WO2004012656A2 - Thiophene and furan derivatives as prostaglandin agonists and use thereof - Google Patents

Thiophene and furan derivatives as prostaglandin agonists and use thereof Download PDF

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Publication number
WO2004012656A2
WO2004012656A2 PCT/US2003/023165 US0323165W WO2004012656A2 WO 2004012656 A2 WO2004012656 A2 WO 2004012656A2 US 0323165 W US0323165 W US 0323165W WO 2004012656 A2 WO2004012656 A2 WO 2004012656A2
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methyl
phenoxy
alkyl
furoic acid
amino
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PCT/US2003/023165
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French (fr)
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WO2004012656A3 (en
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Gian Luca Araldi
Srinivasa Karra
Adulla P. Reddy
Yihua Liao
Zhong Zhao
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Applied Research Systems Ars Holding N.V.
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Priority to AU2003252149A priority Critical patent/AU2003252149A1/en
Publication of WO2004012656A2 publication Critical patent/WO2004012656A2/en
Publication of WO2004012656A3 publication Critical patent/WO2004012656A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention provides substituted furan and thienyl compounds, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds.
  • Compounds of the invention are useful for a variety of therapies, including preterm labor, ovulation induction, cervical ripening, dysmenorrhea, asthma, hypertension, infertility or fertility disorder, undesired blood clotting, preeclampsia or eclampsia, an eosinophil disorder, sexual dysfunction, osteporosis and other destructive bone disease or disorder, renal dysfunction (acute and chronic), immune deficiency disorder or disease, dry eye, skin disorders such as ichthyosis, elevated intraocular pressure such as associated with glaucoma, sleep disorders, ulcers, urinary dysfunction, pain, gastric motility disorders, hyperchlorhydia, and other diseases and disorders associated with the prostaglandin and receptors thereof.
  • Prostaglandins which belong to the prostanoids family are known to have diverse biological activities such as contraction and relaxation of smooth muscle, inhibition and enhancement of neurotransmitter release, inhibition of lipolysis, inhibition of gastric secretion, inhibition of inflammatory mediator release (Coleman et al. Prostanoids and their Receptors. In Comprehensive Medicinal Chemistry, vol. 3, Ed J. C. Emmett, 643-714, Pergamon Press, Oxford, UK, 1990) that are mediated by different receptor subtypes (Coleman et al. Pharmacological Reviews 199446 (2), 205-229).
  • Four subtypes of the prostaglandin EP receptor have been identified: EP1, EP2, EP3, and EP4. See also U.S. Patents 5,605,814 and 5,759,789.
  • Renal Prostaglandin E2 is crucial of normal renal function by dilating the glomerular microcirculation and vasa recta, supplying the renal medulla and modulating salt and water transport in the distal tubule.
  • Prostaglandin E2 is a natural ligand for all sub-types of the EP receptor. Consequently, selective effects on one of the sub-types of the EP receptor is impossible to achieve with the endogenous prostaglandins.
  • prostaglandin ligands and analogs have been reported to provide biological activity associated with prostaglandin. See, for instance, U.S. Patents 6,288,120; 6,211,197; 4,090,019; and 4,033,989. See also U.S. Patent 4,003,911.
  • E- type prostaglandin reported to be mediated through interaction with the prostaglandin E receptor(s).
  • Four subtypes of the prostaglandin EP receptor have been identified: EP1, EP2, EP3, and EP4. See U.S. Patents 5,605,814 and 5,759,789.
  • EP2 agonists have been developed (US 6,235,780 and WO 9933794).
  • the combination of an EP2 agonist in combination of an EP4 agonist has been developed for osteoporosis treatment (US 20010056060).
  • EP4 selective agonists have been developed for the treatment of bone disorders (WO 0242268, WO 0146140 and WO03009872), erectile dysfunction (WO 9902164) and other prostaglandin related disorders (WO 0224647, US 20020004495, WO 0003980 and WO03007941). It would be desirable to have new compounds and methods for treatment of diseases and disorders associated with the prostaglandin family of compounds.
  • analgesic gastric motility disorders (as an anti-diarrheal), hyperchlorhydia, inflammatory disorders, hepatitis and other diseases and disorders associated with the prostaglandin family of compounds and receptors thereof.
  • an object of the invention to provide pharmaceutical compositions for the treatment and/or prevention of infertility, ovulatory disorders, asthma, preterm labor, osteoporosis, sexual dysfunction, inflammation and/or diseases mediated by the EP receptors, especially EP2 and or EP4 receptors. It is finally an object of the invention to provide a method for the treatment and/or prevention of disorders selected from infertility, ovulatory disorders, asthma, preterm labor, osteoporosis, sexual dysfunction, inflammation and other disorders related to prostaglandins.
  • the invention provides a method for treating a mammal suffering from preterm labor, ovulation induction, cervical ripening, dysmenorrhea, asthma, hypertension, infertility or fertility disorder, including ovulatory disorders, undesired blood clotting, preeclampsia or eclampsia, an eosinophil disorder, sexual dysfunction, including erectile dysfunction, bone disorders, including osteoporosis and other destructive bone disease or disorder, renal dysfunction (acute and chronic), immune deficiency disorder or disease, dry eye, skin disorders such as ichthyosis, elevated intraocular pressure such as associated with glaucoma, sleep disorders, ulcers, urinary dysfunction, pain (e.g.
  • analgesic gastric disorders, including motility disorders (as an antidiarrheal) and gastric ulcers, hyperchlorhydia, inflammatory disorders including rheumatoid arthritis, vascular inflammation, inflammatory pain and hyperlagesia, hepatitis and other diseases and disorders associated with the prostaglandin family.
  • the method comprising administering a compound according to Formula I.
  • G is a carboxy, optionally substituted alkoxycarbonyl or optionally substituted tetrazole moiety
  • X is oxygen, optionally substituted nitrogen, sulfur, sulfmyl, or sulfonyl
  • Y is oxygen or sulfur; each R 2 and R 3 is independently hydrogen, optionally substituted C ⁇ -C 6 alkyl or halogen;
  • R 4 is selected from the group comprising or consisting of hydrogen, sulfonyl, amino, d-C ⁇ -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, wherein said alkyl, alkenyl, alkynyl chains may be interrupted by a heteroatom selected from N, O or S, aryl, heteroaryl, saturated or unsaturated 3-8-membered cycloalkyl, heterocycloalkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, an acyl moiety, Cj-Cg-alkyl aryl, Ci-C ⁇ -alkyl heteroaryl, C 2 -C 6 -alkenyl aryl, C 2 -C 6 -alkenyl heteroaryl, C
  • the invention provides the use of a compound of Formula I for the preparation of a pharmaceutical composition useful for the treatment, including alleviating, preventing and/or treating preterm labor, ovulation induction, cervical ripening, dysmenorrhea, asthma, hypertension, infertility or fertility disorder, including ovulatory disorders, undesired blood clotting, preeclampsia or eclampsia, an eosinophil disorder, sexual dysfunction, including erectile dysfunction, osteoporosis and other destructive bone disease or disorder, renal dysfunction (acute and chronic), immune deficiency disorder or disease, dry eye, skin disorders such as ichthyosis, elevated intraocular pressure such as associated with glaucoma, sleep disorders, ulcers, urinary dysfunction, pain (e.g.
  • analgesic gastric disorders, including motility disorders (as an antidiarrheal) and gastric ulcers, hyperchlorhydia, inflammatory disorders including rheumatoid arthritis, vascular inflammation, inflammatory pain and hyperlagesia, hepatitis and other diseases and disorders associated with the prostaglandin family.
  • the invention provides furan derivatives of Formula V (compounds of Formula I wherein X and Y are O; G is COOH; R 2 and R 3 are independently hydrogen; and R 4 is va.pa.ra position on the phenyl ring):
  • R is defined above.
  • the present invention provides a furan or a thiophene derivative of Formula I for use as a medicament.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a furan or a thiophene derivative of Formula I, together with a pharmaceutically acceptable excipient or carrier.
  • the invention provides a use of a furan or a thiophene derivative of Formula I for the preparation of a pharmaceutical composition for the treatment and or prevention of prostaglandin related disorders including preterm labor, ovulation induction, cervical ripening, dysmenorrhea, asthma, hypertension, infertility or fertility disorder, including ovulatory disorders, undesired blood clotting, preeclampsia or eclampsia, an eosinophil disorder, sexual dysfunction, including erectile dysfunction, osteoporosis and other destructive bone disease or disorder, renal dysfunction (acute and chronic), immune deficiency disorder or disease, dry eye, skin disorders such as ichthyosis, elevated intraocular pressure such as associated with glaucoma, sleep disorders, ulcers, urinary dysfunction, pain (e.g.
  • gastric disorders including motility disorders (as an antidiarrheal) and gastric ulcers, hyperchlorhydia, inflammatory disorders including rheumatoid arthritis, vascular inflammation, inflammatory pain and hyperlagesia and hepatitis.
  • substituted furan and thienyl compounds of the above Formulae I and V are useful for treatment of a variety of disorders, particularly diseases and disorders associated with prostaglandin, such as by inhibiting prostanoid- induced smooth muscle contraction.
  • d-C 6 -alkyl refers to monovalent alkyl groups having 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl and the like.
  • Aryl refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl).
  • Preferred aryl include phenyl, naphthyl, anthracenyl, acenaphthyl, phenanthrenyl and the like.
  • d-C 6 -alkyl aryl refers to Ci-C ⁇ -alkyl groups having an aryl substituent, including benzyl, phenethyl and the like.
  • Heteroaryl refers to a monocyclic heteroaromatic, or a bicyclic or a tricyclic fused-ring heteroaromatic group.
  • Particular examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, benzoxazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadia-zolyl, 1,2,5-oxadiazolyl, l,3,4-oxadiazolyl,l,3,4- triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothi
  • Ci-C ⁇ -alkyl heteroaryl refers to d-C ⁇ -alkyl groups having a heteroaryl substituent, including 2-furylmethyl, 2-thienylmethyl, 2-(lH-indol-3-yl)ethyl and the like.
  • C 2 -C 6 -alkenyl refers to alkenyl groups preferably having from 2 to 6 carbon atoms and having at least 1 or 2 sites of alkenyl unsaturation.
  • C 2 -C 6 -alkenyl aryl refers to C 2 -C 6 -alkenyl groups having an aryl substituent, including 2-phenylvinyl and the like.
  • C 2 -C 6 -alkenyl heteroaryl refers to C 2 -C 6 -alkenyl groups having a heteroaryl substituent, including 2-(3-pyridinyl)vinyl and the like.
  • C 2 -C 6 -alkynyl refers to alkynyl groups preferably having from 2 to 6 carbon atoms and having at least 1-2 sites of alkynyl unsaturation, preferred alkynyl groups include ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), and the like.
  • d-C ⁇ -alkynyl aryl refers to C 2 -C6-alkynyl groups having an aryl substituent, including phenylethynyl and the like.
  • C 2 -C 6 -alkynyl heteroaryl refers to C 2 -C 6 -alkynyl groups having a heteroaryl substituent, including 2-thienylethynyl and the like.
  • C 3 -C 8 -cycloalkyl refers to a saturated carbocyclic group of from 3 to 8 carbon atoms having a single ring (e.g., cyclohexyl) or multiple condensed rings (e.g., norbornyl).
  • Preferred cycloalkyl include cyclopentyl, cyclohexyl, norbornyl and the like.
  • Heterocycloalkyl refers to a C 3 -C 8 -cycloalkyl group according to the definition above, in which up to 3 carbon atoms are replaced by heteroatoms chosen from the group consisting of O, S, NR, R being defined as hydrogen, C 1-6 alkyl, alkoxy and the like.
  • Preferred heterocycloalkyl include pyrrolidine, piperidine, piperazine, 1- methylpiperazine, mo ⁇ holine, and the like.
  • d-C 6 -alkyl cycloalkyl refers to Ci-C ⁇ -alkyl groups having a cycloalkyl substituent, including cyclohexylmethyl, cyclopentylpropyl, and the like.
  • d-d-alkyl heterocycloalkyl refers to Ci-C ⁇ -alkyl groups having a heterocycloalkyl substituent, including 2-(l-pyrrolidinyl)ethyl, 4-mo ⁇ holinylmethyl, (1- methyl-4-piperidinyl)methyl and the like.
  • Carboxy refers to the group -C(O)OH.
  • d-C ⁇ -alkyl carboxy refers to d-d-a-kyl groups having an carboxy substituent, including 2-carboxyethyl and the like.
  • Acyl refers to the group -C(O)R where R includes “d-d-alky.”, "aryl”, “heteroaryl”, “C ⁇ -C 6 -alkyl aryl” or “d-C 6 -alkyl heteroaryl”.
  • d-d-alkyl acyl refers to d-C ⁇ -alkyl groups having an acyl substituent, including 2-acetylethyl and the like.
  • Aryl acyl refers to aryl groups having an acyl substituent, including 2- acetylphenyl and the like.
  • Heteroaryl acyl refers to hetereoaryl groups having an acyl substituent, including 2-acetylpyridyl and the like.
  • C 3 -C8-(hetero)cycloalkyl acyl refers to 3 to 8 membered cycloalkyl or heterocycloalkyl groups having an acyl substituent.
  • Acyloxy refers to the group -OC(O)R where R includes H, "d-C 6 -alkyl”, “C 2 - Ce-alkenyl”, “C 2 -C 6 -alkynyl”, “C 3 -C 8 -cycloalkyl", “heterocycloalkyl",
  • heterocycloalkyl "aryl”, “heteroaryl”, “C C 6 -alkyl aryl” or “d-C 6 -alkyl heteroaryl”, “C 2 -C 6 -alkenyl aryl”, “C 2 -C 6 -alkenyl heteroaryl”, “C 2 -C 6 -alkynyl aryl”, “C 2 -C 6 - alkynylheteroaryl”, “d-C 6 -alkyl cycloalkyl", “d-C 6 -alkyl heterocycloalkyl”.
  • C t -C ⁇ -alkyl acyloxy refers to d-d-alkyl groups having an acyloxy substituent, including 2-(acetyloxy)ethyl and the like.
  • Alkoxy refers to the group -O-R where R includes "d-Ce-alkyl” or “aryl” or “hetero-aryl” or “d-Ce-alkyl aryl” or “d-C ⁇ -alkyl heteroaryl”.
  • Preferred alkoxy groups include by way of example, methoxy, ethoxy, phenoxy and the like.
  • d-C 6 -alkyl alkoxy refers to Ci-Ce-alkyl groups having an alkoxy substituent, including 2-ethoxyethyl and the like.
  • Alkoxycarbonyl refers to the group -C(O)OR where R includes H, "Ci-C ⁇ - alkyl” or “aryl” or “heteroaryl” or "d-C 6 -alkyl aryl” or “d-C 6 -alkyl heteroaryl”.
  • CrCe-alkyl alkoxycarbonyl refers to Cj-Cs-alkyl groups having an alkoxycarbonyl substituent, including 2-(benzyloxycarbonyl)ethyl and the like.
  • Aminocarbonyl refers to the group -C(O)NRR' where each R, R' includes independently hydrogen or d-C 6 -alkyl or aryl or heteroaryl or "Ci-C ⁇ -alkyl aryl” or "Ci-Ce-alkyl hetero-aryl".
  • Ci-C ⁇ -alkyl aminocarbonyl refers to d-Ce-alkyl groups having an aminocarbonyl substituent, including 2-(dimethylaminocarbonyl)ethyl and the like.
  • Acylamino refers to the group -NRC(0)R' where each R, R' is independently hydrogen, "C ⁇ -C 6 -alky ⁇ ", “C 2 -C 6 -alkenyl", “C 2 -C 6 -alkynyl", “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “d-C 6 -alkyl aryl” or "C ⁇ -C 6 -alkyl heteroaryl", “C 2 -C 6 -alkenyl aryl”, “C 2 -C 6 -alkenyl heteroaryl", “C 2 -C 6 -alkynyl aryl", “C 2 -C 6 - alkynylheteroaryl", “d-C 6 -alkyl cycloalkyl", “d-C 6 -alkyl heterocycloalkyl”.
  • Ci-Ce-alkyl acylamino refers to Ci-C ⁇ -alkyl groups having an acylamino substituent, including 2-(propionylamino)ethyl and the like.
  • “Ureido” refers to the group -NRC(O)NR'R" where each R, R', R” is independently hydrogen, "Ci-C 6 -alkyl", “C 2 -C 6 -alkenyl”, “C 2 -C 6 -alkynyl", “C 3 -C 8 - cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “C ⁇ -C 6 -alkyl aryl” or “d-C 6 -alkyl heteroaryl", "C 2 -C 6 -alkenyl aryl", “C 2 -C 6 -alkenyl heteroaryl", “C 2 -C 6 -alkynyl aryl”, “C 2 -C 6 -alkynylheteroaryl”, “C ⁇ -C 6 -alkyl cycloalkyl", “d-C 6 -alkyl heterocycloalkyl", and where R
  • d-C 6 -alkyl ureido refers to d-C 6 -alkyl groups having an ureido substituent, including 2-(N-methylureido)ethyl and the like.
  • “Carbamate” refers to the group - ⁇ RC(O)OR' where each R, R' is independently hydrogen, "d-Ce-alkyl", “C 2 -C 6 -alkenyl”, “C 2 -C 6 -alkynyl", “C 3 -C 8 - cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “Ci-Ce-alkyl aryl” or “d-C 6 -alkyl heteroaryl", “C 2 -C 6 -alkenyl aryl”, “C 2 -C 6 -alkenyl heteroaryl", “C 2 -C 6 -alkynyl aryl", “C 2 -C 6 -alkynylheteroaryl", “Ci-Ce-alkyl cycloalkyl", “Ci-Ce-alkyl heterocycloalkyl”.
  • Amino refers to the group -NRR' where each R,R' is independently hydrogen or "Ci-Ce-alkyl” or “aryl” or “heteroaryl” or “d-C 6 -alkyl aryl” or “C ⁇ -C 6 -alkyl heteroaryl", or "cycloalkyl", or “heterocycloalkyl”, and where R and R', together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered heterocycloalkyl ring.
  • Ci-Ce-alkyl amino refers to Ci-d-alkyl groups having an amino substituent, including 2-(l-pyrrolidinyl)ethyl and the like.
  • Ammonium refers to a positively charged group -N ⁇ RR'R", where each R,R',R" is independently “d-Ce-alkyl” or “d-C 6 -alkyl aryl” or “Ci-Ce-alkyl heteroaryl", or “cycloalkyl", or “heterocycloalkyl”, and where R and R', together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered heterocycloalkyl ring.
  • Ci-C 6 -alkyl ammonium refers to d-d-alky! groups having an ammonium substituent, including 2-(l-pyrrolidinyl)ethyl and the like.
  • Halogen refers to fluoro, chloro, bromo and iodo atoms.
  • “Sulfonyloxy” refers to a group -OSO 2 -R wherein R is selected from H, "d-Ce- alkyl", “d-Ce-alkyl” substituted with halogens, e.g., an -OSO 2 -CF 3 group, "C 2 -C 6 - alkenyl", “C 2 -C 6 -alkynyl", “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “d-Ce-alkyl aryl” or "C ⁇ -C 6 -alkyl heteroaryl", “C 2 -C 6 -alkenyl aryl", “C 2 -C 6 -alkenyl heteroaryl", “C 2 -C 6 -alkynyl aryl", “C 2 -C 6 -alkynylheteroaryl", “d-Ce-alkyl cycl
  • C ⁇ -C 6 -alkyl sulfonyloxy refers to d-Cs-alkyl groups having a sulfonyloxy substituent, including 2-(methylsulfonyloxy)ethyl and the like.
  • “Sulfonyl” refers to group “-S0 2 -R” wherein R is selected from H, "aryl", “heteroaryl”, “C ⁇ -C 6 -alkyl”, “d-Ce-alkyl” substituted with halogens, e.g., an -SO 2 -CF 3 group, "d-Ce-alkenyl”, “C 2 -C 6 -alkynyl", “C 3 -C 8 -cycloalkyl”, “heterocycloalkyl", “aryl”, “heteroaryl”, “d-Ce-alkyl aryl” or “Ci-Ce-alkyl heteroaryl", "C 2 -C 6 -alkenyl aryl", “C 2 -C 6 -alkenyl heteroaryl", “C 2 -C 6 -alkynyl aryl", “C 2 -C 6 -alkynylheteroaryl", "Ci- Ce
  • Ci-Ce-alkyl sulfonyl refers to Ci-d-alkyl groups having a sulfonyl substituent, including 2-(methylsulfonyl)ethyl and the like.
  • “Sulfmyl” refers to a group “-S(0)-R” wherein R is selected from H, “d-Ce- alkyl", “d-Ce-alkyl” substituted with halogens, e.g., an -SO-CF 3 group, "d-d- alkenyl”, “C 2 -C 6 -alkynyl", “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “Ci-Ce-alkyl aryl” or “Ci-Ce-alkyl heteroaryl", "C 2 -C 6 -alkenyl aryl", “C 2 -C 6 -alkenyl heteroaryl", “C 2 -C 6 -alkynyl aryl", “C 2 -C 6 -alkynylheteroaryl", “d-Ce-alkyl cycloalkyl", "d-Ce
  • Ci-Ce-alkyl sulfinyl refers to d-Cs-alkyl groups having a sulfmyl substituent, including 2-(methylsulfinyl)ethyl and the like.
  • Sulfanyl refers to groups -S-R where R includes H, "d-Ce-alkyl", “Ci-Ce- alkyl” substituted with halogens, e.g., an -SO-CF 3 group, "C 2 -C6-alkenyl", “C 2 -Ce- alkynyl", “C 3 -C 8 -cycloalkyl", "heterocycloalkyl", “aryl”, “heteroaryl”, “Ci-Ce-alkyl aryl” or “C ⁇ -C 6 -alkyl heteroaryl", "C 2 -C 6 -alkenyl aryl", “C 2 -C 6 -alkenyl heteroaryl", “C 2 - C 6 -alkynyl aryl", “C 2 -Ce-alkynylheteroaryl", “d-C 6 -alkyl cycloalkyl", "d-Ce-alkyl
  • Ci-C 6 -alkyl sulfanyl refers to d-d-alkyl groups having a sulfanyl substituent, including 2-(ethylsulfanyl)ethyl and the like.
  • “Sulfonylamino” refers to a group -NRSO 2 -R' where each R, R' includes independently hydrogen, "d-Ce-alkyl", “C 2 -C 6 -alkenyl”, “d-Ce-alkynyl”, “C 3 -C 8 - cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “d-Ce-alkyl aryl” or “d-Ce-alkyl heteroaryl", “C 2 -C 6 -alkenyl aryl", “C 2 -C 6 -alkenyl heteroaryl", “C 2 -C 6 -alkynyl aryl", “C 2 -C 6 -alkynylheteroaryl", “d-C 6 -alkyl cycloalkyl", “Ci-Ce-alkyl heterocycloalkyl”.
  • d-C 6 -alkyl sulfonylamino refers to Ci-d-alkyl groups having a sulfonylamino substituent, including 2-(ethylsulfonylamino)ethyl and the like.
  • Aminosulfonyl refers to a group -S0 2 -NRR' where each R, R' includes independently hydrogen, "Ci-Ce-alkyl", “C 2 -C 6 -alkenyl”, “C 2 -C 6 -alkynyl", “C 3 -C 8 - cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “Ci-Ce-alkyl aryl” or “Ci-Ce-alkyl heteroaryl", "C 2 -C 6 -alkenyl aryl", “C 2 -C 6 -alkenyl heteroaryl", “C 2 -C 6 -alkynyl aryl", “d-Ce-alkynylheteroaryi", “Ci-Ce-alkyl cycloalkyl", “Ci-Ce-alkyl heterocycloalkyl”.
  • C ⁇ -C 6 -alkyl aminosulfonyl refers to Ci-C ⁇ -alkyl groups having an aminosulfonyl substituent, including 2-(cyclohexylaminosulfonyl)ethyl and the like.
  • substitution could also comprise situations where neighbouring substituents have undergone ring closure, notably when vicinal functional substituents are involved, thus forming, e.g., lactams, lactons, cyclic anhydrides, but also acetals, thioacetals, aminals formed by ring closure for instance in an effort to obtain a protective group.
  • fertility condition(s) also refers to a condition, particularly infertility, of a female mammal, especially a female patient. This condition includes conditions where ovulation triggering is needed. Examples of female patients in such a condition are female undergoing a treatment for ovulation induction or Assisted Reproductive Technology (ART) therapies.
  • ART Assisted Reproductive Technology
  • OI ovulation induction
  • oocyte (occasionally two or three oocytes) into the fallopian tubes of a female patient, for in vivo fertilisation.
  • OI is used in anovulatory patients [for example, WHO group I patients (hypogonadotrophic hypogonadism) and WHO group II anovulation (hypothalamic-pituitary dysfunction resulting in arrested or attenuated gonadal function), including patients suffering from polycystic ovarian syndrome (PCOS)]. It is usually desired to stimulate the release of a single oocyte, in order to avoid the risks associated with multiple pregnancies.
  • PCOS polycystic ovarian syndrome
  • a typical ovulation induction regimen the patient is administered FSH, an analogue of FSH or a molecule stimulating endogenous FSH production to stimulate follicular growth for several days until at least one follicle is observed (by ultrasound) with a mean diameter of approximately 17 mm or greater.
  • an ovulation trigger hCG
  • the molecules of the invention can replace or supplement the ovulation triggering dose of hCG in an OI regimen.
  • Assisted Reproduction Technology includes for example, in vitro fertilisation (IVF), and intracytoplasmic sperm injection (ICSI). Oocytes are harvested from mature follicles immediately before rupture, and graded before being fertilised in vitro by combination with sperm.
  • IVF in vitro fertilisation
  • ICSI intracytoplasmic sperm injection
  • the resulting embryos are graded for quality, and usually 2 to 3 are selected for placement in the uterus (remaining embryos can be cryopreserved for future attempts). Because of the many factors involved in establishing an ongoing pregnancy, many patients must have oocytes placed in the uterus multiple times before success is achieved. Because of this, in contrast to OI regimens, for ART it is desired to harvest multiple oocytes, in order to maximise the chances of successful pregnancy.
  • the controlled development of multiple preovulatory follicles by administration of exogenous agents capable of inducing follicular growth (such as FSH) is called controlled ovarian hyperstimulation (COH).
  • ovulation is triggered (hCG bolus). Oocytes are usually recovered from pre-ovulatory follicles, by aspiration.
  • the molecules of the invention can replace or supplement the ovulation triggering dose of hCG in an ART regimen.
  • “Pharmaceutically acceptable cationic salts or complexes” is intended to define such salts as the alkali metal salts, (e.g. sodium and potassium), alkaline earth metal salts (e.g. calcium or magnesium), aluminium salts, ammonium salts and salts with organic amines such as with methylamine, dimethylamine, trimethylamine, ethylamine, triethylamine, mo ⁇ holine, N-Me-D-glucamine, N,N'-bis(phenylmethyl)-l,2- ethanediamine, ethanolamine, diethanolamine, ethylenediamine, N-methylmo ⁇ holine, piperidine, benzathine (N,N'-diberLzylethylenediamine), choline, ethylene-diamine, meglumine (N-methylglucamine), benethamine (N-benzylphenethylamine), diethylamine, piperazine, thromethamine (2-amino-2-hydroxy
  • “Pharmaceutically acceptable salts or complexes” refers to salts or complexes of the below-specified compounds of Formulae I to V.
  • Examples of such salts include, but are not restricted, to base addition salts formed by reaction of compounds of formula (I) with organic or inorganic bases such as hydroxide, carbonate or bicarbonate of a metal cation such as those selected in the group consisting of alkali metals (sodium, potassium or lithium), alkaline earth metals (e.g. calcium or magnesium), or with an organic primary, secondary or tertiary alkyl amine.
  • Amine salts derived from methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, mo ⁇ holine, N-Me-D-glucamine, N,N'-bis(phenylmethyl)-l,2-ethanediamine, tromethamine, ethanolamine, diethanolamine, ethylenediamine, N-methylmo ⁇ holine, procaine, piperidine, piperazine and the like are contemplated being within the scope of the instant invention.
  • salts which are formed from to acid addition salts formed with inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), as well as salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, poly-galacturonic acid, citric acid, tartaric acid, gluconic acid, methanesulfonic acid, benzenesulfonic acid, and para- toluenesulfonic acidate.
  • inorganic acids e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like
  • “Pharmaceutically active derivative” refers to any compound that upon administration to the recipient, is capable of providing directly or indirectly, the activity disclosed herein.
  • Enantiomeric excess refers to the percent excess of the enantiomer over the racemate in a mixture of a pure enantiomer (R or S) and a racemate (RS) as defined below.
  • ee 100% x (
  • ) / (R + S)
  • Compounds of the invention can be obtained in an "Enantiomeric excess" by a synthesis comprising an enantioselective step or can be isolated by for example, crystallization or chiral HPLC. , i.e. a synthesis involving non-racemic starting materials and/or reagents or a synthesis comprising at least one enantioselective step, whereby a su ⁇ lus of one enantiomer in the order of at least at or about 50, 52, 70, 80 or 90%.
  • General Formula I and sub-Formulae II, III, IN and N also comprise its tautomers, its geometrical isomers, its optically active forms as enantiomers, diastereomers and its racemate forms, as well as pharmaceutically acceptable salts thereof.
  • Preferred pharmaceutically acceptable salts of the Formulae I, II, III, IN and N are acid addition salts formed with pharmaceutically acceptable acids like hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulfonate, benzenesulfonate, and » ⁇ r ⁇ -toluenesulfonate salts.
  • Generally preferred compounds of Formula I are those having an oxymethylene linkage between furanyl and phenyl rings, i.e. the groups X and Y in Formula (I) are oxygen, such as compounds of the following Formula II (compounds of Formula I wherein X and Y are O and G is COOR 1 ):
  • R 1 is H or optionally substituted C ⁇ -C 6 -alkyl and R 2 , R 3 , R 4 are as above defined in Formula I; and pharmaceutically acceptable salts thereof.
  • R 1 is H or optionally substituted d-d-allcyl and R 4 is as above defined in Formula I; and pharmaceutically acceptable salts thereof.
  • R 1 is H or optionally substituted Ci-C ⁇ -alkyl and R 4 is as above defined in Formula I; and pharmaceutically acceptable salts thereof.
  • Especially compounds of the invention are those of the above formulae that comprise a 2-furoic acid group (i.e. G in Formula I is -COOH and X and Y are O; or R in Formulae II, III or IN is H) or acid addition salts, such as compounds of the following Formula N:
  • R 4 is the same as defined in Formula I; and pharmaceutically acceptable salts thereof.
  • a particularly preferred embodiment of the invention is a compound according to Formula I wherein X is O; Y is O or S; G is selected from -COOR 1 and tetrazolyl, wherein R 1 is selected from H and optionally substituted d-Qj alkyl; R 2 and R 3 are as defined above andR 4 is as defined above and is in para position on the phenyl ring.
  • Another preferred embodiment of the invention is a furan derivative according to Formula I wherein X and Y are O; G is selected from -COOR 1 and tetrazolyl, wherein R 1 is selected from H and optionally substituted -C ⁇ alkyl; R 2 and R 3 are as defined above andR 4 is as defined above and is in para position on the phenyl ring.
  • Another preferred embodiment of the invention is a thiophene derivative according to Formula I wherein X is O; Y is S; G is selected from -COOR 1 and tetrazolyl, wherein R 1 is selected from H and optionally substituted alkyl; R 2 and R 3 are as defined above andR 4 is as defined above and is in para position on the phenyl ring.
  • Another particularly preferred embodiment of the invention is a compound according to Formula I wherein X is O; Y is O or S; G is selected from -COOR 1 and tetrazolyl, wherein R 1 is selected from H and optionally substituted Ci-C ⁇ alkyl; R 2 and R 3 are independently selected from H and optionally substituted Ci-Q alkyl and R 4 is selected from hydrogen; optionally substituted Ci-C ⁇ -alkyl, including tert-pentyl, t-butyl, tetra-methyl butyl, methyl-2 pentyl, methyl-2 butyl and methyl- 1 butyl; optionally substituted heterocycloalkyl, including tri-methyl dihydro chromenyl; optionally substituted C 3 -C 8 cycloalkyl Ci-Ce-alkyl, including methyl cyclohexyl and methyl bicycloheptyl; optionally substituted aryl, including phenyl; optionally substituted and optionally fused C
  • optionally substituted aryl heteroalkyl including benzyl oxy; optionally substituted amino groups wherein the substituents on the amino group are independently selected from optionally substituted d-d alkyl, optionally substituted carbonyl, optionally substituted aryl sulfonyl, optionally substituted and optionally fused aryl, optionally substituted heteroaryl, optionally substituted amino carbonyl.
  • Another particularly preferred embodiment of the invention is a compound according to Formula I wherein X is O; Y is O; G is selected from -COOR 1 and tetrazolyl; R 2 and R 3 are H; and R 4 is in the para position of the phenyl ring and is selected from tetra-methyl butyl; optionally substituted heterocycloalkyl; optionally substituted C 3 -C 8 cycloalkyl Ci-Ce-alkyl, -CH Phenyl, -C(Me) 2 Phenyl and - C(Me) 2 Phenyl-OMe.
  • Another particularly preferred embodiment of the invention is a compound according to Formula I wherein X is O; Y is S; G is -COOH; R 2 and R 3 are H and R 4 is in the para position of the phenyl ring and is selected from tetra-methyl butyl; optionally substituted heterocycloalkyl; optionally substituted C 3 -C 8 cycloalkyl Ci-C 6 -alkyl, - CH 2 Phenyl, -C(Me) 2 Phenyl and -C(Me) 2 Phenyl-OMe.
  • Another particularly preferred embodiment of the invention is a compound according to the invention for use as a medicament.
  • the invention also includes compounds and use of optically active compounds of the above Formulae I through V, particularly compounds of the above Formulae I through V where a single stereoisomer of a chiral compound is present in an enantiomeric excess, e.g. where a single stereoisomer is present in an amount of at least 70 mole percent relative to other stereoisomer(s), more preferably where one stereoisomer is present in an amount of at least about 80, 85, 90, 92, 93, 94, 95, 96, 97, 98 or 99 mole percent relative to other stereosiomer(s).
  • Specifically preferred compounds of the invention include the following depicted compounds (with compound names above the corresponding structure), and pharmaceutically acceptable salts of these compounds.
  • preferred compounds of the invention exhibit good activity in a standard prostaglandin EP2 receptor binding assay.
  • References herein to "standard prostaglandin EP2 receptor binding assay" are intended to refer to the protocol as defined in Example 68, which follows.
  • preferred compounds of the invention have a Ki ( ⁇ M) of about 100 or less, more preferably about 50 or less, still more preferably a Ki ( ⁇ M) of about 10 or 20 or less, even more preferably a Ki ( ⁇ M) of about 5 or less in such a defined standard prostaglandin assay as exemplified by Example 68 which follows.
  • Substituted furan and thienyl compounds of the invention can be readily prepared.
  • a reagent with hydroxy substitution such as phenol can be reacted with a furanyl with activated methyl substitution e.g. halomethyl.
  • a 2-chloromethyl furanyl compound is a particularly suitable reagent.
  • That furanyl reagent may be further substituted as desired e.g. ethyl-5-chloromethyl-2-furoate can be employed to provide a carboxylate furanyl ring substituent.
  • That carboxylate group can be further functionalized, e.g. hydrolyzed to the corresponding acid. See the examples which follow for exemplary preferred procedures.
  • reagents can be employed.
  • a reagent having a reactive amine moiety preferably a primary amine may be employed such as an optionally substituted aniline compound. See, for instance, the procedures of Examples 30 and 31, which follow.
  • a suitable thiol reagent may be reacted with a reactive furane reagent, e.g. optionally substituted benzene thiol.
  • the formed furanyl compound may be oxidized e.g. with hydrogen peroxide or other suitable oxidant to provide compounds where X is sulfmyl or sulfonyl.
  • the corresponding reactive thienyl compound may be employed in place of a furanyl reagent as described herein.
  • a substituted 2-chloromethyl thienyl compound such as a ethyl-5-chloromethyl-2-thienoate, may be employed as a starting reagent and reacted with suitable reagents as discussed above, such as an optionally substituted phenol or aniline reagent or an optionally substituted naphthol, or the like.
  • an initial reagent may be appropriately substituted, e.g. a phenol with one or more ring substituents that provide R 2 , R 3 and/or R 4 groups may be reacted with a suitable reactive furanyl or thienyl compound.
  • a suitable reactive furanyl or thienyl compound e.g. a phenol with one or more ring substituents that provide R 2 , R 3 and/or R 4 groups may be reacted with a suitable reactive furanyl or thienyl compound.
  • phenyl ring substituents also may be further functionalized to provide desired R 2 , R 3 and/or R groups. See, for instance, Examples 38-47 which follow.
  • Such phenol reagents may be suitably obtained from commercial sources, or synthesized by known methods, e.g. by Friedel-Crafts reaction or other ring substitution.
  • the present invention includes methods for treating or preventing prostaglandin mediated or associated diseases or disorders.
  • Preferred therapeutic methods of the invention include inhibiting undesired smooth muscle contraction, including undesired prostanoid-induced smooth muscle contraction.
  • Methods of the invention include treatment of a patient suffering from or susceptible to dysmenorrhea, premature labor, asthma and other conditions that can be relieved by bronchodilation, inflammation, hypertension, undesired blood-clotting (e.g. to reduce or prevent thromboses) and other undesired platelet activities, preeclampsia and/or eclampsia and eosinophil-related disorders (eosinophil disorders).
  • the method for treating and/or preventing a disease or disorder associated with prostaglandins comprises the administration to a subject in need thereof an effective amount of a compound of the invention, wherein the subject can be human or animal, preferably human.
  • the method of treatment comprises comprises the administration to a subject in need thereof an effective amount of a compound of Formula I wherein X is O; Y is O or S; G is selected from -COOR 1 and tetrazolyl, wherein R 1 is selected from H and d-d alkyl; R 2 and R 3 are as defined above andR 4 is as defined above and is in para position on the phenyl ring.
  • the method of treatment comprises comprises the administration to a subject in need thereof an effective amount of a compound of Formula I wherein X and Y are O; G is selected from -COOR 1 and tetrazolyl, wherein R 1 is selected from H and Ci- alkyl; R 2 and R 3 are as defined above and R 4 is as defined above and is in para position on the phenyl ring.
  • the method of treatment comprises comprises the administration to a subject in need thereof an effective amount of a compound of Formula I wherein A method of claim 1 wherein the compound of Formula I is such as X is O; Y is S; G is selected from -COOR 1 and tetrazolyl, wherein R 1 is selected from H and Ci-d alkyl; R 2 and R 3 are as defined above andR is as defined above and is in para position on the phenyl ring.
  • the method of treatment comprises comprises the administration to a subject in need thereof an effective amount of a compound of Formula I wherein X is O; Y is O or S; G is selected from -COOR and tetrazolyl, wherein R 1 is selected from H and C ⁇ -C 6 alkyl; R 2 and R 3 are independently selected from H and d-d alkyl; R 4 is selected from hydrogen; d-d- alkyl, heterocycloalkyl, C 3 -C 8 cycloalkyl Ci-Ce-alkyl, aryl, C 3 -C ⁇ o cycloalkyl, aryl Ci- Ce-alkyl, heteroalkyl, aryl heteroalkyl and amino group wherein the substituents on the amino group are independently selected from d-d alkyl, carbonyl, aryl sulfonyl, aryl, heteroaryl and amino carbonyl.
  • the method of treatment comprises comprises the administration to a subject in need thereof an effective amount of a compound of Formula I wherein X is O; Y is O; G is selected from -COOR 1 and tetrazolyl; R 2 and R are H; and R 4 is in the para position of the phenyl ring and is selected from tetra-methyl butyl; heterocycloalkyl; C 3 -C 8 cycloalkyl Ci-C ⁇ -alkyl, - CH 2 Phenyl, -C(Me) 2 Phenyl and -C(Me) 2 Phenyl-OMe.
  • the method of treatment comprises comprises the administration to a subject in need thereof an effective amount of a compound of Formula I wherein X is O; Y is S; G is -COOH; R 2 and R 3 are H and R 4 is in the para position of the phenyl ring and is selected from tetra-methylbutyl; heterocycloalkyl; C 3 -C 8 cycloalkyl Ci-d-alkyl, -CH 2 Phenyl, -C(Me) 2 Phenyl and - C(Me) 2 Phenyl-OMe.
  • Treatment and/or prevention of undesired blood clotting may include treatment and prophylaxis of venous thrombosis and pulmonary embolism, arterial thrombosis e.g. myocardial ischemia, myocardial infarction, unstable angina, stroke associated with thrombosis, and peripheral arterial thrombosis.
  • Furan and thienyl compounds of the invention also may be useful for anticoagulation involving artificial organs, cardiac valves, medical implementation (e.g. an indwelling device such as a catheter, stent, etc.) and the like.
  • the invention also includes methods for treatment of infertility, which generally comprise administration of one or more substituted furan and/or thienyl compounds of the invention to a mammal, particularly a primate such as a human, suffering from or suspected of suffering from infertility.
  • a mammal particularly a primate such as a human
  • identification of patients suffering from or suspected of suffering from infertility which in the case of humans, can include failure to conceive within one year of unprotected intercourse.
  • the treatment methods of the invention may be particularly beneficial for female mammals suffering from an ovulatory disorder.
  • compounds of the invention can be administered to females undergoing assisted reproductive treatments such as in-vitro fertilization, ovulation induction or an Assisted Reproductive Therapy (ART), e.g. to stimulate follicular development and maturation or to trigger ovulation, as well as implantation procedures.
  • treatment methods of the invention may be used in conjunction with in vitro fertilization technology to enhance survival and/or fertilization of a mammalian egg such as in IVF setting.
  • Treatment methods of the invention also may be employed for control of cervical ripening in late pregnancy (e.g. in humans, late pregnancy would be third trimester, particularly week 30 onward).
  • Therapeutic methods of the invention also include treatment of glaucoma or other disorder involving elevated intra-ocular pressure.
  • Treatment methods of the invention also include inhibition or prevention of bone loss such as to treat osteoporosis, and for promoting bone formation (e.g. to use as a therapy in a bone fracture) and other bone diseases such as Paget's disease.
  • the invention also includes methods for treating a mammal that has low bone mass, or is susceptible to low bone mass such as a mammal having a condition that can present low bone mass, e.g. osteoporosis.
  • the invention also includes methods for treatment of inflammatory disorders including inflammatory pain,
  • the invention also includes therapeutic methods for other bone mass augmentation treatments or enhancement, such as enhancing bone graft success rates or replacement of the need of such grafts, bone extension, bone healing following facial reconstruction and other treatments.
  • Such treatment also may be used in coordination with an appropriate medical device, such as an orthopedic device e.g. a spinal case, bone pins and screws, and other bone fixation devices.
  • such therapies are useful for any condition which can present low bone mass, which conditions include those where the level of bone mass is below the age specific normal as defined in standards by the World Health Organization "Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis (1994), World Health Organization Technical Series 843.” More particularly, such conditions include periodontal disease, alveolar bone loss, post- osteotomy and childhood idiopathic bone loss, and primary and second osteoporosis as discussed above and complications thereof such as curvature of the spine, loss of height and prosthetic surgery.
  • Subject particularly suitable for such bone growth promotion therapies include subjects suffering from acute injuries that can involve bone damage, subjects having undergone related surgery such as facial reconstruction, and subjects that are at increased risk of the above discussed disorders and diseases such as post-menopausal women and men and women over the age of 50 or 60.
  • Compounds of the invention also will be useful to treat sexual dysfunction, including male erectile dysfunction.
  • Compounds of the invention also are useful for treatment of a subject suffering from or susceptible to renal dysfunction, including a mammal suffering from or susceptible to acute or chronic renal failure. Such treatment methods can promote repair and/or regeneration of kidney tissue in a mammal, particularly a human.
  • Compounds of the invention also are useful for treatment of a subject suffering from or susceptible to an immune disorder including an immune deficiency disease or disorder, including such a disorder associated with a viral infection particularly a retroviral infection such as an HIV infection. Particularly benefited by such therapies will be a human suffering from or susceptible to AIDS.
  • Compounds of the invention will be further useful to reduce elevated intraocular pressure of a subject, e.g. through relaxation of pre-contracted isolated ciliary muscle.
  • a mammal such as a human suffering from or susceptible to glaucoma or other disorder associated with elevated intra-ocular pressure.
  • Compounds of the invention also will be useful for treatment of a mammal, particularly a human that is suffering from or susceptible to dry eye.
  • Compounds of the invention will be also useful to reduce inflammatory disorders including rheumatoid arthritis and inflammatory pain.
  • Compounds of the invention also will be useful for promoting sleep in a subject, e.g. to treat a mammal particularly a human suffering from or susceptible to a sleep disorder such as may be associated with advanced age, such as a human of 65 years or older.
  • Compounds of the invention may be used for the preparation of a medicament for the treatment and/or prevention of a disease associated with prostaglandins such as preterm labor, ovulation induction, cervical ripening, dysmenorrhea, asthma, hypertension, infertility or fertility disorder, undesired blood clotting, preeclampsia or eclampsia, an eosinophil disorder, sexual dysfunction, osteporosis and other destructive bone disease or disorder, renal dysfunction (acute and chronic), immune deficiency disorder or disease, dry eye, skin disorders such as ichthyosis, elevated intraocular pressure such as associated with glaucoma, sleep disorders, urinary dysfunction, inflammatory disorders including rheumatoid arthritis and inflammatory pain, gastric disorders such as gastric motility disorders and gastric ulcers.
  • a disease associated with prostaglandins such as preterm labor, ovulation induction, cervical ripening, dysmenorrhea, asthma, hypertension
  • the therapeutic methods of the invention generally comprise administration of an effective amount of one or more compounds of the invention to a subject including a mammal, such as a primate, especially a human, in need of such treatment.
  • Typical candidates for treatment in accordance with the methods of the invention persons suffering from or suspected of suffering from any of the above disorders or diseases, such as a female susceptible or suffering from preterm labor, or a subject suffering from or susceptible to dysmenorrhea or undesired bone loss.
  • the treatment methods of the invention also will be useful for treatment of mammals other than humans, including for veterinary applications such as to treat horses and livestock e.g. cattle, sheep, cows, goats, swine and the like, and pets such as dogs and cats. Methods of the invention to treat premature labor will be particularly useful for such veterinary applications. Therapeutic methods of the invention also will be useful for treatment of infertility in such veterinary applications.
  • a wide variety of mammals will be suitable subjects including rodents (e.g. mice, rats, hamsters), rabbits, primates and swine such as inbred pigs and the like.
  • rodents e.g. mice, rats, hamsters
  • rabbits e.g. primates and swine
  • primates and swine such as inbred pigs and the like.
  • body fluids e.g., blood, plasma, serum, cellular interstitial fluid, saliva, feces and urine
  • cell and tissue samples of the above subjects will be suitable for use.
  • Substituted furan and/or thienyl compounds may be administered as a "cocktail" formulation with other therapeutics, i.e. coordinated administration of one or more compounds of the invention together with one or more other active therapeutics, particularly one or more other known fertility agents, for simultaneous, sequential or separate use.
  • one or more compounds of the invention may be administered in coordination with a regime of a pain relief agent, an anti-inflammatory agent, or an anti-cogulant for simultaneous, sequential or separate use, depending on the indication being treated.
  • Suitable anti-coagulants for such coordinated drug therapies include e.g. warfarin, heparin, hirudin or hirulog or an antiplatelet such as ReoPro for simultaneous, sequential or separate use.
  • one or more compounds of the invention may be suitably administered in coordination with known fertility agents such as Follicle Stimulating and/or Leutinizing Hormone such as Gonal-F, Metrodin HP or Pergonal, for simultaneous, sequential or separate use.
  • known fertility agents such as Follicle Stimulating and/or Leutinizing Hormone such as Gonal-F, Metrodin HP or Pergonal, for simultaneous, sequential or separate use.
  • Substituted furan and/or thienyl compounds of the invention either as the sole active therapeutic or in a coordinated regime with one or more other therapeutics can be administered by a variety of routes, such as orally or by injection, e.g., intramuscular, intraperitoneal, subcutaneous or intravenous injection, or topically such as transdermally, vaginally and the like.
  • routes such as orally or by injection, e.g., intramuscular, intraperitoneal, subcutaneous or intravenous injection, or topically such as transdermally, vaginally and the like.
  • Substituted furan and thienyl compounds of the invention may be suitably administered to a subject in the protonated and water-soluble form, e.g., as a pharmaceutically acceptable salt of an organic or inorganic acid, e.g., hydrochloride, sulfate, hemi-sulfate, phosphate, nitrate, acetate, oxalate, citrate, maleate, mesylate, etc.
  • an acidic group e.g. a carboxy group
  • base addition salts may be prepared. Lists of additional suitable salts may be found, e.g. in Part 5 of Remington 's Pharmaceutical Sciences, 20 th Edition, 2000, Marck Publishing Company, Easton, Pennsylvania, which is inco ⁇ orated herein by reference.
  • Compounds of the invention can be employed, either alone or in combination with one or more other therapeutic agents as discussed above, as a pharmaceutical composition in mixture with conventional excipient, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, enteral or topical application which do not deleteriously react with the active compounds and are not deleterious to the recipient thereof.
  • conventional excipient i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, enteral or topical application which do not deleteriously react with the active compounds and are not deleterious to the recipient thereof.
  • Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc.
  • the pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsif ⁇ ers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously react with the active compounds.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsif ⁇ ers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously react with the active compounds.
  • compositions of the invention may preferably include a substituted furan and/or thienyl compound packaged together with instructions (written) for therapeutic use of the compound to treat e.g. premature labor, dysmenorrhea or asthma, or other disorder as disclosed herein, such as a disease or disorder associated with or mediated by prostaglandin.
  • compositions containing one or more substituted furan and/or thienyl compounds of the invention may be formulated as e.g. tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, elixers and the like.
  • suitable are tablets, dragees or capsules having talc and/or carbohydrate carrier binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch.
  • a syrup, elixir or the like can be used wherein a sweetened vehicle is employed.
  • Sustained release compositions can be formulated including those wherein the active component is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc.
  • parenteral application e.g., sub-cutaneous, mtraperitoneal or intramuscular
  • solutions preferably oily or aqueous solutions as well as suspensions, emulsions, or implants, including suppositories.
  • Ampules are convenient unit dosages.
  • a suitable effective dose of one or more substituted furan and/or thienyl compounds of the invention will be in the range of from 0.01 to 100 milligrams per kilogram of bodyweight of recipient per day, preferably in the range of from 0.01 to 20 milligrams per kilogram bodyweight of recipient per day, more preferably in the range of 0.05 to 4 milligrams per kilogram bodyweight of recipient per day.
  • the desired dose is suitably administered once daily, or several sub- doses, e.g. 2 to 4 sub-doses, are administered at appropriate intervals through the day, or other appropriate schedule.
  • Such sub-doses may be administered as unit dosage forms, e.g., containing from 0.05 to 10 milligrams of compound(s) of the invention, per unit dosage.
  • unit dosage forms e.g., containing from 0.05 to 10 milligrams of compound(s) of the invention, per unit dosage.
  • BSA Bovine Serum Albumin
  • cAMP cyclic adenosine monophophate
  • DMF dimethylformamide
  • DMSO Dimethyl Sulfoxide
  • EDTA ethylenediaminetetraacetic acid
  • FBS Fetal Bovine Serum
  • MES Bis(N- M ⁇ holino)ethanesulfonic Acid
  • PGE2 Prostaglandin E2
  • SPA Scintillation Proximity Assay
  • THF tetrahydrofuran
  • TLC Thin Layer Chromatography
  • Phenol (2mM) is dissolved in 5mL of DMF and was added to the pre cooled heterogeneous DMF solution of NaH (95%, 2.5 mmol, 1.25 equivalents) at 0° C, while stirring and continued stirring for 30 minutes.
  • Ethyl- 5-chloromethyl-2-furoate (2mM, 1 equivalent) in lmL of DMF is added to the above solution dropwise and the solution was stirred for overnight at room temperature.
  • the reaction mixture is diluted with 100 mL of water.
  • the gummy solid that separated is extracted in to ethyl acetate and the organic extract was washed with water, 5% NaHCO 3 , brine and dried over anhydrous MgSO 4 .
  • ImM amount of compound is weighed in to vial and dissolved in MeOH. To this an equimolar amount of IN NaOH in EtOH is added. The ethanol solution was diluted with water. The solution is lyophilized and evaporated under vacuum to get sodium salt as white solid.
  • Example 7 Synthesis of 5- ⁇ [4-(4-oxocyclohexyl) phenoxy] methyl ⁇ -2-furoic acid.
  • Example 8 Synthesis of 5- ⁇ [4-(2,3-dihydro-lH-inden-l-yl) phenoxy] methyl ⁇ -2- furoic acid.
  • Example 10 Synthesis of 5- ⁇ [4-(l,l,3,3-tetramethylbutyl) phenoxy] methyl ⁇ -2-furoic acid.
  • Example 11 Synthesis of 5-[(2-methyl-4- (2 methyl, 2-ehtyl) n-proylphenoxy) methyl] -2-furoic acid.
  • Example 13 Synthesis of 5-[(2,6-dichloro-4-tert-pentylphenoxy) methyl]-2-furoic acid.
  • Example 14 Synthesis of 5-[(2,6-dimethyl-4-tert-pentylphenoxy) methyl]-2-furoic acid.
  • Example 15 Synthesis of 5- ⁇ [4-(l-phenylethyl) phenoxy] methyl ⁇ -2-furoic acid.
  • Example 16 Synthesis of 5- ⁇ [4-(l,3-dimethylbutyl) peony] methyl ⁇ -2-furoic acid.
  • Example 17 Synthesis of 5- ⁇ [4-(2,2,4-trimethyl-3, 4-dihydro-2H-chromen-4-yl) phenoxy] methyl ⁇ -2-furoic acid.
  • Example 18 Synthesis of 5- ⁇ [4-(l-adamantyl) phenoxy] methyl ⁇ -2-furoic acid.
  • Example 19 Synthesis of 5-( ⁇ 4-[l-(4-methoxyphenyl)-l-methylethyl] phenoxy ⁇ methyl)-2-furoic acid.
  • Example 20 Synthesis of 5- ⁇ [4-(benzyloxy) phenoxy] methyl ⁇ -2-furoic acid.
  • Example 22 Synthesis of 5-[(4- ⁇ [(tert-butylamino) carbonyl] amino ⁇ phenoxy) methyl] -2-furoic acid.
  • Example 23 Synthesis of 5-( ⁇ 4-[(tert-butoxycarbonyl) amino] phenoxy ⁇ methyl)-2- furoic acid.
  • Example 24 Synthesis of 5-[(4- ⁇ [6-chloro-2- (methylthio) pyrimidin-4-yl] amino ⁇ phenoxy) methyl] -2-furoic acid.
  • the gummy material was purified by flash column chromatography using hexane: EtOAc (9:1) as eluant to provide the pure ethyl 5- ⁇ [4- (substituted)phenylamino] methyl ⁇ -2-furoate.
  • N-methyl (alkyl) derivative Preparation of N-methyl (alkyl) derivative.
  • the ethyl ester derivative synthesized in step a) of Example 30 above (1 mmol) is dissolved in DMF (2 mL) is added to the pre cooled solution of NaH (95 %, 1.2 m mol) in DMF (2 mL) at 0°C and stirred at 0 C for 30 minutes.
  • Mel (1.2 m mol) was added to the above solution.
  • the temperature of the reaction was allowed to raise to room temperature and continued the stirring for overnight.
  • the excess NaH was decomposed by adding few drops of MeOH and the solution added to the excess of water.
  • Example 32 Synthesis of 5-(5- ⁇ [4-(l,l,3,3-tetramethylbutyl) phenoxy] methyl ⁇ -2- furyl)-2H-tetraazole .
  • Example 33 Synthesis of 5-( ⁇ 4-[methyl(3,5,5-trimethylhexyl)amino]phenoxy ⁇ methyl)-2-furoic acid.
  • Example 35 Synthesis of 5-( ⁇ 4-[methyl(neopentyl)amino]phenoxy ⁇ methyl)-2-furoic acid.
  • Example 36 Synthesis of 5-( ⁇ 4-[methyl(3,5-dimethylbenzyl)amino]phenoxy ⁇ methyl)-2-furoic acid.
  • Example 37 Preparation of Sodium salt of 5- ⁇ [(6-butylpyridin-3-yl)oxy]methyl ⁇ -2- furoic acid.
  • Part 1 Preparation of 6-formylpyridin-3-yl benzenesulfonate.
  • Example 38 Synthesis of methyl 5-( ⁇ 4-[(trifluoroacetyl)amino]phenoxy ⁇ methyl)-2- furoate.
  • Example 40 Synthesis of methyl 5-( ⁇ 4-[(phenylsulfonyl)amino]phenoxy ⁇ methyl)-2- furoate.
  • Example 41 Synthesis of 5-( ⁇ 4- [(phenylsulfonyl)amino]phenoxy ⁇ methyl)-2-furoic acid.
  • Example 42 Synthesis of methyl 5-( ⁇ 4-[isopropyl(phenylsulfonyl) amino]phenoxy ⁇ methyl)-2-furoate.
  • Example 45 Synthesis of 5-( ⁇ 4-[ethyl(phenylsulfonyl)amino]phenoxy ⁇ methyl)-2-furoic acid.
  • Example 48 Synthesis of ethyl 5-[(4-benzoylphenoxy)methyl]-2-furoate.
  • Example 50 Synthesis of 5-( ⁇ 4-[hydroxy(phenyl)methyl]phenoxy ⁇ methyl)-2-furoic acid.
  • Example 53 Synthesis of 5- ⁇ [4-(methoxymethyl)phenoxy]methyl ⁇ -2-furoic acid.
  • Example 54 Synthesis of ethyl 5-[(4-butyrylphenoxy)methyl]-2-furoate.
  • Example 58 Synthesis of ethyl 5- ⁇ [4-( 1 , 1 -dimethylbutyl)phenoxy]methyl ⁇ -2-furoate.
  • Example 60 Synthesis of ethyl 5- ⁇ [4-(l-cyclohexyl-l-methylethyl)phenoxy]methyl ⁇ -2- furoate.
  • Example 61 Synthesis of 5- ⁇ [4-(l-cyclohexyl-l-methylethyl)phenoxy]methyl ⁇ -2-furoic acid.
  • Example 62 Synthesis of ethyl 5- ⁇ [4-(4,4,5,5-tetramethyl-l,3-dioxolan-2-yl)phenoxy] methyl ⁇ -2-furoate.
  • Example 63 Synthesis of 5- ⁇ [4-(4,4,5,5-tetramethyl-l,3-dioxolan-2-yl)phenoxy] methyl ⁇ -2-furoic acid.
  • Example 64 Synthesis of ethyl 5- ⁇ [4-(l,3,4-oxadiazol-2-yl)phenoxy]methyl ⁇ -2-furoate.
  • Example 65 Synthesis of 5- ⁇ [4-(l,3,4-oxadiazol-2-yl)phenoxy]methyl ⁇ -2-furoic acid.
  • Example 69 EP2 cAMP assay.
  • HEK293-EB ⁇ A cells transfected with pCEP4-hEP2 receptors were seeded in 96 well opaque plate (Costar #3917) at 4x10 4 cells per well in 100 ⁇ l of culture medium (D- MEM/F12 supplemented with 10% FBS, 2 nM L-glutamine, and 250 ⁇ g/ml of hygromycin; all from GibcoBRL) and incubated at 37°C.
  • Example 70 In vivo ovulation assay:
  • Ovulation induction activity of compounds of the invention may be tested in a mature mouse ovulation induction model.
  • the compounds of the invention are then diluted with saline or other diluents such as PBS or NP3S (5% N-methyl-pyrrolidinone/30% PEG400/25% PEG200/20% Propylene Glycol in saline).
  • PMSG stimulates ovarian follicular development. After PMSG stimulation, the mature follicules can be stimulated to rupture and release oocytes by an ovulation trigger, such as hCG or a compound of the invention.
  • test protocol is employed for the test animals (typically 5 animals per test group).
  • Guinea pig pulmonary-cholinergic in vivo model is generally used to test the materials for the treatments of asthma in human (Fleisc et al., 1985)
  • Compounds of the invention can be tested in this methacholine-induced bronchomuscle constriction model as described below.
  • Groups of 3 Duncan Hartley derived male or female guinea pigs weighing 250 + 50 g are anesthetized with pentobarbital sodium (50 mg/kg i.p., plus an additional 15 mg/kg i.p. if required) and succinylcholine chloride (2 mg/animal i.p.) is subsequently administered to prevent spontaneous respiration. Body temperature is maintained at 37° to 38°C.
  • the trachea is cannulated and the guinea pig is ventilated with a Harvard rodent respirator in a closed system. Tracheal pressure is recorded through a side-arm of the cannula connected to a P23ID Statham transducer. Respiratory rate is set at 50 strokes/minute with a stroke volume (approximately 1 ml/100 g) sufficient to produce a baseline tracheal pressure of 6 cm H 2 0.
  • Mean arterial pressure (BP) is monitored from a cannulated carotid artery, and heart rate (HR) is obtained from chest electrodes arranged for lead II.
  • the jugular vein is cannulated for i.v. vehicle or drug administration in a volume of 1 ml/kg.
  • MED medium effective dose
  • a 50 percent or greater (>50%) inhibition of the induced broncho-constriction relative to vehicle treated control animals is considered significant.
  • Compounds of the invention are administered i.v. (10 mg/kg) 5 minutes before the methacholine challenge in 3 guinea pigs. A percent or more (>50) inhibition of the induced bronchoconstriction relative to vehicle treated contiol animals is considered significant.
  • Example 72 In vivo inhibition of LPS-induced TNF ⁇ release in mice.
  • Prostaglandin E2 is suggested to be an endogenous inhibitor of inflammation through the EP4 receptor. Therefore EP2 and/or EP4 agonists are supposed to have an anti-inflammatory activity.
  • Endotoxins are the lipopolysaccharides (LPS) constituents of the outer membrane of Gram negative bacteria. Response to LPS has been shown to involve the activation of different cell populations and to lead to the expression of various inflammatory cytokines that include tumor necrosis factor-alpha (TNF ⁇ ) and interferon gamma (TFN- ⁇ ).
  • LPS lipopolysaccharides
  • the anti-inflammatory activity of compounds of the invention may be assessed after a LPS challenge using the following protocol:
  • mice Eight weeks old C3H/HEN mice (IFFA-CREDO, L'avesle, France) receive an oral treatment with compounds of the invention 6 different doses (0.001, 0.01, 0.1, 1 or 3 and 10 mg/kg in 0.5% CMC/0.25% tween-20). Six mice are used by group. Fifteen minutes later, endotoxins (0111:B4 Sigma, 0.3 mg/kg) are intraperitoneally injected. Heparinized whole blood is collected by decapitation. TNF ⁇ level is determined in plasma by ELISA (R & D Systems, Abdingdon, UK). Control animals receive 0.5% CMC/0.25% tween-20 (10 ml/kg) as vehicle.
  • Example 73 In vivo effect on penile corpus cavernosum tissue relaxation.
  • Penile erection is based on three main physiological events: an increase in the arterial blood flow, a relaxation of the expansive tissue of the corpora carvernosa and the corpus spongiosum, and an obstruction of the venous return by mechanical compression of the veins caused by the expansive tissue.
  • PGEl is used in the treatment of erectile dysfunction to relax smooth muscle and therefore to promote the development of erection.
  • the administration of PGEl is performed by local injection into the cavernous tissue of the penis.
  • PGEl has a low selectivity for prostanoid receptors and has irritant effects.
  • Selective agonists EP2 and/or EP4 have been developed for the treatment of erectile dysfunction (WO 9902164)
  • the effect of compounds of the invention on the relaxation of penile corpus cavernosal tissue strips may be assayed for example in an assay on human or rabbit tissue as described below:
  • Cavernosal tissue is obtained from patients undergoing penile prosthesis implantation surgery for treatment of erectile dysfunction.
  • biopsies of the corpora cavernosa are immediately placed in chilled (4°C) physiologic salt solution and transported to the laboratory. Tissue strips, measuring approximately 3 mm x 3 mm x 10 mm, are cut and prepared for organ bath studies.
  • Rabbit tissue procurement Adult male New Zealand White rabbits (4.5 - 5.0 kg) are sedated with ketamine (35 mg/kg) and xylazine (5 mg/kg) and euthanized with sodium pentobarbital (60 mg/kg body weight). Following exsanguination, the penis is excised and cleaned by removing the corpus spongiosum and urethra. Corpus cavernosum tissue strips are dissected away from the surrounding tunica albuginea and prepared for organ bath studies. Preparation of compound stock solutions and dose responses. PGE] (Cayman Chemical Co., Ann Arbor, Ml) is stored at -20°C in solid form until the day of use.
  • Stock solutions are made by adding 1 ml of 70% DMSO to a vial containing 1 mg of PGEi. Compounds of the mention are dissolved in 1 ml of 70% DMSO, divided into 100 ⁇ l aliquots and stored at -20 °C until use.
  • stock solutions of PGEi and compounds of the invention are diluted with 70% DMSO to make the highest concentration and then serially diluted with 2% DMSO for all other doses. In a typical dose response curve, the concentration of DMSO is checked to remain below 0.1% in the 25 ml bath and to not exceed 0.5% at the highest dose.
  • the solution is gassed with 95% air / 5% C0 2 to attain a pH of 7.4 and the temperature is maintained at 37°C.
  • All tissue strips are treated with 3 ⁇ M indomethacin to inhibit endogenous prostanoid production and minimize spontaneous contractile activity.
  • the corpus cavernosum tissue is stretched incrementally and the optimal resting isometric tension for contraction is determined. After every 3 - 4 stretches (1 g tension/stretch), the tissue is contracted with 1 ⁇ M phenylephrine. When the amplitude of the phenylephrine-induced contraction is within 10% of the previous contraction, that tension is considered optimal for isometric contraction.
  • All tissue strips are extensively washed with fresh PSS. Tissue strips are then contracted with 1 ⁇ M phenylephrine. After stable tone is achieved, tissue strips are exposed to increasing concentrations of PGEi or compounds of the invention.
  • Example 74 In vivo effect on bone loss prevention.
  • the activity of compounds of the invention as a bone anabolic agent can be tested for example in a rat ovariectomy model such as follows.
  • Rats Virgin female Sprague Dawley rats Rats are randomized into treatment groups based on pre-dose body weight measurements. The aim iss to achieve approximately the same average body weight for every treatment group.
  • the ovary is located and cut at the junction of the uterine horn and removed.
  • the uterus is replaced and the muscles sutured. Repeat on the contra-lateral side.
  • the ovaries are located and exteriorized, but not removed.
  • the uterus and ovaries are replaced into the abdominal cavity and the muscles sutured.
  • the muscle layers are closed with suture and the skin incision closed using wound clips.
  • Dosing is commenced one day after the surgery is performed.
  • the animals receive daily subcutaneous injections for 6 weeks following surgery.
  • the doses of 0.1, 1.0, 10.0 mg/kg of compounds of the invention are used.
  • a contiol group receives daily subcutaneous injections of 17 ⁇ estradiol (Sigma Chemicals) of 30 ⁇ g/kg for 6 weeks following surgery.
  • Control groups of animal are injected s.c. vehicle (saline).
  • Body weights are recorded weekly, beginning one week prior to the commencement of tieatment and continuing until the conclusion of the treatment period.
  • the rats are observed daily for signs of ill health or reaction to treatment.
  • An eighteen-hour urine specimen is collected from each animal prior to the sacrifice using metabolic cages. At sacrifice, blood samples are collected from each rat, under inhalation anesthesia (ether) from the retro-orbital sinus. Following parameters are measured in urine and serum.
  • ether inhalation anesthesia
  • Urinary deoxypyridinoline is measured by Immuno-assay (Pyrilinks-D Quidel, Mt. Niew,CA); Urinary creatinine is measured by COBAS chemistry instrument (Creatinine Reagent Roche Diagnostics, Indianapolis, IN); Serum osteocalcin is measured by Immuno-assay (Rat OSU IRMA, Immunotopics San Clemente, CA)
  • Bone Mineral Density Scans All animals are subjected to the following procedure. Terminal body weights are recorded. A gross examination is performed and a check for abnormalities is performed. The following investigation are performed, as detailed: Bone Mineral Density Scans:
  • L2-L4 lumbar vertebrae is subjected to DXA (Dual-energy X-ray absorptiometry) scan using a PIXImus instrument (Lunar Corp. Madison, WI). Bone mineral content, area and density are determined from the PIXI scan. Bone mineral density measurements by DXA are described in Formica et al. 1998.
  • Right femur is subject to pQCT (peripheral quantitative computed tomography) scan using a Stiatec XCT RM and associated software (Stratectechnik Gmbh, Pforzheim, Germany. Software version 5.40 C).
  • the femur is scanned at two sites, 20% of the distal femur and 50% of the mid-femur. The position is verified using scout views and scan results from one 0.5 mm slice perpendicular to the long axis of the femur shaft is recorded.
  • Total bone mineral content, total bone area, total bone mineral density, trabecular bone mineral content, trabecular bone area and trabecular bone mineral density are analyzed from the scan of the distal femur.
  • For the midshaft femur total bone mineral content, total bone area, total bone mineral density, cortical bone mineral content, cortical bone area, cortical bone mineral density, periosteal perimeter and endosteal perimeter are analyzed.
  • Bone mineral density measurements by pQCT are described in Formica et al., 1998 and in Tsugeno 2002.
  • L5 Lumbar vertebra is isolated from L5-L6 and prepared for mechanical testing by removing the vertebral arch and pedicle using a low-speed diamond saw. The cranial and caudal ends of each vertebral body are also removed to produce a vertebral body specimen with two parallel surfaces and a height of approximately 4 mm. The width of the vertebral body in the medial-lateral and anterior-posterior directions is measured using electronic digital calipers. These values are recorded and used in the calculation of cross-sectional area. The height of the vertebral body specimen is also taken with an electronic caliper and recorded. The specimens are then placed between two platens and load applied at a displacement rate of 6 mm/min until failure in an Instron Mechanical Testing Instrument (Instron 4465, retrofitted to 5500).
  • Instron Mechanical Testing Instrument Instron 4465, retrofitted to 5500.
  • the anterior to posterior diameter at the midpoint of the femoral shaft is taken with an electronic caliper and recorded.
  • Femur is then placed on the lower supports of a three point bending fixture with anterior side facing downward in an Instron Mechanical Testing Instrument (Instron 4465, retrofitted to 5500).
  • the span between the two lower supports is set at 14 mm.
  • the upper loading device aligned to the center of the femoral shaft.
  • the load is applied at a constant displacement rate of 6 mm/min until the femur breaks.
  • the locations of maximal load, stiffness and energy absorbed are selected manually and values calculated by instrument's software (Merlin II, Instron).
  • the intrinsic properties, stress, elastic modulus and toughness are calculated from maximum load, stiffness, energy absorbed, anterior-posterior diameter, and moment of inertia.
  • a 3 -mm segment of the distal femoral metaphysis is cut directly proximal to the femoral condyle with a low-speed diamond saw.
  • the load is applied with a cylindrical indenter (with a flat testing face of 1.6 mm diameter (d)) to the center of marrow cavity on the distal face of the segment.
  • the indenter is allowed to penetrate the cavity at a constant displacement rate of 6 mm/min to a depth of 2 mm before load reversal.
  • the locations of maximum load, stiffness and energy absorbed is selected manually from load displacement curve and then calculated by the instrument's software (Merlin II, Instron). Stress is calculated by dividing the maximum load by the indenter area.
  • proximal tibia Formalin-fixed samples of proximal tibia are dehydrated in a series of ascending ethanol concentration. Following dehydration, bone samples are infiltrated and embedded in methyl methacrylate-based plastic. Embedded samples of the proximal tibia are sectioned longitudinally using a Leitz motorized rotary microtome equipped with a tungsten-carbide microtome knife. Once the blocks are trimmed, 4 ⁇ m sections are stained with Goldner's trichrome stain for microscopy. The 8 ⁇ m sections are left unstained for epifluorescence microscopy.
  • Static and dynamic histomorphometry of the proximal tibia is performed.
  • the measurement includes the secondary spongiosa (area that is 1.05 from the lowest point of the growth plate).
  • Bone histomorphometry is performed using an OsteoMeasure software program (OsteoMetrics, Inc. Atlanta, GA) interfaced with a Nikon Eclipse E400 light/epifluorescent microscope and video subsystem. Histomorphometry is read in a blinded manner. Total tissue area, trabecular bone area, trabecular bone perimeter, and osteoclast perimeter is measured on 4 ⁇ m thick Goldner's trichrome stained sections. Percent trabecular bone area, tiabecular number, trabecular thickness, trabecular separation and osteoclast perimeter as a percentage of bone surfaces are then calculated according to standardized formulae.
  • single-labeled calcein perimeter, double-labeled calcein perimeter, and interlabel width is measured on 8 ⁇ m thick unstained sections, and the mineralizing surface, mineral apposition rate, bone formation rate-surface referent is calculated.
  • Results are analyzed using analysis of variance (group) using SAS software (SAS Institute, Cory, NC). Group comparison is performed using Dunnett's procedure using "Ovx" + vehicle group as reference group. All results are expressed as mean +/- SD.

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Abstract

Substituted furan and thienyl compounds are provided, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds. Compounds of the invention are useful for a variety of therapies, including treating or preventing preterm labor, dysmenorrhea, asthma, hypertension, infertility or fertility disorder, undesired blood clotting, preeclampsia or eclampsia, an eosinophil disorder, sexual dysfunction, osteporosis and other destructive bone disease or disorder, renal dysfunction, an immune deficiency disorder, dry eye, ichthyosis, elevated intraocular pressure, sleep disorder, gastric ulcer, urinary dysfunction, pain, gastric motility disorders, hyperchlorhydia, inflammatory disorders and other diseases and disorders associated with the prostaglandin family of compounds.

Description

THIOPHENE AND FURAN DERIVATIVES AS PROSTAGLANDIN AGONISTS
AND USE THEREOF
RELATED APPLICATION
The present application claims priority to U.S. provisional application serial no. 60/400,654 filed on August 2, 2002, the contents of which are expressly incorporated herein by reference.
BACKGROUND OF THE INVENTION
1. Field of the Invention.
This invention provides substituted furan and thienyl compounds, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds. Compounds of the invention are useful for a variety of therapies, including preterm labor, ovulation induction, cervical ripening, dysmenorrhea, asthma, hypertension, infertility or fertility disorder, undesired blood clotting, preeclampsia or eclampsia, an eosinophil disorder, sexual dysfunction, osteporosis and other destructive bone disease or disorder, renal dysfunction (acute and chronic), immune deficiency disorder or disease, dry eye, skin disorders such as ichthyosis, elevated intraocular pressure such as associated with glaucoma, sleep disorders, ulcers, urinary dysfunction, pain, gastric motility disorders, hyperchlorhydia, and other diseases and disorders associated with the prostaglandin and receptors thereof.
2. Background.
Prostaglandins (PGs) which belong to the prostanoids family are known to have diverse biological activities such as contraction and relaxation of smooth muscle, inhibition and enhancement of neurotransmitter release, inhibition of lipolysis, inhibition of gastric secretion, inhibition of inflammatory mediator release (Coleman et al. Prostanoids and their Receptors. In Comprehensive Medicinal Chemistry, vol. 3, Ed J. C. Emmett, 643-714, Pergamon Press, Oxford, UK, 1990) that are mediated by different receptor subtypes (Coleman et al. Pharmacological Reviews 199446 (2), 205-229). Four subtypes of the prostaglandin EP receptor have been identified: EP1, EP2, EP3, and EP4. See also U.S. Patents 5,605,814 and 5,759,789.
Knock-out mice lacking each type and sub-type of the EP receptor showed different roles for these receptors (Ushikubi at al. 2000, Jpn. J. Pharmacol. 83, 279-285) in various mechanisms such as ovulation, blood pressure control, closure of ductus arteriosus and bone resoφtion. Additional roles of EP receptors have been reported such as smooth muscle relaxation in cat trachea for EP2, vasodilatation for EP4 (Gardinier, Br. J. Pharmac. 1986, 87, 45-56; Coleman et al. 1994 Pharmacological Reviews 46 (2), 205-229) and anti-inflammatory activity for EP4 (Takayama et al. 2002, The Journal of Biological Chemistry, 277, 46,44147-44154). Renal Prostaglandin E2 (PGE2) is crucial of normal renal function by dilating the glomerular microcirculation and vasa recta, supplying the renal medulla and modulating salt and water transport in the distal tubule. Prostaglandin E2 (PGE2) is a natural ligand for all sub-types of the EP receptor. Consequently, selective effects on one of the sub-types of the EP receptor is impossible to achieve with the endogenous prostaglandins.
Certain prostanoid receptors and modulators of those receptors have been reported. See generally Eicosanoids: From Biotechnology to Therapeutic Applications (Plenum Press, New York); Journal ofLipid Mediators and Cell Signalling 14: 83-87 (1996); The British Journal of Pharmacology, 111: 735-740 (1994); PCT applications WO 96/06822, WO 97/00863, WO 97/00864, WO 96/03380 and WO 98/27053; EP 752421; U.S. Patents 6,211,197, 4,211,876 and 3,873,566; and Bennett et al. J. Med. Chem., 19(5): 715-717 (1976).
Certain prostaglandin ligands and analogs have been reported to provide biological activity associated with prostaglandin. See, for instance, U.S. Patents 6,288,120; 6,211,197; 4,090,019; and 4,033,989. See also U.S. Patent 4,003,911. E- type prostaglandin reported to be mediated through interaction with the prostaglandin E receptor(s). Four subtypes of the prostaglandin EP receptor have been identified: EP1, EP2, EP3, and EP4. See U.S. Patents 5,605,814 and 5,759,789.
Recently, EP2 agonists have been developed (US 6,235,780 and WO 9933794). The combination of an EP2 agonist in combination of an EP4 agonist has been developed for osteoporosis treatment (US 20010056060). EP4 selective agonists have been developed for the treatment of bone disorders (WO 0242268, WO 0146140 and WO03009872), erectile dysfunction (WO 9902164) and other prostaglandin related disorders (WO 0224647, US 20020004495, WO 0003980 and WO03007941). It would be desirable to have new compounds and methods for treatment of diseases and disorders associated with the prostaglandin family of compounds.
SUMMARY OF THE INVENTION
We have now found substituted furan and thienyl compounds that are useful for a variety of therapies, including alleviating, preventing and/or treating preterm labor, ovulation induction, cervical ripening, dysmenorrhea, asthma, hypertension, infertility or fertility disorder, undesired blood clotting, preeclampsia or eclampsia, an eosinophil disorder, sexual dysfunction, osteoporosis and other destructive bone disease or disorder, renal dysfunction (acute and chronic), immune deficiency disorder or disease, dry eye, skin disorders such as ichthyosis, elevated intraocular pressure such as associated with glaucoma, sleep disorders, ulcers, urinary dysfunction, pain (e.g. use as an analgesic), gastric motility disorders (as an anti-diarrheal), hyperchlorhydia, inflammatory disorders, hepatitis and other diseases and disorders associated with the prostaglandin family of compounds and receptors thereof.
It is an object of the invention to provide substances which are suitable for the treatment and/or prevention of disorders related to prostaglandins.
It is also an aspect of the invention to provide substances which are suitable for the treatment and/or prevention of asthma.
It is also an aspect of the invention to provide substances which are suitable for the treatment and/or prevention of preterm labor or dymenorrhea.
It is also an aspect of the invention to provide substances which are suitable for the treatment and/or prevention of bone disorders.
It is also an aspect of the invention to provide substances which are suitable for the treatment and/or prevention of sexual dysfunction, including erectile dysfunction.
It is also an aspect of the invention to provide substances which are suitable for the treatment and/or prevention of infertility, including ovulatory disorders.
It is also an aspect of the invention to provide substances which are suitable for the treatment and/or prevention of inflammatory disorders.
It is furthermore an object of the invention to provide pharmaceutical compositions for the treatment and/or prevention of infertility, ovulatory disorders, asthma, preterm labor, osteoporosis, sexual dysfunction, inflammation and/or diseases mediated by the EP receptors, especially EP2 and or EP4 receptors. It is finally an object of the invention to provide a method for the treatment and/or prevention of disorders selected from infertility, ovulatory disorders, asthma, preterm labor, osteoporosis, sexual dysfunction, inflammation and other disorders related to prostaglandins.
In a first aspect, the invention provides a method for treating a mammal suffering from preterm labor, ovulation induction, cervical ripening, dysmenorrhea, asthma, hypertension, infertility or fertility disorder, including ovulatory disorders, undesired blood clotting, preeclampsia or eclampsia, an eosinophil disorder, sexual dysfunction, including erectile dysfunction, bone disorders, including osteoporosis and other destructive bone disease or disorder, renal dysfunction (acute and chronic), immune deficiency disorder or disease, dry eye, skin disorders such as ichthyosis, elevated intraocular pressure such as associated with glaucoma, sleep disorders, ulcers, urinary dysfunction, pain (e.g. use as an analgesic), gastric disorders, including motility disorders (as an antidiarrheal) and gastric ulcers, hyperchlorhydia, inflammatory disorders including rheumatoid arthritis, vascular inflammation, inflammatory pain and hyperlagesia, hepatitis and other diseases and disorders associated with the prostaglandin family.
The method comprising administering a compound according to Formula I.
Figure imgf000005_0001
wherein
G is a carboxy, optionally substituted alkoxycarbonyl or optionally substituted tetrazole moiety;
X is oxygen, optionally substituted nitrogen, sulfur, sulfmyl, or sulfonyl;
Y is oxygen or sulfur; each R2 and R3 is independently hydrogen, optionally substituted Cι-C6 alkyl or halogen;
R4 is selected from the group comprising or consisting of hydrogen, sulfonyl, amino, d-Cδ-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, wherein said alkyl, alkenyl, alkynyl chains may be interrupted by a heteroatom selected from N, O or S, aryl, heteroaryl, saturated or unsaturated 3-8-membered cycloalkyl, heterocycloalkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, an acyl moiety, Cj-Cg-alkyl aryl, Ci-Cδ-alkyl heteroaryl, C2-C6-alkenyl aryl, C2-C6-alkenyl heteroaryl, C2-C6-alkynyl aryl, C2-C6-alkvnyl heteroaryl, d-Ce-alkyl cycloalkyl, Cι-C6-alkyl heterocycloalkyl, C2-C6- alkenyl cycloalkyl, C2-C6-alkenyl heterocycloalkyl, C2-C6-alkynyl cycloalkyl, C2-C6- alkynyl heterocycloalkyl, alkoxycarbonyl, aminocarbonyl, d-C6-alkyl carboxy, d-C6- alkyl acyl, aryl acyl, heteroaryl acyl, C3-C8-(hetero)cycloalkyl acyl, d-Cβ-alkyl acyloxy, CrCδ-alkyl alkoxy, d-C6-alkyl alkoxycarbonyl, d-Cβ-alkyl aminocarbonyl, Cι-C6- alkyl acylamino, acylamino, d-Cδ-alkyl ureido, Ci-Cδ-alkyl carbamate, Cj-Cβ-alkyl amino, d-Cβ-alkyl ammonium, d-Cs-alkyl sulfonyloxy, d-Cβ-alkyl sulfonyl, d-Cβ- alkyl sulfinyl, d-C6-alkyl sulfanyl, d-Cδ-alkyl sulfonylamino, d-C6-alkyl aminosulfonyl, hydroxy or halogen, all of which R4 substituents may be optionally substituted; and pharmaceutically acceptable salts thereof.
In a second aspect, the invention provides the use of a compound of Formula I for the preparation of a pharmaceutical composition useful for the treatment, including alleviating, preventing and/or treating preterm labor, ovulation induction, cervical ripening, dysmenorrhea, asthma, hypertension, infertility or fertility disorder, including ovulatory disorders, undesired blood clotting, preeclampsia or eclampsia, an eosinophil disorder, sexual dysfunction, including erectile dysfunction, osteoporosis and other destructive bone disease or disorder, renal dysfunction (acute and chronic), immune deficiency disorder or disease, dry eye, skin disorders such as ichthyosis, elevated intraocular pressure such as associated with glaucoma, sleep disorders, ulcers, urinary dysfunction, pain (e.g. use as an analgesic), gastric disorders, including motility disorders (as an antidiarrheal) and gastric ulcers, hyperchlorhydia, inflammatory disorders including rheumatoid arthritis, vascular inflammation, inflammatory pain and hyperlagesia, hepatitis and other diseases and disorders associated with the prostaglandin family.
In a third aspect, the invention provides furan derivatives of Formula V (compounds of Formula I wherein X and Y are O; G is COOH; R2 and R3 are independently hydrogen; and R4 is va.pa.ra position on the phenyl ring):
Figure imgf000007_0001
Wherein R is defined above.
In a fourth aspect, the present invention provides a furan or a thiophene derivative of Formula I for use as a medicament.
In a fifth aspect, the invention provides a pharmaceutical composition comprising a furan or a thiophene derivative of Formula I, together with a pharmaceutically acceptable excipient or carrier.
In a sixth aspect, the invention provides a use of a furan or a thiophene derivative of Formula I for the preparation of a pharmaceutical composition for the treatment and or prevention of prostaglandin related disorders including preterm labor, ovulation induction, cervical ripening, dysmenorrhea, asthma, hypertension, infertility or fertility disorder, including ovulatory disorders, undesired blood clotting, preeclampsia or eclampsia, an eosinophil disorder, sexual dysfunction, including erectile dysfunction, osteoporosis and other destructive bone disease or disorder, renal dysfunction (acute and chronic), immune deficiency disorder or disease, dry eye, skin disorders such as ichthyosis, elevated intraocular pressure such as associated with glaucoma, sleep disorders, ulcers, urinary dysfunction, pain (e.g. use as an analgesic), gastric disorders, including motility disorders (as an antidiarrheal) and gastric ulcers, hyperchlorhydia, inflammatory disorders including rheumatoid arthritis, vascular inflammation, inflammatory pain and hyperlagesia and hepatitis.
DETAILED DESCRIPTION OF THE INVENTION
We have now discovered that substituted furan and thienyl compounds of the above Formulae I and V are useful for treatment of a variety of disorders, particularly diseases and disorders associated with prostaglandin, such as by inhibiting prostanoid- induced smooth muscle contraction.
The following paragraphs provide definitions of the various chemical moieties that make up the compounds according to the invention and are intended to apply uniformly through-out the specification and claims unless an otherwise expressly set out definition provides a broader definition. "d-C6 -alkyl" refers to monovalent alkyl groups having 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl and the like.
"Aryl" refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl). Preferred aryl include phenyl, naphthyl, anthracenyl, acenaphthyl, phenanthrenyl and the like.
"d-C6-alkyl aryl" refers to Ci-Cβ-alkyl groups having an aryl substituent, including benzyl, phenethyl and the like.
"Heteroaryl" refers to a monocyclic heteroaromatic, or a bicyclic or a tricyclic fused-ring heteroaromatic group. Particular examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, benzoxazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadia-zolyl, 1,2,5-oxadiazolyl, l,3,4-oxadiazolyl,l,3,4- triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo[l,2-a]pyridyl, benzothiazolyl, benzoxa-zolyl, quinolizinyl, quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl, napthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8- tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl or benzoquinolyl.
"Ci-Cβ-alkyl heteroaryl" refers to d-Cό-alkyl groups having a heteroaryl substituent, including 2-furylmethyl, 2-thienylmethyl, 2-(lH-indol-3-yl)ethyl and the like.
"C2-C6-alkenyl" refers to alkenyl groups preferably having from 2 to 6 carbon atoms and having at least 1 or 2 sites of alkenyl unsaturation. Preferable alkenyl groups include ethenyl (-CH=CH2), n-2-propenyl (allyl, -CH2CH=CH2) and the like.
"C2-C6-alkenyl aryl" refers to C2-C6-alkenyl groups having an aryl substituent, including 2-phenylvinyl and the like.
"C2-C6-alkenyl heteroaryl" refers to C2-C6-alkenyl groups having a heteroaryl substituent, including 2-(3-pyridinyl)vinyl and the like. "C2-C6-alkynyl" refers to alkynyl groups preferably having from 2 to 6 carbon atoms and having at least 1-2 sites of alkynyl unsaturation, preferred alkynyl groups include ethynyl (-C≡CH), propargyl (-CH2C≡CH), and the like.
"d-Cό-alkynyl aryl" refers to C2-C6-alkynyl groups having an aryl substituent, including phenylethynyl and the like.
"C2-C6-alkynyl heteroaryl" refers to C2-C6-alkynyl groups having a heteroaryl substituent, including 2-thienylethynyl and the like.
"C3-C8-cycloalkyl" refers to a saturated carbocyclic group of from 3 to 8 carbon atoms having a single ring (e.g., cyclohexyl) or multiple condensed rings (e.g., norbornyl). Preferred cycloalkyl include cyclopentyl, cyclohexyl, norbornyl and the like.
"Heterocycloalkyl" refers to a C3-C8-cycloalkyl group according to the definition above, in which up to 3 carbon atoms are replaced by heteroatoms chosen from the group consisting of O, S, NR, R being defined as hydrogen, C1-6 alkyl, alkoxy and the like. Preferred heterocycloalkyl include pyrrolidine, piperidine, piperazine, 1- methylpiperazine, moφholine, and the like.
"d-C6-alkyl cycloalkyl" refers to Ci-Cβ-alkyl groups having a cycloalkyl substituent, including cyclohexylmethyl, cyclopentylpropyl, and the like.
"d-d-alkyl heterocycloalkyl" refers to Ci-Cβ-alkyl groups having a heterocycloalkyl substituent, including 2-(l-pyrrolidinyl)ethyl, 4-moφholinylmethyl, (1- methyl-4-piperidinyl)methyl and the like.
"Carboxy" refers to the group -C(O)OH.
"d-Cδ-alkyl carboxy" refers to d-d-a-kyl groups having an carboxy substituent, including 2-carboxyethyl and the like.
"Acyl" refers to the group -C(O)R where R includes "d-d-alky.", "aryl", "heteroaryl", "Cι-C6-alkyl aryl" or "d-C6-alkyl heteroaryl".
"d-d-alkyl acyl" refers to d-Cβ-alkyl groups having an acyl substituent, including 2-acetylethyl and the like.
"Aryl acyl" refers to aryl groups having an acyl substituent, including 2- acetylphenyl and the like.
"Heteroaryl acyl" refers to hetereoaryl groups having an acyl substituent, including 2-acetylpyridyl and the like.
"C3-C8-(hetero)cycloalkyl acyl" refers to 3 to 8 membered cycloalkyl or heterocycloalkyl groups having an acyl substituent. "Acyloxy" refers to the group -OC(O)R where R includes H, "d-C6-alkyl", "C2- Ce-alkenyl", "C2-C6-alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl",
"heterocycloalkyl", "aryl", "heteroaryl", "C C6-alkyl aryl" or "d-C6-alkyl heteroaryl", "C2-C6-alkenyl aryl", "C2-C6-alkenyl heteroaryl", "C2-C6-alkynyl aryl", "C2-C6- alkynylheteroaryl", "d-C6-alkyl cycloalkyl", "d-C6-alkyl heterocycloalkyl".
"Ct-Cό-alkyl acyloxy" refers to d-d-alkyl groups having an acyloxy substituent, including 2-(acetyloxy)ethyl and the like.
"Alkoxy" refers to the group -O-R where R includes "d-Ce-alkyl" or "aryl" or "hetero-aryl" or "d-Ce-alkyl aryl" or "d-Cδ-alkyl heteroaryl". Preferred alkoxy groups include by way of example, methoxy, ethoxy, phenoxy and the like.
"d-C6-alkyl alkoxy" refers to Ci-Ce-alkyl groups having an alkoxy substituent, including 2-ethoxyethyl and the like.
"Alkoxycarbonyl" refers to the group -C(O)OR where R includes H, "Ci-Cβ- alkyl" or "aryl" or "heteroaryl" or "d-C6-alkyl aryl" or "d-C6-alkyl heteroaryl".
"CrCe-alkyl alkoxycarbonyl" refers to Cj-Cs-alkyl groups having an alkoxycarbonyl substituent, including 2-(benzyloxycarbonyl)ethyl and the like.
"Aminocarbonyl" refers to the group -C(O)NRR' where each R, R' includes independently hydrogen or d-C6-alkyl or aryl or heteroaryl or "Ci-Cδ-alkyl aryl" or "Ci-Ce-alkyl hetero-aryl".
"Ci-Cδ-alkyl aminocarbonyl" refers to d-Ce-alkyl groups having an aminocarbonyl substituent, including 2-(dimethylaminocarbonyl)ethyl and the like.
"Acylamino" refers to the group -NRC(0)R' where each R, R' is independently hydrogen, "Cι-C6-alkyι", "C2-C6-alkenyl", "C2-C6-alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "d-C6-alkyl aryl" or "Cι-C6-alkyl heteroaryl", "C2-C6-alkenyl aryl", "C2-C6-alkenyl heteroaryl", "C2-C6-alkynyl aryl", "C2-C6- alkynylheteroaryl", "d-C6-alkyl cycloalkyl", "d-C6-alkyl heterocycloalkyl".
"Ci-Ce-alkyl acylamino" refers to Ci-Cδ-alkyl groups having an acylamino substituent, including 2-(propionylamino)ethyl and the like.
"Ureido" refers to the group -NRC(O)NR'R" where each R, R', R" is independently hydrogen, "Ci-C6-alkyl", "C2-C6-alkenyl", "C2-C6-alkynyl", "C3-C8- cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "Cι-C6-alkyl aryl" or "d-C6-alkyl heteroaryl", "C2-C6-alkenyl aryl", "C2-C6-alkenyl heteroaryl", "C2-C6-alkynyl aryl", "C2-C6-alkynylheteroaryl", "Cι-C6-alkyl cycloalkyl", "d-C6-alkyl heterocycloalkyl", and where R' and R", together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered heterocycloalkyl ring.
"d-C6-alkyl ureido" refers to d-C6-alkyl groups having an ureido substituent, including 2-(N-methylureido)ethyl and the like.
"Carbamate" refers to the group -ΝRC(O)OR' where each R, R' is independently hydrogen, "d-Ce-alkyl", "C2-C6-alkenyl", "C2-C6-alkynyl", "C3-C8- cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "Ci-Ce-alkyl aryl" or "d-C6-alkyl heteroaryl", "C2-C6-alkenyl aryl", "C2-C6-alkenyl heteroaryl", "C2-C6-alkynyl aryl", "C2-C6-alkynylheteroaryl", "Ci-Ce-alkyl cycloalkyl", "Ci-Ce-alkyl heterocycloalkyl".
"Amino" refers to the group -NRR' where each R,R' is independently hydrogen or "Ci-Ce-alkyl" or "aryl" or "heteroaryl" or "d-C6-alkyl aryl" or "Cι-C6-alkyl heteroaryl", or "cycloalkyl", or "heterocycloalkyl", and where R and R', together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered heterocycloalkyl ring.
"Ci-Ce-alkyl amino" refers to Ci-d-alkyl groups having an amino substituent, including 2-(l-pyrrolidinyl)ethyl and the like.
"Ammonium" refers to a positively charged group -N^RR'R", where each R,R',R" is independently "d-Ce-alkyl" or "d-C6-alkyl aryl" or "Ci-Ce-alkyl heteroaryl", or "cycloalkyl", or "heterocycloalkyl", and where R and R', together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered heterocycloalkyl ring.
"Ci-C6-alkyl ammonium" refers to d-d-alky! groups having an ammonium substituent, including 2-(l-pyrrolidinyl)ethyl and the like.
"Halogen" refers to fluoro, chloro, bromo and iodo atoms.
"Sulfonyloxy" refers to a group -OSO2-R wherein R is selected from H, "d-Ce- alkyl", "d-Ce-alkyl" substituted with halogens, e.g., an -OSO2-CF3 group, "C2-C6- alkenyl", "C2-C6-alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "d-Ce-alkyl aryl" or "Cι-C6-alkyl heteroaryl", "C2-C6-alkenyl aryl", "C2-C6-alkenyl heteroaryl", "C2-C6-alkynyl aryl", "C2-C6-alkynylheteroaryl", "d-Ce-alkyl cycloalkyl", "d-Ce-alkyl heterocycloalkyl".
"Cι-C6-alkyl sulfonyloxy" refers to d-Cs-alkyl groups having a sulfonyloxy substituent, including 2-(methylsulfonyloxy)ethyl and the like. "Sulfonyl" refers to group "-S02-R" wherein R is selected from H, "aryl", "heteroaryl", "Cι-C6-alkyl", "d-Ce-alkyl" substituted with halogens, e.g., an -SO2-CF3 group, "d-Ce-alkenyl", "C2-C6-alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "d-Ce-alkyl aryl" or "Ci-Ce-alkyl heteroaryl", "C2-C6-alkenyl aryl", "C2-C6-alkenyl heteroaryl", "C2-C6-alkynyl aryl", "C2-C6-alkynylheteroaryl", "Ci- Ce-alkyl cycloalkyl", "Ci-Ce-alkyl heterocycloalkyl".
"Ci-Ce-alkyl sulfonyl" refers to Ci-d-alkyl groups having a sulfonyl substituent, including 2-(methylsulfonyl)ethyl and the like.
"Sulfmyl" refers to a group "-S(0)-R" wherein R is selected from H, "d-Ce- alkyl", "d-Ce-alkyl" substituted with halogens, e.g., an -SO-CF3 group, "d-d- alkenyl", "C2-C6-alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "Ci-Ce-alkyl aryl" or "Ci-Ce-alkyl heteroaryl", "C2-C6-alkenyl aryl", "C2-C6-alkenyl heteroaryl", "C2-C6-alkynyl aryl", "C2-C6-alkynylheteroaryl", "d-Ce-alkyl cycloalkyl", "d-Ce-alkyl heterocycloalkyl".
"Ci-Ce-alkyl sulfinyl" refers to d-Cs-alkyl groups having a sulfmyl substituent, including 2-(methylsulfinyl)ethyl and the like.
"Sulfanyl" refers to groups -S-R where R includes H, "d-Ce-alkyl", "Ci-Ce- alkyl" substituted with halogens, e.g., an -SO-CF3 group, "C2-C6-alkenyl", "C2-Ce- alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "Ci-Ce-alkyl aryl" or "Cι-C6-alkyl heteroaryl", "C2-C6-alkenyl aryl", "C2-C6-alkenyl heteroaryl", "C2- C6-alkynyl aryl", "C2-Ce-alkynylheteroaryl", "d-C6-alkyl cycloalkyl", "d-Ce-alkyl heterocycloalkyl". Preferred sulfanyl groups include methylsulfanyl, ethylsulfanyl, and the like.
"Ci-C6-alkyl sulfanyl" refers to d-d-alkyl groups having a sulfanyl substituent, including 2-(ethylsulfanyl)ethyl and the like.
"Sulfonylamino" refers to a group -NRSO2-R' where each R, R' includes independently hydrogen, "d-Ce-alkyl", "C2-C6-alkenyl", "d-Ce-alkynyl", "C3-C8- cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "d-Ce-alkyl aryl" or "d-Ce-alkyl heteroaryl", "C2-C6-alkenyl aryl", "C2-C6-alkenyl heteroaryl", "C2-C6-alkynyl aryl", "C2-C6-alkynylheteroaryl", "d-C6-alkyl cycloalkyl", "Ci-Ce-alkyl heterocycloalkyl".
"d-C6-alkyl sulfonylamino" refers to Ci-d-alkyl groups having a sulfonylamino substituent, including 2-(ethylsulfonylamino)ethyl and the like. "Aminosulfonyl" refers to a group -S02-NRR' where each R, R' includes independently hydrogen, "Ci-Ce-alkyl", "C2-C6-alkenyl", "C2-C6-alkynyl", "C3-C8- cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "Ci-Ce-alkyl aryl" or "Ci-Ce-alkyl heteroaryl", "C2-C6-alkenyl aryl", "C2-C6-alkenyl heteroaryl", "C2-C6-alkynyl aryl", "d-Ce-alkynylheteroaryi", "Ci-Ce-alkyl cycloalkyl", "Ci-Ce-alkyl heterocycloalkyl".
"Cι-C6-alkyl aminosulfonyl" refers to Ci-Cβ-alkyl groups having an aminosulfonyl substituent, including 2-(cyclohexylaminosulfonyl)ethyl and the like.
"Substituted or unsubstituted" or "optionally substituted": Unless otherwise constrained by the definition of the individual substituent, the above set out groups, like "alkyl", "alkenyl", "alkynyl", "aryl" and "heteroaryl" etc. groups can optionally be substituted with from 1 to 5 substituents selected from the group consisting of "Ci-Ce- alkyl", "d-Ce-alkenyl", "C2-C6-alkynyl", "cycloalkyl", "heterocycloalkyl", "Ci-Ce- alkyl aryl", "Cι-C6-alkyl heteroaryl", "Cι-C6-alkyl cycloalkyl", "Ci-Ce-alkyl heterocycloalkyl", "amino", "ammonium", "acyl", "acyloxy", "acylamino", "aminocarbonyl", "alkoxycarbonyl", "ureido", "aryl", "carbamate", "heteroaryl", "sulfmyl", "sulfonyl", "alkoxy", "sulfanyl", "halogen", "carboxy", trihalomethyl, cyano, hydroxy, mercapto, nitro, and the like. Alternatively said substitution could also comprise situations where neighbouring substituents have undergone ring closure, notably when vicinal functional substituents are involved, thus forming, e.g., lactams, lactons, cyclic anhydrides, but also acetals, thioacetals, aminals formed by ring closure for instance in an effort to obtain a protective group.
The term "fertility condition(s)" also refers to a condition, particularly infertility, of a female mammal, especially a female patient. This condition includes conditions where ovulation triggering is needed. Examples of female patients in such a condition are female undergoing a treatment for ovulation induction or Assisted Reproductive Technology (ART) therapies.
The term "ovulation induction" (OI) refers to the stimulation of release of an oocyte (occasionally two or three oocytes) into the fallopian tubes of a female patient, for in vivo fertilisation. OI is used in anovulatory patients [for example, WHO group I patients (hypogonadotrophic hypogonadism) and WHO group II anovulation (hypothalamic-pituitary dysfunction resulting in arrested or attenuated gonadal function), including patients suffering from polycystic ovarian syndrome (PCOS)]. It is usually desired to stimulate the release of a single oocyte, in order to avoid the risks associated with multiple pregnancies. In a typical ovulation induction regimen, the patient is administered FSH, an analogue of FSH or a molecule stimulating endogenous FSH production to stimulate follicular growth for several days until at least one follicle is observed (by ultrasound) with a mean diameter of approximately 17 mm or greater. At this stage, an ovulation trigger (hCG) is given to stimulate rupture of the follicle and release of an oocyte into the fallopian tube ("ovulation triggering"). The molecules of the invention can replace or supplement the ovulation triggering dose of hCG in an OI regimen.
The term "Assisted Reproduction Technology" includes for example, in vitro fertilisation (IVF), and intracytoplasmic sperm injection (ICSI). Oocytes are harvested from mature follicles immediately before rupture, and graded before being fertilised in vitro by combination with sperm.
The resulting embryos are graded for quality, and usually 2 to 3 are selected for placement in the uterus (remaining embryos can be cryopreserved for future attempts). Because of the many factors involved in establishing an ongoing pregnancy, many patients must have oocytes placed in the uterus multiple times before success is achieved. Because of this, in contrast to OI regimens, for ART it is desired to harvest multiple oocytes, in order to maximise the chances of successful pregnancy. The controlled development of multiple preovulatory follicles by administration of exogenous agents capable of inducing follicular growth (such as FSH) is called controlled ovarian hyperstimulation (COH). When there are at least 3 follicles with a mean diameter greater than 16 mm, ovulation is triggered (hCG bolus). Oocytes are usually recovered from pre-ovulatory follicles, by aspiration. The molecules of the invention can replace or supplement the ovulation triggering dose of hCG in an ART regimen.
"Pharmaceutically acceptable cationic salts or complexes" is intended to define such salts as the alkali metal salts, (e.g. sodium and potassium), alkaline earth metal salts (e.g. calcium or magnesium), aluminium salts, ammonium salts and salts with organic amines such as with methylamine, dimethylamine, trimethylamine, ethylamine, triethylamine, moφholine, N-Me-D-glucamine, N,N'-bis(phenylmethyl)-l,2- ethanediamine, ethanolamine, diethanolamine, ethylenediamine, N-methylmoφholine, piperidine, benzathine (N,N'-diberLzylethylenediamine), choline, ethylene-diamine, meglumine (N-methylglucamine), benethamine (N-benzylphenethylamine), diethylamine, piperazine, thromethamine (2-amino-2-hydroxymethyl-l,3-propoanediol), procaine as well as amines of formula -NR,R',R" wherein R, R\ R" is independently hydrogen, alkyl or benzyl. Especially preferred salts are sodium and potassium salts.
"Pharmaceutically acceptable salts or complexes" refers to salts or complexes of the below-specified compounds of Formulae I to V. Examples of such salts include, but are not restricted, to base addition salts formed by reaction of compounds of formula (I) with organic or inorganic bases such as hydroxide, carbonate or bicarbonate of a metal cation such as those selected in the group consisting of alkali metals (sodium, potassium or lithium), alkaline earth metals (e.g. calcium or magnesium), or with an organic primary, secondary or tertiary alkyl amine. Amine salts derived from methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, moφholine, N-Me-D-glucamine, N,N'-bis(phenylmethyl)-l,2-ethanediamine, tromethamine, ethanolamine, diethanolamine, ethylenediamine, N-methylmoφholine, procaine, piperidine, piperazine and the like are contemplated being within the scope of the instant invention.
Also comprised are salts which are formed from to acid addition salts formed with inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), as well as salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, poly-galacturonic acid, citric acid, tartaric acid, gluconic acid, methanesulfonic acid, benzenesulfonic acid, and para- toluenesulfonic acidate.
"Pharmaceutically active derivative" refers to any compound that upon administration to the recipient, is capable of providing directly or indirectly, the activity disclosed herein.
The term "Enantiomeric excess" (ee) refers to the percent excess of the enantiomer over the racemate in a mixture of a pure enantiomer (R or S) and a racemate (RS) as defined below. ee = 100% x (|R - S|) / (R + S) = |%R - %S| where R represents the number of moles of R enantiomer in the sample and S represents the number of moles of S enantiomer in the sample, and |R - S| represents the Absolute Value of the difference of R and S. Compounds of the invention can be obtained in an "Enantiomeric excess" by a synthesis comprising an enantioselective step or can be isolated by for example, crystallization or chiral HPLC. , i.e. a synthesis involving non-racemic starting materials and/or reagents or a synthesis comprising at least one enantioselective step, whereby a suφlus of one enantiomer in the order of at least at or about 50, 52, 70, 80 or 90%.
General Formula I and sub-Formulae II, III, IN and N according to the present invention also comprise its tautomers, its geometrical isomers, its optically active forms as enantiomers, diastereomers and its racemate forms, as well as pharmaceutically acceptable salts thereof. Preferred pharmaceutically acceptable salts of the Formulae I, II, III, IN and N are acid addition salts formed with pharmaceutically acceptable acids like hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulfonate, benzenesulfonate, and »αrα-toluenesulfonate salts.
Generally preferred compounds of Formula I are those having an oxymethylene linkage between furanyl and phenyl rings, i.e. the groups X and Y in Formula (I) are oxygen, such as compounds of the following Formula II (compounds of Formula I wherein X and Y are O and G is COOR1):
Figure imgf000016_0001
wherein R1 is H or optionally substituted Cι-C6-alkyl and R2, R3, R4 are as above defined in Formula I; and pharmaceutically acceptable salts thereof.
Further preferred compounds include those of Formulae I or II where substituents R and R are each hydrogen, such as compounds of the following Formula
III:
Figure imgf000016_0002
wherein R1 is H or optionally substituted d-d-allcyl and R4 is as above defined in Formula I; and pharmaceutically acceptable salts thereof.
Also preferred are compounds of the above Formulae I, II and III that have a /-wα-substituted phenyl moiety as a component of the furan or thienyl ring, such as compounds of the following Formula IN (compounds of Formula I wherein X and Y are O and G is COOR1 and R4 is in para position on the phenyl ring):
Figure imgf000017_0001
wherein R1 is H or optionally substituted Ci-Cβ-alkyl and R4 is as above defined in Formula I; and pharmaceutically acceptable salts thereof.
Especially compounds of the invention are those of the above formulae that comprise a 2-furoic acid group (i.e. G in Formula I is -COOH and X and Y are O; or R in Formulae II, III or IN is H) or acid addition salts, such as compounds of the following Formula N:
Figure imgf000017_0002
wherein R4 is the same as defined in Formula I; and pharmaceutically acceptable salts thereof.
A particularly preferred embodiment of the invention, is a compound according to Formula I wherein X is O; Y is O or S; G is selected from -COOR1 and tetrazolyl, wherein R1 is selected from H and optionally substituted d-Qj alkyl; R2 and R3 are as defined above andR4 is as defined above and is in para position on the phenyl ring. Another preferred embodiment of the invention, is a furan derivative according to Formula I wherein X and Y are O; G is selected from -COOR1 and tetrazolyl, wherein R1 is selected from H and optionally substituted -Cβ alkyl; R2 and R3 are as defined above andR4 is as defined above and is in para position on the phenyl ring.
Another preferred embodiment of the invention, is a thiophene derivative according to Formula I wherein X is O; Y is S; G is selected from -COOR1 and tetrazolyl, wherein R1 is selected from H and optionally substituted alkyl; R2 and R3 are as defined above andR4 is as defined above and is in para position on the phenyl ring.
Another particularly preferred embodiment of the invention, is a compound according to Formula I wherein X is O; Y is O or S; G is selected from -COOR1 and tetrazolyl, wherein R1 is selected from H and optionally substituted Ci-Cβ alkyl; R2 and R3 are independently selected from H and optionally substituted Ci-Q alkyl and R4 is selected from hydrogen; optionally substituted Ci-Cβ-alkyl, including tert-pentyl, t-butyl, tetra-methyl butyl, methyl-2 pentyl, methyl-2 butyl and methyl- 1 butyl; optionally substituted heterocycloalkyl, including tri-methyl dihydro chromenyl; optionally substituted C3-C8 cycloalkyl Ci-Ce-alkyl, including methyl cyclohexyl and methyl bicycloheptyl; optionally substituted aryl, including phenyl; optionally substituted and optionally fused C -Cιo cycloalkyl, including di-hydroindenyl and adamantyl; optionally substituted oxocycloalkyl, including oxocyclohexyl; optionally substituted aryl Ci-Cg- alkyl, including -CH2-phenyl, -CH(Me)Phenyl, -C(Me)2Phenyl, -CH(OH)Phenyl; optionally substituted heteroalkyl, including d-Q alkyloxo (e.g. butoxy); optionally substituted aryl heteroalkyl, including benzyl oxy; optionally substituted amino groups wherein the substituents on the amino group are independently selected from optionally substituted d-d alkyl, optionally substituted carbonyl, optionally substituted aryl sulfonyl, optionally substituted and optionally fused aryl, optionally substituted heteroaryl, optionally substituted amino carbonyl.
Another particularly preferred embodiment of the invention, is a compound according to Formula I wherein X is O; Y is O; G is selected from -COOR1 and tetrazolyl; R2 and R3 are H; and R4 is in the para position of the phenyl ring and is selected from tetra-methyl butyl; optionally substituted heterocycloalkyl; optionally substituted C3-C8 cycloalkyl Ci-Ce-alkyl, -CH Phenyl, -C(Me)2Phenyl and - C(Me)2Phenyl-OMe. Another particularly preferred embodiment of the invention, is a compound according to Formula I wherein X is O; Y is S; G is -COOH; R2 and R3 are H and R4 is in the para position of the phenyl ring and is selected from tetra-methyl butyl; optionally substituted heterocycloalkyl; optionally substituted C3-C8 cycloalkyl Ci-C6-alkyl, - CH2Phenyl, -C(Me)2Phenyl and -C(Me)2Phenyl-OMe.
Another particularly preferred embodiment of the invention, is a compound according to the invention for use as a medicament.
The invention also includes compounds and use of optically active compounds of the above Formulae I through V, particularly compounds of the above Formulae I through V where a single stereoisomer of a chiral compound is present in an enantiomeric excess, e.g. where a single stereoisomer is present in an amount of at least 70 mole percent relative to other stereoisomer(s), more preferably where one stereoisomer is present in an amount of at least about 80, 85, 90, 92, 93, 94, 95, 96, 97, 98 or 99 mole percent relative to other stereosiomer(s).
Specifically preferred compounds of the invention include the following depicted compounds (with compound names above the corresponding structure), and pharmaceutically acceptable salts of these compounds.
5-(phenoxymethyl)-2-furoic acid
Figure imgf000019_0001
5-[(4-benzylphenoxy) methyl]-2-furoic acid
Figure imgf000019_0002
5-[(4-tert-pentylphenoxy) methyl]-2-furoic acid
Figure imgf000019_0003
-[(l,l'-biphenyl-4-yloxy) methyl] -2-furoic acid
Figure imgf000020_0001
- { [4-( 1 -methyl- 1 -phenylethyl)phenoxy]methyl } -2-furoic acid
Figure imgf000020_0002
-{[4-(4-cyclohexyl) phenoxy] methyl} -2-furoic acid
Figure imgf000020_0003
-{[4-(4-oxocyclohexyl) phenoxy] methyl} -2-furoic acid
Figure imgf000020_0004
-{[4-(2,3-dihydro-lH-inden-l-yl) phenoxy] methyl}-2-furoic acid
Figure imgf000020_0005
-[(4-tert-butylphenoxy) methyl] -2-furoic acid
Figure imgf000020_0006
-{[4-(l,l,3,3-tetramethylbutyl) phenoxy] methyl} -2-furoic acid
Figure imgf000021_0001
-[(2-methyl-4- (2 methyl, 2-ethyl) n-proylphenoxy) methyl] -2-furoic acid
Figure imgf000021_0002
-[(2-chloro-4-tert-pentylphenoxy) methyl]-2-furoic acid
Figure imgf000021_0003
-[(2,6-dichloro-4-tert-pentylphenoxy) methyl] -2-furoic acid
Figure imgf000021_0004
-[(2,6-dimethyl-4-tert-pentylphenoxy) methyl] -2-furoic acid
Figure imgf000021_0005
-{[4-(l-phenylethyl) phenoxy] methyl} -2-furoic acid
Figure imgf000021_0006
-{[4-(l,3-dimethylbutyl) peony] methyl} -2-furoic acid
Figure imgf000022_0001
-{[4-(2,2,4-trimethyl-3, 4-dihydro-2H-chromen-4-yl) phenoxy] methyl} -2-furoic acid
Figure imgf000022_0002
-{[4-(l-adamantyl) phenoxy] methyl} -2-furoic acid
Figure imgf000022_0003
-({4-[l-(4-methoxyphenyl)-l-methylethyl] phenoxy} methyl)-2-furoic acid
Figure imgf000022_0004
-{[4-(benzyloxy) phenoxy] methyl} -2-furoic acid
Figure imgf000022_0005
-[(4-butoxyphenoxy) methyl]-2-furoic acid
Figure imgf000023_0001
-{[(4-benzylphenyl) amino] methyl} -2-furoic acid
Figure imgf000023_0002
-{[(4-benzylphenyl)(methyl) amino] methyl} -2 -furoic acid
Figure imgf000023_0003
-({4-[(tert-butoxycarbonyl) amino] phenoxy} methyl)-2-furoic acid
Figure imgf000023_0004
-[(4-{[6-chloro-2- (methylthio) pyrimidin-4-yl] amino} phenoxy) methyl] -2-furoic acid
Figure imgf000023_0005
-[(4-anilinophenoxy)methyl]-2-furoic acid
Figure imgf000023_0006
-( {4-[(4-methylphenyl)amino]phenoxy}methyl)-2-furoic acid
Figure imgf000024_0001
-{[4-(benzyl amino)phenoxy]methyl} -2-furoic acid
Figure imgf000024_0002
- { [4-( 1 -naphthylamino)phenoxy]methyl} -2-furoic acid
Figure imgf000024_0003
- [(3 -anilinophenoxy)methyl] -2-furoic acid
Figure imgf000024_0004
-({4-[memyl(3,5,5-trimethylhexyl)ammo]phenoxy}methyl)-2-furoic acid
Figure imgf000024_0005
5-({4-[(3,3-dimethylbutyl)(methyl)amino]phenoxy}methyl)-2-furoic acid
Figure imgf000025_0001
5-({4-[methyl(neopentyl)amino]phenoxy} methyl)-2-furoic acid
Figure imgf000025_0002
5-({4-[methyl(3,5-dimethylberιzyl)amino]phenoxy}methyl)-2-furoic acid
Figure imgf000025_0003
Methyl 5-( {4-[(trifluoroacetyl)ammo]phenoxy}methyl)-2-iuroate
Methyl 5-[(4-aminophenoxy)methyl]-2-furoate
Figure imgf000025_0005
Methyl 5-( {4-[(phenylsulfonyl)amino]phenoxy} methyl)-2-furoate
Figure imgf000026_0001
5-( {4-[(phenylsulfonyl)amino]phenoxy}methyl)-2-furoic acid
Figure imgf000026_0002
Methyl 5-( {4-[isopropyl(phenylsulfonyl) amino]phenoxy}methyl)-2-furoate
Figure imgf000026_0003
5-({4-[Isopropyl(phenylsulfonyl)amino]phenoxy}methyl)-2-furoic acid
Figure imgf000026_0004
Methyl 5-({4-[ethyl(phenylsulfonyl)amino]phenoxy}methyl)-2-furoate
Figure imgf000027_0001
5-({4-[ethyl(phenylsulfonyl)amino]phenoxy}methyl)-2 -furoic acid
Figure imgf000027_0002
Ethyl 5- { [4-( 1 , 1 -diphenylpropyl)phenoxy]methyl} -2-furoate
Figure imgf000027_0003
5- { [4-( 1 , 1 -diphenylpropyl)phenoxy]methyl} -2-furoic acid
Figure imgf000027_0004
Ethyl 5-[(4-benzoylphenoxy)methyl]-2-furoate
Figure imgf000028_0001
Ethyl 5-({4-[hydroxy(phenyl)methyl]phenoxy}methyl)-2-furoate
Figure imgf000028_0002
5-({4-[hydroxy(phenyl)methyl]phenoxy}methyl)-2-furoic acid
Figure imgf000028_0003
5-[(4-benzoylphenoxy)methyl]-2-furoic acid
Figure imgf000028_0004
Ethyl 5-{[4-(methoxymethyl)phenoxy]methyl}-2-furoate
Figure imgf000028_0005
5-{[4-(methoxymethyl)phenoxy]methyl}-2-furoic acid
Figure imgf000028_0006
Ethyl 5-[(4-butyrylphenoxy)methyl]-2-furoate
Figure imgf000029_0001
5-[(4-butyrylphenoxy)methyl]-2-furoic acid
Figure imgf000029_0002
Ethyl 5- { [4-(l -hydroxybutyl)phenoxy]methyl} -2-furoate
Figure imgf000029_0003
5- { [4-(l -hydroxybutyl)phenoxy]methyl} -2-furoic acid
Figure imgf000029_0004
Ethyl 5-{[4-(l,l -dimethylbutyl)phenoxy]methyl} -2-furoate
Figure imgf000029_0005
5- { [4-(l , 1 -dimethylbutyl)phenoxy]methyl} -2-furoic acid
Figure imgf000030_0001
Ethyl 5- { [4-(l -cyclohexyl- 1 -methylethyl)phenoxy]methyl} -2-furoate
Figure imgf000030_0002
5 - { [4-( 1 -cyclohexyl- 1 -methylethyl)phenoxy]methyl} -2-furoic acid
Figure imgf000030_0003
Ethyl 5-{[4-(4,4,5,5-tetramethyl-l,3-dioxolan-2-yl)phenoxy]methyl}-2-furoate
Figure imgf000030_0004
5-{[4-(4,4,5,5-tetramethyl-l,3-dioxolan-2-yl)phenoxy] methyl} -2-furoic acid
Figure imgf000030_0005
Ethyl 5-{[4-(l,3,4-oxadiazol-2-yl)phenoxy]methyl}-2-furoate
Figure imgf000031_0001
5- { [4-(l ,3 ,4-oxadiazol-2-yl)phenoxy]methyl} -2-furoic acid
Figure imgf000031_0002
Ethyl 5- {[4-(l ,3 -benzoxazol-2-yl)phenoxy]methyl} -2-furoate
Figure imgf000031_0003
5- {[4-(l ,3-benzoxazol-2-yl)phenoxy]methyl} -2-furoic acid
Figure imgf000031_0004
As discussed above, preferred compounds of the invention exhibit good activity in a standard prostaglandin EP2 receptor binding assay. References herein to "standard prostaglandin EP2 receptor binding assay" are intended to refer to the protocol as defined in Example 68, which follows. Generally preferred compounds of the invention have a Ki (μM) of about 100 or less, more preferably about 50 or less, still more preferably a Ki (μM) of about 10 or 20 or less, even more preferably a Ki (μM) of about 5 or less in such a defined standard prostaglandin assay as exemplified by Example 68 which follows. Substituted furan and thienyl compounds of the invention can be readily prepared.
For example, to prepare compounds of Formula I above where group X is oxygen, a reagent with hydroxy substitution such as phenol can be reacted with a furanyl with activated methyl substitution e.g. halomethyl. A 2-chloromethyl furanyl compound is a particularly suitable reagent. That furanyl reagent may be further substituted as desired e.g. ethyl-5-chloromethyl-2-furoate can be employed to provide a carboxylate furanyl ring substituent. That carboxylate group can be further functionalized, e.g. hydrolyzed to the corresponding acid. See the examples which follow for exemplary preferred procedures.
For compounds where group X is other than oxygen, corresponding reagents can be employed. For instance, to provide compounds where X is nitrogen, a reagent having a reactive amine moiety, preferably a primary amine may be employed such as an optionally substituted aniline compound. See, for instance, the procedures of Examples 30 and 31, which follow. To provide compounds of Formula I where group X contain a sulfur, a suitable thiol reagent may be reacted with a reactive furane reagent, e.g. optionally substituted benzene thiol. The formed furanyl compound may be oxidized e.g. with hydrogen peroxide or other suitable oxidant to provide compounds where X is sulfmyl or sulfonyl.
For compounds of the invention where group Y of Formula I is sulfur, the corresponding reactive thienyl compound may be employed in place of a furanyl reagent as described herein. For instance, a substituted 2-chloromethyl thienyl compound, such as a ethyl-5-chloromethyl-2-thienoate, may be employed as a starting reagent and reacted with suitable reagents as discussed above, such as an optionally substituted phenol or aniline reagent or an optionally substituted naphthol, or the like.
To provide varying R2, R3 and R4 substituents of compounds of Formulae I through V above, an initial reagent may be appropriately substituted, e.g. a phenol with one or more ring substituents that provide R2, R3 and/or R4 groups may be reacted with a suitable reactive furanyl or thienyl compound. Such phenyl ring substituents also may be further functionalized to provide desired R2, R3 and/or R groups. See, for instance, Examples 38-47 which follow. Such phenol reagents may be suitably obtained from commercial sources, or synthesized by known methods, e.g. by Friedel-Crafts reaction or other ring substitution.
Additional preferred syntheses of compounds of the invention are detailed in the examples which follow. Exemplary schemes for compound syntheses also are set forth in the examples.
As indicated above, the present invention includes methods for treating or preventing prostaglandin mediated or associated diseases or disorders.
Preferred therapeutic methods of the invention include inhibiting undesired smooth muscle contraction, including undesired prostanoid-induced smooth muscle contraction. Methods of the invention include treatment of a patient suffering from or susceptible to dysmenorrhea, premature labor, asthma and other conditions that can be relieved by bronchodilation, inflammation, hypertension, undesired blood-clotting (e.g. to reduce or prevent thromboses) and other undesired platelet activities, preeclampsia and/or eclampsia and eosinophil-related disorders (eosinophil disorders).
In a preferred embodiment of the invention, the method for treating and/or preventing a disease or disorder associated with prostaglandins, comprises the administration to a subject in need thereof an effective amount of a compound of the invention, wherein the subject can be human or animal, preferably human.
In a further preferred embodiment of the invention, the method of treatment, comprises comprises the administration to a subject in need thereof an effective amount of a compound of Formula I wherein X is O; Y is O or S; G is selected from -COOR1 and tetrazolyl, wherein R1 is selected from H and d-d alkyl; R2 and R3 are as defined above andR4 is as defined above and is in para position on the phenyl ring. In another further preferred embodiment of the invention, the method of treatment, comprises comprises the administration to a subject in need thereof an effective amount of a compound of Formula I wherein X and Y are O; G is selected from -COOR1 and tetrazolyl, wherein R1 is selected from H and Ci- alkyl; R2 and R3 are as defined above and R4 is as defined above and is in para position on the phenyl ring.
In another further preferred embodiment of the invention, the method of treatment, comprises comprises the administration to a subject in need thereof an effective amount of a compound of Formula I wherein A method of claim 1 wherein the compound of Formula I is such as X is O; Y is S; G is selected from -COOR1 and tetrazolyl, wherein R1 is selected from H and Ci-d alkyl; R2 and R3 are as defined above andR is as defined above and is in para position on the phenyl ring.
In a further preferred embodiment of the invention, the method of treatment, comprises comprises the administration to a subject in need thereof an effective amount of a compound of Formula I wherein X is O; Y is O or S; G is selected from -COOR and tetrazolyl, wherein R1 is selected from H and Cι-C6 alkyl; R2 and R3 are independently selected from H and d-d alkyl; R4 is selected from hydrogen; d-d- alkyl, heterocycloalkyl, C3-C8 cycloalkyl Ci-Ce-alkyl, aryl, C3-Cιo cycloalkyl, aryl Ci- Ce-alkyl, heteroalkyl, aryl heteroalkyl and amino group wherein the substituents on the amino group are independently selected from d-d alkyl, carbonyl, aryl sulfonyl, aryl, heteroaryl and amino carbonyl.
In a further preferred embodiment of the invention, the method of treatment, comprises comprises the administration to a subject in need thereof an effective amount of a compound of Formula I wherein X is O; Y is O; G is selected from -COOR1 and tetrazolyl; R2 and R are H; and R4 is in the para position of the phenyl ring and is selected from tetra-methyl butyl; heterocycloalkyl; C3-C8 cycloalkyl Ci-Cβ-alkyl, - CH2Phenyl, -C(Me)2Phenyl and -C(Me)2Phenyl-OMe. In a further preferred embodiment of the invention, the method of treatment, comprises comprises the administration to a subject in need thereof an effective amount of a compound of Formula I wherein X is O; Y is S; G is -COOH; R2 and R3 are H and R4 is in the para position of the phenyl ring and is selected from tetra-methylbutyl; heterocycloalkyl; C3-C8 cycloalkyl Ci-d-alkyl, -CH2Phenyl, -C(Me)2Phenyl and - C(Me)2Phenyl-OMe.
Treatment and/or prevention of undesired blood clotting may include treatment and prophylaxis of venous thrombosis and pulmonary embolism, arterial thrombosis e.g. myocardial ischemia, myocardial infarction, unstable angina, stroke associated with thrombosis, and peripheral arterial thrombosis. Furan and thienyl compounds of the invention also may be useful for anticoagulation involving artificial organs, cardiac valves, medical implementation (e.g. an indwelling device such as a catheter, stent, etc.) and the like.
The invention also includes methods for treatment of infertility, which generally comprise administration of one or more substituted furan and/or thienyl compounds of the invention to a mammal, particularly a primate such as a human, suffering from or suspected of suffering from infertility. See the Merck Manual, vol. 2, pages 12-17 (16th ed.) for identification of patients suffering from or suspected of suffering from infertility, which in the case of humans, can include failure to conceive within one year of unprotected intercourse.
The treatment methods of the invention may be particularly beneficial for female mammals suffering from an ovulatory disorder. Additionally, compounds of the invention can be administered to females undergoing assisted reproductive treatments such as in-vitro fertilization, ovulation induction or an Assisted Reproductive Therapy (ART), e.g. to stimulate follicular development and maturation or to trigger ovulation, as well as implantation procedures. In particular, treatment methods of the invention may be used in conjunction with in vitro fertilization technology to enhance survival and/or fertilization of a mammalian egg such as in IVF setting. Treatment methods of the invention also may be employed for control of cervical ripening in late pregnancy (e.g. in humans, late pregnancy would be third trimester, particularly week 30 onward).
Therapeutic methods of the invention also include treatment of glaucoma or other disorder involving elevated intra-ocular pressure.
Treatment methods of the invention also include inhibition or prevention of bone loss such as to treat osteoporosis, and for promoting bone formation (e.g. to use as a therapy in a bone fracture) and other bone diseases such as Paget's disease. The invention also includes methods for treating a mammal that has low bone mass, or is susceptible to low bone mass such as a mammal having a condition that can present low bone mass, e.g. osteoporosis.
The invention also includes methods for treatment of inflammatory disorders including inflammatory pain,
The invention also includes therapeutic methods for other bone mass augmentation treatments or enhancement, such as enhancing bone graft success rates or replacement of the need of such grafts, bone extension, bone healing following facial reconstruction and other treatments. Such treatment also may be used in coordination with an appropriate medical device, such as an orthopedic device e.g. a spinal case, bone pins and screws, and other bone fixation devices.
In general, such therapies are useful for any condition which can present low bone mass, which conditions include those where the level of bone mass is below the age specific normal as defined in standards by the World Health Organization "Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis (1994), World Health Organization Technical Series 843." More particularly, such conditions include periodontal disease, alveolar bone loss, post- osteotomy and childhood idiopathic bone loss, and primary and second osteoporosis as discussed above and complications thereof such as curvature of the spine, loss of height and prosthetic surgery. Subject particularly suitable for such bone growth promotion therapies include subjects suffering from acute injuries that can involve bone damage, subjects having undergone related surgery such as facial reconstruction, and subjects that are at increased risk of the above discussed disorders and diseases such as post-menopausal women and men and women over the age of 50 or 60.
Compounds of the invention also will be useful to treat sexual dysfunction, including male erectile dysfunction.
Compounds of the invention also are useful for treatment of a subject suffering from or susceptible to renal dysfunction, including a mammal suffering from or susceptible to acute or chronic renal failure. Such treatment methods can promote repair and/or regeneration of kidney tissue in a mammal, particularly a human.
Compounds of the invention also are useful for treatment of a subject suffering from or susceptible to an immune disorder including an immune deficiency disease or disorder, including such a disorder associated with a viral infection particularly a retroviral infection such as an HIV infection. Particularly benefited by such therapies will be a human suffering from or susceptible to AIDS.
Compounds of the invention will be further useful to reduce elevated intraocular pressure of a subject, e.g. through relaxation of pre-contracted isolated ciliary muscle. In particular, a mammal such as a human suffering from or susceptible to glaucoma or other disorder associated with elevated intra-ocular pressure. Compounds of the invention also will be useful for treatment of a mammal, particularly a human that is suffering from or susceptible to dry eye.
Compounds of the invention will be also useful to reduce inflammatory disorders including rheumatoid arthritis and inflammatory pain.
Compounds of the invention also will be useful for promoting sleep in a subject, e.g. to treat a mammal particularly a human suffering from or susceptible to a sleep disorder such as may be associated with advanced age, such as a human of 65 years or older.
Compounds of the invention may be used for the preparation of a medicament for the treatment and/or prevention of a disease associated with prostaglandins such as preterm labor, ovulation induction, cervical ripening, dysmenorrhea, asthma, hypertension, infertility or fertility disorder, undesired blood clotting, preeclampsia or eclampsia, an eosinophil disorder, sexual dysfunction, osteporosis and other destructive bone disease or disorder, renal dysfunction (acute and chronic), immune deficiency disorder or disease, dry eye, skin disorders such as ichthyosis, elevated intraocular pressure such as associated with glaucoma, sleep disorders, urinary dysfunction, inflammatory disorders including rheumatoid arthritis and inflammatory pain, gastric disorders such as gastric motility disorders and gastric ulcers.
The therapeutic methods of the invention generally comprise administration of an effective amount of one or more compounds of the invention to a subject including a mammal, such as a primate, especially a human, in need of such treatment.
Typical candidates for treatment in accordance with the methods of the invention persons suffering from or suspected of suffering from any of the above disorders or diseases, such as a female susceptible or suffering from preterm labor, or a subject suffering from or susceptible to dysmenorrhea or undesired bone loss.
The treatment methods of the invention also will be useful for treatment of mammals other than humans, including for veterinary applications such as to treat horses and livestock e.g. cattle, sheep, cows, goats, swine and the like, and pets such as dogs and cats. Methods of the invention to treat premature labor will be particularly useful for such veterinary applications. Therapeutic methods of the invention also will be useful for treatment of infertility in such veterinary applications.
For diagnostic or research applications, a wide variety of mammals will be suitable subjects including rodents (e.g. mice, rats, hamsters), rabbits, primates and swine such as inbred pigs and the like. Additionally, for in vitro applications, such as in vitro diagnostic and research applications, body fluids (e.g., blood, plasma, serum, cellular interstitial fluid, saliva, feces and urine) and cell and tissue samples of the above subjects will be suitable for use.
Substituted furan and/or thienyl compounds may be administered as a "cocktail" formulation with other therapeutics, i.e. coordinated administration of one or more compounds of the invention together with one or more other active therapeutics, particularly one or more other known fertility agents, for simultaneous, sequential or separate use. For instance, one or more compounds of the invention may be administered in coordination with a regime of a pain relief agent, an anti-inflammatory agent, or an anti-cogulant for simultaneous, sequential or separate use, depending on the indication being treated. Suitable anti-coagulants for such coordinated drug therapies include e.g. warfarin, heparin, hirudin or hirulog or an antiplatelet such as ReoPro for simultaneous, sequential or separate use.
For treatment of fertility disorders, one or more compounds of the invention may be suitably administered in coordination with known fertility agents such as Follicle Stimulating and/or Leutinizing Hormone such as Gonal-F, Metrodin HP or Pergonal, for simultaneous, sequential or separate use.
Substituted furan and/or thienyl compounds of the invention either as the sole active therapeutic or in a coordinated regime with one or more other therapeutics can be administered by a variety of routes, such as orally or by injection, e.g., intramuscular, intraperitoneal, subcutaneous or intravenous injection, or topically such as transdermally, vaginally and the like. Substituted furan and thienyl compounds of the invention may be suitably administered to a subject in the protonated and water-soluble form, e.g., as a pharmaceutically acceptable salt of an organic or inorganic acid, e.g., hydrochloride, sulfate, hemi-sulfate, phosphate, nitrate, acetate, oxalate, citrate, maleate, mesylate, etc. If the compound has an acidic group, e.g. a carboxy group, base addition salts may be prepared. Lists of additional suitable salts may be found, e.g. in Part 5 of Remington 's Pharmaceutical Sciences, 20th Edition, 2000, Marck Publishing Company, Easton, Pennsylvania, which is incoφorated herein by reference.
Compounds of the invention can be employed, either alone or in combination with one or more other therapeutic agents as discussed above, as a pharmaceutical composition in mixture with conventional excipient, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, enteral or topical application which do not deleteriously react with the active compounds and are not deleterious to the recipient thereof. Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc. The pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifϊers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously react with the active compounds.
Pharmaceutical compositions of the invention may preferably include a substituted furan and/or thienyl compound packaged together with instructions (written) for therapeutic use of the compound to treat e.g. premature labor, dysmenorrhea or asthma, or other disorder as disclosed herein, such as a disease or disorder associated with or mediated by prostaglandin.
For oral administration, pharmaceutical compositions containing one or more substituted furan and/or thienyl compounds of the invention may be formulated as e.g. tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, elixers and the like. Typically suitable are tablets, dragees or capsules having talc and/or carbohydrate carrier binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch. A syrup, elixir or the like can be used wherein a sweetened vehicle is employed. Sustained release compositions can be formulated including those wherein the active component is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc.
For parenteral application, e.g., sub-cutaneous, mtraperitoneal or intramuscular, particularly suitable are solutions, preferably oily or aqueous solutions as well as suspensions, emulsions, or implants, including suppositories. Ampules are convenient unit dosages.
It will be appreciated that the actual preferred amounts of active compounds used in a given therapy will vary according to the specific compound being utilized, the particular compositions formulated, the mode of application, the particular site of administration, etc. Optimal administration rates for a given protocol of administration can be readily ascertained by those skilled in the art using conventional dosage determination tests conducted with regard to the foregoing guidelines. See also Remington 's Pharmaceutical Sciences, supra. In general, a suitable effective dose of one or more substituted furan and/or thienyl compounds of the invention, particularly when using the more potent compound(s) of the invention, will be in the range of from 0.01 to 100 milligrams per kilogram of bodyweight of recipient per day, preferably in the range of from 0.01 to 20 milligrams per kilogram bodyweight of recipient per day, more preferably in the range of 0.05 to 4 milligrams per kilogram bodyweight of recipient per day. The desired dose is suitably administered once daily, or several sub- doses, e.g. 2 to 4 sub-doses, are administered at appropriate intervals through the day, or other appropriate schedule. Such sub-doses may be administered as unit dosage forms, e.g., containing from 0.05 to 10 milligrams of compound(s) of the invention, per unit dosage. The entire text of all documents cited herein are incoφorated by reference herein. The following non-limiting examples are illustrative of the invention.
Abbreviations min (minute); hr (hour); g (gram); mg (milligram); μg (microgram); mmol (millimole); mM (millimolar); pM (picomolar); mL (milliliter); μl (microliter); mm (millimeter); nm (nanometer); μm (micrometer); A (Angstrom); cpm (counts per minute); Ci (Curies); RPM (Rotation per minute); rt (room temperature); hr (hour); kDa (KiloDalton); V (Volt); Vol. (volume); BSA (Bovine Serum Albumin); cAMP (cyclic adenosine monophophate); DMF (dimethylformamide); DMSO (Dimethyl Sulfoxide); EDTA (ethylenediaminetetraacetic acid); FBS (Fetal Bovine Serum); MES (2-(N- Mθφholino)ethanesulfonic Acid); PGE2 (Prostaglandin E2); SPA (Scintillation Proximity Assay); THF (tetrahydrofuran); TLC (Thin Layer Chromatography).
Examples 1-29:
In the following synthesis Examples 1 through 29, the following general procedures were employed or similar protocols unless otherwise indicated.
a. Phenol (2mM) is dissolved in 5mL of DMF and was added to the pre cooled heterogeneous DMF solution of NaH (95%, 2.5 mmol, 1.25 equivalents) at 0° C, while stirring and continued stirring for 30 minutes. Ethyl- 5-chloromethyl-2-furoate (2mM, 1 equivalent) in lmL of DMF is added to the above solution dropwise and the solution was stirred for overnight at room temperature. The reaction mixture is diluted with 100 mL of water. The gummy solid that separated is extracted in to ethyl acetate and the organic extract was washed with water, 5% NaHCO3, brine and dried over anhydrous MgSO4. Evaporation of EtOAc solution yields the desired crude material in various yields. The gummy material was purified by flash column chromatography using Hexane: EtOAc ( 9:1) as eluant to get the pure ethyl 5-{[4-(substituted)phenoxy] methyl} -2-furoate. b. Hydrolysis of ethyl ester:
The thus produced ethyl 5-{[4-(substituted)phenoxy]methyl}-2-furoate derivative was dissolved in MeOH and IN NaOH in MeOH (5mL) is added and stirred overnight. The resulting solution is concentrated under vacuum. The resulting solid is dissolved in water and neutralized with 1 N HC1 to get a white fluffy material. This solid is filtered and dried. The crude material is passed through the flash column eluting with EtOAc: MeOH (9:1) resulted in desired pure product. The structure can be confirmed by mass spectra.
c. Preparation of Sodium salt of the carboxylic acid (optional).
ImM amount of compound is weighed in to vial and dissolved in MeOH. To this an equimolar amount of IN NaOH in EtOH is added. The ethanol solution was diluted with water. The solution is lyophilized and evaporated under vacuum to get sodium salt as white solid.
Example 1: Synthesis of (phenoxymethyl)-2 -furoic acid.
Figure imgf000043_0001
Mass spectra: M-H =217 (m/z= 218)
1H NMR: δ 5.0 (s, 2H, 5-methylene of furan), 6.5 (s, C4H of furan), 6.9 ( (dd,
2H,aromatic), 7.1 (s, C3 H of furan), 7.3 (dd, 2H,aromatic).
Example 2 : Synthesis of 5 -[(4-benzylphenoxy) methyl] -2-furoic acid.
Figure imgf000043_0002
Mass spectra: M-H = 307 (m/z = 308)
1H NMR: δ 5.0(s, 2H, 5-methylene of furan), 6.5 (s, C4 H of furan), 6.9 (dd,
2H,aromatic), 7.1 (s, C3 H of furan), 7.3 (dd, 2H,aromatic). Example 3 : Synthesis of 5-[(4-tert-pentylphenoxy) methyl]-2-furoic acid.
Figure imgf000044_0001
Mass spectra; M-H= 287 (m/z= 288)
1H NMR: δ 6.5 (d, CH3, 3H), 1.2 (s, gem dimethyl), 1.5 (q, 2H, -CH2-), 5.0 (s, 2H, -
CH2-furan methyl)), 6.5 (s, furan H), 7.3 (s, furan H), 6.8 (d, 2H aromatic), 7.3 (d, 2H aromatic).
Example 4: Synthesis of 5-[(l,l'-biphenyl-4-yloxy) methyl]-2-furoic acid.
Figure imgf000044_0002
Mass spectra; M-H 293 (m/z= 294)
1H NMR: δ 5.0 (s, 2H, 5-methylene of furan), 6.5 (s, C5 H of furan), 7.1 (s, C3 H of furan), 6.9 (dd, 2H, aromatic), 7.3 (m, 5H, aromatic).
Example 5: Synthesis of 5-{[4-(l-methyl-l-phenylethyl)phenoxy]methyl}-2-furoic acid.
Figure imgf000044_0003
Mass spectra: M-H335 (m/z=336)
1H NMR: δ 1.8(s, 6H, gem dimethyl), 5.0(s, 2H, 5-methylene of furan), 6.5 (s, C4 H of furan), 7.0-7.4 (m, 9H,aromatic), 7.4 (s, C3H of furan). Example 6: Synthesis of 5-{[4-(4-cyclohexyl) phenoxy] methyl} -2-furoic acid.
Figure imgf000045_0001
Mass spectra: M-H=314 (m/z=313)
1H NMR: δ 0.8-1.0 (m, 2H), 1.1-1.3 (m, 4H), 1.45 (b, IH), 1.6 (d, 4H), 2.4 (d, 2H benzyl), 5.0 (s, 2H, 0-CH2-furan), 6.5 (d, IH, C4 H of furan), 7.28 (d, IH, C3 of furan), 6.8 (d, 2H, aromatic), 7.05 (d, 2H, aromatic).
Example 7: Synthesis of 5-{[4-(4-oxocyclohexyl) phenoxy] methyl} -2-furoic acid.
Figure imgf000045_0002
Mass spectra: M-H=314 (m/z=313)
1H NMR: δ 1.9 (m, 2H), 2.2 (, m, IH), 2.5 (m, 4H), 2.9 (m, 2H), 5.0 (s, 2H), 6.5 (s, IH,
C4 of furan), 7.25 (s, IH, C3 of furan), 6.8 (d, 2H, aromatic), 7.12 (d, 2H, aromatic).
Example 8: Synthesis of 5-{[4-(2,3-dihydro-lH-inden-l-yl) phenoxy] methyl}-2- furoic acid.
Figure imgf000045_0003
Mass spectra: M-H=333 (m z=334).
1H NMR: δ 2-3 (m, 5 H), 5.0 (s, 2H of o-CH2-furan), 6.5 (d, IH, C4 H of furan), 6.85
(m, 2H, aromatic), 7.0- 7.2(m, 6H, aromatic), 7.3 (d,lH of C3 of furan). Example 9: Synthesis of 5-[(4-tert-butylphenoxy) methyl] -2-furoic acid.
Figure imgf000046_0001
Mass Spectra; M-H=273 (m/z=274)
1HNMR: δ 1.3 (s, 9H, t-butyl), 5.1 (s, 2H, -OCH2-furan), 6.5 (s, IH, C4 H of furan),
6.8 (d, 2H, aromatic), 7.2 (d, 2H, aromatic), 7.25(s, IH C3 of furan).
Example 10: Synthesis of 5-{[4-(l,l,3,3-tetramethylbutyl) phenoxy] methyl} -2-furoic acid.
Figure imgf000046_0002
Mass spectra: M-H=329 (m/z=330)
1H NMR: δ 0.7 (s, 9H, t-butyl), 1.35 (s, 6H gem dimethyl), 2.7 (s, 2H), 5.0 (s, 2H, OCffi-furan), 6.5 (s, IH, C4 H of furan), 6.9 (d, 2H aromatic), 7.25 (d, 2H, aromatic), 7.8 (s, lH, C3 H of furan).
Example 11 : Synthesis of 5-[(2-methyl-4- (2 methyl, 2-ehtyl) n-proylphenoxy) methyl] -2-furoic acid.
Figure imgf000046_0003
Mass spectra; M-H=315 (m/z=316).
1HNMR: δ 0.5 (q, 6H, 2 x methyl), 1.2 (s, 3H, methyl), 1.4 (m, 2H, -CH2-), 1.6 (m, 2H, -CH2-), 2.1, (s, 3H, methyl), 5.0 (s, 2H, -OCH2-furan), 6.4 (s, IH, C4 H of furan), 6.7(t, IH, aromatic), 6.9-7.1 (m, 2H, aromatic), 7.25 (s, IH, C3 H of furan). Example 12: Synthesis of 5-[(2-chloro-4-tert-pentylphenoxy) methyl] -2-furoic acid.
Figure imgf000047_0001
Mass spectra: M-H=321 (m/z 322)
!H NMR: δ 0.65 (t, 3H, methyl), d 1.25 (s, 6H, gem di methyl), d 1.6 (q, 2H), d 5.2 9 S, H, OCH2-furan), d 6.6 (d, IH, C4 H of furan), d 6.9 (d, IH, aromatic), d 7.1 (d, IH, aromatic), d 7.3 (m, 2H, aromatic).
Example 13 : Synthesis of 5-[(2,6-dichloro-4-tert-pentylphenoxy) methyl]-2-furoic acid.
Figure imgf000047_0002
Mass spectra: M-H=356 (m/z. =357)
!H NMR: δ 0.65 (t, 3H, methyl), d 1.25((s, 6H, gem di methyl), d 1.7 (q, 2H), d 5.1 (s,
2H, OCH2-furan), d 6.6 (s, IH, C4 H of furan), d 7.2-7.4 (3 singlet peaks, 3H, aromatic).
Example 14: Synthesis of 5-[(2,6-dimethyl-4-tert-pentylphenoxy) methyl]-2-furoic acid.
Figure imgf000047_0003
Mass spectra; M-H=315 (m/z=316)
Η NMR: δ 0.6 (t, 3H, methyl), 1.15 (s, 6H, gem dimethyl), 1.5 (q, 2H, -CH2-), 2.1 (s, 6H, 2 x o-Methyl), 4.7 (s, 2H, OCH2-), 6.2 (s, IH, C4H of furan), 6.8 (s, IH, aromatic), 7.0 (s, IH,), 7.2 (s, IH, aromatic).
Example 15: Synthesis of 5-{[4-(l-phenylethyl) phenoxy] methyl} -2-furoic acid.
Figure imgf000048_0001
Mass spectra: M-H=321 (m/z=322) NMR: δ 1.55 (s, 3H), methyl), 5.2 (s, 2H, OCH2-furan), 6.4 (s, IH, C4 H of furan),
6.8 (2H, aromatic), 7.0- 7.4 (m, 7H, aromatic).
Example 16: Synthesis of 5-{[4-(l,3-dimethylbutyl) peony] methyl} -2-furoic acid.
Figure imgf000048_0002
Mass spectra: M-H=287 (m/z=288)
ΗNMR: δ 0.8 (m, 6H, dimethyl), 1.2-1.5 (m, 2H), 2.4-2.6 (m, 2H), 4.9 (d, 2H, OCH2- furan), 6.35 (s, IH, C4 H of furan), 6.8 (m, 2H, aromatic), 7.0 (m, 2H, aromatic), 7.2 (s, 1H, C3H of furan).
Example 17: Synthesis of 5-{[4-(2,2,4-trimethyl-3, 4-dihydro-2H-chromen-4-yl) phenoxy] methyl} -2-furoic acid.
Figure imgf000048_0003
Mass spectra: M-H=391 (m/z = 392)
*H NMR: δ 0.8 (s, 3H, methyl), 1.3 (s, 3H, methyl), 1.6 (s, 3H, methyl), 5.0 (s, 2H,
OCH2-furan), 6.5 (s, IH C4 H of furan), 6.8-7.1 (m, 8H, aromatic), 7.3 (s, IH, C3 H of furan).
Example 18: Synthesis of 5-{[4-(l-adamantyl) phenoxy] methyl} -2-furoic acid.
Figure imgf000049_0001
Mass spectra: M-H=351 (m/z=352)
1H MR: δ 1.6-2.2 (m, 14 H), 2.4 (q, IH), 3.4(t, IH), 4.95 (s, 2H, -OCH2-furan), 6.4 (s,
IH, C4 H of furan), 6.8-7.3 (m, 5H, aromatic).
Example 19: Synthesis of 5-({4-[l-(4-methoxyphenyl)-l-methylethyl] phenoxy} methyl)-2-furoic acid.
Figure imgf000049_0002
Mass spectra: M-H=365 (m/z=366).
!H NMR: δ 1.6 (s, 6H, gem di methyl), 3.8 (s, 3H, O-CH3), 5.0 (s, 2H, -OCH2-furan), 6.55 (s, IH, C4 H of furan), 6.8(dd, 4H, aromatic), 7.1 (m, 4H, aromatic), 7.25 (s, IH, C3 H of furan).
Example 20: Synthesis of 5-{[4-(benzyloxy) phenoxy] methyl} -2-furoic acid.
Figure imgf000049_0003
Mass Spectra: M-H=323 (m/z=324)
Example 21 : Synthesis of 5-[(4-butoxyphenoxy) methyl] -2-furoic acid.
Figure imgf000050_0001
Mass Spectra: M-H=289 (m/z=290)
1HNMR: δ 0.85 (t, 3H, methyl), 1.35(m, 2H, -CH2-), 1.65 (m, 2H, -CH2-), 3.85 (m, 2H, -CH2-O-), 4.85 (s, 2H, -OCH2-furan), 6.4 (s, IH, C4 H of furan), 6.8 (m, 4H, aromatic), 7.25 (s, IH, C3 H of furan).
Example 22: Synthesis of 5-[(4-{[(tert-butylamino) carbonyl] amino} phenoxy) methyl] -2-furoic acid.
Figure imgf000050_0002
Mass Spectra: M-H=331 (m/z=332)
!H NMR: δ 1.3 (s, 9H, t-butyl), 4.9(s, 2H, -OCH2-furan), 6.4 (s, IH, C4H of furan), 6.75
(d, 2H, aromatic), 7.1(dd, 2H, aromatic), 7.25 (s, IH, C3 H of furan).
Example 23: Synthesis of 5-({4-[(tert-butoxycarbonyl) amino] phenoxy} methyl)-2- furoic acid.
Figure imgf000050_0003
Mass spectra: M-H=332 (m/z=333)
1H NMR: δ 1.5 (s, 9H, t-butyl), 5.05(s, 2H, O-CH2-furan), 6.6 (s, IH, C4 H of furan),
6.85(d, 2H, aromatic), 7.3 (m, 3H, aromatic).
Example 24: Synthesis of 5-[(4-{[6-chloro-2- (methylthio) pyrimidin-4-yl] amino} phenoxy) methyl] -2-furoic acid.
Figure imgf000051_0001
Mass Spectra: M-H =390 (M+.=391).
1H NMR: δ 2.4 (s, 3H, -SCH3-), 5.0 (s, 2H, -OCH2-furan), 6.2 (s, IH, C4 H of furan),
6.5 (d, 2H, aromatic), 6.8 (d, 2H, aromatic), 7.05 (s, IH, aromatic), 7.25 (s, IH, C3 H of furan).
Example 25: Synthesis of 5-[(4-anilinophenoxy)methyl]-2-furoic acid.
Figure imgf000051_0002
Mass spectra: M-H=308 (m/z=309)
1H NMR: δ 5.0 (s, 2H, OCH2- furan), 6.45 (d, IH, C3 H of furan), 6.7-7.2 (m, 10H, aromatic).
Example 26: Synthesis of 5-({4-[(4-methylphenyl)amino]phenoxy}methyl)-2-furoic acid.
Figure imgf000051_0003
Mass spectra: M-H=322 (m/z=323)
1H NMR: δ 2.1 (s, 3H, CH3), 4.9 (s, 2H, OCH -furan), 6.4 (s, IH, C3 H of furan), 6.5
7.2 (m, 9H aromatic).
Example 27: Synthesis of 5-{[4-(benzyl amino)phenoxy]methyl} -2-furoic acid.
Figure imgf000052_0001
Mass spectra: M-H=322 (m/z=323)
1H NMR: δ 3.2 (s, 2H, Benzyl), 4.8 (s, 2H, -OCH2-furan), 6.3 - 6.8 (m, 6H, aromatic protons including two fliran protons), 7.3 (s, 5H, aromatic).
Example 28: Synthesis of 5-{[4-(l-naphthylamino)phenoxy]methyl}-2-furoic acid.
Figure imgf000052_0002
Mass spectra: M-H=358 (m/z=359)
1H NMR: δ 4.9(s, 2H,-OCH2-furan), 6.4 (s, IH, C3 H of furan), 6.7 - 7.8 (m, 12 H aromatic).
Example 29: Synthesis of 5-[(3-anilinophenoxy)methyl]-2-furoic acid.
Figure imgf000052_0003
Mass spectra: M+H=308 (m/z=309).
1H NMR: δ 5.0 (s, 2H, -OCH2-furan), 6.35 (d, IH, C3 H of furan), 6.65 (d, IH, IH aromatic), 6.8 (m, 2H aromatic), 6.9- 7.5 (m, 7H, aromatic). Example 30: Synthesis of 5-{[(4-benzylphenyl) amino] methyl} -2-furoic acid.
Figure imgf000053_0001
a. 4-Substituted aniline (2mM) is dissolved in 5mL of DMF and 4 mM of DIEA (Hunig's base) is added to the above solution, 700 μL, while stirring at room temperature and ethyl 5-chloromethyl-2 furoate (2mM) in lmL of DMF was added to the above solution dropwise and the solution stirred for overnight. The reaction mixture was diluted with 50 mL of water. The gummy solid that separated was extracted in to ethyl acetate and the EtOAc extract was washed with water, 5% NaHCO3, brine and dried over anhydrous MgSO4. Evaporation of EtOAc solution yielded the desired crude material in various yields. The gummy material was purified by flash column chromatography using hexane: EtOAc (9:1) as eluant to provide the pure ethyl 5-{[4- (substituted)phenylamino] methyl} -2-furoate.
b. Hydrolysis of ethyl ester. The above ethyl 5-{[4-(substituted) phenoxy] methyl} -2-furoate derivative was dissolved in MeOH and IN NaOH in MeOH (5mL) was added and stirred for overnight. The resulting solution was concentrated under vacuum. The resulting solid was dissolved in water and neutralized with 1 N HC1 to get a white fluffy material. This solid was filtered and dried. The crude material was passed through the flash column eluting with EtOAc: MeOH (9:1) resulted in desired pure product. The structure was confirmed by Mass spectra.
c. Preparation of sodium salt of the above carboxylic acid. ImM amount of compound is weighed in to vial and dissolved in MeOH. To this an equimolar amount of IN NaOH in EtOH is added. The ethanol solution was diluted with water. The solution was lyophilized and evaporated under vacuum to get sodium salt as white solid.
Mass Spectra: M+H=308 (m/z=307)
NMR: δ 3.9 (s, 2H, benzyl), 4.5 (s, 2H, -OCH2-furan), 6.4 (s, IH, C4H of furan), 6.6 (m,
2H, aromatic), 7.0 (m, 2H, aromatic), 7.2-7.5 (m, 6H, aromatic). Example 31: Synthesis of 5-{[(4-benzylphenyl)(methyl) amino] methyl} -2-furoic acid.
Figure imgf000054_0001
Preparation of N-methyl (alkyl) derivative. The ethyl ester derivative synthesized in step a) of Example 30 above (1 mmol) is dissolved in DMF (2 mL) is added to the pre cooled solution of NaH (95 %, 1.2 m mol) in DMF (2 mL) at 0°C and stirred at 0 C for 30 minutes. Mel (1.2 m mol) was added to the above solution. The temperature of the reaction was allowed to raise to room temperature and continued the stirring for overnight. The excess NaH was decomposed by adding few drops of MeOH and the solution added to the excess of water. The solid that separated was extracted in to ethyl acetate and the EtOAc extract was washed with water, 5%NaHC03, brine and dried over anhydrous MgSO4. Evaporation of EtOAc solution yielded the desired crude material in ~85 % yield. The crude material was purified by HPLC using a linear gradient of 10-90% acetonitrile in 60 in. Mass and NMR spectra confirmed the resulted desired pure product. Mass Spectra: M+H=322 (m/z=321).
Example 32: Synthesis of 5-(5-{[4-(l,l,3,3-tetramethylbutyl) phenoxy] methyl}-2- furyl)-2H-tetraazole .
Figure imgf000054_0002
A mixture of the nitrile (5-(5-{[4-(l,l,3,3-tetramethylbutyl) phenoxy] methyl}-2- furyl nitrile, lm mol), dibutyltm oxide (0.4 m mol, 0.4eq. and trimethyl silyl azide (1.1 m mol, 1.1 eq) in 30 mL of toluene was stirred at 150 °C for overnight. The solvent was removed under reduced pressure and triturated with diethyl ether to give a solid, which was purified by flash column chromatography to afford the title compound. Mass Spectra: M+H=356 (m/z=355)
NMR: δ 0.7 (s, 9H, t-butyl), 1.35 (s, 6H, gem di methyl), 1.7 (s, 2H, -CH2-), 5.1 (s, 2H,
-OCH2-furan), 6.6 (s, IH, C4H of furan), 6.9 (d, 2H, aromatic), 7.3 (m, 3H, aromatic)
Examples 33-36.
In the following Examples 33-36, the following general procedures were employed to provide the 5-({4 alkyl/aralkyl amino]phenoxy}methyl)-2-furoic acid compounds. a. 4-Methyl aminophenolsulfate (3.44 gm, 10 mmol) was dissolved in Methanol 200 mL and large excess of Dowex strong base ion exchange resin was added to it and stirred vigorously for 30 minutes. Filtered and filtrate was concentrated to give a whitish solid which has single spot on TLC and showed molecular weight 124(M+H).
5 mmol (615 mg ) of the free base was dissolved in 5 % AcOH in MeOH and 2,5,5- trimethyl hexanal was added at room temperature. The mixture was warmed to 60°C and continued stirring at that temperature for 30 minutes and allowed to cool to room temperature. Sodium cyano borohydride in THF (1M solution) 7.5 moles (1.5 equivalents, 7.5 mL) was added to the above reaction mixture and stirring continued for overnight. Reaction was monitored by TLC and Mass spectra. After reaction complete, the excess MeOH was evaporated under vacuum, diluted with water and the extracted in to Ethyl acetate. Ethyl acetate layer was washed with water, brine and dried over anhydrous MgS04. Evaporation of ethyl acetate resulted in 4-methyl-3,5,5-trimethyl hexyl aminophenol. Mass and NMR confirmed the structure.
b. 4-(N-Methyl, N-3,5,5-trimethyl hexyl amino phenol (2mM) is dissolved in 2mL of DMF and 2.5 mM of NaH (95%) in DMF, lmL) is added while stirring at room temperature and stirring continued for 30 minutes. Ethyl-5-chloromethyl-2 furoate (2mM) in lmL of DMF is added to the above solution drop wise and the solution was stirred for 2 hrs. The excess NaH was decomposed by adding few drops of MeOH and the solution added to the excess of water. The solid that separated was extracted in to ethyl acetate and the EtOAc extract was washed with water, 5% NaHCO3, Brine and dried over anhydrous MgSO4. Evaporation of EtOAc solution yielded the desired crude material in -85 % yield. The crude material was passed through the flash column eluting with Hexane:EtOAc (9:1) resulted in desired pure product. The structure was confirmed by Mass and NMR spectra.
c. Hydrolysis of ethyl ester. The above ethyl 5-{[4-(substituted)phenoxy] methyl-2 -furoate derivative was dissolved in EtOH and IN NaOH in EtOH (3mL) was added and stirred for overnight. The resulting solution was concentrated under vacuum. The solid thus resulted dissolved in water and neutralized with 1 N HC1 to get a white fluffy material, which was extracted in ethyl acetate. Concentration and purification of this compound by HPLC using acetonitrile 20-80% linear gradient resulted in pure product. The structure of the compound was confirmed by Mass and NMR. Yield was quantitative in this step.
d. Preparation of Sodium salt of the above carboxylic acid. lmM amount of compound is weighed in to vial and dissolved in EtOH. To this an equimolar amount of IN NaOH in EtOH is added. The ethanolic solution was diluted with water. The solution was lyophilized and evaporated under vacuum to get sodium salt as white solid.
Example 33: Synthesis of 5-({4-[methyl(3,5,5-trimethylhexyl)amino]phenoxy} methyl)-2-furoic acid.
Figure imgf000056_0001
Mass spectra: M+H=374 (m/z=373).
!H NMR: δ 0.8 (s, 9H, t-butyl), 0.9-1.6(m, 7H, aliphatic), 3.1 (s, 3H, N-CH3), 3.3 (m, 2H, -CH2-N-), 5.0 (s, 2H, OCH2-firran), 6.6 (s, IH, C4 H of furan), 7.0 (d, 2H, aromatic), 7.2 (d, 2H, aromatic), 7.3 (s, IH, C3 H of furan). Example 34: Synthesis of 5-({4-[(3,3 dimethylbutyl)(methyl)amino]phenoxy} methyl)-2 -furoic acid.
Figure imgf000057_0001
Mass spectra: M+H=332 (m/z331)
Example 35: Synthesis of 5-({4-[methyl(neopentyl)amino]phenoxy} methyl)-2-furoic acid.
Figure imgf000057_0002
Mass Spectra: M+H=318 (M+ =317)
Example 36: Synthesis of 5-({4-[methyl(3,5-dimethylbenzyl)amino]phenoxy} methyl)-2-furoic acid.
Figure imgf000057_0003
Mass spectra: M+H=368 (m/z = 367)
Example 37: Preparation of Sodium salt of 5-{[(6-butylpyridin-3-yl)oxy]methyl}-2- furoic acid.
Figure imgf000057_0004
Part 1 : Preparation of 6-formylpyridin-3-yl benzenesulfonate.
Figure imgf000058_0001
The title compound was prepared by using literature procedure (Stephen T. Ross et. al. J. Med. Chem., 50:1309 (1987).
Part 2: Preparation of 6-[(lE) and (lZ)-but-l-enyl]pyridin-3-yl benzenesulfonates.
Figure imgf000058_0002
To a suspension of propyltriphenylphosphonium bromide (4.0g, 10 mmol) in THF (25 mL) was added potassium t-butoxide (11.5 mL, 11.5 mmol) at room temperature. The red colored ylide suspension was stirred for 15 min, and cooled to 0°C. Then 6-formyl pyridin-3-yl benzenesulfonate in THF (10 mL) was added drop wise, and stirred for 15 min. Quenched with water (15 mL), extracted with ethyl acetate (200 mL). Dried, concentrated and purified on a silica gel column by eluting with 15% EtOAc-hexane mixture to obtain the product as a mixture of cis and trans olefins (1.9 g, 96%).
^NMR CDCU): δ 0.98-1.12 (2 t), 2.18-2.30 (m), 2.46-2.58 (m), 5.81-5.91(m), 6.29-6.44 (m), 6.66-6.76 (m), 7.14-7.20 (m), 7.30-7.38 (m), 7.48-7.57 (m), 7.63-7.71 (m), 7.78-7.86 (m), 8.0 (d, J= 2.6 Hz), 8.10 (d, J= 2.6 Hz); 13C NMR (CDC13): 13.9, 14.8, 22.9, 26.5, 121.2, 124.1, 126.4, 127.5, 128.3, 129.2, 129.8, 130.3, 134.4, 134.6, 138.6, 139.9, 142.7, 142.9, 143.8, 155.3; MS calcd. for Cι5Hι5NO3S: 289; Found (m/z): 290 (m+1).
Part 3. Preparation of 6-butylpyridin-3-yl benzenesulfonate.
Figure imgf000058_0003
A solution of olefin mixture (750 mg, 2.59 mmol) in ethyl alcohol (25 mL) was hydrogenated using Pd/C (80 mg) at room temperature using a balloon. The suspension was stirred overnight, and filtered. The filtrate was concentrated to obtain 621 mg (82%o) of the saturated compound.
1H NMR (CDCU): δ 0.88 (t, J= 7.9 Hz, 3H), 1.26-1.38 (m, 2H), 1.58-1.70 (m, 2H), 2.74 (t, J= 8.1 Hz, 2H), 7.12 (d, J= 8.8 Hz, IH), 7.33-7.40 (m, IH), 7.48-7.57 (m, 2H), 1.64-1.12 (m, IH), 7.78-7.84 (m, 2H), 8.03 (d, J= 2.9 Hz, IH); 13C NMR (CDC13): 14.6, 23.0, 32.4, 37.7, 123.3, 128.3, 129.2, 130.6, 134.5, 142.2, 144.2, 160.9 ; MS calcd. for Cι5Hι7N03S: 291; Found (m/z): 292 (m+1)
Part 4. Preparation of 6-butylpyridin-3-ol.
Figure imgf000059_0001
To a solution of 6-butylpyridin-3-yl benzenesulfonate (242 mg, 0.83 mmol) in MeOH (4 mL), water (0.3 mL) was added NaOH (70 mg, 1.75 mmol). The resulting solution was heated under microwave oven for 5 min at 80°C in a sealed tube. Then the reaction mixture was concentrated under reduced pressure. The crude so obtained (115 mg, 91%) was used as such for the alkylation with furan carboxylate.
1H NMR (CDCI3): δ 0.85 (t, J= 1.1 Hz, 3H), 1.20-1.40 (m, 2H), 1.50-1.70 (m, 2H), 2.66 (t, J= 8.2 Hz, 2H), 6.96 (d, J= 8.4 Hz, IH), 7.06-7.20 (m, IH), 8.09 (d, J = 2.9 Hz, IH); MS calcd. for C9H13NO : 151; Found (m/z): 152 (m+1)
Part 5. Preparation of ethyl 5- { [(6-butylpyridin-3 -yl)oxy]methyl} -2- furoate.
Figure imgf000059_0002
To a solution of 6-Butylpyridin-3-ol (115 mg, 0.76 mmol) in methanol was added 0.5 M sodium methoxide (0.8 mL), and stirred for lh. The solvent was evaporated and dried under vacuum. 0.5 ml of dry DMF was added to the residue, followed by furan carboxylate (172 mg, 0.9 mmol) in DMF (0.5 ml) under N2 atmosphere. The mixture was stirred overnight. Purified on a silica gel column by eluting with 20% EtOAc-hexane mixture to get the alkylated product (140 mg) in 61% yield.
1H NMR (CDC13): δ 0.88 (t, J= 7.7 Hz, 3H), 1.30 (m, 2H), 1.33 (t, J= 7.3 Hz, 3H), 1.56-1.66 (m, 2H), 2.68 (t, J= 7.7 Hz, 2H), 4.33 (q, 2H), 5.03 (s, 2H), 6.49 (d, J = 3.3 Hz, IH), 7.02 (d, J= 8.6 Hz, IH), 7.10 (d, J= 3.6 Hz, IH), 7.14 (dd, J, = 8.6 Hz, J2 = 2.9 Hz, IH), 8.22 (d, J= 2.9 Hz, IH); 13C NMR (CDC13): 14.7, 15.1, 23.1, 32.7, 37.6, 61.5, 63.1, 111.6, 118.4, 122.3, 122.7, 136.7, 144.7, 151.9, 153.3, 155.2, 158.1 ; MS calcd. for Cι7H2ιNO4: 303; Found (m/z): 304 (m+1).
Part 6. Preparation of sodium salt of 5-{[(6-butylpyridin-3-yl)oxy] methyl} -2-furoic acid.
Figure imgf000060_0001
To a solution of ethyl 5- {[(6-butylpyridin-3-yl)oxy]methyl} -2-furoate (30 mg, 0.098 mmol) in MeOH (4 mL), water (50 μL) was added NaOH (5 mg, 0.13 mmol). The resulting solution was heated under microwave oven for 15 min at 80°C in a sealed tube. Then the reaction mixture was concentrated under reduced pressure to obtain the sodium salt in quantitative yield (30 mg).
JH NMR (CDC13): δ 0.91 (t, J= 7.3 Hz, 3H), 1.26-1.42 (m, 2H), 1.56-1.70 (m, 2H), 2.69 (t, J= 7.7 Hz, 2H), 5.10 (s, 2H), 6.53 (d, J= 3.3 Hz, IH), 6.90 (d, J= 3.3 Hz, IH), 7.20 (d, J= 8.4 Hz, IH), 7.42 (dd, J7 = 8.6 Hz, J2= 3.0 Hz, IH), 8.13 (d, J= 2.9 Hz, IH); 13C NMR (MeOD): 13.6, 22.6, 32.7, 36.7, 62.9, 111.4, 113.8, 123.0, 123.2, 136.2, 150.4, 151.0, 152.8, 154.1, 164.8; MS calcd. for acid Cι5H17NO4: 275; Found (m/z): 276 (m+1). Examples 38-47:
Compounds of Examples 38-47 were prepared as outlined in the following Scheme.
Figure imgf000061_0001
Figure imgf000061_0002
Figure imgf000061_0003
Figure imgf000062_0001
Figure imgf000062_0002
Example 38: Synthesis of methyl 5-({4-[(trifluoroacetyl)amino]phenoxy}methyl)-2- furoate.
Figure imgf000062_0003
To a solution of 4-trifluoroacetoamide phenol (500 mg, 2.44 mmol) and methyl 5-bromomethyl-2-furancarboxylate (694 mg, 3.17 mmol) in 5 mL of anhydrous DMF was added powder K2CO3 at room temperature under Ar. The mixture was then heated at 60°C for 5 hr. After cooling to room temperature, a solution of 10% HCl was added to adjust pH to ~ 5. The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic phase was washed with brine, dried (MgS0 ), concentrated. Chromatography over silica gel, eluted with 1:5 (ethyl acetate: hexanes) to 1: 2 ratio. The desired compound was obtained as a white solid (260 mg). 1HNMR (CDC13) δ 7.48 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 3.3 Hz, IH), 6.98 (d, J = 8.8 Hz, 2H), 6.53 (d, J = 3.3 Hz, IH), 5.05 (s, 2H), 3.90 (s, 3H).
Example 39: Synthesis of methyl 5-[(4-aminophenoxy)methyl]-2-furoate.
Figure imgf000063_0001
To a solution of methyl 5-({4-[(trifluoroacetyl)amino]phenoxy}methyl)-2- furoate (260 mg, 0.76 mmol) in 4 mL of THF and 10 mL of MeOH was added a solution of Na2CO3 in 2 mL of water. The mixture was stirred at 60°C under Ar for 48 hr, then cooled down to room temperature. Water (5 mL) was added. The mixture was extracted with ethyl acetate (3 x 15 mL), the combined organic phase was washed with brine, dried (Na2S04), concentrated. The crude product was subjected to flash chromatography (silica gel, 1:1 ethyl acetate: hexanes). The product was obtained as a white solid (24.5 mg). MS (m/z) 248.0.
Example 40: Synthesis of methyl 5-({4-[(phenylsulfonyl)amino]phenoxy}methyl)-2- furoate.
Figure imgf000063_0002
To a solution of methyl 5-[(4-aminophenoxy)methyl]-2-furoate (25 mg, 0.101 mmol) and pyridine (41 μL, 0.978 mmol) in 2 mL of dichloromethane, was added benzenesulfonylchloride (16 μL, 0.122 mmol) dropwise under Ar. The mixture was stirred overnight at room temperature. To the mixture was added 5 mL of 10% HCl. The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with brine (10 mL), dried (MgS04), concentrated. Flash chromatography (silica gel, 1:1 ethyl acetate: hexanes) afforded 32 mg (82%) of the product as a white solid. 1H MR (CDCI3) δ 7.70 - 7.68 (m, 2H), 7.54 ~ 7.50 (m, IH), 7.43 - 7.40 (m, 2H), 7.14 (d, J = 3.7 Hz, IH), 6.99 ~ 6.96 (m, 2H), 6.80 - 6.78 (m, 2H), 6.49 (d, J = 3.7 Hz, IH), 4.96 (s, 2H), 3.99 (s, 3H).
Example 41 : Synthesis of 5-( {4- [(phenylsulfonyl)amino]phenoxy} methyl)-2-furoic acid.
Figure imgf000064_0001
To 6.2 mg (0.016 mmol) of methyl 5-({4-[(phenylsulfonyl)amino] phenoxy}methyl)-2-furoate was added 0.25 mL of IN NaOH in MeOH, 0.25 mL of THF and two drops of water. The mixture was stirred at room temperature overnight. After concentration, 5 mL of water were added. Ten percent of HCl was used to adjust pH to - 5. After extraction with ethyl acetate (3 x 7 mL), the organic phase was combined, washed with brine (7 mL), dried (MgS0 ), concentrated. The product was obtained (6.0 mg). 1HNMR (CD3OD) δ 7.70 ~ 7.64 (m, 2H), 7.58 ~ 7.51 (m, IH), 7.48 ~ 7.40 (m, 2H), 7.16 - 7.14 (m, IH), 6.99 - 6.94 (m, 2H), 6.88 - 6.80 (m, 2H), 6.56 ~ 6.58 (m, IH), 5.00 (s, 2H). MS (m/z) 373.8.
Example 42: Synthesis of methyl 5-({4-[isopropyl(phenylsulfonyl) amino]phenoxy}methyl)-2-furoate.
Figure imgf000064_0002
To a solution of methyl 5-[(4-aminophenoxy)methyl]-2-furoate (10.9 mg, 0.0281 mmol) in 0.5 L of DMF was added 7.8 mg (0.0563 mmol) of K2C03 and 5.6 μL (0.0563 mmol) of isopropyl iodide. The reaction mixture was stirred at room temperature overnight then at 50°C for 2 hr. After 2 mL of water were added, 5 mL of 10% HCl were added. The mixture was extracted with ethyl acetate (3 x 7 mL). The combined organic layer was washed with brine, then dried (MgS04), concentrated. Flash chromatography (silica gel, 1:3 ethyl acetate: hexanes) afforded 12.0 mg of the product. Rf = 0.26 (1:3 ethyl acetate:hexanes). 1HNMR (CDC13) δ 7.73 - 7.71 (m, 2H), 7.54 ~ 7.50 (m, IH), 7.47 ~ 7.43 (m, 2H), 7.16 (d, J = 3.7 Hz, IH), 6.95 ~ 6.93 (m, 2H), 6.88 - 6.86 (m, 2H), 6.53 (d, J = 3.7 Hz, IH), 5.03 (s, 2H), 4.62 - 4.58 (m, IH), 3.90 (s, 3H), 1.01(d, J = 6.6 Hz, 6H).
Example 43: Synthesis of 5-({4-[Isopropyl(phenylsulfonyl)amino]phenoxy}methyl)-2- furoic acid.
Figure imgf000065_0001
To methyl 5-({4-[isopropyl(phenylsulfonyl)amino]phenoxy}methyl)-2-furoate (12.0 mg, 0.028 mmol) was added 0.75 mL of IN NaOH in MeOH, 0.25 mL of THF and two drops of water. The mixture was stirred at room temperature overnight. After concentration, 5 mL of water were added. Ten percent of HCl was used to adjust pH to ~ 5. After extraction with ethyl acetate (3 x 7 mL), the organic phase was combined, washed with brine (7 mL), dried (MgS0 ), concentrated. The product was obtained (8.5 mg). 1HNMR (CD3OD) δ 7.74 - 7.71 (m, 2H), 7.64 ~ 7.58 (m, IH), 7.56 - 7.53 (m, 2H), 7.18 (d, J = 3.7 Hz, IH), 7.00 - 6.92 (m, 4H), 6.65 (d, J = 3.7 Hz, IH), 5.09 (s, 2H), 4.62 - 4.52 (m, IH), 3.90 (s, 3H), 1.01(d, J = 7.0 Hz, 6H). MS (m/z) 416.3.
Example 44: Synthesis of methyl 5-({4-[ethyl(phenylsulfonyl)amino]phenoxy}methyl)- 2-furoate.
Figure imgf000065_0002
To a solution of methyl 5-({4-[(phenylsulfonyl)amino]phenoxy}methyl)-2- furoate (10.0 mg, 0.0258 mmol) in 0.5 mL of DMF was added 7.1 mg (0.0516 mmol) of K2C03 and ethyl iodide (6.0 μL, 0.0788 mmol). The mixture was stirred overnight then 50 °C for 1 hr. To the cooled reaction mixture was added 2 mL of water and 5 mL of 10% HCl. After extraction with ethyl acetate (3 x 7 mL), the combined organic phase was washed with brine, dried (MgS0 ). After concentration, flash chromatography (silica gel, 1:3 ethyl acetate :hexanes) afforded 10.6 mg of the desired product. 1HNMR (CDC13) δ 7.62 ~ 7.54 (m, 3H), 7.48 ~ 7.42 (m, 2H), 7.16 (d, J = 3.1 Hz, IH), 6.98 - 6.90 (m, 2H), 6.88 ~ 6.82 (m, 2H), 6.53 (d, J = 3.1 Hz, IH), 5.03 (s, 2H), 3.89 (s, 3H), 3.56 (q, J = 7.0 Hz, 2H), 1.05(t, J = 7.0 Hz, 3H).
Example 45: Synthesis of 5-({4-[ethyl(phenylsulfonyl)amino]phenoxy}methyl)-2-furoic acid.
Figure imgf000066_0001
To methyl 5-({4-[ethyl(phenylsulfonyl)amino]phenoxy}methyl)-2-furoate (11.0 mg, 0.03 mmol) was added 0.5 mL of IN NaOH in MeOH, 0.5 mL of THF and four drops of water. The mixture was stirred at room temperarture overnight. After concentration, 5 mL of water were added. Ten percent of HCl was used to adjust pH to - 5. After extraction with ethyl acetate (3 x 7 mL), the organic phase was combined, washed with brine (7 mL), dried (MgS04), concentrated. The product was obtained (11.0 mg). 1HNMR (CD3OD) δ 7.70 ~ 7.50 (m, 5H), 7.18 (d, J = 3.3 Hz, IH), 7.05 ~ 6.90 (m, 4H), 6.63 (d, J = 3.3 Hz, IH), 5.03 (s, 2H), 3.89 (s, 3H), 3.56 (q, J = 7.0 Hz, 2H), 1.05(t, J = 7.0 Hz, 3H). MS (m/z) 402.1. Example 46: Synthesis of ethyl 5-{[4-(l,l-diphenylpropyl)phenoxy]methyl}-2-furoate.
* 0_ - ~- -rCOOC2H5
Figure imgf000067_0001
To 16.6 mg (0.416 mmol) of NaH (60% in mineral oil) suspension in 2 mL of anhydrous DMF was added 4-(l,l-diphenylpropyl)phenol in 2 mL of DMF at 0°C. After stirring for 0.5 hr, ethyl 5-chloromethyl-2-furancarboxylate was added dropwise. The mixture was stirred overnight warming up to room temperature. Three mL of water were added, followed by 7 mL of 10% HCl. The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic phase was washed with brine, dried (MgS04), concentrated. Flash chromatography (silica gel, 1:10 ethyl acetate :hexanes) afforded 129 mg of the desired product. 1HNMR (CDC13) δ 7.35 ~ 7.15 (m, 13H), 6.83 (d, J = 9.1 Hz, 2H), 6.50 (d, J = 3.3 Hz, IH), 5.02 (s, 2H), 2.60 (q, J = 7.3 Hz, 2H), 0.85 (t, J = 7.3 Hz, 3H).
Example 47: Synthesis of 5-{[4-(l,l-diphenylpropyl)phenoxy]methyl}-2-furoic acid.
Figure imgf000067_0002
To ethyl 5-{[4-(l,l-diphenylpropyl)phenoxy]methyl}-2-furoate (124 mg, 0.28 mmol) was added 5 mL of IN NaOH in MeOH, 5 mL of THF and 1 mL of water. The mixture was stirred at room temperature overnight. After concentration, 5 mL of water were added. Ten percent of HCl was used to adjust pH to ~ 5. After extraction with ethyl acetate (3 x 15 mL), the organic phase was combined, washed with brine (15 mL), dried (MgS04), concentrated. The product was obtained (100 mg). 1HNMR (CDCI3) δ 7.35 ~ 7.10 (m, 13H), 6.89 (d, J = 9.1 Hz, 2H), 6.60 (d, J = 3.3 Hz, IH), 5.05 (s, 2H), 2.62 (q, J = 7.3 Hz, 2H), 0.73 (t, J = 7.3 Hz, 3H).
Examples 48-51:
Compounds of Examples 48-51 were prepared as outlined in the following Scheme.
Figure imgf000068_0001
Example 48: Synthesis of ethyl 5-[(4-benzoylphenoxy)methyl]-2-furoate.
Figure imgf000068_0002
To a suspension of NaH ( 242 mg of 60%, 6.05 mmol) in 25 mL of dry DMF at 0 °C was added a solution of (4-hydroxyphenyl)(phenyl)methanone (1.00 g, 5.04 mmol) in 5 mL of DMF. After stirred at 0°C for 0.5 hour, neat ethyl 5-(chloromethyl) -2- furancarboxylate (0.93 mL, 6.05 mmol) were added dropwise. The mixture was stirred overnight, warming up to room temperature. The mixture was then concentrated. After addition of water (10 mL), it was extracted with EtOAc (3 x 30 mL). The combined organic phase was washed with brine, dried (MgS04), concentrated. Flash chromatography (silica gel, 1:10 EtOAc/Hexanes) afforded the product (0.765 g, 48%). MS (m/z) 351 (M + H).
Example 49: Synthesis of ethyl 5-({4-[hydroxy(phenyl)methyl]phenoxy}methyl)-2- furoate.
Figure imgf000069_0001
To a solution of ethyl 5-[(4-benzoylphenoxy)methyl]-2-furoate (200 mg, 0.57 mmol) in 9 mL of EtOH and 9 mL of water was added CeCl3-7H20 (213 mg, 0.57 mmol). To this stirred mixture at 0°C was added 32 mg of NaBIL, the mixture was stirred 2 hr. the reaction mixture was then diluted with EtOAc, extracted with EtOAc (3 x 40 mL), the combined organic phase was washed with brine (40 mL), dried (NaS04). The crude product was obtained after concentration. Flash chromatography (silica gel, 1 :2 EtOAc/Hexanes) afforded the product (168 mg, 84%), MS (m/z) 375 (M + Na).
Example 50: Synthesis of 5-({4-[hydroxy(phenyl)methyl]phenoxy}methyl)-2-furoic acid.
Figure imgf000069_0002
Ethyl 5-({4-[hydroxy(phenyl)methyl]phenoxy}methyl)-2-furoate (50 mg, 0.142 mmol) was dissolved in 2.2 mL of THF and 1 mL of water. To this mixture was added 2.2 mL of 1.0 M. NaOH in MeOH. After stirring overnight, the mixture was concentrated. Water (10 mL) were added, the pH was adjusted to ~4 with 10% aq. HCl. After extraction the mixture with EtOAc (3 x 10 mL), the combined organic phase was washed with brine, dried (MgS04), concentrated. Thus obtained the product (quantitative). 1HNMR (CD30D) δ 7.20-7.40 (m, 8H), 6.92 (d, J = 8.8 Hz, 2H), 6.54 (d, J = 3.7 Hz, IH), 5.81 (s, IH), 5.06 (s, 2H). MS (m z) 307 (M - H2O). Example 51: Synthesis of 5-[(4-benzoylphenoxy)methyl]-2-furoic acid.
Figure imgf000070_0001
Ethyl 5-[(4-benzoylphenoxy)methyl]-2-furoate (200 mg, 0.57 mmol) was dissolved in 8.6 mL of THF and 4 mL of water. To this mixture was added 8.6 mL of 1.0 M. NaOH in MeOH. After stirring overnight, the mixture was concentrated. Water (10 mL) were added, the pH was adjusted to ~4 with 10% aq. HCl. After extraction the mixture with EtOAc (3 x 10 mL), the combined organic phase was washed with brine, dried (MgS04), concentrated. Thus obtained the product (quantitative). 1HNMR (CD30D) δ 7.83 (d, J = 8.8 Hz, 2H), 7.72-7.78 (m, 2H), 7.53-7.60 (m, IH), 7.45-7.50 (m, 2H), 7.31 (d, J = 3.3 Hz, IH), 7.02 (d, J = 8.7 Hz, 2H), 6.61 (d, J = 3.3 Hz, IH), 5.16 (s, 2H). MS (m/z) 323 (M + H).
Examples 52-53:
Compounds of Examples 52-53 were prepared as outlined in the following Scheme.
Figure imgf000070_0002
Example 52: Synthesis of ethyl 5- {[4-(methoxymethyl)phenoxy]methyl} -2-furoate.
Figure imgf000070_0003
To a suspension of NaH ( 173 mg of 60%, 4.34 mmol) in 15 mL of dry DMF at 0°C was added a solution of 4-(methoxymethyl)phenol (500 mg, 3.62 mmol) in 5 L of DMF. After stirred at 0°C for 0.5 hour, neat ethyl 5-(chloromethyl) -2- furancarboxylate (0.67 mL, 4.34 mmol) were added dropwise. The mixture was stirred overnight, warming up to room temperature. The mixture was then concentrated. After addition of water (40 mL), it was extracted with EtOAc (3 x 50 mL). The combined organic phase was washed with brine, dried (MgS04), concentrated. Flash chromatography (silica gel, 1:4 EtOAc/Hexanes) afforded the product (0.804 g, 77%). 1HNMR (CDC13) δ 7.26 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 3.7 Hz, IH), 6.92 (d, J = 8.8 Hz, 2H), 6.50 (d, J = 3.7 Hz, IH), 5.05 (s, 2H), 4.30-4.45 (m, 4H), 3.35 (s, 3H), 1.37 (t, J = 7.3 Hz, 3H).
Example 53: Synthesis of 5- {[4-(methoxymethyl)phenoxy]methyl} -2-furoic acid.
Figure imgf000071_0001
Ethyl 5- {[4-(methoxymethyl)phenoxy]methyl} -2-furoate (200 mg, 0.69 mmol) was dissolved in 10 mL of THF and 5 mL of water. To this mixture was added 10 mL of 1.0 M NaOH in MeOH. After stirring overnight, the mixture was concentrated. Water (20 mL) were added, the pH was adjusted to -4 with 10% aq. HCl. After extraction the mixture with EtOAc (3 x 150 mL), the combined organic phase was washed with brine, dried (MgS04), concentrated. Thus obtained the product (200 mg, quantitative). 1HNMR (CD30D) δ 7.27 (d, J = 3.3 Hz, 2H), 7.25 (d, J = 8.5 Hz, IH), 6.92 (d, J = 8.5 Hz, 2H), 6.56 (d, J = 3.3 Hz, IH), 5.07 (s, 2H), 4.39 (s, 2H), 3.35 (s, 3H).
Examples 54-57:
Compounds of Examples 54-57 were prepared as outlined in the following Scheme.
Figure imgf000072_0001
Example 54: Synthesis of ethyl 5-[(4-butyrylphenoxy)methyl]-2-furoate.
Part 1. Synthesis of l-(4-hydroxyphenyl)butan-l-one.
Figure imgf000072_0002
To 4-methoxy butyrophenone (5.00 g, 28.1 mmol) in 50 mL of anhydrous DCM at - 78°C was added BBr3 (1.0 M in DCM, 68 mL, pre-cooled at - 78°C dropwise via cannula. After addition was complete, the cold bath was removed, and the reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched with 100 mL of sat. aq. NaHC03 at - 78°C, and allowed to warm to rt. It was extracted with ether (3 x 150 mL). The combined ether phase were combined and washed with brine (100 mL), dried (MgS04), concentration and flash chromatography afforded the product (2.2 g, 44%). 'HNMR (CDC13) δ 7.90 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 2.89 (t, J = 7.3 Hz, 2H), 1.26 (s, 6H), 1.70- 1.80 (m, 2H), 0.99 (t, J = 7.7 Hz, 3H). MS (m/z) 165 (M + H). Part 2. Synthesis of ethyl 5-[(4-butyrylphenoxy)methyl]-2-furoate.
Figure imgf000073_0001
To a suspension of NaH ( 48 mg of 60%, 1.23 mmol) in 5 mL of dry DMF at 0°C was added a solution of l-(4-hydroxyphenyl)butan-l-one (200 mg, 1.22 mmol) in 2 mL of DMF. After stirred at 0°C for 0.5 hour, neat ethyl 5-(chloromethyl) -2- furancarboxylate (0.19 mL, 1.23 mmol) were added dropwise. The mixture was stirred overnight, warming up to room temperature. The mixture was then concentrated. After addition of water (3 mL), it was extracted with EtOAc (3 x 10 mL). The combined organic phase was washed with brine, dried (MgS04), concentrated. Flash chromatography (silica gel, 1:10 EtOAc Hexanes) afforded the product (253 mg, 66%). !HNMR (CDC13) δ 7.94 (d, J = 6.6 Hz, 2H), 7.15 (d, J = 3.2 Hz, IH), 6.98 (d, J = 6.6 Hz, 2H), 6.54 (d, J = 3.2 Hz, IH), 5.10 (s, 2H), 4.36 (q, J = 7.7 Hz, 2H), 2.89 (t, J = 7.3 Hz, 2H), 1.70-1.80 (m, 2H), 1.37 (t, J = 7.2 Hz, 3H), 1.00 (t, J = 7.4 Hz, 3H). MS (m/z) 317 (M + H).
Example 55: Synthesis of 5-[(4-butyrylphenoxy)methyl]-2-furoic acid.
Figure imgf000073_0002
Ethyl 5-[(4-butyrylphenoxy)methyl]-2-furoate (50 mg, 0.16 mmol) was dissolved in 1 mL of THF and 1 mL of MeOH. To this mixture was added 0.2 mL of 1.0 M NaOH in MeOH. After stirring overnight, the mixture was concentrated. Water (2 mL) were added, the pH was adjusted to ~6 with 10% aq. HCl. After extraction the mixture with EtOAc (3 x 10 mL), the combined organic phase was washed with brine, dried (MgS04), concentrated. The title compound was thus obtained (41 mg, quantitative). 1HNMR (CD30D) δ 7.96 (d, J = 9.1 Hz, 2H), 7.07 (d, J = 9.1 Hz, IH), 6.93 (d, J = 3.3 Hz, 2H), 6.55 (d, J = 3.3 Hz, IH), 5.14 (s, 2H), 2.93 (t, J = 7.3 Hz, 2H), 1.69-1.73 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H). MS (m z) 289 (M + H). Example 56: Synthesis of ethyl 5-{[4-(l-hydroxybutyl)phenoxy]methyl}-2-furoate.
Figure imgf000074_0001
To a solution of ethyl 5-[(4-butyrylphenoxy)methyl]-2-furoate (100 mg, 0.32 mmol) in 4.5 mL of EtOH and 4.5 mL of water was added CeCl3-7H20 (118 mg, 0.32 mmol). To this stirred mixture at 0°C was added 60 mg of NaBH (5 eq), the mixture was stirred 2 hr. The reaction mixture was then diluted with EtOAc (10 mL), extracted with EtOAc (3 x 20 mL), the combined organic phase was washed with brine (20 mL), dried (NaS0 ). The crude product was obtained after concentration. Flash chromatography (silica gel, 1:4 EtOAc/Hexanes) afforded the product (78 mg, 78%), 1HNMR (CDC13) δ 7.26 (d, J = 6.6 Hz, 2H), 7.14 (d, J = 3.7 Hz, IH), 6.92 (d, J = 6.6 Hz, 2H), 6.54 (d, J = 3.3 Hz, IH), 5.04 (s, 2H), 4.62 (t, J = 6.2 Hz, IH), 4.35 (q, J = 7.3 Hz, 2H), 1.70 - 1.85 (m, 2H), 1.59-1.69 (m, IH), 1.36 (t, J = 7.2 Hz, 3H), 1.20-1.32 (m, IH), 0.90 (t, J = 7.3 Hz, 3H). MS (m/z) 341 (M + Na).
Example 57: Synthesis of 5-{[4-(l-hydroxybutyl)phenoxy]methyl}-2-furoic acid.
Figure imgf000074_0002
Ethyl 5-{[4-(l-hydroxybutyl)phenoxy]methyl}-2-furoate (56 mg, 0.18 mmol) was dissolved in 2.5 mL of THF and 2.5 mL of MeOH. To this mixture was added 1 mL of 1.0 M aq. NaOH. After stirring overnight, the mixture was concentrated. Water (10 L) were added, the pH was adjusted to ~6 with 10% aq. HCl. After extraction the mixture with EtOAc (3 x 10 mL), the combined organic phase was washed with brine, dried (MgS04), concentrated. Thus obtained the product (54 mg, quantitative). 1HNMR (CD30D) δ 7.23 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 3.3 Hz, IH), 6.96 (d, J = 8.8 Hz, 2H), 6.74 (d, J = 3.3 Hz, IH), 5.10 (s, 2H), 4.45 (t, J = 6.6 Hz, IH), 1.40-1.65 (m, 2H), 1.10- 1.35 (m, 2H), 0.85 (t, J = 7.0 Hz, 3H). MS (m/z) 313 (M + Na). Examples 58-59:
Compounds of Examples 58-59 were prepared as outlined in the following Scheme.
Figure imgf000075_0001
N Mae0OHH/THF/water
Figure imgf000075_0003
Figure imgf000075_0002
Example 58 : Synthesis of ethyl 5- { [4-( 1 , 1 -dimethylbutyl)phenoxy]methyl} -2-furoate.
Part 1. Synthesis of 1 -(1 , 1 -Dimethylbutyl)-4-methoxybenzene.
Figure imgf000075_0004
To 77 L of dry dichloromethane was added 28 mL of 1.0 M TiC (28.1 mmol) in dichloromethane under Ar. To this cooled solution at - 30°C was added 28 mL of 2.0 M AlMβ3 (56.1 mmol) in toluene dropwise under Ar. The mixture was then stirred for 20 min at - 30°C, then cooled down to - 45°C. To this solution was added 4-methoxy butyrophenone (5.00 g, 28.1 mmol) in 35 mL of dry dichloromethane (solution pre- cooled at - 45°C) via cannula dropwise. The reaction mixture was allowed to warm to room temperature overnight while stirring continued. After 12 hr, the mixture was recooled down to - 45 °C, water was added dropwise to the mixture (a lot of gas coming off) while stirred vigorously. After warming up to room temperature, the mixture was diluted with ether (200 mL), 2N HCl (~ 60 mL). After separation, the aq. phase was extracted with ether (3 x 200 mL). Combined ether layer was washed with brine, dried (MgS0 ), concentrated. Flash chromatography over silica gel (eluted with hexanes to 2% EtOAc in hexanes) afforded the product (4.47 g, 83%). 1HNMR (CDC13) δ 7.24 (d, J = 9.1 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 3.79 (s, 3H), 1.50-1.60 ( , 2H), 1.26 (s, 6H), 1.05-1.15 (m, 2H), 0.81 (t, J = 7.3Hz, 3H).
Part 2. Synthesis of 4-(l,l-Dimethylbutyl)phenol.
Figure imgf000076_0001
To l-(l,l-dimethylbutyl)-4-methoxybenzene (1.00 g, 5.20 mmol), and n-Bu NI (2.11 g, 5.72 mmol) in 25 mL of dry dichloromethane at - 78°C was added 7.8 mL of 1.0 M BCI3 in dichloromethane dropwise under Ar. After stirred for 15 min at - 78°C, the mixture was allowed to warm to room temperature and stirred for 2 hours. TLC (1 :2 EtOAc/Hexanes) indicated the reaction was complete. After the reaction mixture was cooled again to - 78°C, 50 mL of sat. aq. NaHCθ3 were added dropwise. The mixture was allowed to warm to room temperature overnight. After separation, the aq. phase was extracted with dichloromethane (2 x 50 mL). The combined organic phase was washed with brine (50 mL), dried (MgS0 ), concentrated. Purification of the crude compound with flash chromatography (silica gel, 1:6 EtOAc/Hexanes) afforded 864 mg (93%) of the product. The TLC was stained with KMnO4. 1HNMR (CDCI3) δ 7.19 (d, J = 8.4 Hz, 2H), 6.76 (d, J = 8.4 Hz, 2H), 1.50-1.60 (m, 2H), 1.26 (s, 6H), 1.05-1.15 (m, 2H), 0.81 (t, J = 7.2Hz, 3H).
Part 3. Synthesis of ethyl 5-{[4-(l,l-dimethylbutyl)phenoxy]methyl}-2-furoate.
Figure imgf000076_0002
To a suspension of NaH ( 233 mg of 60%, 5.82 mmol) in 20 mL of dry DMF at 0°C was added a solution of 4-(l,l-dimethylbutyl)phenol (864 mg, 4.85 mmol) in 5 mL of DMF. After stirred at 0°C for 0.5 hour, neat ethyl 5-(chloromethyl) -2- furancarboxylate (0.90 mL, 5.82 mmol) were added dropwise. The mixture was stirred overnight, warming up to room temperature. The mixture was then concentrated. After addition of water (10 mL), it was extracted with EtOAc (3 x 30 mL). The combined organic phase was washed with brine, dried (MgS04), concentrated. Flash chromatography (silica gel, 1:10 EtOAc Hexanes) afforded the product (0.765 g, 48%). !HNMR (CDC13) δ 7.23 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 3.6 Hz, IH), 6.87 (d, J = 8.8 Hz, 2H), 6.51 (d, J = 3.7 Hz, IH), 5.03 (s, 2H), 4.36 (q, J = 7.3 Hz, 2H), 1.50-1.55 (m, 2H), 1.37 (t, J = 7.2 Hz, 3H), 1.25 (s, 6H), 1.00-1.10 (m, 2H), 0.80 (t, J = 7.2Hz, 3H). MS (m/z) 353.7 (M + Na).
Example 59: Synthesis of 5-{[4-(l,l-dimethylbutyl)phenoxy]methyl}-2-furoic acid.
Figure imgf000077_0001
Ethyl 5-{[4-(l,l-dimethylbutyl)phenoxy]methyl}-2-furoate (738 mg, 2.23 mmol) was dissolved in 7 mL of THF and 10 mL of MeOH. To this mixture was added 5 mL of 1.0 M aq. NaOH. After stirring overnight, the mixture was concentrated. Water (20 mL) were added, the pH was adjusted to -4 with 10% aq. HCl. After extraction the mixture with EtOAc (3 x 150 mL), the combined organic phase was washed with brine, dried (MgS04), concentrated. Thus obtained the product (625 mg, 93%). 1HNMR (CD3OD) δ 7.24 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 3.6 Hz, IH), 6.91 (d, J = 8.8 Hz, 2H), 6.60 (d, J = 3.7 Hz, IH), 5.05 (s, 2H), 1.50-1.55 (m, 2H), 1.25 (s, 6H), 1.00-1.10 (m, 2H), 0.80 (t, J = 7.3Hz, 3H). MS (m/z) 325 (M + Na).
Examples 60-61:
Compounds of Examples 60-61 were prepared as outlined in the following Scheme.
Figure imgf000078_0001
Example 60: Synthesis of ethyl 5-{[4-(l-cyclohexyl-l-methylethyl)phenoxy]methyl}-2- furoate.
Part 1. Synthesis of Cyclohexyl(4-methoxyphenyl)methanone.
Figure imgf000078_0002
To graphite (2.3 g, Aldrich # 28286-3) in 115 mL of dry 1,2-dichloroethane was added 5.0 mL (46.2 mmol) of anisole, followed by cyclohexane carbonyl chloride (9.3 mL, 69.4 mmol) dropwise. The mixture was heated in an oil bath to reflux under Ar for 6 hours. After filtered through Celite, washed with dichloromethane, the combined organic phase was washed with sat. aq. NaHC03. The organic phase was then dried (Na2S04), concentiated. Flash chromatography over silica gel, elution with 1:18 EtOAc/Hexanes afforded the product 7.9 g (79%), Rf = 0.33 (1:9 EtOAC/Hexanes). •HNMR (CDC13) δ 7.92 (d, J = 6.9 Hz, 2H), 6.91 (d, J = 7.0 Hz, 2H), 3.86 (s, 3H), 3.15- 3.25 (m, IH), 1.20-1.90 (m, 10H). MS (m/z) 219.1 (M + H). Part 2. Synthesis of l-(l-Cyclohexyl-l-methylethyl)-4-methoxybenzene.
Figure imgf000079_0001
To 12 mL of dry dichloromethane was added 4.6 mL of 1.0 M TiCl (4.6 mmol) in dichloromethane under Ar. To this cooled solution at - 30°C was added 4.6 mL of 2.0 M AlMe3 (9.6 mmol) in toluene dropwise under Ar. The mixture was then stirred for 20 min at - 30°C, then cooled down to - 45°C. To this solution was added cyclohexyl(4-methoxyphenyl)methanone (1.00 g, 4.6 mmol) in 6 mL of dry dichloromethane (solution pre-cooled at - 45°C) via cannula dropwise. The reaction mixture was allowed to warm to room temperature overnight while stirring continued. After 12 hr, the mixture was recooled down to - 45°C, water was added dropwise to the mixture (a lot of gas coming off) while stirred vigorously. After warming up to room temperature, the mixture was diluted with ether (100 mL), 2N HCl (30 mL). After separation, the aq. phase was extracted with ether (2 x 150 mL). Combined ether layer was washed with brine, dried (MgS04), concentrated. Flash chromatography over silica gel (eluted with hexanes to 4% EtOAc in hexanes) afforded the product (0.993 g, 93%). 1HNMR (CDC13) δ 7.21 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 9.2 Hz, 2H), 3.78 (s, 3H), 1.20- 1.75 (m, 6H), 1.22 (s, 6H), 0.80-1.20 (m, 5H).
Part 3. Synthesis of 4-(l-cyclohexyl-l-methylethyl)phenol.
Figure imgf000079_0002
To 1-(1 -cyclohexyl- l-methylethyl)-4-methoxybenzene (933 mg, 4.02 mmol), and n-Bu4NI (1.63 g, 4.42 mmol) in 25 mL of dry dichloromethane at - 78 °C was added 6.0 mL of 1.0 M BCI3 in dichloromethane dropwise under Ar. After stirred for 15 min at - 78°C, the mixture was allowed to warm to room temperature and stirred for 2 hours. TLC (1:2 EtOAc/Hexanes) indicated the reaction was complete. After the reaction mixture was cooled again to - 78°C, 50 mL of sat. aq. NaHC03 were added dropwise. The mixture was allowed to warm to room temperature overnight. After separation, the aq. phase was extracted with dichloromethane (3 x 50 mL). The combined organic phase was washed with brine (50 mL), dried (MgS0 ), concentrated. Purification of the crude compound with flash chromatography (silica gel, 1:6 EtOAc/Hexanes) afforded 746 mg (85%) of the product. !HNMR (CDC13) δ 7.16 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 8.4 Hz, 2H), 1.20-1.75 (m, 6H), 1.22 (s, 6H), 0.80-1.20 (m, 5H).
Part 4. Synthesis of ethyl 5-{[4-(l-cyclohexyl-l-methylethyl)phenoxy] methyl}- 2-furoate.
Figure imgf000080_0001
To a suspension of NaH (150 mg of 60%, 3.76 mmol) in 15 mL of dry DMF at 0°C was added a solution of 4-(l -cyclohexyl- l-methylethyl)phenol (686 mg, 3.14 mmol) in 5 mL of DMF. After stirred at 0°C for 0.5 hour, neat ethyl 5-(chloromethyl) -2- furancarboxylate 0.58 mL, 3.76 mmol) were added dropwise. The mixture was stirred overnight, warming up to room temperature. The mixture was then concentrated. After addition of water (10 mL), it was extracted with EtOAc (3 x 25 mL). The combined organic phase was washed with brine, dried (MgS0 ), concentrated. Flash chromatography (silica gel, 1:10 EtOAc/Hexanes) afforded the product (0.896 g, 77%). 1HNMR (CDCI3) δ 7.23 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 3.6 Hz, IH), 6.87 (d, J = 8.8 Hz, 2H), 6.51 (d, J = 3.7 Hz, IH), 5.04 (s, 2H), 4.35 (q, J = 7.3 Hz, 2H), 1.45-1.70 (m, 5H), 1.37 (t, J = 7.2 Hz, 3H), 1.25 (s, 6H), 0.80-1.20 (m, 6H).
Example 61: Synthesis of 5-{[4-(l-cyclohexyl-l-methylethyl)phenoxy]methyl}-2-furoic acid.
Figure imgf000080_0002
Ethyl 5-{[4-(l-cyclohexyl-l-methylethyl)phenoxy]methyl}-2-furoate (896 mg, 2.42 mmol) was dissolved in 5 mL of THF and 10 mL of MeOH. To this mixture was added 4.8 mL of 1.0 M aq. NaOH. After stirring overnight, the mixture was concentrated. Water (20 mL) were added, the pH was adjusted to ~4 with 10% aq. HCl. After extraction the mixture with EtOAc (3 x 150 mL), the combined organic phase was washed with brine, dried (MgS0 ), concentrated. Thus obtained the product (691 mg, 83%). 1HNMR (CD3OD) δ 7.24 (d, J = 9.0 Hz, 2H), 7.18 (d, J = 3.3 Hz, IH), 6.90 (d, J = 9.0 Hz, 2H), 6.61 (d, J = 3.3 Hz, IH), 5.05 (s, 2H), 1.45-1.70 (m, 5H), 1.19 (s, 6H), 0.80- 1.20 (m, 6H). MS (m z) 365 (M + Na).
Examples 62-67:
Compounds of Examples 62-67 were prepared as outlined in the following Scheme.
Figure imgf000081_0001
Figure imgf000081_0002
Example 62: Synthesis of ethyl 5-{[4-(4,4,5,5-tetramethyl-l,3-dioxolan-2-yl)phenoxy] methyl} -2-furoate.
Figure imgf000082_0001
To a suspension o NaH (11 mg of 60%, 0.27 mmol) in 4 mL of dry DMF at 0 °C was added a solution of 4-(4,4,5,5-tetramethyl-l,3-dioxolan-2-yl)phenol (50 mg, 0.22 mmol) in 1 mL of DMF. After stirred at 0°C for 0.5 hour, neat ethyl 5-(chloromethyl) - 2- furancarboxylate (0.042 mL, 0.27 mmol) were added dropwise. The mixture was stirred overnight, warming up to room temperature. The mixture was then concentrated. After addition of water (10 mL), it was extracted with EtOAc (3 x 25 mL). The combined organic phase was washed with brine, dried (MgS04), concentrated. Flash chromatography (silica gel, 1:5 EtOAc/Hexanes) afforded the product (52 mg, 63%). 1HNMR (CDC13) δ 7.61-7.63 (m, IH), 7.20-7.30 (m, IH), 7.12 (d, J = 4.0 Hz, IH), 6.95- 7.05 (m, IH), 6.85-6.95 (m, IH), 6.49 (d, J = 3.6 Hz, IH), 6.31 (s, IH), 5.13 (s, 2H), 4.34 (q, J = 7.0 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H), 1.13 (s, 6H), 1.27(s, 6H). MS (m z) 397 (M + Na).
Example 63: Synthesis of 5-{[4-(4,4,5,5-tetramethyl-l,3-dioxolan-2-yl)phenoxy] methyl} -2-furoic acid.
Figure imgf000082_0002
Ethyl 5-{[4-(4,4,5,5-tetramethyl-l,3-dioxolan-2-yl)phenoxy]methyl}-2-furoate (52 mg, 0.14 mmol) was dissolved in 1 mL of THF and 1 mL of MeOH. To this mixture was added 0.35 mL of 1.0 M aq. NaOH. After stirring overnight, the mixture was concentrated. Water (2 mL) were added, the pH was adjusted to -6 with 10% aq. HCl. After extraction the mixture with EtOAc (3 x 5 mL), the combined organic phase was washed with brine, dried (MgS0 ), concentrated. Thus obtained the product (42 mg, 86%). JHNMR (CD3OD) δ 7.58-7.60 (m, IH), 7.28-7.35 (m, IH), 7.17 (d, J = 3.7 Hz, IH), 7.08-7.15 (m, IH), 6.97-7.03 (m, IH), 6.61(d, J = 3.3 Hz, IH), 6.26 (s, IH), 5.15 (s, 2H), 1.13 (s, 6H), 1.27(s, 6H). MS (m/z) 369 (M + Na).
Example 64: Synthesis of ethyl 5-{[4-(l,3,4-oxadiazol-2-yl)phenoxy]methyl}-2-furoate.
Figure imgf000083_0001
To a suspension of NaH (15 mg of 60%, 0.37 mmol) in 4 mL of dry DMF at 0°C was added a solution of 4-(l,3,4-oxadiazol-2-yl)phenol (50 mg, 0.31 mmol) in 1 mL of DMF. After stirred at 0°C for 0.5 hour, neat ethyl 5-(chloromethyl) -2- furancarboxylate (0.057 mL, 0.37 mmol) were added dropwise. The mixture was stirred overnight, warming up to room temperature. The mixture was then concentrated. After addition of water (10 mL), it was extracted with EtOAc (3 x 25 mL). The combined organic phase was washed with brine, dried (MgS04), concentrated. Flash chromatography (silica gel, 1:5 EtOAc/Hexanes) afforded the product (34 mg, 35%). 1HNMR (CDC13) δ 8.42 (s, IH), 8.00 (d, J = 8.8 Hz, IH), 7.15 (d, J = 3.3 Hz, IH), 7.06 (d, J = 8.8 Hz, IH), 6.55 (d, J = 3.6 Hz, IH), 5.13 (s, 2H), 4.37 (q, J = 7.3 Hz, 2H), 1.36 (t, J = 6.9 Hz, 3H). MS (m/z) 337 (M + Na).
Example 65: Synthesis of 5-{[4-(l,3,4-oxadiazol-2-yl)phenoxy]methyl}-2-furoic acid.
Figure imgf000083_0002
Ethyl 5-{[4-(l,3,4-oxadiazol-2-yl)phenoxy]methyl}-2-furoate (34 mg, 0.11 mmol) was dissolved in 1 mL of THF and 1 mL of MeOH. To this mixture was added 0.28 mL of 1.0 M aq. NaOH. After stirring overnight, the mixture was concentrated. Water (2 mL) were added, the pH was adjusted to ~6 with 10% aq. HCl. After extraction the mixture with EtOAc (3 x 5 mL), the combined organic phase was washed with brine, dried (MgS04), concentrated. Thus obtained the product (23 mg, 73%). ]HNMR (CD3OD) δ 8.95 (s, IH), 8.02 (d, J = 8.8 Hz, IH), 7.10-7.25 (m, 3H), 6.68 (d, J = 3.6 Hz, IH), 5.21 (s, 2H). MS (m z) 287.3 (M + H). Example 66: Synthesis of ethyl 5- {[4-(l,3-benzoxazol-2-yl)phenoxy]methyl} -2-furoate.
Figure imgf000084_0001
To a suspension of NaH (11.2 mg of 60%, 0.28 mmol) in 4 mL of dry DMF at 0°C was added a solution of 4-(l,3-benzoxazol-2-yl)phenol (50 mg, 0.24 mmol) in 1 mL of DMF. After stirred at 0°C for 0.5 hour, neat ethyl 5-(chloromethyl) -2- furancarboxylate (0.044 mL, 0.28 mmol) were added dropwise. The mixture was stirred overnight, warming up to room temperature. The mixture was then concentrated. After addition of water (10 mL), it was extracted with EtOAc (3 x 25 mL). The combined organic phase was washed with brine, dried (MgS0 ), concentrated. Flash chromatography (silica gel, 1:5 EtOAc/Hexanes) afforded the product (46 mg, 53%). 1HNMR (CDC13) δ 8.20 (d, J = 8.8 Hz, 2H), 7.70- 7.80 (m, IH), 7.50-7.60 (m, IH), 7.30-7.40 (m, 2H), 7.16 (d, J = 3.7 Hz, IH), 7.08 (d, J = 8.8 Hz, IH), 6.56 (d, J = 3.6 Hz, IH), 5.15 (s, 2H), 4.36 (q, J = 7.3 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H). MS (m/z) 386 (M + Na).
Example 67: Synthesis of 5-{[4-(l,3-benzoxazol-2-yl)phenoxy]methyl}-2-furoic acid.
Figure imgf000084_0002
Ethyl 5- {[4-(l,3-benzoxazol-2-yl)phenoxy]methyl} -2-furoate (45 mg, 0.12 mmol) was dissolved in 1 mL of THF and 1 mL of MeOH. To this mixture was added 0.30 mL of 1.0 M aq. NaOH. After stirring overnight, the mixture was concentrated. Water (2 mL) were added, the pH was adjusted to -6 with 10% aq. HCl. After extraction the mixture with EtOAc (3 x 5 mL), the combined organic phase was washed with brine, dried (MgS0 ), concentrated. Thus obtained the product (45 mg, quantitative). !HNMR (CD3OD) δ 8.19 (d, J = 9.2 Hz, 2H), 7.60- 7.72 (m, 2H), 7.36- 7.42 (m, 2H), 7.30-7.40 (m, 2H), 7.22 (d, J = 9.2 Hz, IH), 7.19 (d, J = 3.3 Hz, IH), 6.70 (d, J = 3.3 Hz, IH), 5.22 (s, 2H). MS (m/z) 336 (M + H). Example 68: Prostaglandin EP2 binding assay
Compounds of the invention were tested in an EP2 receptor binding assay of the following protocol. As referred to herein, the term a "standard EP2 receptor binding assay" designates the following protocol.
A mixture containing 20 μg of EP2 receptor membranes, 0.5 mg of wheat germ agglutinin coated PNT-SPA beads, plus or minus a tested substituted furan compound (25 μl per well) or 10 μM of cold PGE2 at 1 % DMSO and 20 nM 3H-PGE2 in assay buffer containing 25 mM MES, 10 mM MgCl2, 1 mM EDTA, pH 6.0 are incubated in Corning 3600 plates on a plate shaker for 2 hrs at room temperature. H-PGE2 binding is evaluated by counting the plates on the top count using the 3H SPA dpm2 program. Percentage of Binding and Ki value for inhibitors are calculated based on the one site competition parameter using the Graphpad prism program. EP2 Ki values are set forth in the Table 1 which follows Example 69 below.
Example 69: EP2 cAMP assay.
Compounds of the invention were tested in a total cAMP assay as follows. HEK293-EBΝA cells transfected with pCEP4-hEP2 receptors were seeded in 96 well opaque plate (Costar #3917) at 4x104 cells per well in 100 μl of culture medium (D- MEM/F12 supplemented with 10% FBS, 2 nM L-glutamine, and 250 μg/ml of hygromycin; all from GibcoBRL) and incubated at 37°C. After overnight incubation, the medium was removed from each well and replaced with 45 μl of assay medium consisted of phenol red free D-MEM/F-12, 0.1 % BSA (GibcoBRL) and 0.1 mM3- isobutyl-1-methyl-xanthine (Sigma). After 15 minutes of incubation at 37° C, 16-16- dimethyl PGE-2 or compounds at desired concentrations in 20 μl of assay medium were added to cells and further incubated at 37° C for 1 hour. Total cAMP (intra- and extracellular) was measured by using a cAMP-screen ELISA System (Tropix, #CS1000). Results (EP2 EC50 (μM)) are shown in the Table 1 immediately below. Table 1
Figure imgf000086_0001
Example 70: In vivo ovulation assay:
Ovulation induction activity of compounds of the invention may be tested in a mature mouse ovulation induction model.
Mature 10-week-old CD-mice are used. Reagents are prepared as follows: PMSG (pregnant mare serum gonadotiopin) (Calbiochem, cat #367222) and hCG (Serono) are diluted in PBS. PGE2 (Cayman, Ann Arbor MI) is dissolved in ethanol and diluted with 0.154 M NaHC02 Buffer (pH 8.0) to final concentration of ethanol of less than 3 percent. A compound of the invention (based on solubility) is pre-dissolved in ethanol, DMSO or other reagents. The compounds of the invention are then diluted with saline or other diluents such as PBS or NP3S (5% N-methyl-pyrrolidinone/30% PEG400/25% PEG200/20% Propylene Glycol in saline). PMSG stimulates ovarian follicular development. After PMSG stimulation, the mature follicules can be stimulated to rupture and release oocytes by an ovulation trigger, such as hCG or a compound of the invention.
The following test protocol is employed for the test animals (typically 5 animals per test group).
Day 1: Inject 5 IU PMSG in 200 μl PBS (i.p. 15:00 PM) Day 2: No administration
Day 3: Injection of ovulation trigger hCG (i.p.) or hCG replacement (PGE2 or compound of the invention, s.c, i.v. or oral route), 15:00 PM
Day 4: Eighteen hours after injections of the ovulation triggers, animals are sacrificed by C02 asphyxiation and abdominal cavities are opened using fine scissors and forceps. Uterus, oviducts and ovaries are collected and placed in pre-labeled dishes containing phosphate buffered saline (PBS). The collected tissues are transferred to the laboratory and intact oviduct carefully dissected out from uterus and ovary under the dissection microscope. The dissected oviducts are placed on the glass microscopic slide and covered with another slide. Two slides are taped on two edges. The numbers of ovulated ova in the oviducts are counted using upright microscope with 4x objective and recorded.
For evaluating the oral activity of this compound, two experiments are conducted, the first experiment is conducted with non-fasted animals and the second experiment is conducted in 24 h fasted animals (water provided). Compounds of the invention, based on their solubility, are pre-dissolved in ethanol, DMSO or other reagents. Compounds of the invention are then with saline or other diluents such as PBS or NP3S before oral administration (i.e. 5% N-methyl-pyrrolidinone/30% PEG 400/25% PEG 200/20%) Propylene Glycol in saline.
Compounds of the invention are submitted to testing in the in vivo ovulation induction model as described above in order to assess their ability to induce ovulation via subcutaneous (sc), oral (po) and intravenous (iv) routes of administration. Example 71: In vivo inhibition of Guinea Pig broncho-constriction.
The activity of compounds of the invention in dilation of bronchiolar muscles, may be tested in different models. Guinea pig pulmonary-cholinergic in vivo model is generally used to test the materials for the treatments of asthma in human (Fleisc et al., 1985) Compounds of the invention can be tested in this methacholine-induced bronchomuscle constriction model as described below.
Groups of 3 Duncan Hartley derived male or female guinea pigs weighing 250 + 50 g are anesthetized with pentobarbital sodium (50 mg/kg i.p., plus an additional 15 mg/kg i.p. if required) and succinylcholine chloride (2 mg/animal i.p.) is subsequently administered to prevent spontaneous respiration. Body temperature is maintained at 37° to 38°C.
The trachea is cannulated and the guinea pig is ventilated with a Harvard rodent respirator in a closed system. Tracheal pressure is recorded through a side-arm of the cannula connected to a P23ID Statham transducer. Respiratory rate is set at 50 strokes/minute with a stroke volume (approximately 1 ml/100 g) sufficient to produce a baseline tracheal pressure of 6 cm H20. Mean arterial pressure (BP) is monitored from a cannulated carotid artery, and heart rate (HR) is obtained from chest electrodes arranged for lead II. The jugular vein is cannulated for i.v. vehicle or drug administration in a volume of 1 ml/kg.
Cholinergic-induced bronchoconstrictbr responses, reflected as increases in tracheal pressure (cm H20), are elicited by administration of methacholine hydrochloride (10 μg/kg base weight i.v.). In vehicle-treated control animals, methacholine-induced bronchoconstriction ranges from 70 to 90 percent of its own maximum response (about 40 to 65 percent of maximum possible bronchoconstriction obtained by tracheal occlusion).
Compounds of the invention are also tested via intratracheal (IT) route of administration. In this other experiment, compound of the invention, reference compound or vehicle is administered IT 10 (5 min for experiment 1 and 2) minutes before methacholine chloride (10 μg/kg IN) induced bronchoconstriction. Tracheal pressure (ITP), blood pressure and heart rate are measured immediately as indicated in the material and methods sections.
MED (medium effective dose) is measure. A 50 percent or greater (>50%) inhibition of the induced broncho-constriction relative to vehicle treated control animals is considered significant.
Compounds of the invention are administered i.v. (10 mg/kg) 5 minutes before the methacholine challenge in 3 guinea pigs. A percent or more (>50) inhibition of the induced bronchoconstriction relative to vehicle treated contiol animals is considered significant.
Example 72: In vivo inhibition of LPS-induced TNFα release in mice.
Prostaglandin E2 is suggested to be an endogenous inhibitor of inflammation through the EP4 receptor. Therefore EP2 and/or EP4 agonists are supposed to have an anti-inflammatory activity.
Endotoxins are the lipopolysaccharides (LPS) constituents of the outer membrane of Gram negative bacteria. Response to LPS has been shown to involve the activation of different cell populations and to lead to the expression of various inflammatory cytokines that include tumor necrosis factor-alpha (TNFα) and interferon gamma (TFN-β).
The anti-inflammatory activity of compounds of the invention may be assessed after a LPS challenge using the following protocol:
Eight weeks old C3H/HEN mice (IFFA-CREDO, L'arbresle, France) receive an oral treatment with compounds of the invention 6 different doses (0.001, 0.01, 0.1, 1 or 3 and 10 mg/kg in 0.5% CMC/0.25% tween-20). Six mice are used by group. Fifteen minutes later, endotoxins (0111:B4 Sigma, 0.3 mg/kg) are intraperitoneally injected. Heparinized whole blood is collected by decapitation. TNFα level is determined in plasma by ELISA (R & D Systems, Abdingdon, UK). Control animals receive 0.5% CMC/0.25% tween-20 (10 ml/kg) as vehicle. Data obtained from experiments are expressed as the mean + SEM and analysed using one-way analysis of variance (ANOVA) followed by Dunnett's t-test. The activity of the compounds of the invention is expressed as a percentage of inliibition of TNF release and the Inhibitory Dose at 50% of the maximum effect (ID50) is calculated in mg/kg.
Example 73: In vivo effect on penile corpus cavernosum tissue relaxation.
Penile erection is based on three main physiological events: an increase in the arterial blood flow, a relaxation of the expansive tissue of the corpora carvernosa and the corpus spongiosum, and an obstruction of the venous return by mechanical compression of the veins caused by the expansive tissue.
PGEl is used in the treatment of erectile dysfunction to relax smooth muscle and therefore to promote the development of erection. The administration of PGEl is performed by local injection into the cavernous tissue of the penis. However, PGEl has a low selectivity for prostanoid receptors and has irritant effects. Selective agonists EP2 and/or EP4 have been developed for the treatment of erectile dysfunction (WO 9902164) The effect of compounds of the invention on the relaxation of penile corpus cavernosal tissue strips may be assayed for example in an assay on human or rabbit tissue as described below:
Human tissue procurement. Cavernosal tissue is obtained from patients undergoing penile prosthesis implantation surgery for treatment of erectile dysfunction. In the operating room, biopsies of the corpora cavernosa are immediately placed in chilled (4°C) physiologic salt solution and transported to the laboratory. Tissue strips, measuring approximately 3 mm x 3 mm x 10 mm, are cut and prepared for organ bath studies.
Rabbit tissue procurement. Adult male New Zealand White rabbits (4.5 - 5.0 kg) are sedated with ketamine (35 mg/kg) and xylazine (5 mg/kg) and euthanized with sodium pentobarbital (60 mg/kg body weight). Following exsanguination, the penis is excised and cleaned by removing the corpus spongiosum and urethra. Corpus cavernosum tissue strips are dissected away from the surrounding tunica albuginea and prepared for organ bath studies. Preparation of compound stock solutions and dose responses. PGE] (Cayman Chemical Co., Ann Arbor, Ml) is stored at -20°C in solid form until the day of use. Stock solutions are made by adding 1 ml of 70% DMSO to a vial containing 1 mg of PGEi. Compounds of the mention are dissolved in 1 ml of 70% DMSO, divided into 100 μl aliquots and stored at -20 °C until use. For dose responses in organ baths, stock solutions of PGEi and compounds of the invention are diluted with 70% DMSO to make the highest concentration and then serially diluted with 2% DMSO for all other doses. In a typical dose response curve, the concentration of DMSO is checked to remain below 0.1% in the 25 ml bath and to not exceed 0.5% at the highest dose.
Organ bath studies. Human or rabbit cavernosal tissue strips are mounted onto a fixed support with silk ties and attached to a tension transducer (model FT03; Grass- Telefactor, Astro-Med, Inc. West Warwick, RI) with a rigid metal wire. After mounting, tissue strips are immersed in 25 ml baths of physiologic salt solution (PSS; 118.3 mM NaCl, 4.7 mM KCl, 0.6 mM MgS04, 1.2 mM KH2P04, 2.5 mM CaCl2, 25 mM NaHC03, 0.026 mM CaNa2EDTA, 11.1 mM glucose). The solution is gassed with 95% air / 5% C02 to attain a pH of 7.4 and the temperature is maintained at 37°C. All tissue strips are treated with 3 μM indomethacin to inhibit endogenous prostanoid production and minimize spontaneous contractile activity. The corpus cavernosum tissue is stretched incrementally and the optimal resting isometric tension for contraction is determined. After every 3 - 4 stretches (1 g tension/stretch), the tissue is contracted with 1 μM phenylephrine. When the amplitude of the phenylephrine-induced contraction is within 10% of the previous contraction, that tension is considered optimal for isometric contraction. All tissue strips are extensively washed with fresh PSS. Tissue strips are then contracted with 1 μM phenylephrine. After stable tone is achieved, tissue strips are exposed to increasing concentrations of PGEi or compounds of the invention.
Data analysis. At the end of each experiment, all tissue strips are treated with 10 μM papaverine and 10 μM nitroprusside to induce maximal relaxation (100%). The total amount of relaxatory response over the range of drug concentrations tested is determined by the area under the plotted curves. EC50 values are calculated using Prism software (GraphPad, San Diego, CA). For final analysis of data, relaxation parameters are compared using ANONA. If the AΝONA p-value is less than 0.05, paired post-test comparisons is carried out using the Tukey-Kramer test.
Example 74: In vivo effect on bone loss prevention.
The activity of compounds of the invention as a bone anabolic agent can be tested for example in a rat ovariectomy model such as follows.
Virgin female Sprague Dawley rats Rats are randomized into treatment groups based on pre-dose body weight measurements. The aim iss to achieve approximately the same average body weight for every treatment group.
Surgery:
Animals are sedated with Ketamine and Xylazine (SOP ST-AEP007). The hair on the dorsal abdominal surface is shaved and prepped for aseptic surgery. A single incision is made along the midline, starting just anterior to the lumbar region of the spine. The underlying musculature on both sides of the dorso-lateral region of the abdomen is exposed. An incision is made through the musculature to gain access to the abdominal cavity.
For a group of animals ("Ovx"), the ovary is located and cut at the junction of the uterine horn and removed. The uterus is replaced and the muscles sutured. Repeat on the contra-lateral side.
For a control group of animals ("Sham"), the ovaries are located and exteriorized, but not removed. The uterus and ovaries are replaced into the abdominal cavity and the muscles sutured. The muscle layers are closed with suture and the skin incision closed using wound clips.
Dosing
Dosing is commenced one day after the surgery is performed. The animals receive daily subcutaneous injections for 6 weeks following surgery. The doses of 0.1, 1.0, 10.0 mg/kg of compounds of the invention are used. A contiol group receives daily subcutaneous injections of 17βestradiol (Sigma Chemicals) of 30 μg/kg for 6 weeks following surgery. Control groups of animal (the "sham" group and an "Ovx" group) are injected s.c. vehicle (saline).
Fluorochrome Labels
To enable the performance of dynamic histomorphometry, two injections of calcein (10 mg/kg, i.p.) are given 6 and 2 days prior to the necropsy.
Body Weights and Clinical Observations
Body weights are recorded weekly, beginning one week prior to the commencement of tieatment and continuing until the conclusion of the treatment period. In addition, the rats are observed daily for signs of ill health or reaction to treatment.
Blood and Urine Biochemistry
An eighteen-hour urine specimen is collected from each animal prior to the sacrifice using metabolic cages. At sacrifice, blood samples are collected from each rat, under inhalation anesthesia (ether) from the retro-orbital sinus. Following parameters are measured in urine and serum.
Parameter Method
Urinary deoxypyridinoline is measured by Immuno-assay (Pyrilinks-D Quidel, Mt. Niew,CA); Urinary creatinine is measured by COBAS chemistry instrument (Creatinine Reagent Roche Diagnostics, Indianapolis, IN); Serum osteocalcin is measured by Immuno-assay (Rat OSU IRMA, Immunotopics San Clemente, CA)
Necropsy:
Upon completion of dosing and urine/blood collection, animals are euthanized using carbon dioxide asphyxiation.
All animals are subjected to the following procedure. Terminal body weights are recorded. A gross examination is performed and a check for abnormalities is performed. The following investigation are performed, as detailed: Bone Mineral Density Scans:
L2-L4 lumbar vertebrae is subjected to DXA (Dual-energy X-ray absorptiometry) scan using a PIXImus instrument (Lunar Corp. Madison, WI). Bone mineral content, area and density are determined from the PIXI scan. Bone mineral density measurements by DXA are described in Formica et al. 1998.
Right femur is subject to pQCT (peripheral quantitative computed tomography) scan using a Stiatec XCT RM and associated software (Stratec Medizintechnik Gmbh, Pforzheim, Germany. Software version 5.40 C). The femur is scanned at two sites, 20% of the distal femur and 50% of the mid-femur. The position is verified using scout views and scan results from one 0.5 mm slice perpendicular to the long axis of the femur shaft is recorded. Total bone mineral content, total bone area, total bone mineral density, trabecular bone mineral content, trabecular bone area and trabecular bone mineral density are analyzed from the scan of the distal femur. For the midshaft femur, total bone mineral content, total bone area, total bone mineral density, cortical bone mineral content, cortical bone area, cortical bone mineral density, periosteal perimeter and endosteal perimeter are analyzed.
Bone mineral density measurements by pQCT are described in Formica et al., 1998 and in Tsugeno 2002.
Biomechanical Testing of Lumbar Vertebrae and Femurs:
L5 Lumbar vertebra is isolated from L5-L6 and prepared for mechanical testing by removing the vertebral arch and pedicle using a low-speed diamond saw. The cranial and caudal ends of each vertebral body are also removed to produce a vertebral body specimen with two parallel surfaces and a height of approximately 4 mm. The width of the vertebral body in the medial-lateral and anterior-posterior directions is measured using electronic digital calipers. These values are recorded and used in the calculation of cross-sectional area. The height of the vertebral body specimen is also taken with an electronic caliper and recorded. The specimens are then placed between two platens and load applied at a displacement rate of 6 mm/min until failure in an Instron Mechanical Testing Instrument (Instron 4465, retrofitted to 5500).
The load and displacement are recorded by Instron Instrument Software (Merlin II, Instron) and the locations for maximum load at failure, stiffness and energy absorbed are selected manually from the load and displacement curve. The intrinsic properties, stress, elastic modulus and toughness are then calculated from maximum load, stiffness, energy absorbed, cross-sectional area, and height according to the following equations:
After the pQCT scan, the anterior to posterior diameter at the midpoint of the femoral shaft is taken with an electronic caliper and recorded. Femur is then placed on the lower supports of a three point bending fixture with anterior side facing downward in an Instron Mechanical Testing Instrument (Instron 4465, retrofitted to 5500). The span between the two lower supports is set at 14 mm. The upper loading device aligned to the center of the femoral shaft. The load is applied at a constant displacement rate of 6 mm/min until the femur breaks. The locations of maximal load, stiffness and energy absorbed are selected manually and values calculated by instrument's software (Merlin II, Instron). The intrinsic properties, stress, elastic modulus and toughness are calculated from maximum load, stiffness, energy absorbed, anterior-posterior diameter, and moment of inertia.
After the three point bending test, a 3 -mm segment of the distal femoral metaphysis is cut directly proximal to the femoral condyle with a low-speed diamond saw. The load is applied with a cylindrical indenter (with a flat testing face of 1.6 mm diameter (d)) to the center of marrow cavity on the distal face of the segment. The indenter is allowed to penetrate the cavity at a constant displacement rate of 6 mm/min to a depth of 2 mm before load reversal. The locations of maximum load, stiffness and energy absorbed is selected manually from load displacement curve and then calculated by the instrument's software (Merlin II, Instron). Stress is calculated by dividing the maximum load by the indenter area. Bone Histology and Dynamic Histomorphometry: Dehydration, embedding and sectioning
Formalin-fixed samples of proximal tibia are dehydrated in a series of ascending ethanol concentration. Following dehydration, bone samples are infiltrated and embedded in methyl methacrylate-based plastic. Embedded samples of the proximal tibia are sectioned longitudinally using a Leitz motorized rotary microtome equipped with a tungsten-carbide microtome knife. Once the blocks are trimmed, 4μm sections are stained with Goldner's trichrome stain for microscopy. The 8μm sections are left unstained for epifluorescence microscopy.
Histomorphometric determinations
Static and dynamic histomorphometry of the proximal tibia is performed. The measurement includes the secondary spongiosa (area that is 1.05 from the lowest point of the growth plate).
Bone histomorphometry is performed using an OsteoMeasure software program (OsteoMetrics, Inc. Atlanta, GA) interfaced with a Nikon Eclipse E400 light/epifluorescent microscope and video subsystem. Histomorphometry is read in a blinded manner. Total tissue area, trabecular bone area, trabecular bone perimeter, and osteoclast perimeter is measured on 4 μm thick Goldner's trichrome stained sections. Percent trabecular bone area, tiabecular number, trabecular thickness, trabecular separation and osteoclast perimeter as a percentage of bone surfaces are then calculated according to standardized formulae. For dynamic parameters, single-labeled calcein perimeter, double-labeled calcein perimeter, and interlabel width (label thickness) is measured on 8 μm thick unstained sections, and the mineralizing surface, mineral apposition rate, bone formation rate-surface referent is calculated.
Statistics
Results are analyzed using analysis of variance (group) using SAS software (SAS Institute, Cory, NC). Group comparison is performed using Dunnett's procedure using "Ovx" + vehicle group as reference group. All results are expressed as mean +/- SD. The invention has been described in detail with reference to preferred embodiments thereof. However, it will be appreciated that those skilled in the art, upon consideration of this disclosure, may make modifications and improvements within the spirit and scope of the invention
The invention has been described in detail with reference to preferred embodiments thereof. However, it will be appreciated that those skilled in the art, upon consideration of this disclosure, may make modifications and improvements within the spirit and scope of the invention.

Claims

What is claimed is:
1. A method for treating a disease or disorder associated with prostaglandin, comprising administering to a mammal suffering from or susceptible to such a disease or disorder an effective amount of a compound of the following Formula I:
Figure imgf000098_0001
wherein
G is a carboxy, optionally substituted alkoxycarbonyl, or optionally substituted tetrazole;
X is oxygen, optionally substituted nitrogen, sulfur, sulfinyl, or sulfonyl;
Y is oxygen or sulfur each R2 and R3 is independently hydrogen, optionally substituted d- alkyl or halogen;
R4 is selected from the group comprising or consisting of hydrogen, sulfonyl, amino, d-d-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, wherein said alkyl, alkenyl, alkynyl chains may be interrupted by a heteroatom selected from N, O or S, aryl, heteroaryl, saturated or unsaturated 3-8-membered cycloalkyl, heterocycloalkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, an acyl moiety, Ci-Ce-alkyl aryl, Ci-d-alkyl heteroaryl, d-d-alkenyl aryl, d-d-alkenyl heteroaryl, d-d-alkynyl aryl, d-d-alkynyl heteroaryl, d-d-alkyl cycloalkyl, Ci-d-alkyl heterocycloalkyl, d-d- alkenyl cycloalkyl, Ci-d-alkenyl heterocycloalkyl, Ci-d-alkynyl cycloalkyl, d-d- alkynyl heterocycloalkyl, alkoxycarbonyl, aminocarbonyl, d-d-alkyl carboxy, d-d- alkyl acyl, aryl acyl, heteroaryl acyl, C3-C8-(hetero)cycloalkyl acyl, d-d-alkyl acyloxy, d-d-alkyl alkoxy, Ci-d-alkyl alkoxycarbonyl, d-d-alkyl aminocarbonyl, d-d- alkyl acylamino, acylamino, d-C6-alkyl ureido, d-d-alkyl carbamate, Ci-d-alkyl amino, Ci-d-alkyl ammonium, Ci-d-alkyl sulfonyloxy, d-d-alkyl sulfonyl, d-d- alkyl sulfinyl, Ci-Ce-alkyl sulfanyl, Ci-Ce-alkyl sulfonylamino, Ci-d-alkyl aminosulfonyl, hydroxy or halogen, all of which may be optionally substituted; and pharmaceutically acceptable salts thereof.
2. A method of claim 1, wherein the compound has the following Formula
II:
Figure imgf000099_0001
wherein R1 is H or optionally substituted Ci-Ce-alkyl and R2, R3, R4 are as above defined in Formula I; and pharmaceutically acceptable salts thereof.
3. A method of claim 1, wherein the compound has the following Formula III:
Figure imgf000099_0002
wherein R1 is H or optionally substituted Cι-C6-alkyl and R4 is as above defined in Formula I; and pharmaceutically acceptable salts thereof.
4. A method of claim 1 , wherein the compound has the following Formula IN:
Figure imgf000099_0003
wherein R1 is H or optionally substituted Ci-d-alkyl and R4 is as above defined in Formula I; and pharmaceutically acceptable salts thereof.
5. A method of claim 1 wherein the compound of Formula I is such as X is O; Y is O or S; G is selected from -COOR1 and tetrazolyl, wherein R1 is selected from H and Ci- alkyl; R2 and R3 are as defined above and R4 is as defined above and is in para position on the phenyl ring.
6. A method of any of the preceding claims wherein the compound of Formula I is such as X and Y are O; G is selected from -COOR1 and tetrazolyl, wherein R1 is selected from H and Ci- alkyl; R2 and R3 are as defined above andR4 is as defined above and is in para position on the phenyl ring.
7. A method of claim 1 wherein the compound of Formula I is such as X is O; Y is S; G is selected from -COOR1 and tetrazolyl, wherein R1 is selected from H and d-d alkyl; R2 and R3 are as defined above and R4 is as defined above and is in para position on the phenyl ring.
8. A method of claim 1 wherein the compound of Formula I is such as X is O; Y is O or S; G is selected from -COOR1 and tetrazolyl, wherein R1 is selected from H and d- alkyl; R2 and R3 are independently selected from H and Ci- alkyl; R4 is selected from hydrogen; Ci-d-alkyl, heterocycloalkyl, d-C8 cycloalkyl Ci-Ce-alkyl, aryl, -do cycloalkyl, aryl Ci-d-alkyl, heteroalkyl, aryl heteroalkyl and amino group wherein the substituents on the amino group are independently selected from d- alkyl, carbonyl, aryl sulfonyl, aryl, heteroaryl and amino carbonyl.
9. A method according to any of the preceding claims wherein the compound of Formula I is such as X is O; Y is O; G is selected from -COOR1 and tetrazolyl; R2 and R3 are H; and R4 is in the para position of the phenyl ring and is selected from tetra-methyl butyl; heterocycloalkyl; C3-C8 cycloalkyl Ci-d-alkyl, - CH2Phenyl, -C(Me)2Phenyl and -C(Me)2Phenyl-OMe.
10. A method according to claim 1 wherein the compound of Formula I is such as X is O; Y is S; G is -COOH; R2 and R3 are H and R4 is in the para position of the phenyl ring and is selected from tetra-methylbutyl; heterocycloalkyl; C3-C8 cycloalkyl Ci-d-alkyl, -CH2Phenyl, -C(Me)2Phenyl and -C(Me)2Phenyl-OMe.
11. A method of claim 1 wherein the compound of formula I is selected from: 5-{[4-(4-oxocyclohexyl) phenoxy] methyl} -2-furoic acid; 5-{[4-(2,3-dihydro-lH-inden-l-yl) phenoxy] methyl} -2-furoic acid; 5-[(4-tert-butylphenoxy) methyl] -2-furoic acid; 5-{[4-(l,l,3,3-tetramethylbutyl) phenoxy] methyl} -2-furoic acid; 5-[(2-methyl-4- (2 methyl, 2-ehtyl) n-proylphenoxy) methyl] -2-furoic acid; 5-[(2-chloro-4-tert-pentylphenoxy) methyl]-2-furoic acid; 5-[(2,6-dichloro-4-tert-pentylphenoxy) methyl] -2-furoic acid; 5-[(2,6-dimethyl-4-tert-pentylphenoxy) methyl]-2-furoic acid; 5-{[4-(l-phenylethyl) phenoxy] methyl} -2-furoic acid; 5-{[4-(l,3-dimethylbutyl) peony] methyl} -2-furoic acid;
5-{[4-(2,2,4-trimethyl-3, 4-dihydro-2H-chromen-4-yl) phenoxy] methyl} -2-furoic acid; 5-{[4-(l-adamantyl) phenoxy] methyl} -2-furoic acid; 5-({4-[l-(4-methoxyphenyl)-l-methylethyl] phenoxy} methyl)-2-furoic acid; 5-{[4-(benzyloxy) phenoxy] methyl} -2-furoic acid; 5-[(4-butoxyphenoxy) methyl]-2-furoic acid; 5-{[(4-benzylphenyl) amino] methyl} -2-furoic acid; 5-{[(4-benzylphenyl)(methyl) amino] methyl} -2-furoic acid; 5-({4-[(tert-butoxycarbonyl) amino] phenoxy} methyl)-2-furoic acid; 5-[(4-{[6-chloro-2- (methylthio) pyrimidin-4-yl] amino} phenoxy) methyl] -2-furoic acid; 5-[(4-anilinophenoxy)methyl]-2-furoic acid; 5-( {4-[(4-methylphenyl)amino]phenoxy}methyl)-2-furoic acid; 5-{[4-(benzyl amino)phenoxy]methyl} -2-furoic acid; 5- { [4-( 1 -naphthylamino)phenoxy]methyl} -2-furoic acid; 5-[(3-anilinophenoxy)methyl]-2-furoic acid;
5-({4-[methyl(3,5,5-trimethylhexyl)amino]phenoxy}methyl)-2-furoic acid; 5-({4-[(3,3-dimethylbutyl)(methyl)amino]phenoxy}methyl)-2-furoic acid; 5-({4-[methyl(neopentyl)amino]phenoxy} methyl)-2-furoic acid; ■- 5-({4-[methyl(3,5-dimethylbenzyl)amino]phenoxy}methyl)-2-furoic acid; methyl 5-( {4-[(trifluoroacetyl)amino]phenoxy}methyl)-2-furoate; methyl 5-[(4-aminophenoxy)methyl]-2-fiιroate; methyl 5-( {4-[(phenylsulfonyl)amino]phenoxy}methyl)-2-furoate; 5-({4-[(phenylsulfonyl)amino]phenoxy}methyl)-2-furoic acid; methyl 5-( {4-[isopropyl(phenylsulfonyl) amino]phenoxy}methyl)-2-furoate;
5-({4-[isopropyl(phenylsulfonyl)amino]phenoxy}methyl)-2-furoic acid; methyl 5-({4-[ethyl(phenylsulfonyl)amino]phenoxy}methyl)-2-furoate;
5-({4-[ethyl(phenylsulfonyl)amino]phenoxy}methyl)-2 -furoic acid; ethyl 5- {[4-(l , 1 -diphenylpropyl)phenoxy]methyl}-2-furoate;
5- { [4-(l , 1 -diphenylpropyl)phenoxy]methyl} -2-furoic acid; ethyl 5-[(4-benzoylphenoxy)methyl]-2-furoate; ethyl 5-( {4-[hydroxy(phenyl)methyl]phenoxy}methyl)-2 -furoate;
5 -( {4- [hydroxy(phenyl)methyl]phenoxy} methyl)-2-furoic acid;
5-[(4-benzoylphenoxy)methyl]-2-furoic acid; ethyl 5- {[4-(methoxymethyl)phenoxy]methyl} -2-furoate;
5- { [4-(methoxymethyl)phenoxy]methyl} -2-furoic acid; ethyl 5-[(4-butyrylphenoxy)methyl]-2-furoate;
5-[(4-butyrylphenoxy)methyl]-2-furoic acid; ethyl 5- { [4-( 1 -hydroxybutyl)phenoxy]methyl} -2-furoate;
5-{[4-(l-hydroxybutyl)phenoxy]methyl}-2-furoic acid; ethyl 5- { [4-( 1 , 1 -dimethylbutyl)phenoxy]methyl} -2-furoate;
5- { [4-( 1 , 1 -dimethylbutyl)phenoxy]methyl} -2-furoic acid; ethyl 5- { [4-( 1 -cyclohexyl- 1 -methylethyl)phenoxy]methyl} -2-furoate;
5- { [4-( 1 -cyclohexyl- 1 -methylethyl)phenoxy]methyl} -2-furoic acid; ethyl 5-{[4-(4,4,5,5-tetramethyl-l,3-dioxolan-2-yl)phenoxy]methyl}-2-furoate;
5-{[4-(4,4,5,5-tetramethyl-l,3-dioxolan-2-yl)phenoxy] methyl} -2-furoic acid; ethyl 5- { [4-( 1 ,3 ,4-oxadiazol-2-yl)phenoxy]methyl} -2-furoate;
5- { [4-(l ,3,4-oxadiazol-2-yl)phenoxy]methyl} -2-furoic acid; ethyl 5-{[4-(l,3-benzoxazol-2-yl)phenoxy]methyl}-2-furoate;
5-{[4-(l,3-benzoxazol-2-yl)phenoxy]methyl}-2-furoic acid; and pharmaceutically acceptable salts thereof.
12. A method of claim 1 wherein the mammal is suffering from or susceptible to preterm labor.
13. A method of claim 1 wherein the mammal is suffering from or susceptible to dysmenorrhea.
14. A method of claim 1 wherein the mammal is suffering from or susceptible to asthma.
15. A method of claim 1 wherein the mammal is suffering from or susceptible to hypertension.
16. A method of claim 1 wherein the mammal is suffering from or susceptible to infertility or a fertility disorder.
17. A method of claim 1 wherein the mammal is suffering from or susceptible to undesired blood clotting.
18. A method of claim 1 wherein the mammal is suffering from or susceptible to preelampsia or eclampsia.
19. , A method of claim 1 wherein the mammal is suffering from or susceptible to an eosinophil disorder.
20. A method of claim 1 wherein the mammal is suffering from or susceptible to undesired bone loss.
21. A method of claim 1 wherein the mammal is a female in late stage pregnancy and in need of control of cervical ripening.
22. A method of claim 1 wherein the mammal is suffering from sexual dysfunction.
23. A method of claim 1 wherein the mammal is suffering from or susceptible to glaucoma or other disorder involving elevated intraocular pressure.
24. A method of claim 1 wherein the mammal is suffering from or susceptible to renal dysfunction.
25. A method of claim 1 wherein the mammal is suffering from or susceptible to an immune deficiency disease or disorder.
26. A method of claim 1 wherein the mammal is suffering from or susceptible to an inflammatory disorder.
27. A method of claim 1 wherein the mammal is suffering from or susceptible to AIDS.
28. A method of claim 1 wherein the mammal is suffering from or susceptible to ichthyosis.
29. A method of claim 1 wherein the mammal is suffering from or susceptible to dry eye.
30. A method of claim 1 wherein the mammal is suffering from or susceptible to a sleep disorder.
31. A method of claim 1 wherein the mammal is suffering from or susceptible to gastric ulcers.
32. A method of claim 1 wherein the mammal is suffering or susceptible to undesired muscle contraction.
33. A method of any one of claims 1 through 32 wherein the mammal is a human.
34. A method of any one of claims 1 through claim 33 wherein the mammal is a female.
35. A method of claim 34 wherein the female is suffering from or susceptible to infertility.
36. A method of claim 35 wherein the female is suffering from an ovulatory disorder.
37. A method of any one of claims 1 through 33 wherein the mammal is a male.
38. A method for treating a mammal who is suffering from or susceptible to preterm labor, dysmenorrhea, asthma, hypertension, a fertility disorder, undesired blood clotting, preelampsia, eclampsia, an eosinophil disorder, undesired bone loss, sexual dysfunction, renal dysfunction, an immune deficiency disorder, dry eye, ichthyosis, elevated intraocular pressure, a sleep disorder, an inflammatory disorder or a gastric ulcer, comprising administering to the mammal an effective amount of a compound of Formula I wherein X is O; Y is O or S; G is selected from -COOR1 and tetrazolyl, wherein R1 is selected from H and Ci-d alkyl; R2 and R3 are as defined above andR4 is as defined above and is in para position on the phenyl ring.
39. A method according to claim 38 wherein Y is O.
40. A method according to claim 38 wherein Y is S.
41. A method according to claims 38 to 40 wherein R2 and R3 are independently selected from H and Ci-d alkyl; R4 is selected from hydrogen; Ci-d- alkyl, heterocycloalkyl, C3-C8 cycloalkyl Cι-C6-alkyl, aryl, C3-C10 cycloalkyl, aryl Ci- d-all yl, heteroalkyl, aryl heteroalkyl and amino group wherein the substituents on the amino group are independently selected from d- alkyl, carbonyl, aryl sulfonyl, aryl, heteroaryl and amino carbonyl.
42. A compound of Formula V:
Figure imgf000106_0001
wherein R >4 is selected from the group comprising or consisting of hydrogen, sulfonyl, amino, Ci-d-alkyl, d-d-alkenyl, d-d-alkynyl, wherein said alkyl, alkenyl, alkynyl chains may be interrupted by a heteroatom selected from N, O or S, aryl, heteroaryl, saturated or unsaturated 3-8-membered cycloalkyl, heterocycloalkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, an acyl moiety, Ci-Ce-alkyl aryl, Ci-Cβ-alkyl heteroaryl, Ci-d-alkenyl aryl, d-d-alkenyl heteroaryl, d-d-alkynyl aryl, d-d-alkynyl heteroaryl, d-d-alkyl cycloalkyl, Ci-d-alkyl heterocycloalkyl, Ci-d- alkenyl cycloalkyl, Ci-d-alkenyl heterocycloalkyl, Ci-d-alkynyl cycloalkyl, d-d- alkynyl heterocycloalkyl, alkoxycarbonyl, aminocarbonyl, Ci-d-alkyl carboxy, d-d- alkyl acyl, aryl acyl, heteroaryl acyl, C3-C8-(hetero)cycloalkyl acyl, d-d-alkyl acyloxy, Ci-Cβ-alkyl alkoxy, d-d-alkyl alkoxycarbonyl, Ci-d-alkyl aminocarbonyl, Ci-d- alkyl acylamino, acylamino, Ci-d-alkyl ureido, d-Ce-alkyl carbamate, Ci-Ce-alkyl amino, d-d-alkyl ammonium, Ci-d-alkyl sulfonyloxy, Ci-Ce-alkyl sulfonyl, d-d- alkyl sulfinyl, Ci-Ce-alkyl sulfanyl, d-d-alkyl sulfonylamino, Ci-d-alkyl aminosulfonyl, hydroxy or halogen, all of which R4 substituents may be optionally substituted; or a pharmaceutically acceptable salt thereof.
43. A compound according to claim 42 wherein R4 is selected from tetra- methyl butyl; optionally substituted heterocycloalkyl; optionally substituted C3-C8 cycloalkyl Ci-d-alkyl, -CH2Phenyl, -C(Me)2Phenyl and -C(Me)2Phenyl-OMe.
44. A compound of Formula I:
Figure imgf000107_0001
wherein X is O; Y is O; G is selected from -COOR1 and tetrazolyl; R2 and R3 are H; and R4 is in the para position of the phenyl ring and is selected from tetra-methyl butyl; optionally substituted heterocycloalkyl; optionally substituted C3-C8 cycloalkyl Ci-d- alkyl, -CH2Phenyl, -C(Me)2Phenyl and -C(Me)2Phenyl-OMe.
45. A compound of Formula I wherein X is O; Y is S; G is -COOH; R2 and R3 are H and R4 is in the para position of the phenyl ring and is selected from tetra- methyl butyl; optionally substituted heterocycloalkyl; optionally substituted C3-C8 cycloalkyl Crd-alkyl, -CH2Phenyl, -C(Me)2Phenyl and -C(Me)2Phenyl-OMe.
46. A compound according to claims 42 to 45 selected from the following group :
5-(phenoxymethyl)-2-furoic acid; 5-[(4-benzylphenoxy) methyl] -2-furoic acid; 5-[(4-tert-pentylphenoxy) methyl] -2-furoic acid; 5-[(l,l'-biphenyl-4-yloxy) methyl]-2-furoic acid; 5- { [4-(l -methyl- 1 -phenylethyl)phenoxy]methyl} -2-furoic acid; 5 -{[4-(4-cyclohexyl) phenoxy] methyl} -2-furoic acid; 5-{[4-(4-oxocyclohexyl) phenoxy] methyl} -2-furoic acid; 5-{[4-(2,3-dihydro-lH-inden-l-yl) phenoxy] methyl} -2-furoic acid; 5-[(4-tert-butylphenoxy) methyl]-2-furoic acid; 5-{[4-(l,l,3,3-tetramethylbutyl) phenoxy] methyl} -2-furoic acid; 5-[(2-methyl-4- (2 methyl, 2-ehtyl) n-proylphenoxy) methyl]-2-furoic acid; 5-[(2-chloro-4-tert-pentylphenoxy) methyl]-2-furoic acid; 5-[(2,6-dichloro-4-tert-pentylphenoxy) methyl] -2-furoic acid; 5-[(2,6-dimethyl-4-tert-pentylphenoxy) methyl] -2-furoic acid; -{[4-(l-phenylethyl)phenoxy] methyl} -2-furoic acid; -{[4-(l,3-dimethylbutyl)peony] methyl} -2-furoic acid; -{[4-(2,2,4-trimethyl-3, 4-dihydro-2H-chromen-4-yl) phenoxy] methyl} -2-furoic acid; -{[4-(l-adamantyl) phenoxy]methyl} -2-furoic acid; -({4-[l-(4-methoxyphenyl)-l -methylethyl]phenoxy} methyl)-2 -furoic acid; -(5-{[4-(l,l,3,3-tetramethylbutyl) phenoxy]methyl}-2-furyl)-2H-tetraazole; -{[4-(benzyloxy) phenoxy]methyl} -2-furoic acid; -[(4-butoxyphenoxy) methyl] -2-furoic acid; -{[(4-benzylphenyl) amino]methyl} -2-furoic acid; -{[(4-benzylphenyl)(methyl)amino] methyl} -2-furoic acid; -({4-[(tert-butoxycarbonyl)amino] phenoxy} methyl)-2-furoic acid; -[(4-{[6-chloro-2-(methylthio) pyrimidin-4-yl] amino} phenoxy) methyl]-2-furoic acid; -[(4-anilinophenoxy)methyl]-2-furoic acid; -({4-[(4-methylphenyl)amino]phenoxy}methyl)-2-furoic acid; -{[4-(benzyl amino)phenoxy]methyl} -2-furoic acid; -{[4-(l-naphthylamino)phenoxy]methyl}-2-furoic acid; -[(3-anilinophenoxy)methyl]-2-furoic acid; -( {4-[methyl(3 , 5 , 5-trimethylhexyl)amino]phenoxy } methyl)-2-furoic acid; -({4-[(3,3-dimethylbutyl)(methyl)amino]phenoxy}methyl)-2-furoic acid; -({4-[methyl(neopentyl)amino]phenoxy} methyl)-2-furoic acid; -({4-[methyl(3,5-dimethylbenzyl)amino]phenoxy}methyl)-2 -furoic acid; -( {4-[(phenylsulfonyl)amino]phenoxy}methyl)-2-furoic acid; -({4-[Isopropyl(phenylsulfonyl)amino]phenoxy}methyl)-2-furoic acid; -({4-[ethyl(phenylsulfonyl)amino]phenoxy}methyl)-2-furoic acid; - { [4-( 1 , 1 -diphenylpropyl)phenoxy]methyl} -2-furoic acid; -({4-[hydroxy(phenyl)methyl]phenoxy}methyl)-2-furoic acid; -[(4-benzoylphenoxy)methyl]-2-furoic acid; -{[4-(methoxymethyl)phenoxy]methyl}-2-furoic acid; -[(4-butyrylphenoxy)methyl]-2-furoic acid; -{[4-(l-hydroxybutyl)phenoxy]methyl}-2-furoic acid; - { [4-(l , 1 -dimethylbutyl)phenoxy]methyl} -2-furoic acid; - { [4-( 1 -cyclohexyl- 1 -methylethyl)phenoxy]methyl} -2-furoic acid; -{[4-(4,4,5,5-tetramethyl-l,3-dioxolan-2-yl)phenoxy] methyl}-2-furoic acid; 5- { [4-(l ,3 ,4-oxadiazol-2-yl)phenoxy]methyl} -2-furoic acid; 5-{[4-(l,3-benzoxazol-2-yl)phenoxy]methyl}-2-furoic acid; and pharmaceutically acceptable salts thereof.
47. Use of a compound of any one of claims 42 through 46 for preparation of a medicament to treat a disease or disorder associated with prostaglandin.
48. Use of a compound of any one of claims 42 through 46 for preparation of a medicament to treat to preterm labor, dysmenorrhea, asthma, hypertension, a fertility disorder, undesired blood clotting, preelampsia, eclampsia, an eosinophil disorder, undesired bone loss, sexual dysfunction, renal dysfunction, an immune deficiency disorder, dry eye, ichthyosis, elevated intraocular pressure, a sleep disorder, a gastric ulcer, urinary dysfunction, pain, gastric motility disorders, or hyperchlorhydia.
49. A pharmaceutical composition comprising a pharmaceutically acceptable caπier and one or more compounds of any one of claims 42 through 46.
50. A pharmaceutical composition of claim 49 wherein the compound is packaged together with instructions for use of the compound to treat preterm labor, dysmenoπhea, asthma, hypertension, infertility or a fertility disorder, sexual dysfunction, undesired blood clotting, a destructive bone disease or disorder, preeclampsia or eclampsia, an eosinophil disorder, renal dysfunction an immune deficiency disorder, dry eye, ichthyosis, elevated intraocular pressure, sleep disorder, gastric ulcer, urinary dysfunction, pain, gastric motility disorders, hyperchlorhydia or inflammatory disorders.
PCT/US2003/023165 2002-08-02 2003-07-25 Thiophene and furan derivatives as prostaglandin agonists and use thereof WO2004012656A2 (en)

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WO2007017687A3 (en) * 2005-08-09 2007-05-31 Asterand Uk Ltd Ep2 receptor agonists
US7326732B2 (en) 2004-02-12 2008-02-05 Pharmagene Laboratories Limited EP2 receptor agonists
US7524870B2 (en) * 2004-12-03 2009-04-28 Hoffmann-La Roche Inc. Biaryloxymethylarenecarboxylic acids as glycogen synthase activators
EP2098226A1 (en) * 2008-03-06 2009-09-09 Forschungsverbund Berlin e.V. AKAP-PKA interaction inhibitors for use in the treatment of heart diseases
EP2149551A1 (en) 2008-07-30 2010-02-03 Bayer Schering Pharma AG N-(indol-3-ylalkyl)-(hetero)arylamid derivatives as modulators of EP2 receptors
EP2149554A1 (en) 2008-07-30 2010-02-03 Bayer Schering Pharma Aktiengesellschaft Indolyamides as modulators for an EP2 receptor
EP2149552A1 (en) 2008-07-30 2010-02-03 Bayer Schering Pharma AG 5,6 substituted benzamide derivatives as modulators of EP2 receptors
US7700632B2 (en) 2003-06-24 2010-04-20 Hoffmann-La Roche Inc. Biaryloxymethylarenecarboxylic acids as glycogen synthase activator
EP2269611A2 (en) 2006-11-16 2011-01-05 Bayer Schering Pharma Aktiengesellschaft EP2 and EP4 agonists as agents for the treatment of influenza A viral infection
WO2014102413A1 (en) * 2012-12-26 2014-07-03 Consejo Superior De Investigaciones Científicas (Csic) Method for producing organic molecules used as novel surfactant agents
JP2016222687A (en) * 2010-08-04 2016-12-28 ユニバーシティ オブ バージニア パテント ファウンデーション Compositions and methods for treating inflammatory diseases
CN113149941A (en) * 2020-01-22 2021-07-23 中国科学院上海药物研究所 Ether compound and pharmaceutical application thereof in preventing and treating diabetes and metabolic syndrome

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Cited By (19)

* Cited by examiner, † Cited by third party
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US7700632B2 (en) 2003-06-24 2010-04-20 Hoffmann-La Roche Inc. Biaryloxymethylarenecarboxylic acids as glycogen synthase activator
US7842825B2 (en) 2003-06-24 2010-11-30 Hoffmann-La Roche Inc. Biaryloxymethylarenecarboxylic acids as glycogen synthase activator
US7326732B2 (en) 2004-02-12 2008-02-05 Pharmagene Laboratories Limited EP2 receptor agonists
US7803841B2 (en) 2004-02-12 2010-09-28 Asterand Uk Limited EP2 receptor agonists
US7662839B2 (en) 2004-02-12 2010-02-16 Asterand Uk Limited EP2 receptor agonists
US7524870B2 (en) * 2004-12-03 2009-04-28 Hoffmann-La Roche Inc. Biaryloxymethylarenecarboxylic acids as glycogen synthase activators
JP2009505973A (en) * 2005-08-09 2009-02-12 アステランド ユーケイ リミテッド EP2 receptor agonist
US8080567B2 (en) 2005-08-09 2011-12-20 Asterand Uk Limited EP2 receptor agonists
WO2007017687A3 (en) * 2005-08-09 2007-05-31 Asterand Uk Ltd Ep2 receptor agonists
EP2269611A2 (en) 2006-11-16 2011-01-05 Bayer Schering Pharma Aktiengesellschaft EP2 and EP4 agonists as agents for the treatment of influenza A viral infection
US8183286B2 (en) 2006-11-16 2012-05-22 Gemmus Pharma Inc. EP2 and EP4 agonists as agents for the treatment of influenza a viral infection
US8980944B2 (en) 2006-11-16 2015-03-17 Gemmus Pharma Inc. EP2 and EP4 agonists as agents for the treatment of influenza a viral infection
EP2098226A1 (en) * 2008-03-06 2009-09-09 Forschungsverbund Berlin e.V. AKAP-PKA interaction inhibitors for use in the treatment of heart diseases
EP2149552A1 (en) 2008-07-30 2010-02-03 Bayer Schering Pharma AG 5,6 substituted benzamide derivatives as modulators of EP2 receptors
EP2149554A1 (en) 2008-07-30 2010-02-03 Bayer Schering Pharma Aktiengesellschaft Indolyamides as modulators for an EP2 receptor
EP2149551A1 (en) 2008-07-30 2010-02-03 Bayer Schering Pharma AG N-(indol-3-ylalkyl)-(hetero)arylamid derivatives as modulators of EP2 receptors
JP2016222687A (en) * 2010-08-04 2016-12-28 ユニバーシティ オブ バージニア パテント ファウンデーション Compositions and methods for treating inflammatory diseases
WO2014102413A1 (en) * 2012-12-26 2014-07-03 Consejo Superior De Investigaciones Científicas (Csic) Method for producing organic molecules used as novel surfactant agents
CN113149941A (en) * 2020-01-22 2021-07-23 中国科学院上海药物研究所 Ether compound and pharmaceutical application thereof in preventing and treating diabetes and metabolic syndrome

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