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  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/16—Peri-condensed systems

Definitions

• the present invention provides novel substituted hydropyrido[3,2,1 - ij]quinoline compounds, and their uses in medicaments for the treatment of mammals with diseases and conditions that are alleviated by sphingosine-1 - phosphate (S1 P) receptors modulation.
• S1 P sphingosine-1 - phosphate
• Sphingosine is a compound having the chemical structure shown in the general formula described below, in which Y 1 is hydrogen. It is known that various sphingolipids, having sphingosine as a constituent, are widely distributed in the living body including on the surface of cell membranes of cells in the nervous system.
• a sphingolipid is one of the lipids having important roles in the living body.
• a disease called lipidosis is caused by accumulation of a specified sphingolipid in the body.
• Sphingolipids present on cell membranes function to regulate cell growth; participate in the development and differentiation of cells; function in nerves; are involved in the infection and malignancy of cells; etc. Many of the physiological roles of sphingolipids remain to be solved.
• ceramide a derivative of sphingosine, has an important role in the mechanism of cell signal transduction has been indicated, and studies about its effect on apoptosis and cell cycle have been reported.
• Sphingosine-1 -phosphate is an important cellular metabolite, derived from ceramide that is synthesized de novo or as part of the sphingomeyeline cycle (in animals cells). It has also been found in insects, yeasts and plants.
• the enzyme, ceramidase acts upon ceramides to release sphingosine, which is phosphorylated by sphingosine kinase, a ubiquitous enzyme in the cytosol and endoplasmic reticulum, to form sphingosine-1 -phosphate.
• the reverse reaction can occur also by the action of sphingosine phosphatases, and the enzymes act in concert to control the cellular concentrations of the metabolite, which concentrations are always low. In plasma, such concentration can reach 0.2 to 0.9 ⁇ M, and the metabolite is found in association with the lipoproteins, especially the HDL.
• sphingosine-1 -phosphate formation is an essential step in the catabolism of sphingoid bases.
• sphingosine-1 -phosphate is a potent messenger molecule that perhaps uniquely operates both intra- and inter-cellularly, but with very different functions from ceramides and sphingosine.
• the balance between these various sphingolipid metabolites may be important for health. For example, within the cell, sphingosine-1 -phosphate promotes cellular division (mitosis) as opposed to cell death (apoptosis), which it inhibits. Intracellular ⁇ , it also functions to regulate calcium mobilization and cell growth in response to a variety of extracellular stimuli.
• S1 P3 receptor is one of the receptors interacting with sphingosine-1 - phosphate.
• S1 P3 receptor alone or together with other S1 P receptors, involves in many critical biological processes, such as the growth of new blood vessels, vascular maturation, cardiac development and immunity, as well as for directed cell movement. S1 P3 receptor modulators are needed for therapeutic uses. Summary of the Invention
• the compounds of the present invention can be represented by the structural formula:
• B is selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, carbonylalkyl, formyl, oxycarbonyl, aminocarbonyl, alkyl carboxyl, alkyl amide, amino, alkylamino, cyano and X-B together being a heterocyclic ring or ring system;
• R and R 3 are each independently selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halo, hal
• S1 P sphingosine-1 - phsophate
• R and R 3 are each independently selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halo, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, carbonylalkyl, formyl, oxycarbonyl, aminocarbonyl, alkyl carboxyl, alkyl amide, amino, alkylamino, and cyano; each R 1 is independently selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halo, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, formyl, oxycarbonyl, aminocarbonyl, aminocarbonxyl, a Iky I carboxyl, alkyl amide, amino, alkylamino, and cyano; each R 2 is independently selected from
• S1 P sphingosine-1 -phsophate
• S1 P sphingosine-1 -phsophate
• These compounds are useful for the treatment of mammals, including humans, with a range of conditions and diseases that are alleviated by S1 P modulation: not limited to treating glaucoma, elevated intraocular pressure, ischemic neuropathies, optic neuropathy, pain, visceral pain, corneal pain, headache pain, migraine, cancer pain, back pain, irritable bowel syndrome pain, muscle pain and pain associated with diabetic neuropathy, the treatment of diabetic retinopathy, other retinal degenerative conditions, dry eye, angiogenesis and wounds.
• Other uses include:
• Ocular applications Retinopathy of prematurity, diabetic retinopathy, optic neuropathy, glaucomatous retinopathy, macular degeneration, choroidal neovascularization, ocular wound healing, and retinal edema;
• Cardiovascular applications Congestive heart failure, cardiac arrhythmia, atherosclerosis, and bradycardia;
• treat refers to the diagnosis, cure, mitigation, treatment, or prevention of disease or other undesirable condition.
• the compounds of present invention may be identified either by their chemical structures and/or chemical names. If the chemical structure and the chemical name conflict, the chemical structure is determinative of the identity of the compound.
• the compounds of the invention may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double- bond isomers, enantiomers or diastereomers. Accordingly, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers, including the stereoisomerically pure form and enantiomeric and stereoisomer ⁇ mixtures.
• the compounds of the invention may also exist in several tautomeric forms, including but not limiting to, the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms.
• the compounds of the invention also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature.
• a pharmaceutically acceptable salt is any salt of the parent compound that is suitable for administration to a mammal, including human.
• a pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid, another salt, or a prodrug which is converted into an acid or salt.
• a salt comprises one or more ionic forms of the compound, such as a conjugate acid or base, associated with one or more corresponding counter-ions.
• Salts can form from or incorporate one or more deprotonated acidic groups (e.g. carboxylic acids), one or more protonated basic groups (e.g. amines), or both (e.g. zwitterions).
• deprotonated acidic groups e.g. carboxylic acids
• protonated basic groups e.g. amines
• zwitterions e.g. zwitterions
• a prodrug is a compound which is converted to a therapeutically active compound after administration. For example, conversion may occur by hydrolysis of an ester group or some other biologically labile groups. Prodrug preparation is well known in the art. For example, “Prodrugs and Drug Delivery Systems,” which is a chapter in Richard B. Silverman, Organic Chemistry of Drug Design and Drug
• Alternate solid forms are different solid forms than those that may result from practicing the procedures described herein.
• alternate solid forms may be polymorphs, different kinds of amorphous solid forms, glasses, and the like.
• Non-covalent complexes are complexes that may form between the compound and one or more additional chemical species that do not involve a covalent bonding interaction between the compound and the additional chemical species. They may or may not have a specific ratio between the compound and the additional chemical species. Examples include solvates, hydrates, charge transfer complexes, and the like.
• Hydrocarbyl consists of carbon and hydrogen, wherein each carbon has 4 covalent bonds and each hydrogen has a single bond to a carbon atom.
• Hydrocarbyl fragments has the same meaning as “hydrocarbyl,” but is merely used for convenience for counting purposes.
• one or more hydrocarbyl fragments means, 1 , 2, or more distinct parts that each consists of hydrocarbyl, which may be interrupted by another moiety.
• a functional group may be attached to 2 distinct hydrocarbyl fragments.
• Hydrocarbyl includes alkyl, alkenyl, alkynyl, aryl containing only hydrogen and carbon, and combinations thereof. Hydrocarbyl may be linear, branched, cyclic
• Alkyl is a hydrocarbyl having no double bonds. Examples include methyl, ethyl, propyl isomers, butyl isomers, pentyl isomers, hexyl isomers, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
• Alkenyl is a hydrocarbyl having one or more double bonds. Examples include ethenyl, propenyl, butenyl isomers, pentenyl isomers, hexenyl isomers, cyclopentenyl, cyclohexenyl, etc.
• Alkynyl is a hydrocarbyl having one or more triple bonds. Examples include ethynyl, propynyl, butynyl isomers, pentynyl isomers, hexynyl isomers, cyclopentynyl, cyclohexynyl, etc.
• Aryl is a substituted or unsubstituted aromatic ring or ring system. It can be hydrocarbon-aryl or heteroaryl. Examples of hydrocarbon-aryl include substituted and unsubstituted phenyl, naphthyl, and biphenyl. Such aryl group can be bonded to other moieties within the molecule at any position.
• Each hydrogen atom has one covalent bond to carbon (C), nitrogen (N), oxygen (O), or sulfur (S).
• Halo or halo atoms are fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). Each halo atom forms a single bond to a carbon atom.
• Halohydrocarbyl is a hydrocarbyl having one or more F, Cl, Br, or I as substituents.
• Heterohydrocarbyl refers to a hydrocarbyl as defined above with at least one non-carbon atom(s) presented at the backbone, including but not limiting to, oxygen (O), sulfur (S), nitrogen (N), phosphor (P), and halo atoms.
• Heterohydrocarbyl may be linear, branched, cyclic (aromatic or non-aromatic), or combinations thereof, which can be further substituted.
• heterohydrocarbyl examples include: -R 10" G 1 -R 1 1 , -R 10 -HI, -G 1 -R 10 , -G 1 - R 10 -HI, G 1 -R 10 -G 2 , and G 1 -R 10 -G 2 -R 11 , wherein R 10 and R 11 are independently hydrocarbyl or hydrogen (provided that hydrogen is attached to only one C, N, O, or S atom), G 1 and G 2 are independently functional groups, and HI is halo.
• heterohydrocarbyl is depicted below, wherein R 10 , R 11 , R 12 , and R 13 are independently hydrocarbyl or hydrogen. Other possibilities exist, but are not depicted here.
• Heteroaryl is one type of heterohydrocarbyl, referring to an aromatic ring or ring system containing at least one hetero atom selected from N, O, S, P, and combinations thereof.
• heteroaryl include, but not limit to, pyridine, pyrazine, pyrimidine, pyridazine, triazine, furan, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, naphthalene, quinoline, quinoxaline, quinazoline, cinnoline, isoquinoline, benzofuran, indole, benzothiophene, benzimidazole, indazole, benzoxazole, benzisoxazole, benzothiazole, isobenzofuran, isoindole, tetraline, chroman
• Substituted or "a substituent” is hydrogen, one or more hydrocarbyl fragments, one or more heterohydrocarbyl fragments, one or more halo atoms, one or more functional groups, or combinations thereof. Two or more substituents may themselves form an additional ring or ring system.
• a functional group comprises of alkyl, aryl, alkenyl, alkynyl, halo, haloalkyl, hydroxyl, alkoxyl, hydroxyalkyl, oxo, alkylcarbonyl, formyl, carboxyl, alkylcarboxylate, alkylamide, aminocarbonyl, amino, cyano, diazo, nitro, thio, sulfoxyl, sulfonyl, phosphate, phosphinate, and one of the moieties depicted below.
• a functional group is asymmetric, it may be oriented in any way possible.
• ester functional group is intended to indicate both of the structures below.
• one or more hydrocarbyl fragments, one or more heterohydrocarbyl fragments, and/or one or more functional groups may be incorporated into one or more rings or ring systems.
• the dashed lines on the functional groups indicate that any nitrogen atom on a functional group may form an additional bond with another carbon atom, a hydrogen atom, or may form a double bond with one of the depicted bonds so that an ammonium or a quaternary ammonium type of functional group is formed.
• the dashed line functional groups actually represent a group of individual functional groups. For example, the functional group:
• n is an integer of 0, 1 , 2, or 3
• Z and X are each independently selected from the group of oxygen sulfur, and amine moiety NR N ;
• B is selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, carbonylalkyl, formyl, oxycarbonyl, aminocarbonyl, alkyl carboxyl, alkyl amide, amino, alkylamino, cyano and X-B together being a heterocyclic ring or ring system;
• R and R 3 are each independently selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halo, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, carbonylalkyl, formyl, oxycarbonyl, aminocarbonyl, alkyl carboxyl, alkyl amide, amino, alkylamino, and cyano; each R 1 is independently selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halo, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, formyl, oxycarbonyl, aminocarbonyl, aminocarbonxyl, alkylcarboxyl, alkyl alkylcarbonyl, formyl, oxycarbonyl, aminocarbonyl, aminocarbon
• R N is independently selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, carbonylalkyl, formyl, oxycarbonyl, aminocarbonyl, alkyl carboxyl, alkyl amide, amino, alkylamino, and cyano; including their alternate solid forms, tautomers, stereoisomers, enantiomers, diastereomers, prodrugs, and pharmaceutically acceptable salts, hydrates and solvates.
• n O, 1 , 2, or 3;
• Z is O, S, or NR N ;
• X is O, S, or NR N ;
• B is selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, carbonylalkyl, formyl, oxycarbonyl, aminocarbonyl, alkyl carboxyl, alkyl amide, amino, alkylamino, cyano and X-B together being a heterocyclic ring;
• R and R 3 are each independently selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halo, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, carbonylalkyl, formyl, oxycarbonyl, aminocarbonyl, alkyl carboxyl, alkyl amide, amino, alkylamino, and cyano; each R 1 is independently selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halo, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, formyl, oxycarbonyl, aminocarbonyl, aminocarbonxyl, a Iky I carboxyl, alkyl amide, amino, alkylamino, and cyano; each R 2 is independently selected from
• B is selected from the group consisting of hydrogen, a substituent having a formula Co-12Ho-3oNo-30o-5Po-2So-3Fo-6Clo-3Bro-3lo-3, wherein if X is NR N , and X-B being a heterocyclic ring/ ring system.
• Co-12Ho-3oNo-30o-5Po-2So-3Fo-6Clo- 3 Br o- 3lo-3 represents a structure having from 0-12 carbon atoms, from 0-30 hydrogen atoms, from 0-3 nitrogen atoms, from 0-5 oxygen atoms, from 0-2 phosphorous atoms, from 0-3 sulfur atoms, from 0-6 fluorine atoms, from 0-3 chlorine atoms, from 0-3 bromine atoms, and from 0-3 iodine atoms.
• each R A is independently hydrogen, alkyl, aryl, alkenyl, alkynyl, halo, haloalkyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, formyl, carboxyl, alkyl carboxylate, alkyl amide, aminocarbonyl, amino, cyano, diazo, nitro, thio, sulfoxyl, sulfonyl, phosphate, or phosphinate.
• X is O.
• Z is O.
• Z is S.
• B is Ci -6 alkyl, Ci -6 alkenyl, Ci -6 alkynyl, Ci -6 haloalkyl, hydroxyalkyl, phenyl, benzyl, furylmethyl, or wherein X-B is morpholino.
• C- 1 - 6 means having from one to six (1 -6) carbon atoms.
• Ci -6 haloalkyl is Ci -6 alkyl having at least one halo atoms of F, Cl, Br, or I as the substituent.
• haloalkyl examples include -CH2F, -CH 2 CHF 2 , -C 3 H 6 F, -C 4 H 8 F, -C 5 Hi 0 F, -C 6 Hi 2 F, fluorocyclopropyl, fluorocyclobutyl, fluorocyclopentyl, fluorocyclohexyl, -CH 2 CH 2 CI, -C 3 H 6 CI, -C 4 H 8 CI, -C5H 1 0CI, -C 6 H 12 CI, chlorocyclopropyl, chlorocyclobutyl, chlorocyclopentyl, chlorocyclohexyl, -CH 2 CH 2 Br, -CsH 6 Br, -C 4 H 8 Br, -C 5 Hi 0 Br, - C 6 Hi 2 Br, bromocyclopropyl, bromocyclobutyl, bromocyclopentyl, bromocyclohexyl, -CH 2
• R A is hydrogen, C 1 -I2 alkyl, CM 2 alkenyl, CM 2 alkynyl, halo, Ci -12 halohydrocarbyl, C M 2 hydroxyalkyl, C 3-12 cyclic hydrocarbyl, or heteroaryl.
• CM 2 means having from 1 -12 carbon atoms.
• X is NR N .
• the compounds can be represented by the structural formula:
• each R A is independently hydrogen, CM 2 alkyl, CM 2 alkenyl, CM 2 alkynyl, halo, CM 2 halohydrocarbyl, CM 2 hydroxyalkyl, C 3 - I2 cyclic hydrocarbyl, or heteroaryl.
• R N is hydrogen, methyl, ethyl, propyl, or isopropyl.
• R ⁇ N' N i
• B is hydrocarbyl, as described above.
• B is substituted or unsubstituted hydrocarbon- aryl or heterohydrocarbyl.
• heteroaryl include pyridine, pyrazine, pyrimidine, pyridazine, triazine, furan, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, naphthalene, quinoline, quinoxaline, quinazoline, cinnoline, isoquinoline, benzofuran, indole, benzothiophene, benzimidazole, indazole, benzoxazole, benzisoxazole, benzothiazole, isobenzofuran, isoindole, tetraline, chromane, isochromane, thio
• aryl or heteroaryl substituents are the same as those defined above.
• substituents include alkyl, aryl, alkenyl, alkynyl, halo, haloalkyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, formyl, carboxyl, alkyl carboxylate, alkyl amide, aminocarbonyl, amino, cyano, diazo, nitro, thio, sulfoxyl, sulfonyl, phosphate, phosphinate, and the like.
• B may also be a combination of one or more of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted hydrocarbon-aryl, or substituted or unsubstituted heteroaryl.
• B may have one of the structures shown below:
• each R A is independently selected from the group consisting of hydrogen, hydrocarbyl, heterohydrocarbyl, substituted or unsubstituted aryl, halo, halohydrocarbyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, carbonylalkyl, formyl, oxycarbonyl, aminocarbonyl, alkyl carboxyl, alkyl amide, amino, alkylamino, and cyano;
• R and R 3 are each independently selected from the group consisting of hydrogen and a substituent having a formula Co-12Ho-3oNo-30o-5Po-2So-3Fo-6Clo-3Bro-3lo-3; each R N is independently selected from the group consisting of hydrogen and C1-12 hydrocarbyl;
• B is selected from the group consisting of hydrogen, a substituent having a formula Co- ⁇ Ho-soNo-sOo-sPo ⁇ So-aFo-eClo-sBro-slo-s, wherein if X is NR N , and X-B being a heterocyclic ring/ ring system.
• Fo-6Clo-3Br 0 -3lo-3 represents a structure having from 0-12 carbon atoms, from 0-30 hydrogen atoms, from 0-3 nitrogen atoms, from 0-5 oxygen atoms, from 0-2 phosphorous atoms, from 0-3 sulfur atoms, from 0-6 fluorine atoms, from 0-3 chlorine atoms, from 0-3 bromine atoms, and from 0-3 iodine atoms.
• each R A is independently hydrogen, alkyl, aryl, alkenyl, alkynyl, halo, haloalkyl, hydroxyl, alkoxyl, hydroxyalkyl, alkylcarbonyl, formyl, carboxyl, alkyl carboxylate, alkyl amide, aminocarbonyl, amino, cyano, diazo, nitro, thio, sulfoxyl, sulfonyl, phosphate, or phosphinate.
• X is O.
• Z is O.
• Z is S.
• B is Ci -6 alkyl, Ci -6 alkenyl, Ci -6 alkynyl, Ci -6 haloalkyl, hydroxyalkyl, phenyl, benzyl, furylmethyl, or wherein X-B is morpholino.
• Ci- 6 means having from one to six (1 -6) carbon atoms.
• Ci -6 haloalkyl is Ci -6 alkyl having at least one halo atoms of F, Cl, Br, or I as the substituent.
• haloalkyl examples include -CH2F, -CH 2 CHF 2 , -C 3 H 6 F, -C 4 H 8 F, -C 5 Hi 0 F, -C 6 Hi 2 F, fluorocyclopropyl, fluorocyclobutyl, fluorocyclopentyl, fluorocyclohexyl, -CH 2 CH 2 CI, -C 3 H 6 CI, -C 4 H 8 CI, -C5H 1 0CI, -C 6 Hi 2 CI, chlorocyclopropyl, chlorocyclobutyl, chlorocyclopentyl, chlorocyclohexyl, -CH 2 CH 2 Br, -C 3 H 6 Br, -C 4 H 8 Br, -C 5 Hi 0 Br, - C 6 Hi 2 Br, bromocyclopropyl, bromocyclobutyl, bromocyclopentyl, bromocyclohexyl, -CH 2
• the compounds of the present invention can be combined with at least one other therapeutic agent that is already known the art.
• the compounds of invention and the other therapeutic agent(s) can act additively, or more preferably, synergistically.
• the invention is further defined by reference to the following examples, which describe the preparation schemes and methods for obtaining the compounds of the invention, the assays for testing the biological activities of these compounds. It will be apparent to those skilled in the art that many modifications, both to the preparation schemes and assays, may be practiced without departing from the scope of the invention.
• Reaction Schemes A, B, C , D and E are examples of the preparation methods for obtaining the compounds of the invention.
• Method A2 Preparation of methyl (1 S,7S)-1 ,7-dimethyl-1 ,7-diphenyl-1 , 2, 3,5,6,7- hexahvdropyrido[3,2,1 -//1quinolin-9-ylcarbamate, (829), and methyl (1 R,7S)-1 ,7- dimethyl-1 ,7-diphenyl-1 ,2,3,5,6,7-hexahvdropyrido[3,2,1 -/ ' /1quinolin-9-ylcarbamate (353)
• Method B1 Preparation of 1 -(1 ,7-diphenyl-1 ,2,3,5,6,7-hexahvdropyridor3,2,1 - ii1quinolin-9-yl)-3-ethylurea (484)
• Method B2 Preparation of 1 -((1S, 7S)-1 ,7-dimethyl-1 ,7-diphenyl-1 , 2,3,5,6,7- hexahvdropyrido[3,2,1 -//1quinolin-9-yl)-3-ethylurea, 249:
• the compounds of the invention are assessed for their ability to activate or block activation of the human S1 P3 receptor in T24 cells stably expressing the human S1 P3 receptor using the method described in paragraph [0067] of United States Patent Application Publication No. 20070232682, which published on Oct. 4, 2007, which is hereby incorporated by reference in its entirety.
• Ten thousands cells/well are plated into 384-well poly-D-lysine coated plates one day prior to use.
• the growth media for the S1 P3 receptor expressing cell line is McCoy's 5A medium supplemented with 10% charcoal-treated fetal bovine serum (FBS), 1 % antibiotic-antimycotic and 400 ⁇ g/ml geneticin.
• the cells are washed twice with Hank's Balanced Salt Solution supplemented with 20 mM HEPES (HBSS/Hepes buffer).
• the cells are then dye loaded with 2 ⁇ M Fluo-4 diluted in the HBSS/Hepes buffer with 1 .25 mM Probenecid and incubated at 37 0 C for 40 minutes. Extracellular dye is removed by washing the cell plates four times prior to placing the plates in the FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices).
• Ligands are diluted in HBSS/Hepes buffer and prepared in 384-well microplates.
• Sphingosine-1 -phosphate (S1 P) is diluted in HBSS/Hepes buffer with 4 mg/ml fatty acid free bovine serum albumin.
• the FLIPR transfers 12.5 ⁇ l from the ligand microplate to the cell plate and takes fluorescent measurements for 75 seconds, taking readings every second, and then for 2.5 minutes, taking readings every 10 seconds.
• Compounds are tested over the concentration range of 0.61 nM to 10,000 nM.
• Data for calcium ion (Ca +2 ) responses are obtained in arbitrary fluorescence units and not translated into Ca +2 concentrations.
• IC50 values (nM) are determined through a linear regression analysis using the Levenburg Marquardt algorithm.

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