WO2015073140A1 - 1,3,4-alkenyl oxadiazole amino acid derivatives as sphingosine-1-phosphate receptors' modulators - Google Patents

1,3,4-alkenyl oxadiazole amino acid derivatives as sphingosine-1-phosphate receptors' modulators Download PDF

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Publication number
WO2015073140A1
WO2015073140A1 PCT/US2014/059772 US2014059772W WO2015073140A1 WO 2015073140 A1 WO2015073140 A1 WO 2015073140A1 US 2014059772 W US2014059772 W US 2014059772W WO 2015073140 A1 WO2015073140 A1 WO 2015073140A1
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Prior art keywords
oxadiazol
benzyl
amino
acid
phenylhex
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PCT/US2014/059772
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French (fr)
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Ling Li
Janet A. Takeuchi
Ken Chow
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Allergan, Inc.
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Publication of WO2015073140A1 publication Critical patent/WO2015073140A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • C07D413/10—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 carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07F9/653—Five-membered rings
    • C07F9/65306—Five-membered rings containing two nitrogen atoms
    • C07F9/65312—Five-membered rings containing two nitrogen atoms having the two nitrogen atoms in positions 1 and 2

Definitions

  • the present invention relates to 1 ,3,4-alkenyl oxadiazole amino acid
  • the invention relates specifically to the use of these compounds and their pharmaceutical compositions to treat disorders associated with sphingosine-1 - phosphate (S1 P) receptor modulation.
  • Sphingosine-1 phosphate is stored in relatively high concentrations in human platelets, which lack the enzymes responsible for its catabolism, and it is released into the blood stream upon activation of physiological stimuli, such as growth factors, cytokines, and receptor agonists and antigens. It may also have a critical role in platelet aggregation and thrombosis and could aggravate cardiovascular diseases.
  • physiological stimuli such as growth factors, cytokines, and receptor agonists and antigens. It may also have a critical role in platelet aggregation and thrombosis and could aggravate cardiovascular diseases.
  • the relatively high concentration of the metabolite in high-density lipoproteins (HDL) may have beneficial implications for atherogenesis.
  • sphingosine-1 -phosphate together with other lysolipids such as sphingosylphosphorylcholine and lysosulfatide, are responsible for the beneficial clinical effects of HDL by stimulating the production of the potent antiatherogenic signaling molecule nitric oxide by the vascular endothelium.
  • lysophosphatidic acid it is a marker for certain types of cancer, and there is evidence that its role in cell division or proliferation may have an influence on the development of cancers.
  • modulator includes but is not limited to: receptor agonist, antagonist, inverse agonist, inverse antagonist, partial agonist, partial antagonist.
  • This invention describes compounds of Formula I, which have sphingosine-1 - phosphate receptor biological activity.
  • the compounds in accordance with the present invention are thus of use in medicine, for example in the treatment of humans with diseases and conditions that are alleviated by S1 P modulation.
  • the invention provides a compound having Formula I or a
  • R 1 is substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C 5 -8 cycloalkyl, substituted or unsubstituted C 5 -8 cycloalkenyl;
  • R 2 is substituted or unsubstituted Ci-s alkyl
  • R 3 is hydrogen, halogen, substituted or unsubstituted C -8 alkyl, C(0)R 7 or hydroxyl
  • R 4 is hydrogen, halogen, substituted or unsubstituted C -8 alkyl, C(0)R 7 or hydroxyl
  • R 5 is hydrogen, halogen, substituted or unsubstituted Ci -8 alkyl, C(0)R 7 or hydroxyl; substituted or unsubstituted heterocycle
  • R 6 is hydrogen, halogen, substituted or unsubstituted Ci -8 alkyl, C(0)R 7 or hydroxyl; substituted or unsubstituted heterocycle;
  • R 7 is hydrogen , -OR 8 , substituted or unsubstituted C-i-s alkyl
  • R 8 is hydrogen , substituted or unsubstituted Ci -8 alkyl
  • R 9 is OPO 3 H 2 , carboxylic acid, P0 3 H 2 , -P(0)MeOH, -P(0)(H)OH or OR 11 ;
  • R 10 is hydrogen , substituted or unsubstituted Ci -3 alkyl
  • R 11 is hydrogen , substituted or unsubstituted Ci -3 alkyl
  • a is 1 , 2 or 3.
  • the invention provides a compound having Formula II or a pharmaceutically acceptable salt thereof or enantiomers, diastereoisomers, tautomers, zwitterions and pharmaceutically acceptable salts thereof:
  • R 1 is substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C 5 -8 cycloalkyl, substituted or unsubstituted C 5 -8 cycloalkenyl;
  • R 2 is substituted or unsubstituted Ci -8 alkyl
  • R 3 is hydrogen, halogen, substituted or unsubstituted C -8 alkyl, C(0)R 7 or hydroxyl;
  • R 4 is hydrogen, halogen, substituted or unsubstituted C -8 alkyl, C(0)R 7 or hydroxyl;
  • R 5 is hydrogen, halogen, substituted or unsubstituted Ci -8 alkyl, C(0)R 7 , hydroxyl, or substituted or unsubstituted heterocycle;
  • R 6 is hydrogen, halogen, substituted or unsubstituted Ci -8 alkyl, C(0)R 7 , hydroxyl, or substituted or unsubstituted heterocycle;
  • R 7 is hydrogen, -OR 9 , substituted or unsubstituted Ci -8 alkyl
  • R 8 is OPO 3 H 2 , carboxylic acid, P0 3 H 2 , -P(0)MeOH, -P(0)(H)OH or OR 9 ;
  • R 9 is hydrogen or substituted or unsubstituted Ci -8 alkyl
  • R 10 is hydrogen or substituted or unsubstituted Ci -8 alkyl.
  • alkyl refers to saturated, monovalent or divalent hydrocarbon moieties having linear or branched moieties or combinations thereof and containing 1 to 8 carbon atoms.
  • One methylene (-CH 2 -) group, of the alkyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, or by a divalent C3-6 cycloalkyl.
  • Alkyl groups can be substituted by but not limited to halogen, hydroxyl, cycloalkyl, amino, non-aromatic heterocycles, carboxylic acid, phosphonic acid groups, sulphonic acid groups, phosphoric acid.
  • cycloalkyl refers to a monovalent or divalent group of 3 to 8 carbon atoms derived from a saturated cyclic hydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic. Cycloalkyl can be substituted by but not limited to C-
  • cycloalkenyl refers to a monovalent or divalent group of 3 to 8 carbon atoms derived from a saturated cycloalkyl having one double bond. Cycloalkenyl groups can be monocyclic or polycyclic. Cycloalkenyl groups can be substituted by but not limited to C-i-s alkyl groups or halogens.
  • halogen refers to an atom of chlorine, bromine, fluorine, iodine.
  • alkenyl refers to a monovalent or divalent hydrocarbon moiety having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one double bond.
  • C 2-6 alkenyl can be in the E or Z configuration.
  • Alkenyl groups can be substituted by but not limited to d-s alkyl.
  • heterocycle refers to a 3 to 10 membered ring, which can be aromatic or non-aromatic, saturated or non-saturated, containing at least one heteroatom selected form O or N or S or combinations of at least two thereof, interrupting the carbocyclic ring structure.
  • the heterocyclic ring can be saturated or non-saturated.
  • Heterocycles can be monocyclic or polycyclic. Heterocyclic ring moieties can be substituted by but not limited to hydroxyl, C 1-8 alkyl or halogens.
  • aryl refers to an organic moiety derived from an aromatic hydrocarbon consisting of a ring containing 6 to 10 carbon atoms by removal of one hydrogen, which can be substituted by but not limited to halogen atoms or C-i-s alkyl groups.
  • hydroxyl as used herein, represents a group of formula "-OH”.
  • carbonyl as used herein, represents a group of formula "-C(O)”.
  • carboxylic acid as used herein, represents a group of formula "- C(0)OH”.
  • phosphonic acid as used herein, represents a group of formula "- P(0)(OH) 2 ".
  • phosphoric acid as used herein, represents a group of formula "- (0)P(0)(OH) 2 ".
  • sulphonic acid as used herein, represents a group of formula "- S(0) 2 OH”.
  • H as used herein, represents a hydrogen atom.
  • N represents a nitrogen atom
  • Some compounds of Formula I or of Formula II and some of their intermediates may have at least one stereogenic center in their structure.
  • This stereogenic center may be present in an R or S configuration, said R and S notation is used in
  • pharmaceutically acceptable salts refers to salts or complexes that retain the desired biological activity of the above identified compounds and exhibit minimal or no undesired toxicological effects.
  • pharmaceutically acceptable salts according to the invention include therapeutically active, non-toxic base or acid salt forms, which the compounds of Formula I or of Formula II are able to form.
  • the acid addition salt form of a compound of Formula I or of Formula II that occurs in its free form as a base can be obtained by treating the free base with an appropriate acid such as an inorganic acid, such as for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; or an organic acid such as for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric, methylsulfonic, ethanesulfonic, benzenesulfonic, formic and the like (Handbook of Pharmaceutical Salts, P. Heinrich Stahl & Camille G. Wermuth (Eds), Verlag Helvetica Chimica Acta- Zurich, 2002, 329- 345).
  • an appropriate acid such
  • the base addition salt form of a compound of Formula I or of Formula II that occurs in its acid form can be obtained by treating the acid with an appropriate base such as an inorganic base, for example, sodium hydroxide, magnesium hydroxide, potassium hydroxide, calcium hydroxide, ammonia and the like; or an organic base such as for example, L-Arginine, ethanolamine, betaine, benzathine, morpholine and the like.
  • an appropriate base such as an inorganic base, for example, sodium hydroxide, magnesium hydroxide, potassium hydroxide, calcium hydroxide, ammonia and the like
  • an organic base such as for example, L-Arginine, ethanolamine, betaine, benzathine, morpholine and the like.
  • the compounds of the invention are indicated for use in treating or preventing conditions in which there is likely to be a component involving the sphingosine-1 - phosphate receptors.
  • compositions including at least one compound of the invention in a pharmaceutically acceptable carrier.
  • sphingosine-1 -phosphate receptors there are provided methods for treating disorders associated with modulation of sphingosine-1 -phosphate receptors. Such methods can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one compound of the invention.
  • These compounds are useful for the treatment of mammals, including humans, with a range of conditions and diseases that are alleviated by S1 P modulation: not limited to the treatment of diabetic retinopathy, other retinal degenerative conditions, dry eye, angiogenesis and wounds.
  • S1 P modulators are ocular diseases, such as but not limited to: wet and dry age-related macular degeneration, diabetic retinopathy, angiogenesis inhibition, retinopathy of prematurity, retinal edema, geographic atrophy, glaucomatous optic neuropathy, chorioretinopathy, hypertensive retinopathy, ocular ischemic syndrome, prevention of inflammation-induced fibrosis in the back of the eye, various ocular inflammatory diseases including uveitis, scleritis, keratitis, and retinal vasculitis; or systemic vascular barrier related diseases such as but not limited to: various inflammatory diseases, including acute lung injury, its prevention, sepsis, tumor metastasis, atherosclerosis, pulmonary edemas, and ventilation-induced lung injury; or autoimmune diseases and immunosuppression such as but not limited to: rheumatoid arthritis, Crohn's disease, Graves' disease, inflammatory bowel disease, multiple
  • sphingosine-1 -phosphate receptors there are provided methods for treating disorders associated with modulation of sphingosine-1 -phosphate receptors. Such methods can be performed, for example, by administering to a subject in need thereof a therapeutically effective amount of at least one compound of the invention, or any combination thereof, or pharmaceutically acceptable salts, individual enantiomers, and diastereomers thereof.
  • the present invention concerns the use of a compound of Formula I or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of ocular disease, wet and dry age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal edema, geographic atrophy,
  • angiogenesis inhibition glaucomatous optic neuropathy, chorioretinopathy, hypertensive retinopathy, ocular ischemic syndrome, prevention of inflammation- induced fibrosis in the back of the eye, various ocular inflammatory diseases including uveitis, scleritis, keratitis, and retinal vasculitis; or systemic vascular barrier related diseases , various inflammatory diseases, including acute lung injury, its prevention, sepsis, tumor metastasis, atherosclerosis, pulmonary edemas, and ventilation-induced lung injury; or autoimmune diseases and immunosuppression , rheumatoid arthritis, Crohn's disease, Graves' disease, inflammatory bowel disease, multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative colitis, antoimmune uveitis, renal
  • ischemia/perfusion injury contact hypersensitivity, atopic dermititis, and organ transplantation; or allergies and other inflammatory diseases , urticaria, bronchial asthma, and other airway inflammations including pulmonary emphysema and chronic obstructive pulmonary diseases; or cardiac protection , ischemia reperfusion injury and atherosclerosis; or wound healing, scar-free healing of wounds from cosmetic skin surgery, ocular surgery, Gl surgery, general surgery, oral injuries, various mechanical, heat and burn injuries, prevention and treatment of photoaging and skin ageing, and prevention of radiation-induced injuries; or bone formation, treatment of osteoporosis and various bone fractures including hip and ankles; or anti-nociceptive activity , visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, neuropathic pains; or central nervous system neuronal activity in Alzheimer's disease, age-related neuronal injuries; or in organ transplant such as
  • the actual amount of the compound to be administered in any given case will be determined by a physician taking into account the relevant circumstances, such as the severity of the condition, the age and weight of the patient, the patient's general physical condition, the cause of the condition, and the route of administration.
  • the patient will be administered the compound orally in any acceptable form, such as a tablet, liquid, capsule, powder and the like, or other routes may be desirable or necessary, particularly if the patient suffers from nausea.
  • Such other routes may include, without exception, transdermal, parenteral, subcutaneous, intranasal, via an implant stent, intrathecal, intravitreal, topical to the eye, back to the eye,
  • the formulations may be designed to delay release of the active compound over a given period of time, or to carefully control the amount of drug released at a given time during the course of therapy.
  • compositions including at least one compound of the invention in a pharmaceutically acceptable carrier thereof.
  • pharmaceutically acceptable means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions of the present invention can be used in the form of a solid, a solution, an emulsion, a dispersion, a patch, a micelle, a liposome, and the like, wherein the resulting composition contains one or more compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications.
  • Invention compounds may be combined, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
  • the carriers which can be used include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form.
  • Invention compounds are included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or disease condition.
  • compositions containing invention compounds may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of a sweetening agent such as sucrose, lactose, or saccharin, flavoring agents such as peppermint, oil of wintergreen or cherry, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets containing invention compounds in admixture with non-toxic pharmaceutically acceptable excipients may also be manufactured by known methods.
  • the excipients used may be, for example, (1 ) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents such as corn starch, potato starch or alginic acid; (3) binding agents such as gum tragacanth, corn starch, gelatin or acacia, and (4) lubricating agents such as magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • formulations for oral use may be in the form of hard gelatin capsules wherein the invention compounds are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the invention compounds are mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin.
  • water or an oil medium for example, peanut oil, liquid paraffin or olive oil.
  • the pharmaceutical compositions may be in the form of a sterile injectable suspension.
  • This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol.
  • Sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides, fatty acids (including oleic acid), naturally occurring vegetable oils like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyl oleate or the like. Buffers, preservatives, antioxidants, and the like can be incorporated as required.
  • compositions containing invention compounds may be in a form suitable for topical use, for example, as oily suspensions, as solutions or suspensions in aqueous liquids or nonaqueous liquids, or as oil-in-water or water-in-oil liquid emulsions.
  • Pharmaceutical compositions may be prepared by combining a therapeutically effective amount of at least one compound according to the present invention, or a pharmaceutically acceptable salt thereof, as an active ingredient with conventional ophthalmically acceptable pharmaceutical excipients and by preparation of unit dosage suitable for topical ocular use.
  • the therapeutically efficient amount typically is between about 0.0001 and about 5% (w/v), preferably about 0.001 to about 2.0% (w/v) in liquid formulations.
  • solutions are prepared using a
  • physiological saline solution as a major vehicle.
  • the pH of such ophthalmic solutions should preferably be maintained between 4.5 and 8.0 with an appropriate buffer system, a neutral pH being preferred but not essential.
  • the formulations may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants.
  • Preferred preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate.
  • a preferred surfactant is, for example, Tween 80.
  • various preferred vehicles may be used in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose cyclodextrin and purified water.
  • Tonicity adjusters may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjuster.
  • buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
  • an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
  • Other excipient components which may be included in the ophthalmic preparations are chelating agents.
  • the preferred chelating agent is edentate disodium, although other chelating agents may also be used in place of or in conjunction with it.
  • the ingredients are usually used in the following amounts:
  • the actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
  • the ophthalmic formulations of the present invention are conveniently packaged in forms suitable for metered application, such as in containers equipped with a dropper, to facilitate application to the eye.
  • Containers suitable for drop wise application are usually made of suitable inert, non-toxic plastic material, and generally contain between about 0.5 and about 15 ml solution.
  • One package may contain one or more unit doses.
  • Especially preservative-free solutions are often formulated in non- resalable containers containing up to about ten, preferably up to about five units doses, where a typical unit dose is from one to about 8 drops, preferably one to about 3 drops.
  • the volume of one drop usually is about 20-35 ⁇ .
  • Invention compounds may also be administered in the form of suppositories for rectal administration of the drug.
  • compositions may be prepared by mixing the invention compounds with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • the compounds and pharmaceutical compositions described herein are useful as medicaments in mammals, including humans, for treatment of diseases and/or alleviations of conditions which are responsive to treatment by agonists or functional antagonists of sphingosine-1 -phosphate receptors.
  • methods for treating a disorder associated with modulation of sphingosine-1 -phosphate receptors can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one invention compound.
  • the term "therapeutically effective amount” means the amount of the pharmaceutical composition that will elicit the biological or medical response of a subject in need thereof that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the subject in need thereof is a mammal. In some embodiments, the mammal is human.
  • the present invention concerns also processes for preparing the compounds of Formula I.
  • the compounds of Formula I according to the invention can be prepared analogously to conventional methods as understood by the person skilled in the art of synthetic organic chemistry.
  • the synthetic scheme set forth below, illustrates how compounds according to the invention can be made.
  • the present invention concerns also processes for preparing the compounds of Formula II.
  • the compounds of Formula I I according to the invention can be prepared analogously to conventional methods as understood by the person skilled in the art of synthetic organic chemistry.
  • the synthetic scheme set forth below, illustrates how compounds according to the invention can be made.
  • the present invention includes all pharmaceutically acceptable isotopically enriched compounds.
  • Any compound of the invention may contain one or more isotopic atoms enriched or different than the natural ratio such as deuterium 2 H (or D) in place of protium 1 H (or H) or use of 13 C enriched material in place of 12 C and the like. Similar substitutions can be employed for N, O and S.
  • the use of isotopes may assist in analytical as well as therapeutic aspects of the invention. For example, use of deuterium may increase the in vivo half-life by altering the metabolism (rate) of the compounds of the invention.
  • These compounds can be prepared in accord with the preparations described by use of isotopically enriched reagents.
  • characterization of the compounds is performed according to the following methods: NMR spectra are recorded on 300 and/or 600 MHz Varian and acquired at room temperature. Chemical shifts are given in ppm referenced either to internal TMS or to the solvent signal.
  • Some compounds of this invention can generally be prepared in one step from commercially available literature starting materials.
  • Compounds were synthesized and tested for S1 P1 activity using the GTP y 35 S binding assay. These compounds may be assessed for their ability to activate or block activation of the human S1 P1 receptor in cells stably expressing the S1 P1 receptor.
  • GTP y 35 S binding was measured in the medium containing (mM) HEPES 25, pH 7.4, MgCI 2 10, NaCI 100, dithitothreitol 0.5, digitonin 0.003%, 0.2 nM GTP y 35 S, and 5 ⁇ g membrane protein in a volume of 150 ⁇ . Test compounds were included in the concentration range from 0.08 to 5,000 nM unless indicated otherwise.
  • Membranes were incubated with 100 ⁇ 5'-adenylylimmidodiphosphate for 30 min, and subsequently with 10 ⁇ GDP for 10 min on ice. Drug solutions and membrane were mixed, and then reactions were initiated by adding GTP y 35 S and continued for 30 min at 25 °C. Reaction mixtures were filtered over Whatman GF/B filters under vacuum, and washed three times with 3 mL of ice-cold buffer (HEPES 25, pH7.4, MgC 10 and NaCI 100). Filters were dried and mixed with scintillant, and counted for 35 S activity using a ⁇ -counter. Agonist-induced GTP y 35 S binding was obtained by subtracting that in the absence of agonist. Binding data were analyzed using a nonlinear regression method. In case of antagonist assay, the reaction mixture contained 10 nM S1 P1 in the presence of test antagonist at concentrations ranging from 0.08 to 5000 nM.
  • Table 8 shows activity potency: S1 P1 receptor from GTP y 35 S: nM, (EC 5 o)

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Abstract

The present invention relates to 1,3,4-alkenyl oxadiazole amino acid derivatives of formulae I and II, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of sphingosine-1-phosphate receptors.

Description

1 ,3,4-ALKENYL OXADIAZOLE AMINO ACID DERIVATIVES AS SPHINGOSINE-1 -PHOSPHATE RECEPTORS' MODULATORS By inventors: Ling Li, Janet A. Takeuchi and Ken Chow
RELATED APPLICATIONS
This application claims the benefit of United States Provisional Patent
Application Serial No. 61/904,208 filed November 14, 2013, and the benefit of United States Provisional Patent Application Serial No. 61 /904,212 filed November 14, 2013, the disclosure of which are hereby incorporated in their entirety by reference.
FIELD OF THE INVENTION
The present invention relates to 1 ,3,4-alkenyl oxadiazole amino acid
derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of sphingosine-1 -phosphate receptors. The invention relates specifically to the use of these compounds and their pharmaceutical compositions to treat disorders associated with sphingosine-1 - phosphate (S1 P) receptor modulation.
BACKGROUND OF THE INVENTION
Sphingosine-1 phosphate is stored in relatively high concentrations in human platelets, which lack the enzymes responsible for its catabolism, and it is released into the blood stream upon activation of physiological stimuli, such as growth factors, cytokines, and receptor agonists and antigens. It may also have a critical role in platelet aggregation and thrombosis and could aggravate cardiovascular diseases. On the other hand the relatively high concentration of the metabolite in high-density lipoproteins (HDL) may have beneficial implications for atherogenesis. For example, there are recent suggestions that sphingosine-1 -phosphate, together with other lysolipids such as sphingosylphosphorylcholine and lysosulfatide, are responsible for the beneficial clinical effects of HDL by stimulating the production of the potent antiatherogenic signaling molecule nitric oxide by the vascular endothelium. In addition, like lysophosphatidic acid, it is a marker for certain types of cancer, and there is evidence that its role in cell division or proliferation may have an influence on the development of cancers. These are currently topics that are attracting great interest amongst medical researchers, and the potential for therapeutic intervention in sphingosine-1 -phosphate metabolism is under active investigation. SUMMARY OF THE INVENTION
We have now discovered a group of novel compounds which are potent and selective sphingosine-1 -phosphate modulators. As such, the compounds described herein are useful in treating a wide variety of disorders associated with modulation of sphingosine-1 -phosphate receptors. The term "modulator" as used herein, includes but is not limited to: receptor agonist, antagonist, inverse agonist, inverse antagonist, partial agonist, partial antagonist.
This invention describes compounds of Formula I, which have sphingosine-1 - phosphate receptor biological activity. The compounds in accordance with the present invention are thus of use in medicine, for example in the treatment of humans with diseases and conditions that are alleviated by S1 P modulation.
In one aspect, the invention provides a compound having Formula I or a
pharmaceutically acceptable salt thereof or enantiomers, diastereoisomers, tautomers, zwitterions and pharmaceutically acceptable salts thereof:
Figure imgf000003_0001
Formula I
wherein: R1 is substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C5-8 cycloalkyl, substituted or unsubstituted C5-8 cycloalkenyl;
R2 is substituted or unsubstituted Ci-s alkyl;
R3 is hydrogen, halogen, substituted or unsubstituted C -8 alkyl, C(0)R7 or hydroxyl; R4 is hydrogen, halogen, substituted or unsubstituted C -8 alkyl, C(0)R7 or hydroxyl; R5 is hydrogen, halogen, substituted or unsubstituted Ci-8 alkyl, C(0)R7 or hydroxyl; substituted or unsubstituted heterocycle;
R6 is hydrogen, halogen, substituted or unsubstituted Ci-8 alkyl, C(0)R7 or hydroxyl; substituted or unsubstituted heterocycle;
R7 is hydrogen , -OR8, substituted or unsubstituted C-i-s alkyl;
R8 is hydrogen , substituted or unsubstituted Ci-8 alkyl;
R9 is OPO3H2, carboxylic acid, P03H2, -P(0)MeOH, -P(0)(H)OH or OR11 ;
R10 is hydrogen , substituted or unsubstituted Ci-3 alkyl;
R11 is hydrogen , substituted or unsubstituted Ci-3 alkyl; and
a is 1 , 2 or 3.
In another aspect, the invention provides a compound having Formula II or a pharmaceutically acceptable salt thereof or enantiomers, diastereoisomers, tautomers, zwitterions and pharmaceutically acceptable salts thereof:
Figure imgf000004_0001
Formula I wherein:
R1 is substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C5-8 cycloalkyl, substituted or unsubstituted C5-8 cycloalkenyl;
R2 is substituted or unsubstituted Ci-8 alkyl;
R3 is hydrogen, halogen, substituted or unsubstituted C -8 alkyl, C(0)R7 or hydroxyl;
R4 is hydrogen, halogen, substituted or unsubstituted C -8 alkyl, C(0)R7 or hydroxyl;
R5 is hydrogen, halogen, substituted or unsubstituted Ci-8 alkyl, C(0)R7, hydroxyl, or substituted or unsubstituted heterocycle;
R6 is hydrogen, halogen, substituted or unsubstituted Ci-8 alkyl, C(0)R7, hydroxyl, or substituted or unsubstituted heterocycle;
R7 is hydrogen, -OR9, substituted or unsubstituted Ci-8 alkyl;
R8 is OPO3H2, carboxylic acid, P03H2, -P(0)MeOH, -P(0)(H)OH or OR9;
R9 is hydrogen or substituted or unsubstituted Ci-8 alkyl; and
R10 is hydrogen or substituted or unsubstituted Ci-8 alkyl.
The term "alkyl", as used herein, refers to saturated, monovalent or divalent hydrocarbon moieties having linear or branched moieties or combinations thereof and containing 1 to 8 carbon atoms. One methylene (-CH2-) group, of the alkyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, or by a divalent C3-6 cycloalkyl. Alkyl groups can be substituted by but not limited to halogen, hydroxyl, cycloalkyl, amino, non-aromatic heterocycles, carboxylic acid, phosphonic acid groups, sulphonic acid groups, phosphoric acid.
The term "cycloalkyl", as used herein, refers to a monovalent or divalent group of 3 to 8 carbon atoms derived from a saturated cyclic hydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic. Cycloalkyl can be substituted by but not limited to C-|. 8 alkyl groups or halogens.
The term "cycloalkenyl", as used herein, refers to a monovalent or divalent group of 3 to 8 carbon atoms derived from a saturated cycloalkyl having one double bond. Cycloalkenyl groups can be monocyclic or polycyclic. Cycloalkenyl groups can be substituted by but not limited to C-i-s alkyl groups or halogens. The term "halogen", as used herein, refers to an atom of chlorine, bromine, fluorine, iodine.
The term "alkenyl", as used herein, refers to a monovalent or divalent hydrocarbon moiety having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one double bond. C 2-6 alkenyl can be in the E or Z configuration.
Alkenyl groups can be substituted by but not limited to d-s alkyl.
The term "heterocycle" as used herein, refers to a 3 to 10 membered ring, which can be aromatic or non-aromatic, saturated or non-saturated, containing at least one heteroatom selected form O or N or S or combinations of at least two thereof, interrupting the carbocyclic ring structure. The heterocyclic ring can be saturated or non-saturated. The heterocyclic ring can be interrupted by a C=0; the S heteroatom can be oxidized. Heterocycles can be monocyclic or polycyclic. Heterocyclic ring moieties can be substituted by but not limited to hydroxyl, C 1-8 alkyl or halogens.
The term "aryl" as used herein, refers to an organic moiety derived from an aromatic hydrocarbon consisting of a ring containing 6 to 10 carbon atoms by removal of one hydrogen, which can be substituted by but not limited to halogen atoms or C-i-s alkyl groups.
The term "hydroxyl" as used herein, represents a group of formula "-OH".
The term "carbonyl" as used herein, represents a group of formula "-C(O)".
The term "carboxyl" as used herein, represents a group of formula "-C(0)0-".
The term "sulfonyl" as used herein, represents a group of formula "-SO2".
The term "sulfate" as used herein, represents a group of formula "-0-S(0)2-0-".
The term "carboxylic acid" as used herein, represents a group of formula "- C(0)OH".
The term "sulfoxide" as used herein, represents a group of formula "-S=0". The term "phosphonic acid" as used herein, represents a group of formula "- P(0)(OH)2".
The term "phosphoric acid" as used herein, represents a group of formula "- (0)P(0)(OH)2".
The term "sulphonic acid" as used herein, represents a group of formula "- S(0)2OH". The formula "H ", as used herein, represents a hydrogen atom.
The formula "0 ", as used herein, represents an oxygen atom.
The formula "N ", as used herein, represents a nitrogen atom.
The formula "S ", as used herein, represents a sulfur atom. Some compounds of the invention are:
3-[(4-{5-[(1 E)-5-methyl-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propanoic acid;
{3-[(4-{5-[(1 E)-5-methyl-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(4-{5-[(1 E)-2-phenylhept-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)amino]propanoic acid;
{3-[(4-{5-[(1 E)-2-phenylhept-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(4-{5-[(1 Z)-2-phenylhept-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)amino]propanoic acid;
{3-[(4-{5-[(1 Z)-2-phenylhept-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(4-{5-[(1 Z)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)amino]propanoic acid;
{3-[(4-{5-[(1 Z)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(4-{5-[(1 Z)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)amino]propanoic acid;
{3-[(4-{5-[(1 Z)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)amino]propanoic acid;
{3-[(4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)amino]propanoic acid;
{3-[(4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid; 1 -(4-{5-[(1 E)-5-methyl-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid;
1 -(4-{5-[(1 E)-2-phenylhept-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid;
1 -(4-{5-[(1 Z)-2-phenylhept-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid;
1 -(4-{5-[(1 Z)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3-carboxylic acid;
1 -(4-{5-[(1 Z)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid;
1 -(4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3-carboxylic acid;
1 -(4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid;
3-[(3-ethyl-4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propanoic acid;
{3-[(3-ethyl-4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(3-ethyl-4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propanoic acid;
{3-[(3-ethyl-4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(3-methyl-4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propanoic acid;
{3-[(3-methyl-4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(3-methyl-4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propanoic acid;
{3-[(3-methyl-4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
1 -(4-{5-[(1 E)-5-methyl-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid;
1 -(4-{5-[(1 E)-2-phenylhept-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid; 1 -(4-{5-[(1 Z)-2-phenylhept-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid;
1 -(4-{5-[(1 Z)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3-carboxylic acid;
1 -(4-{5-[(1 Z)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid;
1 -(4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3-carboxylic acid;
1 -(4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid;
1 -(3-ethyl-4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid;
1 -(3-ethyl-4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid;
1 -(3-methyl-4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid;
1 -(3-methyl-4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid.
Some compounds of Formula I or of Formula II and some of their intermediates may have at least one stereogenic center in their structure. This stereogenic center may be present in an R or S configuration, said R and S notation is used in
correspondence with the rules described in Pure Appli. Chem. (1976), 45, 1 1 -13. The term "pharmaceutically acceptable salts" refers to salts or complexes that retain the desired biological activity of the above identified compounds and exhibit minimal or no undesired toxicological effects. The "pharmaceutically acceptable salts" according to the invention include therapeutically active, non-toxic base or acid salt forms, which the compounds of Formula I or of Formula II are able to form. The acid addition salt form of a compound of Formula I or of Formula II that occurs in its free form as a base can be obtained by treating the free base with an appropriate acid such as an inorganic acid, such as for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; or an organic acid such as for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric, methylsulfonic, ethanesulfonic, benzenesulfonic, formic and the like (Handbook of Pharmaceutical Salts, P. Heinrich Stahl & Camille G. Wermuth (Eds), Verlag Helvetica Chimica Acta- Zurich, 2002, 329- 345).
The base addition salt form of a compound of Formula I or of Formula II that occurs in its acid form can be obtained by treating the acid with an appropriate base such as an inorganic base, for example, sodium hydroxide, magnesium hydroxide, potassium hydroxide, calcium hydroxide, ammonia and the like; or an organic base such as for example, L-Arginine, ethanolamine, betaine, benzathine, morpholine and the like. (Handbook of Pharmaceutical Salts, P. Heinrich Stahl & Camille G. Wermuth (Eds), Verlag Helvetica Chimica Acta- Zurich, 2002, 329-345).
The compounds of the invention are indicated for use in treating or preventing conditions in which there is likely to be a component involving the sphingosine-1 - phosphate receptors.
In another embodiment, there are provided pharmaceutical compositions including at least one compound of the invention in a pharmaceutically acceptable carrier.
In a further embodiment of the invention, there are provided methods for treating disorders associated with modulation of sphingosine-1 -phosphate receptors. Such methods can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one compound of the invention. These compounds are useful for the treatment of mammals, including humans, with a range of conditions and diseases that are alleviated by S1 P modulation: not limited to the treatment of diabetic retinopathy, other retinal degenerative conditions, dry eye, angiogenesis and wounds. Therapeutic utilities of S1 P modulators are ocular diseases, such as but not limited to: wet and dry age-related macular degeneration, diabetic retinopathy, angiogenesis inhibition, retinopathy of prematurity, retinal edema, geographic atrophy, glaucomatous optic neuropathy, chorioretinopathy, hypertensive retinopathy, ocular ischemic syndrome, prevention of inflammation-induced fibrosis in the back of the eye, various ocular inflammatory diseases including uveitis, scleritis, keratitis, and retinal vasculitis; or systemic vascular barrier related diseases such as but not limited to: various inflammatory diseases, including acute lung injury, its prevention, sepsis, tumor metastasis, atherosclerosis, pulmonary edemas, and ventilation-induced lung injury; or autoimmune diseases and immunosuppression such as but not limited to: rheumatoid arthritis, Crohn's disease, Graves' disease, inflammatory bowel disease, multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative colitis, antoimmune uveitis, renal ischemia/perfusion injury, contact hypersensitivity, atopic dermititis, and organ transplantation; or allergies and other inflammatory diseases such as but not limited to: urticaria, bronchial asthma, and other airway inflammations including pulmonary emphysema and chronic obstructive pulmonary diseases; or cardiac protection such as but not limited to: ischemia reperfusion injury and atherosclerosis; or wound healing such as but not limited to: scar-free healing of wounds from cosmetic skin surgery, ocular surgery, Gl surgery, general surgery, oral injuries, various mechanical, heat and burn injuries, prevention and treatment of photoaging and skin ageing, and prevention of radiation-induced injuries; or bone formation such as but not limited to: treatment of osteoporosis and various bone fractures including hip and ankles; or antinociceptive activity such as but not limited to: visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, neuropathic pains; or central nervous system neuronal activity in Alzheimer's disease, age-related neuronal injuries; or in organ transplant such as renal, corneal, cardiac or adipose tissue transplant. In still another embodiment of the invention, there are provided methods for treating disorders associated with modulation of sphingosine-1 -phosphate receptors. Such methods can be performed, for example, by administering to a subject in need thereof a therapeutically effective amount of at least one compound of the invention, or any combination thereof, or pharmaceutically acceptable salts, individual enantiomers, and diastereomers thereof.
The present invention concerns the use of a compound of Formula I or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of ocular disease, wet and dry age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal edema, geographic atrophy,
angiogenesis inhibition, glaucomatous optic neuropathy, chorioretinopathy, hypertensive retinopathy, ocular ischemic syndrome, prevention of inflammation- induced fibrosis in the back of the eye, various ocular inflammatory diseases including uveitis, scleritis, keratitis, and retinal vasculitis; or systemic vascular barrier related diseases , various inflammatory diseases, including acute lung injury, its prevention, sepsis, tumor metastasis, atherosclerosis, pulmonary edemas, and ventilation-induced lung injury; or autoimmune diseases and immunosuppression , rheumatoid arthritis, Crohn's disease, Graves' disease, inflammatory bowel disease, multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative colitis, antoimmune uveitis, renal
ischemia/perfusion injury, contact hypersensitivity, atopic dermititis, and organ transplantation; or allergies and other inflammatory diseases , urticaria, bronchial asthma, and other airway inflammations including pulmonary emphysema and chronic obstructive pulmonary diseases; or cardiac protection , ischemia reperfusion injury and atherosclerosis; or wound healing, scar-free healing of wounds from cosmetic skin surgery, ocular surgery, Gl surgery, general surgery, oral injuries, various mechanical, heat and burn injuries, prevention and treatment of photoaging and skin ageing, and prevention of radiation-induced injuries; or bone formation, treatment of osteoporosis and various bone fractures including hip and ankles; or anti-nociceptive activity , visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, neuropathic pains; or central nervous system neuronal activity in Alzheimer's disease, age-related neuronal injuries; or in organ transplant such as renal, corneal, cardiac or adipose tissue transplant. The actual amount of the compound to be administered in any given case will be determined by a physician taking into account the relevant circumstances, such as the severity of the condition, the age and weight of the patient, the patient's general physical condition, the cause of the condition, and the route of administration. The patient will be administered the compound orally in any acceptable form, such as a tablet, liquid, capsule, powder and the like, or other routes may be desirable or necessary, particularly if the patient suffers from nausea. Such other routes may include, without exception, transdermal, parenteral, subcutaneous, intranasal, via an implant stent, intrathecal, intravitreal, topical to the eye, back to the eye,
intramuscular, intravenous, and intrarectal modes of delivery. Additionally, the formulations may be designed to delay release of the active compound over a given period of time, or to carefully control the amount of drug released at a given time during the course of therapy.
In another embodiment of the invention, there are provided pharmaceutical compositions including at least one compound of the invention in a pharmaceutically acceptable carrier thereof. The phrase "pharmaceutically acceptable" means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Pharmaceutical compositions of the present invention can be used in the form of a solid, a solution, an emulsion, a dispersion, a patch, a micelle, a liposome, and the like, wherein the resulting composition contains one or more compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications. Invention compounds may be combined, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carriers which can be used include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form. In addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. Invention compounds are included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or disease condition.
Pharmaceutical compositions containing invention compounds may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of a sweetening agent such as sucrose, lactose, or saccharin, flavoring agents such as peppermint, oil of wintergreen or cherry, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets containing invention compounds in admixture with non-toxic pharmaceutically acceptable excipients may also be manufactured by known methods. The excipients used may be, for example, (1 ) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents such as corn starch, potato starch or alginic acid; (3) binding agents such as gum tragacanth, corn starch, gelatin or acacia, and (4) lubricating agents such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
In some cases, formulations for oral use may be in the form of hard gelatin capsules wherein the invention compounds are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the invention compounds are mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
The pharmaceutical compositions may be in the form of a sterile injectable suspension. This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides, fatty acids (including oleic acid), naturally occurring vegetable oils like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyl oleate or the like. Buffers, preservatives, antioxidants, and the like can be incorporated as required.
Pharmaceutical compositions containing invention compounds may be in a form suitable for topical use, for example, as oily suspensions, as solutions or suspensions in aqueous liquids or nonaqueous liquids, or as oil-in-water or water-in-oil liquid emulsions. Pharmaceutical compositions may be prepared by combining a therapeutically effective amount of at least one compound according to the present invention, or a pharmaceutically acceptable salt thereof, as an active ingredient with conventional ophthalmically acceptable pharmaceutical excipients and by preparation of unit dosage suitable for topical ocular use. The therapeutically efficient amount typically is between about 0.0001 and about 5% (w/v), preferably about 0.001 to about 2.0% (w/v) in liquid formulations.
For ophthalmic application, preferably solutions are prepared using a
physiological saline solution as a major vehicle. The pH of such ophthalmic solutions should preferably be maintained between 4.5 and 8.0 with an appropriate buffer system, a neutral pH being preferred but not essential. The formulations may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants. Preferred preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate. A preferred surfactant is, for example, Tween 80. Likewise, various preferred vehicles may be used in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose cyclodextrin and purified water.
Tonicity adjusters may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjuster.
Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
In a similar manner an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene. Other excipient components which may be included in the ophthalmic preparations are chelating agents. The preferred chelating agent is edentate disodium, although other chelating agents may also be used in place of or in conjunction with it.
The ingredients are usually used in the following amounts:
Ingredient Amount (% w/v)
active ingredient about 0.001 -5
preservative 0-0.10
vehicle 0-40
tonicity adjustor 0-10
buffer 0.01 -10
pH adjustor q .s. pH 4.5-7.8
antioxidant as needed
surfactant as needed
purified water to make 100%
The actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
The ophthalmic formulations of the present invention are conveniently packaged in forms suitable for metered application, such as in containers equipped with a dropper, to facilitate application to the eye. Containers suitable for drop wise application are usually made of suitable inert, non-toxic plastic material, and generally contain between about 0.5 and about 15 ml solution. One package may contain one or more unit doses. Especially preservative-free solutions are often formulated in non- resalable containers containing up to about ten, preferably up to about five units doses, where a typical unit dose is from one to about 8 drops, preferably one to about 3 drops. The volume of one drop usually is about 20-35 μΙ. Invention compounds may also be administered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the invention compounds with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
Since individual subjects may present a wide variation in severity of symptoms and each drug has its unique therapeutic characteristics, the precise mode of administration and dosage employed for each subject is left to the discretion of the practitioner. The compounds and pharmaceutical compositions described herein are useful as medicaments in mammals, including humans, for treatment of diseases and/or alleviations of conditions which are responsive to treatment by agonists or functional antagonists of sphingosine-1 -phosphate receptors. Thus, in further embodiments of the invention, there are provided methods for treating a disorder associated with modulation of sphingosine-1 -phosphate receptors. Such methods can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one invention compound. As used herein, the term "therapeutically effective amount" means the amount of the pharmaceutical composition that will elicit the biological or medical response of a subject in need thereof that is being sought by the researcher, veterinarian, medical doctor or other clinician. In some embodiments, the subject in need thereof is a mammal. In some embodiments, the mammal is human.
The present invention concerns also processes for preparing the compounds of Formula I. The compounds of Formula I according to the invention can be prepared analogously to conventional methods as understood by the person skilled in the art of synthetic organic chemistry. The synthetic scheme set forth below, illustrates how compounds according to the invention can be made.
Scheme 1
Figure imgf000018_0001
Figure imgf000018_0002
The present invention concerns also processes for preparing the compounds of Formula II. The compounds of Formula I I according to the invention can be prepared analogously to conventional methods as understood by the person skilled in the art of synthetic organic chemistry. The synthetic scheme set forth below, illustrates how compounds according to the invention can be made.
Scheme 2
Figure imgf000018_0003
Acetone/H20
Figure imgf000018_0004
DETAILED DESCRIPTION OF THE INVENTION It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed. As used herein, the use of the singular includes the plural unless specifically stated otherwise. It will be readily apparent to those skilled in the art that some of the compounds of the invention may contain one or more asymmetric centers, such that the compounds may exist in enantiomeric as well as in diastereomeric forms. Unless it is specifically noted otherwise, the scope of the present invention includes all enantiomers, diastereomers and racemic mixtures. Some of the compounds of the invention may form salts with pharmaceutically acceptable acids or bases, and such pharmaceutically acceptable salts of the compounds described herein are also within the scope of the invention.
The present invention includes all pharmaceutically acceptable isotopically enriched compounds. Any compound of the invention may contain one or more isotopic atoms enriched or different than the natural ratio such as deuterium 2H (or D) in place of protium 1 H (or H) or use of 13 C enriched material in place of 12C and the like. Similar substitutions can be employed for N, O and S. The use of isotopes may assist in analytical as well as therapeutic aspects of the invention. For example, use of deuterium may increase the in vivo half-life by altering the metabolism (rate) of the compounds of the invention. These compounds can be prepared in accord with the preparations described by use of isotopically enriched reagents.
The following examples are for illustrative purposes only and are not intended, nor should they be construed as limiting the invention in any manner. Those skilled in the art will appreciate that variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention.
As will be evident to those skilled in the art, individual diastereomeric forms can be obtained by separation of mixtures thereof in conventional manner,
chromatographic separation may be employed.
Compound names were generated with ACDLab version 12.5; and
Intermediates and reagent names used in the examples were generated with software such as Chem Bio Draw Ultra version 12.0 and/or Auto Norn 2000 from MDL ISIS Draw 2.5 SP1 .
In general, characterization of the compounds is performed according to the following methods: NMR spectra are recorded on 300 and/or 600 MHz Varian and acquired at room temperature. Chemical shifts are given in ppm referenced either to internal TMS or to the solvent signal.
All the reagents, solvents, catalysts for which the synthesis is not described are purchased from chemical vendors such as Sigma Aldrich, Fluka, Bio-Blocks, Combi- blocks, TCI, VWR, Lancaster, Oakwood, Trans World Chemical, Alfa, Fisher, AK Scientific, AmFine Com, Carbocore, Maybridge, Frontier, Matrix, Ukrorgsynth,
Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-lmpex, MIC-scientific, Ltd; however some known intermediates, were prepared according to published procedures.
Usually the compounds of the invention were purified by column
chromatography (Auto-column) on an Teledyne-ISCO CombiFlash with a silica column, unless noted otherwise.
The following abbreviations are used in the examples:
CDI 1 ,1 '-carbonyl diimidazole
EDCI 1 -ethyl-3-(3-dimethylaminopropyl) carbodiimide
KOH potassium hydroxide
MeOH methanol
HCI hydrochloric acid
RT room temperature
CDCI3 deuterated chloroform
THF tertrahydrofuran
n-BuLi n-butyl lithium
MPLC medium pressure liquid chromatography
DMF dimethylformamide
NaHC03 sodium bicarbonate
PPh3 triphenylphosphine
CCI4 carbon tetrachloride CH3CN acetonitrile
Those skilled in the art will be able to routinely modify and/or adapt the following schemes to synthesize any compound of the invention covered by Formula I.
Some compounds of this invention can generally be prepared in one step from commercially available literature starting materials.
Example 1
Intermediate 1 Ethyl 3-phenylpropiolate
Figure imgf000021_0001
To a solution of 3-phenylpropiolic acid (CAS 637-44-5) (5g, 49 mmol) in THF (50 mL) at -78°C was added n-BuLi (2.5M, 33ml_, 81 mmol) dropwise. The resulting mixture was stirred at 0°C for 30 Min then cooled back to-78°C. Ethyl chloroformate (6.7ml_, 70 mmol) was added dropwise. The reaction mixture was stirred from -78°C to RT for 16h. The reaction was quenched with sodium bicarbonate (sat.) and ammonium chloride (sat.) (1 :1 ). The mixture was extracted with ethyl acetate.
Combined ethyl acetate was washed with water and brine, dried over magnesium sulfate, and concentrated. Purification of the residue by MPLC (2 % ethyl acetate in hexanes) gave 4.6 g of intermediate 1 as a yellow oil.
1H NMR (600 MHz, CDCI3) δ: 7.59 (dd, J = 8.0, 1 .0 Hz, 2H), 7.42 - 7.47 (m, 1 H), 7.35 - 7.40 (m, 2H), 4.30 (q, J = 7.1 Hz, 2H), 1 .36 (t, J = 7.2 Hz, 3H)
Example 2
Intermediate 2 (Z)-Ethyl 3-iodo-3-phenylacrylate
Figure imgf000022_0001
To a solution of intermediate 1 (4.6g, 26.4 mmol) in acetic acid (22 ml.) was added sodium iodide (13 g, 87mmol). The reaction was purged with argon and heated at 1 15°C with reflux condenser for 4 h. The reaction mixture was cooled to RT and diluted with water. The mixture was extracted with ether. Combined ether was washed with sodium carbonate (sat.), sodium thiosulfate (sat.), brine, dried over magnesium sulfate, and concentrated to yield 7.55 g intermediate 2 as a yellow oil.
1H NMR (600 MHz, CDCI3) δ: 7.50 - 7.55 (m, 2H), 7.33 - 7.38 (m, 3H), 6.63 (s, 1 H), 4.25 - 4.33 (m, 2H), 1 .30 - 1 .38 (m, 3H).
Example 3
Intermediate 3 (E)-Ethyl 3-phenylhex-2-enoate
Figure imgf000022_0002
To a solution of intermediate 2 ( 2.81 g, 9.3 mmol) in DMF (20 mL) under argon at 0°C was added n-propylzinc bromide (55 mL, 27.5 mmol) followed by
bis(acetonitrile)dichloropalladium (361 mg, 137mmol). The reaction mixture was stirred at RT for 16 h and diluted with ether, washed with HCI (10%), brine, dried over magnesium sulfate and concentrated. Purification of the residue by MPLC (10% ethyl acetate in hexanes) gave 1 .6 g of intermediate 3 as a yellow oil.
1H NMR (600 MHz, CDCI3) δ: 7.40 - 7.45 (m, 2H), 7.34 - 7.40 (m, 3H), 6.03 (s, 1 H), 4.21 (q, J = 7.1 Hz, 2H), 3.04 - 3.12 (m, 2H), 1 .41 - 1 .50 (m, 2H), 1 .28 - 1 .37 (m, 3H), 0.90 - 0.95 (m, 3H). Intermediates 4, 5 and 6 were prepared from Intermediate 2, in a similar manner to the procedure described in Example 3 for Intermediate 3. The results are tabulated below in Table 1 .
Table 1
Figure imgf000023_0002
Example 4
Intermediate 7
(E)-3-phenylhex-2-enoic acid
Figure imgf000023_0001
To the solution of intermediate 3 (1 .6g, 7.3mmol) in dioxane (13ml_) and water (26ml_) was added KOH (1 .48g, 26.6mmol). The reaction mixture was refluxed for 16 h then cooled to RT, diluted with water, HCI (10%) was added until pH=2. The mixture was extracted with ethyl acetate. Combined ethyl acetate was washed with water and brine, dried over magnesium sulfate, and concentrated. Purification of the residue by MPLC (50 % ethyl acetate in hexanes) gave 903 mg of Intermediate 7 as a white solid.
1H NMR (600 MHz, CDCI3) δ: 7.42 - 7.48 (m, 2H), 7.35 - 7.41 (m, 3H), 6.07 (s, 1 H), 3.07 - 3.15 (m, 2H), 1 .43 - 1 .52 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H).
Intermediates 8, 9 and 10 were prepared from the Intermediates 4, 5 and 6 in a similar manner to the procedure described in Example 4 for Intermediate 7. The results are tabulated below in Table 2.
Table 2
Figure imgf000024_0001
1 .36 (m, 2H), 0.90 (d, J =
(E)-6-methyl-3-phenylhept- 6.6 Hz, 6H)
2-enoic acid
Example 5
Intermediate 11
-3-phenyloct-2-enoic acid
Figure imgf000025_0001
A 250 mL round bottom flask was fitted with an argon inlet and thermometer and charged with copper iodidie (8.8 g, 46.2 mmol) and ether (25 mL). The suspension was cooled to -10 to -15 °C and n-pentyl lithium (0.77 M in hexanes) (60 mL, 46.2 mmol) was added while maintaining the temperature at -10 to -15 °C. After 30 minutes the reaction was shielded from light and cooled to -60 °C. Phenylpropiolic acid (2.25 g, 15.4 mmol) was added in three equal portions over 5 min. After 5 hr at - 60 °C it was partitioned between 1 M HCI (100 mL) and CHCI3 (100 mL) then warmed to RT and filtered through celite. The celite was rinsed with CHCI3 (100 mL), the layers were separated and the aqueous layer was extracted with CHCI3 (2x50 mL). The combined organic layers were filtered and concentrated to give a mixture of oil and solid. The mixture was purified by column chromatography (CH2Cl2/Hexanes) to give intermediate 1 1 (1.27 g, 5.8 mmol, 38%) as a crystalline solid.
1H NMR (300 MHz, CDCI3): δ 10.98 (brs, 1 H), 7.38 (m, 3H), 7.17 (m, 2H), 5.83 (s, 1 H), 2.41 (m, 2H), 1.30 (m, 6H), 0.85 (m, 3H).
Intermediates 12 and 13 were prepared from Phenylpropiolic acid, in a similar manner to the procedure described in Example 5 for Intermediate 11. The results are tabulated below in Table 3.
Table 3 Interm. 1H NMR 5 (ppm)
Structure
No. lUPAC Name
1H NMR (300 MHz, CDCI3): δ 10.20 (brs, 1 H), 7.34 (m, 3H), 7.16 (m, 2H), 5.85 (s, 1 H), 2.42
12 (m, 2H), 1 .39 (q, 2H), 0.85 (m,
3H).
(Z)-3-phenylhex-2-enoic acid
1H NMR (300 MHz, CDCI3): δ 1 1 .20 (brs, 1 H), 7.38 (m, 3H), 7.16 (m, 2H), 5.85 (s, 1 H), 2.42
13 (m, 2H), 1 .38 (m, 4H), 0.86 (m,
3H).
(Z)-3-phenylhept-2-enoic acid
Example 6
Intermediate 14
(E)-4-(dimethoxymethyl)-N'-(3-phenylhex-2-enoyl)benzohydrazide
Figure imgf000026_0001
To the solution of intermediate 7 ( 903 mg, 4.75mmol) and 4-
(dimethoxymethyl)benzohydrazide (998 mg, 4.75 mmol) in DMF (70 mL) was added EDCI (1 .19g, 6.1 mmol). The reaction mixture was stirred at RT for 16 h. The mixture was then poured onto NaHCO3 (10%), extracted with ethyl acetate.
Combined ethyl acetate was washed with water and brine, dried over magnesium sulfate, and concentrated. Purification of the residue by MPLC (80% ethyl acetate in hexanes) gave 1 .19 g of intermediate 14 as a white solid. 1 H NM R (600 M Hz, CDCI3) δ: 7.85 (d, J = 8.4 Hz, 2H), 7.39 - 7.46 (m, 2H), 7.36 (d, J = 1 .8 Hz, 2H), 7.24 - 7.33 (m, 3H), 6.28 (s, 1 H), 5.40 (d, J = 3.7 Hz, 1 H), 3.30 (d, J = 3.8 Hz, 6H), 3.08 (m., 2H), 1 .34 - 1 .46 (m, 2H), 0.79 - 0.90 (m, 3H) Intermediates 15 through 20 were prepared from Intermediates 8 through 13, in a similar manner to the procedure described in Example 6 for Intermediate 14. The results are tabulated below in Table 4.
Table 4
Figure imgf000027_0001
enoy enzo y raz e
Figure imgf000028_0001
Figure imgf000029_0001
Example 7
Intermediate 25
(E)-4-(5-(2-phenylpent-1 -en-1 -yl)-1 ,3,4-oxadiazol-2-yl)benzaldehvde
Figure imgf000029_0002
The solution of intermediate 14 (707 mg, 1 .85 mol), t phenylphosphine (971 mg, 3.7 mmol) triethyl amine (0.93ml_, 6.66 mmol) and carbon tetrachloride (0.64 mL, 6.66 mmol) in acetonitrile (40 mL) was stirred at RT for 16 h. The acetonitrile was removed and the residue was taken-up in ethyl acetate. The ethyl acetate was washed with water and brine, dried over magnesium sulfate, and concentrated to give a crude mixture.
The mixture was dissolved in acetone (30 mL):water(0.6mL) and amberlyst (0.5 g) was added. After 2 hr, the reaction was filtered and concentrated. Purification by MPLC (25% ethyl acetate in hexanes) gave 423 mg of intermediate 21 as a white solid.
1H NMR (600 MHz, CDCI3) δ: 10.10 (s, 1 H), 8.26 (d, J = 8.4 Hz, 2H), 8.00 - 8.08 (m, 2H), 7.50 - 7.59 (m, 2H), 7.34 - 7.48 (m, 3H), 6.66 (s, 1 H), 3.16 - 3.29 (m, 2H), 1 .53 - 1 .69 (m, 2H), 0.97 - 1 .08 (m, 3H).
Intermediates 26 through 35 were prepared from Intermediates 15 through 20, in a similar manner to the procedure described in Example 7 for Intermediate 25. The results are tabulated below in Table 5.
Table 5
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Example 8
Compound 1 f 3-Γ(4-{ 5-ΓΠ E)-2-phenylpent-1 -en-1 -yll-1.3.4-oxadiazol-2- yl)benzyl)amino1propyl)phosphonic acid
Figure imgf000032_0002
To a solution of Intermediate 25 (155 mg, 0.49 mmol) and (3-aminopropyl) phosphonic acid (68 mg, 0.49 mmol) in methanol (10 mL) was added
tetrabutylammonium hydroxide (1 M in MeOH, 0.49 mL). The reaction mixture was heated to 50 °C for 1 h with stirring, cooled to RT, then sodium borohydride (28 mg, 0.73 mmol) was added. After the reaction mixture was stirred at RT for 3 h, the mixture was concentrated and purified by MPLC (100% methanol in ethyl acetate) to give 152 mg of Compound 1 as a colorless solid.
1H NMR (600 MHz, CD3OD) δ: 8.18 (d, J = 8.4 Hz, 2H), 7.73 (s, 2H), 7.61 (d, J
= 1 .5 Hz, 2H), 7.44 (d, J = 7.6 Hz, 3H), 6.70 (s, 1 H), 4.32 (s, 2H), 3.18 - 3.27 (m, 4H), 1 .99 - 2.10 (m, 2H), 1 .86 (s, 2H), 1 .58 (s, 2H), 0.98 - 1 .06 (m, 3H)
Compounds 2 through 22 were prepared from the Intermediates 25 through 35, in a similar manner to the procedure described in Example 8 for Compound 1. The results are tabulated below in Table 6.
Table 6
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Example 9
Compound 23
1 -(4-f 5-Γ(1 E)-2-phenylhex-1 -en-1 -yll-1 ,3,4-oxadiazol-2-yl)benzyl)azetidine-3- carboxylic acid
Figure imgf000038_0002
To a solution of Intermediate 25 (103 mg, 0.32 mmol) in methanol (10 mL) was added 3- azetidinecarboxylic acid ([CAS 36476-78-5] 34 mg, 0.34 mmol). After the reaction mixture was stirred at RT for 2.5h, sodium borohydride (18 mg, 0.48 mmol) was added. After the mixture was stirred at RT for 1 .5h, the mixture was concentrated and purified by MPLC (100% methanol in ethyl acetate) to give 44 mg of Compound 23, as a colorless solid.
1H NMR (600 MHz, CD3OD) δ: 8.06 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.53 - 7.58 (m, 2H), 7.36 - 7.44 (m, 3H), 6.64 (s, 1 H), 4.10 (s, 2H), 3.88 - 3.96 (m, 2H), 3.82 (t, J = 8.5 Hz, 2H), 3.32 - 3.38 (m, 1 H), 3.14 - 3.20 (m, 2H), 1 .55 (d, J = 7.8 Hz, 2H), 0.99 (t, J = 7.3 Hz, 3H). Compounds 24 through 33 were prepared from the corresponding Intermediates in a similar manner to the procedure described in Example 9 for Compound 23. The results are tabulated below in Table 7.
Table 7
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Example 10
Biological Data
Compounds were synthesized and tested for S1 P1 activity using the GTP y35S binding assay. These compounds may be assessed for their ability to activate or block activation of the human S1 P1 receptor in cells stably expressing the S1 P1 receptor.
GTP y35S binding was measured in the medium containing (mM) HEPES 25, pH 7.4, MgCI2 10, NaCI 100, dithitothreitol 0.5, digitonin 0.003%, 0.2 nM GTP y35S, and 5 μg membrane protein in a volume of 150 μΙ. Test compounds were included in the concentration range from 0.08 to 5,000 nM unless indicated otherwise.
Membranes were incubated with 100 μΜ 5'-adenylylimmidodiphosphate for 30 min, and subsequently with 10 μΜ GDP for 10 min on ice. Drug solutions and membrane were mixed, and then reactions were initiated by adding GTP y35S and continued for 30 min at 25 °C. Reaction mixtures were filtered over Whatman GF/B filters under vacuum, and washed three times with 3 mL of ice-cold buffer (HEPES 25, pH7.4, MgC 10 and NaCI 100). Filters were dried and mixed with scintillant, and counted for 35S activity using a β-counter. Agonist-induced GTP y35S binding was obtained by subtracting that in the absence of agonist. Binding data were analyzed using a nonlinear regression method. In case of antagonist assay, the reaction mixture contained 10 nM S1 P1 in the presence of test antagonist at concentrations ranging from 0.08 to 5000 nM.
Table 8 shows activity potency: S1 P1 receptor from GTP y35S: nM, (EC5o)
Table 8
Figure imgf000042_0001
{3-[(4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- 4.15 yl}benzyl)amino]propyl}phosphonic acid
1 -(4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- 148 yl}benzyl)azetidine-3-carboxylic acid
1 -(4-{5-[(1 Z)-2-phenylhept-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- 108 yl}benzyl)azetidine-3-carboxylic acid
1 -(4-{5-[(1 Z)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- 63.6 yl}benzyl)azetidine-3-carboxylic acid
1 -(4-{5-[(1 E)-2-phenylhept-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- 108 yl}benzyl)azetidine-3-carboxylic acid
1 -(4-{5-[(1 E)-5-methyl-2-phenylhex-1 -en-1 -yl]-1 ,3,4- 292 oxadiazol-2-yl}benzyl)azetidine-3-carboxylic acid
3-[(3-ethyl-4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4- 237 oxadiazol-2-yl}benzyl)amino]propanoic acid
{3-[(3-ethyl-4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4- 19 oxadiazol-2-yl}benzyl)amino]propyl}phosphonic acid
{3-[(3-ethyl-4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4- 39 oxadiazol-2-yl}benzyl)amino]propyl}phosphonic acid
3-[(3-methyl-4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4- 497 oxadiazol-2-yl}benzyl)amino]propanoic acid
3-[(3-methyl-4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4- 502 oxadiazol-2-yl}benzyl)amino]propanoic acid
{3-[(3-methyl-4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4- 10 oxadiazol-2-yl}benzyl)amino]propyl}phosphonic acid
1 -(3-ethyl-4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4- 561 oxadiazol-2-yl}benzyl)azetidine-3-carboxylic acid
1 -(3-ethyl-4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4- 691 oxadiazol-2-yl}benzyl)azetidine-3-carboxylic acid
1 -(3-methyl-4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4- 500 oxadiazol-2-yl}benzyl)azetidine-3-carboxylic acid

Claims

What is claimed is:
1 . A compound having Formula I, its enantiomers, diastereoisomers, tautomers or a pharmaceutically acceptable salt thereof,
Figure imgf000044_0001
Formula I
wherein:
R1 is substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C5-8 cycloalkyl, substituted or unsubstituted C5-8 cycloalkenyl;
R2 is substituted or unsubstituted C -8 alkyl;
R3 is hydrogen, halogen, substituted or unsubstituted Ci-8 alkyl, C(0)R7 or hydroxy I;
R4 is hydrogen, halogen, substituted or unsubstituted Ci-8 alkyl, C(0)R7 or hydroxy I;
R5 is hydrogen, halogen, substituted or unsubstituted Ci-8 alkyl, C(0)R7 or hydroxyl; substituted or unsubstituted heterocycle;
R6 is hydrogen, halogen, substituted or unsubstituted C-i-s alkyl, C(0)R7 or hydroxyl; substituted or unsubstituted heterocycle;
R7 is hydrogen , -OR8, substituted or unsubstituted Ci-8 alkyl;
R8 is hydrogen , substituted or unsubstituted C -8 alkyl;
R9 is OPO3H2, carboxylic acid, P03H2, -P(0)MeOH, -P(0)(H)OH or OR11;
R11 is hydrogen , substituted or unsubstituted Ci-3 alkyl;
R10 is hydrogen or substituted or unsubstituted Ci-8 alkyl; and
a is 1 , 2 or 3.
2. A compound according to claim 1 selected from:
3-[(4-{5-[(1 E)-5-methyl-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propanoic acid;
{3-[(4-{5-[(1 E)-5-methyl-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(4-{5-[(1 E)-2-phenylhept-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)amino]propanoic acid;
{3-[(4-{5-[(1 E)-2-phenylhept-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(4-{5-[(1 Z)-2-phenylhept-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)amino]propanoic acid;
{3-[(4-{5-[(1 Z)-2-phenylhept-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(4-{5-[(1 Z)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)amino]propanoic acid;
{3-[(4-{5-[(1 Z)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(4-{5-[(1 Z)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)amino]propanoic acid;
{3-[(4-{5-[(1 Z)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)amino]propanoic acid;
{3-[(4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)amino]propanoic acid;
{3-[(4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(3-ethyl-4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propanoic acid;
{3-[(3-ethyl-4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid; 3-[(3-ethyl-4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propanoic acid;
{3-[(3-ethyl-4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(3-methyl-4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propanoic acid;
{3-[(3-methyl-4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(3-methyl-4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propanoic acid; and
{3-[(3-methyl-4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid.
3. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable adjuvant, diluent or carrier.
4. A pharmaceutical composition according to claim 3 wherein the compound is selected from:
3-[(4-{5-[(1 E)-5-methyl-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propanoic acid;
{3-[(4-{5-[(1 E)-5-methyl-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(4-{5-[(1 E)-2-phenylhept-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)amino]propanoic acid;
{3-[(4-{5-[(1 E)-2-phenylhept-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(4-{5-[(1 Z)-2-phenylhept-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)amino]propanoic acid;
{3-[(4-{5-[(1 Z)-2-phenylhept-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid; 3-[(4-{5-[(1 Z)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)amino]propanoic acid;
{3-[(4-{5-[(1 Z)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(4-{5-[(1 Z)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)amino]propanoic acid;
{3-[(4-{5-[(1 Z)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)amino]propanoic acid;
{3-[(4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)amino]propanoic acid;
{3-[(4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(3-ethyl-4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propanoic acid;
{3-[(3-ethyl-4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(3-ethyl-4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propanoic acid;
{3-[(3-ethyl-4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(3-methyl-4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propanoic acid;
{3-[(3-methyl-4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
3-[(3-methyl-4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propanoic acid;
{3-[(3-methyl-4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)amino]propyl}phosphonic acid;
5. A compound having Formula II, its enantiomers, diastereoisomers, tautomers or a pharmaceutically acceptable salt thereof,
Figure imgf000048_0001
Formula II
wherein:
R1 is substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C5-8 cycloalkyl, substituted or unsubstituted C5-8 cycloalkenyl;
R2 is substituted or unsubstituted C -8 alkyl;
R3 is hydrogen, halogen, substituted or unsubstituted Ci-8 alkyl, C(0)R7 or hydroxy I;
R4 is hydrogen, halogen, substituted or unsubstituted Ci-8 alkyl, C(0)R7 or hydroxy I;
R5 is hydrogen, halogen, substituted or unsubstituted Ci-8 alkyl, C(0)R7, hydroxyl, or substituted or unsubstituted heterocycle;
R6 is hydrogen, halogen, substituted or unsubstituted Ci-8 alkyl, C(0)R7, hydroxyl, or substituted or unsubstituted heterocycle;
R7 is hydrogen, -OR9, substituted or unsubstituted Ci-8 alkyl;
R8 is OPO3H2, carboxylic acid, P03H2, -P(0)MeOH, -P(0)(H)OH or OR9;
R9 is hydrogen or substituted or unsubstituted Ci-8 alkyl; and
R10 is hydrogen or substituted or unsubstituted Ci-8 alkyl.
6. A compound according to claim 5 selected from: 1 -(4-{5-[(1 E)-5-methyl-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)azetidine-3-carboxylic acid;
1 -(4-{5-[(1 E)-2-phenylhept-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid;
1 -(4-{5-[(1 Z)-2-phenylhept-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid;
1 -(4-{5-[(1 Z)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid;
1 -(4-{5-[(1 Z)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid;
1 -(4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid;
1 -(4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid;
1 -(3-ethyl-4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid;
1 -(3-ethyl-4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid;
1 -(3-methyl-4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid; and
1 -(3-methyl-4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid.
7. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to claim 5 and a pharmaceutically acceptable adjuvant, diluent or carrier.
8. A pharmaceutical composition according to claim 7 wherein the compound is selected from:
1 -(4-{5-[(1 E)-5-methyl-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)azetidine-3-carboxylic acid;
1 -(4-{5-[(1 E)-2-phenylhept-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid; 1 -(4-{5-[(1 Z)-2-phenylhept-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid;
1 -(4-{5-[(1 Z)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid;
1 -(4-{5-[(1 Z)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid;
1 -(4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid;
1 -(4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine-3- carboxylic acid;
1 -(3-ethyl-4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine- 3-carboxylic acid;
1 -(3-ethyl-4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2-yl}benzyl)azetidine- 3-carboxylic acid;
1 -(3-methyl-4-{5-[(1 E)-2-phenylhex-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)azetidine-3-carboxylic acid; and
1 -(3-methyl-4-{5-[(1 E)-2-phenylpent-1 -en-1 -yl]-1 ,3,4-oxadiazol-2- yl}benzyl)azetidine-3-carboxylic acid.
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