WO2008091967A1 - Composés chimiques - Google Patents

Composés chimiques Download PDF

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Publication number
WO2008091967A1
WO2008091967A1 PCT/US2008/051832 US2008051832W WO2008091967A1 WO 2008091967 A1 WO2008091967 A1 WO 2008091967A1 US 2008051832 W US2008051832 W US 2008051832W WO 2008091967 A1 WO2008091967 A1 WO 2008091967A1
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alkyl
substituted
unsubstituted
branched
straight chain
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PCT/US2008/051832
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English (en)
Inventor
Hongfeng Deng
Ghotas Evindar
Gang Yao
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Smithkline Beecham Corporation
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Publication of WO2008091967A1 publication Critical patent/WO2008091967A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07F9/653—Five-membered rings
    • C07F9/65306—Five-membered rings containing two nitrogen atoms
    • C07F9/65318—Five-membered rings containing two nitrogen atoms having the two nitrogen atoms in positions 1 and 3
    • 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 System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • the sphingosine-1 -phosphate (SlP) receptors 1-5 constitute a family of seven transmembrane G-protein coupled receptors. These receptors, referred to as SlPl to S1P5, are activated via binding by sphingosine-1 -phosphate, which is produced by the sphingosine kinase-catalyzed phosphorylation of sphingosine. SlP receptors are cell surface receptors involved in a variety of cellular processes, including cell proliferation and differentiation, cell survival, cell invasion, lymphocyte trafficking, and cell migration. Sphingosine-1 -phosphate is found in plasma and a variety of other tissues, and exerts autocrine and paracrine effects, including regulating the secretion of growth factors.
  • Ri is alkyl, alkoxy, oxaalkyl, thiaalkyl, azaalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl group, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroarylalkyl group, substituted or unsubstituted cycloalkylalkyl, or substituted or unsubstituted heterocycloalkylalkyl;
  • X1-X5 are each independently C, C-R' N, N-R", S, or O, wherein R' is hydrogen, halo, or alkyl and R" is hydrogen or alkyl;
  • R2 is hydrogen, halogen, cyano, straight chain or branched Ci-C ⁇ -alkyl, straight chain or branched Ci-C ⁇ -alkoxy, straight chain or branched halo-Ci-C 6 -alkyl (e.g., trifluoromethyl), straight chain or branched halo-Ci-C ⁇ -alkoxy, Ci-C 6 -alkoxy-Ci-C6-alkyl, hydroxyl-Ci-C ⁇ - alkyl, carboxy-Ci-Ce-alkyl, d-C 6 -alkyl-SO 2 Or N(R)R', where R and R' are each independently hydrogen, straight chain or branched Ci-C 6 -alkyl, straight chain or branched Ci-C ⁇ -alkoxy, straight chain or branched halo-Ci-C ⁇ -alkyl, straight chain or branched halo- Ci-C ⁇ -alkoxy, Ci-C 6 -alkoxy-C
  • Q is -CH 2 NR-, -CH 2 NR(CO)-, -NH(CO)-, -(CO)NH-, -(CO)-, -0-, -S-, -SO-, -SO 2 -, -NRSO 2 -, -SO 2 -NR-, aryl or heteroaryl, wherein R is hydrogen or straight chain or branched Ci-C ⁇ -alkyl;
  • R 10 and R 11 are each independently H, straight chain or branched Ci-C ⁇ -alkyl, a substituted or unsubstituted aryl group or selected from the group consisting of: Attorney Docket No. PPI-304-1
  • R 4 is H, Ci-Ce-alkyl, hydroxy-Ci-C 6 -alkyl, aryl, or heteroaryl;
  • R 5a and R Jb each independently selected from H, straight chain or branched Ci-C ⁇ - alkyl, or C3-C6-cycloalkyl; taken together Rs 3 and Rs b may form a substituted or unsubstituted C2-C8 fused carbocyclic ring or substituted or unsubstituted C2-Q0 fused heterocyclic rings, which may contain one or more heteroatoms and may be saturated or unsaturated; and m and n are each independently 0, 1, 2, or 3.
  • the invention also provides a compound which is:
  • the invention is also directed to a method of treating an autoimmune disorder, comprising, administering to a subject in need thereof a pharmaceutically acceptable amount of a compound of the invention.
  • the invention is also directed to a method treating transplant rejection comprising, administering to a subject in need thereof a pharmaceutically acceptable amount of a compound of the invention.
  • the invention is also directed to a pharmaceutical composition, comprising a compound of the invention admixed with a pharmaceutically acceptable carrier.
  • the invention is also directed to a process for making a compound of the invention as provided herein.
  • Halogen or "halo” means fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
  • hydrocarbon used alone or as a suffix or prefix, refers to any structure comprising only carbon and hydrogen atoms up to 14 carbon atoms.
  • hydrocarbon radical or "hydrocarbyl” used alone or as a suffix or prefix, refers to any structure as a result of removing one or more hydrogens from a hydrocarbon.
  • alkyP used alone or as a suffix or prefix, refers to monovalent straight or branched chain hydrocarbon radicals comprising 1 to about 12 carbon atoms.
  • alkylene used alone or as suffix or prefix, refers to divalent straight or branched chain hydrocarbon radicals comprising 1 to about 12 carbon atoms, which serves to links two structures together.
  • cycloalkyl used alone or as suffix or prefix, refers to a saturated or partially unsaturated monovalent ring-containing hydrocarbon radical comprising at least 3 up to about 12 carbon atoms.
  • aryl used alone or as suffix or prefix, refers to a monovalent hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, and comprising 5 up to about 14 carbon atoms.
  • heterocycle used alone or as a suffix or prefix, refers to a ring-containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, O and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring(s).
  • Heterocycle may be saturated or unsaturated, containing one or more double bonds, and heterocycle may contain more than one ring.
  • the rings may be fused or unfused.
  • Fused rings generally refer to at least two rings share two atoms therebetween.
  • Heterocycle may have aromatic character or may not have aromatic character.
  • heterocyclic group refers to a radical derived from a heterocycle by removing one or more hydrogens therefrom.
  • heterocyclyl used alone or as a suffix or prefix, refers a monovalent radical derived from a heterocycle by removing one hydrogen therefrom.
  • heteroaryl used alone or as a suffix or prefix, refers to a heterocyclyl having aromatic character.
  • Heterocycle includes, for example, monocyclic heterocycles such as: aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazoline, dioxolane, sulfolane 2,3-dihydrofuran, 2,5-dihydrofuran tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydro-pyridine, piperazine, morpholine, thiomorpholine, pyran, thiopyran, 2,3-dihydropyran, tetrahydropyran, 1 ,4-dihydropyridine, 1 ,4-dioxane, 1 ,3-dioxane, dioxane, homopiperidine, 2,3,4,7-tetrahydro-lH-azepin
  • heterocycle includes aromatic heterocycles (heteroaryl groups), for example, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, furazan, pyrrole, imidazole, thiazole, oxazole, pyrazole, isothiazole, isoxazole, 1 ,2,3-triazole, tetrazole, 1,2,3- thiadiazole, 1,2,3-oxadiazole, 1 ,2,4-triazole, 1,2,4-thiadiazole, 1 ,2,4-oxadiazole, 1 ,3,4- triazole, 1,3,4-thiadiazole, and 1 ,3,4-oxadiazole.
  • aromatic heterocycles heteroaryl groups
  • heterocycle encompass polycyclic heterocycles, for example, indole, indoline, isoindoline, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, 1,4-benzodioxan, coumarin, dihydrocoumarin, benzo furan, 2,3-dihydrobenzo furan, isobenzo furan, chromene, chroman, isochroman, xanthene, phenoxathiin, thianthrene, indolizine, isoindole, indazole, purine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, phenanthridine, perimidine, phenanthroline, phenazine, phenothiazine, phenoxazine, 1,2-benzisoxazole, benzothiophene, benzoxazole
  • heterocycle includes polycyclic heterocycles wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings.
  • bridged heterocycles examples include quinuclidine, diazabicyclo[2.2.1]heptane and 7-oxabicyclo[2.2.1 Jheptane.
  • Heterocyclyl includes, for example, monocyclic heterocyclyls, such as: aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, Attorney Docket No. PPI-304-1
  • pyrazolidinyl pyrazolinyl, dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofiiranyl, tetrahydrofliranyl, thiophanyl, piperidinyl, 1 ,2,3,6-tetrahydro-pyridinyl, piperazinyl, mo ⁇ holinyl, thiomorpholinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl, 1 ,4-dioxanyl, 1 ,3-dioxanyl, dioxanyl, homopiperidinyl, 2,3,4,7- tetrahydro-lH-azepinyl, homopiperazinyl, 1 ,3-dfoxepanyl, 4,7-dihydro-l,3
  • heterocyclyl includes aromatic heterocyclyls or heteroaryl, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, furazanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1 ,2,3-triazolyl, tetrazolyl, 1 ,2,3- thiadiazolyl, 1,2,3-oxadiazolyl, 1 ,2,4-triazolyl, 1,2,4-thiadiazolyl, 1 ,2,4-oxadiazolyl, 1,3,4- triazolyl, 1 ,3,4-thiadiazolyl, and 1 ,3,4 oxadiazolyl.
  • pyridinyl pyrazinyl, pyrimidinyl, pyridazinyl, thi
  • heterocyclyl encompasses polycyclic heterocyclyls (including both aromatic or non-aromatic), for example, indolyl, indolinyl, isoindolinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, 1 ,4-benzodioxanyl, coumarinyl, dihydrocoumarinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, isobenzofuranyl, chromenyl, chromanyl, isochromanyl, xanthenyl, phenoxathiinyl, thianthrenyl, indolizinyl, isoindolyl, indazolyl, purinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, p
  • heterocyclyl includes polycyclic heterocyclyls wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings.
  • bridged heterocycles include quinuclidinyl, diazabicyclo[2.2.1]heptyl; and 7-oxabicyclo[2.2.1]heptyl.
  • five-membered used as prefix refers to a group having a ring that contains five ring atoms.
  • a five-membered heteroaryl ring is a heteroaryl with a ring having five ring atoms wherein 1 , 2 or 3 ring atoms are independently selected from N, O and S.
  • Exemplary five- membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1 ,2,3-triazolyl, tetrazolyl, 1 ,2,3-thiadiazolyl, 1 ,2,3- Attorney Docket No. PPI-304-1
  • a six-membered ring heteroaryl is a heteroaryl with a ring having six ring atoms wherein 1 , 2 or 3 ring atoms are independently selected from N, O and S.
  • Exemplary six- membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
  • cycloalkylalkyl refers to an alkyl group substituted with a cycloalkyl group.
  • heterocycloalkylalkyl refers to an alkyl group substituted with an heterocycloalkyl group.
  • aralkyl refers to an alkyl group substituted with an aryl group.
  • heteroarylkyl refers to an alkyl group substituted with an heteroaryl group.
  • substituted when used as a prefix, refers to a structure, molecule or group, wherein one or more hydrogens are replaced with one or more alkyl groups, or one or more chemical groups containing one or more heteroatoms selected from N, O, S, F, Cl, Br, I, and P.
  • substituted phenyl may refer to nitrophenyl, pyridylphenyl, methoxyphenyl, chlorophenyl, aminophenyl, an so on, wherein the nitro, pyridyl, methoxy, chloro, and amino groups may replace any suitable hvdrogen on the phenyl ring.
  • alkoxy used alone or as a suffix or prefix, refers to radicals of the general -O-alkyl, Exemplary alkoxy groups includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylnethoxy, allyloxy, and propargyloxy.
  • amine or “amino” used alone or as a suffix or prefix, refers -NH 2 .
  • alkylamino used alone or as a suffix or prefix, refers -NH(alkyl).
  • dialkylamino used alone or as a suffix or prefix, refers -NH(alkyl) 2 .
  • Acyl used alone, as a prefix or suffix, means -C(O)-R, wherein R hydrogen, hydroxyl, amino, alkylamino, dialkylamino, or alkoxy, any of which may be substituted as provided by the defiontion of "substituted” given above.
  • Acyl groups include, for example, acetyl, propionyl, benzoyl, phenyl acetyl, carboethoxy, and dimethylcarbamoyl.
  • Some of the compounds in the present invention may exist as stereoisomers, including enantiomers, diastereomers, and geometric isomers. All of these forms, including (R), (S), Attorney Docket No. PPI-304-1
  • the invention also relates to salts of the compounds of the invention and, in particular, to pharmaceutically acceptable salts.
  • a “pharmaceutically acceptable salt” is a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects.
  • the salts can be, for example, salts with a suitable acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like; acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, benzoic acid, pamoic acid, alginic acid, methanesulfonic acid, naphthalenesulfonic acid, and the like.
  • salts of cations such as ammonium, sodium, potassium, lithium, zinc, copper, barium, bismuth, calcium, and the like; or organic cations such as tetralkylammonium and trialkylammonium cations. Combinations of the above salts are also useful. Salts of other acids and/or cations are also included, such as salts with trifluoroacetic acid, chloroacetic acid, and trichloroacetic acid.
  • the invention also includes different crystal forms, hydrates, and solvates of the compounds of the invention.
  • a specific value for Ri is hydrogen. Another specific value for Ri is heptyl. Another specifc value for Ri is hexyl. Another specific value for Ri is pentyl. Another specific value
  • Ri is-"' ⁇ "1 ⁇ .
  • Another specific value for Ri is phenyl.
  • Another specific value for Ri is cyclopentyl.
  • Another specific value for Ri is cyclohexyl.
  • Another specific value for Ri is a cyclopentyl or cyclohexyl group, bearing an alkyl substitutent, such as a propyl group, Attorney Docket No. PPI-304-1 although other alkyl substituents may be employed.
  • Another specific value for Ri is .
  • Another specific value for Ri is .
  • Another specific value for Ri is .
  • Ri is benzyl. Another specific value for R] is
  • Another specific value for 2 is .
  • Another specific value for 3 is .
  • a specific value for Q is s .
  • Another specific value for Q is
  • a specific value for R 3 is -OH. Another specific value for R3 is OPO2H2. Another specific value for R3 is OPO2Me 2 . Another specific value for R 3 is OPO 2 Et 2 . Another specific value for R 3 is -CO 2 H. Another specific value for R 3 is -CO 2 Me or -CO 2 Et.
  • a specific value for R 4 is hydrogen. Another specific value for R 4 is methyl. Another specific value for R 4 is hydroxymethyl.
  • R 5a and Rs b independently include hydrogen or alkyl.
  • the compounds of the present invention include R 2 which is a selectivity enhancing moiety.
  • SEM selectivity enhancing moiety
  • the term "selectivity enhancing moiety (SEM)" is defined in United States Application Ser. No. 11/349069 filed on February 6, 2006 which is assigned to the assignee of the present application, the contents of which are incorporated herein by reference, refers to one or more moieties that provide an enhancement in the selectivity of the compound to which they are attached for the SlPl receptor, as compared to the compound not containing the moiety or moieties.
  • the SEM confers selectivity to the compound to which it is attached for the SlPl receptor as compared to, for example, the S 1P2 to S1P5 receptors.
  • the enhancement conferred to a compound by the SEM may be measured by, for example, determining the binding specificity of a compound for the S lPl receptor and one or more of the other S 1 P receptors wherein enhancement conferred to a compound by the SEM may be in the form of increased potency.
  • the SEM of the present application is defined in one embodiment as for R 2 .
  • the SEM is a halo-substituted alkyl group such as CF 3 , CF 2 CF 3 , CF 2 CF 2 CF 3 , CFHCF 3 , CH 2 CF 3 , CH 2 CH 2 CF 3 , CHCl 2 , or CH 2 Cl.
  • the SEM may possess a selectivity enhancing orientation (SEO).
  • SEO selectivity enhancing orientation
  • SEO selectivity enhancing orientation
  • the SEO refers to the relative selectivity enhancement of a compound based on the orientation of the SEM as well as the additional substitutents on the ring, either alone or in combination with each other.
  • the SEO may result from the orientation of the SEM on the ring to which it is attached, in relation to any other ring and/or moiety attached to
  • the SEM on " ⁇ is in the ortho position relative to X3 in Formula I. In another specific embodiment, the SEM is in the meta position relative to X 3 .
  • a specific value for R2 is trifluoromethyl. Another specific value for R2 is fluoro. Another specific value for R 2 is chloro. Another specific value for R2 is bromo. Another specific value for R 2 is cyano. Another specific value for R 2 is methyl.
  • a specific group of compounds of the invention are compounds of formula I which are of formula IA.
  • Another specific group of compounds of the invention are compounds of formula I which are compounds of formula IB.
  • mice Male C57B1/6 mice were divided into groups of three. A control group received the 3% BSA vehicle only. The other groups received a single dose of either a specified dose of test compound in vehicle administered orally (PO) and intravenously (IV). After 6 hours, the mice were anesthesized with isoflurane and approximately 250 ⁇ L of blood was removed from the retroorbital sinus and collected in an EDTA microtainer, mixed with an anticoagulant and placed on a tilt table until complete blood count (CBC) analysis. Oral administration (10 mg/K) of these compounds induced increased lymphopenia versus the vehicle.
  • PO vehicle administered orally
  • IV intravenously
  • the compounds of the invention selective for the SlPl receptor as compared to one or more of the other SlP receptors.
  • one set of compounds includes compounds which are selective for the SlPl receptor relative to the S1P3 receptor.
  • Compounds selective for the SlPl receptor can be agonists of the SlPl receptor, significantly weaker agonists of one or more other receptors and/or antagonists of one or more other receptors.
  • a compound is "selective" for the S lPl receptor relative to a second receptor, if the EC50 of the compound for the second receptor is at least two-fold greater than the EC50 for the SlPl receptor.
  • the EC50 of a compound is determined using the 35 S-GTPyS binding assay, as described in WO 03/061567, the entire contents of which are incorporated herein by reference. Additionally or alternatively, a compound is "selective" for the Sl Pl receptor relative to a second receptor, if the IC 50 of the compound for the second receptor is at least two-fold greater than the ICs 0 for the SlPl receptor.
  • agonist or "SlPl receptor agonist” as used herein include the compounds described herein which bind to and/or agonize the SlPl receptor.
  • the SlP receptor agonists have an IC50 for the SlPl receptor of about 100 nM - 0.25 nM, about 50 nM - 0.25 nM, about 25 nM - 0.5 nM, about 100 nM or less, about 75 nM or less, about 50 nM or less, about 40 nM or less, about 30 nM or less, about 20 nM or less, about 10 nM or less, about 5 nM or less, about 1 nM or less, about 0.5 nM or less, or about 0.25 nM or less.
  • the compounds' IC 50 for the SlPl receptor can be measured using the binding assays described in Example 13 or those described in WO 03/061567.
  • Compounds of the invention generally had an IC50 in the range of 100 pM (picomolar) to 100 M.
  • Ranges intermediate to the above recited values are also intended to be part of this invention.
  • ranges using a combination of any of the above recited values as upper and/or lower limits are intended to be included.
  • the SlP receptor agonist has an IC 5 0 value for the S1P3 receptor of about 10 nM - 10,000 nM, about 100 nM - 5000 nM, about 100 nM - 3000 nM, about 10 nM or greater, about 20 nM or greater, about 40 nM or greater, about 50 nM or greater, about 75 nM or greater, or about 100 nM or greater.
  • the Sl P compound of the invention binds the S1P3 receptor with an IC 50 of 1000 nM or greater, 2000 nM or greater, 3000 nM or greater, 5000 nM or greater, 10,000 nM or greater.
  • the IC50 for of S1P3 receptor can be measured using the binding assays described herein or those described in WO 03/061567, the entire contents of which are incorporated herein by reference.
  • the S lP receptor agonists described herein have an IC 50 value for the SlPl receptor that is about 5-fold lower, about 10-fold lower, about 20-fold lower, about 50-fold lower, about 100-fold lower, about 200-fold lower, about 500-fold lower or about 1000-fold lower than their IC 50 value for the S1 P3 receptor.
  • Ranges intermediate to the above recited values are also intended to be part of this invention.
  • ranges using a combination of any of the above recited values as upper and/or lower limits are intended to be included.
  • plasmid DNA was transfected into HEK 293 T cells using the FuGENE 6 transfection protocol (publicly available from Roche). Briefly, subconfluent monolayers of HEK 293 T cells were transfected with the DNA mixture containing FuGENE 6 (using a 1 :3 ratio). The dishes containing the cells were then placed in a tissue culture incubator (5% CO 2 , 37°C). The cells were harvested 48 hours after addition of the DNA by scraping in HME buffer (in mM: 20 HEPES, 5 MgCl 2 , 1 EDTA, pH 7.4, 1 itiM PMSF) containing 10% sucrose on ice, and disrupted using a Dounce homogenizer.
  • HME buffer in mM: 20 HEPES, 5 MgCl 2 , 1 EDTA, pH 7.4, 1 itiM PMSF
  • [ 33 P] sphingosine 1 -phosphate obtained from American Radiolabeled Chemicals, Inc was added to membranes in 200 ⁇ l in 96-well plates with assay concentrations of 2.5 pM [ 33 P]sphingosine 1 -phosphate, 4 mg/ml BSA, 50 mM HEPES, pH 7.5, 100 mM NaCl, 5 mM MgCl 2 , and 5 ⁇ g of protein. Binding was performed for 60 minutes at room temperature with gentle mixing and terminated by collecting the membranes onto GF/B filter plates.
  • the compounds of the invention do not include the compounds described in WO 06/020951 A2, WO 05/041899A2, WO 04/010949A2, WO 04/024673 Al Attorney Docket No. PPI-304-1
  • the invention relates to a method for treating a subject suffering from a sphingosine 1 -phosphate associated disorder, comprising administering to a subject an effective amount of a compound of the invention; that is, a compound of formula I or compounds otherwise described herein, such that the subject is treated for a sphingosine 1- phosphate associated disorder.
  • a compound of the invention that is, a compound of formula I or compounds otherwise described herein, such that the subject is treated for a sphingosine 1- phosphate associated disorder.
  • sphingosine 1 -phosphate associated disorder includes disorders, diseases or conditions which are associated with or caused by a misregulation in SlP receptor function and/or signaling or SlP receptor ligand function.
  • the term also includes diseases, disorders or conditions which can be treated by administering to a subject an effective amount of a sphingosine 1 -phosphate receptor agonist.
  • Such disorders include disorders that are associated with an inappropriate immune response and conditions associated with an overactive immune response, e.g., autoimmune diseases.
  • Treatment is defined as the application or administration of a therapeutic agent such as a compound of formula I to a subject who has a shingosine 1 -phosphate associated disorder as described herein, with the purpose to cure, heal, alleviate, delay, relieve, alter, remedy, ameliorate, improve or affect the disease or disorder, or symptoms of the disease or disorder.
  • treatment or “treating” is also used herein in the context of administering agents prophylactically.
  • the efficacy of the compounds of the present invention can be measured by comparing a value, level, feature, characteristic, property, etc. to a "suitable control".
  • a "suitable control” is any control or standard familiar to one of ordinary skill in the art useful for comparison purposes.
  • a "suitable control” is a value, level, feature, characteristic, property, etc. determined prior to administering a composition of the present invention.
  • the immune response, etc. can be determined prior to introducing a compound of the invention into a cell or subject.
  • a "suitable control” is a value, level, feature, characteristic, property, etc.
  • a "suitable control” is a predefined value, level, feature, characteristic, property, etc.
  • a "suitable control” can be a pre-defined level of binding to a specified Sl P receptor.
  • An additional embodiment of the invention pertains to a method for treating a subject suffering from a sphingosine 1 -phosphate associated disorder, comprising administering to a subject a compound, such that the subject is treated for a sphingosine 1 -phosphate associated disorder by a compound of the invention; that is, a compound of formulae I or compounds otherwise described herein.
  • the present invention is also directed to a method of selectively treating a sphingosine 1 -phosphate associated disorder, comprising administering to a subject an effective amount of a compound of the invention, e.g., compounds of any of Formulae I or compounds otherwise described herein, such that the subject is selectively treated for a sphingosine 1 -phosphate associated disorder.
  • the sphingosine 1 -phosphate associated disorder is a sphingosine l-phosphate-(l) associated disorder.
  • the sphingosine l- ⁇ hos ⁇ hate-(l) associated disorder is selectively treated as compared with a sphingosine l-phosphate-(3) associated disorder.
  • the present invention provides a method of treating a condition associated with an activated immune system.
  • diseases or disorders include rejection of transplanted organs, tissue or cells; graft-versus-host diseases brought about by transplantation; autoimmune syndromes including rheumatoid arthritis; systemic lupus erythematosus; antiphospholipid syndrome; Hashimoto's thyroiditis; lymphocytic thyroiditis; multiple sclerosis; myasthenia gravis; type I diabetes; uveitis; episcleritis; scleritis; Kawasaki's disease, uveo-retinitis; posterior uveitis; uveitis associated with Behcet's disease; uveomeningitis syndrome; allergic encephalomyelitis; chronic allograft vasculopathy; postinfectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; inflammatory and hyperproliferative skin diseases; psorias
  • the term "subject" includes warm-blooded animals, e.g. , mammals, including humans, cats, dogs, horses, bears, lions, tigers, ferrets, rabbits, mice, cows, sheep, pigs, etc.
  • the subject is a primate.
  • the primate is a human.
  • administering includes dispensing, delivering or applying a compound of the invention in a pharmaceutical formulation (as described Attorney Docket No. PPI-304-1
  • any suitable route for delivery of the compound to the desired location in the subject including delivery by either the parenteral or oral route, intramuscular injection, subcutaneous/intradermal injection, intravenous injection, buccal administration, topical delivery, transdermal delivery and administration by the rectal, colonic, vaginal, intranasal or respiratory tract route.
  • the term "effective amount" includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result, e.g., sufficient to treat the condition in a subject.
  • An effective amount of a compound of the invention, as defined herein, may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response.
  • An effective amount is also one in which any toxic or detrimental effects (e.g., side effects) of the compound are outweighed by the therapeutically beneficial effects.
  • a therapeutically effective amount of a compound of the invention may range from about O.001 to 30 mg/kg body weight, for example, about O.Ol to 25 mg/kg body weight, for example, about 0.1 to 20 mg/kg body weight. It is to be understood that all values and ranges between those listed are intended to be encompassed by the present invention. The skilled artisan will appreciate that certain factors may influence the dosage required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a compound of the invention can include a single treatment or, for example, can include a series of treatments.
  • the effective dosage of the compound used for treatment may increase or decrease over the course of a particular treatment.
  • the methods of the invention further include administering to a subject a therapeutically effective amount of a compound of the invention in combination with another pharmaceutically active compound known to treat the disease or condition, e.g., an immunomodulatory agent or an anti- inflammatory agent.
  • Pharmaceutically active compounds that may be used depend upon the condition to be treated, but include as examples cyclosporin, rapamycin, FK506, methotrexate, etanercept, infliximab, adalimumab, non-steroidal anti-inflammatory agents, eye looxygenase-2 -inhibitors, such as celecoxib and rofecoxib, and corticosteroids.
  • Other suitable compounds can be found in Harrison's Principles of Internal Medicine, Thirteenth Edition, Eds. T. R. Harrison et al. McGraw-Hill N.Y., N. Y.; and the Physicians Desk Reference 50th Edition 1997, Oradell New Jersey, Attorney Docket No. PPI-304-1
  • the compound of the invention and the additional pharmaceutically active compound may be administered to the subject in the same pharmaceutical composition or in different pharmaceutical compositions (at the same time or at different times).
  • the present invention also provides pharmaceutically acceptable formulations and compositions comprising one or more compounds of the invention; that is, compounds of formula I or compounds otherwise described herein.
  • the compound of the invention is present in the formulation in a therapeutically effective amount; that is, an amount effective to treat a sphingosine 1 -phosphate associated disorder.
  • the invention pertains to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention; that is, compounds of formula I or compounds otherwise described herein, and a pharmaceutically acceptable carrier.
  • the invention is directed to a packaged pharmaceutical composition
  • a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the invention; that is, compounds of formula I or compounds otherwise described herein; and instructions for using the compound to treat a sphingosine 1 -phosphate associated disorder in a subject.
  • the term "container” includes any receptacle for holding the pharmaceutical composition.
  • the container is the packaging that contains the pharmaceutical composition.
  • the container is not the packaging that contains the pharmaceutical composition, i.e., the container is a receptacle, such as a box or vial that contains the packaged pharmaceutical composition or unpackaged pharmaceutical composition and the instructions for use of the pharmaceutical composition.
  • packaging techniques are well known in the art. It should be understood that the instructions for use of the pharmaceutical composition may be contained on the packaging containing the pharmaceutical composition, and as such the instructions form an increased functional relationship to the packaged product. However, it should be understood that the instructions can contain information pertaining to the compound's ability to perform its intended function, e.g. , treating, preventing, or reducing a sphingosine 1 -phosphate associated disorder in a subject.
  • Another embodiment of the invention relates to a packaged pharmaceutical composition
  • a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the invention; that is, a compound of formula I or compounds otherwise described herein, and instructions for using the compound to selectively treat a sphingosine 1 - phosphate associated disorder in a subject.
  • Such pharmaceutically acceptable formulations typically include one or more compounds of the invention as well as one or more pharmaceutically acceptable carriers and/or excipients.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the compounds of the invention, use thereof in the pharmaceutical compositions is contemplated.
  • Supplementary pharmaceutically active compounds known to treat transplant or autoimmune disease i.e., immunomodulatory agents and anti- inflammatory agents, as described above, can also be incorporated into the compositions of the invention.
  • Suitable pharmaceutically active compounds that may be used can be found in Harrison's Principles of Internal Medicine.
  • a pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral, transdermal (topical), transmucosal, and rectal administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • compositions suitable for injection include sterile aqueous solutions (where water soluble) or dispersions, or sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ElTM (BASF, Parsippany, NJ.) Attorney Docket No. PPI-304-1
  • the pharmaceutical composition must be sterile and should be fluid to the extent that easy syringability exists. It must also be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the compound of the invention in the required amount in an appropriate solvent with one or a combination of the ingredients enumerated above, as needed, followed by filtered sterilization.
  • dispersions are prepared by incorporating the compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the compound plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets.
  • the compound of the invention can be incorporated with excipients and used in the form of tablets, troches, or capsules.
  • Oral compositions can also include an enteric coating.
  • Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed.
  • Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a Attorney Docket No. PPI-304-1
  • disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a suitable propellant e.g. , a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the compounds of the invention are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the present pharmaceutical compositions can also be prepared in the form of suppositories (e.g. , with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
  • the compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,81 1, U.S. Pat. No. 5,455,044 and U.S. Pat. No. 5,576,018, and U.S. Pat. No. 4,883,666, the contents of all of which are incorporated herein by reference.
  • the compounds of the invention can also be incorporated into pharmaceutical compositions which allow for the sustained delivery of the compounds to a subject for a period of at least several weeks to a month or more.
  • Such formulations are described in published PCT application no. WO 02/74247, incorporated herein by reference.
  • unit dosage forms of the invention are dictated by and directly dependent on the unique characteristics of the compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such compounds for the treatment of individuals.
  • R 2 O-allyl, Cl, Br, or I
  • R 2 O-allyl Et 2 NH, THF Et 3 N, DCM
  • the title compound was prepared from 4-fluoro-3-(trifluoromethyl)benzoic acid (Ia) in >99% (5.65 g) yield.
  • HPLC retention time on a C8(2) column (30 x 3.00 mm, 3 ⁇ ) was 2.53 minutes with gradient 20-98% acetonitrile-H 2 O (0.1 % trifluoro acetic acid (TFA)) in 4.0 minutes as mobile phase.
  • Benzoic acid 2 (1.0 equivalent) was stirred with HATU (1.1 equivalents) and Diisopropylethyl amine (DIEA (3.0 equivalents) in dichloromethane (DCM)-dimethyl formamide (DMF) (2:1) for 20 minutes. The solution was then added to a solution of hydrazine mono-hydrate (5.0) in DCM-DMF (2:1). The reaction mixture was stirred at room temperature for 1 hour, then diluted with ethyl acetate and washed with 10% NH 4 CI (2x) and saturated NaCl (1 time). The organic layer was dried over MgSC ⁇ , filtered, and the solvent was removed in vacuo to afford benzohydrazide 3.
  • R 3 H or protecting group

Abstract

L'invention concerne des composés de formule (I), leur préparation et leur utilisation en tant qu'agents immunosuppresseurs pharmaceutiquement actifs pour le traitement de maladies autoimmunes, du rejet de la transplantation d'organes, de troubles associés avec un système immunitaire activé, ainsi que d'autres troubles modulés par la lymphopénie ou les récepteurs SlP.
PCT/US2008/051832 2007-01-26 2008-01-24 Composés chimiques WO2008091967A1 (fr)

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US7750040B2 (en) 2004-07-29 2010-07-06 Actelion Pharmaceuticals Ltd Thiophene derivatives
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US8003800B2 (en) 2006-01-11 2011-08-23 Actelion Pharmaceuticals Ltd. Thiophene derivatives as S1P1/EDG1 receptor agonists
US8133910B2 (en) 2006-09-07 2012-03-13 Actelion Pharmaceuticals Ltd. Thiophene derivatives as S1P1/EDGE1 receptor agonists
US8580824B2 (en) 2006-09-07 2013-11-12 Actelion Pharmaceuticals Ltd. Pyridin-4-yl derivatives as immunomodulating agents
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US8044076B2 (en) 2006-09-21 2011-10-25 Actelion Pharmaceuticals Ltd. Phenyl derivatives and their use as immunomodulators
US8592460B2 (en) 2007-03-16 2013-11-26 Actelion Pharmaceuticals Ltd. Amino-pyridine derivatives as S1P1 /EDG1 receptor agonists
US8299086B2 (en) 2007-11-01 2012-10-30 Actelion Pharmaceuticals Ltd. Pyrimidine derivatives
US8148410B2 (en) 2007-12-10 2012-04-03 Actelion Pharmaceuticals Ltd. Thiophene derivatives as agonists of S1P1/EDG1
US8410151B2 (en) 2008-03-07 2013-04-02 Actelion Pharmaceuticals Ltd Aminomethyl benzene derivatives
US8580841B2 (en) 2008-07-23 2013-11-12 Arena Pharmaceuticals, Inc. Substituted 1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid derivatives useful in the treatment of autoimmune and inflammatory disorders
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US9108969B2 (en) 2008-08-27 2015-08-18 Arena Pharmaceuticals, Inc. Substituted tricyclic acid derivatives as S1P1 receptor agonists useful in the treatment of autoimmune and inflammatory disorders
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WO2010043377A1 (fr) * 2008-10-14 2010-04-22 Almirall, S.A. Nouveaux dérivés de 2-amidothiadiazole
CN102186847A (zh) * 2008-10-14 2011-09-14 奥米罗有限公司 新颖2-酰胺基噻二唑衍生物
US8658675B2 (en) 2009-07-16 2014-02-25 Actelion Pharmaceuticals Ltd. Pyridin-4-yl derivatives
US8399451B2 (en) 2009-08-07 2013-03-19 Bristol-Myers Squibb Company Heterocyclic compounds
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US9085581B2 (en) 2010-03-03 2015-07-21 Arena Pharmaceuticals, Inc. Processes for the preparation of S1P1 receptor modulators and crystalline forms thereof
US8835470B2 (en) 2010-04-23 2014-09-16 Bristol-Myers Squibb Company Mandelamide heterocyclic compounds
US9187437B2 (en) 2010-09-24 2015-11-17 Bristol-Myers Squibb Company Substituted oxadiazole compounds
US8288555B2 (en) 2010-12-03 2012-10-16 Allergan, Inc. Alkene derivatives as sphingosine 1-phosphate (S1P) receptor modulators
WO2012074732A1 (fr) * 2010-12-03 2012-06-07 Allergan, Inc. Nouveaux dérivés d'oxadiazole phénylique utilisés comme modulateurs des récepteurs de la sphingosine 1-phosphate (s1p)
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US8697733B2 (en) 2010-12-03 2014-04-15 Allergan, Inc. Pyridine derivatives as sphingosine 1-phosphate (S1P) receptor modulators
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US8492410B2 (en) 2010-12-03 2013-07-23 Allergan, Inc. Pyridine derivatives as sphingosine 1-phosphate (S1P) receptor modulators
US8486918B2 (en) 2010-12-03 2013-07-16 Allergan, Inc. Phenyl oxadiazole derivatives as sphingosine 1-phosphate (S1P) receptor
WO2012074718A1 (fr) * 2010-12-03 2012-06-07 Allergan, Inc. Nouveaux dérivés d'oxadiazole utilisés comme modulateurs des récepteurs de la sphingosine 1-phosphate (s1p)
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