WO2015073556A1 - Disubstituted phenoxy derivatives as sphingosine-1-phosphate (s1p) receptor modulators - Google Patents

Disubstituted phenoxy derivatives as sphingosine-1-phosphate (s1p) receptor modulators Download PDF

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Publication number
WO2015073556A1
WO2015073556A1 PCT/US2014/065262 US2014065262W WO2015073556A1 WO 2015073556 A1 WO2015073556 A1 WO 2015073556A1 US 2014065262 W US2014065262 W US 2014065262W WO 2015073556 A1 WO2015073556 A1 WO 2015073556A1
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Prior art keywords
dimethylphenyl
amino
butoxy
benzyl
alkyl
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PCT/US2014/065262
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French (fr)
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Wenkui K. Fang
Evelyn G. Corpuz
Ken Chow
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Allergan, Inc.
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Publication of WO2015073556A1 publication Critical patent/WO2015073556A1/en

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    • 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
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/14—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of carbon skeletons containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • 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
    • C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
    • C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring

Definitions

  • the present invention relates to di-substituted phenoxy 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:
  • A is C-6-10 aryl, heterocycle, C3-8 cycloalkyl or C3-8 cycloalkenyl;
  • B is C-6-10 aryl, heterocycle, C3-8 cycloalkyl or C3-8 cycloalkenyl
  • R 1 is H, halogen, -OCi -8 alkyl, C 1-8 alkyl, CN, C(0)R 13 , NR 14a R 14b or hydroxyl
  • R 2 is H, halogen, -OCi -8 alkyl, d-e alkyl, CN, C(0)R 13 , NR 14a R 14b or hydroxyl
  • R 3 is H, halogen, -OCi -8 alkyl, d-e alkyl, CN, C(0)R 13 , NR 14a R 14b or hydroxyl
  • R 4 is H, halogen, -OCi -8 alkyl, C 1-8 alkyl, CN, C(0)R 13 , NR 15a R 15b or hydroxyl
  • R 5 is H, halogen, -OCi -8 alkyl, Ci -8 alkyl, CN, C(0)R 13 , NR 15a R 15b or hydroxyl
  • R 6 is H, halogen, -OC
  • R 8 is H, halogen, -OCi -8 alkyl, C -8 alkyl, CN, C(0)R 13 , C 6 -io aryl, heterocycle, C 3 - 8 cycloakyl, C 3 -s cycloalkenyl, NR 15a R 15b or hydroxyl;
  • R 9 is H, halogen, -OCi -8 alkyl, C -8 alkyl, CN, C(0)R 13 , C 6 -io aryl, heterocycle, C 3-8 cycloakyl, C 3 . 8 cycloalkenyl, NR 15a R 5b or hydroxyl;
  • R 10 is H, halogen, -OCi -8 alkyl, Ci_ 8 alkyl, CN, C(0)R 13 , C 6 -io aryl, heterocycle, C 3- s cycloakyl, C 3 - 8 cycloalkenyl, NR 15a R 15b or hydroxyl;
  • R 11 is H or Ci- 8 alkyl
  • R 12 is -OP0 3 H 2 , carboxylic acid, -P0 3 H 2 , -P(0)MeOH, -P(0)(H)OH or OH;
  • L 1 isO, SorCH 2;
  • L 2 is -CH(R 16 )-, -0-, -S-, -N(R 17 )- or -C(O)-;
  • a 1, 2, 3 or 4;
  • b 0, 1, 2, 3 or 4;
  • R 13 isH,OH or Ci-8 alkyl
  • R 14a isHorCi-s alkyl
  • R 14b isHorCi -8 alkyl
  • R 15a isHorCi- 8 alkyl
  • R 15b isHorCi- 8 alkyl
  • R 16 is H or Ci-8 alkyl
  • R 7 is H or C-i-8 alkyl
  • the invention provides a compound having Formula I, wherein L 1 is CH 2 ; L 2 is -CH(R 16 )- wherein R 16 is H; and b is 0 or 1.
  • the invention provides a compound having Formula I, wherein
  • a is 2 or 3.
  • the invention provides a compound having Formula I, wherein R 12 is carboxylic acid or -PO 3 H 2 .
  • the invention provides a compound having Formula I, wherein
  • the invention provides a compound having Formula I, wherein
  • the invention provides a compound having Formula I, wherein is selected from:
  • 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.
  • cycloalkyi refers to a monovalent or divalent group of 3 to 8 carbon atoms, derived from a saturated cyclic hydrocarbon. Cycloalkyi groups can be monocyclic or polycyclic.
  • Cycloalkyi can be independently substituted by one or more halogen, nitro groups, cyano groups, -OCi -6 alkyl groups, -SC1-6 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 Ci -8 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 -8 cycloalkyl groups and/or hydroxyl groups.
  • 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.
  • 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 as used herein, represents a group of formula "-N0 2 ".
  • amide as used herein, 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 as used herein, represents a group of formula "-C(0)H”.
  • esters as used herein, 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 represents a group of formula "-C(O)”.
  • carboxyl as used herein, represents a group of formula "-C(0)O”.
  • sulfonyl represents a group of formula "-S0 2 ".
  • sulfate 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 "-
  • 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”.
  • N 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
  • 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.
  • 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, 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
  • 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.
  • A is C-6-10 aryl, heterocycle, C3-8 cycloalkyl or C3-8 cycloalkenyl;
  • B is C-6-10 aryl, heterocycle, C3-8 cycloalkyl or C3-8 cycloalkenyl
  • R 1 is H, halogen, -OCi -8 alkyl, C 1-8 alkyl, CN, C(0)R 13 , NR 14a R 14b or hydroxyl
  • R 2 is H, halogen, -OCi -8 alkyl, d-e alkyl, CN, C(0)R 13 , NR 14a R 14b or hydroxyl
  • R 3 is H, halogen, -OCi -8 alkyl, d-e alkyl, CN, C(0)R 13 , NR 14a R 14b or hydroxyl
  • R 4 is H, halogen, -OC 1-8 alkyl, C 1-8 alkyl, CN, C(0)R 13 , NR 15a R 15b or hydroxyl
  • R 5 is H, halogen, -OCi -8 alkyl, Ci -8 alkyl, CN, C(0)R 13 , NR 15a R 15b or hydroxyl
  • R 6 is H, halogen, -OCi
  • R 8 is H, halogen, -OCi -8 alkyl, Ci -8 alkyl, CN, C(0)R 13 , C 6 -io aryl, heterocycle, C 3 - 8 cycloakyl, C 3 - 8 cycloalkenyl, NR 15a R 15b or hydroxyl;
  • R 9 is H, halogen, -OCi -8 alkyl, Ci -8 alkyl, CN, C(0)R 13 , C 6 -io aryl, heterocycle, C 3-8 cycloakyl, C 3-8 cycloalkenyl, NR 15a R 15b or hydroxyl;
  • R 10 is H, halogen, -OCi -8 alkyl, Ci -8 alkyl, CN, C(0)R 13 , C 6 -io aryl, heterocycle, C 3- 8 cycloakyl, C 3-8 cycloalkenyl, NR 15a R 15b or hydroxyl;
  • R 11 is H or Ci-8 alkyl
  • R 12 is -OP0 3 H 2 , carboxylic acid, -P0 3 H 2 , -P(0)MeOH, -P(0)(H)OH or OH;
  • L 1 is O, S or CH 2;
  • L 2 is -CH(R 16 )-, -0-, -S-, -N(R 17 )- or -C(O)-;
  • a is 1 , 2, 3 or 4;
  • b is 0, 1 , 2, 3 or 4;
  • R 13 is H, OH or Ci -8 alkyl
  • R 14a is H or Ci- 8 alkyl
  • R 14b is H or Ci -8 alkyl
  • R 15a is H or Ci_8 alkyl
  • R 15b is H or Ci -8 alkyl
  • R 16 is H or Ci-8 alkyl
  • R 17 is H or Ci-8 alkyl
  • 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, halogen, and d-s alkyl.
  • each Ci-s alkyl is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and t-butyl.
  • L 1 is CH 2 ;
  • L 2 is -CH(R 16 )-, wherein R 16 is H;
  • a is 2 or 3;
  • b is 0 or 1 ;
  • 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;
  • R 11 is H
  • R 12 is carboxylic acid or -P0 3 H 2 ;
  • a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to any one of embodiments (1 ) through (13) and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutical composition according to embodiment (14) wherein the compound is selected from:
  • 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 (13).
  • embodiment (17) there is provided the method of embodiment (16), 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
  • ischemia/perfusion injury contact hypersensitivity, atopic dermatitis, 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.
  • embodiment (18) there is provided the method of embodiment (16) or (17), 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

The present invention relates to di-substituted phenoxy derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of sphingosine-1-phosphate receptors.

Description

DISUBSTITUTED PHENOXY DERIVATIVES AS SPHINGOSINE-1-PHOSPHATE (S1 P) RECEPTOR MODULATORS
RELATED APPLICATIONS
This application claims priority to U.S. Provisional Patent Application No.
61 /903,652, filed November 13, 2013, the entire disclosure of which is incorporated herein by this specific reference.
FIELD OF THE INVENTION
The present invention relates to di-substituted phenoxy 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.
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
A group of disubstituted phenoxy azetidine derivatives, which are potent and selective sphingosine-1 -phosphate modulators has been discovered. As such, the compounds described herein are useful in treating a wide variety of disorders associated with modulation of the 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:
Figure imgf000004_0001
Formula I wherein:
A is C-6-10 aryl, heterocycle, C3-8 cycloalkyl or C3-8 cycloalkenyl;
B is C-6-10 aryl, heterocycle, C3-8 cycloalkyl or C3-8 cycloalkenyl;
R1 is H, halogen, -OCi-8 alkyl, C1-8 alkyl, CN, C(0)R13, NR14aR14b or hydroxyl; R2 is H, halogen, -OCi-8 alkyl, d-e alkyl, CN, C(0)R13, NR14aR14b or hydroxyl; R3 is H, halogen, -OCi-8 alkyl, d-e alkyl, CN, C(0)R13, NR14aR14b or hydroxyl; R4 is H, halogen, -OCi-8 alkyl, C1-8alkyl, CN, C(0)R13, NR15aR15b or hydroxyl; R5 is H, halogen, -OCi-8 alkyl, Ci-8 alkyl, CN, C(0)R13, NR15aR15b or hydroxyl; R6 is H, halogen, -OCi-8 alkyl, Ci-8 alkyl, CN, C(0)R13, NR15aR5b or hydroxyl; R7 is H, halogen, -OCi-8 alkyl, Ci-8 alkyl, CN, C(0)R13, C6-io aryl, heterocycle, C3-s cycloakyl, C 3-e cycloalkenyl, NR5aR5b or hydroxyl;
R8 is H, halogen, -OCi-8 alkyl, C-8alkyl, CN, C(0)R13, C6-io aryl, heterocycle, C3-8 cycloakyl, C 3-s cycloalkenyl, NR15aR15b or hydroxyl;
R9 is H, halogen, -OCi-8 alkyl, C-8alkyl, CN, C(0)R13, C6-io aryl, heterocycle, C3-8 cycloakyl, C 3.8 cycloalkenyl, NR15aR5b or hydroxyl;
R10 is H, halogen, -OCi-8 alkyl, Ci_8 alkyl, CN, C(0)R13, C6-io aryl, heterocycle, C3- s cycloakyl, C3-8 cycloalkenyl, NR15aR15b or hydroxyl;
R11 is H or Ci-8 alkyl;
R12 is -OP03H2, carboxylic acid, -P03H2, -P(0)MeOH, -P(0)(H)OH or OH;
L1 isO, SorCH2;
L2 is -CH(R16)-, -0-, -S-, -N(R17)- or -C(O)-;
a is 1, 2, 3 or 4;
b is 0, 1, 2, 3 or 4;
R13 isH,OH or Ci-8 alkyl;
R14aisHorCi-s alkyl;
R14bisHorCi-8alkyl;
R15aisHorCi-8 alkyl;
R15bisHorCi-8 alkyl;
R16 is H or Ci-8 alkyl; and
R7 is H or C-i-8 alkyl;
or an enantiomer, diastereomer or tautomer thereof;
or a pharmaceutically acceptable salt of any of the foregoing.
In another aspect, the invention provides a compound having Formula I, wherein L1 is CH2; L2 is -CH(R16)- wherein R16 is H; and b is 0 or 1.
In another aspect, the invention provides a compound having Formula I, wherein
a is 2 or 3. In another aspect, the invention provides a compound having Formula I, wherein R12 is carboxylic acid or -PO3H2.
In another aspect, the invention provides a compound having Formula I, wherein
Figure imgf000006_0001
is selected from:
Figure imgf000006_0002
In another aspect, the invention provides a compound having Formula I, wherein
Figure imgf000006_0003
In another aspect, the invention provides a compound having Formula I, wherein
Figure imgf000007_0001
is selected from:
Figure imgf000007_0002
and
Figure imgf000007_0003
The term "alkyl", as used herein, refers to saturated, monovalent 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 C3-8 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. The term "cycloalkyi", as used herein, refers to a monovalent or divalent group of 3 to 8 carbon atoms, derived from a saturated cyclic hydrocarbon. Cycloalkyi groups can be monocyclic or polycyclic. Cycloalkyi can be independently substituted by one or more halogen, nitro groups, cyano groups, -OCi-6 alkyl groups, -SC1-6 alkyl groups, -Ci-6 alkyl groups, -C2-6 alkenyl groups, -C2-6 alkynyl groups, C3-8 cycloalkyi groups, carboxylic acid groups, ester groups, ketone groups, aldehyde groups, amide groups, amine groups, sulfonamide groups and/or hydroxyl groups.
The term "cycloalkenyl", as used herein, 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, -C2-6 alkenyl groups, -C2-6 alkynyl groups, carboxylic acid groups, ester groups, ketone groups, aldehyde groups, amide groups, amine groups, sulfonamide groups, C3-8 cycloalkyi groups and/or hydroxyl groups.
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 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 Ci-8 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, 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. 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 one or more halogen, nitro groups, cyano groups, -OCi-6 alkyl groups, -SC-i-6 alkyl groups, -Ci-6 alkyl groups, -C2-6 alkenyl groups, -C2-6 alkynyl groups, carboxylic acid groups, ester groups, ketone groups, aldehyde groups, amide groups, amine groups, sulfonamide groups, C3-8 cycloalkyl groups and/or hydroxyl groups.
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. 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, -C2-6 alkenyl groups, -C2-6 alkynyl groups, carboxylic acid groups, ester groups, ketone groups, aldehyde groups, amide groups, amine groups, sulfonamide groups, C3-8 cycloalkyl groups and/or hydroxyl groups. Usually aryl is phenyl. Preferred substitution sites on aryl are meta and para positions.
The term "cyano" as used herein, represents a group of formula "-CN".
The term "nitro" as used herein, represents a group of formula "-N02".
The term "amide" as used herein, represents a group of formula "-C(0)NRxRy " wherein Rx and Ry can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, or heterocyle as defined above.
The term "amine" as used herein, represents a group of formula "-NRxRy ",wherein Rx and Ry can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, or heterocyle as defined above. The term "ketone" as used herein, represents an organic compound having a carbonyl group linked to a carbon atom such as -(CO)Rx wherein Rx can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocyle as defined above.
The term "aldehyde" as used herein, represents a group of formula "-C(0)H".
The term "ester" as used herein, represents a group of formula "-C(0)ORx", wherein Rx can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocyle as defined above.
The term "sulfonamide" as used herein, represents a group of formula "- S(0)2NRxRy" wherein Rx and Ry can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, or heterocyle as defined above. 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)O". The term "sulfonyl" as used herein, represents a group of formula "-S02". 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 Ή", 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-[4-(3,4-dimethylphenyl)-4-(3- fluorophenyl)butoxy]benzyl}amino)propanoic acid;
[3-({4-[4-(3,4-dimethylphenyl)-4-(3- fluorophenyl)butoxy]benzyl}amino)propyl]phosphonic acid; 3-({4-[4-(3,5-difluorophenyl)-4-(3,4- dimethylphenyl)butoxy]benzyl}amino)propanoic acid;
[3-({4-[4-(3,5-difluorophenyl)-4-(3,4-dimethylphenyl)butoxy]benzyl}amino) propyl]phosphonic acid;
3-({4-[4-(2,4-difluorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- fluorobenzyl}amino)propanoic acid;
[3-({4-[4-(2,4-difluorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- fluorobenzyl}amino)propyl]phosphonic acid;
3-({4-[4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- fluorobenzyl}amino)propanoic acid;
[3-({4-[4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- fluorobenzyl}amino)propyl]phosphonic acid;
3-[(4-{[5-(2,4-difluorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}-3- methylbenzyl)amino]propanoic acid;
{3-[(4-{[5-(2,4-difluorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}-3- methylbenzyl)amino]propyl}phosphonic acid;
3-[(4-{[5-(2,4-difluorophenyl)-5-(3,4- dimethylphenyl)pentyl]oxy}benzyl)amino]propanoic acid;
{3-[(4-{[5-(2,4-difluorophenyl)-5-(3,4- dimethylphenyl)pentyl]oxy}benzyl)amino]propyl}phosphonic acid;
3-({4-[4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- methylbenzyl}amino)propanoic acid;
[3-({4-[4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- methylbenzyl}amino)propyl]phosphonic acid;
3-[(4-{[5-(3,4-dimethylphenyl)-5-(3- fluorophenyl)pentyl]oxy}benzyl)amino]propanoic acid;
{3-[(4-{[5-(3,4-dimethylphenyl)-5-(3- fluorophenyl)pentyl]oxy}benzyl)amino]propyl}phosphonic acid;
3-({4-[4-(3,4-dimethylphenyl)-4-(2-thienyl)butoxy]benzyl}amino)propanoic acid;
[3-({4-[4-(3,4-dimethylphenyl)-4-(2- thienyl)butoxy]benzyl}amino)propyl]phosphonic acid;
3-({4-[4-(3,4-dimethylphenyl)-4-(3-thienyl)butoxy]benzyl}amino)propanoic acid; [3-({4-[4-(3,4-dimethylphenyl)-4-(3- thienyl)butoxy]benzyl}amino)propyl]phosphonic acid;
[3-({4-[4-(2,4-difluorophenyl)-4-(3,4- dimethylphenyl)butoxy]benzyl}amino)propyl]phosphonic acid;
[3-({4-[4-(3,4-difluorophenyl)-4-(3,4- dimethylphenyl)butoxy]benzyl}amino)propyl]phosphonic acid;
3-({4-[4-(2,4-difluorophenyl)-4-(3,4- dimethylphenyl)butoxy]benzyl}amino)propanoic acid;
[3-({4-[4-(3-chlorophenyl)-4-(3,4- dimethylphenyl)butoxy]benzyl}amino)propyl]phosphonic acid; and
3-({4-[4-(3-chlorophenyl)-4-(3,4- dimethylphenyl)butoxy]benzyl}amino)propanoic acid.
Some compounds of Formula I and some of their intermediates 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 Appl. 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 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
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 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).
Compounds of Formula I and their salts can be in the form of a solvate, which is included within the scope of the present invention. Such solvates include for example hydrates, alcoholates and the like.
With respect to the present invention reference to a compound or compounds, is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof unless the particular isomeric form is referred to specifically.
Compounds according to the present invention may exist in different polymorphic forms. Although not explicitly indicated in the above formula, such forms are intended to be included within the scope of the present invention.
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.
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.
Therapeutic utilities of 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,
atherosclerosis, pulmonary edemas, and ventilation-induced lung injury;
Autoimmune diseases and immnuosuppression: rheumatoid arthritis, Crohn's disease, Graves' disease, inflammatory bowel disease, multiple sclerosis, Myasthenia gravis, psoriasis, ulcerative colitis, antoimmune uveitis, renal ischernia/perfusion injury, contact hypersensitivity, atopic dermatitis, and organ transplantation;
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.
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, 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;
Autoimmune diseases and immnuosuppression: 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 dermatitis, and organ transplantation;
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.
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 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.
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 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.
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 imgf000023_0001
A suitably substituted acid chloride and a suitably substituted arene were mixed and cooled to -78 C, then AICI3 (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, 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.
Extraction with ethyl acetate followed by washing with brine, then dried with sodium sulfate gave the desired bromo alcohol which was dissolved in dichloromethane and cooled to 0°C. TFA was added, followed by addition of triethylsilane. The reaction mixture was stirred at room temperature for 4 hours, then concentrated to give the desired bromo compound. This bromo compound was mixed with the appropriately substituted 4-hdroxybenzalde in DMF, and the resulting reaction was stirred at 125 C for 16 hours then cooled to room temperature. The reaction mixture was diluted with EtOAc, then washed with water and brine. The organic phase was dried with sodium sulfate and concentrated to give the crude aldehyde which was purified by MPLC to give the desired benzaldehyde intermediate. A sample of the benzaldehyde intermediate, β-alanine (1 .3 eq) and TEA (1 .3 eq) were mixed with MeOH (10ml). Upon stirring at 60°C for 90 min, the reaction solution was cooled to RT. NaBH4 was added and stirred at RT for 2 hour. The reaction was quenched with 0.5 mL of water and concentrated to minimal amount. The titled compound was isolated by reverse phase MPLC using 0 to 90% H20 in AcCN.
A mixture of (3-aminopropyl)phosphonic acid and Bu4NOH in MeOH was stirred at 30 C for a few minutes. The above prepared benzaldehyde dissolved in minimum amount of THF was added. The reaction mixture was stirred at 50 C for 3 hours, then NaCNBH3 dissolved in minimum amount of MeOH was added. The resulting mixture was stirred at 5°C for 3 hours, cooled to room temperature and quenched with water. It was then concentrated on the rotary evaporator and purified by MPLC to give the title compound.
The following abbreviations are used in the general procedures and in the examples:
AICIs aluminum chloride
TEA triethylamine
HCI hydrochloric acid
NaBH4 sodium borohydride
Bu4NOH tetrabutylammonium hydroxide
AcCN acetonitrile
MgBr magnesium bromide
TFA trifluoroacetic acid TMS tetramethylsilane
MeOH methanol
NaH sodium hydride
CDCI3 deuterated chloroform
MPLC medium pressure liquid chromatography
DMF dimethylformamide
NaCNBH3 sodium cyanoborohydride
HOAc acetic acid
Et3SiH triethylsilane
Those skilled in the art will be able to routinely modify and/or adapt the following scheme to synthesize any compounds of the invention covered by Formula I.
DRAWINGS
Figure 1 shows the structure of Formula I. 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 1H (or H) or use of 13C-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.
The following are non-limiting embodiments of the invention.
In embodiment (1 ), there is provided a compound having Formula I:
Figure imgf000026_0001
Formula I
wherein:
A is C-6-10 aryl, heterocycle, C3-8 cycloalkyl or C3-8 cycloalkenyl;
B is C-6-10 aryl, heterocycle, C3-8 cycloalkyl or C3-8 cycloalkenyl;
R1 is H, halogen, -OCi-8 alkyl, C1-8 alkyl, CN, C(0)R13, NR14aR14b or hydroxyl; R2 is H, halogen, -OCi-8 alkyl, d-e alkyl, CN, C(0)R13, NR14aR14b or hydroxyl; R3 is H, halogen, -OCi-8 alkyl, d-e alkyl, CN, C(0)R13, NR14aR14b or hydroxyl; R4 is H, halogen, -OC1-8 alkyl, C1-8 alkyl, CN, C(0)R13, NR15aR15b or hydroxyl; R5 is H, halogen, -OCi-8 alkyl, Ci-8 alkyl, CN, C(0)R13, NR15aR15b or hydroxyl; R6 is H, halogen, -OCi-8 alkyl, Ci-8 alkyl, CN, C(0)R13, NR15aR15b or hydroxyl; R7 is H, halogen, -OCi-8 alkyl, Ci-8 alkyl, CN, C(0)R13, C6-io aryl, heterocycle, C3-s cycloakyl, C3-8 cycloalkenyl, NR15aR15b or hydroxyl;
R8 is H, halogen, -OCi-8 alkyl, Ci-8 alkyl, CN, C(0)R13, C6-io aryl, heterocycle, C3-8 cycloakyl, C3-8 cycloalkenyl, NR15aR15b or hydroxyl;
R9 is H, halogen, -OCi-8 alkyl, Ci-8 alkyl, CN, C(0)R13, C6-io aryl, heterocycle, C3-8 cycloakyl, C 3-8 cycloalkenyl, NR15aR15b or hydroxyl;
R10 is H, halogen, -OCi-8 alkyl, Ci-8 alkyl, CN, C(0)R13, C6-io aryl, heterocycle, C3- 8 cycloakyl, C3-8 cycloalkenyl, NR15aR15b or hydroxyl;
R11 is H or Ci-8 alkyl;
R12 is -OP03H2, carboxylic acid, -P03H2, -P(0)MeOH, -P(0)(H)OH or OH;
L1 is O, S or CH2;
L2 is -CH(R16)-, -0-, -S-, -N(R17)- or -C(O)-;
a is 1 , 2, 3 or 4;
b is 0, 1 , 2, 3 or 4;
R13 is H, OH or Ci-8 alkyl;
R14a is H or Ci-8 alkyl;
R14b is H or Ci-8 alkyl;
R15a is H or Ci_8 alkyl;
R15b is H or Ci-8 alkyl;
R16 is H or Ci-8 alkyl; and
R17 is H or Ci-8 alkyl;
or an enantiomer, diastereomer or tautomer thereof;
or a pharmaceutically acceptable salt of any of the foregoing.
In embodiment (2), there is provided a compound according to embodiment (1 ), wherein L1 is CH2; L2 is -CH(R16)-, wherein R 6 is H; and b is 0 or 1.
In embodiment (3), there is provided a compound according to embodiment (1 ) or (2), wherein a is 2 or 3.
In embodiment (4), there is provided a compound according to any one of embodiments (1 ) through (3), wherein R12 is carboxylic acid or -P03H2. In embodiment (5), there is provided a compound according to any one of embodiments (1 ) through (4), wherein:
Figure imgf000028_0001
is selected from:
Figure imgf000028_0002
In embodiment (6), there is provided a compound according to any one of embodiments (1 ) through (5), wherein:
Figure imgf000028_0003
In embodiment (7), there is provided a compound according to any one of embodiments (1 ) through (6), wherein:
Figure imgf000029_0001
is selected from:
Figure imgf000029_0002
and
Figure imgf000029_0003
In embodiment (8), there is provided a compound according to any one of embodiments (1 ) through (7), wherein each of R1 , R2, R3, R4, R5 R6, R7, R8, R9 and R10 is independently selected from H, halogen, and d-s alkyl.
In embodiment (9), there is provided a compound according to any one of embodiments (1 ) through (8), wherein R11 is H. In embodiment (10), there is provided a compound according to any one of embodiments (1 ) through (9), wherein each halogen is independently selected from F, CI, Br and I.
In embodiment (1 1 ), there is provided a compound according to any one of embodiments (1 ) through (10), wherein each Ci-s alkyl is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and t-butyl.
In embodiment (12), there is provided a compound according to any preceding embodiment, wherein:
L1 is CH2;
L2 is -CH(R16)-, wherein R16 is H;
a is 2 or 3;
b is 0 or 1 ;
Figure imgf000030_0001
is selected from:
Figure imgf000030_0002
Figure imgf000031_0001
each of R1 , R2, R3, R4, R5 R6, R7, R8, R9 and R10 is independently selected from H, F, CI, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and t-butyl;
R11 is H; and
R12 is carboxylic acid or -P03H2;
or an enantiomer, diastereomer or tautomer thereof;
or a pharmaceutically acceptable salt of any of the foregoing.
In embodiment (13), there is provided compound according to embodiment (1 ), selected from:
3-({4-[4-(3,4-dimethylphenyl)-4-(3-fluorophenyl)butoxy]benzyl}amino)propanoic acid;
[3-({4-[4-(3,4-dimethylphenyl)-4-(3- fluorophenyl)butoxy]benzyl}amino)propyl]phosphonic acid;
3-({4-[4-(3,5-difluorophenyl)-4-(3,4- dimethylphenyl)butoxy]benzyl}amino)propanoic acid;
[3-({4-[4-(3,5-difluorophenyl)-4-(3,4-dimethylphenyl)butoxy]benzyl}amino) propyl] phosphonic acid;
3-({4-[4-(2,4-difluorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- fluorobenzyl}amino)propanoic acid;
[3-({4-[4-(2,4-difluorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- fluorobenzyl}amino)propyl]phosphonic acid;
3-({4-[4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- fluorobenzyl}amino)propanoic acid;
[3-({4-[4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- fluorobenzyl}amino)propyl]phosphonic acid;
3-[(4-{[5-(2,4-difluorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}-3- methylbenzyl)amino]propanoic acid; {3-[(4-{[5-(2,4-difluorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}-3- methylbenzyl)amino]propyl}phosphonic acid;
3-[(4-{[5-(2,4-difluorophenyl)-5-(3,4- dimethylphenyl)pentyl]oxy}benzyl)amino]propanoic acid;
{3-[(4-{[5-(2,4-difluorophenyl)-5-(3,4- dimethylphenyl)pentyl]oxy}benzyl)amino]propyl}phosphonic acid;
3-({4-[4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- methylbenzyl}amino)propanoic acid;
[3-({4-[4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- methylbenzyl}amino)propyl]phosphonic acid;
3-[(4-{[5-(3,4-dimethylphenyl)-5-(3- fluorophenyl)pentyl]oxy}benzyl)amino]propanoic acid;
{3-[(4-{[5-(3,4-dimethylphenyl)-5-(3- fluorophenyl)pentyl]oxy}benzyl)amino]propyl}phosphonic acid;
3-({4-[4-(3,4-dimethylphenyl)-4-(2-thienyl)butoxy]benzyl}amino)propanoic acid;
[3-({4-[4-(3,4-dimethylphenyl)-4-(2- thienyl)butoxy]benzyl}amino)propyl]phosphonic acid;
3-({4-[4-(3,4-dimethylphenyl)-4-(3-thienyl)butoxy]benzyl}amino)propanoic acid;
[3-({4-[4-(3,4-dimethylphenyl)-4-(3- thienyl)butoxy]benzyl}amino)propyl]phosphonic acid;
[3-({4-[4-(2,4-difluorophenyl)-4-(3,4- dimethylphenyl)butoxy]benzyl}amino)propyl]phosphonic acid;
[3-({4-[4-(3,4-difluorophenyl)-4-(3,4- dimethylphenyl)butoxy]benzyl}amino)propyl]phosphonic acid;
3-({4-[4-(2,4-difluorophenyl)-4-(3,4- dimethylphenyl)butoxy]benzyl}amino)propanoic acid;
[3-({4-[4-(3-chlorophenyl)-4-(3,4- dimethylphenyl)butoxy]benzyl}amino)propyl]phosphonic acid; and
3-({4-[4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]benzyl}amino)propanoic acid;
and enantiomers, diastereomer and tautomers thereof;
and pharmaceutically acceptable salts of the foregoing. In embodiment (14), there is provided a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to any one of embodiments (1 ) through (13) and a pharmaceutically acceptable adjuvant, diluent or carrier. In embodiment (15), there is provided the pharmaceutical composition according to embodiment (14), wherein the compound is selected from:
3-({4-[4-(3,4-dimethylphenyl)-4-(3-fluorophenyl)butoxy]benzyl}amino)propanoic acid;
[3-({4-[4-(3,4-dimethylphenyl)-4-(3- fluorophenyl)butoxy]benzyl}amino)propyl]phosphonic acid;
3-({4-[4-(3,5-difluorophenyl)-4-(3,4- dimethylphenyl)butoxy]benzyl}amino)propanoic acid;
[3-({4-[4-(3,5-difluorophenyl)-4-(3,4-dimethylphenyl)butoxy]benzyl}amino) propyl]phosphonic acid;
3-({4-[4-(2,4-difluorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- fluorobenzyl}amino)propanoic acid;
[3-({4-[4-(2,4-difluorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- fluorobenzyl}amino)propyl]phosphonic acid;
3-({4-[4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- fluorobenzyl}amino)propanoic acid;
[3-({4-[4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- fluorobenzyl}amino)propyl]phosphonic acid;
3-[(4-{[5-(2,4-difluorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}-3- methylbenzyl)amino]propanoic acid;
{3-[(4-{[5-(2,4-difluorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}-3- methylbenzyl)amino]propyl}phosphonic acid;
3-[(4-{[5-(2,4-difluorophenyl)-5-(3,4- dimethylphenyl)pentyl]oxy}benzyl)amino]propanoic acid;
{3-[(4-{[5-(2,4-difluorophenyl)-5-(3,4- dimethylphenyl)pentyl]oxy}benzyl)amino]propyl}phosphonic acid;
3-({4-[4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- methylbenzyl}amino)propanoic acid; [3-({4-[4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- methylbenzyl}amino)propyl]phosphonic acid;
3-[(4-{[5-(3,4-dimethylphenyl)-5-(3- fluorophenyl)pentyl]oxy}benzyl)amino]propanoic acid;
{3-[(4-{[5-(3,4-dimethylphenyl)-5-(3- fluorophenyl)pentyl]oxy}benzyl)amino]propyl}phosphonic acid;
3-({4-[4-(3,4-dimethylphenyl)-4-(2-thienyl)butoxy]benzyl}amino)propanoic acid;
[3-({4-[4-(3,4-dimethylphenyl)-4-(2- thienyl)butoxy]benzyl}amino)propyl]phosphonic acid;
3-({4-[4-(3,4-dimethylphenyl)-4-(3-thienyl)butoxy]benzyl}amino)propanoic acid;
[3-({4-[4-(3,4-dimethylphenyl)-4-(3- thienyl)butoxy]benzyl}amino)propyl]phosphonic acid;
[3-({4-[4-(2,4-difluorophenyl)-4-(3,4- dimethylphenyl)butoxy]benzyl}amino)propyl]phosphonic acid;
[3-({4-[4-(3,4-difluorophenyl)-4-(3,4- dimethylphenyl)butoxy]benzyl}amino)propyl]phosphonic acid;
3-({4-[4-(2,4-difluorophenyl)-4-(3,4- dimethylphenyl)butoxy]benzyl}amino)propanoic acid;
[3-({4-[4-(3-chlorophenyl)-4-(3,4- dimethylphenyl)butoxy]benzyl}amino)propyl]phosphonic acid; and
3-({4-[4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]benzyl}amino)propanoic acid.
In embodiment (16), there is provided 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 (13).
In embodiment (17), there is provided the method of embodiment (16), 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 sclerosis,
Myasthenia gravis, psoriasis, ulcerative colitis, autoimmune uveitis, renal
ischemia/perfusion injury, contact hypersensitivity, atopic dermatitis, 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.
In embodiment (18), there is provided the method of embodiment (16) or (17), wherein the mammal is a human.
Compound names were generated with ACDLabs 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 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 NMR spectrometer 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, M IC- 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 examples were prepared according to the general procedures described above.
Example 1
Intermediate 1
4-r4-(3,4-dimethylphenyl)-4-(3-fluorophenyl)butoxy1benzaldehvde
Figure imgf000036_0001
Spectroscopic data: 1H NMR (300 MHz, CDCI3) δ ppm 1 .71 - 1 .86 (m, 2 H) 2.12 - 2.28 (m, 8 H) 3.88 (t, J=7.76 Hz, 1 H) 4.03 (t, J=6.15 Hz, 2 H) 6.86 (t, J=8.64 Hz, 1 H) 6.91 - 7.01 (m, 5 H) 7.01 - 7.10 (m, 2 H) 7.17 - 7.29 (m, 1 H) 7.81 (d, J=8.79 Hz, 2 H) 9.87 (s, 1 H).
Example 2
Compound 1
-((4-r4-(3,4-dimethylphenyl)-4-(3-fluorophenyl)butoxy1benzyl)amino)propanoic
Figure imgf000036_0002
Spectroscopic data: 1 H NMR (300 MHz, CD3OD) δ ppm 1 .60 - 1 .78 (m, 2 H) 2.07 - 2.16 (m, 2 H) 2.19 (br. s., 6 H) 2.49 (t, J=6.01 Hz, 2 H) 3.13 (t, J=6.01 Hz, 2 H) 3.80 - 4.02 (m, 3 H) 4.10 (br. s, 2 H) 6.79 - 6.89 (m, 1 H) 6.90 - 7.10 (m, 7 H) 7.16 - 7.29 (m, 1 H) 7.36 (d, J=8.20 Hz, 2 H).
Example 3
Compound 2
r3-({4-r4-(3,4-dimethylphenyl)-4-(3- fluorophenyl)butoxy1benzyl)amino)propyl1phosphonic acid
Sp
Figure imgf000037_0001
7 (m, 4 H)
1 .86 - 2.04 (m, 2 H) 2.1 1 - 2.18 (m, 2 H) 2.20 (br. s, 6 H) 2.99 - 3.14 (m, 2 H) 3.89 (t, J=7.30 Hz, 1 H) 3.98 (t, J=6.20 Hz, 2 H) 4.05 (br. s, 2 H) 6.80 - 6.90 (m, 1 H) 6.90 - 7.12 (m, 7 H) 7.18 - 7.31 (m, 1 H) 7.38 (d, J=8.20 Hz, 2 H). Example 4
Intermediate 2
4-r4-(3,5-difluorophenyl)-4-(3,4-dimethylphenyl)butoxy1benzaldehvde
Figure imgf000037_0002
Spectroscopic data: 1H NMR (300 MHz, CDCI3) δ ppm 1 .68 - 1 .87 (m, 2 H)
2.1 1 - 2.20 (m, 2 H) 2.22 (br. s., 6 H) 3.85 (t, J=7.91 Hz, 1 H) 4.03 (t, J=6.15 Hz, 2 H) 6.60 (t, J=8.79 Hz, 1 H) 6.78 (d, J=7.03 Hz, 2 H) 6.91 - 7.02 (m, 4 H) 7.07 (d, J=7.62 Hz, 1 H) 7.81 (d, J=8.50 Hz, 2 H) 9.87 (s, 1 H). Example 5
Compound 3
3-({4-r4-(3,5-difluorophenyl)-4-(3,4- dimethylphenyl)butoxy1benzyl)amino)propanoic acid Spectroscopic
Figure imgf000038_0001
1 .62 - 1 .78 (m, 2 H) 2.1 1 - 2.17 (m, 2 H) 2.22 (br. s, 6 H) 2.40 - 2.55 (m, 2 H) 3.07 - 3.19 (m, 2 H) 3.86 - 4.04 (m, 3 H) 4.1 1 (br. s, 2 H) 6.59 - 6.77 (m, 1 H) 6.85 (d, J=8.20 Hz, 2 H) 6.91 - 7.12 (m, 5 H) 7.37 (d, J=8.50 Hz, 2 H).
Example 6
Compound 4
r3-(f4-r4-(3.5-difluorophenyl)-4-(3.4- dimethylphenyl)butoxy1benzyl)amino)propyl1phosphonic acid
S
Figure imgf000038_0002
(m, 4 H) 1 .85 - 2.05 (m, 2 H) 2.10 - 2.19 (m, 2 H) 2.22 (br. s, 6 H) 2.99 - 3.12 (m, 2 H) 3.85 - 4.03 (m, 3 H) 4.05 (s, 2 H) 6.59 - 6.77 (m, 1 H) 6.86 (d, J=7.00 Hz, 2 H) 6.90 - 7.10 (m, 5 H) 7.38 (d, J=8.50 Hz, 2 H).
Example 7
Intermediate 3
4-r4-(2,4-difluorophenyl)-4-(3,4-dimethylphenyl)butoxy1-3-fluorobenzaldehvde
Figure imgf000038_0003
Spectroscopic data: 1H NMR (300 MHz, CDCI3) δ ppm 1 .78 - 1 .91 (m, 2 H) 2.14 - 2.29 (m, 2 H) 2.21 (s, 3 H) 2.22 (s, 3 H) 4.1 1 (t, J=6.15 Hz, 2 H) 4.22 (t, J=7.91 Hz, 1 H) 6.69 - 6.76 (m, 1 H) 6.77 - 6.85 (m, 1 H) 6.95 - 7.02 (m, 3 H) 7.03 - 7.09 (m, 1 H) 7.18 - 7.29 (m, 1 H) 7.55 - 7.59 (m, 1 H) 7.60 - 7.64 (m, 1 H) 9.84 (d, J=2.05 Hz, 1 H).
Example 8
Compound 5
3-((4-r4-(2,4-difluorophenyl)-4-(3,4-dimethylphenyl)butoxy1-3-
Spectroscopic d
Figure imgf000039_0001
m 1.69 - 1.79 (m, 2 H) 2.1 1 - 2.18 (m, 2 H) 2.19 (s, 3 H) 2.19 (s, 3 H) 2.49 (t, J=6.46 Hz, 2 H) 3.13 (t, J=6.31 Hz, 2 H) 4.05 (t, J=6.16 Hz, 2 H) 4.12 (s, 2 H) 4.19 (t, J=7.92 Hz, 1 H) 6.80 - 6.90 (m, 2 H) 6.94 - 6.98 (m, 1 H) 6.99 - 7.04 (m, 2 H) 7.07 (t, J=8.51 Hz, 1 H) 7.19 (d, J=8.51 Hz, 1 H) 7.24 - 7.28 (m, 1 H) 7.31 - 7.38 (m, 1 H). Example 9
Compound 6
r3-(f4-r4-(2.4-difluorophenvn-4-(3.4-dimethylphenyl)butoxy1-3- fluorobenzyl)amino)propyl1phosphonic acid
Figure imgf000039_0002
1.72 - 1.79 (m, 2 H) 1.90 - 2.01 (m, 2 H) 2.14 - 2.19 (m, 1 H) 2.20 (s, 3 H) 2.21 (s, 3 H) 2.21 - 2.26 (m, 1 H) 3.07 (t, J=6.16 Hz, 2 H) 4.02 - 4.1 1 (m, 4 H) 4.20 (t, J=7.63 Hz, 1 H) 6.80 - 6.92 (m, 2 H) 6.94 - 6.99 (m, 1 H) 7.00 - 7.04 (m, 2 H) 7.07 (t, J=8.66 Hz, 1 H) 7.20 (d, J=9.10 Hz, 1 H) 7.26 (m, J=1.00 Hz, 1 H) 7.32 - 7.40 (m, 1 H).
Example 10 Intermediate 4
4-r4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy1-3-fluorobenzaldehvde
Figure imgf000040_0001
Spectroscopic data: 1 H N MR (300 MHz, CDCI3) δ ppm 1 .79 - 1 .88 (m, 3 H)
2.21 (s, 3 H) 2.22 (s, 3 H) 3.71 - 3.78 (m, 1 H) 3.87 (t, J=7.91 Hz, 1 H) 4.10 (t, J=6.30 Hz, 2 H) 6.94 - 7.02 (m, 3 H) 7.03 - 7.09 (m, 1 H) 7.1 1 - 7.14 (m, 1 H) 7.14 - 7.16 (m, 1 H) 7.1 7 - 7.21 (m, 1 H) 7.22 - 7.25 (m, 1 H) 7.55 - 7.59 (m, 1 H) 7.59 - 7.63 (m, 1 H) 9.84 (d, J=2.05 Hz, 1 H).
Example 1 1
Compound 7
3-(f4-r4-(3-chlorophenyl)-4-(3.4-dimethylphenyl)butoxy1-3- fluorobenzyl)amino)propanoic acid
Spectroscopic d
Figure imgf000040_0002
m 1 .62 - 1 .72 (m, 2 H) 2.08 - 2.14 (m, 2 H) 2.15 (s., 3 H) 2.16 (s., 3 H) 2.51 (t, J=6.46 Hz, 2 H) 3.13 (t, J=6.46 Hz, 2 H) 3.85 (t, J=7.92 Hz, 1 H) 3.97 (t, J=6.31 Hz, 2 H) 4.1 1 (s, 2 H) 6.93 (d, J=7.63 Hz, 1 H) 6.97 - 7.04 (m, 3 H) 7.09 - 7.12 (m, 1 H) 7.13 - 7.16 (m, 1 H) 7.16 - 7.20 (m, 2 H) 7.20 - 7.23 (m, 1 H) 7.24 - 7.29 (m, 1 H).
Example 12
Compound 8
r3-(f4-r4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy1-3- fluorobenzyl)amino)propyl1phosphonic acid Spectroscopic data: 1 H NMR (300 MHz, CD3OD) δ ppm 1 .70 - 1 .77 (m, 2 H) 2.15 - 2.19 (m, 2 H) 2.20 (s, 3 H) 2.21 (s, 3 H) 3.34 - 3.40 (m, 1 H) 3.91 (t, J=7.78 Hz, 1 H) 4.06 (t, J=6.16 Hz, 2 H) 4.08 - 4.12 (m, 4 H) 4.21 (s, 2 H) 6.96 - 6.99 (m, 1 H) 7.00 - 7.05 (m, 2 H) 7.05 - 7.10 (m, 1 H) 7.12 - 7.18 (m, 2 H) 7.18 - 7.25 (m, 4 H).
Example 13
Compound 9
3-r(4-fr5-(2.4-difluorophenvn-5-(3.4-dimethylphenyl)pentvnoxy)-3- methylbenzvDaminolpropanoic acid
Spectroscopic
Figure imgf000041_0001
1 .38 - 1 .48 (m, 2 H) 1 .74 - 1 .83 (m, 2 H) 1 .98 - 2.06 (m, 2 H) 2.08 (s, 3 H) 2.16 (s, 6 H) 2.50 (t, J=6.31 Hz, 2 H) 3.12 (t, J=6.46 Hz, 2 H) 3.90 (t, J=6.16 Hz, 2 H) 4.06 (s, 2 H) 4.14 (t, J=7.92 Hz, 1 H) 6.77 - 6.86 (m, 3 H) 6.91 - 6.96 (m, 1 H) 6.97 - 7.01 (m, 2 H) 7.18 - 7.24 (m, 2 H) 7.26 - 7.32 (m, 1 H).
Example 14
Compound 10
f3-r(4-fr5-(2.4-difluorophenvn-5-(3.4-dimethylphenyl)pentvnoxy)-3- methylbenzvDaminolpropyDphosphonic acid
Spectrosco
Figure imgf000041_0002
9 - 1 .49 (m, 2 H) 1 .61 - 1 .70 (m, 2 H) 1 .77 - 1 .84 (m, 2 H) 1 .90 - 1 .99 (m, 2 H) 2.00 - 2.07 (m, 2 H) 2.09 (s, 3 H) 2.18 (s, 6 H) 3.02 (t, J=6.31 Hz, 2 H) 3.93 (t, J=6.16 Hz, 2 H) 3.99 (s, 2 H) 4.15 (t, J=7.92 Hz, 1 H) 6.78 - 6.82 (m, 1 H) 6.82 - 6.88 (m, 2 H) 6.94 (d, J=7.63 Hz, 1 H) 6.96 - 7.02 (m, 2 H) 7.19 - 7.26 (m, 2 H) 7.28 - 7.34 (m, 1 H).
Example 15
Compound 1 1
3-r(4-fr5-(2,4-difluorophenyl)-5-(3,4- dimethylphenyl)pentyl1oxy)benzyl)amino1propanoic acid
Spec
Figure imgf000042_0001
45 (m, 2 H) 1 .74 - 1 .82 (m, 2 H) 1 .99 - 2.12 (m, 2 H) 2.18 (s, 3 H) 2.19 (s, 3 H) 2.49 (t, J=6.31 Hz, 2 H) 3.13 (t, J=6.46 Hz, 2 H) 3.92 (t, J=6.46 Hz, 2 H) 4.1 1 (s, 2 H) 4.14 (t, J=7.92 Hz, 1 H) 6.79 - 6.88 (m, 2 H) 6.91 (d, J=8.51 Hz, 2 H) 6.94 (d, J=7.63 Hz, 1 H) 6.98 (br. s, 1 H) 7.00 (d, J=7.90 Hz, 1 H) 7.29 - 7.34 (m, 1 H) 7.36 (d, J=8.51 Hz, 2 H). Example 16
Compound 12
f3-r(4-fr5-(2,4-difluorophenyl)-5-(3,4- dimethylphenyl)pentvnoxy)benzyl)amino1propyl)phosphonic acid
Figure imgf000042_0002
Spectroscopic data: 1 H NMR (300 MHz, CD3OD) δ ppm 1 .35 - 1 .49 (m, 2 H) 1 .61 - 1 .84 (m, 4 H) 1 .89 - 2.12 (m, 4 H) 2.19 (s, 6 H) 3.05 (t, J=6.30 Hz, 2 H) 3.93 (t, J=6.30 Hz, 2 H) 4.04 (s, 2 H) 4.15 (s, 1 H) 6.78 - 6.87 (m, 2 H) 6.88 - 6.97 (m, 3 H) 6.97 - 7.04 (m, 2 H) 7.28 - 7.35 (m, 1 H) 7.38 (d, J=8.50 Hz, 2 H).
Example 17
Intermediate 5
4-r4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy1-3-methylbenzaldehvde
Figure imgf000043_0001
Spectroscopic data: 1H NMR (300 MHz, CDCI3) δ ppm 1 .72 - 1 .88 (m, 2 H) 2.17 - 2.20 (m, 1 H) 2.21 (s, 3 H) 2.22 (s, 3 H) 2.23 - 2.25 (m, 1 H) 2.27 (s, 3 H) 3.87 (t, J=7.91 Hz, 1 H) 4.04 (t, J=6.15 Hz, 2 H) 6.84 (d, J=8.79 Hz, 1 H) 6.94 - 7.01 (m, 2 H) 7.03 - 7.09 (m, 1 H) 7.1 1 - 7.14 (m, 1 H) 7.14 - 7.17 (m, 1 H) 7.17 - 7.21 (m, 1 H) 7.22 - 7.25 (m, 1 H) 7.61 - 7.71 (m, 2 H) 9.84 (s, 1 H).
Example 18
Compound 13
3-(f4-r4-(3-chlorophenvn-4-(3.4-dimethylphenyl)butoxy1-3- methylbenzyl)amino)propanoic acid
Spectroscopic d
Figure imgf000043_0002
m 1 .67 - 1 .81 (m, 2 H)
2.18 - 2.24 (m, 1 H) 2.21 (br. s, 9 H) 2.47 (t, J=6.45 Hz, 2 H) 3.12 (t, J=6.30 Hz, 3 H) 3.91 (t, J=7.91 Hz, 1 H) 4.00 (t, J=6.30 Hz, 2 H) 4.08 (s, 2 H) 6.88 (d, J=9.08 Hz, 1 H) 6.94 - 7.08 (m, 3 H) 7.10 - 7.17 (m, 1 H) 7.18 - 7.27 (m, 5 H). Example 19
Compound 14
r3-(f4-r4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy1-3- methylbenzyl)amino)propyl1phosphonic acid
Figure imgf000043_0003
Spectroscopic data: 1 H NMR (300 MHz, CD3OD) δ ppm 1 .62 - 1 .70 (m, 3 H) 1 .71 - 1 .79 (m, 3 H) 1 .90 - 2.00 (m, 2 H) 2.20 (s, 3 H) 2.21 (s, 6 H) 3.06 (t, J=6.46 Hz, 2 H) 3.90 (t, J=7.92 Hz, 1 H) 3.99 (t, J=6.31 Hz, 2 H) 4.01 (s, 2 H) 6.87 (d, J=8.51 Hz, 1 H) 6.96 - 6.99 (m, 1 H) 7.01 (br. s, 1 H) 7.04 (d, J=7.63 Hz, 1 H) 7.12 - 7.16 (m, 1 H) 7.18 - 7.21 (m, 1 H) 7.21 - 7.26 (m, 4 H).
Example 20
Compound 15
3-[(4-{[5-(3,4-dimethylphenyl)-5-(3- fluorophenyl)pentyl]oxy}benzyl)amino]propanoic acid
Spectroscopic
Figure imgf000044_0001
1 .35 - 1 .47 (m, 2 H) 1 .70 - 1 .85 (m, 2 H) 2.01 - 2.14 (m, 2 H) 2.19 (s, 3 H) 2.20 (s, 3 H) 2.48 (t, J=6.45 Hz, 2 H) 3.13 (t, J=6.45 Hz, 2 H) 3.86 (t, J=7.76 Hz, 1 H) 3.94 (t, J=6.30 Hz, 2 H) 4.1 1 (s, 2 H) 6.80 - 6.88 (m, 1 H) 6.89 - 6.95 (m, 3 H) 6.95 - 7.01 (m, 3 H) 7.02 - 7.09 (m, 1 H) 7.18 - 7.29 (m, 1 H) 7.36 (d, J=8.79 Hz, 2 H).
Example 21
Compound 16
{3-[(4-{[5-(3,4-dimethylphenyl)-5-(3- fluorophenyl)pentyl]oxy}benzyl)amino]propyl}phosphonic acid
Figure imgf000044_0002
Spectroscopic data: 1 H NMR (300 MHz, CD3OD) δ ppm 1 .61 - 1 .71 (m, 4 H) 1 .76 - 1 .84 (m, 2 H) 1 .90 - 2.00 (m, 2 H) 2.03 - 2.12 (m, 2 H) 2.20 (s, 3 H) 2.21 (s, 3 H) 3.04 (t, J=6.31 Hz, 2 H) 3.86 (t, J=7.78 Hz, 1 H) 3.94 (t, J=6.46 Hz, 2 H) 4.03 (s, 2 H) 6.81 - 6.88 (m, 1 H) 6.90 (d, J=8.51 Hz, 2 H) 6.93 - 6.98 (m, 2 H) 7.00 (br. s, 1 H) 7.02 (d, J=7.92 Hz, 1 H) 7.06 (d, J=7.92 Hz, 1 H) 7.19 - 7.26 (m, 1 H) 7.37 (d, J=8.51 Hz, 2 H).
Example 22
Intermediate 6
4-r4-(3,4-dimethylphenyl)-4-(2-thienyl)butoxylbenzaldehvde
Figure imgf000045_0001
Spectroscopic data: 1H NMR (300 MHz, CDCI3) δ ppm 1 .71 - 1 .92 (m, 2 H) 2.10 - 2.20 (m, 1 H) 2.23 (s, 6 H) 2.26 - 2.37 (m, 1 H) 4.02 (t, J=6.30 Hz, 2 H) 4.12 (t, J=7.76 Hz, 1 H) 6.84 (m, 1 H) 6.87 - 6.98 (m, 3 H) 6.98 - 7.19 (m, 4 H) 7.81 (d, J=8.79 Hz, 2 H) 9.87 (s, 1 H).
Example 23
Compound 17
3-(f4-r4-(3,4-dimethylphenyl)-4-(2-thienyl)butoxy1benzyl)amino)propanoic acid
Figure imgf000045_0002
) 2.1 1 - 2.19 (m, 1 H) 2.21 (s, 3 H) 2.22 (s, 3 H) 2.23 - 2.28 (m, 1 H) 2.48 (t, J=6.31 Hz, 2 H) 3.13 (t, J=6.46 Hz, 2 H) 3.97 (t, J=6.31 Hz, 2 H) 4.1 1 (s, 3 H) 6.83 - 6.86 (m, 1 H) 6.87 - 6.90 (m, 1 H) 6.94 (d, J=8.51 Hz, 2 H) 6.98 (d, J=8.80 Hz, 1 H) 7.02 - 7.06 (m, 2 H) 7.17 (dd, J=5.14, 1 .03 Hz, 1 H) 7.36 (d, J=8.51 Hz, 2 H).
Example 24
Compound 18
r3-(f4-r4-(3.4-dimethylphenyl)-4-(2- thienyl)butoxy1benzyl)amino)propyl1phosphonic acid Spectroscopic data: 1H NMR (300 MHz, CD3OD) δ ppm 1.64 - 1.79 (m, 4 H) 1.90 - 2.01 (m, 2 H) 2.13 - 2.20 (m, 1 H) 2.21 (s, 3 H) 2.22 (s, 3 H) 2.23 - 2.28 (m, 1 H) 3.07 (t, J=6.46 Hz, 2 H) 3.97 (t, J=6.46 Hz, 2 H) 4.05 (s, 2 H) 4.12 (t, J=7.78 Hz, 1 H) 6.84 - 6.86 (m, 1 H) 6.87 - 6.90 (m, 1 H) 6.93 (d, J=8.80 Hz, 2 H) 6.97 - 7.01 (m, 1 H) 7.02 - 7.06 (m, 2 H) 7.17 (dd, J=5.28, 1.17 Hz, 1 H) 7.38 (d, J=8.80 Hz, 2 H).
Example 25
Compound 19
3-((4-r4-(3,4-dimethylphenyl)-4-(3-thienyl)butoxy1benzyl)amino)propanoic acid
Figure imgf000046_0001
) 2.05 - 2.14 (m, 2 H) 2.19 (s, 3 H) 2.20 (s, 3 H) 2.48 (t, J=6.46 Hz, 2 H) 3.12 (t, J=6.46 Hz, 2 H) 3.91 - 3.96 (m, 3 H) 4.10 (s, 2 H) 6.91 (dd, J=4.99, 1.17 Hz, 1 H) 6.93 (d, J=8.80 Hz, 2 H) 6.94 - 6.96 (m, 1 H) 6.98 (br. s, 1 H) 7.01 (d, J=7.92 Hz, 1 H) 7.04 - 7.07 (m, 1 H) 7.25 (dd, J=4.99, 2.93 Hz, 1 H) 7.36 (d, J=8.80 Hz, 2 H).
Example 26
Compound 20
r3-({4-r4-(3,4-dimethylphenyl)-4-(3- thienyl)butoxy1benzyl)amino)propyl1phosphonic acid
Spect
Figure imgf000046_0002
1.74 (m, 4 H) 1.91 - 2.01 (m, 2 H) 2.06 - 2.15 (m, 2 H) 2.20 (s, 3 H) 2.21 (s, 3 H) 3.07 (t, J=6.31 Hz, 2 H) 3.94 (d, J=7.92 Hz, 1 H) 3.97 (t, J=6.46 Hz, 2 H) 4.05 (s, 2 H) 6.91 - 6.92 (m, 1 H) 6.92 - 6.93 (m, 1 H) 6.93 - 6.95 (m, 1 H) 6.95 - 6.96 (m, 1 H) 6.99 (br. s, 1 H) 7.02 (d, J=7.92 Hz, 1 H) 7.06 - 7.09 (m, 1 H) 7.26 (dd, J=4.99, 2.93 Hz, 1 H) 7.37 (d, J=8.80 Hz, 2 H).
Example 27
Compound 21
r3-(f4-r4-(2,4-difluorophenyl)-4-(3,4- dimethylphenyl)butoxy1benzyl)amino)propyl1phosphonic acid
S
Figure imgf000047_0001
(m, 4 H) 1 .91 - 1 .99 (m, 2 H) 2.1 1 - 2.18 (m, 2 H) 2.19 (s, 3 H) 2.20 (s, 3 H) 3.04 (t, J=6.31 Hz, 2 H) 3.97 (t, J=6.31 Hz, 2 H) 4.03 (s, 2 H) 4.18 (t, J=7.92 Hz, 1 H) 6.81 - 6.90 (m, 2 H) 6.93 (d, J=8.80 Hz, 2 H) 6.95 - 6.98 (m, 1 H) 7.00 - 7.03 (m, 2 H) 7.33 - 7.37 (m, 1 H) 7.38 (d, J=8.80 Hz, 2 H). Example 28
Intermediate 7
4-r4-(3,4-difluorophenyl)-4-(3,4-dimethylphenyl)butoxy1lbenzaldehvde
Figure imgf000047_0002
Spectroscopic data: 1H NMR (300 MHz, CDCI3) δ ppm 1 .70 - 1 .82 (m, 2 H)
2.07 - 2.19 (m, 2 H) 2.22 (s, 6 H) 3.80 - 3.92 (m, 1 H) 4.03 (t, J=6.15 Hz, 2 H) 6.88 7.00 (m, 5 H) 7.01 - 7.14 (m, 3 H) 7.81 (d, J=8.50 Hz, 2 H) 9.88 (s, 1 H).
Example 29
Compound 22
r3-({4-r4-(3.4-difluorophenyl)-4-(3.4- dimethylphenyl)butoxy1benzyl)amino)propyl1phosphonic acid Spectroscopic d
Figure imgf000048_0001
m 1.64 - 1.73 (m, 4 H) 1.91 - 2.00 (m, 2 H) 2.13 - 2.19 (m, 2 H) 2.20 (s, 3 H) 2.22 (s, 3 H) 3.07 (t, J=6.31 Hz, 2 H) 3.89 (t, J=7.92 Hz, 1 H) 3.99 (t, J=6.31 Hz, 2 H) 4.05 (s, 2 H) 6.94 (d, J=8.80 Hz, 2 H) 6.95 - 6.99 (m, 1 H) 7.01 (br. s, 1 H) 7.04 (d, J=7.63 Hz, 2 H) 7.1 1 - 7.16 (m, 2 H) 7.38 (d, J=8.50 Hz, 2 H).
Example 30
Compound 23
3-({4-r4-(2.4-difluorophenyl)-4-(3.4- dimethylphenyl)butoxy1benzyl)amino)propanoic acid
Spect
Figure imgf000048_0002
1.76 (m, 2 H) 2.12 - 2.18 (m, 2 H) 2.20 (s, 3 H) 2.21 (s, 3 H) 2.48 (t, J=6.31 Hz, 2 H) 3.13 (t, J=6.31 Hz, 2 H) 3.99 (t, J=6.31 Hz, 2 H) 4.12 (s, 2 H) 4.19 (t, J=7.92 Hz, 1 H) 6.80 - 6.91 (m, 2 H) 6.93 - 6.99 (m, 3 H) 7.00 - 7.05 (m, 2 H) 7.37 (d, J=8.51 Hz, 3 H).
Example 31
Intermediate 8
4-r4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy1lbenzaldehvde
Figure imgf000048_0003
Spectroscopic data: 1H NMR (300 MHz, CDCI3) δ ppm 1.69 - 1 .86 (m, 2 H) 2.13 - 2.19 (m, 2 H) 2.21 (s., 3 H) 2.22 (s., 3 H) 3.85 (t, J=7.91 Hz, 1 H) 4.03 (t, J=6.30 Hz, 2 H) 6.89 - 7.02 (m, 4 H) 7.03 - 7.09 (m, 1 H) 7.1 1 - 7.21 (m, 3 H) 7.24 (s, 1 H) 7.81 (d, J=8.79 Hz, 2 H) 9.87 (s, 1 H).
Example 32
Compound 24
r3-(f4-r4-(3-chlorophenyl)-4-(3,4- dimethylphenyl)butoxy1benzyl)amino)propyl1phosphonic acid
S
Figure imgf000049_0001
(m, 4 H) 1.90 - 2.00 (m, 2 H) 2.14 - 2.19 (m, 2 H) 2.20 (s, 3 H) 2.22 (s, 3 H) 3.07 (t, J=6.31 Hz, 2 H) 3.89 (t, J=8.07 Hz, 1 H) 3.99 (t, J=6.31 Hz, 2 H) 4.05 (s, 2 H) 6.94 (d, J=8.80 Hz, 2 H) 6.96 - 6.99 (m, 1 H) 7.01 (br. s, 1 H) 7.04 (d, J=7.63 Hz, 1 H) 7.12 - 7.16 (m, 1 H) 7.18 - 7.21 (m, 1 H) 7.22 (d, J=7.63 Hz, 1 H) 7.23 - 7.25 (m, 1 H) 7.38 (d, J=8.80 Hz, 2 H).
Example 33
Compound 25
3-({4-r4-(3-chlorophenyl)-4-(3.4- dimethylphenyl)butoxy1benzyl)amino)propanoic acid
Spect
Figure imgf000049_0002
1.69 (m, 2 H) 2.10 - 2.15 (m, 2 H) 2.16 (s, 3 H) 2.17 (s, 3 H) 3.35 - 3.43 (m, 1 H) 3.84 (t, J=7.92 Hz, 1 H) 3.91 (t, J=6.31 Hz, 2 H) 4.12 (d, J=8.20 Hz, 4 H) 4.22 (s, 2 H) 6.91 (d, J=8.80 Hz, 2 H) 6.92 - 6.95 (m, 1 H) 6.98 (br. s, 1 H) 7.00 (d, J=7.90 Hz, 1 H) 7.09 - 7.13 (m, 1 H) 7.13 - 7.16 (m, 1 H) 7.18 (d, J=7.63 Hz, 1 H) 7.22 (t, J=1 .91 Hz, 1 H) 7.34 (d, J=8.80 Hz, 2 H).
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, MgCI2 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 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 y35S: nM, (EC50).
Activity potency: S1 P1 receptor from GTP y35S: nM, (EC50).
Table 1 Compound S1 P1 lUPAC name
No. ECso (nM)
3-({4-[4-(3,4-dimethylphenyl)-4-(3-fluorophenyl)
1 1 15.24 butoxy]benzyl}amino)propanoic acid
[3-({4-[4-(3,4-dimethylphenyl)-4-(3-fluorophenyl)
2 15.94 butoxy]benzyl}amino)propyl]phosphonic acid
3-({4-[4-(3,5-difluorophenyl)-4-(3,4-dimethylphenyl)
3 44.62 butoxy]benzyl}amino)propanoic acid
[3-({4-[4-(3,5-difluorophenyl)-4-(3,4-dimethylphenyl)
4 10.27 butoxy]benzyl}amino)propyl]phosphonic acid
3-({4-[4-(2,4-difluorophenyl)-4-(3,4-
5 6.52 dimethylphenyl)butoxy]-3-fluorobenzyl}amino)propanoic acid
[3-({4-[4-(2,4-difluorophenyl)-4-(3,4-
6 2.14 dimethylphenyl)butoxy]-3- fluorobenzyl}amino)propyl]phosphonic acid
3-({4-[4-(3-chlorophenyl)-4-(3,4-
7 39.02 dimethylphenyl)butoxy]-3-fluorobenzyl}amino)propanoic acid
[3-({4-[4-(3-chlorophenyl)-4-(3,4-
8 1 .95 dimethylphenyl)butoxy]-3- fluorobenzyl}amino)propyl]phosphonic acid
3-[(4-{[5-(2,4-difluorophenyl)-5-(3,4-
9 18.83 dimethylphenyl)pentyl]oxy}-3-methylbenzyl)amino]propanoic
acid
{3-[(4-{[5-(2,4-difluorophenyl)-5-(3,4-
10 2.21 dimethylphenyl)pentyl]oxy}-3- methylbenzyl)amino]propyl}phosphonic acid
3-[(4-{[5-(2,4-difluorophenyl)-5-(3,4-
1 1 485.43 dimethylphenyl)pentyl]oxy}benzyl)amino]propanoic acid
{3-[(4-{[5-(2,4-difluorophenyl)-5-(3,4-
12 4.21 dimethylphenyl)pentyl]oxy}benzyl)amino]propyl}phosphonic
acid
3-({4-[4-(3-chlorophenyl)-4-(3,4-
13 36.12 dimethylphenyl)butoxy]-3-methylbenzyl}amino)propanoic acid
[3-({4-[4-(3-chlorophenyl)-4-(3,4-
14 1 .79 dimethylphenyl)butoxy]-3- methylbenzyl}amino)propyl]phosphonic acid
3-[(4-{[5-(3,4-dimethylphenyl)-5-(3-
15 358.07 fluorophenyl)pentyl]oxy}benzyl)amino]propanoic acid
{3-[(4-{[5-(3,4-dimethylphenyl)-5-(3-
16 5.56 fluorophenyl)pentyl]oxy}benzyl)amino]propyl}phosphonic acid
3-({4-[4-(3,4-dimethylphenyl)-4-(2-
17 294.89 thienyl)butoxy]benzyl}amino)propanoic acid
[3-({4-[4-(3,4-dimethylphenyl)-4-(2-
18 31 .33 thienyl)butoxy]benzyl}amino)propyl]phosphonic acid
3-({4-[4-(3,4-dimethylphenyl)-4-(3-
19 39.75 thienyl)butoxy]benzyl}amino)propanoic acid
[3-({4-[4-(3,4-dimethylphenyl)-4-(3-
20 6.1 1 thienyl)butoxy]benzyl}amino)propyl]phosphonic acid
[3-({4-[4-(2,4-difluorophenyl)-4-(3,4-
21 4.28 dimethylphenyl)butoxy]benzyl}amino)propyl]phosphonic acid
[3-({4-[4-(3,4-difluorophenyl)-4-(3,4-
22 13.06 dimethylphenyl)butoxy]benzyl}amino)propyl]phosphonic acid
3-({4-[4-(2,4-difluorophenyl)-4-(3,4-
23 149.60 dimethylphenyl)butoxy]benzyl}amino)propanoic acid
[3-({4-[4-(3-chlorophenyl)-4-(3,4-
24 1 .59 dimethylphenyl)butoxy]benzyl}amino)propyl]phosphonic acid
3-({4-[4-(3-chlorophenyl)-4-(3,4-
25 37.94 dimethylphenyl)butoxy]benzyl}amino)propanoic acid

Claims

What is claimed is:
1. A compound having Formula I:
Figure imgf000053_0001
Formula I
wherein:
A is C-6-10 aryl, heterocycle, C3-8 cycloalkyl or C3-8 cycloalkenyl;
B is C-6-10 aryl, heterocycle, C3-8 cycloalkyl or C3-8 cycloalkenyl;
R1 is H, halogen, -OCi-8 alkyl, C1-8 alkyl, CN, C(0)R13, NR14aR14b or hydroxyl;
R2 is H, halogen, -OCi-8 alkyl, d-e alkyl, CN, C(0)R13, NR14aR14b or hydroxyl; R3 is H, halogen, -OCi-8 alkyl, Ci-8 alkyl, CN, C(0)R13, NR14aR14b or hydroxyl;
R4 is H, halogen, -OCi-8 alkyl, Ci-8 alkyl, CN, C(0)R13, NR15aR15b or hydroxyl;
R5 is H, halogen, -OCi-8 alkyl, Ci-8 alkyl, CN, C(0)R13, NR15aR15b or hydroxyl;
R6 is H, halogen, -OCi-8 alkyl, Ci-8 alkyl, CN, C(0)R13, NR15aR15b or hydroxyl;
R7 is H, halogen, -OCi-8 alkyl, Ci-8 alkyl, CN, C(0)R13, C6-io aryl, heterocycle, C3-s cycloakyl, C 3-8 cycloalkenyl, NR15aR15b or hydroxyl;
R8 is H, halogen, -OCi-8 alkyl, C -8 alkyl, CN, C(0)R13, C6-io aryl, heterocycle, C3-8 cycloakyl, C 3-8 cycloalkenyl, NR15aR15b or hydroxyl;
R9 is H, halogen, -OCi-8 alkyl, C -8 alkyl, CN, C(0)R13, C6-io aryl, heterocycle, C3-8 cycloakyl, C 3-8 cycloalkenyl, NR15aR15b or hydroxyl;
R10 is H, halogen, -OCi-8 alkyl, Ci-8 alkyl, CN, C(0)R13, C6-io aryl, heterocycle, C3- 8 cycloakyl, C3-8 cycloalkenyl, NR15aR15b or hydroxyl;
R11 is H or C1-8 alkyl;
R12 is -OP03H2, carboxylic acid, -P03H2, -P(0)MeOH, -P(0)(H)OH or OH;
L1 is O, S or CH2;
L2 is -CH(R16)-, -0-, -S-, -N(R17)- or -C(O)-;
a is 1 , 2, 3 or 4; b is 0, 1, 2, 3 or 4;
R13 isH,OH orCi-8 alkyl;
R14aisHorCi-8 alkyl;
R4bisHorCi-8 alkyl;
R5aisHorCi-8 alkyl;
R15bisHorCi-8 alkyl;
R16 is H or Ci-8 alkyl; and
R17 is H or Ci-8 alkyl;
or an enantiomer, diastereomer or tautomer thereof;
or a pharmaceutically acceptable salt of any of the foregoing.
2. The compound according to claim 1 , wherein L1 is CH2; L2 is -CH(R16)-, wherein R16 is H; and b is 0 or 1.
3. The compound according to claim 1 , wherein a is 2 or 3.
4. The compound according to claim 1 , wherein R12 is carboxylic acid or -P03
5. The compound according to claim 1 , wherein:
Figure imgf000054_0001
is selected from:
Figure imgf000055_0001
6. The compound according to claim 1 , wherein
Figure imgf000055_0002
The compound according to claim 1 , wherein
Figure imgf000055_0003
is selected from:
Figure imgf000056_0001
and
Figure imgf000056_0002
8. The compound according to claim 1 , wherein each of R1 , R2, R3, R4, R5 , R6, R7, R8, R9 and R10 is independently selected from H, halogen, and Ci-s alkyl; and
11
R is H.
9. The compound according to claim 8, wherein each halogen is independently selected from F, CI, Br and I.
10. The compound according to claim 8, wherein each C-i-s alkyl is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and t- butyl.
1 1 . The compound according to claim 1 , wherein:
L1 is CH2;
\ 16
is -CH(R16)-, wherein R ID is H
a is 2 or 3; b is 0 or 1 ;
Figure imgf000057_0001
is selected from:
Figure imgf000057_0002
each of R1 , R2, R3, R4, R5 , R6, R7, R8, R9 and R 0 is independently selected from H, F, CI, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and t-butyl;
R11 is H; and
R12 is carboxylic acid or -PO3H2.
12. The compound according to claim 1 , selected from: 3-({4-[4-(3,4-dimethylphenyl)-4-(3-fluorophenyl)butoxy]benzyl}amino)propanoic acid;
[3-({4-[4-(3,4-dimethylphenyl)-4-(3- fluorophenyl)butoxy]benzyl}amino)propyl]phosphonic acid;
3-({4-[4-(3,5-difluorophenyl)-4-(3,4- dimethylphenyl)butoxy]benzyl}amino)propanoic acid;
[3-({4-[4-(3,5-difluorophenyl)-4-(3,4-dimethylphenyl)butoxy]benzyl}amino) propyl] phosphonic acid;
3-({4-[4-(2,4-difluorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- fluorobenzyl}amino)propanoic acid;
[3-({4-[4-(2,4-difluorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- fluorobenzyl}amino)propyl]phosphonic acid;
3-({4-[4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- fluorobenzyl}amino)propanoic acid;
[3-({4-[4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- fluorobenzyl}amino)propyl]phosphonic acid;
3-[(4-{[5-(2,4-difluorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}-3- methylbenzyl)amino]propanoic acid;
{3-[(4-{[5-(2,4-difluorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}-3- methylbenzyl)amino]propyl}phosphonic acid;
3-[(4-{[5-(2,4-difluorophenyl)-5-(3,4- dimethylphenyl)pentyl]oxy}benzyl)amino]propanoic acid
{3-[(4-{[5-(2,4-difluorophenyl)-5-(3,4- dimethylphenyl)pentyl]oxy}benzyl)amino]propyl}phosphonic acid;
3-({4-[4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- methylbenzyl}amino)propanoic acid;
[3-({4-[4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- methylbenzyl}amino)propyl]phosphonic acid;
3-[(4-{[5-(3,4-dimethylphenyl)-5-(3- fluorophenyl)pentyl]oxy}benzyl)amino]propanoic acid;
{3-[(4-{[5-(3,4-dimethylphenyl)-5-(3- fluorophenyl)pentyl]oxy}benzyl)amino]propyl}phosphonic acid;
3-({4-[4-(3,4-dimethylphenyl)-4-(2-thienyl)butoxy]benzyl}amino)propanoic acid; [3-({4-[4-(3,4-dimethylphenyl)-4-(2- thienyl)butoxy]benzyl}amino)propyl]phosphonic acid;
3-({4-[4-(3,4-dimethylphenyl)-4-(3-thienyl)butoxy]benzyl}amino)propanoic acid;
[3-({4-[4-(3,4-dimethylphenyl)-4-(3- thienyl)butoxy]benzyl}amino)propyl]phosphonic acid;
[3-({4-[4-(2,4-difluorophenyl)-4-(3,4- dimethylphenyl)butoxy]benzyl}amino)propyl]phosphonic acid;
[3-({4-[4-(3,4-difluorophenyl)-4-(3,4- dimethylphenyl)butoxy]benzyl}amino)propyl]phosphonic acid;
3-({4-[4-(2,4-difluorophenyl)-4-(3,4- dimethylphenyl)butoxy]benzyl}amino)propanoic acid;
[3-({4-[4-(3-chlorophenyl)-4-(3,4- dimethylphenyl)butoxy]benzyl}amino)propyl]phosphonic acid;
3-({4-[4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]benzyl}amino)propanoic acid;
and enantiomers, diastereomer and tautomers thereof;
and pharmaceutically acceptable salts of the foregoing.
13. 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.
14. The pharmaceutical composition according to claim 13 wherein the compound is selected from:
3-({4-[4-(3,4-dimethylphenyl)-4-(3-fluorophenyl)butoxy]benzyl}amino)propanoic acid;
[3-({4-[4-(3,4-dimethylphenyl)-4-(3- fluorophenyl)butoxy]benzyl}amino)propyl]phosphonic acid;
3-({4-[4-(3,5-difluorophenyl)-4-(3,4- dimethylphenyl)butoxy]benzyl}amino)propanoic acid;
[3-({4-[4-(3,5-difluorophenyl)-4-(3,4-dimethylphenyl)butoxy]benzyl}amino) propyl]phosphonic acid;
3-({4-[4-(2,4-difluorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- fluorobenzyl}amino)propanoic acid; [3-({4-[4-(2,4-difluorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- fluorobenzyl}amino)propyl]phosphonic acid;
3-({4-[4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- fluorobenzyl}amino)propanoic acid;
[3-({4-[4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- fluorobenzyl}amino)propyl]phosphonic acid;
3-[(4-{[5-(2,4-difluorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}-3- methylbenzyl)amino]propanoic acid;
{3-[(4-{[5-(2,4-difluorophenyl)-5-(3,4-dimethylphenyl)pentyl]oxy}-3- methylbenzyl)amino]propyl}phosphonic acid;
3-[(4-{[5-(2,4-difluorophenyl)-5-(3,4- dimethylphenyl)pentyl]oxy}benzyl)amino]propanoic acid;
{3-[(4-{[5-(2,4-difluorophenyl)-5-(3,4- dimethylphenyl)pentyl]oxy}benzyl)amino]propyl}phosphonic acid;
3-({4-[4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- methylbenzyl}amino)propanoic acid;
[3-({4-[4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]-3- methylbenzyl}amino)propyl]phosphonic acid;
3-[(4-{[5-(3,4-dimethylphenyl)-5-(3- fluorophenyl)pentyl]oxy}benzyl)amino]propanoic acid;
{3-[(4-{[5-(3,4-dimethylphenyl)-5-(3- fluorophenyl)pentyl]oxy}benzyl)amino]propyl}phosphonic acid;
3-({4-[4-(3,4-dimethylphenyl)-4-(2-thienyl)butoxy]benzyl}amino)propanoic acid;
[3-({4-[4-(3,4-dimethylphenyl)-4-(2- thienyl)butoxy]benzyl}amino)propyl]phosphonic acid;
3-({4-[4-(3,4-dimethylphenyl)-4-(3-thienyl)butoxy]benzyl}amino)propanoic acid;
[3-({4-[4-(3,4-dimethylphenyl)-4-(3- thienyl)butoxy]benzyl}amino)propyl]phosphonic acid;
[3-({4-[4-(2,4-difluorophenyl)-4-(3,4- dimethylphenyl)butoxy]benzyl}amino)propyl]phosphonic acid;
[3-({4-[4-(3,4-difluorophenyl)-4-(3,4- dimethylphenyl)butoxy]benzyl}amino)propyl]phosphonic acid;
3-({4-[4-(2,4-difluorophenyl)-4-(3,4- dimethylphenyl)butoxy]benzyl}amino)propanoic acid; [3-({4-[4-(3-chlorophenyl)-4-(3,4- dimethylphenyl)butoxy]benzyl}amino)propyl]phosphonic acid; and
3-({4-[4-(3-chlorophenyl)-4-(3,4-dimethylphenyl)butoxy]benzyl}amino)propanoic acid.
15. 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 claim 1 .
16. The method of claim 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 sclerosis, Myasthenia gravis, psoriasis, ulcerative colitis, autoimmune uveitis, renal ischemia/perfusion injury, contact hypersensitivity, atopic dermatitis, 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.
7. The method of claim 15, wherein the mammal is a human.
PCT/US2014/065262 2013-11-13 2014-11-12 Disubstituted phenoxy derivatives as sphingosine-1-phosphate (s1p) receptor modulators WO2015073556A1 (en)

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