WO2015163936A1 - Dérivés bicycliques utilisés comme modulateurs des récepteurs de la sphingosine-1-phosphate - Google Patents

Dérivés bicycliques utilisés comme modulateurs des récepteurs de la sphingosine-1-phosphate Download PDF

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WO2015163936A1
WO2015163936A1 PCT/US2014/059769 US2014059769W WO2015163936A1 WO 2015163936 A1 WO2015163936 A1 WO 2015163936A1 US 2014059769 W US2014059769 W US 2014059769W WO 2015163936 A1 WO2015163936 A1 WO 2015163936A1
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substituted
methyl
unsubstituted
amino
oxy
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PCT/US2014/059769
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English (en)
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Janet A. Takeuchi
Ling Li
Wha Bin Im
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Allergan, Inc.
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Publication of WO2015163936A1 publication Critical patent/WO2015163936A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—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
    • C07F9/28—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
    • 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
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/60—Quinoline or hydrogenated quinoline ring systems
    • 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
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
    • C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems

Definitions

  • the present invention relates to novel bicyclic derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of sphingosine-1 -phosphate receptors.
  • the invention relates specifically to the use of these compounds and their pharmaceutical compositions to treat disorders associated with sphingosine-1 -phosphate (S1 P) receptor modulation.
  • Sphingosine-1 -phosphate is stored in relatively high concentrations in human platelets, which lack the enzymes responsible for its catabolism, and it is released into the blood stream upon activation of physiological stimuli, such as growth factors, cytokines, and receptor agonists and antigens. It may also have a critical role in platelet aggregation and thrombosis and could aggravate cardiovascular diseases.
  • physiological stimuli such as growth factors, cytokines, and receptor agonists and antigens. It may also have a critical role in platelet aggregation and thrombosis and could aggravate cardiovascular diseases.
  • the relatively high concentration of the metabolite in high-density lipoproteins (HDL) may have beneficial implications for atherogenesis.
  • sphingosine-1 -phosphate together with other lysolipids such as sphingosylphosphorylcholine and lysosulfatide, are responsible for the beneficial clinical effects of HDL by stimulating the production of the potent antiatherogenic signaling molecule nitric oxide by the vascular endothelium.
  • lysophosphatidic acid it is a marker for certain types of cancer, and there is evidence that its role in cell division or proliferation may have an influence on the development of cancers.
  • modulator includes but is not limited to: receptor agonist, antagonist, inverse agonist, inverse antagonist, partial agonist, partial antagonist.
  • This invention describes compounds of Formula I, which have sphingosine-1 - phosphate receptor biological activity.
  • the compounds in accordance with the present invention are thus of use in medicine, for example in the treatment of humans with diseases and conditions that are alleviated by S1 P modulation.
  • the invention provides a compound having Formula I, its enantiomers, its diastereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof:
  • R 1 is substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted 5-8 cycloalkyl, substituted or unsubstituted C 5 -8
  • R 2 is hydrogen, halogen, substituted or unsubstituted C -6 alkyl, C(0)R 10 or hydroxyl
  • R 3 is hydrogen, halogen, substituted or unsubstituted C -6 alkyl, C(0)R 10 or hydroxyl
  • R 4 isCH, S, O, N, NH orCH 2 ;
  • R 5 isCH, S, O, N, NH orCH 2 ;
  • R 6 is CH, S, O, NH or CH 2 ;
  • R 7 is H, halogen, -OCi -6 alkyl, substituted or unsubstituted Ci -6 alkyl;
  • R 8 is H or C1-6 alkyl
  • R 9 is OPO3H2, carboxylic acid, P0 3 H 2 , -P(0)MeOH, -P(0)(H)OH or OR 11 ;
  • R 10 is hydroxyl or substituted or unsubstituted C-i-6 alkyl
  • R 11 is H or substituted or unsubstituted C-i-6 alkyl
  • a is 5, 6, 7 or 8;
  • b is 0 or 1;
  • the invention provides a compound having Formula I, wherein:
  • R 1 is substituted or unsubstituted aryl
  • R 2 is hydrogen, halogen, substituted or unsubstituted C -6 alkyl
  • R 3 is hydrogen, halogen, substituted or unsubstituted C -6 alkyl
  • R 4 isCH, OorCH 2 ;
  • R 5 isCH, OorCH 2 ;
  • R 6 isCH orCH 2 ;
  • R 7 is H
  • R 8 is H or C1-6 alkyl
  • R 1 is H
  • a is 5, 6, 7 or 8;
  • b is 0 or 1 ;
  • the invention provides a compound having Formula I, wherein:
  • R 1 is substituted or unsubstituted aryl
  • R 2 is hydrogen
  • R 3 is hydrogen
  • R 4 is CH 2 ;
  • R 5 is CH 2 ;
  • R 6 is CH 2 ;
  • R 7 is H
  • R 8 is H
  • R 9 is P0 3 H 2 ;
  • a 5;
  • the invention provides a compound having Formula I, wherein:
  • R is substituted or unsubstituted aryl
  • R 2 is hydrogen
  • R 3 is hydrogen
  • R 4 is CH, O
  • R 5 is CH, O
  • R 6 is CH; R 7 is H;
  • R 8 is H
  • R 9 is OPO3H2, PO3H2 or OR ⁇ 1 1 1.
  • R 11 is H
  • a 5;
  • b is 0 or 1 ;
  • the invention provides a compound having Formula I, wherein:
  • R 1 is substituted or unsubstituted aryl
  • R 2 is hydrogen
  • R 3 is hydrogen
  • R 4 is CH, O
  • R 5 is CH, 0;
  • R 6 is CH
  • R 7 is H
  • R 8 is H
  • R 11 is H
  • a 5;
  • R 1 is substituted or unsubstituted aryl
  • R 2 is hydrogen
  • R 3 is hydrogen
  • R 4 is CH, O;
  • R 5 is CH, O;
  • R 6 is CH
  • R 7 is H
  • R 8 is H
  • R 11 is H
  • a 5;
  • b is 0 or 1 ;
  • the invention provides a compound having Formula II, its enantiomers, its diastereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof:
  • R 1 is substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C 5-8 cycloalkyl, substituted or unsubstituted C 5-8 cycloalkenyl or hydrogen;
  • R 2 is hydrogen, halogen, substituted or unsubstituted C -3 alkyl, C(0)R 10 or hydroxyl
  • R 3 is hydrogen, halogen, substituted or unsubstituted C -3 alkyl, C(0)R 10 or hydroxyl
  • R 4 is CH, S, O, N, NH or CH 2 ;
  • R 5 is CH, S, O, N, NH or CH 2 ;
  • R 6 is CH or CH 2 ;
  • R 7 is H, halogen, -OC1-3 alkyl, substituted or unsubstituted Ci -3 alkyl;
  • R 8 is H or C1-3 alkyl;
  • R 9 is OPO3H2, carboxylic acid, P0 3 H 2 , -P(0)MeOH, -P(0)(H)OH or OR 11 ;
  • R 10 is hydroxyl or substituted or unsubstituted d- 3 alkyl;
  • R 11 is H or substituted or unsubstituted C -3 alkyl
  • a is 5, 6, 7 or 8;
  • b is 0 or 1 ;
  • the invention provides a compound of Formula II, wherein
  • R 1 i substituted or unsubstituted aryl, or hydrogen
  • R 2 i hydrogen, halogen, substituted or unsubstituted Ci -3 alkyl
  • R 3 i hydrogen, halogen, substituted or unsubstituted Ci -3 alkyl
  • R 5 i sCH orN
  • a is 5, 6, 7 or 8;
  • b is 0 or 1;
  • R 1 is substituted or unsubstituted aryl
  • R 2 is hydrogen
  • R 3 is hydrogen
  • R 4 is CH
  • R 5 is N
  • R 6 is CH
  • R 7 is H
  • R 8 is H
  • R 9 is OPO 3 H 2 , carboxylic acid, P0 3 H 2 or OR 11
  • R is H
  • a is 5, 6, 7 or 8;
  • b is 0 or 1 ;
  • the invention provides a compound of Formula II, wherein: R 1 is substituted or unsubstituted aryl, or hydrogen;
  • R 2 is hydrogen
  • R 3 is hydrogen
  • R 4 is CH
  • R 5 is CH; R is CH;
  • R 7 is H
  • R 8 is H
  • R 9 is P0 3 H 2 ;
  • a is 5, 6, 7 or 8;
  • b is 0 or 1 ;
  • R 1 s substituted or unsubstituted aryl, or hydrogen
  • R 2 s hydrogen
  • R 3 s hydrogen
  • R is H
  • a is 5, 6, 7 or 8;
  • alkyl refers to saturated, monovalent or divalent hydrocarbon moieties having linear or branched moieties or combinations thereof and containing 1 to 6 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 3-6 cycloalkyl.
  • Alkyl groups can be substituted by halogen, hydroxyl, cycloalkyl, amino, non-aromatic heterocycles, carboxylic acid, phosphonic acid groups, sulphonic acid groups, phosphoric acid.
  • cycloalkyl refers to a monovalent or divalent group of 3 to 8 carbon atoms, preferably 3 to 5 carbon atoms derived from a saturated cyclic hydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic. Cycloalkyl can be substituted by 1 to 3 C i -3 alkyl groups or 1 or 2 halogens.
  • cycloalkenyl refers to a monovalent or divalent group of 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms derived from a saturated cycloalkyl having one double bond. Cycloalkenyl groups can be monocyclic or polycyclic. Cycloalkenyl groups can be substituted by alkyl groups or halogens.
  • halogen refers to an atom of chlorine, bromine, fluorine, iodine.
  • alkenyl refers to a monovalent or divalent hydrocarbon moiety having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one double bond.
  • C2-6 alkenyl can be in the E or Z configuration.
  • Alkenyl groups can be substituted by alkyl groups.
  • alkynyl refers to a monovalent or divalent hydrocarbon moiety having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one triple bond.
  • heterocycle refers to a 3 to 10 membered ring, which can be aromatic or non-aromatic, saturated or non-saturated, containing at least one heteroatom selected form O or N or S or combinations of at least two thereof, interrupting the carbocyclic ring structure.
  • Heterocycles can be monocyclic or polycyclic. Heterocyclic ring moieties can be substituted by hydroxyl, alkyl or halogens. Usually, in the present case, heterocyclic groups are 5 or 6 membered rings.
  • aryl refers to an organic moiety derived from an aromatic hydrocarbon consisting of a ring containing 6 to 10 carbon atoms by removal of one hydrogen, which can be substituted by halogen atoms or by alkyl groups.
  • hydroxyl as used herein, represents a group of formula "-OH”.
  • carbonyl as used herein, represents a group of formula "-C(O)".
  • carboxyl as used herein, represents a group of formula "-C(0)O”.
  • sulfonyl as used herein, represents a group of formula "-SO2”.
  • 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 ".
  • boronic acid represents a group of formula "- B(OH) 2 ".
  • N represents a nitrogen atom
  • Compounds of the invention are: (3- ⁇ [(7- ⁇ [5-(3-methoxyphenyl)pentyl]oxy ⁇ -2,3-dihydro-1 H-inden-4-yl)methyl] amino ⁇ propyl)phosphonic acid;
  • Some compounds of Formula I or of Formula II 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 Appli. 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.
  • 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 or of Formula II that occurs in its free form as a base can be obtained by treating the free base with an appropriate acid such as an inorganic acid, such as for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; or an organic acid such as for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric, methylsulfonic, ethanesulfonic, benzenesulfonic, formic and the like (Handbook of Pharmaceutical Salts, P. Heinrich Stahl & Camille G. Wermuth (Eds), Verlag Helvetica Chimica Acta- Zurich, 2002, 329- 345).
  • an appropriate acid such
  • the base addition salt form of a compound of Formula I or of Formula II that occurs in its acid form can be obtained by treating the acid with an appropriate base such as an inorganic base, for example, sodium hydroxide, magnesium hydroxide, potassium hydroxide, calcium hydroxide, ammonia and the like; or an organic base such as for example, L-Arginine, ethanolamine, betaine, benzathine, morpholine and the like.
  • an appropriate base such as an inorganic base, for example, sodium hydroxide, magnesium hydroxide, potassium hydroxide, calcium hydroxide, ammonia and the like
  • an organic base such as for example, L-Arginine, ethanolamine, betaine, benzathine, morpholine and the like.
  • compositions including at least one compound of the invention in a pharmaceutically acceptable carrier.
  • sphingosine-1 -phosphate receptors there are provided methods for treating disorders associated with modulation of sphingosine-1 -phosphate receptors. Such methods can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one compound of the invention.
  • These compounds are useful for the treatment of mammals, including humans, with a range of conditions and diseases that are alleviated by S1 P modulation: not limited to the treatment of diabetic retinopathy, other retinal degenerative conditions, dry eye, angiogenesis and wounds.
  • S1 P modulators are ocular diseases, such as but not limited to: wet and dry age-related macular degeneration, diabetic retinopathy, angiogenesis inhibition, retinopathy of prematurity, retinal edema, geographic atrophy, glaucomatous optic neuropathy, chorioretinopathy, hypertensive retinopathy, ocular ischemic syndrome, prevention of inflammation-induced fibrosis in the back of the eye, various ocular inflammatory diseases including uveitis, scleritis, keratitis, and retinal vasculitis; or systemic vascular barrier related diseases such as but not limited to: various inflammatory diseases, including acute lung injury, its prevention, sepsis, tumor metastasis, atherosclerosis, pulmonary edemas, and ventilation-induced lung injury; or autoimmune diseases and immunosuppression such as but not limited to: rheumatoid arthritis, Crohn's disease, Graves' disease, inflammatory bowel disease, multiple
  • sphingosine-1 -phosphate receptors there are provided methods for treating disorders associated with modulation of sphingosine-1 -phosphate receptors. Such methods can be performed, for example, by administering to a subject in need thereof a therapeutically effective amount of at least one compound of the invention, or any combination thereof, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual isomers, enantiomers, and diastereoisomers thereof.
  • the present invention concerns the use of a compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of ocular disease, wet and dry age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal edema, geographic atrophy, angiogenesis inhibition, glaucomatous optic neuropathy, chorioretinopathy, hypertensive retinopathy, ocular ischemic syndrome, prevention of inflammation- induced fibrosis in the back of the eye, various ocular inflammatory diseases including uveitis, scleritis, keratitis, and retinal vasculitis; or systemic vascular barrier related diseases , various inflammatory diseases, including acute lung injury, its prevention, sepsis, tumor metastasis, atherosclerosis, pulmonary edemas, and ventilation-induced lung injury; or autoimmune diseases and immunosuppression , rheumatoid arthritis, Crohn's disease, Grav
  • 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; or central nervous system neuronal activity in Alzheimer's disease, age-related neuronal injuries; or in organ transplant such as
  • the actual amount of the compound to be administered in any given case will be determined by a physician taking into account the relevant circumstances, such as the severity of the condition, the age and weight of the patient, the patient's general physical condition, the cause of the condition, and the route of administration.
  • the patient will be administered the compound orally in any acceptable form, such as a tablet, liquid, capsule, powder and the like, or other routes may be desirable or necessary, particularly if the patient suffers from nausea.
  • routes may include, without exception, transdermal, parenteral, subcutaneous, intranasal, via an implant stent, intrathecal, intravitreal, topical to the eye, back to the eye,
  • the formulations may be designed to delay release of the active compound over a given period of time, or to carefully control the amount of drug released at a given time during the course of therapy.
  • compositions including at least one compound of the invention in a pharmaceutically acceptable carrier thereof.
  • pharmaceutically acceptable means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions of the present invention can be used in the form of a solid, a solution, an emulsion, a dispersion, a patch, a micelle, a liposome, and the like, wherein the resulting composition contains one or more compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications.
  • Invention compounds may be combined, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
  • the carriers which can be used include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form.
  • Invention compounds are included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or disease condition.
  • compositions containing invention compounds may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of a sweetening agent such as sucrose, lactose, or saccharin, flavoring agents such as peppermint, oil of wintergreen or cherry, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets containing invention compounds in admixture with non-toxic pharmaceutically acceptable excipients may also be manufactured by known methods.
  • the excipients used may be, for example, (1 ) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents such as corn starch, potato starch or alginic acid; (3) binding agents such as gum tragacanth, corn starch, gelatin or acacia, and (4) lubricating agents such as magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • formulations for oral use may be in the form of hard gelatin capsules wherein the invention compounds are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the invention compounds are mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • the pharmaceutical compositions may be in the form of a sterile injectable suspension.
  • This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol.
  • Sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides, fatty acids (including oleic acid), naturally occurring vegetable oils like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyl oleate or the like. Buffers, preservatives, antioxidants, and the like can be incorporated as required.
  • 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.
  • the present invention concerns also processes for preparing the compounds of Formula II.
  • the compounds of Formula II according to the invention can be prepared analogously to conventional methods as understood by the person skilled in the art of synthetic organic chemistry.
  • the synthetic scheme set forth below, illustrates how compounds according to the invention can be made.
  • the compounds of the invention may contain one or more asymmetric centers, such that the compounds may exist in enantiomeric as well as in diastereoisomeric forms. Unless it is specifically noted otherwise, the scope of the present invention includes all enantiomers, diastereoisomers 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.
  • 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.
  • characterization of the compounds is performed according to the following methods: NMR spectra are recorded on 300 and/or 600 MHz Varian and acquired at room temperature. Chemical shifts are given in ppm referenced either to internal TMS or to the solvent signal. All the reagents, solvents, catalysts for which the synthesis is not described are purchased from chemical vendors such as Sigma Aldrich, Fluka, Bio-Blocks, Combi- blocks, TCI, VWR, Lancaster, Oakwood, Trans World Chemical, Alfa, Fisher, AK Scientific, AmFine Com, Carbocore, Maybridge, Frontier, Matrix, Ukrorgsynth, Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-lmpex, MIC-scientific, Ltd; however some known intermediates, were prepared according to published procedures.
  • Some compounds of this invention can generally be prepared in one step from commercially available literature starting materials.
  • triphenylphosphine (964mg, 3.7mmol) in THF(15mL) was added diisopropyl azodicarboxylate (0.73ml_, 3.7mmol). The mixture was stirred at rt for 16 hr before concentration. Purification by MPLC (30% ethyl acetate in hexanes) to afford 487mg of Intermediate 27 as colorless solid.
  • Biological Data 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, dithiothreitol 0.5, digitonin 0.003%, 0.2 nM GTP y 35 S, and 5 ⁇ 9 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'-adenylyl immido diphosphate 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 P1 in the presence of test antagonist at concentrations ranging from 0.08 to 5000 nM.
  • Table 14 shows activity potency: S1 P1 receptor from GTP y 35 S: nM, (EC 50 ) Table 14

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Abstract

La présente invention concerne de nouveaux dérivés bicycliques, des procédés pour leur préparation, des compositions pharmaceutiques les contenant et leur utilisation comme produits pharmaceutiques en tant que modulateurs des récepteurs de la sphingosine-1-phosphate.
PCT/US2014/059769 2014-04-24 2014-10-08 Dérivés bicycliques utilisés comme modulateurs des récepteurs de la sphingosine-1-phosphate WO2015163936A1 (fr)

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WO2022256284A1 (fr) 2021-06-02 2022-12-08 Fmc Corporation Pyridines fusionnées pour lutter contre les invertébrés nuisibles

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US20050020837A1 (en) * 2002-01-18 2005-01-27 Doherty George A. N-(benzyl)aminoalkylcarboxylates, phosphinates, phosphonates and tetrazoles as edg receptor agonists
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US20050020837A1 (en) * 2002-01-18 2005-01-27 Doherty George A. N-(benzyl)aminoalkylcarboxylates, phosphinates, phosphonates and tetrazoles as edg receptor agonists
US20050033055A1 (en) * 2002-01-18 2005-02-10 Bugianesi Robert L. Edg receptor agonists

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022256284A1 (fr) 2021-06-02 2022-12-08 Fmc Corporation Pyridines fusionnées pour lutter contre les invertébrés nuisibles

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