WO2006138187A1 - Enhanced tissue penetration prodrugs - Google Patents

Enhanced tissue penetration prodrugs Download PDF

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Publication number
WO2006138187A1
WO2006138187A1 PCT/US2006/022671 US2006022671W WO2006138187A1 WO 2006138187 A1 WO2006138187 A1 WO 2006138187A1 US 2006022671 W US2006022671 W US 2006022671W WO 2006138187 A1 WO2006138187 A1 WO 2006138187A1
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Prior art keywords
compound
dimethyl
dione
pyrrolidin
carbonyl
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PCT/US2006/022671
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French (fr)
Inventor
Yong-Qian Wu
Gregory S. Hamilton
Sergei Belyakov
Daniel Waldon
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Yong-Qian Wu
Hamilton Gregory S
Sergei Belyakov
Daniel Waldon
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Publication of WO2006138187A1 publication Critical patent/WO2006138187A1/en

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    • 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
    • C07D233/60—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 oxygen or sulfur atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
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    • 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
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/06—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D249/18—Benzotriazoles
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/28—Oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2

Definitions

  • the present invention relates to derivatives of carboxy-containing drugs for enhancing tissue penetration, pharmaceutical compositions comprising such derivatives and methods of treatment using such derivatives.
  • a fundamental principle of drug action is that a medicament must be capable, upon administration, of distributing throughout the body, and achieving therapeutically relevant concentrations in the target tissue or tissues. Most drugs distribute throughout the body in the blood plasma. See Goldstein et at, The Principles of Drug Action: The Basis of Pharmacology (2d ed. 1974). Thus, in order to act, most drugs must first enter the circulatory system. From the circulatory system, they reach the tissues of an organ at a rate determined by the blood flow throughout that organ and by the diffusion of the drug molecules across the capillary bed and into the cells of the tissues in question.
  • the permeability of the BBB to non-ionized forms of a weak electrolyte is so much greater than to the ionized forms that, for all practical purposes, the latter may as well be considered as not penetrating the BBB at all.
  • Goldstein et al. p. 191.
  • a drug to act upon the CNS by systemic administration, a drug must have a suitable combination of those properties that confer ready penetration, namely, low ionization at plasma pH, low binding to plasma proteins, and fairly high lipid/water partition coefficient.
  • FIG. 1 is a graph showing naproxen levels in rat plasma following i.v. administration of a single 10 mg/kg i.v. dose of naproxen, Compound 1 or Compound
  • FIG. 2 is a graph showing naproxen levels in rat brain following i.v. administration of a single 10 mg/kg dose of naproxen, Compound 1 or Compound 2.
  • FIG. 3 is a graph showing naproxen levels in rat muscle following i.v. administration of a single 10 mg/kg dose of naproxen, Compound 1 or Compound 2.
  • FIG. 4 is a graph showing naproxen levels in rat plasma following oral administration of a single 10 mg/kg dose of naproxen or Compound 1.
  • FIG. 5 is a graph showing naproxen levels in rat brain following oral administration of a single 10 mg/kg dose of naproxen or Compound 1.
  • FIG. 6 is a graph showing naproxen levels in rat muscle following oral administration of a single 10 mg/kg dose of naproxen or Compound 1.
  • FIG. 7 is a graph showing naproxen levels in rat muscle and plasma following oral administration of a single 10 mg/kg dose of naproxen or Compound 4.
  • FIG. 8 is a graph showing naproxen levels in rat plasma following i.v. administration of a single 10 mg/kg dose of naproxen or Compound 4.
  • FIG. 9 is a graph showing naproxen levels in rat heart, kidney and liver following i.v. administration of a single 10 mg/kg dose of naproxen or Compound 4.
  • FIG. 10 is a graph showing naproxen levels in rat intestines and stomach following i.v. administration of a single 10 mg/kg dose of naproxen or Compound 4.
  • FIG. 11 is a graph showing naproxen levels in rat brain, plasma and muscle following i.v. administration of a single 10 mg/kg dose of naproxen or Compound 5.
  • FIG. 12 is a graph showing ibuprofen levels in rat plasma following i.v. administration of a single 10 mg/kg dose of ibuprofen, Compound 20 or Compound 21.
  • FIG. 13 is a graph showing ibuprofen levels in rat brain following i.v. administration of a single 10 mg/kg dose of ibuprofen, Compound 20 or Compound 21.
  • FIG. 14 is a graph showing valproic acid levels in rat plasma following i.v. administration of a single 10 mg/kg dose of valproic acid or Compound 27.
  • FIGS. 15A and 15B are graphs showing naproxen levels in rat plasma (FIG. 15B) and knee joint (FIG. 15A) from a single 10 mg/kg dose of naproxen or Compound 4.
  • FIGS. 16A and 16B are graphs showing the anti-inflammatory activity (FIG. 16A) and gastrointestinal toxicity (FIG. 16B) of naproxen and Compound 4.
  • FIGS. 17A and 17B are graphs showing concentrations of Compound A in rat plasma and brain following oral administration of a single (FIG. 17A) or i.v. (FIG. 17B) 10 mg/kg dose of Compound A or Compound 36.
  • FIG. 18 is a graph showing concentrations of Compound A in rat plasma and brain following i.v. administration of a single 10 mg/kg dose of Compound 37.
  • FIG. 19 is a graph showing concentrations of Compound A in rat plasma and brain following i.v. administration of a single 10 mg/kg dose of Compound 38.
  • FIG. 20 is a graph showing concentrations of Compound A in rat plasma and brain following i.v. administration of a single 10 mg/kg dose of Compound 39.
  • FIG. 21 is a graph showing concentrations of Compound A in rat plasma and brain following i.v. administration of a single 10 mg/kg dose of Compound 44.
  • FIG. 22 is a graph showing concentrations of Compound A in rat plasma and brain following i.v. administration of a single 10 mg/kg dose of Compound 46.
  • FIG. 23 is a graph showing concentrations of Compound A in rat plasma and brain following i.v. administration of a single 10 mg/kg dose of Compound 50.
  • FIG. 24 is a graph showing concentrations of Compound A in rat plasma and brain following i.v. administration of a single 10 mg/kg dose of Compound 51.
  • FIG. 25 is a graph showing concentrations of Compound A in rat plasma and brain following i.v. administration of a single 10 mg/kg dose of Compound 49.
  • FIG. 26 is a graph showing concentrations of Compound A in rat plasma and brain following i.v. administration of a single 10 mg/kg dose of Compound 53.
  • FIG. 27 is a graph showing concentrations of Compound A in rat plasma and brain following i.v. administration of a single 10 mg/kg dose of Compound 54.
  • FIG. 28 is a graph showing concentrations of Compound A in rat plasma and brain following i.v. administration of a single 10 mg/kg dose of Compound 59.
  • FIG. 29 is a graph showing concentrations of Compound A in dog plasma or brain following i.v. administration of a single 10 mg/kg dose of Compound A or Compound 49.
  • Compound A is l-(3,3-dimethyl-2-oxo-pentanoyl)-pyrrolidine-2- carboxylic acid.
  • Alkyl refers to a saturated straight or branched chain hydrocarbon radical. Examples include without limitation methyl, ethyl, propyl, iso-propyl, butyl, iso- butyl, tert-butyl, n-pentyl and n-hexyl.
  • Alkenyl refers to an unsaturated straight or branched chain hydrocarbon radical comprising at least one carbon to carbon double bond. Examples include without limitation ethenyl, propenyl, iso-propenyl, butenyl, iso-butenyl, fe/t-butenyl, n-pentenyl and n-hexenyl.
  • Alkoxy refers to an alkyl group bonded through an oxygen linkage.
  • Alkenoxy refers to an alkenyl group bonded through an oxygen linkage.
  • Halo refers to a fluoro, chloro, bromo or iodo radical.
  • Carbocyclic ring refers to a mono- or poly-cyclic alkyl radical. Non- limiting examples of a carbocyclic ring include cyclobutyl, cycopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Non-limiting examples of an "aromatic carbocyclic ring” include phenyl, benzyl, naphthyl, anthracenyl, phenanthracenyl and biphenyl.
  • "Heterocyclic ring” refers to a carbocyclic ring, in which one or more carbon atoms is/are replaced by one or more heteroatom(s), such as nitrogen, phosphorous, oxygen, sulfur, silicon, germanium, selenium and/or boron.
  • the heteroatom(s) is/are nitrogen, oxygen and/or sulfur.
  • heterocyclic rings include piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl and pyrrolidinyl.
  • aromatic heterocyclic ring include pyrryl, furanyl, thienyl, pyridinyl, oxazolyl, thiazolyl, benzofuranyl, benzothienyl, benzofuranyl and benzothienyl.
  • Effectivee amount refers to the amount required to produce a desired effect, for example, enhancing tissue penetration, or treating a disease, disorder and/or condition in a mammal.
  • “Pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ or portion of the body.
  • a pharmaceutically acceptable material, composition or vehicle such as a liquid or solid filler, diluent, excipient or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ or portion of the body.
  • Each carrier is “acceptable” in the sense of being compatible with the other ingredients of the formulation and suitable for use with the patient. Examples of
  • materials that can serve as a pharmaceutically acceptable carrier include without limitation: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide
  • “Pharmaceutically acceptable salt” refers to an acid or base salt of the inventive compounds, which salt possesses the desired pharmacological activity and is neither biologically nor otherwise undesirable.
  • the salt can be formed with acids that include without limitation acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride hydrobromide, hydroiodide, 2-hydroxyethane-sulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, o
  • Examples of a base salt include without limitation ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine and lysine.
  • the basic nitrogen-containing groups can be quarternized with agents including lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl
  • lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such as decyl, lauryl, myristyl
  • stearyl chlorides bromides and iodides
  • aralkyl halides such as phenethyl bromides
  • “Isomers” refer to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing with respect to the arrangement or configuration of the atoms.
  • Stepoisomers refer to isomers that differ only in the arrangement of the atoms in space.
  • Diastereoisomers refer to stereoisomers that are not mirror images of each other. Diastereoisomers occur in compounds having two or more asymmetric carbon atoms; thus, such compounds have 2 n optical isomers, where n is the number of asymmetric carbon atoms.
  • Enantiomers refers to stereoisomers that are non-superimposable mirror images of one another.
  • Enantiomer-enriched refers to a mixture in which one enantiomer predominates.
  • Racemic refers to a mixture containing equal parts of individual enantiomers.
  • Non-racemic refers to a mixture containing unequal parts of individual enantiomers.
  • Examples include, without limitation, members of the human, equine, porcine, bovine, murine, canine and feline species.
  • an "animal” may also be referred to as a "patient.”
  • “Mammal” refers to a warm-blooded vertebrate animal.
  • Treating refers to: (i) preventing a disease, disorder or condition from occurring in an animal that may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; (ii) inhibiting a disease, disorder or condition, i.e., arresting its development; and/or (iii) relieving a disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition.
  • the present invention provides derivatives of carboxy-containing drugs.
  • One aspect of the present invention relates to a compound of formula (I)
  • R is an acyl group of a carboxy-containing drug
  • W, X, Y and Z form with the nitrogen atom a five-membered saturated or unsaturated heterocyclic ring; which said heterocyclic ring is unsubstituted or substituted with one to three substituent(s) independently selected from halo, hydroxyl, mercapto, nitro, trifluoromethyl, acetyl, aminocarbonyl, methylsulfonyl, oxo, cyano, carboxy, C 1 - C 6 alkyl, C 2 - C 6 alkenyl, C 1 - C 4 alkoxy, C 2 - C 4 alkenyloxy, phenoxy, phenyl, benzyloxy, benzyl and amino, wherein said phenyl, phenoxy, benzyloxy or benzyl is unsubstituted or substituted with one or more substituent(s) independently selected from halo, hydroxyl, mercapto, nitro, trifluoromethyl, acetyl, amino
  • oxo cyano, carboxy, C 1 - C 6 alkyl, C 2 - C 6 alkenyl, C 1 - C 4 alkoxy and C 2 - C 4 alkenyloxy.
  • W, X, Y and Z formula and the nitrogen atom is non-substituted.
  • Non-limiting examples of such embodiments include:
  • the five-membered heterocyclic ring is fused to a second five- or six-membered ring.
  • Non-limiting examples of such embodiments include:
  • the fused or non-fused heterocyclic ring is substituted with one or more substituent(s).
  • the one or more substituent(s) is/are independently selected from halo, hydroxyl, nitro, trifluoromethyl, acetyl, cyano, carboxy, C 1 - C 6 alkyl, C 1 - C 4 alkoxy, phenoxy, phenyl, substituted phenyl and amino, hi yet further embodiments, the one or more substituent(s) is/are independently selected from halo, acetyl, Ci - C 6 alkyl, C 1 - C 4 alkoxy, phenyl, substituted phenyl and amino.
  • substituted phenyl refers to a phenyl that is substituted with one or more substituent(s) independently selected from halo, hydroxyl, mercapto, nitro, trifluoromethyl, acetyl, aminocarbonyl, methylsulfonyl, oxo, cyano, carboxy, C 1 - C 6 alkyl, C 2 - C 6 alkenyl, Ci - C 4 alkoxy and C 2 - C 4 alkenyloxy.
  • W, X, Y and Z may be divalent or trivalent radicals independently selected from CH 2 , CH, C, O, NH, N and S. In some embodiments, W, X, Y and Z are divalent radicals independently selected from CH 2 , CH, O, NH, N and S. In other embodiments, W, X, Y and Z are divalent radicals independently selected from CH 2 , CH, NH and N.
  • the carboxy-containing drug may be any drug containing a carboxyclic acid.
  • Representative classes of carboxy-containing drugs include, without limitation, CNS drugs, a non-steroidal anti-inflammatory drugs (NSAIDs) and antibiotics.
  • Non- limiting examples of carboxy-containing drugs include naproxen, aspirin, ibuprofen, indomethacin, sulindac, valproic acid, R-flurbiprofen, gamma-hydroxybutyrate (GHB) and penicillins, such as ampicillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin, fiucloxacillin, nafcillin, oxacillin, penicillin G, penicillin V,
  • the carboxy-containing drug is naproxen, aspirin, ibuprofen, indomethacin, sulindac, valproic acid, R-flurbiprofen, GHB or penicillin G.
  • the carboxy-containing drug is naproxen, ibuprofen or valproic acid.
  • the carboxy-containing drug is Compound A.
  • the "acyl group" as used herein would have the general formula R 5 CO-.
  • Non-limiting examples of an acyl group of a carboxy-containing drug, as designated by R include moieties of formulae (A), (B), (C), (D), (E), (F), (G), (H), (I) and (J):
  • R is a moiety of formula A, B, C, D, E, F, G, H or I. In other embodiments, R is a moiety of formula A, C, D 5 F or J. In yet other embodiments, R is a moiety of formula (J) and the compound is represented by formula (II)
  • R is a moiety of formula (L) and the compound is represented by formula IV:
  • the compounds of the present invention may be less polar and/or more lipophilic than the parent carboxy-containing drugs. As such, the compounds of the present invention may distribute rapidly in the body and penetrate target tissues, so as to deliver the parent drugs into target tissues at higher concentrations than would be achieved by administering the parent drugs themselves. Thus, in some embodiments, the compounds of the present invention may exhibit enhanced tissue penetration relative to the parent drugs. Due to their enhanced tissue penetration, the compounds of the present invention may also be more efficacious than the parent drugs in treating a given disease, disorder or condition in a mammal.
  • the compounds of the present invention may possess one or more asymmetric carbon center(s), they may exist in the form of an optical isomer or, as part of a racemic or non-racemic mixture.
  • the R configuration may be enriched while in other non-racemic mixtures, the S configuration may be enriched.
  • Another aspect of the present invention relates to a method for enhancing tissue penetration of a carboxy-containing drug, which comprises combining the carboxy-containing drug with a five-membered heterocyclic ring of formula (III)
  • tissue penetration is determined by the concentration of the carboxy-containing drug in a target tissue, as measured by methods known in the art or described herein.
  • "enhancing tissue penetration” means that administration of a compound of the present invention achieves a higher concentration of the parent carboxy-containing drug in the target tissue than administration of the carboxy-containing drug itself.
  • the target tissue may be any tissue that is administered to a target tissue.
  • Another aspect of the present invention relates to a method for treating a disease, disorder or condition, which comprises administering a compound of the present invention to a mammal in need thereof.
  • the disease, disorder or condition may be any disease, disorder or condition treatable by a carboxy-containing drug, non-limiting examples of which include those disclosed in U.S. Patent Publications Nos. 2003-0186961 Al and US 2003-0203890 Al, as well as, nerve damage, neurological disorder, bacterial infection, inflammation, pain, fever, headache, arthritis, stroke and heart attack.
  • the compounds of the present invention are less toxic and/or more efficacious in treating a disease, disorder or condition than the parent carboxy-containing drugs.
  • the compounds of the present invention may exhibit improved anti-inflammatory efficacy and/or reduced gastrointestinal toxicity relative to the parent carboxy-containing NSAID drugs.
  • the compounds of the present invention may be administered by any means known to an ordinarily skilled artisan, for example, orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, intracranial, and intraosseous injection and infusion techniques.
  • the compounds of the present invention may be administered by a single dose, multiple discrete doses or continuous infusion. Pump means, particularly subcutaneous pump means, are useful for continuous infusion.
  • Dose levels on the order of about 0.001 mg/kg/d to about 10,000 mg/kg/d may be useful for the inventive methods. In some embodiments, the dose level is about 0.1 mg/kg/d to about 1,000 mg/kg/d. In other embodiments, the dose level is about 1 mg/kg/d to about 100 mg/kg/d.
  • the appropriate dose level and/or administration protocol for any given patient may vary depending upon various factors, including the activity and the possible toxicity of the specific compound employed; the age, body weight, general health, sex and diet of the patient; the time of
  • any administration regimen well known to an ordinarily skilled artisan for regulating the timing and sequence of drug delivery can be used and repeated as necessary to effect treatment in the inventive methods.
  • the regimen may include pretreatment and/or co-administration with additional therapeutic agents.
  • the compounds of the present invention are administered alone or in combination with one or more additional therapeutic agent(s) for simultaneous, separate, or sequential use.
  • the additional agent(s) may be any therapeutic agent(s), including without limitation one or more compound(s) of the present invention.
  • the compounds of the present invention may be co-administered with one or more therapeutic agent(s) either (i) together in a single formulation, or (ii) separately in individual formulations designed for optimal release rates of their respective active agent.
  • composition comprising:
  • inventive pharmaceutical compositions may comprise one or more additional pharmaceutically acceptable ingredient(s), including without limitation one or more wetting agent(s), buffering agent(s), suspending agent(s), lubricating agent(s), emulsif ⁇ er(s), disintegrant(s), absorbent(s), preservative(s), surfactant(s), colorant(s), flavorant(s), sweetener(s) and additional therapeutic agent(s).
  • inventive pharmaceutical composition may be formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (for example, aqueous or non-aqueous
  • solutions or suspensions for example, those targeted for buccal, sublingual and systemic absorption), boluses, powders, granules, pastes for application to the tongue, hard gelatin capsules, soft gelatin capsules, mouth sprays, emulsions and microemulsions;
  • parenteral administration for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or a sustained-release formulation
  • topical application for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin
  • intravaginally or intrarectally for example, as a pessary, cream or foam
  • sublingually (6) ocularly; (7) transdermally; or (8) nasally.
  • Compounds of the invention may be prepared by standard methods known to those skilled in the chemical arts.
  • the carboxylic acid group of the parent drug may be converted to an activated derivative such as an acyl chloride or mixed anhydride, and this activated derivative may be reacted with a variety of heterocyclic amines to furnish the prodrugs of the parent drugs.
  • Example 1 Synthesis of 1 -imidazole- 1-yl -2-(6-methoxy-naphthalen-2-yl)- propan-1-one (1) ,
  • Example 2 Synthesis of l-pyrazole-l-yl-2-(6-methoxy-naphthalen-2-yl)- propan-1-one
  • Example 5 Synthesis of acetic acid 2-(4-methyl-5-vinyl-imidazole-l- carbonyl)-phenyl ester
  • Example 6 Synthesis of l-benzotriazol-l-yl-2-(2-fluoro-biphenyl-4-yl)- propan-1-one
  • Acid chloride (2) was dissolved in dichloromethane (10 mL) and added dropwise to a stirred solution of 1-benzotriazole (0.12 g, 1.02 mmol) and triethylamine (0.17 mL, 1.22 mmol) in dichloromethane (25 mL) at room temperature. After addition, stirring was continued for 20 hours. The formed solution was concentrated in vacuum, and the resulting solid was subjected to the column chromatography (silica gel, eluent- EtOAc : hexanes 2:3).
  • Example 7 Synthesis of acetic acid 4-oxo-4-(3-phenyl-pyrazol-l-yl)-butyl ester
  • Acetic acid 4-oxo-4-(3-phenyl-pyrazol-l-yl)-butyI ester V.
  • Example 8 Synthesis of l-[2-(imidazole-l-carbonyl)-pyrrolidin-l-yl]-3,3- dimethyl-pentane-1, 2-dione (36)
  • Example 8 Following the same protocol described above, in Example 8, the desired product was obtained.
  • Example 10 Synthesis of l-[2-(2-isopropyl-imidazole-l-carbonyl)- pyrrolidin- 1 -yl]-3,3-dimethyl-pentane- 1 ,2-dione (38)
  • Example 8 Following the same protocol described above, in Example 8, the desired product was obtained.
  • Example 12 Synthesis of 3,3-dimethyl-l-[2-(3-phenyl-pyrazole-l- carbonyl)-pyrrolidin- 1 -yl]-pentane- 1 ,2-dione (40)
  • Example 8 Following the same protocol described above, in Example 8, the desired product was obtained.
  • Example 8 Following the same protocol described above, in Example 8, the desired product was obtained.
  • Example 14 Synthesis of l-[2-(3,5-diisopropyl-pyrazole-l-carbonyl) ⁇ ⁇ yrrolidin-1 -yl]-3,3-dimethyl-pentane-l,2-dione (42)
  • Example 15 Synthesis of l-[2-(3,5-dimethyl-pyrazole-l-carbonyl)- pyrrolidm-l-yl]-3,3-dimethyl- ⁇ entane-l,2-dione (43)
  • Example 16 Synthesis of l-[2-(indazole-l-carbonyl)-pyrrolidin-l-yi]-3,3- dimethyl-pentane-l,2-dione (44)
  • Example 8 Following the same protocol described above, in Example 8, the desired product was obtained.
  • 1 H NMR (CDCl 3 , 400 MHz): ⁇ 0.89(t, 3H); 1.26(m, 6H); 1.74(m, 3H); 2.09(m, 3H); 2.5 l(m IH); 3.06(m, 2H); 5.88(q, IH); 7.41(t, IH); 7.57(t, IH); 7.76(d, IH); 8.45(d, IH).
  • Example 17 Synthesis of l-[2-(4,4-dimethyl-4,5-dmydro-imidazole-l- carbonyl)-pyrrolidin- 1 -yl] -3 ,3-dimethyl-pentane- 1 ,2-dione (45) Following the same protocol described above, in Example 8, the desired product was obtained.
  • 1 H NMR (CDCl 3 , 400 MHz): ⁇ 0.88(t, 3H); 1.38(m, 6H); 1.38(s, 6H); 1.65- 1.81(m, 2H); 2.00(m, 2H); 2.17-2.33(m, 2H); 3.58(m, 4H); 4.75(m, IH); 7.89(m, IH).
  • Example 18 Synthesis of l-[2-(benzotriazole-l-carbonyl)-pyrrolidin-l-yl]- 3,3-dimethyl-pentane-l ,2-dione (46)
  • Example 20 Synthesis of l-[2-(5-acetyl-pyrazole-l-carbonyl)-pyrrolidin-l- yl] -3 ,3 -dimethyl-pentane- 1 ,2-dione (48)
  • Example 21 Synthesis of l-[2-(2-isopropyl-benzoimidazole-l-carbonyl)- pyrrolidin-l-yl]-3 5 3-dimethyl-pentane-l 5 2-dione (49)
  • Example 22 Synthesis of 3,3-dimethyl-l-[2-(2-methyl-benzoimidazole-l- carbonyl)-pyrrolidin- 1 -yl]-pentane- 1 ,2-dione (50)
  • Example 8 Following the same protocol described above, in Example 8, the desired product was obtained.
  • Example 25 Synthesis of l-[2-(5,6-dimethoxy-benzoimidazole-l- carbonyl)-pyrrolidin-l-yl]-3,3-dimethyl-pentane-l,2-dione (53) Following the same protocol described above, in Example 8, the desired product was obtained.
  • Example 26 Synthesis of l-[2-(imidazo[4,5-Z>]pyridine-l-carbonyl)- pyrrolidin- 1 -yl] -3 ,3 -dimethyl-pentane- 1 ,2-dione (54)
  • Example 8 Following the same protocol described above, in Example 8, the desired product was obtained.
  • Example 27 Synthesis of l-[2-(2,3-dihydro-indole-l-carbonyl)-pyrrolidin- 1 -yl] -3, 3 -dimethyl-pentane- 1 ,2-dione (55)
  • Example 8 Following the same protocol described above, in Example 8, the desired product was obtained.
  • Example 28 Synthesis of l-[2-(l,3-dihydro-isoindole-2-carbonyl)- pyrrolidin-l-yl]-3,3-dimethyl-pentane-l,2-dione (56)
  • Example 29 Synthesis of l-[2-(2-chloro-purine-9-carbonyl)-pyrrolidin-l- yl] -3 ,3 -dimethyl-pentane- 1 ,2-dione (57)
  • Example 31 Synthesis of l-[2-(2 -dimethylamino-purine-9-carbonyl)- pyrrolidin-1 -yl] -3 ,3 -dimethyl-pentane- 1 ,2-dione (59)
  • Example 8 Following the same protocol described above, in Example 8, the desired product was obtained.
  • Example 32 Synthesis of l-[2-(benzoimidazole-l-carbonyl)-pi ⁇ eridin-l- yl]-3,3-dimethyl-pentane-l,2-dione (60)
  • Example 33 Synthesis of l-[2-(indazole-l-carbonyl)-piperidin-l-yl]-3 5 3- dimethyl-pentane-lj2-dione (61)
  • Example 8 Following the same protocol described above, in Example 8, the desired product was obtained.
  • 1 H NMR (CDCl 3 , 400 MHz): ⁇ 0.87(t, 3H); 1.24(m, 6H); 1.57-1.75(m, 6H); 1.99(m, IH); 2.40(d, IH); 3.48(d, IH); 3.85(t, IH); 6.3(d, IH); 7.35(t, IH); 7.55(t, IH); 7.71(d, IH); 8.14(s, IH); 8.40(d, IH).
  • Example 34 Synthesis of 3,3-dimethyl-l-[2-(pyrazole-l-carbonyl)- piperidin- 1 -yl] -pentane- 1 ,2-dione (62)
  • Example 8 Following the same protocol described above, in Example 8, the desired product was obtained.
  • 1 HNMR (CDCl 3 , 400 MHz): ⁇ 0.88(t, 3H); 1.26(m, 6H); 1.73(m, 6H); 2.03(m, IH); 2.41(d, IH); 3.54(d, IH); 3.76(t, IH); 6.25(d, IH); 6.48(d, IH); 7.76(s, IH); 8.25(d 5 IH).
  • Example 35 Synthesis of l-[2-(2-isopropyl-benzoimidazole-l-carbonyl)- piperidin- 1 -yl] -3 ,3 -dimethyl-pentane- 1 ,2-dione (63)
  • Example 8 Following the same protocol described above, in Example 8, the desired product was obtained.
  • Example 36 Evaluation of target tissue concentrations of carboxy- containing drugs delivered by carboxy-containing drugs or by prodrug derivatives in rats
  • mice Male Sprague-Dawley rats (250-300 g) were dosed orally (10 mg/kg) or intravenously (1 ml/kg) with a carboxy-containing drug or a prodrug derivative dissolved in a standard vehicle (45% polycarbonate glycol, 45% PEG-400, 10% ethanol). Two animals per time point (i.e., 15 minutes, 30 minutes, 1 hour, 3 hour) post-dose were euthanized with CO 2 gas.
  • rats with singular jugular vein cannulas were used. These cannulas were externalized from the subcutaneous space and cleared with 0.9% saline solution. After dosing, the cannulas were tied off or pinched close with a microclip.
  • Rats dosed via oral administration were fasted overnight. Prior to tissue dissection/harvestation from each rat, 5-10 ml of blood was drawn via cardiac stick. The collected blood was then placed into respective 1.5 ml Li-heparinized microcentrifuge tubes and stored on wet ice (for a maximum of 5 minutes) until it was centrifugated at 13K RPM for 10 minutes. Thereafter, the top layer of each tube (plasma) was aspirated via transfer pipette, dispensed into a clean non-heparinized microcentrifuge tube, and stored at -70 0 C. Collected tissues were weighed and placed into 20 ml scintillation vials and flash frozen on dry ice. AU samples were stored at -70 0 C until subsequent analysis.
  • the brain weight was added in volume of 20% MeOH and then homogenized.
  • Other tissues (kidney, small intestine, stomach, knee joint, thigh, liver, and heart) were thawed in water bath, cut up using shears, and then added to 2X the tissue weight in volume of 2X 20% MeOH. Plasma samples were thawed, vortexed and used directly.
  • Quantification of parent drug in rat plasma was done against calibration curves generated by spiking the parent drug into blank heparinized rat plasma (1, 5, 10, 50,
  • Test groups of four to six male Sprague Dawley rats weighing 110-130 g were used for each drug concentration or vehicle control. The animals had free access to food and water prior to testing. On the day of the experiment, all animals were weighed and marked for identification. To assess the effectiveness of the compounds on inflammation, rats were dosed with the experimental compound, vehicle or water 15 minutes to 1 hour prior to injecting 100 ⁇ l of 1% carrageenan into the plantar region of the right hind paw. The left footpad was used as a negative test control by injecting a similar volume of saline (100 ⁇ l). Isofluorane anesthesia was used during the administration of the carrageenan.

Abstract

The present invention relates to derivatives of carboxy-containing drugs for enhancing tissue penetration and pharmaceutical compositions comprising such derivatives.

Description

Atty. Dkt. No.: 054707-1271
ENHANCED TISSUE PENETRATION PRODRUGS
[0001] The present invention relates to derivatives of carboxy-containing drugs for enhancing tissue penetration, pharmaceutical compositions comprising such derivatives and methods of treatment using such derivatives. [0002] A fundamental principle of drug action is that a medicament must be capable, upon administration, of distributing throughout the body, and achieving therapeutically relevant concentrations in the target tissue or tissues. Most drugs distribute throughout the body in the blood plasma. See Goldstein et at, The Principles of Drug Action: The Basis of Pharmacology (2d ed. 1974). Thus, in order to act, most drugs must first enter the circulatory system. From the circulatory system, they reach the tissues of an organ at a rate determined by the blood flow throughout that organ and by the diffusion of the drug molecules across the capillary bed and into the cells of the tissues in question. The time course of drug action depends in a complex way upon the relative rates of these processes. [0003] Organs that are highly vascularized take up larger quantities of the drug during the initial distribution than those with lower perfusion. Thus, the kidney and liver generally have higher drug exposure than other organs, such as the brain, muscle, heart and skin. Mutschler et at, Drug Actions: Basic Principles and Therapeutic Aspects p. 11 (1995).
[0004] Interactions with plasma proteins greatly influence a drug's distribution and access to sites of action. For example, the binding of a drug to plasma proteins will lower the apparent volume of distribution and decrease tissue exposure. By far, the plasma protein that most influences drug binding is albumin. Each molecule of albumin contains many residues that are capable of interacting with positively charged, negatively charged, polar, lipophilic, and hydrophilic groups in drugs. Indeed, albumin contains more residues that interact with anions than any other plasma protein. As a result, drugs that are weak acids, such as naproxen, bind extensively to albumin and manifest very small volumes of distribution. Goldstein et
WASHJ 625836.1 Atty. Dkt. No.: 054707-1271
al,, supra. Because non-ionized acidic and basic drags have less affinity for albumin than their ionized counterparts, they are preferentially absorbed. [0005] Drugs that have their site of action within the central nervous system (CNS) face an additional obstacle in the blood-brain barrier (BBB). Lipophilic compounds cross the BBB much more easily than hydrophilic compounds. Mutschler et al, p. 16. For ionized drugs with pKa between 2.9-7.8, the brain to plasma ratio is only a few percent. The permeability of the BBB to non-ionized forms of a weak electrolyte is so much greater than to the ionized forms that, for all practical purposes, the latter may as well be considered as not penetrating the BBB at all. Goldstein et al., p. 191. Thus, to act upon the CNS by systemic administration, a drug must have a suitable combination of those properties that confer ready penetration, namely, low ionization at plasma pH, low binding to plasma proteins, and fairly high lipid/water partition coefficient. Goldstein et al, p. 195.
[0006] A need, therefore, exists for compounds possessing the aforementioned properties.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] FIG. 1 is a graph showing naproxen levels in rat plasma following i.v. administration of a single 10 mg/kg i.v. dose of naproxen, Compound 1 or Compound
2.
[0008] FIG. 2 is a graph showing naproxen levels in rat brain following i.v. administration of a single 10 mg/kg dose of naproxen, Compound 1 or Compound 2.
[0009] FIG. 3 is a graph showing naproxen levels in rat muscle following i.v. administration of a single 10 mg/kg dose of naproxen, Compound 1 or Compound 2.
[0010] FIG. 4 is a graph showing naproxen levels in rat plasma following oral administration of a single 10 mg/kg dose of naproxen or Compound 1.
[0011] FIG. 5 is a graph showing naproxen levels in rat brain following oral administration of a single 10 mg/kg dose of naproxen or Compound 1.
[0012] FIG. 6 is a graph showing naproxen levels in rat muscle following oral administration of a single 10 mg/kg dose of naproxen or Compound 1.
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[0013] FIG. 7 is a graph showing naproxen levels in rat muscle and plasma following oral administration of a single 10 mg/kg dose of naproxen or Compound 4.
[0014] FIG. 8 is a graph showing naproxen levels in rat plasma following i.v. administration of a single 10 mg/kg dose of naproxen or Compound 4.
[0015] FIG. 9 is a graph showing naproxen levels in rat heart, kidney and liver following i.v. administration of a single 10 mg/kg dose of naproxen or Compound 4.
[0016] FIG. 10 is a graph showing naproxen levels in rat intestines and stomach following i.v. administration of a single 10 mg/kg dose of naproxen or Compound 4.
[0017] FIG. 11 is a graph showing naproxen levels in rat brain, plasma and muscle following i.v. administration of a single 10 mg/kg dose of naproxen or Compound 5.
[0018] FIG. 12 is a graph showing ibuprofen levels in rat plasma following i.v. administration of a single 10 mg/kg dose of ibuprofen, Compound 20 or Compound 21.
[0019] FIG. 13 is a graph showing ibuprofen levels in rat brain following i.v. administration of a single 10 mg/kg dose of ibuprofen, Compound 20 or Compound 21.
[0020] FIG. 14 is a graph showing valproic acid levels in rat plasma following i.v. administration of a single 10 mg/kg dose of valproic acid or Compound 27.
[0021] FIGS. 15A and 15B are graphs showing naproxen levels in rat plasma (FIG. 15B) and knee joint (FIG. 15A) from a single 10 mg/kg dose of naproxen or Compound 4.
[0022] FIGS. 16A and 16B are graphs showing the anti-inflammatory activity (FIG. 16A) and gastrointestinal toxicity (FIG. 16B) of naproxen and Compound 4.
[0023] FIGS. 17A and 17B are graphs showing concentrations of Compound A in rat plasma and brain following oral administration of a single (FIG. 17A) or i.v. (FIG. 17B) 10 mg/kg dose of Compound A or Compound 36.
[0024] FIG. 18 is a graph showing concentrations of Compound A in rat plasma and brain following i.v. administration of a single 10 mg/kg dose of Compound 37.
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[0025] FIG. 19 is a graph showing concentrations of Compound A in rat plasma and brain following i.v. administration of a single 10 mg/kg dose of Compound 38.
[0026] FIG. 20 is a graph showing concentrations of Compound A in rat plasma and brain following i.v. administration of a single 10 mg/kg dose of Compound 39.
[0027] FIG. 21 is a graph showing concentrations of Compound A in rat plasma and brain following i.v. administration of a single 10 mg/kg dose of Compound 44.
[0028] FIG. 22 is a graph showing concentrations of Compound A in rat plasma and brain following i.v. administration of a single 10 mg/kg dose of Compound 46.
[0029] FIG. 23 is a graph showing concentrations of Compound A in rat plasma and brain following i.v. administration of a single 10 mg/kg dose of Compound 50.
[0030] FIG. 24 is a graph showing concentrations of Compound A in rat plasma and brain following i.v. administration of a single 10 mg/kg dose of Compound 51.
[0031] FIG. 25 is a graph showing concentrations of Compound A in rat plasma and brain following i.v. administration of a single 10 mg/kg dose of Compound 49.
[0032] FIG. 26 is a graph showing concentrations of Compound A in rat plasma and brain following i.v. administration of a single 10 mg/kg dose of Compound 53.
[0033] FIG. 27 is a graph showing concentrations of Compound A in rat plasma and brain following i.v. administration of a single 10 mg/kg dose of Compound 54.
[0034] FIG. 28 is a graph showing concentrations of Compound A in rat plasma and brain following i.v. administration of a single 10 mg/kg dose of Compound 59.
[0035] FIG. 29 is a graph showing concentrations of Compound A in dog plasma or brain following i.v. administration of a single 10 mg/kg dose of Compound A or Compound 49.
Definitions
[0036] "Compound A" is l-(3,3-dimethyl-2-oxo-pentanoyl)-pyrrolidine-2- carboxylic acid.
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[0037] "Alkyl" refers to a saturated straight or branched chain hydrocarbon radical. Examples include without limitation methyl, ethyl, propyl, iso-propyl, butyl, iso- butyl, tert-butyl, n-pentyl and n-hexyl.
[0038] "Alkenyl" refers to an unsaturated straight or branched chain hydrocarbon radical comprising at least one carbon to carbon double bond. Examples include without limitation ethenyl, propenyl, iso-propenyl, butenyl, iso-butenyl, fe/t-butenyl, n-pentenyl and n-hexenyl.
[0039] "Alkoxy" refers to an alkyl group bonded through an oxygen linkage. [0040] "Alkenoxy" refers to an alkenyl group bonded through an oxygen linkage. [0041] "Halo" refers to a fluoro, chloro, bromo or iodo radical. [0042] "Carbocyclic ring" refers to a mono- or poly-cyclic alkyl radical. Non- limiting examples of a carbocyclic ring include cyclobutyl, cycopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Non-limiting examples of an "aromatic carbocyclic ring" include phenyl, benzyl, naphthyl, anthracenyl, phenanthracenyl and biphenyl. [0043] "Heterocyclic ring" refers to a carbocyclic ring, in which one or more carbon atoms is/are replaced by one or more heteroatom(s), such as nitrogen, phosphorous, oxygen, sulfur, silicon, germanium, selenium and/or boron. In some embodiments, the heteroatom(s) is/are nitrogen, oxygen and/or sulfur. Nonlimiting examples of heterocyclic rings include piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl and pyrrolidinyl. Nonlimiting examples of an "aromatic heterocyclic ring" include pyrryl, furanyl, thienyl, pyridinyl, oxazolyl, thiazolyl, benzofuranyl, benzothienyl, benzofuranyl and benzothienyl. [0044] "Effective amount" refers to the amount required to produce a desired effect, for example, enhancing tissue penetration, or treating a disease, disorder and/or condition in a mammal.
[0045] "Pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ or portion of the body. Each carrier is "acceptable" in the sense of being compatible with the other ingredients of the formulation and suitable for use with the patient. Examples of
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materials that can serve as a pharmaceutically acceptable carrier include without limitation: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical formulations. [0046] "Pharmaceutically acceptable salt" refers to an acid or base salt of the inventive compounds, which salt possesses the desired pharmacological activity and is neither biologically nor otherwise undesirable. The salt can be formed with acids that include without limitation acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride hydrobromide, hydroiodide, 2-hydroxyethane-sulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, thiocyanate, tosylate and undecanoate. Examples of a base salt include without limitation ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine and lysine. In some embodiments, the basic nitrogen-containing groups can be quarternized with agents including lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl
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and stearyl chlorides, bromides and iodides; and aralkyl halides such as phenethyl bromides.
[0047] "Isomers" refer to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing with respect to the arrangement or configuration of the atoms.
[0048] "Stereoisomers" refer to isomers that differ only in the arrangement of the atoms in space.
[0049] "Diastereoisomers" refer to stereoisomers that are not mirror images of each other. Diastereoisomers occur in compounds having two or more asymmetric carbon atoms; thus, such compounds have 2n optical isomers, where n is the number of asymmetric carbon atoms.
[0050] "Enantiomers" refers to stereoisomers that are non-superimposable mirror images of one another.
[0051] "Enantiomer-enriched" refers to a mixture in which one enantiomer predominates.
[0052] "Racemic" refers to a mixture containing equal parts of individual enantiomers.
[0053] "Non-racemic" refers to a mixture containing unequal parts of individual enantiomers.
[0054] "Animal" refers to a living organism having sensation and the power of voluntary movement, and which requires for its existence oxygen and organic food.
Examples include, without limitation, members of the human, equine, porcine, bovine, murine, canine and feline species. In the case of a human, an "animal" may also be referred to as a "patient."
[0055] "Mammal" refers to a warm-blooded vertebrate animal.
[0056] "Treating" refers to: (i) preventing a disease, disorder or condition from occurring in an animal that may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; (ii) inhibiting a disease, disorder or condition, i.e., arresting its development; and/or (iii) relieving a disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition.
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[0057] Unless the context clearly dictates otherwise, the definitions of singular terms may be extrapolated to apply to their plural counterparts as they appear in the application; likewise, the definitions of plural terms may be extrapolated to apply to their singular counterparts as they appear in the application.
Compounds of the Present Invention
[0058] The present invention provides derivatives of carboxy-containing drugs.
[0059] One aspect of the present invention relates to a compound of formula (I)
Figure imgf000009_0001
(i)
[0060] or a pharmaceutically acceptable salt or solvate thereof, wherein:
R is an acyl group of a carboxy-containing drug; and
W, X, Y and Z form with the nitrogen atom a five-membered saturated or unsaturated heterocyclic ring; which said heterocyclic ring is unsubstituted or substituted with one to three substituent(s) independently selected from halo, hydroxyl, mercapto, nitro, trifluoromethyl, acetyl, aminocarbonyl, methylsulfonyl, oxo, cyano, carboxy, C1 - C6 alkyl, C2 - C6 alkenyl, C1 - C4 alkoxy, C2 - C4 alkenyloxy, phenoxy, phenyl, benzyloxy, benzyl and amino, wherein said phenyl, phenoxy, benzyloxy or benzyl is unsubstituted or substituted with one or more substituent(s) independently selected from halo, hydroxyl, mercapto, nitro, trifluoromethyl, acetyl, aminocarbonyl, methylsulfonyl, oxo, cyano, carboxy, C1 - C6 alkyl, C2 - C6 alkenyl, C1 - C4 alkoxy and C2 - C4 alkenyloxy; and which said heterocyclic ring is optionally fused to a second five- or six- membered ring, wherein said second ring is carbocyclic, aromatic carbocyclic, heterocyclic, or aromatic heterocyclic, and wherein said second ring is unsubstituted or substituted with one to three substituent(s) independently selected from halo, hydroxyl, mercapto, nitro, trifluoromethyl, acetyl, aminocarbonyl, methylsulfonyl,
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WASHJ 625836.1 Atty. Dkt. No.: 054707-1271
oxo, cyano, carboxy, C1 - C6 alkyl, C2 - C6 alkenyl, C1 - C4 alkoxy and C2 - C4 alkenyloxy.
[0061] In some embodiments, the five-membered heterocyclic ring, as formed by
W, X, Y and Z formula and the nitrogen atom, is non-substituted. Non-limiting examples of such embodiments include:
Figure imgf000010_0001
[0062] In other embodiments, the five-membered heterocyclic ring is fused to a second five- or six-membered ring. Non-limiting examples of such embodiments include:
Figure imgf000010_0002
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Figure imgf000011_0001
Figure imgf000011_0003
Figure imgf000011_0002
[0063] In yet other embodiments, the fused or non-fused heterocyclic ring is substituted with one or more substituent(s). In further embodiments, the one or more substituent(s) is/are independently selected from halo, hydroxyl, nitro, trifluoromethyl, acetyl, cyano, carboxy, C1 - C6 alkyl, C1 - C4 alkoxy, phenoxy, phenyl, substituted phenyl and amino, hi yet further embodiments, the one or more substituent(s) is/are independently selected from halo, acetyl, Ci - C6 alkyl, C1 - C4 alkoxy, phenyl, substituted phenyl and amino. As used herein, "substituted phenyl" refers to a phenyl that is substituted with one or more substituent(s) independently selected from halo, hydroxyl, mercapto, nitro, trifluoromethyl, acetyl, aminocarbonyl, methylsulfonyl, oxo, cyano, carboxy, C1 - C6 alkyl, C2 - C6 alkenyl, Ci - C4 alkoxy and C2 - C4 alkenyloxy.
[0064] W, X, Y and Z may be divalent or trivalent radicals independently selected from CH2, CH, C, O, NH, N and S. In some embodiments, W, X, Y and Z are divalent radicals independently selected from CH2, CH, O, NH, N and S. In other embodiments, W, X, Y and Z are divalent radicals independently selected from CH2, CH, NH and N.
[0065] The carboxy-containing drug may be any drug containing a carboxyclic acid. Representative classes of carboxy-containing drugs include, without limitation, CNS drugs, a non-steroidal anti-inflammatory drugs (NSAIDs) and antibiotics. Non- limiting examples of carboxy-containing drugs include naproxen, aspirin, ibuprofen, indomethacin, sulindac, valproic acid, R-flurbiprofen, gamma-hydroxybutyrate (GHB) and penicillins, such as ampicillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin, fiucloxacillin, nafcillin, oxacillin, penicillin G, penicillin V,
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pivampicillin, pivmecillinam, methicillin, mezlocillin, piperacillin, and ticarcillin. In some embodiments, the carboxy-containing drug is naproxen, aspirin, ibuprofen, indomethacin, sulindac, valproic acid, R-flurbiprofen, GHB or penicillin G. In other embodiments, the carboxy-containing drug is naproxen, ibuprofen or valproic acid. In yet further embodiments, the carboxy-containing drug is Compound A. [0066] For a carboxy-containing drug having a general formula R'COOH, the "acyl group" as used herein would have the general formula R5CO-. Non-limiting examples of an acyl group of a carboxy-containing drug, as designated by R, include moieties of formulae (A), (B), (C), (D), (E), (F), (G), (H), (I) and (J):
Figure imgf000012_0001
(E)
Figure imgf000012_0002
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WASH_1625836.1 Atty. Dkt. No.: 054707-1271
Figure imgf000013_0001
[0067] In some embodiments, R is a moiety of formula A, B, C, D, E, F, G, H or I. In other embodiments, R is a moiety of formula A, C, D5 F or J. In yet other embodiments, R is a moiety of formula (J) and the compound is represented by formula (II)
Figure imgf000013_0002
(II)
[0068] or a pharmaceutically acceptable salt or solvate thereof, wherein, W, X, Y, Z are as defined above.
[0069] In some embodiments of formula II, when said five-membered heterocyclic ring is fused to a second six-membered aromatic carbocyclic ring, such as via attachment to Y and Z, and one of W and X is N, then the other of W and X is CH2, CH, O or S. In other embodiments of formula II, when W is N and X is N, then Y and Z are divalent radicals independently selected from CH2, CH, O, NH, N and S. [0070] In yet other embodiments, R is a moiety of formula (K) and the compound is represented by formula (III):
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WASHJ 625836.1 Atty. Dkt. No.: 054707-1271
Figure imgf000014_0001
(HI)
[0071] or a pharmaceutically acceptable salt or solvate thereof, wherein, W, X3 Y, Z are as defined above.
[0072] In yet other embodiments, R is a moiety of formula (L) and the compound is represented by formula IV:
Figure imgf000014_0002
(IV)
[0073] or a pharmaceutically acceptable salt or solvate thereof, wherein, W, X, Y, Z are as defined above.
[0074] The compounds of the present invention may be less polar and/or more lipophilic than the parent carboxy-containing drugs. As such, the compounds of the present invention may distribute rapidly in the body and penetrate target tissues, so as to deliver the parent drugs into target tissues at higher concentrations than would be achieved by administering the parent drugs themselves. Thus, in some embodiments, the compounds of the present invention may exhibit enhanced tissue penetration relative to the parent drugs. Due to their enhanced tissue penetration, the compounds of the present invention may also be more efficacious than the parent drugs in treating a given disease, disorder or condition in a mammal.
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[0075] Non-limiting examples of the compounds of the present invention are set forth in Table I.
TABLE I
-
Figure imgf000015_0001
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Figure imgf000016_0001
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Figure imgf000017_0001
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■
Figure imgf000018_0001
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Atty. Dkt. No.: 054707-1271
Figure imgf000019_0001
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No. STRUCTURE NAME
25 2-[l-(4-chloro-benzoyl)-2- methyl-l/f-indol-3-yl]- 1 - pyrazol-1 -yl-ethanone
26 2-[6-fluoro-3-(4- methanesulfinyl-benzylidene)- 2-methyl-3H-inden- 1 -yl] - 1 - imidazol- 1 -yl-ethanone
27 1 -benzbimidazol-1 -yl-2- propyl-pentan- 1 -one
28 2-(2-fluoro-biphenyl-4-yl)- 1 - indazol- 1 -yl-propan- 1 -one
Figure imgf000020_0001
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Figure imgf000021_0001
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1-
Figure imgf000022_0001
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No. STRUCTURE NAME
37 l-[2-(benzoimidazole-l - carbonyl)-pyrrolidin- 1 -yl] - 3,3-dimethyl-pentane-l ,2- dione
38 1 -[2-(2-isopropyl-imidazole- 1 -carbonyl)-pyrrolidin- 1 -yl]- 3,3-dimethyl-pentane-l ,2- dione
39 3,3-dimethyl-l -[2-(pyrazole- 1 -carbonyl)-pyrrolidin- 1 -yl] - pentane- 1 ,2-dione
40 3,3-dimethyl-l-[2-(3-phenyl- pyrazole- 1 -carbonyl)- pyrrolidin- 1 -yl] -pentane- 1 ,2- dione
Figure imgf000023_0001
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Figure imgf000024_0001
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Figure imgf000025_0001
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No. STRUCTURE NAME
47 3,3-dimethyl-l -[2-(tetrazole- 1 -carbonyl)-pyrrolidin- 1 -yl] - pentane- 1 ,2-dione
48 1 -[2-(5-acetyl-pyrazole-l - carbonyl)-pyrrolidin- 1 -yl] - 3,3-dimethyl-pentane-l ,2- dione
49 1 - [2-(2-isopropyl- benzoimidazole- 1 -carbonyl)- pyrrolidin-1 -yl]-3,3-dimethyl- pentane-1 ,2-dione
50 3 ,3-dimethyl- 1 - [2-(2-methyl- benzoimidazole- 1 -carbonyl)- pyrrolidin- 1 -yl] -pentane- 1 ,2- dione
Figure imgf000026_0001
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No. STRUCTURE NAME
51 l-[2-(5-methoxy~ benzoimidazole- 1 -carbonyl)- pyrrolidin-1 -yl]-3,3-dimethyl- pentane- 1 ,2-dione
52 3,3-dimethyl- 1 -[2-(3-methyl- pyrazole-1 -carbonyl)- pyrrolidin- 1 -yl] -pentane- 1,2- dione
53 1 -[2-(5 ,6-dimethoxy- benzoimidazole- 1 -carbonyl)- pyrrolidin-l-yl]-3,3-dimethyl- pentane- 1 ,2-dione
54 1 -[2-(imidazo[455-έ]pyridine- 1 -carbonyl)-pyrrolidin- 1 -yl]- 3,3-dimethyl-pentane- 1 ,2- dione
Figure imgf000027_0001
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Atty. DkL No.: 054707-1271
No. STRUCTURE NAME
55 l-[2-(2,3-dihydro-indole-l- carbonyl)-pyrrolidin- 1 -yl] - 3 ,3-dimethyl-pentane- 1 ,2- dione
56 1 -[2-(1 ,3-dihydro-isoindole-2- carbonyl)-pyrrolidin- 1 -yl] - 3,3-dimethyl-pentane- 1 ,2- dione
57 1 -[2-(2-chloro-ρurine-9- carbonyl)-pyrrolidin- 1 -yl] - 3,3-dimethyl-ρentane-l ,2- dione
58 1 -[2-(2-methoxy-purine-9- carbonyl)-ρyrrolidin- 1 -yl] - 3,3-dimethyl-pentane-l ,2- dione
Figure imgf000028_0001
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Figure imgf000029_0001
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Figure imgf000030_0002
[0076] Since the compounds of the present invention may possess one or more asymmetric carbon center(s), they may exist in the form of an optical isomer or, as part of a racemic or non-racemic mixture. In some non-racemic mixtures, the R configuration may be enriched while in other non-racemic mixtures, the S configuration may be enriched.
Methods of the Present Invention
[0077] Another aspect of the present invention relates to a method for enhancing tissue penetration of a carboxy-containing drug, which comprises combining the carboxy-containing drug with a five-membered heterocyclic ring of formula (III)
Figure imgf000030_0001
[0078] wherein W5 X, Y and Z are as defined above.
[0079] In some embodiments, tissue penetration is determined by the concentration of the carboxy-containing drug in a target tissue, as measured by methods known in the art or described herein. In such embodiments, "enhancing tissue penetration" means that administration of a compound of the present invention achieves a higher concentration of the parent carboxy-containing drug in the target tissue than administration of the carboxy-containing drug itself. The target tissue may be any
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tissue of the body, including without limitation tissue of the liver, kidney, stomach, small intestines, large intestines, brain, muscle, cartilage, skin or heart. [0080] Another aspect of the present invention relates to a method for treating a disease, disorder or condition, which comprises administering a compound of the present invention to a mammal in need thereof. The disease, disorder or condition may be any disease, disorder or condition treatable by a carboxy-containing drug, non-limiting examples of which include those disclosed in U.S. Patent Publications Nos. 2003-0186961 Al and US 2003-0203890 Al, as well as, nerve damage, neurological disorder, bacterial infection, inflammation, pain, fever, headache, arthritis, stroke and heart attack. In some embodiments, the compounds of the present invention are less toxic and/or more efficacious in treating a disease, disorder or condition than the parent carboxy-containing drugs. For example, the compounds of the present invention may exhibit improved anti-inflammatory efficacy and/or reduced gastrointestinal toxicity relative to the parent carboxy-containing NSAID drugs.
[0081] The compounds of the present invention may be administered by any means known to an ordinarily skilled artisan, for example, orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, intracranial, and intraosseous injection and infusion techniques.
[0082] The compounds of the present invention may be administered by a single dose, multiple discrete doses or continuous infusion. Pump means, particularly subcutaneous pump means, are useful for continuous infusion. [0083] Dose levels on the order of about 0.001 mg/kg/d to about 10,000 mg/kg/d may be useful for the inventive methods. In some embodiments, the dose level is about 0.1 mg/kg/d to about 1,000 mg/kg/d. In other embodiments, the dose level is about 1 mg/kg/d to about 100 mg/kg/d. The appropriate dose level and/or administration protocol for any given patient may vary depending upon various factors, including the activity and the possible toxicity of the specific compound employed; the age, body weight, general health, sex and diet of the patient; the time of
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administration; the rate of excretion; other therapeutic agent(s) combined with the compound; and the severity of the disease, disorder or condition. Typically, in vitro dosage-effect results provide useful guidance on the proper doses for patient administration. Studies in animal models are also helpful. The considerations for determining the proper dose levels and administration protocol are known to those of ordinary skill in the medical profession.
[0084] Any administration regimen well known to an ordinarily skilled artisan for regulating the timing and sequence of drug delivery can be used and repeated as necessary to effect treatment in the inventive methods. For example, the regimen may include pretreatment and/or co-administration with additional therapeutic agents. In some embodiments, the compounds of the present invention are administered alone or in combination with one or more additional therapeutic agent(s) for simultaneous, separate, or sequential use. The additional agent(s) may be any therapeutic agent(s), including without limitation one or more compound(s) of the present invention. The compounds of the present invention may be co-administered with one or more therapeutic agent(s) either (i) together in a single formulation, or (ii) separately in individual formulations designed for optimal release rates of their respective active agent.
Pharmaceutical Compositions of the Present Invention
[0085] Yet another aspect of the present invention relates to a pharmaceutical composition comprising:
(i) an effective amount of a compound of the present invention; and ' (ii) a pharmaceutically acceptable carrier.
[0086] The inventive pharmaceutical compositions may comprise one or more additional pharmaceutically acceptable ingredient(s), including without limitation one or more wetting agent(s), buffering agent(s), suspending agent(s), lubricating agent(s), emulsifϊer(s), disintegrant(s), absorbent(s), preservative(s), surfactant(s), colorant(s), flavorant(s), sweetener(s) and additional therapeutic agent(s). [0087] The inventive pharmaceutical composition may be formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (for example, aqueous or non-aqueous
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solutions or suspensions), tablets (for example, those targeted for buccal, sublingual and systemic absorption), boluses, powders, granules, pastes for application to the tongue, hard gelatin capsules, soft gelatin capsules, mouth sprays, emulsions and microemulsions; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or a sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally. [0088] It will be apparent to one of ordinary skill in the art that specific embodiments of the present invention may be directed to one, some or all of the above-indicated aspects as well as other aspects, and may encompass one, some or all of the above- and below- indicated embodiments, as well as other embodiments. [0089] Other than in the working examples, or where otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified by the term "about". Accordingly, unless indicated to the contrary, such numbers are approximations that may vary depending upon the-desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding techniques.
[0090] While the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the working examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
EXAMPLES i
[0091] The following examples are illustrative of the present invention and are not intended to be limitations thereon.
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Compound Synthesis
[0092] Compounds of the invention may be prepared by standard methods known to those skilled in the chemical arts. The carboxylic acid group of the parent drug may be converted to an activated derivative such as an acyl chloride or mixed anhydride, and this activated derivative may be reacted with a variety of heterocyclic amines to furnish the prodrugs of the parent drugs.
[0093] Example 1: Synthesis of 1 -imidazole- 1-yl -2-(6-methoxy-naphthalen-2-yl)- propan-1-one (1) ,
Figure imgf000034_0001
A solution of naproxen (1.38 g, 6 mmol) and thionyl chloride (1.06 g, 9 mmol) in 100 mL of methylene chloride was refluxed for 5 hours, before the removal of the solvent under vacuo. Without further purification, the residue was dissolved in 5 mL of methylene chloride, and this solution was added dropwise to a mixture of imidazole (0.41 g, 6 mmol) and triethylamine (1.7 mL, 12 mmol) in 20 mL of methylene chloride. After the mixture was allowed to stir for additional 4 hours, the solvent was removed, and the crude residue was purified on a silica gel column, eluting with 30% ethyl acetate in hexane. The desired product was obtained 1.5 g (90% yield) as an oil first, which was then triturated with ether/hexane to give a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 1.57 (d, J = 6 Hz, 3H); 3.86 (s, 3H); 4.88 (dd, J = 6 Hz, IH); 7.01 (s, IH); 7.15 (dd, J = 3 Hz, IH); 7.29 (s, IH); 7.48 (dd, J = 3 Hz, IH); 7.75 (t, J = 3 Hz, IH); 7.79 (d, J = 3 Hz5 IH); 7.82 (d, J = 3 Hz, IH); 7.88 (s, IH); 8.54 (s, 1H).8.25 (s, IH); 7.52 (s, IH); 7.14 (s, IH); 5.13 (dd, J=4.0 and 9.2 Hz, IH); 3.77- 3.55 (m, 2H); 2.53-2.34 (m, IH); 2.20-2.01 (m, 3H); 1.92-1.61 (m, 2H), 1.23 (s, 6H), 0.88 (t, J=7.6 Hz, 3H). Anal. Calcd. for C17H16N2O2: C, 72.8; H, 5.8; N, 10.0. Found: C, 72.5; H, 5.8; N5 9.9. TLC: Rf = 0.3 (60% EtOAc/hexane).
[0094] Example 2: Synthesis of l-pyrazole-l-yl-2-(6-methoxy-naphthalen-2-yl)- propan-1-one
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Figure imgf000035_0001
Following the same protocol described above, the desired product was obtained in 75% yield as a white solid. 1H NMR (DMSO-d63, 400 MHz): δ .60(d, J=7. IHz, 3H); 3.85(s, 3H); 5.25(q, J=7.1Hz, IH); 6.59(dd, J=I.5, 1.3Hz5 IH); 7.15(dd, J=8.8, 2.5Hz, IH); 7.27(d, J=2.3Hz, IH); 7.49(dd, J=8.6, 1.5Hz, IH); 7.76-7.84(m, 3H); 7.89(s, IH); 8.44(d, J=2.8Hz, IH). Rf= 0.7 (30% EtOAc/hexane).
Example 3: Synthesis of 1- (6-Methoxy-benzoimidazol)-l-yl-2-(6-methoxy- naphthalen-2-yl)-propan- 1 -one
Figure imgf000035_0002
Following the same protocol described above, the desired product was obtained as a
white solid. 1H NMR (DMSO-dβ, 300 MHz): δ 9.04 (s, IH), 8.10 (d, J = 9 .0 Hz,
IH), 7.93 (s, IH), 7.81-7.78 (m, 3H), 7.58 (d, J = 9.0 Hz, IH), 7.26 (d, J - 9.0 Hz, IH), 7.15 (d, J = 9.0 Hz, IH), 7.02 (d, J = 8.0 Hz, IH), 5.06 (q, J = 8.0 Hz and 16.0 Hz, IH), 3.84 (s, 3H), 3.83 (s, 3H), 1.63 (d, J = 8 .0 Hz, 3H). Anal. Calcd. for C22H20N2O3: C, 72.06; H, 5.69; N, 7.64. Found: C, 71.71; H, 5.82; N, 7.72. Rf= 0.5 (50% EtOAc/hexane).
Example 4: Synthesis of l-(benzotriazol)-l-yl-2-(4-isobutyl-phenyl)-propan-l-one
Figure imgf000035_0003
WASH_1625836 1 Atty. Dkt. No.: 054707-1271
Following the same protocol described above, the desired product was obtained as a
white solid in 50% yield. 1H NMR (DMSO-d63, 300 MHz): δ 8,27-8.21 (m, 2H),
7.78 (t, J = 8.0 Hz, IH), 7.60 (t, J = 8.0 Hz, IH), 7.35 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H)5 5.31 (q, J = 9.0 and 17.0 Hz, IH), 2.37 (d, J = 8.0 Hz, 2H), 1.81-1.72 (m, IH), 1.64 (d, J = 8.0 Hz, 3H), 0.81 (d, J = 8.0 Hz, 6H). Anal. Calcd. for C19H21N3O: C, 74.2; H, 6.9; N, 13.7. Found: C, 74.4; H, 7.0; N, 13.4. Rf= 0.5 (20% EtOAc/hexane).
[0095] Example 5: Synthesis of acetic acid 2-(4-methyl-5-vinyl-imidazole-l- carbonyl)-phenyl ester
Figure imgf000036_0001
Following the same protocol described above except without silica gel column purification, the desired product was obtained as an oil in 70% yield. H NMR (DMSO-d6, 300 MHz): δ 8.27 (s, IH), 8.07-8.04 (m, IH), 7.87-7.75 (m, 3H), 7.54- 7.41 (m, 4H), 2.05 (s, 3H). Anal. Calcd. for C16H12N2O3: C, 66.0; H, 4.6; N, 9.6. Found: C, 66.0; H, 4.9; N, 9.3. Rf = 0.3 (30% EtOAc/hexane).
[0096] Example 6: Synthesis of l-benzotriazol-l-yl-2-(2-fluoro-biphenyl-4-yl)- propan-1-one
Figure imgf000036_0002
To a solution of (R)-(-)-2-(2-fluorobiphenyl-4-yl)propionic acid (0.25 g, 1.02 mmol) in dichloromethane (15 niL) was added thionyl chloride (0.12 mL, 1.53 mmol). The
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mixture was stirred and refluxed for 4 hours. The solvent was evaporated in vacuum to give acid chloride (2) as clear oil, which was used further without purification. Acid chloride (2) was dissolved in dichloromethane (10 mL) and added dropwise to a stirred solution of 1-benzotriazole (0.12 g, 1.02 mmol) and triethylamine (0.17 mL, 1.22 mmol) in dichloromethane (25 mL) at room temperature. After addition, stirring was continued for 20 hours. The formed solution was concentrated in vacuum, and the resulting solid was subjected to the column chromatography (silica gel, eluent- EtOAc : hexanes 2:3). Fractions with R/= 0.5 were collected, solvents evaporated in vacuum to give clear oil, which solidified under vacuum to give amide (3) as white microcrystals. Yield: 0.25 g (72%). Anal. Calcd. for C21H16FN3O: C, 73.03; H, 4.67; N, 12.17. Found: C, 73.06; H, 4.57; N5 12.22. M.p. = 60-62 °C. 1HNMR (CDCl3, 300 MHz): δ: 8.30 (d, J=8.4 Hz, IH); 8.09 (d, J=8.4 Hz, IH); 7.61 (t, J=7.9 Hz, IH); 7.55-7.41 (iti, 3H); 7.47-7.27 (m, 6H); 5.46 (dd, JJ=6.9 and 14.0 Hz, IH); 1.79 (d, J=7.4 Hz, 3H). 13C NMR (CDCl3, 300 MHz): δ 173.3; 161.8; 158.5; 146.7; 141.0; 135.7; 131.7; 131.5; 130.9; 129.3; 128.8; 128.1; 126.7; 124.6; 120.6; 116.3; 116.0; 114.9; 44.8; 19.0.
[0097] Example 7: Synthesis of acetic acid 4-oxo-4-(3-phenyl-pyrazol-l-yl)-butyl ester
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Figure imgf000038_0001
[0098] 4-Hydroxy-butyric acid benzyl ester (II). A mixture of 17.2g (0.2 mol) of dihydro-furan-2-one and 200 niL of 1.0 M tetrabutylammonium hydroxide in methanol was heated to reflux for 2 hours. The solvent was removed in vacuo to afford an oil. After the oil was dissolved in 200 mL of DMF, 34 g (0.2 mol) of benzyl bromide was added slowly. After the resulting mixture was stirred for 2 hours at room temperature, 300 mL of water was added. It was then extracted with ethyl acetate (3 X 300 mL). The organic layers were conbined, dried (NaSO4), concentrated in vacuo and purified (silica gel, 3:1 hexanes/EtOAc) to afford 19.5 g (50%) of oil of (II). 1H NMR (CDCl3, 300 MHz): δ 7.32-7.24 (m, 5H); 5.06 (s, 2H); 3.62 (t, J=6Hz, 2H); 2.43 (t, J=7.2 Hz5 2H); 1.84 (q, J=7 Hz, 2H).
[0099] 4-Acetoxy-butyric acid benzyl ester (III). To a solution of 1.2g (6.2 mmol) of 4-hydroxy-butyric acid benzyl ester in 20 mL of dichloromethane, at 0-5 0C, was added 0.1 g of 4-(dirnethylamino)pyridine, about 0.87 mL (6.2 mmol) of triethylamine and 0.56 mL (6.1 mmol) of acetic anhydride. After it was stirred at room temperature for one hour, 30 mL of water was added. It was then extracted with chloroform (2 X 100 mL). The organic layers were dried (NaSO4), concentrated in
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vacuo and purified (silica gel, 3:1 hexanes/EtOAc) to afford 0.7g (48%) of oil of (III). 1H NMR (CDCl3, 300 MHz): δ 7.31-7.19 (m, 5H); 5.02 (s, 2H); 3.99 (t, J= 6.5 Hz, 2H); 2.35 (t, J= 7.4 Hz5 2H); 1.95-1.82 (m, 5H).
[0100] 4-Acetoxy-butyric acid (IV). 0.7 g (3 mmol) of 4-Acetoxy-butyric acid benzyl ester(III), 0.16 g of 10% Pd on carbon and 20 mL of ethanol were placed in a Parr hydrogenation flask. The whole was hydrogenated at 35 psi and room temperature for half hour. The mixture was filtered through a Celite plug, the solvent was evaporated from the filtrate to afford 0.3 g (67%) of an oil (IV). 1H NMR (CDCl3, 300 MHz):, δ 4.1 l(t, J=6.3 Hz, 2H); 2.45(t, J= 7.2 Hz, 2H); 2.04(s, 3H); 1.96(q, J= 7.2 Hz, 2H).
[0101] Acetic acid 4-oxo-4-(3-phenyl-pyrazol-l-yl)-butyI ester (V). To a stirred solution of 0.5 g (3.5 mmol) of 4-acetoxy-butyric acid (IV) in 35 mL of THF was added 0.42g (4.1 mmol) of triethylamine at 0-5 0C. After five minutes, 0.56 g (4.1 mmol) of isopropyl chloroformate was added slowly. The mixture was then stirred at this temperature for 45 minutes. A solution of 0.59 g (4.1 mmol) of 3 -phenyl- IH- pyrazole in 5 mL of THF was added to the mixture. After it was stirred at room temperature for 2 days, 100 mL of ethyl acetate was added, followed by washing with water (2 X 15 mL). The ethyl acetate solution was dried over sodium sulphate, concentrated and purified (silica gel, 7:1 hexanes/EtOAc) to afford 0.55 g (59%) of (V). 1H NMR (DMSO-d6, 300 MHz): δ 8.49 (d, J=3.5, IH); 7.98-7.94 (m, 2H); 7.52- 7.41 (m, 3H); 7.17(d, J=3, IH); 4.13(t, J=6.3 Hz5 2H); 3.27(t, J=7.35 2H); 2.03(q, J=7.1 Hz5 2H); 1.98 (s, 3H). Anal. Calcd. for (C15H16N2O3): C5 66.16; H5 5.92; N5 10.29. Found: C5 66.10; H, 6.00; N, 10.29.
[0102] Example 8: Synthesis of l-[2-(imidazole-l-carbonyl)-pyrrolidin-l-yl]-3,3- dimethyl-pentane-1, 2-dione (36)
isobutyl chloroformate
Figure imgf000039_0001
Figure imgf000039_0002
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[0103] A solution of (2S)- 1 -(3, 3-dimetliyl-2-oxo-pentanoyl)-pyrrolidine- carboxylic acid (482 mg, 2 mmol) and triethylamine (0.386 mL, 3 mmol) in 5 ml of methylene chloride was cooled to 0 0C5 and isobutylchloroformate (0.26 mL, 2 mmol) was added dropwise. After stirring for 15 minutes, this mixture was treated with 136 mg (2 mmol) of imidazole in 1 mL methylene chloride, added dropwise. After 1 hour, TLC indicated that the reaction was complete. The solvent was removed in vacuo, and the crude residue was purified on a silica gel column, eluting with 90% ethyl acetate in hexane, to obtain 100 mg (17%) of the desired product as an oil. 1H NMR (CDCl3, 400 MHz): δ 8.25 (s, IH); 7.52 (s, IH); 7.14 (s, IH); 5.13 (dd, J=4.0 and 9.2 Hz, IH); 3.77-3.55 (m, 2H); 2.53-2.34 (m, IH); 2.20-2.01 (m, 3H); 1.92-1.61 (m, 2H), 1.23 (s, 6H), 0.88 (t, J=7.6 Hz, 3H). Anal. Calcd. for C15H21N3O3: C, 60.4; H, 7.4; N, 14.1. Found: C, 60.4; H,7.3; N, 13.8. TLC: Rf= 0.48 (90% EtOAc/hexane), MS (M+= 291).
[0104] Example 9: Synthesis of l-[2-(benzoimidazole-l-carbonyl)-pyrrolidin-l- yl]-3,3-dimethyl-pentane-l ,2-dione (37)
Following the same protocol described above, in Example 8, the desired product was obtained. 1H NMR (CDCl3, 400 MHz): δ 0.89(t, 3H); 1.29(m, 6H); 1.69(m, IH); 1.82(m, IH); 2.19(m, 3H); 2.45(m, IH); 3.71(m, 2H); 5.29(q, IH); 7.44(m, 2H); 7.84(m, IH); 8.22(m, IH); 8.52(s, IH).
[0105] Example 10: Synthesis of l-[2-(2-isopropyl-imidazole-l-carbonyl)- pyrrolidin- 1 -yl]-3,3-dimethyl-pentane- 1 ,2-dione (38)
Following the same protocol described above, in Example 8, the desired product was obtained. 1H NMR (CDCl3, 400 MHz): δ 0.88(t, 3H); 1.24-1.34(m, 12H); 1.68(m, IH); 1.82(m, IH); 2.09(m, 3H); 2.40(m, IH); 3.64(m, 3H); 5.07(q, IH); 6.96(s, IH); 7.30(s, IH).
[0106] Example 11: Synthesis of 3,3-dimethyl-l-[2-(pyrazole-l-carbonyl)- pyrrolidin- 1 -yl]-pentane- 1 ,2-dione (39)
Following the same protocol described above, in Example 8, the desired product was obtained in 32% yield. 1HNMR (CDCl3, 400 MHz): δ 0.88(t, 3H); 1.29(m, 6H);
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1.68(m, IH); 1.84(m, IH); 2.06(m, 3H); 2.5(m, IH); 3.62(m, 2H); 5.75(q, IH); 6.47(d, IH); 7.74(s, IH); 8.25(d, IH). GC-MS (M+291), Rf = 0.6 (50% EtOAc/hexane).
[0107] Example 12: Synthesis of 3,3-dimethyl-l-[2-(3-phenyl-pyrazole-l- carbonyl)-pyrrolidin- 1 -yl]-pentane- 1 ,2-dione (40)
Following the same protocol described above, in Example 8, the desired product was obtained. 1H NMR (CDCl3, 400 MHz): δ 0.89(t, 3H); 1.25(d, 6H); 1.71-1.83(m, 2H); 2.11(m, 3H); 2.55(m, IH); 3.66(m, 2H); 5.85(q, IH); 6.79(d, IH); 7.45(m, 3H); 7.88(m, 2H); 8.28(d, IH).
[0108] Example 13: Synthesis of 3,3-dimethyl-l-[2-(thiazole-2-carbonyl)- pyrrolidin- 1 -yl]-pentane- 1 ,2-dione (41)
Following the same protocol described above, in Example 8, the desired product was obtained. 1H NMR (CDCl3, 400 MHz): δ 0.78(t, 3H); 1.26(m, 6H); 1.77(m, 2H); 2.02(m, IH): 2.17(m, IH): 2.28(m, 2H); 3.64(m, 2H); 4.81 (m, IH); 7.07(d, IH); 7.5(d, IH).
[0109] Example 14: Synthesis of l-[2-(3,5-diisopropyl-pyrazole-l-carbonyl)~ ρyrrolidin-1 -yl]-3,3-dimethyl-pentane-l,2-dione (42)
Following the same protocol described above, in Example 8, the desired product was obtained. 1H NMR (CDCl3, 400 MHz): δ 0.87(t, 3H); 1.24(m, 18H); 1.66(m, 2H); 1.81(m. IH); 2.03(m, 3H); 2.48(m, IH); 2.89(m, IH); 3.65(m, 2H); 5.75(m, IH); 6.07(m, IH).
[0110] Example 15: Synthesis of l-[2-(3,5-dimethyl-pyrazole-l-carbonyl)- pyrrolidm-l-yl]-3,3-dimethyl-ρentane-l,2-dione (43)
Following the same protocol described above, in Example 8, the desired product was obtained. 1HNMR (CDCl3, 400 MHz): δ 0.85(t, 3H); 1.26(d, 6H); 1.67-1.78(m, 2H):
1.99(M, 3H); 2.2(S5 3H); 2.47(M, IH); 2.51(S, 3H); 3.6(M, 2H); 5.73(Q, IH): 5.94(S,
IH).
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[0111] Example 16: Synthesis of l-[2-(indazole-l-carbonyl)-pyrrolidin-l-yi]-3,3- dimethyl-pentane-l,2-dione (44)
Following the same protocol described above, in Example 8, the desired product was obtained. 1H NMR (CDCl3, 400 MHz): δ 0.89(t, 3H); 1.26(m, 6H); 1.74(m, 3H); 2.09(m, 3H); 2.5 l(m IH); 3.06(m, 2H); 5.88(q, IH); 7.41(t, IH); 7.57(t, IH); 7.76(d, IH); 8.45(d, IH).
[0112] Example 17: Synthesis of l-[2-(4,4-dimethyl-4,5-dmydro-imidazole-l- carbonyl)-pyrrolidin- 1 -yl] -3 ,3-dimethyl-pentane- 1 ,2-dione (45) Following the same protocol described above, in Example 8, the desired product was obtained. 1H NMR (CDCl3, 400 MHz): δ 0.88(t, 3H); 1.38(m, 6H); 1.38(s, 6H); 1.65- 1.81(m, 2H); 2.00(m, 2H); 2.17-2.33(m, 2H); 3.58(m, 4H); 4.75(m, IH); 7.89(m, IH).
[0113] Example 18: Synthesis of l-[2-(benzotriazole-l-carbonyl)-pyrrolidin-l-yl]- 3,3-dimethyl-pentane-l ,2-dione (46)
Following the same protocol described above, in Example 8, the desired product was obtained. 1H NMR (CDCl3, 400 MHz): δ 0.81 (t, J = 9 Hz, 6 Hz, 3H); 1.19 (s, 3H); 1.22 (s, 3H); 1.62-1.73 (m, 2H); 2.03-2.11 (m, 2H); 2.22-2.23 (m, IH); 2.54-2.61 (m, IH); 3.54-3.64 (m, 2H); 5.83-5.87 (m, IH); 7.65 (t, J = 9 Hz, 6 Hz, IH); 7.81 (t, J = 9 Hz, 6 Hz, IH); 8.24 (d, J = 9 Hz, IH); 8.31 (d, J = 9 Hz, IH).
[0114] Example 19: Synthesis of 3,3-dimethyl-l-[2-(tetrazole-l-carbonyl)- pyrrolidin- 1 -yl] -pentane- 1 ,2-dione (47)
Following the same protocol described above, in Example 8, the desired product was obtained. 1H NMR (CDCl3, 400 MHz): δ 0.89 (t, J = 9 Hz, 6 Hz, 3H); 1.16 (s, 7H); 1.83-1.91 (m, 2H); 2.04-2.21 (m, 2H); 2.18-2.39 (m, IH); 3.38 (t, J = 9 Hz, 6 Hz, IH); 3.67-3.72 (m, 2H); 8.86 (s, IH).
[0115] Example 20: Synthesis of l-[2-(5-acetyl-pyrazole-l-carbonyl)-pyrrolidin-l- yl] -3 ,3 -dimethyl-pentane- 1 ,2-dione (48)
Following the same protocol described above, in Example 8, the desired product was obtained. 1H NMR (CDCl3, 400 MHz): δ 0.91(t, 3H); 1.30(d, 6H); 1.68-1.81(m, 2H);
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2.11(m, 3H); 2.57(m, IH); 2.66(s, 3H); 3.71(m, 2H); 5.81(q, IH); 6.94(d, IH); 8.28(d, IH).
[0116] Example 21: Synthesis of l-[2-(2-isopropyl-benzoimidazole-l-carbonyl)- pyrrolidin-l-yl]-353-dimethyl-pentane-l52-dione (49)
Following the same protocol described above, in Example 8, the desired product was obtained in 25% yield. 1H NMR (CDCl3, 400 MHz): δ 0.92(t, 3H); 1.32(d, 6H);
1.44(m, 6H); 1.69-1.88(m, 2H); 2.07(s, IH); 2.13(m, 3H); 2.42(m, IH); 3.72(m, 2H);
5.50(q, IH); 7.37(t, 2H); 7.79(t, 2H). GC-MS (M+383), Rf= 0.35 (20%
EtOAc/hexane).
[0117] Example 22: Synthesis of 3,3-dimethyl-l-[2-(2-methyl-benzoimidazole-l- carbonyl)-pyrrolidin- 1 -yl]-pentane- 1 ,2-dione (50)
Following the same protocol described above, in Example 8, the desired product was obtained. 1H NMR (CDCl3, 400 MHz): δ 0.91(t, 3H); 1.27(d, 6H); 1.74-1.85(m, 2H); 2.19(m, 3H); 2.47(m, IH); 2.89(s, 3H); 3.71(m, 2H); 5.44(q, IH); 7.39(m, 2H); 7.74* ;! 7.8 l(m, 2H).
[0118] Example 23: Synthesis of l-[2-(5-methoxy-benzoimidazole-l-carbonyl)- pyrrolidin- 1 -yl]-3,3-dimethyl-pentane- 1 ,2-dione (51)
Following the same protocol described above, in Example 8, the desired product was obtained. 1H NMR (CDCl3, 400 MHz): δ 0.87(m, 3H); 1.25(m, 6H); 1.75(m, 2H); 2.23(m, 3H); 2.64(m, IH); 3.72(m, 2H); 3.92(s, 3H); 5.48(m, IH); 7.12(t, IH); 7.35(m, IH); 7.84(m, IH); 8.22(d, IH).
[0119] Example 24: Synthesis of 3,3-dimethyl-l-[2-(3-methyl-pyrazole-l- carbonyl)-pyrrolidin- 1 -yl] -pentane- 1 ,2-dione (52)
Following the same protocol described above, in Example 8, the desired product was obtained. 1HNMR (CDCl3, 400 MHz): δ 0.90(t, 3H); 1.30(d, 6H); 1.74-1.81(m, 2H);
2.06(m, 3H); 2.34(s, 3H); 2.51(m, IH): 3.63(m, 2H); 5.76(q, IH); 6.28(d, IH): 8.15(d,
IH).
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[0120] Example 25: Synthesis of l-[2-(5,6-dimethoxy-benzoimidazole-l- carbonyl)-pyrrolidin-l-yl]-3,3-dimethyl-pentane-l,2-dione (53) Following the same protocol described above, in Example 8, the desired product was obtained. 1H NMR (CDCl3, 400 MHz): δ 0.80(t, 3H); 1.20(m, 6H); 1.63-1.69(m, 2H); 2.1 l(m, 3H); 2.53(m, IH); 3.60(m, 2H); 3.90(s, 6H); 5.36(q, IH); 7.23(s, IH); 7.74(s, IH); 9.23(s, IH).
[0121] Example 26: Synthesis of l-[2-(imidazo[4,5-Z>]pyridine-l-carbonyl)- pyrrolidin- 1 -yl] -3 ,3 -dimethyl-pentane- 1 ,2-dione (54)
Following the same protocol described above, in Example 8, the desired product was obtained. 1H NMR (CDCl3, 400 MHz): δ 0.86(t, 3H); 1.25(m, 6H); 1.67-1.77(m, 2H); 2.19(m, 3H); 2.52(m, IH); 3.69(m, 2H); 5.35(q, IH); 7.43(q, IH); 8.59(d, IH); 8.66(d, IH); 8.92(s, IH).
[0122] Example 27: Synthesis of l-[2-(2,3-dihydro-indole-l-carbonyl)-pyrrolidin- 1 -yl] -3, 3 -dimethyl-pentane- 1 ,2-dione (55)
Following the same protocol described above, in Example 8, the desired product was obtained. 1H NMR (CDCl3, 400 MHz): δ 0.86(t, 3H); 1.27(d, 6H); 1.66-1.8(m, 2H); 2.01(m, 3H): 2.24(m, 2H); 3.24(m, 2H): 3.59(m, 2H); 4.06(m, IH); 4.42(q, IH); 4.73(q, IH); 7.00(q, IH); 7.16(m, 2H); 8.20(t, IH).
[0123] Example 28: Synthesis of l-[2-(l,3-dihydro-isoindole-2-carbonyl)- pyrrolidin-l-yl]-3,3-dimethyl-pentane-l,2-dione (56)
Following the same protocol described above, in Example 8, the desired product was obtained. 1H NMR (CDCl3, 400 MHz): δ 0.88(t, 3H); 1.28(d, 6H); 1.66-1.79(m, 2H); 1.99(m, 3H); 2.22(m, 2H); 3.58(m, 2H); 4.75(t, 2H); 4.87(m, 2H); 5.22(d, IH); 7.32(m, 4H).
[0124] Example 29: Synthesis of l-[2-(2-chloro-purine-9-carbonyl)-pyrrolidin-l- yl] -3 ,3 -dimethyl-pentane- 1 ,2-dione (57)
Following the same protocol described above, in Example 8, the desired product was obtained. 1H NMR (CDCl3, 300 MHz): δ 0.77 (t, J = 9 Hz, 6 Hz, 3H); 1.17 (d, J = 9
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Hz, 6H); 1.58-1.70 (m, 2H); 1.95-2.06 (m, 2H); 2.14-2.25 (m, IH); 3.57 (bs, 2H); 6.00-6.04 (m, IH); 9.00 (s, IH); 9.26 (s, IH).
[0125] Example 30: Synthesis of l-[2-(2-methoxy-purine-9-carbonyl)-pyrrolidin-
1 -yl] -3 ,3 -dimethyl-pentane- 1 ,2-dione (58)
Following the same protocol described above, in Example 8, the desired product was obtained. 1H NMR (CDCl3, 400 MHz): δ 0.86(t, 3H); 1.26(d, 6H); 1.7-1.79(m, 2H);
2.09(m, 3H); 2.65(m, IH); 3.69(m, 2H); 4.2(s, 3H); 6.22(q, IH); 8.6(s, IH); 8.64(s,
IH).
[0126] Example 31: Synthesis of l-[2-(2 -dimethylamino-purine-9-carbonyl)- pyrrolidin-1 -yl] -3 ,3 -dimethyl-pentane- 1 ,2-dione (59)
Following the same protocol described above, in Example 8, the desired product was obtained. 1H NMR (CDCl3, 400 MHz): δ 0.81(t, 3H); 1.20(d, 6H); 1.63-1.7(m, 2H); 2.00(m, 3H); 2.55(m, IH); 3.53-3.62(m, 8H); 6.13(q, IH); 8.36(s, IH); 8.41(s, IH).
[0127] Example 32: Synthesis of l-[2-(benzoimidazole-l-carbonyl)-piρeridin-l- yl]-3,3-dimethyl-pentane-l,2-dione (60)
[0128] Following the same protocol described above, in Example 8, the desired product was obtained. 1H NMR (CDCl3, 400 MHz): δ 0.79(t, J=7.6Hz5 3H); 1.13(s, 6H); 1.47-1.78(m, 6H); 1.93-2.04(m, IH); 2.11-2.19(m, IH); 3.35-3.53(m, 2H); 5.91(dd, J=6.1, 3.3Hz, IH); 7.40-7.50(m, 2H); 7.81(dd, J=7.3, 1.3Hz, IH); 8.20(dd, J=7.3, 1.3Hz, IH); 9.09(s, IH).
[0129] Example 33: Synthesis of l-[2-(indazole-l-carbonyl)-piperidin-l-yl]-353- dimethyl-pentane-lj2-dione (61)
[0130] Following the same protocol described above, in Example 8, the desired product was obtained. 1H NMR (CDCl3, 400 MHz): δ 0.87(t, 3H); 1.24(m, 6H); 1.57-1.75(m, 6H); 1.99(m, IH); 2.40(d, IH); 3.48(d, IH); 3.85(t, IH); 6.3(d, IH); 7.35(t, IH); 7.55(t, IH); 7.71(d, IH); 8.14(s, IH); 8.40(d, IH).
[0131] Example 34: Synthesis of 3,3-dimethyl-l-[2-(pyrazole-l-carbonyl)- piperidin- 1 -yl] -pentane- 1 ,2-dione (62)
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[0132] Following the same protocol described above, in Example 8, the desired product was obtained. 1HNMR (CDCl3, 400 MHz): δ 0.88(t, 3H); 1.26(m, 6H); 1.73(m, 6H); 2.03(m, IH); 2.41(d, IH); 3.54(d, IH); 3.76(t, IH); 6.25(d, IH); 6.48(d, IH); 7.76(s, IH); 8.25(d5 IH).
[0133] Example 35: Synthesis of l-[2-(2-isopropyl-benzoimidazole-l-carbonyl)- piperidin- 1 -yl] -3 ,3 -dimethyl-pentane- 1 ,2-dione (63)
[0134] Following the same protocol described above, in Example 8, the desired product was obtained. 1H NMR (CDCI3^OO MHZ): δ θ.91(t, 3H); 1.25(m, 6H); 1.51-1.60(m, 7H); 1.67-1.8(m, 5H); 2.00(m, 2H); 3.58(m, IH); 3.70(m, 2H); 6.06(t, IH); 7.45(m, 2H); 7.90(m, 2H).
[0135] Example 36: Evaluation of target tissue concentrations of carboxy- containing drugs delivered by carboxy-containing drugs or by prodrug derivatives in rats
[0136] Procedure for dosing animals
Male Sprague-Dawley rats (250-300 g) were dosed orally (10 mg/kg) or intravenously (1 ml/kg) with a carboxy-containing drug or a prodrug derivative dissolved in a standard vehicle (45% polycarbonate glycol, 45% PEG-400, 10% ethanol). Two animals per time point (i.e., 15 minutes, 30 minutes, 1 hour, 3 hour) post-dose were euthanized with CO2 gas. For intravenous administration, rats with singular jugular vein cannulas were used. These cannulas were externalized from the subcutaneous space and cleared with 0.9% saline solution. After dosing, the cannulas were tied off or pinched close with a microclip. Rats dosed via oral administration were fasted overnight. Prior to tissue dissection/harvestation from each rat, 5-10 ml of blood was drawn via cardiac stick. The collected blood was then placed into respective 1.5 ml Li-heparinized microcentrifuge tubes and stored on wet ice (for a maximum of 5 minutes) until it was centrifugated at 13K RPM for 10 minutes. Thereafter, the top layer of each tube (plasma) was aspirated via transfer pipette, dispensed into a clean non-heparinized microcentrifuge tube, and stored at -70 0C. Collected tissues were weighed and placed into 20 ml scintillation vials and flash frozen on dry ice. AU samples were stored at -70 0C until subsequent analysis.
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[0137] Sample Extraction from Rat Plasma/Brain/Tissue
For brain samples, 2X the brain weight was added in volume of 20% MeOH and then homogenized. Other tissues (kidney, small intestine, stomach, knee joint, thigh, liver, and heart) were thawed in water bath, cut up using shears, and then added to 2X the tissue weight in volume of 2X 20% MeOH. Plasma samples were thawed, vortexed and used directly.
[0138] Samples were prepared by solid phase extraction in single cartridge format.
A 50 μL aliquot of sample [or 5 μL stock and 45μL of blank matrix for standard] was combined with 200 μL of 1% phosphoric acid spiked with an internal standard
(ketoprofm, 100 ng/mL). The solution was mixed for 5 minutes at 950 rpm and then centrifuged for 10 minutes at 12,000 rpm. Waters Oasis HLB 1 cc (30 mg) extraction cartridges were equilibrated sequentially with 1 mL of H2O. A 1 mL aliquot of the plasma, brain or other tissue mixture was added to the extraction cartridge and vacuumed through. The samples were washed with 1 mL of 5% methanol in water.
After washing, the samples were eluted with 800 μL of 100% acetonitrile. The eluates were evaporated to dryness under N2 at 4O0C. The residue was reconstituted with lOOμL of 10% acetonitrile / 90% 5 mM ammonium acetate, p H7. The resulting solutions were analyzed by LC/MS/MS.
[0139] C - Quantification
Quantification of parent drug in rat plasma was done against calibration curves generated by spiking the parent drug into blank heparinized rat plasma (1, 5, 10, 50,
100, 500, 1000 ng/mL final concentrations).
[0140] Instrumentation
Representative High Performance Liquid Chromatography (HPLC) conditions for naproxen
Instrument: Agilent 1100 Series, LC Binary Pump, 100 vial tray autosampler
Column: Keystone Hypersil BDS C18 30 x 2.1 mm, 3 μm
Mobile Phase A: 5mM ammonium acetate, pH 7 (aqueous)
Mobile Phase B: 100% Acetonitrile
Flow rate: 300 μL/min
Injection Volume: 30μL
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Run Time: 8.0 min Equilibration Time: 2.0 min Temperature: Ambient
Autosampler wash: 1 :1 :1 water: acetonitrile: isopropanol with 0.2% formic acid
[0141] Gradient / Step Table
Figure imgf000048_0001
[0142] Results
The results are presented in FIGS. 1 to 15 and in FIGS. 17 to 29.
[0143] Example 37: Carrageenan Edema in Rats
Test groups of four to six male Sprague Dawley rats weighing 110-130 g were used for each drug concentration or vehicle control. The animals had free access to food and water prior to testing. On the day of the experiment, all animals were weighed and marked for identification. To assess the effectiveness of the compounds on inflammation, rats were dosed with the experimental compound, vehicle or water 15 minutes to 1 hour prior to injecting 100 μl of 1% carrageenan into the plantar region of the right hind paw. The left footpad was used as a negative test control by injecting a similar volume of saline (100 μl). Isofluorane anesthesia was used during the administration of the carrageenan. AU animals were returned to their home cages following the carrageenan administration, and prior to evaluating the inflammatory response. After the test period, the rats were euthanized, and the left and right hind paws amputated at the knee and weighed. A comparison was made (individual
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WASH 1625836 1 Atty. Dkt. No.: 054707-1271
animals) by comparing the weights of left to right hind limb (% change), summating the differences within each group, and comparing the results between test groups. [0144] The results are presented in FIG. 16A.
[0145] Example 38: Gastric Irritation in Rats
Test groups of five Long Evans derived male or female rats weighing 150-170 g were used for each drug or dose. The animals had fasted overnight prior to testing. On the day of the experiment, aspirin (150 mg/kg) or a test substance (50 mg/kg or 100 mg/kg) was administered p.o to rats in each group. Four hours later, the animals were sacrificed and gastric irritation ulceration was scored as follows: 0 = no hyperemia or bleeding, 1 = hyperemia, 2 = slight spot bleeding, 3 = hyperemia plus slight spot bleeding, 4 = hyperemia plus spot bleeding within entire stomach.
[0146] The results are presented in FIG. 16B. A test substance-induced score of 50 percent or more relative to the aspirin-treated (150 mg/kg p.o.) group is considered positive.
[0147] All publications, patents and/or patent applications identified above are herein incorporated by reference.
[0148] The invention being thus described, it will be apparent to those skilled in the art that the same may be varied in many ways without departing from the spirit and scope of the invention. Such variations are included within the scope of the invention to be claimed.
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WASH 1625836.1

Claims

Atty. Dkt. No.: 054707-1271WHAT IS CLAIMED IS:
1. A compound of formula (I)
Figure imgf000050_0001
wherein R is an acyl group of a carboxy-containing drug and
W, X, Y and Z form a saturated or unsaturated pharmaceutically acceptable heterocyclic ring; wherein the heterocyclic ring is unsubstituted or substituted with one to three substituent(s) independently selected from halo, hydroxyl, mercapto, nitro, trifluoromethyl, acetyl, aminocarbonyl, methylsulfonyl, oxo, cyano, carboxy, Ci - C6 alkyl, C2 - C6 alkenyl, C1 - C4 alkoxy, C2 - C4 alkenyloxy, phenoxy, phenyl, benzyloxy, benzyl and amino, wherein said phenyl, phenoxy, benzyloxy or benzyl is unsubstituted or substituted with one or more substituent(s) independently selected from halo, hydroxyl, mercapto, nitro, trifluoromethyl, acetyl, aminocarbonyl, methylsulfonyl, oxo, cyano, carboxy, C1 - C6 alkyl, C2 - C6 alkenyl, C1 - C4 alkoxy and C2 - C4 alkenyloxy; and the heterocyclic ring is optionally fused to a second five- or six-membered ring, wherein said second ring is carbocyclic, aromatic carbocyclic, heterocyclic, or aromatic heterocyclic, and wherein said second ring is unsubstituted or substituted with one to three substituent(s) independently selected from halo, hydroxyl, mercapto, nitro, trifluoromethyl, acetyl, aminocarbonyl, methylsulfonyl, oxo, cyano, carboxy, C1 - C6 alkyl, C2 - C6 alkenyl, C1 - C4 alkoxy and C2 - C4 alkenyloxy; or a pharmaceutically acceptable salt or solvate thereof.
2. The compound of claim 1, wherein the optionally substituted heterocyclic ring is selected from the group consisting of
Figure imgf000050_0002
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WASHJ625836.1 Atty. Dkt. No.: 054707-1271
Figure imgf000051_0001
3. The compound of claim 1, wherein the optionally substituted heterocyclic ring is selected from the group consisting of
Figure imgf000051_0003
Figure imgf000051_0004
Figure imgf000051_0002
4. The compound of claim 1, wherein W, X5 Y and Z are divalent or trivalent radicals independently selected from CH2, CH, C, O, NH5 N and S.
5. The compound of claim 4, wherein W, X, Y and Z are divalent radicals independently selected from CH2, CH, O5 NH, N and S.
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WASH 1625836.1 Atty. Dkt. No.: 054707-1271
6. The compound of claim 5, wherein W, X, Y and Z are divalent radicals independently selected from CH2, CH, NH and N.
7. The compound of claim 1, wherein R is a CNS drug, a non-steroidal antiinflammatory drugs (NSAIDs) or an antibiotic.
8. The compound of claim 1, wherein R is naproxen, aspirin, ibuprofen, indomethacin, sulindac, valproic acid, R-flurbiprofen, gamma-hydroxybutyrate (GHB) and penicillins, such as ampicillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, nafcillin, oxacillin, penicillin G, penicillin V, pivampicillin, pivmecillinam, methicillin, mezlocillin, piperacillin, and ticarcillin.
9. The compound of claim 8, wherein R is naproxen, aspirin, ibuprofen, indomethacin, sulindac, valproic acid, R-flurbiprofen, GHB or penicillin G.
10. The compound of claim 9, wherein R is naproxen, ibuprofen or valproic acid.
11. The compound of claim 1, wherein R is Compound A.
12. The compound of claim 1, wherein the compound is represented by Formula II
Figure imgf000052_0001
and wherein, W, X, Y, Z are as defined above.
13. The compound of claim 12, wherein the optionally substituted heterocyclic ring is selected from the group consisting of
Figure imgf000052_0002
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WASH 1625836.1 Atty. Dkt No.: 054707-1271
Figure imgf000053_0001
14. The compound of claim 12, wherein the optionally substituted heterocyclic ring is fused to a second six-membered aromatic carbocyclic ring.
15. The compound of claim 12, wherein the second six-membered aromatic carbocyclic ring is fused via attachment to Y and Z, and one of W and X is N, and the other of W and X is CH2, CH, O or S.
16. The compound of claim 14, wherein the optionally substituted heterocyclic ring is selected from the group consisting of
Figure imgf000053_0002
Figure imgf000053_0003
Figure imgf000053_0005
Figure imgf000053_0004
17. The compound of claim 1, wherein the compound is represented by Formula III
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WASH 1625836.1 Atty. Dkt. No.: 054707-1271
Figure imgf000054_0001
and wherein, W, X, Y, Z are as defined above.
18. The compound of claim 17, wherein the optionally substituted heterocyclic ring is selected from the group consisting of
Figure imgf000054_0002
19. The compound of claim 17, wherein the optionally substituted heterocyclic ring is fused to a second six-membered aromatic carbocyclic ring.
20. The compound of claim 17, wherein the second six-membered aromatic carbocyclic ring is fused via attachment to Y and Z, and one of W and X is N, and the other of W and X is CH2, CH, O or S.
21. The compound of claim 19, wherein the optionally substituted heterocyclic ring is selected from the group consisting of
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WASH 1625836.1 Atty. Dkt. No.: 054707-1271
Figure imgf000055_0002
Figure imgf000055_0003
Figure imgf000055_0001
22. The compound of claim 1, wherein the compound is represented by Formula IV
Figure imgf000055_0004
and wherein, W, X, Y, Z are as defined above.
23. The compound of claim 22, wherein the optionally substituted heterocyclic ring is selected from the group consisting of
Figure imgf000055_0005
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WASH 1625836.1 Atty. Dkt. No.: 054707-1271
Figure imgf000056_0001
24. The compound of claim 22, wherein the optionally substituted heterocyclic ring is fused to a second six-membered aromatic carbocyclic ring.
25. The compound of claim 22, wherein the second six-membered aromatic carbocyclic ring is fused via attachment to Y and Z, and one of W and X is N, and the other of W and X is CH2, CH, O or S.
26. The compound of claim 24, wherein the optionally substituted heterocyclic ring is selected from the group consisting of
Figure imgf000056_0002
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WASH 1625836.1 Atty. Dkt. No.: 054707-1271
Figure imgf000057_0001
27. A compound selected from:
1 - [2-(imidazole- 1 -carbonyl)-pyrrolidin- 1 -yl] -3,3 -dimethyl-pentane- 1 ,2-dione; 1 -[2-(benzoimidazole-l -carbonyl)-pyrrolidin- 1 -yl]-3,3-dimethyl-pentane- 1 ,2-dione; 1 - [2-(2-isopropyl-imidazole- 1 -carbonyl)-pyrrolidin- 1 -yl] -3,3 -dimethyl-pentane- 1 ,2- dione;
3 ,3 -dimethyl- 1 - [2-(pyrazole- 1 -carbonyl)-pyrrolidin- 1 -yl] -pentane- 1 ,2-dione ; 1 - [2-(indazole- 1 -carbony l)-pyrrolidin- 1 -yl] -3 ,3 -dimethyl-pentane- 1 ,2-dione; l-[2-(benzotriazole-l-carbonyl)-pyrrolidin-l-yl]-3,3-dimethyl-pentane-l,2-dione; 3,3-dimethyl-l-[2-(2-methyl-benzoimidazole-l-carbonyl)-pyrrolidin-l-yl]-pentane- 1,2-dione;
1 -[2-(5-methoxy-benzoimidazole-l -carbonyl)-pyrrolidin- 1 -yl]-3 ,3-dimethyl-pentane- 1,2-dione;
1 -[2-(2-isoρropyl-benzoimidazole- 1 -carbonyl)-pyrrolidin- 1 -yl]-3,3-dimethyl-pentane- 1,2-dione;
1 -[2-(5,6-dimethoxy-benzoimidazole- 1 -carbonyl)-pyrrolidin- 1 -yl]-3,3-dimethyl- pentane- 1 ,2-dione; l-[2-(imidazo[4,5-ό]pyridine-l-carbonyl)-pyrrolidin-l-yl]-3,3-dimethyl-pentane-l52- dione; and l-[2-(2-dimethylamino-purine-9-carbonyl)-pyrrolidin-l-yl]-3,3-dimethyl-ρentane-l,2- dione.
28. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
29. A pharmaceutical composition comprising the compound of claim 27 and a pharmaceutically acceptable carrier.
30. A method of preparing the compound of claim 1, comprising bonding to the acyl group of the carboxy-containing drug a compound of the formula (Ia),
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WASH_1625836.1 Atty. Dkt. No.: 054707-1271
Figure imgf000058_0001
(Ia), wherein the compound of formula (I) is formed.
31. A method of making a derivative of a carboxy-containing drug comprising
bonding a compound of Formula (Ia)
Figure imgf000058_0002
to the carboxy-containing drug
R, thereby forming a compound of Formula (I)
Figure imgf000058_0003
wherein R is an acyl group of a carboxy-containing drug and
W, X, Y and Z form a saturated or unsaturated pharmaceutically acceptable heterocyclic ring; wherein the heterocyclic ring is unsubstituted or substituted with one to three substituent(s) independently selected from halo, hydroxyl, mercapto, nitro, trifluoromethyl, acetyl, aminocarbonyl, methylsulfonyl, oxo, cyano, carboxy, C1 - C6 alkyl, C2 - C6 alkenyl, C1 - C4 alkoxy, C2 - C4 alkenyloxy, phenoxy, phenyl, benzyloxy, benzyl and amino, wherein said phenyl, phenoxy, benzyloxy or benzyl is unsubstituted or substituted with one or more substituent(s) independently selected from halo, hydroxyl, mercapto, nitro, trifluoromethyl, acetyl, aminocarbonyl, methylsulfonyl, oxo, cyano, carboxy, C1 - C6 alkyl, C2 - C6 alkenyl, C1 - C4 alkoxy and C2 - C4 alkenyloxy; and the heterocyclic ring is optionally fused to a second five- or six-membered ring, wherein said second ring is carbocyclic, aromatic carbocyclic, heterocyclic, or aromatic heterocyclic, and wherein said second ring is unsubstituted or substituted with one to three substituent(s) independently selected from halo, hydroxyl, mercapto, nitro, trifluoromethyl, acetyl, aminocarbonyl, methylsulfonyl, oxo, cyano, carboxy, C1 - C6 alkyl, C2 - C6 alkenyl, C1 - C4 alkoxy and C2 - C4 alkenyloxy.
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WASHJ 625836.1
PCT/US2006/022671 2005-06-13 2006-06-09 Enhanced tissue penetration prodrugs WO2006138187A1 (en)

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WO2000032588A2 (en) * 1998-12-03 2000-06-08 Gpi Nil Holdings, Inc. Carboxylic acids and carboxylic acid isosteres of n-heterocyclic compounds

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2000032588A2 (en) * 1998-12-03 2000-06-08 Gpi Nil Holdings, Inc. Carboxylic acids and carboxylic acid isosteres of n-heterocyclic compounds

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013106631A1 (en) * 2012-01-11 2013-07-18 Abbvie Inc. Processes for making hcv protease inhibitors
CN104136453A (en) * 2012-01-11 2014-11-05 艾伯维公司 Processes for making hcv protease inhibitors
US9346785B2 (en) 2012-01-11 2016-05-24 Abbvie Inc. Process for making HCV protease inhibitors
CN104136453B (en) * 2012-01-11 2018-01-12 艾伯维公司 method for preparing HCV protease inhibitor
CN107964006A (en) * 2012-01-11 2018-04-27 艾伯维公司 It is used to prepare the method for HCV protease inhibitor

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