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WO2015073547A1 - Dérivés de phénoxy azétidine disubstitutés utilisés comme modulateurs du récepteur de la sphingosine 1-phosphate (s1p) - Google Patents

Dérivés de phénoxy azétidine disubstitutés utilisés comme modulateurs du récepteur de la sphingosine 1-phosphate (s1p) Download PDF

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Publication number
WO2015073547A1
WO2015073547A1 PCT/US2014/065239 US2014065239W WO2015073547A1 WO 2015073547 A1 WO2015073547 A1 WO 2015073547A1 US 2014065239 W US2014065239 W US 2014065239W WO 2015073547 A1 WO2015073547 A1 WO 2015073547A1
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WIPO (PCT)
Prior art keywords
dimethylphenyl
azetidine
carboxylic acid
alkyl
butoxy
Prior art date
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PCT/US2014/065239
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English (en)
Inventor
Wenkui K. Fang
Evelyn G. Corpuz
Ken Chow
Original Assignee
Allergan, Inc.
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Filing date
Publication date
Application filed by Allergan, Inc. filed Critical Allergan, Inc.
Publication of WO2015073547A1 publication Critical patent/WO2015073547A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to disubstituted phenoxy azetidine derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals, as modulators of the 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.
  • 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.
  • a group of disubstituted phenoxy azetidine derivatives, which are potent and selective sphingosine-1 -phosphate modulators has been discovered.
  • the compounds described herein are useful in treating a wide variety of disorders associated with modulation of the sphingosine-1 -phosphate receptors.
  • 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 pharmaceutically acceptable salt thereof or stereoisomeric forms thereof, or the geometrical isomers, enantiomers, diastereoisomers, tautomers, zwitterions and pharmaceutically acceptable salts thereof
  • A is C-6-10 aryl, heterocycle, C 3 -8 cycloalkyl or C 3 -8 cycloalkenyl;
  • B is C-6-10 aryl, heterocycle, C 3 -8 cycloalkyl or C 3 -8 cycloalkenyl;
  • R 1 is H, halogen, -OCi- 8 alkyl, Ci -8 alkyl, CN, C(0)R 11 , NR 12 R 13 or hydroxyl
  • R 2 is H, halogen, -OCi -8 alkyl, C 1-8 alkyl, CN, C(0)R 11 , NR 12 R 13 or hydroxyl;
  • R 3 is H, halogen, -OCi -8 alkyl, C 1-8 alkyl, CN, C(0)R 11 , NR 12 R 13 or hydroxyl;
  • R 4 is H, halogen, -OCi -8 alkyl, Ci -8 alkyl, CN, C(0)R 11 , NR 12 R 13 or hydroxyl;
  • R 5 is H, halogen, -OCi -8 alkyl, Ci -8 alkyl, CN, C(0)R 11 , NR 12 R 13 or hydroxyl;
  • R 6 is H, halogen, -OCi -8 alkyl, Ci -8 alkyl, CN, C(0)R 11 , NR 12 R 13 or hydroxyl;
  • R 7 is H, halogen, -OCi -8 alkyl, Ci -8 alkyl, CN, C(0)R 11 , C 6 -io aryl, heterocycle, C 3 - 8 cycloakyl, C 3 - 8 cycloalkenyl, NR 12 R 13 or hydroxyl;
  • R 8 is H, halogen, -OCi -8 alkyl, Ci -8 alkyl, CN, C(0)R 11 , C 6 -io aryl, heterocycle, C 3 - 8 cycloakyl, C 3 - 8 cycloalkenyl, NR 12 R 13 or hydroxyl;
  • R 9 is H, halogen, -OCi -8 alkyl, Ci -8 alkyl, CN, C(0)R 11 , C 6 -io aryl, heterocycle, C 3-8 cycloakyl, C 3-8 cycloalkenyl, NR 12 R 13 or hydroxyl;
  • R 10 is H, halogen, -OCi -8 alkyl, Ci -8 alkyl, CN, C(0)R 11 , C 6 -io aryl, heterocycle, C 3-8 cycloakyl, C 3-8 cycloalkenyl, NR 12 R 13 or hydroxyl;
  • L is O, S or CH 2;
  • R 11 is H, OH or Ci- 8 alkyl
  • a is 1 , 2, 3 or 4;
  • R 12 is H or Ci-8 alkyl
  • R 13 is H or Ci- 8 alkyl.
  • the invention provides a compound having Formula I wherein
  • L is CH 2 .
  • the invention provides a compound having Formula I wherein a is 2 or 3.
  • the invention provides a compound having Formula I wherein
  • the invention provides a compound having Formula I wherein
  • alkyl refers to saturated, monovalent 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 C 3 -8 cycloalkyl.
  • Alkyl groups can be independently substituted by one or more halogen atoms, hydroxyl groups, cycloalkyl groups, amine groups, heterocyclic groups, carboxylic acid groups, phosphonic acid groups, sulphonic acid groups, phosphoric acid groups, nitro groups, amide groups and/or sulfonamides groups.
  • 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 independently substituted by one or more halogen, nitro groups, cyano groups, -OCi -6 alkyl groups, -SCi -6 alkyl groups, -Ci -6 alkyl groups, -C 2 -6 alkenyl groups, -C 2 -6 alkynyl groups, C 3 -8 cycloalkyi groups, carboxylic acid groups, ester groups, ketone groups, aldehyde groups, amide groups, amine groups, sulfonamide groups and/or hydroxyl groups.
  • cycloalkenyl refers to a monovalent or divalent group of 3 to 8 carbon atoms, derived from a saturated cycloalkyi having one double bond. Cycloalkenyl groups can be monocyclic or polycyclic.
  • Cycloalkenyl groups can be independently substituted by one or more halogen atoms, nitro groups, cyano groups, -OCi -6 alkyl groups, -SCi -6 alkyl groups, -Ci -6 alkyl groups, -C 2-6 alkenyl groups, -C 2-6 alkynyl groups, carboxylic acid groups, ester groups, ketone groups, aldehyde groups, amide groups, amine groups, sulfonamide groups, C 3 -8 cycloalkyi groups and/or hydroxyl groups.
  • halogen refers to an atom of chlorine, bromine, fluorine, iodine.
  • alkenyl refers to a monovalent or divalent hydrocarbon radical 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 C-i-s alkyl.
  • heterocycle refers to a 3 to 10 membered ring, which can be aromatic or non-aromatic, saturated or non-saturated, monocyclic or polycyclic, containing at least one heteroatom selected from O or N or S or combinations of at least two thereof, interrupting the carbocyclic ring structure.
  • Heterocycles can be monocyclic or polycyclic.
  • Heterocyclic ring moieties can be substituted by one or more halogen, nitro groups, cyano groups, -OCi -6 alkyl groups, -SC-i-6 alkyl groups, -Ci-6 alkyl groups, -C 2- 6 alkenyl groups, -C 2- 6 alkynyl groups, carboxylic acid groups, ester groups, ketone groups, aldehyde groups, amide groups, amine groups, sulfonamide groups, C 3 -s cycloalkyi groups and/or hydroxyl groups.
  • aryl refers to an organic moiety derived from aromatic hydrocarbon consisting of a ring containing 6 to 10 carbon atoms by removal of one hydrogen.
  • Aryl can be monocyclic or polycyclic.
  • Aryl can be substituted by one or more halogen atoms, nitro groups, cyano groups, -OCi -6 alkyl groups, -SCi -6 alkyl groups, -Ci -6 alkyl groups, -C 2 -6 alkenyl groups, -C 2 -6 alkynyl groups, carboxylic acid groups, ester groups, ketone groups, aldehyde groups, amide groups, amine groups, sulfonamide groups, C 3 -8 cycloalkyl groups and/or hydroxyl groups.
  • aryl is phenyl.
  • Preferred substitution sites on aryl are meta and para positions.
  • cyano as used herein, represents a group of formula "-CN”.
  • nitro represents a group of formula "-N0 2 ".
  • amide represents a group of formula "-C(0)NR x R y " wherein R x and R y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, or heterocyle as defined above.
  • amine as used herein, represents a group of formula "-NR x R y ",wherein R x and R y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, or heterocyle as defined above.
  • ketone represents an organic compound having a carbonyl group linked to a carbon atom such as -(CO)R x wherein R x can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocyle as defined above.
  • aldehyde represents a group of formula "-C(0)H”.
  • ester represents a group of formula "-C(0)OR x ", wherein R x can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocyle as defined above.
  • sulfonamide represents a group of formula "- S(0) 2 NR x R y " wherein R x and R y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, or heterocyle as defined above.
  • hydroxyl represents a group of formula "-OH”.
  • carbonyl as used herein, represents a group of formula "-C(O)”.
  • carboxyl as used herein, represents a group of formula "-C(0)O".
  • sulfonyl as used herein, represents a group of formula "-S0 2 ".
  • sulfate as used herein, represents a group of formula "-0-S(0) 2 -0-
  • 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”.
  • the formula ⁇ represents a hydrogen atom.
  • the formula "0”, as used herein, represents an oxygen atom.
  • the formula "N”, as used herein, represents a nitrogen atom.
  • 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 Appl. Chem. (1976), 45, 1 1 -13.
  • 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 are able to form.
  • the acid addition salt form of a compound of Formula I 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, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; or an organic acid such as for example, acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, malonic acid, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric acid, methylsulfonic acid, ethanesulfonic acid, benzenesulfonic acid, formic and the like (Handbook of an inorganic acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; or an organic acid such as for example,
  • the base addition salt form of a compound of Formula I 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).
  • 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 (Handbook of Pharmaceutical Salts, P.Heinrich Stahl& Camille G. Wermuth (
  • solvates include for example hydrates, alcoholates and the like.
  • 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.
  • S1 P modulators include diseases, such as but not limited to:
  • Ocular Diseases wet and dry age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal edema, dry eye, 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;
  • Systemic vascular barrier related diseases various inflammatory diseases, including acute lung injury, its prevention, sepsis, tumor metastasis,
  • Allergies and other inflammatory diseases urticaria, bronchial asthma, and other airway inflammations including pulmonary emphysema and chronic obstructive pulmonary diseases;
  • Cardiac functions bradycardia, congestional heart failure, cardiac arrhythmia, prevention and treatment of atherosclerosis, and ischemia/reperfusion injury;
  • 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;
  • Bone formation treatment of osteoporosis and various bone fractures including hip and ankles;
  • Anti-nociceptive activity visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, neuropathic pains;
  • Anti-fibrosis ocular, cardiac, hepatic and pulmonary fibrosis, proliferative vitreoretinopathy, cicatricial pemphigoid, surgically induced fibrosis in cornea, conjunctiva and tenon;
  • Pains and anti-inflammation acute pain, flare-up of chronic pain, musculoskeletal pains, visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, bursitis, neuropathic pains; CNS neuronal injuries: Alzheimer's disease, age-related neuronal injuries;
  • Organ transplants renal, corneal, cardiac and adipose tissue transplants.
  • 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, hydrates, solvates, crystal forms and individual isomers, 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 Diseases wet and dry age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal edema, dry eye, 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;
  • 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;
  • Allergies and other inflammatory diseases urticaria, bronchial asthma, and other airway inflammations including pulmonary emphysema and chronic obstructive pulmonary diseases; Cardiac functions: bradycardia, congestional heart failure, cardiac arrhythmia, prevention and treatment of atherosclerosis, and ischemia/reperfusion injury;
  • 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;
  • Bone formation treatment of osteoporosis and various bone fractures including hip and ankles;
  • Anti-nociceptive activity visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis,
  • Anti-fibrosis ocular, cardiac, hepatic and pulmonary fibrosis, proliferative vitreoretinopathy, cicatricial pemphigoid, surgically induced fibrosis in cornea, conjunctiva and tenon; Pains and anti-inflammation: acute pain, flare-up of chronic pain, musculoskeletal pains, visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, bursitis, neuropathic pains; CNS neuronal injuries: Alzheimer's disease, age-related neuronal injuries;
  • Organ transplants renal, corneal, cardiac and adipose tissue transplants.
  • 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
  • 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.
  • 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.
  • 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.
  • 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
  • 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 adjustors 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 adjustor.
  • 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.
  • 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 ml.
  • 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.
  • 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.
  • 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.
  • a suitably substituted acid chloride and a suitably substituted arene were mixed and cooled to -78 °C, then AICI 3 (1 .5 eq) was added, the resulting reaction mixture was stirred at this temperature for 60 minutes, then quenched with concentrated HCI.
  • the reaction mixture thus created was diluted with ethyl acetate and washed with brine, then concentrated. Flash chromatography gave the desired ketone. This ketone was dissolved in THF, then cooled to 0°C, and a properly substituted aryl Grignard was added. The resulting reaction mixture was stirred at this temperature for 30 minutes, then quenched with saturated ammonium chloride.
  • FIG. 1 shows the structure of Formula I. DETAILED DESCRIPTION OF THE INVENTION
  • 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.
  • 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 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.
  • B is C-6-10 aryl, heterocycle, C 3 -8 cycloalkyl or C 3 -8 cycloalkenyl;
  • R 1 is H, halogen, -OC 1-8 alkyl, Ci -8 alkyl, CN, C(0)R 11 , NR 12 R 13 or hydroxyl;
  • R 2 is H, halogen, -OC 1-8 alkyl, Ci -8 alkyl, CN, C(0)R 11 , NR 12 R 13 or hydroxyl;
  • R 3 is H, halogen, -OCi -8 alkyl, Ci-8 alkyl, CN, C(0)R 11 , NR 12 R 13 or hydroxyl;
  • R 4 is H, halogen, -OCi -8 alkyl, Ci -8 alkyl, CN, C(0)R 11 , NR 12 R 13 or hydroxyl;
  • R 5 is H, halogen, -OCi- 8 alkyl, Ci -8 alkyl, CN, C(0)R 11 , NR 12 R 13 or hydroxyl;
  • R 6 is H, halogen, -OCi- 8 alkyl, Ci -8 alkyl, CN, C(0)R 11 , NR 12 R 13 or hydroxyl;
  • R 7 is H, halogen, -OCi- 8 alkyl, Ci -8 alkyl, CN, C(0)R 11 , C 6 -io aryl, heterocycle, C 3 -s cycloakyl, C 3-8 cycloalkenyl, NR 12 R 13 or hydroxyl;
  • R 8 is H, halogen, -OCi -8 alkyl, Ci -8 alkyl, CN, C(0)R 11 , C 6 -io aryl, heterocycle, C 3-8 cycloakyl, C 3-8 cycloalkenyl, NR 12 R 13 or hydroxyl;
  • R 9 is H, halogen, -OCi -8 alkyl, Ci -8 alkyl, CN, C(0)R 11 , C 6 -io aryl, heterocycle, C 3-8 cycloakyl, C 3-8 cycloalkenyl, NR 12 R 13 or hydroxyl;
  • R 10 is H, halogen, -OCi -8 alkyl, Ci -8 alkyl, CN, C(0)R 11 , C 6 -io aryl, heterocycle, C 3 . 8 cycloakyl, C 3 - 8 cycloalkenyl, NR 12 R 13 or hydroxyl;
  • L is O, S or CH 2;
  • R 11 is H, OH or Ci -8 alkyl
  • R 12 is H or Ci- 8 alkyl
  • R 13 is H or Ci- 8 alkyl
  • a is 1 , 2, 3 or 4;
  • each halogen is independently selected from F, CI, Br and I.
  • each C-i-s alkyl is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and t-butyl.
  • L is CH 2 ;
  • a is 2 or 3;
  • each of R 1 , R 2 , R 3 , R 4 , R 5 R 6 , R 7 , R 8 , R 9 and R 10 is independently selected from H, F, CI, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and t-butyl.
  • compositions comprising as active ingredient a therapeutically effective amount of a compound according to any one of embodiments (1 ) through (12) and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a method of treating a disorder associated with sphingosine-1 -phosphate receptor modulation which comprises administering to a mammal in need thereof, a pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to any one of embodiments (1 ) through (12).
  • embodiment (16) there is provided a method of embodiment (15), wherein the pharmaceutical composition is administered to the mammal to treat ocular disease, wet and dry age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal edema, geographic atrophy, glaucomatous optic neuropathy, chorioretinopathy, hypertensive retinopathy, dry eye, 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 s
  • embodiment (17) there is provided a method of embodiment (15) or (16) wherein the mammal is a human.
  • characterization of the compounds is performed according to the following methods: NMR spectra are recorded on 300 and/or 600 MHz Varian NMR spectrometer and acquired at room temperature. Chemical shifts are given in ppm referenced either to internal TMS or to the solvent signal.
  • 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, MgCI 2 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 non-linear regression method. In case of antagonist assay, the reaction mixture contained 10 nM S1 P in the presence of test antagonist at concentrations ranging from 0.08 to 5000 nM.
  • Table 1 shows activity potency: S1 P1 receptor from GTP y 35 S: nM, (EC 50 ).

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Abstract

L'invention concerne des dérivés de phénoxy azétidine disusbstitués, des procédés pour leur préparation, des compositions pharmaceutiques les contenant et leur utilisation en tant que produits pharmaceutiques et modulateurs de récepteurs de la sphingosine-1-phosphate.
PCT/US2014/065239 2013-11-13 2014-11-12 Dérivés de phénoxy azétidine disubstitutés utilisés comme modulateurs du récepteur de la sphingosine 1-phosphate (s1p) WO2015073547A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011066179A1 (fr) * 2009-11-24 2011-06-03 Allergan, Inc. Nouveaux composés comme modulateurs de récepteurs présentant une utilité thérapeutique
WO2013126428A1 (fr) * 2012-02-21 2013-08-29 Allergan, Inc. Dérivés phénoxy en tant que modulateurs de récepteurs de la sphingosine-1-phosphate (s1p)
WO2013126381A1 (fr) * 2012-02-21 2013-08-29 Allergan, Inc. Dérivés de phenoxy-azétidine utilisés comme modulateurs des récepteurs de la sphingosine 1-phosphate (s1p)

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011066179A1 (fr) * 2009-11-24 2011-06-03 Allergan, Inc. Nouveaux composés comme modulateurs de récepteurs présentant une utilité thérapeutique
WO2013126428A1 (fr) * 2012-02-21 2013-08-29 Allergan, Inc. Dérivés phénoxy en tant que modulateurs de récepteurs de la sphingosine-1-phosphate (s1p)
WO2013126381A1 (fr) * 2012-02-21 2013-08-29 Allergan, Inc. Dérivés de phenoxy-azétidine utilisés comme modulateurs des récepteurs de la sphingosine 1-phosphate (s1p)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HARUTO KURATA ET AL: "Discovery of S1P agonists with a dihydronaphthalene scaffold", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 21, no. 13, 1 July 2011 (2011-07-01), pages 3885 - 3889, XP055166461, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2011.05.029 *

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