thinking and memory by blocking these messages between nerve cells.
[0005] Plaques and tangles are found in the same brain regions that are affected by neuronal and synaptic loss. Neuronal and synaptic loss is universally recognized as the primary cause of decline in cognitive function in AD patients. The number of tangles is more highly correlated with cognitive decline than amyloid load in patients with AD (Albert PNAS 93: 13547-13551 (1996)). The cellular, biochemical, and molecular events responsible for neuronal and synaptic loss in AD are not known. A number of studies have demonstrated that amyloid can be directly toxic to neurons resulting in behavioral impairment (see, e.g., Iversen et al. Biockem. J. 311 : 1 -16 (1995); Weiss et al. J. Neurochem. 62:372-375 (1994); Lorenzo et al. Ann N Y Acad. Sci. 777:89-95 (1996); and Storey et al. Neuropathol. Appl. Neurobiol. 2:81-97 (1999)). The toxicity of amyloid or tangles is potentially aggravated by activation of the complement cascade (Rogers et al. PNAS 21 : 10016-10020 (1992); Rozemuller et al. Res. Immunol. 6:646-9 (1992); Rogers et al. Res Immunol. 6:624-30 (1992); and Webster et al. J. Neurochem. 69(l):388-98 (1997)).
[0006] Evidence that amyloid β protein (A/?) deposition causes some forms of AD was provided by genetic and molecular studies of some familial forms of AD (FAD). {See, e.g. , Ii Drugs Aging 7(2):97-109 (1995); Hardy PNAS 94(6):2095-7 (1997); and Selkoe J. Biol. Chem. 271(31): 18295-8 (1996)). The amyloid plaque buildup in AD patients suggests that abnormal processing of Aβ may be a cause of AD. Aβ is a peptide of 39 to 42 amino acids and is the core of senile plaques observed in all Alzheimer's disease cases. If abnormal processing is the primary cause of AD3 then familial Alzheimer's disease (FAD) mutations that are linked (genetically) to FAD may induce changes that, in one way or another, foster Aβ deposition. Mutations in the FAD genes can result in increased Aβ deposition. It is noted that the vast majority of Alzheimer's disease cases are not a result of mutations in FAD genes.
[0007] The first of the FAD genes codes for the Aβ precursor, amyloid precursor protein (APP) (Selkoe J. Biol. Chem. 271 (31 ): 18295-8 (1996)). Mutations in the APP gene are very rare, but all of them cause AD with 100% penetrance and result in elevated production of either total A/3 or A/?42, both in model transfected cells and transgenic animals. Two other FAD genes code for presenilin 1 and 2 (PSl , PS2) (Hardy PNAS 94(6):2095-7 (1997)). The presenilins contain 8 transmembrane domains and several lines of evidence suggest that they are involved in intracellular protein trafficking. Other studies suggest that the presenilins function as proteases. Mutations in the presenilin genes are more common than in the APP genes, and all of them also cause FAD with 100% penetrance. Similar to APP mutants, studies have demonstrated that PS l and PS2 mutations shift APP metabolism, resulting in elevated AjS42 production {in vitro and in vivo).
[0008J In the United States alone, four million adults suffer from Alzheimer's disease (AD). Not only is Alzheimer's disease significantly impacting the lives of countless families today, it is threatening to become even more of a problem as the baby boom generation matures. The economic burden of AD is estimated to cost over $100 billion a year and the average lifetime cost per patient is estimated to be $174,000. Unfortunately, there is no cure available for AD. Of the five drugs currently being used in the US for the treatment of AD, four of them - tacrine (Cognex®), donepezil (Aricept®), rivastigmine (Exelon®), and galantamine (Reminyl®), are inhibitors of acetylcholine esterase. Another drug, memantine, was recently approved for treating moderate-to-severe AD. More recently it was reported that memantine showed efficacy in treating mild-to-moderate AD. Memantine is a NMDA receptor antagonist.
[0009] The drugs currently used for treating AD, including memantine and the acetylcholine esterase inhibitors, are marginally efficacious and have undesirable side- effects. Thus, there is a large unmet need for better and safer drugs.
BRIEF SUMMARY OF THE INVENTION
[0010] The invention provides prodrugs of phenyl alkanoic acids and analogs thereof. In general, the compounds of the invention are comprised of a phenyl alkanoic acid moiety and a prodrug moiety. In a specific embodiment, the invention provides prodrugs of 2-halo-4-biphenyl alkanoic acids. The prodrugs of the invention can enhance and/or improve delivery of the phenyl alkanoic acid moiety to a desired target tissue. [0011] In one embodiment, the invention provides a compound which is a phenyl alkanoic acid (e.g., 2-halo-4-biphenyl alkanoic acid) prodrug where the prodrug moiety is covalently linked to the active moiety through the alkanoic acid moiety. In one aspect of this embodiment, the prodrug moiety enhances delivery of the phenyl alkanoic acid moiety (e.g., 2-halo-4-biphenyl alkanoic acid) to a desired target tissue, organ, and/or cell-type. For example, the prodrug can facilitate delivery of the 2-halo- 4-biphenyl alkanoic acid across the blood-brain-barrier. In some aspects, the prodrug moiety enhances delivery of the phenyl alkanoic acid moiety e.g., (2-halo-4-biphenyl alkanoic acid) to a tumor or cancer cell.
[0012] In another embodiment, the invention provides a pharmaceutical composition having a phenyl alkanoic acid prodrug and a pharmaceutically acceptable carrier. In one aspect, the phenyl alkanoic acid moiety is a 2-halo-4-biphenyl alkanoic acid. In one aspect of this embodiment, the pharmaceutical composition is suitable for oral administration. In another aspect of this embodiment, the pharmaceutical composition is formulated in a capsule or tablet unit dosage form.
[0013] In an embodiment, the invention provides a pharmaceutically acceptable salt of a phenyl alkanoic acid prodrug (e.g., 2-halo-4-biphenyl alkanoic acid prodrug).
[0014] In another embodiment, the invention provides a compound which is a phenyl alkanoic acid (e.g., 2-halo-4-biphenyl alkanoic acid) prodrug where the prodrug moiety is covalently linked to the active moiety through the alkanoic acid. According to this embodiment, the prodrug enhances the efficacy and/or improves the safety profile of the parent phenyl alkanoic acid. An enhancement of efficacy and/or improvement is safety profiles can be accomplished e.g., by improving bioavailability, improving up-take in a target tissue, and/or improving patient adherence to dosing regimens. In one aspect of this embodiment, the prodrug moiety enhances delivery of the 2-halo-4-biphenyl alkanoic acid to a desired target tissue, organ, and/or cell-type. For example, the prodrug can facilitate delivery of the 2-halo-4-biphenyl alkanoic acid across the blood-brain-barrier. In some aspects, the prodrug moiety enhances delivery of the 2-halo-4-biphenyl alkanoic acid to a tumor or cancer cell. [0015] In still another embodiment, the invention provides a method of treating a patient in need of such treatment by administering to the patient a therapeutically effective amount of a pharmaceutical composition having one or more prodrugs of the invention.
[0016] In still yet another embodiment, the invention provides a method of treating a disease characterized by abnormal amyloid precursor protein processing by (1) identifying a patient in need of such treatment, and (2) administering to the patient a therapeutically effective amount of a pharmaceutical composition having one or more phenyl alkanoic acid prodrugs of the invention (e.g., 2-halo-4-biphenyl alkanoic acid prodrug). Examples of biochemical disease markers include, for example, amyloid beta peptide (A/3), AjS42, and tau.
[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
[0018] Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.
DETAILED DESCRIPTION OF THE INVENTION
[0019] The invention general relates to compounds of Formula I and analogs thereof:
Figure imgf000007_0001
FORMULA I [0020] wherein
[0021] Rl is chosen from -H and C1-C6 alkyl;
[0022] R2 is chosen from -H and C1 -C6 alkyl; or
[0023] Rl and R2 can be taken together to form a C3-C7 carbocyclic ring;
[0024] R3 is a moiety chosen from a central nervous system penetration enhancer, a blood-brain-barrier penetration enhancer, a bioavailability enhancer, and a tumor targeting agent;
[0025] X is chosen from chloro, fluoro, bromo, and iodo; and
[0026] L can be saturated, partially saturated, or unsaturated, and is chosen from -(CH2V(CH2),,-, -(CH2)nC(=O)(CH2)n-, -(CH2)nC(=O)N(CH2)π-, - (CH2)nNC(=O)O(CH2)n-, -(CH2)nNC(=O)N(CH2)n-, -(CH2)nNC(=S)S(CH2)n-, - (CH2)nOC(=O)S(CH2)n-, -(CH2)nNH(CH2)n-, -(CH2)πO(CH2)n-, -(CH2)nS(CH2)n-, - (CH2)nNC(=S)N(CH2)n-, where each n is independently chosen from 0, 1 , 2, 3, 4, 5, 6, 7, and 8, and wherein each carbon and/or nitrogen can be optionally substituted with one or more substituents independently chosen hydroxyl, halo, alkoxy, C1-3 alkyl, and C3-6 cycloalkyl groups.
[0027] In some embodiments and aspects of the invention, L is a covalent bond in the compounds of Formulae I-III.
[0028] In some embodiments and aspects of the invention, X is fluoro in the compounds of Formulae I-III.
[0029] In some embodiments of the invention, Rl is -CH3 in the compounds of Formulae I-III. In one aspect of this embodiment, R2 is hydro. In another aspect of this embodiment, the carbon attached to Rl and R2 is chiral and has the (R) stereochemical configuration.
[0030] In some embodiments of the invention, in the compounds of Formulae I-III, Rl and R2 are independently chosen from -H, -CH3, -CH2CH3, -CH2CH2CH3, - CH(CH3)2, -C(CH3)3, -CH(CH3)CH2CH3, -CH2CH2CH2CH3, and -CH2CH(CH3)CH3.
[0031] In some embodiments and aspects of the invention, the stereochemical configuration at the carbon attached to Rl and R2 is (R) in the compounds of Formulae I-III. In some embodiments and aspects of the invention, the stereochemical configuration at the carbon attached to Rl and R2 is (S) in the compounds of Formulae I-III. In some embodiments and aspects of the invention, the stereochemical configuration at the carbon attached to Rl and R2 is (+) in the compounds of Formulae I-III. In some embodiments and aspects of the invention, the stereochemical configuration at the carbon attached to Rl and R2 is (-) in the compounds of Formulae I-III. In some embodiments and aspects of the invention, in the compounds of Formulae I-III, the carbon attached to Rl and R2 is chiral, and the compound is in a racemic form. In some embodiments and aspects of the invention, in the compounds of Formula I, the carbon attached to Rl and R2 is chiral, and the composition has a ratio of more than 50:50, 60:40, 75:25; 90:10, 95:5, 98:2 or 99: 1 (R) to (S) enantiomer.
[0032] In one embodiment, R3 is chosen from -NH2, -
NHCH2CH2OCH2CH2OCH2CH2NH2, pyridinyl, cyclopentyl, 4-methoxy-phenyl, - cyclopropyl, phenyl-CH2-imadozolyl, 2,4-dimethyl-phenyl, phenyl, 3,5-dimethoxy- phenyl, -C(CHs)2, 1-methyl-pyrrolidinyl, 4-trifluoromethoxy-phenyl, -CH2CH2CH3, 4- trifluoromethyl-phenyl, 3-chloro-phenyl, 3-fluoro-phenyl, -pyridinyl, 3,4-dimethoxy- phenyl, 3-fluoro-phenyl, 3-trifluoromethyl-phenyl, 3-methoxy-phenyl, 3-fluoro-phenyl, 4-cyclohexyl-phenyl, lH-indolyl, 4-methyl-phenyl, 4-dimethylamino-phenyl, 3,4- dimethyl-phenyl, 3,4-dichloro-phenyl, 3-methyl-phenyl, 254-difluoro-phenyl, IH- tetrazolyl, lH-indazolyl, 4-morpholinyl-phenyl, -N(CH2CH3)2, - N(CH3)CH2CH2N(CH3)2, 4-methyl-piperazin-l-yl, 4-pyrrolidin-l -yl-piperidinyl, thiazolidinyl, morpholinyl, piperidinyl, 4-phenyl-piperazinyl, 3-dimethylamino- pyrrolidinyl, -N(CH3)CH2(phenyl), -N(CH3)2, and -N(CH3)(phenyl), - NHS(=O)2(naphthalenyl) -NHS(=O)2N(CH3)2, -NHS(=O)2(4-methyl-phenyl), - NHS(=0)2(4-trifluoromethyl-phenyl), -NHS(=O)2(4-methoxy-phenyl), -NHS(=O)2(4- chloro-phenyl), -NHS(=O)2CH3, -NHS(=O)2(3-fluoro-phenyl), -NHS(=O)2(phenyl), - NHS(=O)2(5-dimethyl-naphthalenyl), -NHS(=O)2(5-methyl-pyridinyl), -NHS(=O)2(2- methyl-4-fluorq-phenyl), -NHS(=O)2CF3, -NHS(=O)2(2-methoxy-4-methyl-phenyl), - NHS(=O)2CH2(phenyl), -NHS(=0)2(2-trifluoromethoxy-phenyl), and - N(CH3)CH2CH2OCH3. In some aspects of this embodiment, L is a bond. In some aspects of this embodiment, L is -(CH2)nNH(CH2)n-.
[0033] In one embodiment, -L-R3, taken together, is chosen from - NHCH2CH2CH2CH2NH2, -NHCH2CH2OCH2CH2OCH2CH2NH25 -NHCH2-ρyridinyl, - NH-cyclopentyl, -NHCH2(4-methoxy-phenyl), -NH-cyclopropyl, ~NHCH2(phenyl)CH2- imadozolyl, -NHCH2CH2(2,4-dimethyl-phenyl)> -NHCH2(phenyl), -NHCH2(3,5- dimethoxy-phenyl), -NHC(CH3)2, -NHCH2CH2(I -methyl-pyrrolidinyl), -NHCH2(4- trifluoromethoxy-phenyl), -NHCH2CH2CH3, -NHCH2(4-trifluoromethyl-ρhenyl), - NHCH2(3-chloro-phenyl), -NHCH2(3-fluoro-phenyl), -NH(pyridinyl), -NH(3,4- dimethoxy-phenyl), -NH(3-fluoro-phenyl), -NH(3-trifluoromethyl-phenyl), -NH(3- methoxy-phenyl), -NH(3-fluoro-phenyl), -NH(4-cyclohexyl-phenyl), -NH(lH-indolyl), -NH(4-methyl-phenyl), -NH(4-dimethylamino-phenyl), -NH(3,4-dimethyl-phenyl), - NH(3,4-dichloro-phenyl), -NH(3-methyl-phenyl), -NH(2,4-difluoro-phenyl), -NH(IH- tetrazolyl), -NH(lH-indazolyl), -NH(4-morpholinyl-phenyl), -N(CH2CH3)2, -N(CH3) CH2CH2N(CH3)2, 4-methyl-piperazin-l-yl), 4-pyrrolidin-l-yl-piperidinyl, - thiazolidinyl, -morpholinyl, -piperidinyl, 4-phenyl-piperazinyl, 3-dimethylamino- pyrrolidinyl, -N(CH3)CH2(phenyl), -N(CH3)2, and -N(CH3)(phenyl).
[0034] In one embodiment, -L-R3 is chosen from -NHS(=O)2(naphthalenyl), - NHS(=O)2N(CH3)2, -NHS(=O)2(4-methyl-phenyl), -NHS(=0)2(4-trifluoromethyl- phenyl), -NHS(=O)2(4-methoxy-phenyl), -NHS(=O)2(4-chloro-phenyl), -NHS(=O)2CH3, -NHS(=O)2(3-fluoro-phenyl), -NHS(=O)2(phenyl), -NHS(=O)2(5-dimethyl- naphthalenyl), -NHS(=O)2(5-methyl-pyridmyl), -NHS(=O)2(2-methyl-4-fluoro-phenyl), -NHS(=O)2CF3, -NHS(=O)2(2-methoxy-4-methyl-phenyl), -NHS(=O)2CH2(phenyl), - NHS(=O)2(2-trifluoromethoxy-phenyl), -N(CH3)CH2CH2OCH3. In some aspects of this embodiment, L is a bond.
[0035] In one embodiment, -L-R3 is chosen from -NCH2S(O)2OH, -NCH2 CH2S(O)2OH, -NCH2CH2CH2S(O)2OH, -NCH2CH2CH2CH2S(O)2OH, - NCH2CH2CH2CH2CH2S(O)2OH, -NCH2CH2CH2CH2CH2CH2S(O)2OH, -NCH2 CH2CH2CH2CH2CH2CH2S(O)2OH1 -NCH2CH2CH2CH2CH2CH2CH2CH2S(O)2OH1 -N CH2CH2CH2CH2CH2CH2CH2CH2CH2S(O)2OH, -
NCH2CH2CH2CH2CH2CH2CH2CH2CH2CH2S(O)2OH. In one aspect, of this embodiment, one or more carbons of — L-R3 can be substituted with one or more substituents.
[0036] In one embodiment, R3 is chosen from cis-inositol, epi-inositol, allo- inositol, neo-inositol, myo-inositol, muco-inositol, scyllo-inositol, L-(-)-chiro-inositol, and R-(+)-chiro-inositol. According to this embodiment, the —OH groups of the inositol moiety can be substituted with 6, 5, 4, 3, 2 or 1 compounds of Formulae I-III. In one aspect, the phenyl alkanoic acid moiety of the prodrug is a 2-halo-4-biphenyl alkanoic acid. In one aspect, the phenyl alkanoic acid moiety of the prodrug is 2-(2-fluoro- biphenyl-4-yl)-propionic acid.
[0037] In some embodiments, R3 is chosen from, -CH3, -dehydroascorbate, - CH2CH2(4-trifluoromethyl-phenyl), -CH2CH2O(4-trifluoromethyl-phenyl), -CH2(4- fluoro-phenyl), -CH2CH2OCH2CH2N(CH3)2, -CH2CH2OCH2CH2OCH3, -CH2CH2(3- methoxy-phenyl), -CH2CH2(morpholino), -CH2CH2(phenyl), -CH2CH2(cycloproρyl), - CH2CH2(imidazolyl), -CH2CH2(piperidinyl), -CH2CH2O(4-chloro-phenyl), -CH2(4- dimethylamino-phenyl), -phenyl, -(4-chloro-phenyl), -(4-methoxy-phenyl), -(4-fluoro- phenyl), -(3-chloro-phenyl), -(3-methoxy-phenyl), -(napthalenyl), -(4-trifluoromethyl- phenyl), -(3-fluoro-phenyl), -(4-biphenylyl), -(5,6,7,8-tetrahydro-napthalenyl), -(3,5 dimethoxy-phenyl), -(indanyl), -(3-isopropyl-phenyl), -(4-trifluoromethoxy-phenyl), and -(m-tolyl). In some aspects of this embodiment, L is a bond. In some aspects of this embodiment, L is -(CH2)nO(CH2)n-. In some aspects of this embodiment, L is -O-. In some aspects of this embodiment, X is fluoro. In some aspects of this embodiment, Rl is -CH3. In one aspect of this embodiment, R2 is hydro. In another aspect of this embodiment, the carbon attached to Rl and R2 is chiral and has the (R) configuration. In some aspects of this embodiment, Rl is -CH3. In some aspects of this embodiment, Rl and R2 are independently chosen from -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, - C(CH3)3, -CH(CH3)CH2CH3, -CH2CH2CH2CH3, and -CH2CH(CH3)CH3.
[0038] In some embodiments R3 is chosen from, -OCH3, dehydroascorbate, - OCH2CH2(4-trifIuoromethyl-phenyl), -OCH2CH2O(4-trifluoromethyl-phenyl), -OCH2(4- fluoro-phenyl), -OCH2CH2OCH2CH2N(CH3)2, -OCH2CH2OCH2CH2OCH3, - OCH2CH2(3-methoxy-phenyl), -OCH2CH2(morpholino), -OCH2CH2(phenyl), - OCH2CH2(cyclopropyl), -OCH2CH2(imidazolyl), -OCH2CH2(piperidinyl), - OCH2CH2O(4-chloro-phenyl), -OCH2(4-dimethylamino-phenyl), -O(ρhenyl), -O(4- chloro-phenyl), -O(4-methoxy-phenyl), -O(4-fluoro-phenyl), -O(3-chloro-phenyl), - O(3-methoxy-phenyl), O(napthalenyl), -O(4-trifluoromethyl-ρhenyl), -O(3-fluoro- phenyl), -O(4-biphenylyl), -O(5,6,7,8-tetrahydro-napthalenyl), -O(3,5 dimethoxy- phenyl), O(indanyl), -O(3-isopropyl-phenyl), -O(4-trifluoromethoxy-phenyl), and -(m- tolyl).
[0039] In some embodiments, R3 is chosen from -C(R0)CC=O)OH, - C(CH2OH)3, -CH2CH2NC(=O)(pyridinyl), -CH2PO3, and -CH2CH2(phenyl) wherein R0 is chosen from haloalkyl and alkyl.
[0040] In some embodiments, R3 is chosen from -
OCH2CH2OCH2CH2OCH2CH2OCH3, -OCH2CH2(morpholino), -OCH2CH2NHC(=O)(1- methyl-l ,4-dihydro-pyridinyl), -0(CH2)OC(=0)(l -methyl-l ,4-dihydro-pyridinyl), - OCH2CH2N=C(I -hydroxy-5-fluoro-phenyl)(pyrrolyl), and - OCH(CH3)OC(=O)OCH2CH3.
[0041] In some embodiments, — L-R3 taken together is chosen from — NHC(RO)C(=O)OH, -NHC(CH2OH)3, -OCH2CH2NC(=O)(pyridinyl), -NCH2PO3, and - NCH2CH2(phenyl) wherein R0 is chosen from haloalkyl and alkyl.
[0042] In some embodiments, — L-R3 taken together is chosen from - OCH2CH2OCH2CH2OCH2CH2OCH3, -OCH2CH2(morpholino), -OCH2CH2NHC(=O)(1- methyl-l,4-dihydro-pyridinyl), -O(CH2)OC(=O)(l-methyl-l ,4-dihydro-pyridinyl), - OCH2CH2N=C(I-hydroxy-5-fluoro-phenyl)(pyrrolyI), and - OCH(CH3)OCC=O)OCH2CH3.
[0043] In some embodiments, -R3 is capable of enhancing CNS penetration and/or penetration of the blood-brain barrier. In one aspect of this embodiment, -R3 is chosen from ascorbic acid analogs, choline, choline analogs, taurine, taurine analogs, amino acids, glycine, tris, and GABA. In one aspect of this embodiment, -R3 is chosen from Vitamin B3 and Vitamin B3 analogs.
[0044] In one embodiment, -R3 is chosen from vitamin D and vitamin D3 analogs.
[0045] In one embodiment, -R3 is chosen from sulfonates and phosphates.
[0046] In one embodiment, -R3 is chosen from morpholine and morpholine salts.
[0047] In one embodiment, -R3 is chosen from phenethylamines, dihydropyridine, and azomethines. [0048] In one embodiment, -R3 is chosen from esters, amino acid, peptide, carbamate, polyethylene glycol, vitamins, phosphates, neuroactive amines, amidines, and imines.
[0049] In one embodiment, -R3 is a glyceride or glyceride analog.
[0050] In one embodiment — R3 is a moiety chosen from ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 1-propanesulfonic acid, 1 ,3-propanedisulfonic acid, 1 ,4- butanedisulfonic acid, 1,5-pentanedisulfonic acid, 2-aminoethanesulfonic acid, 4- hydroxybutane-1-sulfonic acid. In a related embodiment, -R3 is a moiety chosen from 1-butanesulfonic acid, 1-decanesulfonic acid, 2-propanesulfonic acid, 3-pentanesulfonic acid, and 4-heptanesulfonic acid. In another related embodiment, -R3 is a moiety chosen from l ,7-dihydroxy-4-heptanesulfonic acid and 3-amino-l-propanesulfonic acid.
[0051] In some embodiments, -R3 is
Figure imgf000013_0001
[0053] where the phenyl alkanoic acid moiety can be attached through any of
Ra-Rg and Ra-Rg can be optionally substituted, and are independently chosen from -H, halo, -OH, alkyl, aryl, amine, ether, amide, ester, urea, carbamate, imine, nitro, sulfide, sulfoxide, and sulfone.
[0054] In some embodiments, -R3 is
Figure imgf000013_0002
[0056] where at least one R is a phenyl alkanoic acid moiety and the other R- groups are independently chosen from a phenyl alkanoic acid moiety, -H, or an optionally substituted alkyl or acyl group. [0057] In some embodiments, the compounds of the invention are of Formula II below, wherein the substituents are defined as in any of the other embodiments (and/or aspects) of the invention and Z is chosen from N or S.
Figure imgf000014_0001
FORMULA II
(0058] In some embodiments, the invention provides prodrugs of a compound of Formula III below
Figure imgf000014_0002
[0060] wherein Rl , R2, R3, and L are as defined in any of the embodiments above and the carbazole core can be substituted with one or more substituents chosen from hydroxyl, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, -N(C]-3 alkyl)2, -NH(Ci-3 alkyl), -CC=O)NH2, -C(=O)NH(C,-3 alkyl), -C(=O)N(C,-3 alkyl)2, -S(=O)2(C,.3alkyl), - SC=O)2NH2, -SC=O)2N(C1-3 alkyl)2, -SC=O)2NHCC1 -3 alkyl), -CHF2, -OCF3, -OCHF2, - SCF3, -CF3, -CN, -NH2, and -NO2.
[0061 ] The prodrugs of the invention Ce. g., those of Formula I-III) can improve a number of therapeutically important properties of the parent drug, such as improved blood-brain barrier penetration, improved bioavailability, improved delivery to cancerous tissue, improved tableting properties, improved metabolic stability, improved, improved pharmacokinetic properties, and the such. [0062] In one embodiment, the phenyl alkanoic acid moiety of the prodrug, or analog thereof, is an abeta42 (AjS42) lowering agent. The AjS42 lowering agents for use in the invention can be a known Aj342 lowering agents such as (R)-2-(2-fluoro-4- biphenylyl)propionic acid, 5 [ 1 -(2-Fluoro-biphenyl-4-yl)- 1 -methyl-ethyl]-2H-tetrazole, 2-(4-isobutyl-phenyl)-2-methyl propionic acid, or 2-(2-fluoro-l,l '-biphenyl-4-yl)-2- methylpropionic acid. Examples of AjS42 lowering agents for use in the combination formulations and treatments of the invention are given in, e.g., WO 01/78721, WO 2004/073705, WO 2004/064771, and WO 2004/074232, and PCT/US2005/009595 (each of which is herein incorporated by reference). Thus, in one aspect of this embodiment, the phenyl alkanoic acid moiety is replaced with an A/342 lowering agent, and the — L-R3 moiety can be as in any of the other embodiments or aspects of the invention.
[0063] AjS42 lowering agents include, but are not limited to, those having the following Formulae (the R-groups in these compounds below are to be taken as independent of the R-groups identified elsewhere in the specification):
Figure imgf000015_0001
Figure imgf000015_0002
(R4)π (R4)π
Figure imgf000016_0001
R,
Figure imgf000016_0002
Figure imgf000016_0003
[0064] Where R, is chosen from -H5 -CH3, -CH2CH3, -CH2CH2CH3, and CH2CH2CH2CH3 (or can be taken together with R2 to give a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or a cyclohexyl ring);
[0065] R2 is chosen from -H, -CH3, -CH2CH3. -CH2CH2CH3, and - CH2CH2CH2CH3, (or can be taken together with Ri to give a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or a cyclohexyl ring); [0066] R3 is chosen from -COOH5 -COOR6, -CONH2, -CONHR6, -CONR6R7, -CONHSO2R6, tetrazolyl, and a -COOH bioisostere;
[0067] R4 is chosen from -Cl, -F, -Br, -I, -CF3, -OCF3, -SCF3, -OCH3, - OCH2CH3, -CN, -CH=CH2, -CH2OH, and -NO2;
[0068] R5 is chosen from -Cl, -F, -Br, -I, -CF3, -OCF3, -SCF3, -OCH3, - OCH2CH3, -CN, -CH=CH2, -CH2OH, and -NO2;
[0069] R6 is chosen from -CH3, -CH2CH3, -CH2CH2CH3, and - CH2CH2CH2CH3.
[0070] R7 is chosen from -CH3, -CH2CH3, -CH2CH2CH3, and - CH2CH2CH2CH3.
[0071] m is an integer chosen from 0, 1, 2, and 3.
[0072] n is an integer chosen from 0, 1, 2, and 3.
[0073] Examples of the phenyl alkanoic acid moiety of the prodrug compounds for use in the invention include those as shown above (and below), including enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts thereof. The compounds described in this invention disclosure can be made by an ordinary artisan skilled in the art of organic chemistry synthesis.
[0074] Additional phenyl alkanoic acid moieties (or analogs thereof) of A/342 lowering agents that can be used in the prodrugs of the invention include: 2-methyl-2- (2-fluoro-4'-trifluoromethylbiphen-4-yl) propionic acid; 2-methyl-2-(2-fluoro- 4'cyclohexyl biphen-4-yl) propionic acid;l- (2-fluoro-4'-trifluoromethylbiphenyl-4-yl) cyclopropanecarboxylic acid;l-(4'-cyclohexyl-2-fluorobiphenyl-4-yl) cyclopropanecarboxylic acid;l-(4'-benzyloxy-2-fluorobiphenyl-4-yl) cyclopropanecarboxylic acid;l-(2-fluoro-4'~isopropyloxybiphenyl-4-yl) cyclopropanecarboxylic acid;l-(2-fluoro-3'-trifluoromethoxybiphenyl-4-yl) cyclopropanecarboxylic acid;l-(2-fluoro-4'-trifluoromethoxybiphenyl-4-yl) cyclopropanecarboxylic acid;l-(2-fluoro-3'-trifluoromethylbiphenyl-4-yl) cyclopropanecarboxylic acid; 1 -(4'-cyclopentyl-2-fluorobiphenyl-4-yl) cyclopropanecarboxylic acid; l-(4'-cycloheptyl-2-fluorobiphenyl-4-yl) cyclopropanecarboxylic acid;l-(2'-cyclohexyl-2-fluorobiphenyl-4-yl) cyclopropanecarboxylic acid; 1 -(2-fluoro-4'-hydroxybiphenyl-4-yl) cyclopropanecarboxylic acid; l-[2-fluoro-4'- (tetrahydropyran-4-yloxy) biphenyl-4-yl]- cyclopropane-carboxylic acid; l (2, 3',4'-trifluorobiphenyl-4-yl) cyclopropanecarboxylic acid; l-(3', 4'-dichloro-2-fluorobiphenyl-4-yl) cyclopropanecarboxylic acid; l -(3', 5'- dichloro-2-fluorobiphenyl-4-yl) cyclopropanecarboxylic acid l-(3'-chloro-2, 4'- difluorobiphenyl-4-yl) cyclopropanecarboxylic acid; l-(4-benzo [b] thiophen-3-yl-3- fluorophenyl) cyclopropanecarboxylic acid; l-(2-fluoro-4'-prop-2-inyloxy-biphenyl-4- yl)-cyclopropanecarboxylic acid; l-(4'-cyclohexyloxy-2-fluoro-biphenyl-4-yl)- cyclopropanecarboxylic acid; l-[2-fluoro-4'- (tetrahydropyran-4-yl)-biphenyl-4-yl]- cyclopropanecarboxylic acid; 1 -[2-fluoro-4'-(4-oxo-cyclohexyl)-biphenyl-4-yl]- cyclopropanecarboxylic acid; 2-(2"-fluoro-4-hydroxy-[l, 1' : 4',1 "] tert-phenyl-4"-yl)- cyclopropanecarboxylic acid; l -[4'- (4, 4-dimethylcyclohexyl)-2-fluoro [1, l'-biphenyl]- 4-yl] -cyclopropane- carboxylic acid; l-[2-fluoro-4'-[[4-(trifluoromethyl) benzoyl] ammino] [l ,l'-biphenyl]-4-yl]-cyclopropanecarboxylic acid; l -[2-fluoro-4'-[£4- (trifluoromethyl) cyclohexyl] oxy] [i,l'-biphenyl]-4-yl]- cyclopropanecarboxylic acid; l - [2-fluoro-4'- [ (3, 3,5, 5-tetramethylcyclohexyl) oxy] [l ,l'-biphenyl]-4-yl]- cyclopropanecarboxylic acid;l- [4'- [ (4, 4-dimethylcyclohexyl) oxy] -2-fluoro [1,I 1- biphenyl]-4-yl]- cyclopropanecarboxylic acid; 1- (2, 3r, 4"-trifluoro[l , 1 ': 4', l "-tert- phenyl]-4-yl)-cyclopropanecarboxylic acid; l-(2, 2', 4"-trifluoro[l , 1' : 4',l"-tert- phenyl]-4-yl)-cyclopropanecarboxylic acid; l-(2, 3'-difluoro-4"-hydroxy [1 , 1' : 4',1 "- tert-phenyl]-4-yl)-cyclopropane- carboxylic acid;l-(2, 2'-difluoro-4"-hydroxy [1, 1' : 4',l"-tert-phenyl]-4-yl)-cyclopropane- carboxylic acid; 2- (2-fluoro-3'3 5'-bis (chloro) biphen-4-yl) propionic acid amide; 2- (2-fluoro-4'-trifluoromethylbiphen-4-yl) propionic acid; 2- (2-fluoro-3'-trifluoromethylbiphen-4-yl) propionic acid; 2- (2-fluoro- 3', 5'-bis (trifluoromethyl) biphen-4-yl) propionic acid; 2-(4'-cyclohexyl-2- fluorobiphen-4-yl) propionic acid; 2-(2-Fluoro-l , l'-biphenyl-4-yl)-2-methylpropanoic acid; 2-Methyl-2- (3-phenoxy-phenyl)-propionic acid; 2-(4-Isobutyl-phenyl)-2-methyl- propionic acid; 2-(6-Chloro-9H-carbazol-2-yl)-2-methyl-propionic acid; 2-[l-(4- Chloro-benzoyl)-5-methoxy-2-methyl-lH-indol-3-yl]-2-methyl-propionic acid; and 5- [1 - (2-Fluoro-biphenyl-4-yl)-l -methyl-ethyl]-2H-tetrazole.
[0075] As used herein, "acylamino" (or "acylamido") groups are any C 1-6 acyl (alkanoyl) as defined herein, attached to an amino nitrogen, e.g., acetamido, chloroacetamido, propionamido, butanoylamido, pentanoylamido and hexanoylamido, as well as aryl-substituted Cl-6 acylamino groups, e.g., benzoylamido, and pentafluorobenzoylamido.
[0076] As used herein, "acyloxy" groups are any Cl -6 acyl (alkanoyl) as definided herein, attached to an oxy (— O— ) group, e.g., formyloxy, acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy, and hexanoyloxy.
[0077] As used herein, the term "alkenyl" refers to, by itself or as part of another group, a straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, including at least one double bond between two of the carbon atoms in the chain. Typical non-limiting examples of alkenyl groups include ethenyl, 1 -propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl and 2-butenyl.
[0078] As used herein, the term "alkoxy" refers to both an -O-alkyl and an -O- cycloalkyl group, as defined herein. Lower alkoxy refers to -O-lower alkyl groups. Non-limiting alkoxy groups include oxygen substituted by one of the Cl -10 alkyl groups mentioned above, which may be optionally substituted. Alkoxy substituents include, without limitation, halo, morpholino, amino including alkylamino and dialkylamino, and carboxy including esters thereof.
[0079] As used herein, the term "alkyl" refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups. In one aspect, the alkyl group has 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as " 1 to 20" refers to each integer in the given range; e.g., "1 to 20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms). In another aspect, it is a medium size alkyl having 1 to 10 carbon atoms. In yet another aspect, it is a lower alkyl having 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. The alkyl group may be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more individually selected from cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C- amido, N-amido, C-carboxy, O-carboxy, cyanato, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, and amino. Typical non-limiting examples of Cl-10 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec butyl, tert butyl, 3 pentyl, hexyl and octyl groups, which may be optionally substituted.
[0080] As used herein, the term "alkylthio" group refers to both an S-alkyl and an -S-cycloalkyl group, as defined herein. Non-limiting alkylthio groups include sulfur substituted by one of the Cl-10 alkyl groups mentioned above, which may be optionally substituted. Also included are the sulfoxides and sulfones of such alkylthio groups.
[0081] As used herein, the term "alkynyl" refers to a straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, wherein there is at least one triple bond between two of the carbon atoms in the chain. Typical alkynyl groups include ethynyl, 1-propynyl, l-methyl-2-propynyl, 2-propynyl, 1- butynyl and 2-butynyl.
[0082] As used herein, the term "amino" refers to an — NR17R18 group, with Ri7 and Rig being hydro to give an -NH2 group. Independently, R] 7 and Ris may also be hydro, C l-10 alkyl or cycloalkyl groups, or Rj7 and R)7 are combined with the N to form a ring structure, such as a piperidine, or Ri7 and Rig are combined with the N to form a ring, such as a piperazine. One of Ri7 and Ri8 can be hydro and the other alkyl or cycloalkyl. The alkyl or cycloalkyl group may be optionally substituted.
[0083] As used herein, the term "aryl" refers to, by itself or as part, of another group a monocyclic, bicyclic or tricyclic aromatic groups containing from 6 to 14 carbons in the ring portion. Non-limiting aryl groups include C6-14 aryl, preferably C6-10 aryl. Typical C6-14 aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups.
[0084] As used herein, the term "arylalkyl" refers to any of the Cl-10 alkyl groups substituted by any of the above-mentioned C6-14 aryl groups as defined herein. Preferably the arylalkyl group is benzyl, phenethyl or naphthylmethyl.
[0085] As used herein, the term "arylalkenyl" is used herein to mean any of the above-mentioned C2-10 alkenyl groups substituted by any of the above-mentioned C6-14 aryl groups.
[0086] As used herein, the term "arylalkynyl" refers to any of C2-10 alkynyl groups substituted by any of the above-mentioned C6-14 aryl groups as defined herein. [0087] As used herein, the term "arylalkoxy" refers to any of the Cl-IO alkoxy groups substituted by any of the aryl groups as defined herein, which may be optionally substituted. Examples of arylalkoxy groups include benzyloxy and phenethyloxy.
[0088] As used herein, the term "aryloxy" refers to oxygen substituted by any of the C6-14 aryl groups defined herein, which may be optionally substituted. Examples of aryloxy groups include phenoxy and 4-methylphenoxy.
[0089] As used herein, the term "arylthio" group refers to both an -S-aryl and an -S-heteroaryl group, as defined herein.
[0090] As used herein, the term "carbocycle" or "carbocyclic" refers to cycloalkyl and partially saturated carbocyclic groups. Non-limiting carbocyclic groups are C3-8 cycloalkyl and cycloalkenyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, and cycloheptyl.
[0091] As used herein, the term "cyano" refers to a -C ≡N group.
[0092] As used herein, the term "cyanato" refers to a -CNO group.
[0093] As used herein, the term "halo" or "halogen group" refers to a fluoro, chloro, bromo and iodo group.
[0094] As used herein, the term "haloalkyl" refers to Cl-10 alkyl groups substituted by one or more fluoro, chloro, bromo or iodo groups, e.g., fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1 ,1-difluoroethyl, chloromethyl, chlorofluoromethyl and trichloromethyl groups. The halo groups can be independently selected.
[0095] As used herein, the term "halophenyl" refers to a phenyl group ' substituted with one or more fluoro, chloro, bromo or iodo groups. The halo groups can be independently chosen, e.g., a di halo substituted phenyl can have a fluoro and a chloro substituent.
[0096] As used herein, the term "hydro" refers to an — H group.
[0097] As used herein, the term "hydroxyl" refers to an -OH group.
[0098] As used herein, the term "heteroaryl" refers to groups having 5 to 14 ring atoms; 6, 10 or 14 π electrons shared in a cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms. Non-limiting heteroaryl groups include thienyl (thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (furanyl), isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, including without limitation 2H-pyrrolyl? imidazolyl, pyrazolyl, pyridyl (pyridinyl), including without limitation 2-pyridyl, 3-pyridyl, and 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl. quinozalinyl, cinnolinyl, pteridinyl, carbazolyl, α-carbolinyl, phenanthridinyl, acrindinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, l,4-dihydroquinoxaline-2,3-dione, 7 aminoisocoumarin, pyndo[ l ,2-a]pyrimidin-4-one, pyrazolo[ l ,5-a]pyrimidinyl, including without limitation pyrazolo[l ,5-a]pyrimidin-3-yl, l ,2-benzoisoxazol-3-yl, benzimidazolyl, 2-oxindolyl and 2 oxobenzimidazolyl. Where the heteroaryl group contains a nitrogen atom in a ring, such nitrogen atom may be in the form of an N-oxide, e.g., a pyridyl N oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide. Heteroaryl groups can be monocyclic, bicyclic, tricyclic, and/or polycyclic.
[0099] As used herein, the term "heteroaryloxy" refers to oxygen substituted by a heteroaryl group as defined herein, which may be optionally substituted. Non- limiting heteroaryloxy groups include pyridyloxy, pyrazinyloxy, pyrrol yloxy, pyrazolyloxy, imidazolyloxy and thiophenyloxy.
[00100] As used herein, the term "heterocycle" or heterocyclic" refers to a saturated or partially saturated 3-7 membered monocyclic, 7-10 membered bicyclic ring system, or 7-14 membered polycyclic ring system, which consists of carbon atoms and from one to five heteroatoms independently selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, the nitrogen can be optionally quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, and wherein the heterocyclic ring can be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Non-limiting saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetronoyl and tetramoyl groups. [00101] As used herein, the term "heteroarylalkoxy" refes to a Cl-IO alkoxy groups substituted by a heteroaryl group as defined herein, which may be optionally substituted.
[00102] As used herein, the term "isocyanato" refers to a -NCO group.
[00103] As used herein, the term "isothiocyanato" refers to a -NCS group.
[00104] As used herein, the term "nitro" refers to a -NO2 group.
[00105] As used herein, the term "sulfinyl" refers to a -S(=O)R" group. R" can be a cycloalkyl or alkyl group. The alkyl or cycloalkyl group may be optionally substituted.
[00106] As used herein, the term "sulfonyl" refers to a -S(=O)2R" group. R" can be a cycloalkyl or alkyl group. The alkyl or cycloalkyl group may be optionally substituted.
[00107] As used herein, the term "sulfonamido" refers to a
Figure imgf000023_0001
7Ri8. - Independently, Rj7 and Rj 8 may be hydro, Cl-10 alkyl or cycloalkyl groups, or Ri7 and Ri 8 are combined with the N to form a ring structure, such as a piperidine, or R]7 and Rig are combined with the N and to form a ring, such as a piperazine. One Of Ri7. and Ri 8 can be hydro and the other alkyl or cycloalkyl. The alkyl or cycloalkyl group may be optionally substituted.
[00108] As used herein, the term "thiocarbonyl" group refers to a -C(=S)R" group. R" can be a cycloalkyl or alkyl group. The alkyl or cycloalkyl group may be optionally substituted.
[00109] As used herein, the term "thiocyanato" refers to a -CNS group.
[00110] As used herein, the term "trihalomethanesulfonamido" refers to a
Figure imgf000023_0002
-group with X being independently selected halo groups and Ri7 as defined herein.
[OOlllJ As used herein, the term "O-carbamyl" refers to a
Figure imgf000023_0003
, group. Ri7 and Ris may be hydro, Cl -10 alkyl or cycloalkyl groups, or Ri7 and Rig are combined with the N to form a ring structure, such as a piperidine, or Ri7 and Rj g are combined with the N and to form a ring, such as a piperazine. One of R] 7 and Ri s can be hydro and the other alkyl or cycloalkyl. The alkyl or cycloalkyl group may be optionally substituted. [00112] As used herein, the term "N-carbamyl" refers to a Ri 8OC(=O)NRi 7- group. Ri8 may be hydro; Ri7 and Rig may be Cl -I O alkyl or cycloalkyl groups, or R]7 and Ri 8 are combined with the N to form a ring structure, such as a piperidine, or Rj7 and Rig are combined with the N and to form a ring, such as a piperazine. One of R17 and Ri 8 can be hydro and the other alkyl or cycloalkyl. The alkyl or cycloalkyl group may be optionally substituted.
[00113] As used herein, the term "O-thiocarbamyl" refers to a -OC(=S)NR] 7RI 8 group. Ri7 and R^ may be hydro, Cl- 10 alkyl or cycloalkyl groups, or Ri7 and Ris are combined with the N to form a ring structure, such as a piperidine, or R]7 and Ri $ are combined with the N and to form a ring, such as a piperazine. One of Ri7 and Ri 8 can be hydro and the other alkyl or cycloalkyl. The alkyl or cycloalkyl group may be optionally substituted.
[00114] As used herein, the term "N-thiocarbamyl" refers to a Ri7OC(=S)NR] 8- group,. Ri7 may be hydro; Ri7 and Ris may be Cl-10 alkyl or cycloalkyl groups. The alkyl or cycloalkyl group may be optionally substituted.
[00115] As used herein, the term "C-amido" refers to a -C(=O)NRi7Ri8 group. An "N-amido" refers to a Ri7C(=O)NRi8- group (Ri8 is not hydro). Ri7 and R] 8 may be hydro, C l-10 alkyl or cycloalkyl groups, or R)7 and Rig are combined with the N to form a ring structure, such as a piperidine, or Ri7 and Ri 8 are combined with the N and to form a ring, such as a piperazine. One of Rj7 and Ri8 can be hydro and the other alkyl or cycloalkyl. The alkyl or cycloalkyl group may be optionally substituted.
[00116] In some embodiments, optional substituents include one or more halo, hydroxy, carboxyl, amino, nitro, cyano, C1 -C6 acylamino, C1-C6 acyloxy, C 1 -C6 alkoxy, aryloxy, alkylthio, C6-C10 aryl, C4-C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl(C2-C6)alkenyl, C6-C10 aryl(C2-C6)alkynyl, saturated and unsaturated heterocyclic or heteroaryl unless otherwise specified.
[00117] In some embodiments, optional substituents include one or more halo, C1 -C6 haloalkyl, C6-C 10 aryl, C4-C7 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl(Cl-C6)alkyl, C6-C10 aryl(C2-C6)alkenyl, C6-C10 aryl(C2- C6)alkynyl, C1 -C6 hydroxyalkyl, nitro, amino, ureido, cyano, C1 -C6 acylamino, hydroxy, thiol, C1 -C6 acyloxy, azido, C1-C6 alkoxy, carboxy or Cl -2 alkylenedioxy (e.g., methylenedioxy) unless otherwise specified.
[00118] As used herein, the term "ascorbic acid analog" refers to compounds such as ό-Bromo-ό-deoxy-L-ascorbic acid, dehydroascorbic acid (dehydroascorbate), 6- halo-ascorbates, 6-bromo-6-deoxy dehydroascorbic acid, 6-halo-dehydroascorbic acids, and the such (see e.g., Corpe et al. JBC 280:5211-20 (2005)).
[00119] As used herein, the term "choline analogs" refers to compounds such as CDP-choline (cytidine 5'-diphosphocholine) and N-cyclohexylcholine, see e.g., Buccafusco et al. J Alzheimers Dis. 2004 Dec;6(6 Suppl):S85-92; Geldenhuys et al. J Drug Target. 2005 May;13(4):259-66; and US patent publication no. 2005/0227993, pubished Oct. 13, 2005, each of which is herein incorporated by reference in its entirety.
[00120] As used herein, the term "glyceride" refers to a compound of Formula I wherein -R3 or -L-R3 has a glyceride moiety, e.g., CH2OR3CtCHORgCH2ORg, CH2OgRCHORaCtCH2ORg, or CH2ORgCHORgCH2ORac where Ract is the active agent and each Rg is independently chosen from — H, acyl, alkyl, acyloxy, and cycloalkyl, and optionally substituted versions thereof. See e.g., Kahn et al. Eur J Med Chem. 2005 Apr;40(4):371-6 and Kahn et al. Pharmazie 2005 Feb;60(2): 1 10-4, each of which is herein incorporated by reference in its entirety.
[00121] As used herein, the term "taurine analog" refers to a compound of Formula I wherein -R3 or — L-R3 is a taurine analog or derivative such as taltrimide, tramiprosate, acamprosate, tauromustine, N-pivaloyltaurine, 2- aminocycloalkanesulfonic acids, See e.g., Gupta et al. Curr Med Chem. 2005;12(17):2021-39 and Machetti et al. Adv Exp Med Biol. 2000;483:399-401 , each of which is herein incorporated by reference in its entirety.
[00122] As used herein, the term "prodrug" refers to a derivative of a parent drug molecule that requires transformation within the body in order to release the active drug, and that has improved physical and/or delivery properties over the parent drug molecule. Prodrugs are designed to enhance pharmaceutically and/or pharmacokinetically based properties associated with the parent drug molecule. The advantage of a prodrug lies in its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent drug, or it enhances absorption from the digestive tract, or it may enhance drug stability for long- term storage.
[00123] As is understood by the skilled artisan, certain variables in the list of substituents are repetitive (different name for same substituent), generic to other terms in the list, and/or partially overlap in content with other terms. In the compounds of the invention, the skilled artisan recognizes that substituents may be attached to the remainder of the molecule via a number of positions and the preferred positions are as illustrated in the Examples.
[00124] Specific examples of compounds of Formulae I-III are given in the Examples. The invention also includes pharmaceutical compositions having one or more compounds of Formulae I-III and a pharmaceutically acceptable carrier.
[00125] A pharmaceutically acceptable salt of the compound of the present invention is exemplified by a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like, and a salt with an organic acid such as acetic acid, propionic acid, succinic acid, maleic acid, fumaric acid, benzoic acid, citric acid, malic acid, methanesulfonic acid, benzenesulfonic acid and the like. Their hydrates (1 hydrate, 2 hydrate, 3 hydrate, 1/2 hydrate, 3/2 hydrate, 1/4 hydrate, 4/5 hydrate, 1/5 hydrate, 3/4 hydrate, 1/3 hydrate, 5/3 hydrate, 5/4 hydrate etc.), solvates and the like are also encompassed in the compound of the present invention. In addition, N-oxide compounds are also encompassed in the compound of the present invention.
[00126] In addition, pharmaceutically acceptable salts include acid salt of inorganic bases, such as salts containing alkaline cations (e.g., Li+, Na+ or K+), alkaline earth cations (e.g., Mg++, Ca++ or Ba++), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations, such as those arising from protonation of peralkylation of thriethylamine, N,N-diethylamine, N,N-dicyclohexylamine, pyridine, N5N- dimethylaminopyridine (DMAP), l,4-diazabiclo[2.2.2]octane (DABCO), 1,5- diazavicyclo[4.3.0]non-5-ene (DBN) and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU). [00127] Additionally, the compounds of Formulae I-III can contain asymmetric carbon atoms and can therefore exist in racemic and optically active forms. Thus, optical isomers or enantiomers, racemates, and diastereomers are also encompassed in the compounds of Formula I-III. The methods of present invention include the use of all such isomers and mixtures thereof. Methods of separation of enantiomeric and diastereomeric mixtures are well known to one skilled in the art. The present invention encompasses any isolated racemic or optically active form of compounds described in Formulae I-III, or any mixture thereof.
[00128] ROUTES OF ADMINISTRATION AND FORMULATIONS
[00129] The compounds of this invention are typically administered in combination with a pharmaceutically acceptable carrier through any appropriate route, e.g., parenteral, oral, or topical administration, in a therapeutically acceptable amount.
[00130] In general, there are three general methods of tablet preparation: (1) the wet-granulation method; (2) the dry-granulation method; and (3) direct compression. These methods are well known to those skilled in the art. See, Remington's Pharmaceutical Sciences. 16th and 18th Eds., Mack Publishing Co., Easton, Pa. (1980 and 1990). See, also, U.S. Pharmacopeia XXI. U.S. Pharmacopeial Convention, Inc., Rockville, Md. (1985).
[00131 ] The phenyl alkanoic acid prodrug tablets can be manufactured using e.g., a high shear wet granulation method incorporating pre-blending and pre-milling to reduce the size of the large particles in the drug substance. Once granulated, the material can be dried, milled and blended again. The final powder blend can be compressed into tablets on a high-speed rotary press and the resulting tablets coated in a perforated pan.
[00132] Soft gelatin capsules can be prepared in which capsules contain a mixture of the active pharmaceutical ingredient and vegetable oil or non-aqueous, water miscible materials such as, for example, polyethylene glycol and the like. Hard gelatin capsules may contain granules of the active pharmaceutical ingredient in combination with a solid, pulverulent carrier, such as, for example, lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin. [00133] Tablets are typically made by molding, by compression or by generally accepted tablet forming methods. Accordingly, compressed tablets are usually prepared by large-scale production methods while molded tablets often involve small- scale operations.
[00134] Tablets for oral use are typically prepared in the following manner, although other techniques may be employed. The solid substances are ground or sieved to a desired particle size, and the binding agent is homogenized and suspended in a suitable solvent. The active pharmaceutical ingredient and auxiliary agents are mixed with the binding agent solution. The resulting mixture is moistened to form a uniform suspension. The moistening typically causes the particles to aggregate slightly, and the resulting mass is gently pressed through a stainless steel sieve having a desired size. The layers of the mixture are then dried in controlled drying units for determined length of time to achieve a desired particle size and consistency. The granules of the dried mixture are gently sieved to remove any powder. To this mixture, disintegrating, antifriction, and anti-adhesive agents are added. Finally, the mixture is pressed into tablets using a machine with the appropriate punches and dies to obtain the desired tablet size. The operating parameters of the machine may be selected by the skilled artisan.
[00135] Various tablet formulations may be made in accordance with the present invention. These include tablet dosage forms such as sugar-coated tablets, film- coated tablets, enteric-coated tablets, multiple-compressed tablets, prolonged action tablets and the like. Sugar-coated tablets (SCT) are compressed tablets containing a sugar coating. Such coatings may be colored and are beneficial in covering up drug substances possessing objectionable tastes or odors and in protecting materials sensitive to oxidation. Film-coated tablets (FCT) are compressed tablets that are covered with a thin layer or film of a water-soluble material. A number of polymeric substances with film-forming properties may be used. The film coating imparts the same general characteristics as sugar coating with the added advantage of a greatly reduced time period required for the coating operation. Enteric-coated tablets are also suitable for use in the present invention. Enteric-coated tablets (ECT) are compressed tablets coated with substances that resist dissolution in gastric fluid but disintegrate in the intestine. Enteric coating can be used for tablets containing drug substances that are inactivated or destroyed in the stomach, for those which irritate the mucosa or as a means of delayed release of the medication.
[00136] Multiple compressed tablets (MCT) are compressed tablets made by more than one compression cycle, such as layered tablets or press-coated tablets. Layered tablets are prepared by compressing additional tablet granulation on a previously compressed granulation. The operation may be repeated to produce multilayered tablets of two, three or more layers. Typically, special tablet presses are required to make layered tablets. See, for example, U.S. Pat. No. 5,213,738, incorporated herein in its entirety by reference thereto.
[00137] Press coated tablets are another form of multiple compressed tablets. Such tablets, also referred to as dry-coated tablets, are prepared by feeding previously compressed tablets into a tableting machine and compressing another granulation layer around the preformed tablets. These tablets have all the advantages of compressed tablets, i.e. , slotting, monogramming, speed of disintegration, etc., while retaining the attributes of sugar coated tablets in masking the taste of the drug substance in the core tablet. Press-coated tablets can also be used to separate incompatible drug substances. Further, they can be used to provide an enteric coating to the core tablets. Both types of tablets (i.e., layered tablets and press-coated tablets) may be used, for example, in the design of prolonged-action dosage forms of the present invention.
[00138] Pharmaceutical compositions or unit dosage forms of the present invention in the form of prolonged-action tablets may comprise compressed tablets formulated to release the drug substance in a manner to provide medication over a period of time. There are a number of tablet types that include delayed-action tablets in which the release of the drug substance is prevented for an interval of time after administration or until certain physiological conditions exist. Repeat action tablets may be formed that periodically release a complete dose of the drug substance to the gastrointestinal fluids. Also, extended release tablets that continuously release increments of the contained drug substance to the gastrointestinal fluids may be formed.
[00139] In practical use, the phenyl alkanoic acid prodrug can be combined as the active pharmaceutical ingredient in intimate admixture with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques. The pharmaceutically acceptable carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral, parenteral (including intravenous, subcutaneous, intrathecal, and intramuscular), transdermal, and topical. In preparing the compositions for oral dosage form, any of the usual pharmaceutical media or excipients may be employed. These include, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations such as suspensions, elixirs and solutions; or aerosols; or excipients such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, capsules, caplets, and tablets. Solid oral preparations are generally preferred over liquid ones. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical pharmaceutically acceptable excipients are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Preferred solid oral preparations are tablets and capsules.
[00140] Pharmaceutical stabilizers may be used to stabilize compositions comprising the phenyl alkanoic acid prodrug, or pharmaceutically acceptable salts, solvates, or clathrates thereof. Acceptable stabilizers include, but are not limited to, L- cysteine hydrochloride, glycine hydrochloride, malic acid, sodium metabisulfite, citric acid, tartaric acid, and L-cystine dihydrochloride. See, e.g. , U.S. Patent Nos.: 5,731 ,000; 5, 763,493;'5, 541 ,231 ; and 5,358,970, all o'f which are incorporated herein by reference.
[00141] In addition to the common dosage forms set out above, the active pharmaceutical ingredient (i.e., phenyl alkanoic acid prodrug) can be administered by controlled release means and/or delivery devices capable of releasing the active pharmaceutical ingredient at a rate required to maintain constant pharmacological activity for a desirable period of time. Such dosage forms provide a supply of a drug to the body during a predetermined period of time and thus maintain drug levels in the therapeutic range for longer periods of time than conventional non-controlled formulations. Examples of controlled release pharmaceutical compositions and delivery devices which may be adapted for the administration of the active pharmaceutical ingredient of the invention are described in U.S. Patent Nos.: 3,847,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200; 4,008,719; 4,687,610; 4,769,027; 5,674,533; 5,059,595; 5,591,767; 5, 120,548; 5,073,543; 5,639,476; 5,354,566; and 5,733,566, the disclosures of which are incorporated herein by reference.
[00142] Pharmaceutical compositions of the invention suitable for oral administration may be presented as discrete units such as capsules, cachets, caplets, or tablets or aerosol sprays, each containing a predetermined amount of the active pharmaceutical ingredient as a powder, as granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy which include the step of bringing into association the active pharmaceutical ingredient with a pharmaceutically acceptable carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active pharmaceutical ingredient with a liquid pharmaceutically acceptable carrier or a finely divided solid pharmaceutically acceptable carrier, or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active pharmaceutical ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, disintegrating .agent, and/or surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert, liquid diluent.
[00143] INACTIVE PHARMACEUTICAL INGREDIENTS [00144] The formulations and unit dosage forms of the invention can have a number of different ingredients. Depending on the dosage strength, a unit dosage form has an amount of active pharmaceutical ingredient (API) sufficient for achieving a therapeutic effect in a target population. Additionally "inactive pharmaceutical ingredients" need to be present to achieve a therapeutically effect release of the API. Thus the amount and type of inactive ingredients help achieve a therapeutically effective release of the therapeutic agent. In one aspect of the invention, a tablet unit dosage form is provided having the following inactive ingredients: one or more disintegrants in an amount sufficient to facilitate break-up (disintegration) of the tablet after administration (e.g., provide an immediate release dissolution profile), one or more binders in an amount sufficient to impart adequate cohesiveness to the tablet and/or provide adequate free flowing qualities by formulation of granules of desired size/hardness, one or more diluents in an amount sufficient to impart satisfactory compression characteristics, one or more lubricants in an amount sufficient to provide an adequate flow rate of the granulation and/or prevent adhesion of the material to the die/punch, reduce interparticle friction, and/or facilitate ejection from the die, and if desired, optional ingredients.
[00145] The disintegration rate, and often the dissolution rate of a compacted solid pharmaceutical formulation in an aqueous environment (e.g., the patient's stomach) may be increased by the addition of a disintegrant to the formulation. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac-Di-Sol® Primellose®.), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab®) and starch.
[00146] Solid pharmaceutical formulations that are compacted into a dosage form, such as a tablet, may include excipients whose functions include helping to bind the active pharmaceutical ingredient and other excipients together after compression. Binders for solid pharmaceutical formulations include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methylcellulose (e.g. Methocel®), lactose, liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate and starch. Glidants can be added to improve the flowability of a non-compacted solid formulation and to improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
[00147] When a dosage form such as a tablet is made by the compaction of a powdered formulation, the formulation is subjected to pressure from a punch and dye. Some excipients and active pharmaceutical ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the formulation to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
[00148] Examples of diluents include, but are not limited to, calcium carbonate, calcium phosphate, calcium sulfate, cellulose, cellulose acetate, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, ethyl cellulose, fructose, fumaric acid, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, medium chaim glyceride, microcrystalline cellulose, polydextrose, polymefhylacrylates, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelantized starch, sterilizabfe maize, sucrose, sugar spheres, talc, tfagacanth, trehalose, and xylitol. , :
[00149] Examples of disintegrants include, but are not limited to, alginic acid, calcium phosphate, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, powdered cellulose, chitosan, crospovidone, docusate sodium, guar gum, hydroxylpropyl cellulose, magnesium aluminum silicate, methylcellulose, poidone, sodium alginate, sodium starch glycolate, starch, and pregelantinized starch.
[00150] Example of binders (binding agents) include, but are not limited to, acacia, alginic acid, carbomers, carboxymethyl cellulose sodium, carrageenan, cellulose acetate phthalate, ceratonia, chitosan, confectioners sugar, cottonseed oil, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glucose, glyceryl behenate, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxylpropyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, maltodextrin, maltose, methylcellulose, microcrystalline cellulose, poloxamer, polydextrose, polyethylene oxide, polymethyl acrylates, povidone, sodium alginate, starch, pregelantized starch, stearic acid, sucrose, sunflower oil, and zein.
[00151] Examples of lubricants include, but are not limited to, calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium lauryl sulfate, magnesium stearate, medium chain triglycerides, mineral oil, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
[00152] Examples of glidants include, but are not limited to, calcium phosphate, calcium silicate, cellulose powdered, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, silicon dioxide, starch, and talc.
[00153] Optional ingredients in the formulations of the invention include, but are not limited to, flavors, coloring agents, and stabilizers.
[00154] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the formulation of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid.
[00155] Solid and liquid formulations may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
[00156] General Synthetic Procedures
[00157] The phenyl alkanoic acid prodrugs of the invention (i.e., those of Formulae I-III) can be synthesized by an ordinary skilled artisan apprised of the instant invention, in view of the example below. For example, various phenyl alkanoic acids can be substituted for the 2-(2-fluoro-biphenyl-4-yl)-propionic acid starting material used in the example below to give the corresponding phenyl alkanoic acid prodrug. [00158] EXAMPLES
[00159J Chemicals were purchased from standard commercial vendors and used as received unless otherwise noted. Otherwise their preparation is facile and known to one of ordinary skill in the art, or it is referenced or described herein. Abbreviations are consistent with those in the ACS Style Guide, plus: satd (saturated), "dry" glassware means oven/desiccator dried. Solvents were ACS grade unless otherwise noted.
[00160]
[00161] Example 1 : Synthesis of Compounds of the Invention
[00162] The R-groups used in the schemes in the examples are taken independent of the other R-groups in this specification.
[00163] (R)-N-(4-Amino-butyl)-2-(2-fluoro-biphenyl-4-yI)-propionamide: To a solution of (R)-flurbiprofen (0.83 g, 3.40 mmol) in THF (5 mL) was added CDI (0.54 g, 3.33 mmol). The reaction was stirred at room temperature for 45 minutes. N-(4- aminobutyl)carbamic acid tert-butyl ester (0.65 mL, 3.40 mmol) was added and the reaction was stirred for 2 hours at room temperature. Ethyl acetate was added and washed with brine. The organic portion was dried (MgSO4) and evaporated to dryness. This product was dissolve in acetonitrile (50 mL) and 12 N HCl (4 mL) then stirred at room temperature for 1 hour. The reaction was poured over 5 M NaOH (70 mL) in ice then extracted with ethyl acetate (3x 20 mL). The organic portion was washed with brine and dried.. (MgSO4). Purified by Prep TLC (1 :3 methanol:methylene chloride).
Figure imgf000035_0001
[00165] (R)-N-{2-[2-(2-Amino-ethoxy)-ethoxy]-ethyl}-2-(2-fIuoro-biphenyl-4- yl)-propionamide: To a solution of (R)-flurbiprofen (1.00 g, 4.09 mmol) in THF (5 mL) was added CDI (0.65 g, 4.01 mmol). The reaction was stirred at room temperature for 45 minutes. This reaction mixture was added dropwise to a solution of 1,2-Bis(2- aminoethoxy)ethane (0.60 mL, 4.09 mmol) in THF (5 mL) the reaction was stirred for 5 hours at room temperature. Water (10 mL) and 1 M NaOH (1 mL) were added and the reaction extracted with ethyl ether (3 x 10 mL) then the organics were washed with brine and dried (MgSO4). Purified by flash chromatography (1 :9 triethyl amine:ethyl acetate then 1 :2.5:6.5 triethyl amine:methanol:ethylacetate).
Chiral
Figure imgf000036_0001
[00167] (R)-N- {2-[2-(2-Amino-ethoxy)-ethoxy]-ethyl}-2-(2-fluoro-biphenyl-4- yl)-propionamide: To a solution of (R)-flurbiprofen (1.00 g, 4.09 mmol) in THF (5 mL) was added CDI (0.65 g, 4.01 mmol). The reaction was stirred at room temperature for 45 minutes. This reaction mixture was added dropwise to a solution of 1 ,2-Bis(2- aminoethoxy)ethane (0.60 mL, 4.09 mmol) in THF (5 mL) the reaction was stirred for 5 hours at room temperature. Water (10 mL) and 1 M NaOH (1 mL) were added and the reaction extracted with ethyl ether (3 x 10 mL) then the organics were washed with brine and dried (MgSO4). Purified by flash chromatography (1 :9 triethyl aminerethyl acetate then 1 :2.5:6.5 triethyl amine:methanol:ethylacetate).
[00168] 2-(2-Fluoro-biphenyl-4-yl)propionamide: Neat acetyl chloride (0.90 mL; 12.7 mmol) was added to dry methanol (25 mL) at 00C. After warming to rt over 10 min, solid (R)-flurbiprofen (6.109 g; 25.0 mmol) was added. The reaction was concentrated on a rotary evaporator after 26 h. The resulting oil was dissolved in ethyl acetate (40 mL) then washed with 1 M NaOH (1 x 10 mL), 1 M HCl (1 x 10 mL) and saturated NaCl (1 x 10 mL). The organic portion was dried (MgSO4), filtered and concentrated to give 6.3 g of (R)-2-(2-fluoro-biphenyl-4-yl)-propionic acid methyl ester as a clear, colorless liquid (98%). IH NMR (300 MHz,CDC13) d 7.55 - 7.48 (m, 2H), 7.48 - 7.30 (m, 4H), 7.18 - 7.05 (m, 2H), 3.76 (q, J = 7.1 Hz, IH), 3.70 (s, 3H), 1.54 (d, J = 7.1 Hz5 3H).
Figure imgf000037_0001
[00170] General synthesis (A) for amides:
[00171] To a solution of amine (0.34 mmol) and (R)-flurbiprofen (0.35 mmol) in DMF (0.38 mL) was added l-hydroxy-7-azabenzotriazole (HOAt) (0.37 mmol) in DMF (0.50 mL), l-(3-dimethylaminopropyI)-3-ethylcarbodiimide hydrochloride (EDCI) (0.37 mmol) in DMF (0.53 mL) and 2,4,6-trimethylpyridine (92.5 uL, 0.70 mmol). The reactions were stirred at room temperature overnight then diluted with dichloromethane and washed with satd NaHCO3. The compounds were purified by flash chromatography.
Figure imgf000037_0002
[00173] General synthesis (B) for esters and sulfonamides:
[00174] To a solution of (R)-flurbiprofen (4.62 g, 18.9 mmol) in toluene (65 mL) was placed oxalyl chloride (6.5 mL) and DMF (0.05 mL). The reaction was refluxed for 3 hours then reaction was concentrated on rotary evaporator. The (R)-2-(2- Fluorobiphenyl-4-yl)-propionyl chloride was dissolved in dichloromethane (21 mL). To a solution of alcohol, phenol, or sulfonamide (0.34 mmol) in dichloromethane (0.2 mL) and triethyl amine (0.1 mL) was added (R)-2-(2-Fluorobiphenyl-4-yl)-propionyl chloride (0.4 mL, 0.36 mmol) and DMAP (0.04 mmol). The reactions were stirred overnight at room temperature then diluted with dichloromethane and washed with sat'd NaHCO3. The reactions were purified by flash chromatography.
[00175] Example 2: Compounds having the structures given in the table below were synthesized using general synthetic scheme A or B as described above.
[00176] TABLE l : 2-Halo-4-biphenyl alkanoic acid prodrugs
Structure Chemical General Synthetic Name Scheme
(R)-N -(4-Amino-butyl)-2-(2-fluoro- biphenyl-4-yl)-propionamide See Example 1
(R)-N-{2-[2-(2-Amino-ethoxy)-ethoxy]- ethyl} -2-(2-fluoro-biphenyl-4-yl)- propionamide See Example 1
2-(2-Fluoro-biphenyl-4- yl)propionamide See Example 1
(R)-2-(2-Fluoro-biphenyl-4-yI)-N- pyridin-3-ylmethyl-propionamide
(R)-N-Cyclopentyl-2-(2-fluoro-
Figure imgf000038_0001
biphenyl-4-yl)-propionamide (R)-2-(2-Fluoro-biphenyl-4-yl)-N-(4- methoxy-benzyl)-propionamide A
(R)-N-CyclopropyL-2-(2-fluoro- biphenyl-4-yl)-propionamide
(R)-2-(2-Fluoro-biphenyl-4-yl)-N-(3- imidazol- 1 -yl-propyl)-propionamide
(R)-N-[2-(2,4-Dimethyl-phenyl)-ethyl]-
2-(2-fluoro-biphenyl-4-yl)- propionamide
(R)-N-Benzyl-2-(2-fluoro-biphenyl-4- yl)-propionamide
(R)-N-(3,5-Dimethoxy-benzyl)-2-(2- fluoro-biphenyl-4-yl)-propionamide
(R)-2-(2-Fluoro-biphenyl-4-yl)-N-
Figure imgf000039_0001
isopropyl-propionamide (R)-2-(2-Fluoro-biphenyl-4-yl)-N-[2-(l- methyl-pyrrolidin-2-yl)-ethyl]- propionamide A
(R)-2-(2-Fluoro-biphenyl-4-yl)-N-(4- trifluoromethoxy-benzyl)-propionamide A
(R)-2-(2-Fluoro-biphenyl-4-yl)-N- propyl-propionamide
(R)-2-(2-Fluoro-biphenyl-4-yl)-N-(4- trifluoromethy]-benzy])-propioπamide
(R)-N-(3-Chloro-benzyl)-2-(2-fluoro- biphenyl-4-yl)-propionamide
(R)-N-(3-Fluoro-benzyl)-2-(2-fluoro- biphenyl-4-yl)-propionamide
(R)-2-(2-Fluoro-biphenyl-4-yl)-N- pyridin-3-yl-propionamide A (R)-N-(3,4-Dimethoxy-phenyl)-2-(2- fluoro-biphenyl-4-yl)-propionamide A
(R)-2-(2-Fluoro-biphenyt-4-yl)-N-(3- fluoro-phenyl)-propionamide
(R)-2-(2-Fluoro-biphenyl-4-yl)-N-(3- trifluoromethyl-phenyl)-propionamide
(R)-2-(2-Fluoro-bipheπyl-4-y1)-N-(3- methoxy-phenyl)-propionamide
(R)-N-(3-Chloro-phenyl)-2-(2-fluoro- biphenyl-4-yl)-propionamide
(R)-N-(4-Cyclohexyl-phenyl)-2-(2- flυoro-biphenyl-4-yl)-propionamide
(R)-2-(2-Fluoro-biphenyl-4-yl)-N-(lH-
Figure imgf000041_0001
indol-5-yl)-propionamide (R)-2-(2-Fluoro-biphenyl-4-yl)-N-p- tolyl-propionamide A
(R)-N-(4-Dimethylamino-phenyl)-2-(2- fluoro-biphenyl-4-yl)-propionamide A
(R)-N-(3,4-Dimethyl-phenyl)-2-(2- fluoro-biphenyl-4-yl)-ρropionamide
(R)-N-(3,4-Dichloro-phenyl)-2-(2- fluoro-biphenyl-4-yl)-propionamide
(R)-2-(2-Fluoro-biphenyl-4-yl)-N-m- tolyl-propionamide
(R)-N-(2,4-Difluoro-phenyl)-2-(2- fluoro-biphenyl-4-yl)-propionamide
(R)-2-(2-Fluoro-biphenyl-4-yl)-N-(lH-
Figure imgf000042_0001
tetrazol-5-yl)-propionamide (R)-2-(2-Fluoro-biphenyl-4-yl)-N-(lH- indazol-6-yl)-propionamide
(R)-2-(2-Fluoro-biphenyi-4-yl)-N-(4- morpholin-4-yl-phenyl)-p'ropionamide
(R)-N, N-Diethyl-2-(2-fluoro-biphenyl- 4-yl)-propionamide
(R)-N-(2-Dimethylamino-ethyl)-2-(2- fluoro-bipheπyl-4-yl)-N-methyl- propionamide
(R)-2-(2-Fluoro-biphenyl-4-yl)- 1 -(4-
Figure imgf000043_0001
methyl-piperazin-l-yl)-ρropan-l-one
uoro-biphenyl-4-yl)-l -(4- l -yl-piperidin-l-yl)-propan-
Figure imgf000043_0002
(R)-2-(2-Fluoro-biphenyl-4-yl)-l -
Figure imgf000043_0003
thiazolidin-3-yl-propan-l-one (R)-2-<2-Fluoro-biphenyl-4-yl)- 1 - morpholin-4-yl-propan-l-one
(R)-2-(2-Fluoro-biphenyl-4-yl)- l- piperidin- 1 -yl-propan- 1 -one
(R)-2-(2-Fluoro-biphenyl-4-yl)- 1 -(4-
Figure imgf000044_0001
phenyl-piperazin-l-yl)-propan-l-one
Figure imgf000044_0002
(R)-N-Benzyl-2-(2-fluoro-biphenyl-4- yl)-N-methyl-propionamide
(R)-2-(2-Fluoro-biphenyl-4-yl)-N,N- dimethyl-propionamide
(R)-2-(2-Fluoro-biphenyl-4-yl)-N-
Figure imgf000044_0003
methyl-N-phenyl-propionamide (R)-2-(2-Fluoro-biphenyl-4-yl> propionic acid 2-phenoxy-ethyl ester B
(R)-2-(2-Fluoro-biρhenyl-4-yl)- propionic acid 2-(4-trifluoromethyl- phenyl)-ethyl ester B
(R)-2-(2-Fluoro-biphenyL-4-yl)- propioπic acid 4-fluoro-benzyl ester B
(R)-2-(2-Fluoro-biphenyl-4-yl)- propionic acid 2-(2-dimethylamino- ethoxy)-ethyl ester B
(R)-2-(2-Fiuoro-biphenyl-4-yl)- propionic acid 2-(2-methoxy-ethoxy)- ethyl ester B
(R)-2-(2-Fluoro-biphenyl-4-yl)- propionic acid 2-(3-methoxy-phenyl)- ethyl ester B
(R)-2-(2-Fluoro-biphenyl-4-yl)- propionic acid 2-morpholin-4-yl-ethyl
Figure imgf000045_0001
ester B (R)-2-(2-Fluoro-biphenyl-4-yl)- propionic acid phenethyl ester B
(R)-2-(2-Fluoro-biphenyl-4-yl)- propionic acid 2-cyclopropyl-ethyl ester B
(R)-2-(2-Fluoro-biphenyl-4-yl)- propionic acid 2-imidazol-l-yl-ethyl ester B
(R)-2-(2-Fluoro-biphenyl-4-yl)- propionic acid 2-piperidin-l-yl-ethyl ester B
(R)-2-(2-Fluoro-biphenyl~4-yl)- propionic acid 2-(4-chloro-phenoxy)- ethyl ester B
(R)-2-(2-Fluoro-biphenyl-4-yI)- propionic acid 4-dimethylamino-benzyI ester
(R)-2-(2-Fluoro-biphenyl-4-yl)-
Figure imgf000046_0001
propionic acid phenyl ester B (R)-2-(2-Fluoro-biphenyl-4-yl)- propionic acid 4-chloro-phenyl ester
(R)-2-(2-Fluoro-biphenyl-4-yl)- propionic acid 4-methoxy-phenyl ester B
(R)-2-(2-Fluoro-biphenyl-4-yl)- propioπic acid 4-fluoro-phenyl ester B
(R)-2-(2-Fluoro-biphenyl-4-yl)- propionic acid 3-chloro-phenyl ester
(R)-2-(2-Fluoro-biphenyl-4-yl)- propionic acid 3-methoxy-phenyl ester B
(R)-2-(2-Fiuorc-biphenyl-4-yl)- propionic acid naphthalen-2-yI ester B
(R)-2-(2-Fluoro-biphenyl-4-yl)- propionic acid 4-trifluoromethyl-phenyl
Figure imgf000047_0001
ester B (R)-2-(2-Fluoro-biphenyl-4-yl)- propionic acid 3-fluoro-phenyI ester B
(R)-2-(2-Fluoro-biphenyl-4-yl)- propionic acid biphenyl-4-yl ester B
(R)-2-(2-Fluoro-biphenyl-4-yl)- pTopionic acid 5,6,7,8-tetrahydro- naphthalen-1-yl ester B
(R)-2-(2-Fluoro-biphenyl-4-yl)- propionic acid 3,5-dimethoxy-phenyl ester
(R)-2-(2-Fluoro-biphenyl-4-yl)- propionic acid indan-5-yl ester
(R)-2-(2-Fluoro-biphenyl-4-yl)- propionic acid 3-isopropyl-pheny] ester B
(R)-2-(2-Fluoro-biphenyl-4-yl)- propionic acid 3,4,5-trirnethoxy-pheπyl
Figure imgf000048_0001
ester B (R)-2-(2-Fluoro-biphenyl-4-yl)- propionic acid 4-trifluoromethoxy- phenyl ester B
(R)-2-(2-Fluoro-biphenyl-4-yl)- propionic acid m-tolyl ester B
NaphthaIene-2-sulfonic acid [(R)-2-(2- fluoro-bipheπyI-4-yl)-propionyl] -amide B
(2R)-N-[(dimethylamino)sulfonyl]-2-(2- fluorobiphenyl-4-yl)propanamide B
N-[(R)-2-(2-Fluoro-biphenyl-4-yl)- propionyl]-4-methyl- benzenesulfonamide B
N-[(R)-2-(2-Fluoro-biphenyl-4-yl)- propionyl]-4-trifluoromethyl- benzenesulfonamide
N-[(R)-2-(2-Fluoro-biphenyl-4-yl)- propionyl]-4-methoxy-
Figure imgf000049_0001
benzenesulfo'namide B 4-Chloro-N-[(R)-2-(2-fluoro-biphenyl- 4-yl)-propionylj-benzenesulfonamide B
N-[(R)-2-(2-Fluoro-biphenyl-4-yl)- propionyl]-methanesulfonamide B
3-Fluoro-N-[(R)-2-(2-fluoro-biphenyi- 4-yl)-propionyl]-benzenesulfonamide B
N-[(R)-2-(2-Fluoro-biphenyl-4-yl)- propionyl]-benzenesulfonamide
5-Dimethylamino-naphthalene-l- sulfonic acid [(R)-2-(2-fluoro-biphenyl- 4-yl)-propionyl]-amide B
5-Methyl-pyridine-2-sulfonic acid [(R)- 2-(2-fluoro-biphenyl-4-yl)-proρionyl]- amide B
4-Fluoro-N-[(R)-2-(2-fluoro-biphenyl-
4-yl)-propionyl]-2-methyl-
Figure imgf000050_0001
benzenesulfonamide B C,C,C-TriΩuoro-N-[(R)-2-(2-fluoro- biphenyl-4-yl)-propionyI]- methanesulfonamide B
N-[(R)-2-(2-Fluoro-biphenyl-4-yl)- propionyl]-2-methoxy-4-methyl- benzenesulfonamide B
N-[(R)-2-(2-Fluoro-biphenyl-4-yl)- propionylJ-C-phenyl- methanesulfonamide
N-[(R)-2-(2-Fluoro-biphenyl-4-yl)- propϊonyl]-2-trifluoromethoxy- benzenesulfoπamide B
(R)-2-(2-Fluoro-biphenyl-4-yl)-N-(2-
Figure imgf000051_0001
methoxy-ethyl)-N-methyl-propionamide A
[00177] Example 3: Assay for testing ability to cross the blood brain barrier.
[00178] A high throughput screen for membrane permeability can be used to assay for blood-brain barrier permeability. For example, the method disclosed in Di et al. Eur. J. Med. Chem. 38:223-32 (2003) can be used to assess the ability of a compound of the invention to cross the blood-brain barrier.
[00179] Example 4a: Tablets
Figure imgf000051_0002
Figure imgf000052_0001
The tablets are prepared using art known procedures.
Example 4b: Coated tablets
Figure imgf000052_0002
The coated tablets are produced using art known procedures.
Example 4b: Capsules
Figure imgf000052_0003
The capsules are produced using art known procedures.
Example 4d: Tablets
Figure imgf000053_0001
Example 5: Treatment of Alzheimer's disease with a compound of Formulae I-III
The compounds of Formulae I-III can be administered twice daily as tablets containing 400 mg of active ingredient or as a capsule containing 400 mg of the active ingredient. A higher dose can be administered to the patient in need of such treatment which can involve the patient talcing e.g., a 800 mg dose of a compound of Formulae I- III in the morning and a 800 mg dose of a compound of Formulae I-III in the evening. Typically, for the treatment of mild-to-moderate Alzheimer's disease, an individual is diagnosed by a doctor as having the disease using a suitable combination of observations. One criterion indicating a likelihood of mild-to-moderate Alzheimer's disease is a score of about 15 to about 26 on the MMSE test. Another criteria indicating mild-to-moderate Alzheimer's disease is a decline in cognitive function. Compounds of Formulae I-III can also be administered in liquid dosage forms. The dosages can also be divided or modified, and taken with or without food. For example, the 400 mg dose can be divided into two 200 mg tablets or capsules.
Depending on the stage of the disease, the compound {i.e., Formulae I-III) can also be administered twice daily in liquid, capsule, or tablet dosage forms where the dose has various amounts (i.e., 850 mg, 750 mg, 700 mg, 650 mg, 600 mg, 550 mg, 500 mg, 450 mg, 350 mg, 300 mg, 250 mg, 200 mg, 150 mg, and 100 mg). Again, the dosages can also be divided or modified, and taken with or without food. The doses can be taken during treatment with other medications for treating Alzheimer's disease or symptoms thereof. For example, the compound can be administered in the morning as a tablet containing 400 mg of active ingredient (i.e., a compound of Formulae I-III) and an acetylcholine esterase inhibitor (i.e., tacrine (Cognex®), donepezil (Aricept®), rivastigmine (Exelon®), and galantamine (Reminyl®)), and/or an NMDA antagonist (i.e., memantine). It may be desirable to lower the amount of acetylcholine esterase inhibitor (and/or NMDA antagonist) to avoid adverse side effects associated with higher doses of these compounds. Alternatively, the acetylcholine esterase inhibitor (and/or NMDA antagonist) and prodrug of the invention can be co-formulated into a single dosage form, i.e., liquid, tablet, capsule, etc.
Patients having mild-to-moderate Alzheimer's disease undergoing the treatment regimen of this example with a compound of Formulae I-III in doses of about 20 mg to 1600 mg per day can experience a lessening in decline of cognitive function (as measured by the ADAS-cog or CDR sum of boxes), plaque pathology, and/or biochemical disease marker progression.
[00180] All publications and patent applications mentioned in the specification are indicative of the level of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The mere mentioning of the publications and patent applications does not necessarily constitute an admission that they are prior art to the instant application.
[00181] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be obvious that certain changes and modifications may be practiced within the scope of the appended claims.

Claims

CLAIMSWhat is claimed is:
1. A prodrug of a 2-halo-4-biphenyl alkanoic acid wherein the alkanoic acid moiety is. a propionic acid moiety and the prodrug moiety enhances delivery of the 2- halo-4-biphenyl alkanoic acid to the brain or across the blood-brain-barrier. as compared to the parent 2-halo-4-biphenyl alkanoic acid.
2. The prodrug of claim 1 wherein said prodrug is of Formula 1 :
Figure imgf000055_0001
. - - ' ■ . FORMULA I wherein
Rl is chosen from — H and C1 -C6 alkyl;
R2 is chosen from — H and C1-C6 alkyl; or
Rl and R2 can be taken together to form a C3-C7 carbocyclic ring;
R3 is a moiety chosen from a central nervous system penetration enhancer, a blood-brain-barrier penetration enhancer, a bioavailability enhancer, and a tumor targeting agent;
X is chosen from chloro, fluoro, bromo, and iodo; and
L can be saturated, partially saturated, or unsaturated, and is chosen from
-(CH2V(CH2),,-, -(CH2)nC(=O)(CH2)n-, -(CH2)nC(=O)N(CH2)n-, -
(CH2)nNC(=O)O(CH2)n-, -(CH2)nNC(=O)N(CH2)n-, -
(CH2)nNC(=S)S(CH2)n-, -(CH2)nOC(=O)S(CH2)n-, -(CHa)nNH(CH2V, -
(CH2)HO(CH2V, -(CH2)nS(CH2V, -(CH2)nNC(=S)N(CH2)n-, where each n is independently chosen from 0, 1 , 2, 3, 4, 5, 6, 7, and 8, and wherein each carbon and/or nitrogen can be optionally substituted with one or more substituents independently chosen hydroxyl, halo, alkoxy, Ci -3 alkyl, and C3.6 cycloalkyl groups.
3. The prodrug of claim 2 wherein R3 is a blood-brain barrier penetration enhancer.
4. The prodrug of claim 2 wherein X is a fluoro.
5. The prodrug of claim 2 wherein one of Rl and R2 is an — H group, and the other of Rl and R2 is a -CH3, and the stereochemical configuration at the carbon attached to Rl and R2 is the same as in (R)-2-(2-fluoro-4-biphenylyl)propionic acid.
6. The prodrug of claim 2 wherein L is a covalent bond.
PCT/US2007/004189 2006-02-15 2007-02-15 Prodrugs WO2007095383A2 (en)

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