US20090124695A1 - Prostaglandin e1 and e2 analogs for the treatment of various medical conditions - Google Patents

Prostaglandin e1 and e2 analogs for the treatment of various medical conditions Download PDF

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US20090124695A1
US20090124695A1 US12/271,798 US27179808A US2009124695A1 US 20090124695 A1 US20090124695 A1 US 20090124695A1 US 27179808 A US27179808 A US 27179808A US 2009124695 A1 US2009124695 A1 US 2009124695A1
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compound
enyl
general formula
hept
hydroxy
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Nancy S. Barta
Gregory W. Endres
Andrei M. Kornilov
Kirk M. Maxey
Adam Uzieblo
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Cayman Chemical Co Inc
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Cayman Chemical Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • the present invention relates to pharmaceutically active compounds and more particularly to prostaglandin analogs with selectivity for prostaglandin E (EP) receptors and demonstrating EP agonist activity, and the use of such compounds and compositions thereof for the treatment of various medical conditions.
  • EP prostaglandin E
  • Prostanoids are ubiquitous lipid mediator biomolecules involved in numerous physiological processes, such as the contraction and relaxation of smooth muscle, vasodilation, vasoconstriction, pain, regulation of blood pressure, and modulation of inflammation.
  • Prostanoids are a family of eicosanoids that comprise prostaglandins (PGs), prostacyclins (PGIs), and thromboxanes (Txs).
  • PGs prostaglandins
  • PKIs prostacyclins
  • Txs thromboxanes
  • GPCR G-protein coupled receptor
  • DP prostaglandin D
  • EP prostaglandin E
  • FP prostaglandin F
  • IP prostaglandin I
  • TP Thromboxane A
  • Prostanoids are synthesized from essential fatty acids comprising twenty carbon atoms, such as arachidonic acid and 8,11,14-eicosatrienoic acid. Prostanoids are synthesized in response to both extracellular and intracellular stimuli and are then rapidly released from the cells. In general, the short half-lives of most prostanoids ensure they act near the sites of their biosynthesis.
  • Prostaglandin E 2 is a potent endogenous EP receptor agonist derived from arachidonic acid, shown below, and possesses two carbon-carbon double bonds, one in each the ⁇ -chain and co-chain, and is thus called a “Series 2” prostaglandin.
  • Prostaglandin E 1 (PGE 1 ) is derived from 8,11,14-eicosatrienoic acid and possesses only one carbon-carbon double bond, located in the co-chain, and is thus called a “Series 1” prostaglandin.
  • EP receptor agonists may have a number of utilities. These include, but are not limited to treatment of influenza (WO 2008/058766), bone fracture healing (Li, M., et al., J. Bone Miner. Res., 18(11), 2003, 2033-2042; Paralkar, V.
  • EP receptor agonists may also be useful for expansion of hematopoietic stem cell populations (WO 2008/073748; North, T. E., et al., Nature, 447, 200 7, 1007-1011).
  • the exemplary embodiments may be directed to compounds of structural formula (I) that may be used to expand hematopoietic stem cell populations or to treat or prevent influenza, bone fracture, bone disease, glaucoma, ocular hypertension, dysmenorrhoea, pre-term labor, immune disorders, osteoporosis, asthma, allergy, male sexual dysfunction, female sexual dysfunction, periodontal disease, gastric ulcer, renal disease, or other EP receptor-mediated conditions wherein C 9 , C 11 , R 1 , Z 1 , Z 2 , Z 3 , Z 4 , Z 1 , Z 6 , and Z 7 are defined herein:
  • Another aspect of the embodiment is a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to formula (I), any stereoisomer or geometric isomer thereof, or a prodrug thereof, or a hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier.
  • Another aspect of the embodiment is directed to a method of expanding hematopoietic stem cell populations in a culture or patient in need thereof by administering to the culture or patient a compound according to formula (I), any stereoisomer or geometric isomer thereof, or a prodrug thereof, or a hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof.
  • Another aspect of the embodiment is directed to a method of treating or preventing influenza, bone fracture, bone disease, glaucoma, ocular hypertension, dysmenorrhoea, pre-term labor, immune disorders, osteoporosis, asthma, allergy, male sexual dysfunction, female sexual dysfunction, periodontal disease, gastric ulcer, renal disease, or other EP receptor-mediated conditions in a patient in need thereof by administering to the patient a compound according to formula (I), any stereoisomer or geometric isomer thereof, or a prodrug thereof, or a hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof.
  • the exemplary embodiments are directed to a compound of formula (I), their preparation, pharmaceutical compositions comprising these compounds, and their pharmaceutical use in the prevention and treatment of EP receptor-mediated diseases or conditions.
  • the compounds of formula (I) are shown below:
  • dashed bonds may each independently represent a second carbon-carbon bond in order to give a carbon-carbon double bond with either (E) or (Z) geometry or may be ignored in order to give a carbon-carbon single bond;
  • C 9 and C 11 each is independently C ⁇ CH 2 , C ⁇ O, CF 2 , CHF (any stereoisomer), or C(H)OH (any stereoisomer) with the proviso that C 9 does not equal C 11 , and also with the proviso that when one of either C 9 or C 11 is C ⁇ O, and the other is C(H)OH, at least one of Z 2 , Z 3 , Z 4 , and Z 5 is fluorine, and also with the proviso that when one of either C 9 or C 11 is CHF, the other is not C(H)OH;
  • R 1 is CO 2 R 3 , CH 2 OR 3 , CONR 4 R 5 , COCH 2 OH, CONR 4 SO 2 R 5 , P(O)(OR 4 ) 2 , or
  • R 3 is hydrogen or (C 1 -C 6 )-alkyl; R 4 and R 5 each is independently hydrogen or (C 1 -C 6 )-alkyl; Z 1 are hydrogen or fluorine; Z 2 and Z 3 each is independently hydrogen or fluorine; Z 4 and Z 5 each is independently hydrogen, fluorine, hydroxy, or methyl, or together are an oxygen atom that form a carbonyl group with the adjoining carbon atom of the ⁇ chain; Z 6 and Z 7 each is independently hydrogen, fluorine, hydroxy, or methyl, or together are an oxygen atom that form a carbonyl group with the adjoining carbon atom of the ⁇ chain;
  • the exemplary embodiment above may also include any stereoisomer or geometric isomer thereof, or an equivalent thereof, or a prodrug thereof, or a hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof.
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein C 9 is C ⁇ O and C 11 is C ⁇ CH 2 .
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein C 9 is C(H)OH and C 11 is C ⁇ CH 2 .
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein C 9 is C ⁇ CH 2 and C 11 is C ⁇ O.
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein C 9 is C ⁇ O and C 11 is CF 2 .
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein C 9 is C(H)OH and C 11 is CF 2 .
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein C 9 is CF 2 and C 11 is C ⁇ O.
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein C 9 is CF 2 and C 11 is C(H)OH.
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein C 9 is C ⁇ O and C 11 is CHF.
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein C 9 is CHF and C 11 is C ⁇ O.
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein R 1 is CO 2 H.
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein R 1 is CO 2 i Pr.
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein R 1 is CON(H)Et.
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein R 1 is CON(H)SO 2 Me.
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein R 1 is CH 2 OH.
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein R 1 is
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein Z 1 is hydrogen.
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein Z 1 is fluorine.
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein Z 2 is fluorine and Z 3 is hydrogen.
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein Z 2 is hydrogen and Z 3 is fluorine.
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein each Z 4 and Z 5 is fluorine.
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein each Z 4 and Z 5 is methyl.
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein Z 4 is hydroxy and Z 5 is methyl.
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein Z 4 and Z 5 together is an oxygen atom that form a carbonyl with the adjoining carbon atom.
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein each Z 6 and Z 7 is hydrogen.
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein each Z 6 and Z 7 is fluorine.
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein each Z 6 and Z 7 is methyl.
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein Z 6 is hydroxy and Z 7 is hydrogen.
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein Z 6 is hydroxy and Z 7 is methyl.
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein Z 6 is methyl and Z 7 is hydrogen.
  • Another exemplary embodiment may be directed to a compound of formula (I) wherein Z 6 and Z 7 together is an oxygen atom that form a carbonyl with the adjoining carbon atom.
  • Another exemplary embodiment may be directed to a more specific embodiment of the compound of formula (I), namely to a compound of formula (I):
  • Another exemplary embodiment may be directed to a more specific embodiment of the compound of formula (I), namely to a compound of formula (III):
  • Another exemplary embodiment may be directed to a more specific embodiment of the compound of formula (I), namely to a compound of formula (IV):
  • Another exemplary embodiment may be directed to a more specific embodiment of the compound of formula (I), namely to a compound of formula (V):
  • Another exemplary embodiment may be a compound selected from the group consisting of: (Z)-2,2-difluoro-7-((1R,2R)-2-((S,E)-3-hydroxyoct-1-enyl)-3-methylene-5-oxocyclopentyl)hept-5-enoic acid; (Z)-7-((1R,2R)-2-((1R,3S)-1-fluoro-3-hydroxyoctyl)-3-methylene-5-oxocyclopentyl)hept-5-enoic acid; (Z)-7-((1R,2R)-2-((1S,3S)-2-fluoro-3-hydroxyoctyl)-3-methylene-5-oxocyclopentyl)hept-5-enoic acid; (Z)-7-((1R,2R)-2-((2R,3S)-2-fluoro-3-hydroxyoctyl)-3-methylene-5-oxocyclopenty
  • Another exemplary embodiment may be a compound selected from the group consisting of: (Z)-7-((1R,2R)-2-((E)-3,3-difluorooct-1-enyl)-5-methylene-3-oxocyclopentyl)hept-5-enoic acid; (Z)-7-((1R,2R)-3,3-difluoro-2-((S,E)-3-hydroxy-3-methyloct-1-enyl)-5-oxocyclopentyl)hept-5-enoic acid; (Z)-7-((1R,2R,3R)-2-((E)-3,3-difluorooct-1-enyl)-3-hydroxy-5-methylenecyclopentyl)hept-5-enoic acid; (Z)-7-((1R,2R,3R)-3-fluoro-2-((R,E)-3-hydroxy-4,4-dimethyloct-1-enyl)-5
  • the exemplary embodiments may also be directed to a method of preventing or treating a disease or condition mediated at least in part by agonism of an EP receptor, in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of any exemplary embodiment of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof; the use of a compound of any exemplary embodiment of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for the manufacture of a medicament for preventing or treating a disease or condition mediated at least in part by agonism of an EP receptor; a compound of any exemplary embodiment of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use as a medicament; a compound of any exemplary embodiment of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for use in the prevention or treatment of a disease or condition mediated at least in part by agonism of an EP receptor; a pharmaceutical composition compris
  • the diseases and conditions mediated at least in part by agonism of an EP receptor may include allergy and allergic inflammation.
  • Diseases and conditions of this kind may be allergic respiratory conditions such as allergic rhinitis, nasal congestion, rhinorrhea, perennial rhinitis, nasal inflammation, asthma of all types, chronic obstructive pulmonary disease (COPD), chronic or acute bronchoconstriction, chronic bronchitis, small airways obstruction, emphysema, chronic eosinophilic pneumonia, adult respiratory distress syndrome, exacerbation of airways hyper-reactivity consequent to other drug therapy, airways disease that may be associated with pulmonary hypertension, acute lung injury, bronchiectasis, sinusitis, allergic conjunctivitis, or atopic dermatitis, particularly asthma or chronic obstructive pulmonary disease.
  • allergic respiratory conditions such as allergic rhinitis, nasal congestion, rhinorrhea, perennial rhinitis, nasal inflammation, asthma of all types, chronic obstructive pulmonary
  • Types of asthma may include atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiologic disturbances, extrinsic asthma caused by environmental factors, essential asthma of unknown or inapparent cause, bronchitic asthma, emphysematous asthma, exercise-induced asthma, exertion asthma, allergen-induced asthma, cold air induced asthma, occupational asthma, infective asthma caused by bacterial, fungal, protozoal, or viral infection, non-allergic asthma, incipient asthma, whez infant syndrome, and bronchiolytis.
  • any exemplary embodiment of formula (I) for the treatment of asthma may be palliative treatment for the symptoms and conditions of asthma such as wheezing, coughing, shortness of breath, tightness in the chest, shallow or fast breathing, nasal flaring (nostril size increases with breathing), retractions (neck area and between or below the ribs moves inward with breathing), cyanosis (gray or bluish tint to skin, beginning around the mouth), runny or stuffy nose, and headache.
  • the exemplary embodiments may also be directed to any of the uses, methods, or compositions as defined above wherein the compound of any exemplary embodiment of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, may be used in combination with another pharmacologically active compound.
  • Specific combinations useful for the treatment of allergy or asthma may include combinations comprising a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and (i) a glucocorticosteroid or DAGR (dissociated agonist of the corticoid receptor); (ii) a ⁇ 2 agonist, an example of which is a long-acting ⁇ 2 agonist; (iii) a muscarinic M3 receptor antagonist or anticholinergic agent; (iv) a histamine receptor antagonist or inverse agonist, which may be an H1 or an H3 antagonist or inverse agonist; (v) a 5-lipoxygenase inhibitor; (vi) a thromboxane inhibitor; (vii) an LTD 4 inhibitor; (viii) a kinase inhibitor; or (ix) a vaccine.
  • the compounds of the combination may be administered together as a formulation in association with one or more pharmaceutically acceptable excipients.
  • EP receptor agonists may also be useful for expansion of hematopoietic stem cell populations.
  • compounds of formula (I) may also be useful for veterinary treatment of companion animals, exotic animals, and farm animals.
  • terapéuticaally effective is intended to qualify the amount of compound or pharmaceutical composition, or the combined amount of active ingredients in the case of combination therapy. This amount or combined amount may achieve the goal of treating the relevant condition.
  • treatment means administration of the compound, pharmaceutical composition, or combination to effect preventative, palliative, supportive, restorative, or curative treatment.
  • treatment encompasses any objective or subjective improvement in a subject with respect to a relevant condition or disease.
  • prevention treatment means that the compound, pharmaceutical composition, or combination may be administered to a subject to inhibit or stop the relevant condition from occurring in a subject, particularly in a subject or member of a population that may be significantly predisposed to the relevant condition.
  • support treatment means that the compound, pharmaceutical composition, or combination may be administered to a subject as part of a regimen of therapy, but that such therapy is not limited to administration of the compound, pharmaceutical composition, or combination.
  • supportive treatment may embrace preventative, palliative, restorative, or curative treatment, particularly when the compounds or pharmaceutical compositions are combined with another component of supportive therapy.
  • restorative treatment means that the compound, pharmaceutical composition, or combination may be administered to a subject to modify the underlying progression or etiology of a condition.
  • Non-limiting examples include an increase in forced expiratory volume in one second (FEV 1) for lung disorders, inhibition of progressive nerve destruction, reduction of biomarkers associated and correlated with diseases or disorders, a reduction in relapses, improvement in quality of life, and the like.
  • curative treatment means that the compound, pharmaceutical composition, or combination may be administered to a subject for the purpose of bringing the disease or disorder into complete remission, or that the disease or disorder in undetectable after such treatment.
  • alkyl alone or in combination, means an acyclic radical, linear or branched, preferably containing from 1 to about 6 carbon atoms.
  • examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, heptyl, octyl, and the like.
  • alkyl radicals may be optionally substituted with groups consisting of hydroxy, sulfhydryl, methoxy, ethoxy, amino, cyano, chloro, and fluoro.
  • the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating a lower and upper number of carbon atoms in the moiety, that is, the prefix C i -C j indicates a moiety of the integer “i” to the integer “j” carbon atoms, inclusive.
  • the prefix C i -C j indicates a moiety of the integer “i” to the integer “j” carbon atoms, inclusive.
  • ‘(C 1 -C 8 )-alkyl’ refers to alkyl of one to eight carbon atoms, inclusive.
  • hydroxy and “hydroxyl,” as used herein, mean an OH radical.
  • sulfhydryl means an SH radical
  • oxo means a doubly bonded oxygen
  • alkoxy means a radical comprising an alkyl radical that is bonded to an oxygen atom, such as a methoxy radical.
  • aryl means a fully unsaturated mono- or multi-ring cycloalkyl having a cyclic array of p-orbitals containing 4n+2 electrons, including, but not limited to, substituted or unsubstituted phenyl, naphthyl, or anthracenyl optionally fused to a carbocyclic radical wherein aryl may be optionally substituted with one or more substituents from the group consisting of halo, methoxy, ethoxy, (C 1 -C 6 )-alkyl, phenyl, O-phenyl, cyano, nitro, hydroxyl, sulfhydryl, or trifluoromethyl.
  • halo means one of the following group consisting of fluoro, chloro, bromo, or iodo.
  • heterocycle refers to a saturated or unsaturated mono- or multi-ring cycloalkyl wherein one or more carbon atoms is replaced by N, S, or O.
  • heterocycle refers to a saturated or unsaturated mono- or multi-ring cycloalkyl wherein one or more carbon atoms is replaced by N, S, or O.
  • heterocycle refers to a saturated or unsaturated mono- or multi-ring cycloalkyl wherein one or more carbon atoms is replaced by N, S, or O.
  • heterocycle include fully saturated ring structures such as piperazinyl, dioxanyl, tetrahydrofuranyl, oxiranyl, aziridinyl, morpholinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, and others.
  • heterocycle also include partially unsaturated ring structures such as dihydrofuranyl, pyrazolinyl, imidazolinyl, pyrrolinyl, chromanyl, dihydrothiphenyl, and others.
  • heteroaryl refers to an aromatic heterocyclic group.
  • Heteroaryl is preferably: (a) a five-membered aromatic heterocyclic group containing either (i) 1-4 nitrogen atoms or (ii) 0-3 nitrogen atoms and 1 oxygen or 1 sulfur atom; (b) a six-membered aromatic heterocyclic group containing 1-3 nitrogen atoms; (c) a nine-membered bicyclic heterocyclic group containing either (i) 1-5 nitrogen atoms or (ii) 0-4 nitrogen atoms and 1 oxygen or 1 sulfur atom; or (d) a ten-membered bicyclic aromatic heterocyclic group containing 1-6 nitrogen atoms; each of said groups (a)-(d) being optionally substituted by one or more of (C 1 -C 6 )-alkyl, (C 1 -C 6 )-fluoroalkyl, (C 3 -C 6 )-cycloalkyl, hydroxy(C 3 -C
  • heteroaryl examples include pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thionyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl, optionally substituted as specified above.
  • heterocycle or “heteroaryl,” the point of attachment to the molecule of interest may be at a heteroatom or elsewhere within the ring.
  • cycloalkyl means a mono- or multi-ringed cycloalkyl wherein each ring contains three to ten carbon atoms, preferably three to six carbon atoms. “Cycloalkyl” is preferably a monocyclic cycloalkyl containing from three to six carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • excipient is used herein to describe any ingredient other than a compound of formula (I).
  • excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • excipient encompasses diluents, carrier, or adjuvant.
  • Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof.
  • Suitable acid addition salts are formed by acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, propionate, pyroglutamate
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts.
  • Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.
  • suitable salts see Handbook of Pharmaceutical Salts: Properties, Selection, and Use , by Stahl and Wermuth (Wiley-VCH, 2002).
  • the compounds of any exemplary embodiment of formula (I) may also exist in unsolvated and solvated forms.
  • solvate is used herein to describe a molecular complex comprising the compound of any exemplary embodiment of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • hydrate is employed when said solvent is water.
  • multi-component complexes other than salts and solvates wherein the compound of formula (I) and at least one other component are present in stoichiometric or non-stoichiometric amounts.
  • the compounds of any exemplary embodiment of formula (I) may exist in a continuum of solid states ranging from fully amorphous to fully crystalline.
  • the compounds of any exemplary embodiment of formula (I) may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions.
  • the mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution).
  • references to compounds of any exemplary embodiment of formula (I) include references to salts, solvates, multi-component complexes, and liquid crystals thereof and to solvates, multi-component complexes, and liquid crystals of salts thereof.
  • Compounds of any exemplary embodiment of formula (I) may be administered orally, topically, transdermally, intranasally, by inhalation, directly into the bloodstream, into muscle, into an internal organ, into the eye, into the ear, into the rectum, or by other means.
  • Mass spectra (MS) methods include positive electrospray ionization (ESI + ), negative electrospray ionization (ESI ⁇ ), positive atmospheric pressure chemical ionization (APCI + ), or negative atmospheric pressure chemical ionization (APCI ⁇ ).
  • Step A Preparation of (3aR,4R,5R,6aS)-2-oxo-4-((E)-3-oxooct-1-enyl)hexahydro-2H-cyclopenta[b]furan-5-yl Benzoate
  • Step B Preparation of (3aR,4R,5R,6aS)-4-((E)-3-hydroxy-3-methyloct-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl Benzoate
  • Step C Preparation of (3aR,4R,5R,6aS)-4-((E)-3-(tert-butyldiphenylsilyloxy)-3-methyloct-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl Benzoate
  • Step D Preparation of (3aR,4R,5R,6aS)-4-((E)-3-(tert-butyldiphenylsilyloxy)-3-methyloct-1-enyl)-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-one
  • Step E Preparation of (3aR,4R,5R,6aS)-4-((E)-3-(tert-butyldiphenylsilyloxy)-3-methyloct-1-enyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one
  • Step F Preparation of (3aR,4R,5R,6aS)-4-((E)-3-(tert-butyldiphenylsilyloxy)-3-methyloct-1-enyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-ol
  • a stirring mixture consisting of (3aR,4R,5R,6aS)-4-((E)-3-(tert-butyldiphenylsilyloxy)-3-methyloct-1-enyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one (limiting reagent, prepared in Step E) in anhydrous THF (0.5 M) under a nitrogen atmosphere was cooled to ⁇ 78° C. A solution consisting of DIBAL-H (1 M in toluene, 2 molar equivalents) was added to the reaction mixture dropwise and stirred for 3 hours.
  • Step G Preparation of (Z)-7-((1R,2R,3R,5S)-2-((E)-3-(tert-butyldiphenylsilyloxy)-3-methyloct-1-enyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoic Acid
  • lactol (3aR,4R,5R,6aS)-4-((E)-3-(tert-butyldiphenylsilyloxy)-3-methyloct-1-enyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-ol (limiting reagent, prepared in Step F) was dissolved in THF and added dropwise to the reaction mixture containing the ylide. The reaction mixture became lighter orange in color and was stirred for 2 hours at ⁇ 15° C. and was subsequently allowed to warm to room temperature and stir overnight. The reaction mixture became dark red and TLC analysis indicated no remaining starting material.
  • the reaction mixture was acidified with 5% KHSO 4 , diluted with brine (250 mL), and extracted with ethyl acetate (200 mL). The aqueous layer was extracted with another portion of ethyl acetate (50 mL) and the combined organic extracts were washed twice with brine (2 ⁇ 250 mL), dried over sodium sulfate, and evaporated.
  • the crude product was purified by flash chromatography on regular silica gel using hexanes-ethyl acetate with 0.4% acetic acid as eluent to afford the title intermediate.
  • Step H Preparation of (Z)-methyl 7-((1R,2R,3R,5S)-2-((E)-3-(tert-butyldiphenylsilyloxy)-3-methyloct-1-enyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoate
  • a stirring mixture consisting of (Z)-7-((1R,2R,3R,5S)-2-((E)-3-(tert-butyldiphenylsilyloxy)-3-methyloct-1-enyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoic acid (prepared in Step G) in diethyl ether (0.1 M) was cooled to 0° C. under a nitrogen atmosphere. Diazomethane (freshly prepared solution in diethyl ether) was added to the stirring mixture until a light-yellow color persisted. The completion of the reaction was confirmed by the absence of starting material as judged by TLC. Upon completion, the solvents were evaporated and the product was purified by flash chromatography using hexanes-ethyl acetate as eluent to afford the title intermediate.
  • Step I Preparation of (Z)-methyl 7-((1R,2R,3R,5S)-5-(tert-butyldiphenylsilyloxy)-2-((E)-3-(tert-butyldiphenylsilyloxy)-3-methyloct-1-enyl)-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoate
  • reaction mixture was diluted with ethyl acetate and was washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and evaporated. The crude product was purified by flash chromatography on regular silica gel eluted with hexanes-ethyl acetate to afford the title intermediate.
  • Step J Preparation of (Z)-methyl 7-((1R,2R,3R,5S)-5-(tert-butyldiphenylsilyloxy)-2-((E)-3-(tert-butyldiphenylsilyloxy)-3-methyloct-1-enyl)-3-hydroxycyclopentyl)hept-5-enoate
  • Step K Preparation of (Z)-methyl 7-((1R,2R,5S)-5-(tert-butyldiphenylsilyloxy)-2-((E)-3-(tert-butyldiphenylsilyloxy)-3-methyloct-1-enyl)-3-oxocyclopentyl)hept-5-enoate
  • the reaction was quenched with isopropyl alcohol and the crude reaction mixture was diluted with ethyl acetate, washed three times with brine, and dried over magnesium sulfate. After filtration and solvent evaporation the product was purified by flash chromatography using hexanes-ethyl acetate as eluent to afford the title intermediate.
  • Step L Preparation of (Z)-methyl 7-((1R,2R,5S)-5-(tert-butyldiphenylsilyloxy)-2-((E)-3-(tert-butyldiphenylsilyloxy)-3-methyloct-1-enyl)-3-methylenecyclopentyl)hept-5-enoate
  • a stirring mixture consisting of (Z)-methyl 7-((1R,2R,5S)-5-(tert-butyldiphenylsilyloxy)-2-((E)-3-(tert-butyldiphenylsilyloxy)-3-methyloct-1-enyl)-3-oxocyclopentyl)hept-5-enoate (limiting reagent, prepared in Step K) in DCM (0.05 M) under a nitrogen atmosphere was cooled to 0° C.
  • a zinc methylenedibromide titanium tetrachloride solution was prepared by combining stirring zinc dust (2.3 g) in THF (40 mL) with methylene dibromide (0.81 mL) at ⁇ 40° C.
  • Step M Preparation of (Z)-7-((1R,2R,5S)-5-(tert-butyldiphenylsilyloxy)-2-((E)-3-(tert-butyldiphenylsilyloxy)-3-methyloct-1-enyl)-3-methylenecyclopentyl)hept-5-enoic Acid
  • Step N Preparation of (Z)-7-((1R,2R,5S)-5-hydroxy-2-((E)-3-hydroxy-3-methyloct-1-enyl)-3-methylenecyclopentyl)hept-5-enoic Acid
  • Step O Preparation of (Z)-7-((1R,2R)-2-((E)-3-hydroxy-3-methyloct-1-enyl)-3-methyl-5-oxocyclopent-3-enyl)hept-5-enoic Acid
  • the product was purified by flash chromatography using hexanes-ethyl acetate as eluent to afford an epimeric mixture of the title compound.
  • the 15-hydroxy and 15-methyl epimers may be resolved or used as an epimeric mixture.
  • Step A Preparation of (3aR,4R,5R,6aS)-4-((E)-3,3-difluorooct-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl Benzoate
  • Step B Preparation of (3aR,4R,5R,6aS)-4-((E)-3,3-difluorooct-1-enyl)-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-one
  • the title intermediate may be prepared from (3aR,4R,5R,6aS)-4-((E)-3,3-difluorooct-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate (prepared in Step A) using a procedure described in Example 1, Step D for the removal of the benzoate group.
  • Step C Preparation of (3aR,4R,5R,6aS)-4-((E)-3,3-difluorooct-1-enyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one
  • the title intermediate may be prepared from (3aR,4R,5R,6aS)-4-((E)-3,3-difluorooct-1-enyl)-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-one (prepared in Step B) using the THP-protection procedure described in Example 1, Step E.
  • Step D Preparation of (3aR,4R,5R,6aS)-4-((E)-3,3-difluorooct-1-enyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-ol
  • the title intermediate may be prepared from (3aR,4R,5R,6aS)-4-((E)-3,3-difluorooct-1-enyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one (prepared in Step C) using the procedure described in Example 1, Step F.
  • Step E (Z)-7-((1R,2R,3R,5S)-2-((E)-3,3-difluorooct-1-enyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoic Acid
  • the title intermediate may be prepared from the lactol (3aR,4R,5R,6aS)-4-((E)-3,3-difluorooct-1-enyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-ol (prepared in Step D) using the procedure described in Example 1, Step G.
  • Step F Preparation of (Z)-methyl 7-((1R,2R,3R,5S)-2-((E)-3,3-difluorooct-1-enyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoate
  • the title intermediate may be prepared from (Z)-7-((1R,2R,3R,5S)-2-((E)-3,3-difluorooct-1-enyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoic acid (prepared in Step E) using the diazomethane procedure described in Example 1, Step H.
  • Step G Preparation of (Z)-methyl 7-((1R,2R,3R,5S)-5-(tert-butyldiphenylsilyloxy)-2-((E)-3,3-difluorooct-1-enyl)-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoate
  • the title intermediate may be prepared from (Z)-methyl 7-((1R,2R,3R,5S)-2-((E)-3,3-difluorooct-1-enyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoate (prepared in Step F) using the silylation procedure described in Example 1, Step I.
  • Step H Preparation of (Z)-methyl 7-((1R,2R,3R,5S)-5-(tert-butyldiphenylsilyloxy)-2-((E)-3,3-difluorooct-1-enyl)-3-hydroxycyclopentyl)hept-5-enoate
  • the title intermediate may be prepared form (Z)-methyl 7-((1R,2R,3R,5S)-5-(tert-butyldiphenylsilyloxy)-2-((E)-3,3-difluorooct-1-enyl)-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoate (prepared in Step G) using the THP-deprotection procedure described in Example 1, Step J.
  • Step I Preparation of (Z)-methyl 7-((1R,2R,5S)-5-(tert-butyldiphenylsilyloxy)-2-((E)-3,3-difluorooct-1-enyl)-3-oxocyclopentyl)hept-5-enoate
  • the title intermediate may be prepared from (Z)-methyl 7-((1R,2R,3R,5S)-5-(tert-butyldiphenylsilyloxy)-2-((E)-3,3-difluorooct-1-enyl)-3-hydroxycyclopentyl)hept-5-enoate (prepared in Step H) using the Jones oxidation procedure described in Example 1, Step K.
  • Step J Preparation of (Z)-methyl 7-((1R,2R,5S)-5-(tert-butyldiphenylsilyloxy)-2-((E)-3,3-difluorooct-1-enyl)-3-methylenecyclopentyl)hept-5-enoate
  • the title intermediate may be prepared from (Z)-methyl 7-((1R,2R,5S)-5-(tert-butyldiphenylsilyloxy)-2-((E)-3,3-difluorooct-1-enyl)-3-oxocyclopentyl)hept-5-enoate (prepared in Step I) using the procedure described in Example 1, Step L.
  • Step K Preparation of (Z)-7-((1R,2R,5S)-5-(tert-butyldiphenylsilyloxy)-2-((E)-3,3-difluorooct-1-enyl)-3-methylenecyclopentyl)hept-5-enoic Acid
  • the title intermediate may be prepared from (Z)-methyl 7-((1R,2R,5S)-5-(tert-butyldiphenylsilyloxy)-2-((E)-3,3-difluorooct-1-enyl)-3-methylenecyclopentyl)hept-5-enoate (prepared in Step J) using the ester hydrolysis procedure described in Example 1, Step M.
  • Step L Preparation of (Z)-7-((1R,2R,5S)-2-((E)-3,3-difluorooct-1-enyl)-5-hydroxy-3-methylenecyclopentyl)hept-5-enoic Acid
  • the title compound may be prepared from (Z)-7-((1R,2R,5S)-5-(tert-butyldiphenylsilyloxy)-2-((E)-3,3-difluorooct-1-enyl)-3-methylenecyclopentyl)hept-5-enoic acid (prepared in Step K) using the silyl-deprotection procedure described in Example 1, Step N.
  • Step M Preparation of (Z)-7-((1R,2R)-2-((E)-3,3-difluorooct-1-enyl)-3-methyl-5-oxocyclopent-3-enyl)hept-5-enoic Acid
  • the title compound may be prepared from (Z)-7-((1R,2R,5S)-2-((E)-3,3-difluorooct-1-enyl)-5-hydroxy-3-methylenecyclopentyl)hept-5-enoic acid (prepared in Step L) using the Jones oxidation procedure described in Example 1, Step O.
  • Step B Preparation of (3aR,4R,5R,6aS)-2-oxo-4-((E)-3-oxo-4-(tetrahydro-2H-pyran-2-yloxy)oct-1-enyl)hexahydro-2H-cyclopenta[b]furan-5-yl Benzoate
  • a reactor equipped with a mechanical stirrer purged with nitrogen gas is charged with (3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate (99.2 g, 0.362 mol) dissolved in DCM and lithium chloride (0.362 mol) dissolved in THF. Some lithium chloride precipitates from solution when the THF and DCM solutions are mixed. Dimethyl 2-oxo-3-(tetrahydro-2H-pyran-2-yloxy)heptylphosphonate (0.362 mol, prepared in Step A) is added NEAT and rinsed into the reaction vessel with DCM.
  • Step C Preparation of (3aR,4R,5R,6aS)-4-((E)-3,3-difluoro-4-(tetrahydro-2H-pyran-2-yloxy)oct-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl Benzoate
  • the title intermediate may be prepared from (3aR,4R,5R,6aS)-4-((E)-4-(tert-butyldimethylsilyloxy)-3-oxooct-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate (prepared in Step B) using the DAST fluorination procedure described in Example 2, Step A.
  • Step D Preparation of (3aR,4R,5R,6aS)-4-((E)-3,3-difluoro-4-(tetrahydro-2H-pyran-2-yloxy)oct-1-enyl)-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-one
  • the title intermediate may be prepared from (3aR,4R,5R,6aS)-4-((E)-3,3-difluoro-4-(tetrahydro-2H-pyran-2-yloxy)oct-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate (prepared in Step C) using a procedure described in Example 1, Step D for the removal of the benzoate group.
  • Step E Preparation of (3aR,4R,5R,6aS)-4-((E)-3,3-difluoro-4-(tetrahydro-2H-pyran-2-yloxy)oct-1-enyl)hexahydro-2H-cyclopenta[b]furan-2,5-diol
  • the title intermediate may be prepared from (3aR,4R,5R,6aS)-4-((E)-3,3-difluoro-4-(tetrahydro-2H-pyran-2-yloxy)oct-1-enyl)-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-one (prepared in Step D) using the reduction procedure described in Example 1, Step F.
  • Step F Preparation of (Z)-7-((1R,2R,3R,5S)-2-((E)-3,3-difluoro-4-(tetrahydro-2H-pyran-2-yloxy)oct-1-enyl)-3,5-dihydroxycyclopentyl)hept-5-enoic Acid
  • the title intermediate may be prepared from (3aR,4R,5R,6aS)-4-((E)-3,3-difluoro-4-(tetrahydro-2H-pyran-2-yloxy)oct-1-enyl)hexahydro-2H-cyclopenta[b]furan-2,5-diol (prepared in Step E) using the procedure described in Example 1, Step G.
  • Step G Preparation of (Z)-7-((1R,2R,5S)-2-((E)-3,3-difluoro-4-(tetrahydro-2H-pyran-2-yloxy)oct-1-enyl)-5-hydroxy-3-oxocyclopentyl hept-5-enoic acid and (Z)-7-((1R,2R,3R)-2-((E)-3,3-difluoro-4-(tetrahydro-2H-pyran-2-yloxy)oct-1-enyl)-3-hydroxy-5-oxocyclopentyl)hept-5-enoic Acid
  • Step H Preparation of (Z)-7-((1R,2R,3R)-2-((E)-3,3-difluoro-4-hydroxyoct-1-enyl)-3-hydroxy-5-oxocyclopentyl)hept-5-enoic Acid
  • the title compound may be prepared from (Z)-7-((1R,2R,3R)-2-((E)-3,3-difluoro-4-(tetrahydro-2H-pyran-2-yloxy)oct-1-enyl)-3-hydroxy-5-oxocyclopentyl)hept-5-enoic acid (prepared in Step G) using the THP-deprotection procedure described in Example 1, Step J.
  • the title compound may be prepared from (Z)-7-((1R,2R,5S)-2-((E)-3,3-difluoro-4-(tetrahydro-2H-pyran-2-yloxy)oct-1-enyl)-5-hydroxy-3-oxocyclopentyl)hept-5-enoic acid (prepared in Example 3, Step G) using the THP-deprotection procedure described in Example 1, Step J.
  • Step A Preparation of (Z)-methyl 7-((1R,2R,5S)-2-((E)-3,3-difluoro-4-(tetrahydro-2H-pyran-2-yloxy)oct-1-enyl)-5-hydroxy-3-oxocyclopentyl)hept-5-enoate
  • the title intermediate may be prepared from (Z)-7-((1R,2R,5S)-2-((E)-3,3-difluoro-4-(tetrahydro-2H-pyran-2-yloxy)oct-1-enyl)-5-hydroxy-3-oxocyclopentyl)hept-5-enoic acid (prepared in Example 3, Step G) using the diazomethane procedure described in Example 1, Step H.
  • Step B Preparation of (Z)-methyl 7-((1R,2R,5S)-5-(tert-butyldiphenylsilyloxy)-2-((E)-3,3-difluoro-4-(tetrahydro-2H-pyran-2-yloxy)oct-1-enyl)-3-oxocyclopentyl)hept-5-enoate
  • the title intermediate may be prepared from (Z)-methyl 7-((1R,2R,5S)-2-((E)-3,3-difluoro-4-(tetrahydro-2H-pyran-2-yloxy)oct-1-enyl)-5-hydroxy-3-oxocyclopentyl)hept-5-enoate (prepared in Step A) using the silylation procedure described in Example 1, Step I.
  • Step C Preparation of (Z)-methyl 7-((1R,2R,5S)-5-(tert-butyldiphenylsilyloxy)-2-((E)-3,3-difluoro-4-(tetrahydro-2H-pyran-2-yloxy)oct-1-enyl)-3-methylenecyclopentyl)hept-5-enoate
  • the title intermediate may be prepared from (Z)-methyl 7-((1R,2R,5S)-5-(tert-butyldiphenylsilyloxy)-2-((E)-3,3-difluoro-4-(tetrahydro-2H-pyran-2-yloxy)oct-1-enyl)-3-oxocyclopentyl)hept-5-enoate (prepared in Step B) using the procedure described in Example 1, Step L.
  • Step D Preparation of (Z)-methyl 7-((1R,2R,5S)-2-((E)-3,3-difluoro-4-(tetrahydro-2H-pyran-2-yloxy)oct-1-enyl)-5-hydroxy-3-methylenecyclopentyl)hept-5-enoate
  • the title intermediate may be prepared from (Z)-methyl 7-((1R,2R,5S)-5-(tert-butyldiphenylsilyloxy)-2-((E)-3,3-difluoro-4-(tetrahydro-2H-pyran-2-yloxy)oct-1-enyl)-3-methylenecyclopentyl)hept-5-enoate (prepared in Step C) using the TBDPS-deprotection procedure described in Example 1, Step N.
  • Step E Preparation of (Z)-7-((1R,2R,5S)-2-((E)-3,3-difluoro-4-(tetrahydro-2H-pyran-2-yloxy)oct-1-enyl)-5-hydroxy-3-methylenecyclopentyl)hept-5-enoic Acid
  • the title intermediate may be prepared from (Z)-methyl 7-((1R,2R,5S)-2-((E)-3,3-difluoro-4-(tetrahydro-2H-pyran-2-yloxy)oct-1-enyl)-5-hydroxy-3-methylenecyclopentyl)hept-5-enoate (prepared in Step D) using the ester hydrolysis procedure described in Example 1, Step M.
  • Step F Preparation of (Z)-7-((1R,2R,5S)-2-((E)-3,3-difluoro-4-hydroxyoct-1-enyl)-5-hydroxy-3-methylenecyclopentyl)hept-5-enoic Acid
  • the title compound may be prepared from (Z)-7-((1R,2R,5S)-2-((E)-3,3-difluoro-4-(tetrahydro-2H-pyran-2-yloxy)oct-1-enyl)-5-hydroxy-3-methylenecyclopentyl)hept-5-enoic acid (prepared in Step E) using the THP-deprotection procedure described in Example 1, Step J.
  • Step A Preparation of (Z)-7-((1R,2R)-2-((E)-3,3-difluoro-4-(tetrahydro-2H-pyran-2-yloxy)oct-1-enyl)-3-methyl-5-oxocyclopent-3-enyl)hept-5-enoic Acid
  • the title intermediate may be prepared from (Z)-7-((1R,2R,5S)-2-((E)-3,3-difluoro-4-(tetrahydro-2H-pyran-2-yloxy)oct-1-enyl)-5-hydroxy-3-methylenecyclopentyl)hept-5-enoic acid (prepared in Example 5, Step E) using the Jones oxidation procedure described in Example 1, Step O.
  • Step B Preparation of (Z)-7-((1R,2R)-2-((E)-3,3-difluoro-4-hydroxyoct-1-enyl)-3-methyl-5-oxocyclopent-3-enyl)hept-5-enoic Acid
  • the title compound may be prepared from (Z)-7-((1R,2R)-2-((E)-3,3-difluoro-4-(tetrahydro-2H-pyran-2-yloxy)oct-1-enyl)-3-methyl-5-oxocyclopent-3-enyl)hept-5-enoic acid (prepared in Step A) using the THP-deprotection procedure described in Example 1, Step J.
  • the ability of compounds to bind the EP receptors and their selectivity for each receptor can be demonstrated in radioligand competition displacement binding experiments using the cell lines described above which stably overexpress the human EP receptors.
  • the ability of compounds to activate the receptors can be demonstrated in second messenger functional assays, measuring changes in intracellular calcium for EP 1 and changes in cAMP formation for EP 2 , EP 3 and EP 4 .
  • Membranes are prepared from cells stably transfected with human EP receptor DNA. In brief, cells are cultured to confluence, scraped from culture flasks and centrifuged to pellet (800 ⁇ g, 5 minutes, 4° C.). Cells are washed twice with ice-cold homogenization buffer containing 10 mM Tris-HCl, 1 mM EDTA, 250 mM sucrose, 1 mM PMSF, 300 ⁇ M indomethacin, pH 7.4, homogenized by sonication and centrifuged as before. The supernatant is stored on ice; the pellets are rehomogenized and respun. Supernatants are pooled and centrifuged at 100,000 ⁇ g for 10 minutes at 4° C. The resultant membrane pellet is stored at ⁇ 80° C. until use.
  • membranes from cells expressing human EP 1 , EP 2 , EP 3 or EP 4 receptors are added to assay buffer (10 mM MES, pH 6.0, 10 mM MgCl 2 , 1 mM EDTA, 3 ⁇ M indomethacin) containing 5 nM [ 3 H]-PGE 2 (GE Healthcare) and 0.1 to 10,000 nM concentrations of compounds to be tested. Incubations are performed at suitable temperatures and times to allow equilibration to be reached. Non-specific binding is determined in the presence of 10 ⁇ M PGE 2 . Reactions are terminated by the addition of ice-cold buffer followed by rapid filtration through Whatman GF/B filters. The filters are dried after washing, and membrane-bound radioactivity is quantified by scintillation counting.
  • EP 1 Receptor Agonism Assay Intracellular Calcium Assay
  • Calcium fluorescence is measured using an Analyst AD (Molecular Devices) with an excitation wavelength of 485 nm, emission wavelength of 560 nm, and emission cutoff of 505 nm. Responses are quantified as peak fluorescence intensity minus basal fluorescence intensity.
  • Evaluation of the agonist activity of compounds at the human EP 1 receptor in transfected HEK-293 cells determined by measuring their effect on cytosolic Ca 2+ ion mobilization using a fluorimetric detection method.
  • the cells are suspended in DMEM buffer (Invitrogen), then distributed in microplates at a density of 3 ⁇ 10 4 cells/well.
  • the fluorescent probe (Fluo4 NW, Invitrogen) mixed with probenicid in HBSS buffer (Invitrogen) complemented with 20 mM Hepes (Invitrogen) (pH 7.4) is then added into each well and equilibrated with the cells for 30 minutes at 37° C. then 30 minutes at 22° C.
  • the assay plates are positioned in a microplate reader (CellLux, PerkinElmer) which is used for the addition of the test compound, reference agonist or HBSS buffer (basal control), and the measurements of changes in fluorescence intensity which varies proportionally to the free cytosolic Ca 2+ ion concentration.
  • a microplate reader CellLux, PerkinElmer
  • PGE 2 at 100 nM is added in separate assay wells.
  • the results are expressed as a percent of the control response to 100 nM PGE 2 .
  • the standard reference agonist is PGE 2 , which is tested in each experiment at several concentrations to generate a concentration-response curve from which its EC 50 value is calculated.
  • the cells are suspended in DMEM buffer (Invitrogen), then distributed in microplates at a density of 3 ⁇ 10 4 cells/well.
  • the fluorescent probe (Fluo4 NW, Invitrogen) mixed with probenicid in HBSS buffer (Invitrogen) complemented with 20 mM Hepes (Invitrogen) (pH 7.4) is then added into each well and equilibrated with the cells for 30 minutes at 37° C. then 30 minutes at 22° C.
  • the assay plates are positioned in a microplate reader (CellLux, PerkinElmer) which is used for the addition of the test compound, reference antagonist or HBSS buffer (basal control), then 5 minutes later 3 nM PGE 2 , and the measurements of changes in fluorescence intensity which varies proportionally to the free cytosolic Ca 2+ ion concentration. The results are expressed as a percent inhibition of the control response to 3 nM PGE 2 .
  • the standard reference antagonist is SC 51322, which is tested in each experiment at several concentrations to generate a concentration-response curve from which its IC 50 value is calculated.
  • the cells are suspended in HBSS buffer (Invitrogen) complemented with HEPES 20 mM (pH 7.4) and 500 ⁇ M IBMX, then distributed in microplates at a density of 10 4 cells/well and incubated for 30 minutes at 37° C. in the absence (control) or presence of the test compound or the reference agonist. For stimulated control measurements, separate assay wells contain 10 ⁇ M PGE 2 . Following incubation, the cells are lysed and the fluorescence acceptor (D2-labeled cAMP) and fluorescence donor (anti-cAMP antibody labeled with europium cryptate) are added.
  • D2-labeled cAMP fluorescence acceptor
  • fluorescence donor anti-cAMP antibody labeled with europium cryptate
  • the cAMP concentration is determined by dividing the signal measured at 665 nm by that measured at 620 nm (ratio). The results are expressed as a percent of the control response to 10 ⁇ M PGE 2 .
  • the standard reference agonist is PGE 2 , which is tested in each experiment at several concentrations to generate a concentration-response curve from which its EC 50 value is calculated.
  • the cells are suspended in HBSS buffer (Invitrogen) complemented with HEPES 20 mM (pH 7.4) and 500 ⁇ M IBMX, then distributed in microplates at a density of 10 4 cells/well and preincubated for 5 minutes at room temperature in the absence (control) or presence of the test compound or the reference antagonist. Thereafter, the reference agonist PGE 2 is added at a final concentration of 300 nM. For basal control measurements, separate assay wells do not contain PGE 2 . Following 30 minutes incubation at 37° C., the cells are lysed and the fluorescence acceptor (D2-labeled cAMP) and fluorescence donor (anti-cAMP antibody labeled with europium cryptate) are added.
  • HBSS buffer Invitrogen
  • HEPES 20 mM pH 7.4
  • IBMX 500 ⁇ M IBMX
  • the cAMP concentration is determined by dividing the signal measured at 665 nm by that measured at 620 nm (ratio). The results are expressed as a percent inhibition of the control response to 300 nM PGE 2 .
  • the standard reference antagonist is AH 6809, which is tested in each experiment at several concentrations to generate a concentration-response curve from which its IC 50 value is calculated.
  • EP 3 Receptor Agonism Assay Inhibition of Forskolin-induced cAMP Generation Assay
  • cAMP accumulation induced by forskolin following treatment with compounds is measured.
  • Cells expressing the EP 3 receptor are plated in 24-well plates in normal growth medium and allowed to come to confluence. When the cells have come to confluence, the medium is replaced with 450 ⁇ l of serum-free medium containing 0.25 mM IBMX and 20 ⁇ M indomethacin. Cells are incubated in this medium for one hour. Fifty microliters of this same buffer containing 3 ⁇ M forskolin and various concentrations of PGE 2 or compounds to be tested are subsequently added to the cells. After incubation at 37° C. for 10 minutes, reactions are terminated by the addition of 500 ⁇ l of 10% TCA.
  • cAMP measurements of the cell lysates are performed using Cayman Chemical's cAMP EIA Kit following the instructions provided in the kit booklet.
  • the cells are suspended in HBSS buffer (Invitrogen) complemented with HEPES 20 mM (pH 7.4) and 500 ⁇ M IBMX, then distributed in microplates at a density of 2 ⁇ 10 4 cells/well and incubated for 10 minutes at room temperature in the absence (control) or presence of the test compound or the reference agonist. For stimulated control measurements, separate assay wells contain 1 ⁇ M PGE 2 . Following incubation, the cells are lysed and the fluorescence acceptor (D2-labeled cAMP) and fluorescence donor (anti-cAMP antibody labeled with europium cryptate) are added.
  • D2-labeled cAMP fluorescence acceptor
  • fluorescence donor anti-cAMP antibody labeled with europium cryptate
  • the cAMP concentration is determined by dividing the signal measured at 665 nm by that measured at 620 nm (ratio). The results are expressed as a percent of the control response to 1 ⁇ M PGE 2 .
  • the standard reference agonist is PGE 2 , which is tested in each experiment at several concentrations to generate a concentration-response curve from which its EC 50 value is calculated.
  • the cells are suspended in HBSS buffer (Invitrogen) complemented with HEPES 20 mM (pH 7.4) and 500 ⁇ M IBMX, then distributed in microplates at a density of 2 ⁇ 10 4 cells/well and preincubated for 5 minutes at room temperature in the absence (control) or presence of the test compound or the reference antagonist.
  • HBSS buffer Invitrogen
  • HEPES 20 mM pH 7.4
  • IBMX 500 ⁇ M IBMX
  • the reference agonist PGE 2 is added at a final concentration of 10 nM.
  • the cells are lysed and the fluorescence acceptor (D2-labeled cAMP) and fluorescence donor (anti-cAMP antibody labeled with europium cryptate) are added.
  • the cAMP concentration is determined by dividing the signal measured at 665 nm by that measured at 620 nm (ratio). The results are expressed as a percent inhibition of the control response to 10 nM PGE 2 . There is no standard reference antagonist for this assay.

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US12/271,798 2007-11-14 2008-11-14 Prostaglandin e1 and e2 analogs for the treatment of various medical conditions Abandoned US20090124695A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112645861A (zh) * 2020-12-21 2021-04-13 上海彩迩文生化科技有限公司 一种分离卡前列素15位异构体的方法
CN112979599A (zh) * 2021-03-01 2021-06-18 河北赛谱睿思医药科技有限公司 一种卡前列素氨丁三醇中间体的制备方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112645861A (zh) * 2020-12-21 2021-04-13 上海彩迩文生化科技有限公司 一种分离卡前列素15位异构体的方法
CN112979599A (zh) * 2021-03-01 2021-06-18 河北赛谱睿思医药科技有限公司 一种卡前列素氨丁三醇中间体的制备方法

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US8063240B2 (en) 2011-11-22
WO2009065070A4 (fr) 2009-10-01
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