WO2008097819A2 - Chemical compounds - Google Patents

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WO2008097819A2
WO2008097819A2 PCT/US2008/052735 US2008052735W WO2008097819A2 WO 2008097819 A2 WO2008097819 A2 WO 2008097819A2 US 2008052735 W US2008052735 W US 2008052735W WO 2008097819 A2 WO2008097819 A2 WO 2008097819A2
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alkyl
alkylene
compounds
compound
halogen
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PCT/US2008/052735
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French (fr)
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WO2008097819A3 (en
Inventor
Aaron Coffin
Ghotas Evindar
Gang Yao
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Smithkline Beecham Corporation
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Publication of WO2008097819A3 publication Critical patent/WO2008097819A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/5532—Seven-(or more) membered 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
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/568—Four-membered 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
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered 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
    • C07F9/553—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
    • C07F9/59—Hydrogenated pyridine 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
    • C07F9/6558—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 Sl P-I to S1P-5, 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 hydrogen, halogen, cyano, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroalkyl, -O-alkyl, -O-aryl, -O-heteroaryl, -S-alkyl, alkylene-O-alkyl, alkylene- CO 2 H, alkylene-CO 2 alkyl, alkylSO 2 , alkylenesulfonyl, alkylene-CO-amino, alkylene-CO- alkylamino, alkylene-CO-dialkylamino, alkylene-NH-CO 2 H, alkylene-NH-CO 2 alkyl - ATTORNEY DOCKET NO PPI-305-1
  • A is (Ci-C 2 o)alkylene, (C 2 -C 2 o)alkenylene, or (C 2 -C 2 o)alkynylene, each of which may be optionally substituted on carbon with 1, 2, or 3 groups selected from OH, CO 2 H,
  • ⁇ is phenyl or pyridyl
  • Q is CH 2 , O, CH 2 O, S, -S(O), -S(O) 2 , -C(O)-, CH 2 C(O)-, NR x , or CH 2 NR x , wherein R x is H, (Ci-C 6 )alkyl; R 3 is hydrogen, (C r C 6 )alkyl, aralkyl, heteroalkyl, CO 2 (d-C 6 )alkyl, -C(O)- (d-
  • R 4 is hydrogen, (Ci-C 6 )alkyl which may be optionally substituted on carbon with 1, 2, or 3 groups selected from halo, alkyl, OH, or -O-alkyl;
  • Z' is hydroxyl or halogen
  • Z" is H or halogen
  • R p i and R p2 are each independently hydrogen, Ci-C ⁇ -alkyl, aryl, or one of the following groups:
  • H 2 ;and x, y, and z are each independently an integer selected from 0, 1 , 2, or 3.
  • 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 an compound 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. When a heterocycle contains 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
  • 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- ATTORNEY DOCKET NO.
  • aromatic heterocycles heteroaryl groups
  • heterocycle encompass polycyclic heterocycles, for example, indole, indoline, isoindoline, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, 1 ,4-benzodioxan, coumarin, dihydrocoumarin, benzofuran, 2,3-dihydrobenzofi ⁇ ran, isobenzofliran, 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, be
  • 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 include quinuclidine, diazabicyclo[2.2.1 ]heptane and 7-oxabicyclo[2.2.1 ]heptane.
  • Heterocyclyl includes, for example, monocyclic heterocyclyls, such as: aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl, thiophanyl, piperidinyl, 1 ,2,3,6-tetrahydro-pyridinyl, piperazinyl, morpholinyl, thiomo ⁇ holinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1 ,4-dihydropyridiny
  • 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, ATTOR
  • pteridinyl phenanthridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phe ⁇ oxazinyl, 1 ,2-benzisoxazolyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carboHnyl, acridinyl, pyrolizidinyl, and quinolizidinyl.
  • 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.
  • the term "six-membered" used as prefix refers to a group having a ring that contains six ring atoms.
  • 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- oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1 ,3,4-triazolyl, 1 ,3,4-triazolyl, 1 ,3,4- thiadiazolyl, and 1,3,4- oxadiazolyl.
  • 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.
  • aralkyl refers to an alkyl group substituted with an aryl group.
  • heterooaralkyl 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, and 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, hydro xyl, amino, alkylamino, dialkylamino, or alkoxy, any of which may be substituted as provided by the definition 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), epimers, diastereomers, cis, trans, syn, anti, solvates (including hydrates), tautomers, and mixtures thereof, are contemplated in the compounds of the present invention.
  • 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, naphthalene sulfonic acid, and the like. Also included are 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.
  • a suitable acid such as hydrochloric acid, hydrobromic
  • the invention also includes different crystal forms, hydrates, and solvates of the compounds of the invention.
  • phosphate precursor and "phosphate precursor analog” as used herein, refer to substituent moieties in invention compounds that may be directly phosphorylated in vivo, or which may be cleaved in vivo to reveal a moiety that may then be phosphorylated in vivo.
  • the phosphate precursor may be Li-O-H or Li-O-L 2 , wherein Li is a linking moiety and L 2 is a labile moiety.
  • Exemplary embodiments of the phosphate precursor include but are not limited to -alkyl-OH, -halo-alkyl-OH, alkoxy-OH, -alkyl- ATTORNEY DOCKET NO.
  • R c is selected from the group consisting of hydrogen, straight chain or branched Ci- C ⁇ -alkyl, straight chain or branched halo-Ci-C ⁇ -alkyl, substituted or unsubstituted aryl group, or one of the following groups.
  • linking moiety may contain 1-8 atoms or may be a bond, and serves as the connection point through which the phosphate mimic, phosphate derivative, or phosphate precursor substituent moieties are linked to the remaining structure of the compounds of the invention.
  • the linking moiety may include, but is not limited to, substituted or unsubstituted alkyl (e.g., methylene chains), substituted or unsubstituted alkenyl (e.g.
  • the linking moiety may be carbonyl derivatized.
  • labile moiety refers to a moiety that is subject to cleavage, for instance, by hydrolysis or enzymatic degradation.
  • the labile moiety is an ester moiety, which may result in a carboxylate or hydroxyl derivative, depending on the orientation of the ester functionality in the molecule prior to cleavage.
  • phosphate derivative refers to substituent moieties in invention compounds that contain a phosphate or phosphate ester group.
  • the phosphate derivative may be selected from the group consisting of -(CH 2 ) q OPO 2 R d R e , - (CH 2 ) q OPO 3 R d R e , and -(CH 2 ) q OPO 2 (S)R d R e , wherein q is an integer between 0 and 4; and
  • R d and R e are each independently selected from the group consisting of hydrogen, straight chain or branched Ci-C ⁇ -alkyl, straight chain or branched halo-Ci-Ce-alkyl, substituted or unsubstituted aryl group, and a prodrug derivatizing moiety (PDM).
  • PDM prodrug derivatizing moiety
  • phosphate mimic refers to substituent moieties in invention compounds in which a phosphate substrate has been replaced with a non-hydrolyzable functional group, resulting in a moiety that mimics the biological function of a phosphate or phosphate ester moiety.
  • the phosphate mimic is -Li-Z 2 , wherein Li is a linking moiety and Z 2 is a non-hydrolyzable moiety covalently bonded, to Li.
  • the phosphate mimic is selected from the group consisting of - (CH 2 ) q CH 2 PO 3 R d R e , and -(CH 2 ) q C(Yi)(Y 2 )PO 3 R d R e , wherein q is an integer between 0 and 4;
  • Yi and Y 2 are independently selected from the group consisting of hydrogen, straight chain or branched Ci-C ⁇ -alkyl, all of which may be optionally substituted with OH, halogen, straight chain or branched Ci-C ⁇ -alkoxy, straight chain or branched halo-Ci-C ⁇ -alkyl, straight chain or branched halo-Ci-C 6 -alkoxy, Ci-Q-alkoxy-Ci-CValkyl, hydroxyl-Ci-C ⁇ -alkyl, carboxy-Ci-C ⁇ -alkyl, substituted or unsubstituted C 3 -C 10 carbocyclic rings, and substituted or unsubstituted C 3 -C10 heterocyclic rings, which may contain one or more heteroatoms and may be saturated or unsaturated; and
  • R d and R e are each independently selected from the group consisting of hydrogen, straight chain or branched C]-C 6 -alkyl, straight chain or branched halo-Ci-C 6 -alkyl, substituted or unsubstituted aryl group, and a prodrug derivatizing moiety (PDM).
  • PDM prodrug derivatizing moiety
  • non-hydrolyzable moiety refers to moieties containing bonds, such as carbon-phosphorous bonds, that are not hydrolyzable in vivo.
  • a specific value for Ri is hydrogen. Another specific value for Ri is phenyl.
  • a specific value for A is (C 2 -C 7 )alkylene.
  • a specific value for Xi is a bond. Another specific value for Xi is CH 2 . Another specific value for Xi is O.
  • R' and R" independently are hydrogen.
  • a specific value for R2 is cyano, halo or trifluoroalkyl.
  • a specific value for is phenyl. Another specific value for is pyridyl;
  • a specific value for Q is O.
  • a specific value for R3 is hydrogen.
  • Another specific value for R3 is (Ci-C6)alkyl such as methyl or ethyl.
  • a specific value for R 4 is hydrogen.
  • a specific value for R 5 is -OH. Another specific value for R 5 is -CO 2 H. Another specific value for R 5 is -OPO 2 H 2 .
  • the compounds of the present invention include a selectivity enhancing moiety.
  • SEM selectivity enhancing moiety
  • the SEM confers selectivity to the compound to which it is attached for the S 1 Pl receptor as compared to, for example, the S 1 P2 to S 1 P5 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 SlPl receptor and one or more of the other SlP 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 and R 3 .
  • the SEM is a halo-substituted alkyl group such as CF3, CF2CF3, 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 selective enhancing orientation
  • SEM selective enhancing orientation
  • SEM selective 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 Xi in Formula I. In another specific embodiment, the SEM is in the meta position relative to Xi.
  • a specific group of compounds of the invention are compounds of formula 1-1.
  • Another specific group of compounds of the invention are compounds of formula 1-2.
  • Another specific group of compounds of the invention are compounds of formula 1-3. or a pharmaceutically acceptable salt thereof.
  • Another specific group of compounds of the invention are compounds of formula 1-4. or a pharmaceutically acceptable salt thereof.
  • Another specific group of compounds of the invention are compounds of formula 1-5. or a pharmaceutically acceptable salt thereof.
  • Another specific group of compounds of the invention are compounds of formula 1-6. or a pharmaceutically acceptable salt thereof.
  • Another specific group of compounds of the invention are compounds of formula 1-7.
  • Another specific group of compounds of the invention are compounds of formula 1-8.
  • Another specific group of compounds of the invention are compounds of formula 1-9.
  • Another specific group of compounds of the invention are compounds of formula I- 10.
  • compounds of the invention include compounds listed in the "Summary of the Invention".
  • the compounds of the invention do not include the compounds described in WO 05/041899, WO 04/010949, WO 04/02463, WO 06/020951 , and USSN 11/349069, the latter two of which are assigned to the same assignee as the present application.
  • 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 SlP-I receptor as compared to one or more of the other SlP receptors.
  • one set of compounds includes compounds which are selective for the SlP-I receptor relative to the S1 P-3 receptor.
  • Compounds selective for the S lP-I receptor can be agonists of the SlP-I 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 lP-I receptor relative to a second receptor, if the EC 50 of the compound for the second receptor is at least two-fold greater than the EC 5 0 for the SlPl receptor.
  • the EC 5 0 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 SlP-I receptor relative to a second receptor, if the IC50 of the compound for the second receptor is at least two-fold greater than the IC 5 0 for the SlP-I receptor.
  • the IC50 of a compound is determined using the [ 33 P]sphingosine 1 -phosphate binding assay, as described in Davis, M.D. et al, Sphingosine 1 -Phosphate Analogs as Receptor Antagonists. J. Biol. Chem.
  • the terms "agonist” or "SlP-I receptor agonist” as used herein include the compounds described herein which bind to and/or agonize the SlP-I receptor.
  • the SlP receptor agonists have an IC 50 for the SlP-I 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, ATTORNEY DOCKET NO.
  • IC 5 0 for the SlP-I 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 IC 50 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. For example, ranges using a combination of any of the above recited values as upper and/or lower limits are intended to be included.
  • the S IP receptor agonist has an IC50 value for the S1P-3 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 SlP compound of the invention binds the S1P-3 receptor with an IC50 of 1000 nM or greater, 2000 nM or greater, 3000 nM or greater, 5000 nM or greater, 10,000 nM or greater.
  • the IC 50 for of SlP- 3 receptor can be measured using the binding assays described herein or those described in WO 03/061567.
  • the S lP receptor agonists described herein have an IC50 value for the SlP-I 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 S1P-3 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 0 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 mM PMSF) containing 10% sucrose on ice, and disrupted using a Dounce homogenizer. After ATTORNEY DOCKET NO. PPI-305-1
  • [ 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 MgC12, 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 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 Sl P 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 sphingosine 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. determined in a cell or organism, e.g.
  • a control or normal cell or organism exhibiting, for example, normal traits.
  • 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 SlP 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 1 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-VIII or compounds otherwise described herein, such that the subject is selectively treated for a sphingosine 1- ATTORNEY DOCKET NO. PPI-305-1
  • the sphingosine 1 -phosphate associated disorder is a sphingosine l-phosphate-(l ) associated disorder.
  • the sphingosine l-phos ⁇ hate-(l) associated disorder is selectively treated as compared with a sphingosine l-phos ⁇ hate-(3) associated disorder.
  • Another embodiment of the invention is a method of selectively treating a sphingosine
  • the sphingosine 1 -phosphate associated disorder comprising administering to a subject a compound, such that the subject is selectively treated for a sphingosine 1 -phosphate associated disorder by a compound of the invention, or compounds otherwise described herein.
  • the sphingosine 1 -phosphate associated disorder is a sphingosine 1-phosphate- (1) associated disorder.
  • the sphingosine l-phosphate-(l) associated disorder is selectively treated as compared with a sphingosine 1 - ⁇ hosphate-(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 herein), to a subject by any suitable route for delivery of the compound to the desired location ATTORNEY DOCKET NO. PPI-305-1
  • 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 0.001 to 30 mg/kg body weight, for example, about 0.01 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, cyclooxygenase-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, Medical Economics Co., the complete contents of which are expressly incorporated herein by ATTORNEY DOCKET NO. PPI-305-1
  • 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 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 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 ATTORNEY DOCKET NO. PPI-305-1
  • 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 (e.g., inhalation), 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.
  • 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
  • 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, N.J.) or phosphate buffered saline (PBS).
  • the pharmaceutical composition must be sterile and should be fluid to the extent that easy syringability exists. It must also be stable ATTORNEY DOCKET NO. PPI-305-1
  • 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. For the purpose of oral therapeutic administration, 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 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 ATTORNEY DOCKET NO. PPI-305-1
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a 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
  • sucrose or saccharin such as sucrose or saccharin
  • a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • the compounds of the invention are delivered in the form of an aerosol spray from a pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
  • 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.
  • 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.
  • suppositories e.g. , with conventional suppository bases such as cocoa butter and other glycerides
  • 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. 4,522,811, 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.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of a compound of the invention ATTORNEY DOCKET NO. PPI-305-1
  • the alcohol 5 was treated with a solution of 10-50 % trifluoroacetic acid in dichloromethane and anisole (0.01 equivalents) as scavenger. The reaction was allowed to stir at rt for 3-6 hours and the solvent was removed in vacuo to give crude pyrrolidine-alcohol 6.
  • the product 6 was purified by prep HPLC on a C8(2) column ((Luna, 5 ⁇ , 100 x 21.10 mm) with acetonitrile-H 2 O (0.1% TFA) as mobile phase and gradient 30-98% in 20 min.

Abstract

The invention provides compounds formula I, their preparation, and their use as pharmaceutically active immunosuppressive agents for the treatment of autoimmune disorders, organ transplant rejection, disorders associated with an activated immune system, as well as other disorders modulated by lymphopenia or SlP receptors.

Description

ATTORNEY DOCKET NO. PPI-305-1
CHEMICAL COMPOUNDS
BACKGROUND OF THE INVENTION
The sphingosine-1 -phosphate (SlP) receptors 1-5 constitute a family of seven transmembrane G-protein coupled receptors. These receptors, referred to as Sl P-I to S1P-5, 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.
Administration of SlP to an animal results in sequestration of lymphocytes into the lymph nodes and Peyers patches without causing lymphocyte depletion. This activity, which is of potential utility in treating diseases or conditions associated with inappropriate immune response, including transplant rejection, autoimmune diseases, as well as other disorders modulated by lymphocyte trafficking, is believed to proceed via activation of the SlP-I receptor. Administration of SlP in vivo has been shown to cause hypotension and bradycardia, which are believed to be due to signaling through one or more of the other SlP receptors, i.e. S1P-2 to S1P-5. Accordingly, there is a need for compounds which are potent and selective agonists of the SlP-I receptor.
SUMMARY OF THE INVENTION
These and other needs are met by the present invention which is directed to a compound of formula I
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof, wherein:
Ri is hydrogen, halogen, cyano, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroalkyl, -O-alkyl, -O-aryl, -O-heteroaryl, -S-alkyl, alkylene-O-alkyl, alkylene- CO2H, alkylene-CO2alkyl, alkylSO2, alkylenesulfonyl, alkylene-CO-amino, alkylene-CO- alkylamino, alkylene-CO-dialkylamino, alkylene-NH-CO2H, alkylene-NH-CO2alkyl - ATTORNEY DOCKET NO PPI-305-1
CO2alkyl, -OH, -C(O)-alkyl, -C(0)O-alkyl, -CONH2, -CO-alkylamino, -CO-dialkylamino, amino, alkylamino, or dialkylamino, any of which may be optionally substituted on carbon with 1 , 2, or 3 groups selected from halo, alkyl, OH, or -O-alkyl;
A is (Ci-C2o)alkylene, (C2-C2o)alkenylene, or (C2-C2o)alkynylene, each of which may be optionally substituted on carbon with 1, 2, or 3 groups selected from OH, CO2H,
CO2alkyl, halogen, amino, alkylamino, dialkylamino, -O-alkyl, alkylene-O-alkyl, alkylene- OH, or alkylene-CO2H;
Xi is a bond or is CH2, O, -CH2O-, S, -S(O), -S(O)2, -C(O)-, -C(O)O-, or NRx, wherein Rx is H or (Ci-C6)alkyl; R' and R" are each independently hydrogen, halogen, alkyl optionally substituted on carbon with halogen, alkyl, or taken together with the carbon to which they are attached form C=O or a 3, 4, 5,or 6-membered ring, optionally containing 1 or 2 heteroatoms selected from O NH, N-alkyl, SO, or SO2, any of which may be optionally substituted on carbon with alkyl or halogen; R2 is cyano, halogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroalkyl, -O-alkyl, -O-aryl, -O-heteroaryl, aralkoxy, heteroaralkoxy, -S-alkyl, alkylene-O- alkyl, alkylene-CO2H, alkylene-CO2alkyl, alkylSO2, alkylenesulfonyl, alkylene-CO-amino, alkylene-CO-alkylamino, alkylene-CO-dialkylamino, alkylene-NH-CO2H, alkylene-NH- C02alkyl -CO2alkyl, -OH, -C(O)-alkyl, -C(O)O-alkyl, -CONH2, -CO-alkylamino, -CO- dialkylamino, amino, alkylamino, and dialkylamino, any of which may be optionally substituted on carbon with 1 , 2, or 3 groups selected from halo, alkyl, OH, or -O-alkyl;
^^ is phenyl or pyridyl;
Q is CH2, O, CH2O, S, -S(O), -S(O)2, -C(O)-, CH2C(O)-, NRx, or CH2NRx, wherein Rx is H, (Ci-C6)alkyl; R3 is hydrogen, (CrC6)alkyl, aralkyl, heteroalkyl, CO2(d-C6)alkyl, -C(O)- (d-
C6)alkyl, -C(O)O-alkyl, -CONH2, -CO-alkylamino, -CO-dialkylamino, any of which may be optionally substituted on carbon with 1, 2, or 3 groups selected from halo, alkyl, OH, or -O- alkyl;
R4 is hydrogen, (Ci-C6)alkyl which may be optionally substituted on carbon with 1, 2, or 3 groups selected from halo, alkyl, OH, or -O-alkyl; and
R5 is selected from the group consisting of -OH, alkylene-OH, -CO2H, alkylene- CO2H, - alkylene-CO2-alkyl, -CH2=CHCO2H, -CH2=CHC(O)O-alkyl, -CH2=CHC(O)O-aryl, ATTORNEY DOCKET NO. PPI-305-1
-OPO2RpiRP2, -OPO3RpiRP2, -CH2PO3RpiRP2, -OPO2(S)Rp, R p2, and -C(Z')(Z")PO3RPiRP2, any of which may be optionally substituted on carbon with halogen, alkyl, hydroxyl, carboxy, or alkoxy; and wherein
Z' is hydroxyl or halogen;
Z" is H or halogen;
Rpi and Rp2 are each independently hydrogen, Ci-Cβ-alkyl, aryl, or one of the following groups:
Figure imgf000005_0001
-NH2
-CH2- -NH
I— CHo X vc' -N:
H2 ;and x, y, and z are each independently an integer selected from 0, 1 , 2, or 3.
What is also provided is a compound which is:
Figure imgf000005_0002
ATTORNEY DOCKET NO. PPI-305-1
Figure imgf000006_0001
ATTORNEY DOCKET NO. PPI-305-1
Figure imgf000007_0001
ATTORNEY DOCKET NO. PPI-305-1
Figure imgf000008_0001
ATTORNEY DOCKET NO. PPI-305-1
Figure imgf000009_0001
ATTORNEY DOCKET NO. PPI-305-1
Figure imgf000010_0001
ATTORNEY DOCKET NO. PPI-305-1
Figure imgf000011_0001
as well as pharmaceutically acceptable salts, phosphate derivatives, phosphate mimics, or phosphate precursor analogs thereof.
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 an compound as provided herein.
DETAILED DESCRIPTION OF THE INVENTION Definitions
The following definitions are used, unless otherwise described.
"Halogen" or "halo" means fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
The term "hydrocarbon" used alone or as a suffix or prefix, refers to any structure comprising only carbon and hydrogen atoms up to 14 carbon atoms. The term "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.
The term "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. ATTORNEY DOCKET NO. PPI-305-1
The term "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.
The term "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.
The term "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. The term "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. When a heterocycle contains 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.
The terms "heterocyclic group", "heterocyclic moiety", "heterocyclic", or "heterocyclo" used alone or as a suffix or prefix, refers to a radical derived from a heterocycle by removing one or more hydrogens therefrom.
The term "heterocyclyl" used alone or as a suffix or prefix, refers a monovalent radical derived from a heterocycle by removing one hydrogen therefrom.
The term "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-azepine homopiperazine, 1 ,3-dioxepane, 4,7-dihydro-l ,3-dioxeρin, and hexamethylene oxide.
In addition, 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- ATTORNEY DOCKET NO. PPI-305-1
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.
Additionally, heterocycle encompass polycyclic heterocycles, for example, indole, indoline, isoindoline, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, 1 ,4-benzodioxan, coumarin, dihydrocoumarin, benzofuran, 2,3-dihydrobenzofiιran, isobenzofliran, 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, benzthiazole, benzimidazole, benztriazole, thioxanthine, carbazole, carboline, acridine, pyrolizidine, and quinolizidine.
In addition to the polycyclic heterocycles described above, 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. Examples of such bridged heterocycles include quinuclidine, diazabicyclo[2.2.1 ]heptane and 7-oxabicyclo[2.2.1 ]heptane.
Heterocyclyl includes, for example, monocyclic heterocyclyls, such as: aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl, thiophanyl, piperidinyl, 1 ,2,3,6-tetrahydro-pyridinyl, piperazinyl, morpholinyl, thiomoφholinyl, 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-dioxepanyl, 4,7-dihydro-l,3-dioxepinyl, and hexamethylene oxidyl.
In addition, 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.
Additionally, 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, ATTORNEY DOCKET NO. PPI-305-1
pteridinyl, phenanthridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, pheπoxazinyl, 1 ,2-benzisoxazolyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carboHnyl, acridinyl, pyrolizidinyl, and quinolizidinyl. In addition to the polycyclic heterocyclyls described above, 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. Examples of such bridged heterocycles include quinuclidinyl, diazabicyclo[2.2.1]heptyl; and 7-oxabicyclo[2.2.1 ]heptyl. The term "six-membered" used as prefix refers to a group having a ring that contains six ring atoms.
The term "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- 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. 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. The term "aralkyl" refers to an alkyl group substituted with an aryl group. The term "heteroaralkyl" refers to an alkyl group substituted with an heteroaryl group. Unless otherwise specified, the term "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. Exemplary chemical groups containing one or more heteroatoms include heterocyclyl, -NO2, -O-alkyl, halo, -CF3, -CO2H, -CO2R, -NH2, -SH, - NHR, -NR2, -SR, -SO3H, -SO2R, -S(O)R, -CN, -OH, -C(O)NR2, -NRC(O)R, oxo (=0), imino (=NR), thio (=S), and oximino (=N-OR), wherein each "R" is alkyl as defined above. For example, substituted phenyl may refer to nitrophenyl, pyridylphenyl, methoxyphenyl, chlorophenyl, aminophenyl, and so on, wherein the nitro, pyridyl, methoxy, chloro, and amino groups may replace any suitable hvdrogen on the phenyl ring. ATTORNEY DOCKET NO. PPI-305-1
The term "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.
The term "amine" or "amino" used alone or as a suffix or prefix, refers -NH2. The term "alkylamino" used alone or as a suffix or prefix, refers — NH(alkyl).
The term "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, hydro xyl, amino, alkylamino, dialkylamino, or alkoxy, any of which may be substituted as provided by the definition 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), epimers, diastereomers, cis, trans, syn, anti, solvates (including hydrates), tautomers, and mixtures thereof, are contemplated in the compounds of the present invention. 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, naphthalene sulfonic acid, and the like. Also included are 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.
The terms "phosphate precursor" and "phosphate precursor analog" as used herein, refer to substituent moieties in invention compounds that may be directly phosphorylated in vivo, or which may be cleaved in vivo to reveal a moiety that may then be phosphorylated in vivo. In certain embodiments, the phosphate precursor may be Li-O-H or Li-O-L2, wherein Li is a linking moiety and L2 is a labile moiety. Exemplary embodiments of the phosphate precursor, include but are not limited to -alkyl-OH, -halo-alkyl-OH, alkoxy-OH, -alkyl- ATTORNEY DOCKET NO. PPI-305-1
OCORa, -halo-alkyl-OCORa, -alkoxy-OCOR\ -alkyl-OC(O)NRa Rb, -halo-alkyl- OC(O)NHR3 Rb, -alkoxy-OC(O)NRaRb, -(CH2)qCO2Rc, and -(CH2)nCH2=CHC(O)ORc, wherein q is an integer between 0 and 4; Ra and Rb are independently selected from the group consisting of hydrogen, straight chain or branched Ci-C6-alkyl, all of which may be optionally substituted with OH, halogen, straight chain or branched Ci-Q-alkoxy, straight chain or branched halo-Ci-Cβ-alkyl, straight chain or branched halo-Ci-Cβ-alkoxy, Ci-Cβ-alkoxy-d-Cβ-alkyl, hydroxyl-Ci-Cβ-alkyl, carboxy-Ci-Cβ-alkyl, substituted or unsubstituted C3-C10 carbocyclic rings, and substituted or unsubstituted C3-C10 heterocyclic rings, which may contain one or more heteroatoms and may be saturated or unsaturated; and
Rc is selected from the group consisting of hydrogen, straight chain or branched Ci- Cβ-alkyl, straight chain or branched halo-Ci-Cδ-alkyl, substituted or unsubstituted aryl group, or one of the following groups.
Figure imgf000016_0001
The "linking moiety," may contain 1-8 atoms or may be a bond, and serves as the connection point through which the phosphate mimic, phosphate derivative, or phosphate precursor substituent moieties are linked to the remaining structure of the compounds of the invention. In certain embodiments, the linking moiety may include, but is not limited to, substituted or unsubstituted alkyl (e.g., methylene chains), substituted or unsubstituted alkenyl (e.g. , n-alkenes), substituted or unsubstituted alkynyl, substituted or unsubstituted halo-alkyl, substituted or unsubstituted alkoxy, and substituted or unsubstituted halo-alkoxy. In specific embodiments, the linking moiety may be carbonyl derivatized. ATTORNEY DOCKET NO. PPI-305-1
The language "labile moiety" refers to a moiety that is subject to cleavage, for instance, by hydrolysis or enzymatic degradation. In certain embodiments, the labile moiety is an ester moiety, which may result in a carboxylate or hydroxyl derivative, depending on the orientation of the ester functionality in the molecule prior to cleavage. The term "phosphate derivative" refers to substituent moieties in invention compounds that contain a phosphate or phosphate ester group. When a compound of the invention containing a phosphate derivative is administered to a subject, the compound may act as is in vivo or the phosphate derivative (within the compound) may be cleaved and then re-phosphorylated in vivo leading to an active compound. In certain embodiments, the phosphate derivative may be selected from the group consisting of -(CH2 )q OPO2RdRe, - (CH2)qOPO3RdRe, and -(CH2)qOPO2(S)RdRe, wherein q is an integer between 0 and 4; and
Rd and Re are each independently selected from the group consisting of hydrogen, straight chain or branched Ci-Cδ-alkyl, straight chain or branched halo-Ci-Ce-alkyl, substituted or unsubstituted aryl group, and a prodrug derivatizing moiety (PDM).
The term "phosphate mimic" refers to substituent moieties in invention compounds in which a phosphate substrate has been replaced with a non-hydrolyzable functional group, resulting in a moiety that mimics the biological function of a phosphate or phosphate ester moiety. In certain embodiments, the phosphate mimic is -Li-Z2, wherein Li is a linking moiety and Z2 is a non-hydrolyzable moiety covalently bonded, to Li. In certain embodiments, the phosphate mimic is selected from the group consisting of - (CH2)qCH2PO3RdRe, and -(CH2)qC(Yi)(Y2)PO3RdRe, wherein q is an integer between 0 and 4;
Yi and Y2 are independently selected from the group consisting of hydrogen, straight chain or branched Ci-Cβ-alkyl, all of which may be optionally substituted with OH, halogen, straight chain or branched Ci-Cβ-alkoxy, straight chain or branched halo-Ci-Cβ-alkyl, straight chain or branched halo-Ci-C6-alkoxy, Ci-Q-alkoxy-Ci-CValkyl, hydroxyl-Ci-Cβ-alkyl, carboxy-Ci-Cβ-alkyl, substituted or unsubstituted C3-C10 carbocyclic rings, and substituted or unsubstituted C3-C10 heterocyclic rings, which may contain one or more heteroatoms and may be saturated or unsaturated; and
Rd and Re are each independently selected from the group consisting of hydrogen, straight chain or branched C]-C6-alkyl, straight chain or branched halo-Ci-C6-alkyl, substituted or unsubstituted aryl group, and a prodrug derivatizing moiety (PDM). ATTORNEY DOCKET NO. PPI-305-1
The language "non-hydrolyzable moiety" is art-recognized, and refers to moieties containing bonds, such as carbon-phosphorous bonds, that are not hydrolyzable in vivo.
Invention Compounds We turn now to a compound of formula I, wherein the variables are as defined in the
"Summary of the Invention."
Figure imgf000018_0001
or a pharmaceutically acceptable salt thereof, wherein: A specific value for Ri is hydrogen. Another specific value for Ri is phenyl.
A specific value for A is (C2-C7)alkylene.
A specific value for Xi is a bond. Another specific value for Xi is CH2. Another specific value for Xi is O.
Specific values for R' and R" independently are hydrogen. A specific value for R2 is cyano, halo or trifluoroalkyl.
A specific value for
Figure imgf000018_0002
is phenyl. Another specific value for is pyridyl;
A specific value for Q is O.
A specific value for R3 is hydrogen. Another specific value for R3 is (Ci-C6)alkyl such as methyl or ethyl. A specific value for R4 is hydrogen.
A specific value for R5 is -OH. Another specific value for R5 is -CO2H. Another specific value for R5 is -OPO2H2.
A specific value for x, y, and z each independently is an integer selected from 0, 1, 2, or 3. The compounds of the present invention include a selectivity enhancing moiety. The term "selectivity enhancing moiety (SEM)" is defined in United States Application Ser. No. 11/349069 filed on February 9, 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 ATTORNEY DOCKET NO. PPI-305-1
moieties. The SEM confers selectivity to the compound to which it is attached for the S 1 Pl receptor as compared to, for example, the S 1 P2 to S 1 P5 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 SlPl receptor and one or more of the other SlP 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 R2 and R3.
More specifically, the SEM is a halo-substituted alkyl group such as CF3, CF2CF3, CF2CF2CF3, CFHCF3, CH2CF3, CH2CH2CF3, CHCl2, or CH2Cl. In certain embodiments, the SEM may possess a selectivity enhancing orientation
(SEO). The term "selectivity enhancing orientation" or "SEO," is defined in United States Application Ser. No. 11/349069 filed on February 9, 2006 which is assigned to the assignee of the present application, the contents of which are incorporated herein by reference and as used herein 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. In particular, 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
A the same ring. In one embodiment, the SEM on ""-"" is in the ortho position relative to Xi in Formula I. In another specific embodiment, the SEM is in the meta position relative to Xi.
A specific group of compounds of the invention are compounds of formula 1-1.
Figure imgf000019_0001
or a pharmaceutically acceptable salt thereof. Another specific group of compounds of the invention are compounds of formula 1-2.
Figure imgf000019_0002
or a pharmaceutically acceptable salt thereof. ATTORNEY DOCKET NO. PPI-305-1
Another specific group of compounds of the invention are compounds of formula 1-3.
Figure imgf000020_0001
or a pharmaceutically acceptable salt thereof.
Another specific group of compounds of the invention are compounds of formula 1-4.
Figure imgf000020_0002
or a pharmaceutically acceptable salt thereof.
Another specific group of compounds of the invention are compounds of formula 1-5.
Figure imgf000020_0003
or a pharmaceutically acceptable salt thereof.
Another specific group of compounds of the invention are compounds of formula 1-6.
Figure imgf000020_0004
or a pharmaceutically acceptable salt thereof.
Another specific group of compounds of the invention are compounds of formula 1-7.
Figure imgf000020_0005
1-7 ATTORNEY DOCKET NO. PPI-305-1
or a pharmaceutically acceptable salt thereof.
Another specific group of compounds of the invention are compounds of formula 1-8.
Figure imgf000021_0001
or a pharmaceutically acceptable salt thereof.
Another specific group of compounds of the invention are compounds of formula 1-9.
Figure imgf000021_0002
or a pharmaceutically acceptable salt thereof.
Another specific group of compounds of the invention are compounds of formula I- 10.
Figure imgf000021_0003
or a pharmaceutically acceptable salt thereof.
In some embodiments, compounds of the invention include compounds listed in the "Summary of the Invention".
In one embodiment, the compounds of the invention do not include the compounds described in WO 05/041899, WO 04/010949, WO 04/02463, WO 06/020951 , and USSN 11/349069, the latter two of which are assigned to the same assignee as the present application. ATTORNEY DOCKET NO. PPI-305-1
Biological Activity of Invention Compounds Lymphopenia Assay
Several of the compounds described herein were evaluated for the ability to induce lymphopenia in 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 μL 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.
Binding to SlPl or S1P3 Receptors
In certain embodiments, the compounds of the invention selective for the SlP-I receptor as compared to one or more of the other SlP receptors. For example, one set of compounds includes compounds which are selective for the SlP-I receptor relative to the S1 P-3 receptor. Compounds selective for the S lP-I receptor can be agonists of the SlP-I 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 lP-I 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 35S-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 SlP-I receptor relative to a second receptor, if the IC50 of the compound for the second receptor is at least two-fold greater than the IC50 for the SlP-I receptor. The IC50 of a compound is determined using the [33P]sphingosine 1 -phosphate binding assay, as described in Davis, M.D. et al, Sphingosine 1 -Phosphate Analogs as Receptor Antagonists. J. Biol. Chem. (2005) 280:9833-9841, the entire contents of which are incorporated herein by this reference. The terms "agonist" or "SlP-I receptor agonist" as used herein include the compounds described herein which bind to and/or agonize the SlP-I receptor. In one embodiment, the SlP receptor agonists have an IC50 for the SlP-I 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, ATTORNEY DOCKET NO. PPI-305-1
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' IC50 for the SlP-I 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. For example, ranges using a combination of any of the above recited values as upper and/or lower limits are intended to be included.
In a further embodiment, the S IP receptor agonist has an IC50 value for the S1P-3 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. In another embodiment, the SlP compound of the invention binds the S1P-3 receptor with an IC50 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 SlP- 3 receptor can be measured using the binding assays described herein or those described in WO 03/061567.
In addition, it should be understood that the ranges intermediate to the above recited values are also intended to be part of this invention. For example, ranges using a combination of any of the above recited values as upper and/or lower limits are intended to be included.
In yet another embodiment, the S lP receptor agonists described herein have an IC50 value for the SlP-I 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 IC50 value for the S1P-3 receptor.
Ranges intermediate to the above recited values are also intended to be part of this invention. For example, ranges using a combination of any of the above recited values as upper and/or lower limits are intended to be included.
The ability of several of the compounds described herein to bind to the SlP-I or SlP- 3 receptor was also tested as follows.
For the membrane preparation, 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% CO2, 370C). The cells were harvested 48 hours after addition of the DNA by scraping in HME buffer (in mM: 20 HEPES, 5 MgCl2, 1 EDTA, pH 7.4, 1 mM PMSF) containing 10% sucrose on ice, and disrupted using a Dounce homogenizer. After ATTORNEY DOCKET NO. PPI-305-1
centrifligation at 800 g, the supernatant was diluted with HME without sucrose and centrifuged at 17,000 g for 1 hour. This crude membrane pellet was resuspended in HME with sucrose, aliquoted, and snap-frozen by immersion in liquid nitrogen. The membranes were stored at -70 C. Protein concentration was determined spectroscopically by Bradford protein assay.
For the binding assay, [33P]sphingosine 1-phosphate (obtained from American Radiolabeled Chemicals, Inc) was added to membranes in 200 μl in 96-well plates with assay concentrations of 2.5 pM [33P]sphingosine 1-phosphate, 4 mg/ml BSA, 50 mM HEPES, pH 7.5, 100 mM NaCl, 5 mM MgC12, and 5 μg 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. After drying the filter plates for 10 minutes, 50 μl of Microscint40 was added to each well, and filter-bound radionuclide was measured on a Packard Top Count. Nonspecific binding was defined as the amount of radioactivity remaining in the presence of excess of unlabeled SlP.
Binding activity for two of the invention compounds is as follows:
Figure imgf000024_0001
C OH SlPl = 900 ΠM, S1P3 = >10 000 nM
Figure imgf000024_0002
SlPl = 138 nM, S1P3 = 3000 nM
Methods of Using Invention Compounds
The compounds of the invention have been determined to be useful in the treatment of sphingosine 1-phosphate associated disorders. Accordingly, in one embodiment, 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. ATTORNEY DOCKET NO. PPI-305-1
The term "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 Sl P 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", or "treating" as used herein, is defined as the application or administration of a therapeutic agent such as a compound of formula I to a subject who has a sphingosine 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. The term "treatment" or "treating" is also used herein in the context of administering agents prophylactically.
In some embodiments, 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. In one embodiment, a "suitable control" is a value, level, feature, characteristic, property, etc. determined prior to administering a composition of the present invention. For example, the immune response, etc. can be determined prior to introducing a compound of the invention into a cell or subject. In another embodiment, a "suitable control" is a value, level, feature, characteristic, property, etc. determined in a cell or organism, e.g. , a control or normal cell or organism, exhibiting, for example, normal traits. In yet another embodiment, a "suitable control" is a predefined value, level, feature, characteristic, property, etc. For example a "suitable control" can be a pre-defined level of binding to a specified SlP 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 1 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-VIII or compounds otherwise described herein, such that the subject is selectively treated for a sphingosine 1- ATTORNEY DOCKET NO. PPI-305-1
phosphate associated disorder. In certain embodiments, the sphingosine 1 -phosphate associated disorder is a sphingosine l-phosphate-(l ) associated disorder. In a particular embodiment, the sphingosine l-phosρhate-(l) associated disorder is selectively treated as compared with a sphingosine l-phosρhate-(3) associated disorder. Another embodiment of the invention is a method of selectively treating a sphingosine
1 -phosphate associated disorder, comprising administering to a subject a compound, such that the subject is selectively treated for a sphingosine 1 -phosphate associated disorder by a compound of the invention, or compounds otherwise described herein. In certain embodiments, the sphingosine 1 -phosphate associated disorder is a sphingosine 1-phosphate- (1) associated disorder. In a particular embodiment, the sphingosine l-phosphate-(l) associated disorder is selectively treated as compared with a sphingosine 1 -ρhosphate-(3) associated disorder.
In another embodiment, the present invention provides a method of treating a condition associated with an activated immune system. Such 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; psoriasis; psoriatic arthritis; atopic dermatitis; myopathy; myositis; osteomyelitis; contact dermatitis; eczematous dermatitis; seborrhoeic dermatitis; lichen plan us; pemph igus; bullous pemphigoid; epidermolysis bullosa; urticaria; angioedema; vasculitis; erythema; cutaneous eosinophilia; acne; scleroderma; alopecia areata; keratoconjunctivitis; vernal conjunctivitis; keratitis; herpetic keratitis; dystrophia epithelialis corneas; corneal leukoma; ocular pemphigus; Mooren's ulcer; ulcerative keratitis; scleritis; Graves' ophthalmopathy; Vogt-Koyanagi- Harada syndrome; sarcoidosis; pollen allergies; reversible obstructive airway disease; bronchial asthma; allergic asthma; intrinsic asthma; extrinsic asthma; dust asthma; chronic or inveterate asthma; late asthma and airway hyper-responsiveness; bronchiolitis; bronchitis; endometriosis; orchitis; gastric ulcers; ischemic bowel diseases; inflammatory bowel diseases; necrotizing enterocolitis; intestinal lesions associated with thermal burns; coeliac disease; proctitis; eosinophilic gastroenteritis; mastocytosis; Crohn's disease; ulcerative ATTORNEY DOCKET NO. PPI-305-1
colitis; vascular damage caused by ischemic diseases and thrombosis; atherosclerosis; fatty heart; myocarditis; cardiac infarction; aortitis syndrome; cachexia due to viral disease; vascular thrombosis; migraine; rhinitis; eczema; interstitial nephritis; IgA-induced nephropathy; Goodpasture's syndrome; hemolytic- uremic syndrome; diabetic nephropathy; glomerulosclerosis; glomerulonephritis; tubulointerstitial nephritis; interstitial cystitis; multiple myositis; Guillain-Barre syndrome; Meniere's disease; polyneuritis; multiple neuritis; myelitis; mononeuritis; radiculopathy; hyperthyroidism; Basedow's disease; thyrotoxicosis; pure red cell aplasia; aplastic anemia; hypoplastic anemia; idiopathic thrombocytopenic purpura; autoimmune hemolytic anemia; autoimmune thrombocytopenia; agranulocytosis; pernicious anemia; megaloblastic anemia; anerythroplasia; osteoporosis; fibroid lung; idiopathic interstitial pneumonia; dermatomyositis; leukoderma vulgaris; ichthyosis vulgaris; photoallergy sensitivity; cutaneous T cell lymphoma; polyarteritis nodosa; Huntington's chorea; Sydenham's chorea; myocardosis; myocarditis; scleroderma; Wegener's granuloma; Sjogren's syndrome; adiposis; eosinophilic fascitis; lesions of gingiva, periodontium, alveolar bone, substantia ossea dentis; male pattern alopecia or alopecia senilis; muscular dystrophy; pyoderma; Sezar/s syndrome; hypophysitis; chronic adrenal insufficiency; Addison's disease; ischemia-reperfusion injury of organs which occurs upon preservation; endotoxin shock; pseudomembranous colitis; colitis caused by drug or radiation; ischemic acute renal insufficiency, chronic renal insufficiency; lung solid cancer; malignancy of lymphoid origin; acute or chronic lymphocytic leukemias; lymphoma; psoriasis; pulmonary emphysema; cataracts; siderosis; retinitis pigmentosa; senile macular degeneration; vitreal scarring; corneal alkali burn; dermatitis erythema; ballous dermatitis; cement dermatitis; gingivitis; periodontitis; sepsis; pancreatitis; peripheral artery disease; carcinogenesis; solid cancer tumors; metastasis of carcinoma; hypobaropathy; autoimmune hepatitis; primary biliary cirrhosis; sclerosing cholangitis; partial liver resection; acute liver necrosis; cirrhosis; alcoholic cirrhosis; hepatic failure; fulminant hepatic failure; late-onset hepatic failure; "acute-on-chronic" liver failure.
As used herein, 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. In a particular embodiment, the subject is a primate. In a specific embodiment, the primate is a human.
As used herein, the term "administering" to a subject includes dispensing, delivering or applying a compound of the invention in a pharmaceutical formulation (as described herein), to a subject by any suitable route for delivery of the compound to the desired location ATTORNEY DOCKET NO. PPI-305-1
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. As used herein, 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 (i.e., an effective dosage) may range from about 0.001 to 30 mg/kg body weight, for example, about 0.01 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. It will also be appreciated that 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, cyclooxygenase-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, Medical Economics Co., the complete contents of which are expressly incorporated herein by ATTORNEY DOCKET NO. PPI-305-1
reference. 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).
Pharmaceutical Compositions Comprising Invention Compounds
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. In certain embodiments, 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.
Accordingly, in one embodiment, the invention pertains to 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. In another embodiment, the invention is directed to 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. For example, in one embodiment, the container is the packaging that contains the pharmaceutical composition. In other embodiments, 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. Moreover, 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 comprising a container holding a therapeutically effective amount of a ATTORNEY DOCKET NO. PPI-305-1
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. As used herein, "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. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), 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. Pharmaceutical 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. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor El™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the pharmaceutical composition must be sterile and should be fluid to the extent that easy syringability exists. It must also be stable ATTORNEY DOCKET NO. PPI-305-1
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. In many cases, it will be preferable to include 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. Generally, 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. In the case of sterile powders for the preparation of sterile injectable solutions, 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. For the purpose of oral therapeutic administration, 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 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 ATTORNEY DOCKET NO. PPI-305-1
agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
For administration by inhalation, the compounds of the invention are delivered in the form of an aerosol spray from a pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such 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. For transdermal administration, 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.
In one embodiment, 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. 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. 4,522,811, 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.
It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of a compound of the invention ATTORNEY DOCKET NO. PPI-305-1
calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the 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.
This invention is further illustrated by the following examples, which should not be construed as limiting. The contents of all references, patents, patent applications cited throughout this application are incorporated herein by reference. It should be understood that the use of any of the compounds described herein are within the scope of the present invention and are intended to be encompassed by the present invention and are expressly incorporated herein for all purposes.
Examples
General approach to synthesis of proline and pyrrolidine based analogs Synthesis of proline and pyrrolidine derivatives is described in Scheme 1. Mitsunobu reaction of phenol 1 with desired alcohol 2 afforded the intermediate 3 which was used to generate both amino acid 4 and amino alcohol 5. Saponification of the ester 3 followed by removal of Boc protecting group gave amino acid 4. Consequently, reduction of the ester 3 to alcohol 5 followed by Boc removal provided amino-alcohol 6. Either Boc-protected amino- alcohol 5 or de-salted (if TFA salt) amino-alcohol 6 were utilized under diethyl chlorophosphate phosphorylation and TMSBr deprotection to gave the corresponding phosphate 7.
ATTORNEY DOCKET NO. PPI-305-1
Scheme 1
Figure imgf000034_0001
LiAlH4 THF "
Figure imgf000034_0002
General protocol for Mitsunobu reaction (3)
Figure imgf000034_0003
To a suspension of triphenyl phosphine, polymer bound [3mmol/g loading] (1.2 equivalents) in DCM was added a stirred solution of protected proline-based amino acid ester (1.0 equivalent) and the substituted phenol (1.0 equivalent). The reaction was then cooled to 0 0C and diisopropyl azodicarboxylate (DIAD) (1.0 equivalent) was added. The reaction was then allowed to warm to room temperature and stirred for 4-12 hours. Filtration of the heterogeneous solution followed by removal of the organic solvent gives the crude reaction product which was taken on to the next step with no further purification.
General procedure for deprotection of 3 to 4
Figure imgf000034_0004
ATTORNEY DOCKET NO. PPI-305-1
Protected pyrrolidine 3 was dissolved in DCM and treated with LiOH (2 M, 100 equivalents). The reaction was stirred at rt for 1 hr, then acidified with TFA and stirred an additional hour. The desired product 4 was purified by prep HPLC on a C8(2) column ((Luna, 5 μ, 100 x 21.10 mm) with acetonitrile-H2O (0.1% TFA) as mobile phase and gradient 40-80% in 20 min.
General synthesis of pyrrolidine-alcohol 6
Figure imgf000035_0001
To a solution of ester 3 (1.0 equivalent) in THF at 0 0C was added a solution of LiAIRi in THF (IM, 1.5 equivalents) drop wise. The reaction was stirred at 0 0C for 10 minutes then was slowly warmed to room temperature and stirred an additional 1-4 hours. Upon complete reduction of the ester, as monitored by LC-MS, the reaction mixture was cooled to 0 0C and a solution of 10% KOH (excess) was added dropwise. The reaction mixture was then warmed to room temperature and stirred for an additional 1 hour. The generate white precipitate was removed by filtration through a plug of celite, the product was eluted with ether. The organic layers were combined and washed with sodium phosphate buffer (0.1 N, pH 7.0). The product was further extracted with ether and the solvent was removed in vacuo to afford alcohol 5.
The alcohol 5 was treated with a solution of 10-50 % trifluoroacetic acid in dichloromethane and anisole (0.01 equivalents) as scavenger. The reaction was allowed to stir at rt for 3-6 hours and the solvent was removed in vacuo to give crude pyrrolidine-alcohol 6. The product 6 was purified by prep HPLC on a C8(2) column ((Luna, 5μ, 100 x 21.10 mm) with acetonitrile-H2O (0.1% TFA) as mobile phase and gradient 30-98% in 20 min.
(25',45)-4-(4-Octylphenoxy)pyrrolidine-2-carboxylic acid (4a)
Figure imgf000035_0002
The title compound was prepared from methyl ester 3a in 32 % (5.1 mg). HPLC retention time on a Synergi-Max RP column (2 x 20 mm, 2 μL) is 1.60 min with gradient 20- 95% acetonitrile-H2O (0.1 % TFA) in 2 min as mobile phase. MS (ESl, M+H*) = 320.1; 1H ATTORNEY DOCKET NO. PPI-305-1
NMR (400 MHz, CD3OD) δ 7.00 (d, 2H, J= 8.4 Hz), 6.75 (d, 2H, J= 8.4 Hz), 4.99 (d, IH, J = 3.6 Hz), 4.20 (t, IH, J= 6.8 Hz), 3.58 (d, IH, J= 12.4 Hz), 3.39 (dd, IH, J= 12.4 Hz, J = 4. Hz), 2.42-2.49 (m, 4H), 1.46 (t, 2H, J= 7.2 Hz), 1.18-1.20 (m, 10H), 0.79 (t, 3H, J= 7.2 Hz).
(25',4/?)-4-(4-Octylphenoxy)pyrrolidine-2-carboxylic acid (4b)
Figure imgf000036_0001
The title compound was prepared from methyl ester 3b in 17 % (2.7 mg). HPLC retention time on a Synergi-Max RP column (2 x 20 mm, 2 μL) is 1.66 min with gradient 20- 95% acetonitrile-H2O (0.1 % TFA) in 2 min as mobile phase. MS (ESI, M+H4) = 320.1; 1H NMR (400 MHz, CD3OD) δ 7.13 (d, 2H, J= 8.8 Hz), 6.88 (d, 2H, J= 8.4 Hz), 5.15 (t, IH, J = 4 Hz), 4.31 (dd, IH, J= 10.4 Hz, J= 10.4 Hz), 3.51-3.55 (m, 2H), 2.64-2.69 (m, IH), 2.56 (t, 2H, J= 7.6 Hz), 2.26-2.33 (m, IH), 1.56-1.60 (m, 2H), 1.26-1.32 (m, 10H), 0.90 (t, 3H, J = 6.8 Hz).
(2/?,45)-4-(4-Octylphenoxy)pyrrolidine-2-carboxylic acid (4c)
Figure imgf000036_0002
OH
The title compound was prepared from methyl ester 3c in 46 % (7.4 mg). HPLC retention time on a Synergi-Max RP column (2 x 20 mm, 2 μL) is 1.64 min with gradient 20- 95% acetonitrile-H2O (0.1 % TFA) in 2 min as mobile phase. MS (ESI, M+H4) = 320.1; 1H NMR (400 MHz, CD3OD) δ 7.13 (d, 2H, J= 8.8 Hz), 6.88 (d, 2H, J= 8.4 Hz), 5.15 (t, IH, J = 4.0 Hz), 4.43 (dd, IH, J= 10.2 Hz, J= 8.0 Hz), 3.51-3.55 (m, 2H), 2.64-2.69 (m, IH), 2.56 (t, 2H, J= 7.6 Hz), 2.26-2.33 (m, IH), 1.56-1.60 (m, 2H), 1.26-1.32 (m, 10H), 0.90 (t, 3H, J = 6.8 Hz).
((25,45)-4-(4-Octylphenoxy)pyrrolidin-2-yl)methanol (6a)
Figure imgf000036_0003
ATTORNEY DOCKET NO. PPI-305-1
The title compound was prepared from methyl ester 3a in 44 % (20.0 mg). HPLC retention time on a Synergi-Max RP column (2 x 20 mm, 2 μL) is 1.63 min with gradient 20- 95% acetonitrile-H2O (0.1 % TFA) in 2 min as mobile phase. MS (ESI, M+H4) = 306.1; 1H NMR (400 MHz, CD3OD) δ 7.11 (d, 2H, J= 8.4 Hz), 6.85 (d, 2H, J = 8.4 Hz), 5.09-5.14 (m, IH), 3.69-3.91 (m, 3H), 3.48-3.59 (m, 2H), 2.54 (t, 3H, J= 7.6 Hz), 1.96-2.02 (m, IH), 1.57 (t, 2H, J= 7.2 Hz), 1.28-1.30 (m, 10H), 0.89 (t, 3H, J= 6.4 Hz).
((25',4/?)-4-(4-OctyIphenoxy)pyrrolidin-2-yl)methanol (6b)
Figure imgf000037_0001
The title compound was prepared from methyl ester 3b in 37 % (16.8 mg). HPLC retention time on a Synergi-Max RP column (2 x 20 mm, 2 μL) is 1.63 min with gradient 20- 95% acetonitrile-H2O (0.1 % TFA) in 2 min as mobile phase. MS (ESI, M+H4) = 306.1; 1H NMR (400 MHz, CD3OD) δ 7.12 (d, 2H, J= 8.4 Hz), 6.87 (d, 2H, J = 8.4 Hz), 5.15 (t, IH, J = 4.0 Hz), 3.96-4.00 (m, IH), 3.87-3.91 (m, IH), 3.64-3.74 (m, IH), 3.49-3.55 (m, 2H), 2.55 (t, 3H, J= 7.6 Hz), 2.32-2.35 (m, IH), 2.12-2.16 (m, IH), 1.57 (t, 2H, J= 7.6 Hz), 1.28-1.31 (m, 10H), 0.89 (t, 3H, J= 6.8 Hz).
((2/ϊ,45)-4-(4-Octylphenoxy)pyrrolidin-2-yl)methanol (6c)
Figure imgf000037_0002
The title compound was prepared from methyl ester 3c in 41 % (2.0 mg). HPLC retention time on a Synergi-Max RP column (2 x 20 mm, 2 μL) is 1.65 min with gradient 20- 95% acetonitrile-H2O (0.1 % TFA) in 2 min as mobile phase. MS (ESI, M+H4) = 306.1 ; 1H NMR (400 MHz, CD3OD) δ 7.12 (d, 2H, J= 8.4 Hz), 6.87 (d, 2H, J= 8.4 Hz), 5.15 (t, IH, J = 4.0 Hz), 3.96-4.00 (m, IH), 3.87-3.91 (m, IH), 3.64-3.74 (m, IH), 3.49-3.55 (m, 2H), 2.55 (t, 3H, J= 7.6 Hz), 2.32-2.35 (m, IH), 2.12-2.16 (m, IH), 1.57 (t, 2H, J= 7.6 Hz), 1.28-1.31 (m, 10H), 0.89 (t, 3H, J= 6.8 Hz).
General method for phosphate synthesis (7) ATTORNEY DOCKET NO. PPI-305-1
To a solution of protected or unprotected desired amino alcohol (1.0 equivalent) in dry DCM at room temperature was added excess diethyl chlorophosphate (10.0 equivalents) and triethylamine (20.0 equivalents) and the reaction was stirred for 12-18 hours. The reaction was monitored by LC-MS. The crude reaction mixture was then evaporated to dryness in vacuo. The resulting phospho-diester intermediate was reacted with excess bromotrimethylsilane (10.0-20.0 equivalents) in dry DCM at room temperature over a period of 6-10 hours to afford the final phosphate which was purified by reverse-phase preparative HPLC after evaporation of the solvent and excess reagent.
((25',45)-4-(4-Octylphenoxy)pyrrolidiii-2-yl)methyl dihydrogen phosphate (7a)
Figure imgf000038_0001
MS (ESI, M+H^ = 386.0; HPLC retention time on a Synergi-Max RP column (2 x 20 mm, 2 μL) is 1.55 min with gradient 20-95% acetonitrile-H2O (0.1 % TFA) in 2 min as mobile phase.
((2£,4Λ)-4-(4-Octylphenoxy)pyrrolidin-2-yl)methyl dihydrogen phosphate (7b)
Figure imgf000038_0002
MS (ESI, M+H+) = 386.1 ; HPLC retention time on a Synergi-Max RP column (2 x 20 mm, 2 μL) is 1.58 min with gradient 20-95% acetonitrile-H2O (0.1 % TFA) in 2 min as mobile phase.
((2/?,4S)-4-(4-Octylphenoxy)pyrrolidin-2-yl)methyl dihydrogen phosphate (7c)
Figure imgf000038_0003
MS (ESI, M+H4) = 386.1 ; HPLC retention time on a Synergi-Max RP column (2 x 20 mm, 2 μL) is 1.60 min with gradient 20-95% acetonitrile-H2O (0.1 % TFA) in 2 min as mobile phase.

Claims

ATTORNEY DOCKET NO. PPI-305-1
A compound of formula I
Figure imgf000039_0001
or a pharmaceutically acceptable salt thereof, wherein:
Ri is hydrogen, halogen, cyano, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroalkyl, -O-alkyl, -O-aryl, -O-heteroaryl, -S-alkyl, alkylene-O-aikyl, alkylene- CO2H, alkylene-CO2alkyl, alkylSO2, alkylenesulfonyl, alkylene-CO-amino, alkylene-CO- alkylamino, alkylene-CO-dialkylamino, alkylene-NH-CO2H, alkylene-NH-CO2alkyl -
CO2alkyl, -OH, -C(O)-alkyl, -C(O)O-alkyl, -CONH2, -CO-alkylamino, -CO-dialkylamino, amino, alkylamino, or dialkylamino, any of which may be optionally substituted on carbon with 1 , 2, or 3 groups selected from halo, alkyl, OH, or -O-alkyl;
A is (Ci-C2o)alkylene, (C2-C2o)alkenylene, or (C2-C2o)alkynylene, each of which may be optionally substituted on carbon with 1 , 2, or 3 groups selected from OH, CO2H,
Cθ2alkyl, halogen, amino, alkylamino, dialkylamino, -O-alkyl, alkylene-O-alkyl, alkylene- OH, or alkylene-CO2H;
Xi is a bond or is CH2, O, -CH2O-, S, -S(O), -S(O)2, -C(O)-, -C(O)O-, or NRx, wherein Rx is H or (Ci-C6)alkyl; R' and R" are each independently hydrogen, halogen, alkyl optionally substituted on carbon with halogen, alkyl, or taken together with the carbon to which they are attached form C=O or a 3, 4, 5,or 6-membered ring, optionally containing 1 or 2 heteroatoms selected from O NH, N-alkyl, SO, or SO2, any of which may be optionally substituted on carbon with alkyl or halogen; R2 is cyano, halogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroalkyl, -O-alkyl, -O-aryl, -O-heteroaryl, aralkoxy, heteroaralkoxy, -S-alkyl, alkylene-O- alkyl, alkylene-CO2H, alkylene-CO2alkyl, alkylSO2, alkylenesulfonyl, alkylene-CO-amino, alkylene-CO-alkylamino, alkylene-CO-dialkylamino, alkylene-NH-CO2H, alkylene-NH- CO2alkyl -CO2alkyl, -OH, -C(O)-alkyl, -C(O)O-alkyl, -CONH2, -CO-alkylamino, -CO- dialkylamino, amino, alkylamino, and dialkylamino, any of which may be optionally substituted on carbon with 1 , 2, or 3 groups selected from halo, alkyl, OH, or -O-alkyl; ATTORNEY DOCKET NO. PPI-305-1
A is phenyl or pyridyl;
Q is CH2, O, CH2O, S, -S(O), -S(O)2, -C(O)-, CH2C(O)-, NRx, or CH2NRx, wherein Rx is H, (Ci-C6)alkyl;
R3 is hydrogen, (Ci-Ce)alkyl, aralkyl, heteroalkyl, CO2(Ci -C6)alkyl, -C(O)- (Ci- C6)alkyl, -C(O)O-alkyl, -CONH2, -CO-alkylamino, -CO-dialkyl amino, any of which may be optionally substituted on carbon with 1, 2, or 3 groups selected from halo, alkyl, OH, or -O- alkyl;
R4 is hydrogen, (Ci-C6)alkyl which may be optionally substituted on carbon with 1 , 2, or 3 groups selected from halo, alkyl, OH, or -O-alkyl; and R5 is selected from the group consisting of -OH, alkylene-OH, -CO2H, alkylene-
CO2H, - alkylene-CO2-alkyl, -CH2=CHCO2H, -CH2=CHC(O)O-alkyl, -CH2=CHC(O)O-aryl, -OPO2RpiRp2, -OPO3RpiRp2, -CH2PO3RpiRp2, -OPO2(S)RpiRp2, and -C(Z')(Z")PO3RplRp2, any of which may be optionally substituted on carbon with halogen, alkyl, hydroxyl, carboxy, or alkoxy; and wherein Z' is hydroxyl or halogen;
Z" is H or halogen;
Rpi and Rp2 are each independently hydrogen, Q-Ce-alkyl, aryl, or one of the following groups:
Figure imgf000040_0001
H2 O μ O I 0 I
^0-V c A .c!oΛoΛ. i-H2c.0Λ0J<
Figure imgf000040_0002
x, y, and z are each independently an integer selected from 0, 1 , 2, or 3.
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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103619828A (en) * 2011-04-14 2014-03-05 阿勒根公司 Phenyl bicyclic methyl amine derivatives as sphingosine-1 phosphate receptors modulators
US9085581B2 (en) 2010-03-03 2015-07-21 Arena Pharmaceuticals, Inc. Processes for the preparation of S1P1 receptor modulators and crystalline forms thereof
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
US9126932B2 (en) 2008-07-23 2015-09-08 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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US10301262B2 (en) 2015-06-22 2019-05-28 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compund1) for use in SIPI receptor-associated disorders
US10995068B2 (en) 2015-09-24 2021-05-04 The Regents Of The University Of California Synthetic sphingolipid-like molecules, drugs, methods of their synthesis and methods of treatment
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
CN114957332A (en) * 2022-05-30 2022-08-30 苏州正永生物医药有限公司 Avanafil phosphate compound and preparation method and application thereof
US11478448B2 (en) 2017-02-16 2022-10-25 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of inflammatory bowel disease with extra-intestinal manifestations
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007142028A1 (en) * 2006-06-06 2007-12-13 Gifu University Pyrrolidine analogue for preventing neurogenic pain and method for production thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007142028A1 (en) * 2006-06-06 2007-12-13 Gifu University Pyrrolidine analogue for preventing neurogenic pain and method for production thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HUANG ET AL. ANGEW. CHEM. INT. ED. vol. 46, 2007, pages 9073 - 9077 *
MA ET AL. FENZI CUIHUA vol. 19, no. 2, 2005, pages 126 - 130 *

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