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  • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
  • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
  • C07D253/06—1,2,4-Triazines
  • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
  • C07D253/07—1,2,4-Triazines having three 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
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  • A61P37/00—Drugs for immunological or allergic disorders
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
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  • C07D213/50—Ketonic radicals
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
  • C07D213/53—Nitrogen atoms
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
  • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/79—Acids; Esters
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
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  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
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  • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
  • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
  • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • C07—ORGANIC CHEMISTRY
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  • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
  • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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
  • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

• the present invention relates to derivatives and/or analogues of sphingosine and pharmaceutical compositions, including such derivatives and/or analogues, which are useful as drugs for the treatment of fungal infections, allergic diseases, immune disorders, etc.
• 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 sphingo lipid is one of the lipids having important roles in the living body.
• a disease called lipidosis is caused by accumulation of a specified sphingo lipid 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 spingosine 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.
• sphingosine- 1 -phosphate promotes cellular division (mitosis) as opposed to cell death (apoptosis), which it inhibits. Intracellularly, it also functions to regulate calcium mobilization and cell growth in response to a variety of extracellular stimuli.
• sphingosine- 1 -phosphate In common with the lysophospholipids, especially lysophosphatidic acid, with which it has some structural similarities, sphingosine- 1 -phosphate exerts many of its extra-cellular effects through interaction with five specific G protein-coupled receptors on cell surfaces. These are important for the growth of new blood vessels, vascular maturation, cardiac development and immunity, and for directed cell movement.
• Sphingosine-1 phosphate is stored in relatively high concentrations in human platelets, which lack the enzymes responsible for its catabolism, and it is released into the blood stream upon activation of physiological stimuli, such as growth factors, cytokines, and receptor agonists and antigens. It may also have a critical role in platelet aggregation and thrombosis and could aggravate cardiovascular disease.
• physiological stimuli such as growth factors, cytokines, and receptor agonists and antigens. It may also have a critical role in platelet aggregation and thrombosis and could aggravate cardiovascular disease.
• the relatively high concentration of the metabolite in high-density lipoproteins (HDL) may have beneficial implications for atherogenesis.
• sphingosine-1 - phosphate together with other lysolipids such as sphingosylphosphorylcholine and lysosulfatide, are responsible for the beneficial clinical effects of HDL by stimulating the production of the potent antiatherogenic signaling molecule nitric oxide by the vascular endothelium.
• lysophosphatidic acid it is a marker for certain types of cancer, and there is evidence that its role in cell division or proliferation may have an influence on the development of cancers.
• Fungi and plants have sphingolipids and the major sphingosine contained in these organisms has the formula described below. It is known that these lipids have important roles in the cell growth of fungi and plants, but details of the roles remain to be solved.
• derivatives of sphingo lipids and their related compounds exhibit a variety of biological activities through inhibition or stimulation of the metabolism pathways. These compounds include inhibitors of protein kinase C, inducers of apoptosis, immuno-suppressive compounds, antifungal compounds, and the like. Substances having these biological activities are expected to be useful compounds for various diseases.
• the present invention provides a derivative or analogue of sphingosine that is able to regulate the functions of sphingo lipid, and pharmaceutical compositions comprising said derivative or analogue.
• X is selected from the group consisting of CR 3 , N and NO;
• Y is selected from the group consisting of CR , N and NO;
• Z is selected from the group consisting of CR 3 , N and NO; and at least one of X, Y and Z is N or NO; V is O or NOR 4 R 1 is an aryl group; R 2 is an aryl group;
• R 3 is selected from the group consisting of H and alkyl; and 2 of said R 3 groups may together form a cyclic alkyl ring having from 3 to 6 carbon atoms;
• R 4 is selected from the group consisting of H and alkyl; a is 0 or an integer of from 1 to 6; b is 0 or 1 ; c is 0 or 1 ; f is 0 or an integer of 1 or 2; x is 0 or 1 ; y is 0 or an integer of from 1 to 3; and z is 0 or an integer of from 1 to 3.
• Specific Examples of the compounds of formula I include
• R H, alkyl (1 1 ) Seperated by MPLC
• R 1 , R 2 , R 3 H, alkyl
• a diphenylethyl-l,2-dione e.g. benzil
• methyl oxalamidrazonate in ethanol e.g. benzil
• methyl oxalamidrazonate in ethanol e.g. 1,3-bis(trimethyl)
• methyl 5,6-diphenyl-l,3,4-triazine-2- carboxylate as a mixture of geometric isomers if the dione is asymmetrical.
• These triazines can undergo Diels-Aler reactions with a pyrrolidine enamine compound to give a methyl 5,6-diphenylpyridine-2-carboxylate derivative.
• aldehyde derivatives can be reduced with diisobutylaluminum hydride to the corresponding aldehyde derivatives, which then can be converted into a number of homo logs and derivatives.
• the aldehyde can be converted into a secondary amine by reacting it with a primary amine in the presence of a reducing agent, such as sodium cyanoborohydride.
• a reducing agent such as sodium cyanoborohydride.
• the aldehyde may be reduced to an alcohol and treated with an alkyl halide in the presence of a mild base to produce alkyl ethers.
• these compounds may be used to prepare many other homo logs, many of which are described in the Specific Examples section below.
• reference to a compound should be construed broadly to include pharmaceutically acceptable salts, prodrugs, tautomers, alternate solid forms, non-covalent complexes, and combinations thereof, of a chemical entity of the depicted structure or chemical name.
• a pharmaceutically acceptable salt is any salt of the parent compound that is suitable for administration to an animal or 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).
• 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 group.
• 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 Action, 2d Ed., Elsevier Academic Press: Amsterdam, 2004, pp. 496-557, provides further detail on the subject.
• Tautomers are isomers that are in rapid equilibrium with one another. For example, tautomers may be related by transfer of a proton, hydrogen atom, or hydride ion. Unless stereochemistry is explicitly depicted, a structure is intended to include every possible stereoisomer, both pure or in any possible mixture.
• 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 might include solvates, hydrates, charge transfer complexes, and the like.
• R 3 and R 4 may be independently selected from the group consisting of hydrogen, straight or branched chain alkyl having 1 to 12 carbons, cycloalkyl having 3 to 6 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds, aryl, preferably a carbocyclic aryl group having from 6 to 14 carbon atoms or a heterocyclic aryl group having from 2 to 14 carbon atoms and from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, halo, e.g. fluoro or chloro, Ci to C ⁇ haloalkyl, e.g.
• R 1 and R 2 are aryl groups which may be any carbocyclic aryl or heterocyclic aryl group including but not limited to benzene, pyridine, pyrazine, pyridazine, pyrimidine, triazine, thiophene, furan, thiazole, thiadiazole, isothiazole, oxazole,oxadiazole, isooxazole, naphthalene, quinoline, tetralin, chroman, thiochroman, tetrahydroquinoline, dihydronaphthalene, tetrahydronaphthalen, chromene, thiochromene, dihydroquinoline, indan, dihydrobenzofuran, dihydrobenzothiophene, indene, benzofuran, benzothiophene, coumarin and coumarinone.
• Such aryl groups can be bonded to the above moiety at any position.
• Such aryl group may itself be substituted with any common organic functional group including but not limited to alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, hydroxyl, alkoxyl, alkylcarbonyl, formyl, oxycarbonyl, carboxyl, alkyl carboxylate, alkyl amide, aminocarbonyl, amino, cyano, diazo, nitro, thio, sulfoxyl, or sulfonyl groups.
• the carbocyclic aryl group will comprise from 6 to 14 carbon atoms, e.g. from 6 to 10 carbon atoms.
• the heterocyclic aryl group will comprise from 2 to 14 carbon atoms and one or more, e.g. from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
• Rl is selected from the groups consisting of phenyl and substituted derivatives thereof;
• R 2 is selected, preferably from the group consisting of phenyl, furanyl, thienyl, pyridyl, pyranyl and substituted derivatives thereof;
• R is selected from the group consisting of H and lower alkyl
• R 4 is selected from the group consisting of H and lower alkyl; and a is 0 or an integer of from 1 to 3.
• R 3 is H.
• R 1 is represented, preferably, by the general formula
• R 5 is selected from the group consisting of H, alkyl, trifluoromethyl, trifluoromethyloxy, halo, e. g.chloro, and loweralkylthio.
• R 2 is selected from the group consisting of furanyl, thienyl, pyridyl and pyranyl or R 2 is
• R 5 is selected from the group consisting of H, alkyl, trifluoromethyl, trifluoromethyloxy, halo, e. g. chloro, and loweralkylthio .
• X and Y are CR 3 and Z is N.
• the compounds have a side chain which is terminated with carboxylic acid or carboxylic ester group, i.e. b is 0, c is 1, xis 1, y is 1 and z is 0.
• a is 0 and more preferably R 4 is alkyl.
• R 1 is a carbocyclic aryl having from 6 to 10 carbon atoms which may be substituted with an alkyl or halo alkyl group.
• R 1 is phenyl which may be substituted with an alkyl or haloalkyl group.
• R 2 is a carbocyclic aryl having from 6 to 10 carbon atoms which may be substituted with an alkyl or haloalkyl group or R 2 is pyridyl.
• said alkyl group is a lower alkyl radical and said haloalkyl group is trifluoromethy 1.
• R 3 is H
• c is 1, 2 or 3 and a is 1.
• Z is N
• X and Y are CR 3
• W is NR 3
• R 2 is phenyl and R 5 is selected from the group consisting of H and methyl or R 2 is pyridyl and R 5 is ethyl
• d is 0 and therefore the compounds have a side chain which terminates in a carbon-oxygen radical such as a carboxylic acid, an ester thereof, an ether, an alcohol, or an alkyl carboxy group.
• a carbon-oxygen radical such as a carboxylic acid, an ester thereof, an ether, an alcohol, or an alkyl carboxy group.
• R 1 may be represented by the general formula
• R 5 is selected from the group consisting of H, alkyl, trifluoromethyl, trifluoromethyloxy, halo, e. g. chloro, and loweralkylthio
• R 2 may also be represented by the general formula
• R 5 is selected from the group consisting of H, lower alkyl, trifluoromethyl, trifluoromethyloxy, halo, e. g. chloro, and loweralkylthio or R 2 is selected from the group consisting of furanyl, thienyl, pyridyl and pyranyl.
• R 3 is H and more preferably, a is 1.
• x is 1
• z is 0
• R 4 is selected from the group consisting of H, methyl and ethyl.
• the carbon-oxygen compounds of this invention preferably is Z is N, X and Y are CR 3 , R 2 is pyridyl, R 4 is selected from the group consisting of methyl and ethyl and R 5 is selected from the group consisting of H, methyl, ethyl, propyl and trifluoromethyl, or X, Y and Z are N, R 4 is selected from the group consisting of methyl and ethyl and R 5 is selected from the group consisting of H, methyl, ethyl, propyl and trifluoromethyl, or
• X and Z are N and Y is CR
• Me refers to methyl
• tBu refers to t-butyl
• iPr refers to i-propyl
• Ph refers to phenyl
• “Pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid and the like.
• Alkyl refers to a straight-chain, branched or cyclic saturated aliphatic hydrocarbon.
• the alkyl group has 1 to 12 carbons. More preferably, it is a lower alkyl of from 1 to 7 carbons, most preferably 1 to 4 carbons.
• Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and the like.
• alkenyl refers to a straight-chain, branched or cyclic unsaturated hydrocarbon group containing at least one carbon—carbon double bond.
• the alkenyl group has 2 to 12 carbons. More preferably it is a lower alkenyl of from 2 to 7 carbons, most preferably 2 to 4 carbons.
• the alkenyl group may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy, O, S, NO 2 , halogen, dimethyl amino, and SH.
• Alkynyl refers to a straight-chain, branched or cyclic unsaturated hydrocarbon containing at least one carbon—carbon triple bond.
• the alkynyl group has 2 to 12 carbons. More preferably it is a lower alkynyl of from 2 to 7 carbons, most preferably 1 to 4 carbons.
• the alkynyl group may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy, O, S, NO 2 , halogen, dimethyl amino, and SH.
• Alkoxyl refers to an “O-alkyl” group.
• Aryl refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups.
• the aryl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxyl, SH, OH, NO 2 , amine, thioether, cyano, alkoxy, alkyl, and amino.
• Alkaryl refers to an alkyl that is covalently joined to an aryl group. Preferably, the alkyl is a lower alkyl.
• Carbocyclic aryl refers to an aryl group wherein the ring atoms are carbon.
• Heterocyclic aryl refers to an aryl group having from 1 to 3 heteroatoms as ring atoms, the remainder of the ring atoms being carbon. Heteroatoms include oxygen, sulfur, and nitrogen.
• Hydrocarbyl refers to a hydrocarbon radical having only carbon and hydrogen atoms.
• the hydrocarbyl radical has from 1 to 20 carbon atoms, more preferably from 1 to 12 carbon atoms and most preferably from 1 to 7 carbon atoms.
• Substituted hydrocarbyl refers to a hydrocarbyl radical wherein one or more, but not all, of the hydrogen and/or the carbon atoms are replaced by a halogen, nitrogen, oxygen, sulfur or phosphorus atom or a radical including a halogen, nitrogen, oxygen, sulfur or phosphorus atom, e.g. fluoro, chloro, cyano, nitro, hydroxyl, phosphate, thiol, etc.
• Amide refers to -C(O)-NH-R', wherein R' is alkyl, aryl, alkylaryl or hydrogen.
• Thioamide refers to -C(S)-NH-R, wherein R is alkyl, aryl, alkylaryl or hydrogen.
• “Amine” refers to a — N(R")R" group, wherein R" and R'" are independently selected from the group consisting of alkyl, aryl, and alkylaryl.
• Thioether refers to — S— R", wherein R" is alkyl, aryl, or alkylaryl.
• Compounds were also assessed for their ability to activate or block activation of the human S1P3 receptor in T24 cells stably expressing the human S1P3 receptor.
• Ten thousand cells/well were plated into 384-well poly-D-lysine coated plates one day prior to use.
• the growth media for the S1P3 receptor expressing cell line was McCoy's 5 A medium supplemented with 10% charcoal-treated fetal bovine serum (FBS), 1% antibiotic-antimycotic and 400 ⁇ g/ml geneticin.
• FBS charcoal-treated fetal bovine serum
• the cells were washed twice with Hank's Balanced Salt Solution supplemented with 20 mM HEPES (HBSS/Hepes buffer).
• the cells were then dye loaded with 2 uM Fluo-4 diluted in the HBSS/Hepes buffer with 1.25 mM Probenecid and incubated at 37 0 C for 40 minutes. Extracellular dye was removed by washing the cell plates four times prior to placing the plates in the FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices).
• Ligands were diluted in HBSS/Hepes buffer and prepared in 384-well microplates.
• the positive control, Sphingosine-1 -Phosphate (SlP) was diluted in HBSS/Hepes buffer with 4 mg/ml fatty acid free bovine serum albumin.
• the FLIPR transferred 12.5 ⁇ l from the ligand microplate to the cell plate and took fluorescent measurements for 75 seconds, taking readings every second, and then for 2.5 minutes, taking readings every 10 seconds. Drugs were tested over the concentration range of 0.61 nM to 10,000 nM. Data for Ca +2 responses were obtained in arbitrary fluorescence units and not translated into Ca +2 concentrations. IC50 values were determined through a linear regression analysis using the Levenburg Marquardt algorithm.
• NA is defined as “Not Active”
• ND is defined as “Not Determined”
• % efficacy is defined as “percent of receptor activity induced by a test compound at the highest dose test (10 ⁇ M) relative to the receptor activity induced by 5 nM sphingosine-1- phosphate.”
• % inhibition is defined as "percent of receptor activity induced by 5 nM sphingosine-1 -phosphate that is inhibited by a test compound at the highest dose tested (10 ⁇ M)."
• SlP increases capsaicin responsiveness of DRG neurons SlP pathway, S1P3, SlPl deregulated in multiple pain models (EHT/AGN) Glaucoma
• Angiogenesis disorders siRNA knockdown of SlPl and S1P3 inhibits angiogenesis S IP 1/3 subtypes expressed in VEC promote VEC migration promote barrier assembly and integrity
• RuC12(PPh3)4 Na: sodium NaOEt: sodium ethoxide
• NaBH 4 sodium borohydride
• NaBH 3 CN sodium cyanoborohydride
• THF tetrahydrofuran
• Pd(PPlIs) 4 palladium tetrakis(tripenylphosphine)
• R Me 11
• R CF 3 14
• R 1 H-Pr 20
• R 2 H-C 9 H 19 10
• R W-C 9 H 19 15
• R 1 CF 3
• Example 1 l-(2-p-Tolylethynyl)benzene (Compound 1).
• General Procedure A To a solution of lithium phenylacetylide (15.2 ml, 15.2 mmol) in DME (20 ml) under Argon at -78 0 C was added triisopropoxylborane (3.5 ml, 15.2 mmol). The mixture was stirred at -78 0 C for 1.5 hours.
• Example 2 l-(2-(4-Ethylphenyl)ethynyl)benzene (Compound 2) Following General Procedure A, lithium phenylacetylide (14.0 ml, 14.1 mmol), triisopropoxylborane (3.2 ml, 14.1 mmol), l-bromo-4-ethylbenzene (2 g, 10.8 mmol) and Pd(PPh 3 ) 4 (375 mg, 0.32 mmol) in DME (30ml) and THF (10 ml) were reacted to obtain the title compound as a yellow oil.
• Example 4 l-(2-(4-Trifluoromethylphenyl)ethynyl)benzene (Compound 4) Following General Procedure A, lithium phenylacetylide (17.3 ml, 17.3 mmol), triisopropoxylborane (4.0 ml, 17.3 mmol), l-bromo-4-trifluoromethyl-benzene (3 g, 13.3 mmol) and Pd(PPh 3 ) 4 (462 mg, 0.40 mmol) in DME (40 ml) and THF (15 ml) were reacted to obtain the title compound as a yellow solid.
• Example 5 l-(2-(4-n-Nonanylphenyl)ethynyl)benzene (Compound 5) Following General Procedure A, lithium phenylacetylide (12.4 ml, 12.4 mmol), triisopropoxylborane (2.8 ml, 12.4 mmol), l-bromo-4-n-nonanylbenzene (2.7 g, 9.5 mmol) and Pd(PPh 3 ) 4 (331 mg, 0.40 mmol) in DME (30 ml) and THF (10 ml) were reacted to obtain the title compound as a yellow solid.
• Example 6 l-Phenyl-2-p-tolylethane-l,2-dione (Compound 6).
• General Procedure B To a suspension of iodosobenzene (2.5 g, 11.3 mmol) in CH 2 Cl 2 (30 ml) was added RuCl 2 (PPh 3 ) 4 (45 mg, 0.04 mmol). A solution of 1 -(2-p-tolylethynyl)benzene (Compound 1, 835 mg, 4.3 mmol) in CH 2 Cl 2 (10 ml) was cannulated into the suspension. The resulting mixture was stirred at room temperature overnight resulting in a homogeneous solution. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (10% ethyl acetate in hexane) to produce the title compound as a yellow oil.
• Example 7 l-(4-Ethyl-phenyl)-2-phenyl-ethane-l,2-dione (Compound 7).
• iodosobenzene 1.5g, 6.7 mmol
• RuCl 2 (PPh S ) 4 21 mg, 0.02 mmol
• l-(2-(4-ethylphenyl)ethynyl)benzene Compound 2, 360 mg, 1.8 mmol
• CH 2 Cl 2 (30 ml)
• Example 8 l-(4-n-Propyl-phenyl)-2-phenyl-ethane-l,2-dione (Compound 8).
• iodosobenzene 2.2 g, 10.0 mmol
• RuCl 2 (PPhS) 4 38 mg, 0.04 mmol
• l-(2-(4-/?-propylphenyl)ethynyl)benzene Compound 3, 860 mg, 3.9 mmol
• CH 2 Cl 2 50 ml
• Ethyl 5,6-Diphenyl-l,2,4-triazine-3-carboxylate (Compound 11).
• General Procedure C A solution of ethyl oxalamidrazonate (Compound 37, 236 mg, 1.8 mmol) in ethanol (20 ml) was cannulated slowly into a stirring solution of benzil (500 mg, 2.4 mmol) in ethanol (20 ml) under argon at room temperature. After the addition was completed, the reaction was stirred at room temperature overnight ( ⁇ 16 hours). The mixture was then refluxed for 1 hour. The solvent was removed in vacuo, and the crude products was purified by column chromatography (silica gel, 20% ethyl acetate in hexane) to obtain the title compound as an oil.
• Example 13 and Example 18 Ethyl 6-(4-Ethylphenyl)-5-phenyl -l,2,4-triazine-3-carboxylate (Compound 13), and Ethyl 5-(4-Ethylphenyl)-6-phenyl-l,2,4-triazine-3-carboxylate (Compound 18).
• Ethyl 5-Phenyl-6-(4-propylphenyl)-l,2,4-triazine-3-carboxylate (Compound 14). Following General Procedure C, ethyl oxalamidrazonate (Compound 37, 460 mg, 1.5 mmol) and l-(4-n-propylphenyl)-2-phenyl-ethane-l,2-dione (Compound 8, 588 mg, 2.3 mmol) in ethanol (40 ml) were reacted and the product was recrystalized from 5% ethyl acetate in hexane to produce the title compound as yellow solid.
• Example 15 and Example 19 Ethyl 6-(4-Trifluoromethyl-phenyl)-5-phenyl -1,2,4— triazine-3-carboxylate (Compound 15), and Ethyl 5-(4-Trifluoromethylphenyl)-6-phenyl- 1,2,4— triazine-3-carboxylatate (Compound 19).
• Ethyl 6-Phenyl-5-p-tolyl-pyridine-2-carboxylate (Compound 22). Following General Procedure D, ethyl 5-phenyl-6-/?-tolyl-l,2,4— triazine-3-carboxylate (Compound 12, 177 mg, 0.56 mmol) and crude 1-vinylpyrrolidine (Compound 38, 730 mg) in CHCl 3 (10 ml) were reacted to produce the title compound as a yellow solid.
• Ethyl 6-Phenyl-5-(4-propylphenyl)-pyridine-2-carboxylate (Compound 24). Following General Procedure D, ethyl 5-phenyl-6-(4-propyl-phenyl)- 1,2,4— triazine-3-carboxylate (Compound 14), (153 mg, 0.46 mmol) and crude 1- vinylpyrrolidine (Compound 38, 2 g) in CHCl 3 (10 ml) were reacted to produce the title compound as a yellow oil.
• Ethyl 6-Phenyl-5-(4-trifluoromethylphenyl)-pyridine-2-carboxylate (Compound 25). Following General Procedure D, ethyl 6-(4- tirfluoromethylphenyl)-5 -phenyl -l,2,4-triazine-3-carboxylate (Compound 15), (378 mg, 1.01 mmol) and crude 1-vinylpyrrolidine (Compound 38, 780 mg) in CHCl 3 (10 ml) were reacted to produce the title compound as a yellow oil.
• Example 26 Ethyl 5-(4-Ethylphenyl)-3-methyl-6-phenyl-pyridine-2-carboxylate (Compound 26). Following General Procedure D, ethyl 6-(4-ethylphenyl)-5- phenyl-1,2,4— triazine-3-carboxylate (Compound 13, 200 mg, 0.60 mmol) and crude 1-propenyl-pyrrolidine (Compound 39, 2 g) in CHCI3 (10 ml) were reacted to produce the title compound as a yellow oil.
• Example 27 Ethyl 5-Phenyl-6-p-tolyl-pyridine-2-carboxylate (Compound 27). Following General Procedure D, ethyl 6-phenyl-5-/?-tolyl-l,2,4-triazine-3-carboxylate (Compound 17, 361 mg, 1.13 mmol) and crude 1-vinylpyrrolidine (Compound 38, 806 mg) in CHCl 3 (10 ml) were reacted to produce the title compound as a yellow oil.
• Example 29 Ethyl 5-Phenyl-6-(4-trifluoromethyl-phenyl)-pyridine-2-carboxylate (Compound 29). Following General Procedure D, ethyl 5-(4- trifluoromethylphenyl)-6-phenyl-l,2,4 ⁇ triazine-3-carboxylate (Compound 19, 1 g, 2.68 mmol) and crude 1-vinylpyrrolidine (Compound 38, 1.4 g) in CHCI3 (20 ml) were reacted to produce the title compound as a yellow oil.
• Methyl 5,6-diphenylpyridine-2-carboxylate (Compound 30).
• General Procedure E A solution of ethyl 5,6-diphenylpyridine-2-carboxylate (Compound 21, 30 mg, 0.1 mmol) and cone. H 2 SO 4 (3 drops) in MeOH (5 ml) was heated at 50 0 C overnight. The mixture was diluted with water, and the products were extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over Na 2 SO 4 . The filtered solvent was concentrated in vacuo and the residue was purified by column chromatography (20 % ethyl acetate in hexane) to obtain the title compound as a yellow solid.
• Methyl 5-(4-Ethylphenyl)-6-phenyl-pyridine-2-carboxylate (Compound 32). Following General Procedure E, ethyl 5-(4-ethylphenyl)- 6-phenylpyridine-2- carboxylate (Compound 23, 45 mg, 0.15 mmol) and cone. H 2 SO 4 (3 drops) in MeOH (3 ml) were reacted to produce title compound as a yellow solid.
• Example 35 Methyl 5-Phenyl-6-(4-trifluoromethylphenyl)-pyridine-2-carboxylate (Compound 35). Following General Procedure E, ethyl 5-phenyl-6-(4- trifluoromethylphenyl)-pyridine-2-carboxylate (Compound 29, 103 mg, 0.28 mmol) and cone. H 2 SO 4 (5 drops) in MeOH (5 ml) were reacted to produce the title compound as a white solid.
• Ethyl oxalamidrazonate (Compound 37).
• a solution of anhydrous hydrazine (0.5 ml, 15.0 mmol) in ethanol (5 ml) was added dropwise to a stirred solution of ethyl thiooxamate (2 g, 15.0 mmol) in ethanol (45 ml) under argon at room temperature.
• the mixture was stirred at room temperature for 1 hour, and the solvent was removed in vacuo and dried under high vacuum to get a white solid which was maintained in argon atmosphere after drying. The white solid was used in the next step without further purification.
• Example 38 1-vinylpyrrolidine (Compound 38).
• General Procedure F To a suspension of K2CO3 (3.8 g, 28.1 mmol) and pyrrolidine (1 g, 14.0 mmol) in toluene (10 ml) was added acetylaldehyde under argon at 0 0 C. The mixture was stirred at room temperature overnight. After filtration, the filtrate was concentrated in vacuo to yield a crude oil which was used in the next reaction without further purification.
• Example 39 To a suspension of K2CO3 (3.8 g, 28.1 mmol) and pyrrolidine (1 g, 14.0 mmol) in toluene (10 ml) was added acetylaldehyde under argon at 0 0 C. The mixture was stirred at room temperature overnight. After filtration, the filtrate was concentrated in vacuo to yield a crude oil which was used in the next reaction without further purification.
• Example 39 To a suspension of K2
• the resulting white precipitate was filtered off, rinsed with THF (10 ml), and the combined filtrates were added to a solution OfNaBH 4 (945 mg, 24.9 mmol) in H 2 O (20 ml) slowly in order to maintain an internal temperature of 10 0 C to 15 0 C. After the addition was completed, the reaction was stirred at room temperature for 4 hours, and then it was made acidic with HCl (20 %). The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with NaHCO 3 (aq), and water, and brine, and dried over Na 2 SO 4 . The filtered solution was concentrated in vacuo, and the residue was purified by column chromatography (20 % ethyl acetate in hexane) to yield a white solid.
• Example 55 and Example 60 ⁇ -Phenyl-S-p-tolylpyridine-l-carbaldehyde (Compound 55) and (6-phenyl-5-p- tolylpyridin-2-yl)methanol (Compound 60).
• ethyl ⁇ -phenyl-S-p-tolylpyridine ⁇ -carboxylate (Compound 22, 1.1 g, 3.47 mmol) and DIBAL-H (5.2 ml, 5.21 mmol, 1.0M in cyclohexane) in CH 2 Cl 2 (30 ml) were reacted to produce Compound 55 and Compound 60 after separation by column chromatography (silica gel, 15% ethyl acetate in hexane).
• Example 76 l-(5,6-Diphenyl-pyridin-2-yl)-propan-l-one (Compound 76).
• ethyl 5,6-diphenylpyridine-2-carboxylate Compound 21, 267 mg, 0.81 mmol
• toluene 5 ml
• N, N'-dimethylethylenediamine DMEDA, 85 mg, 0.97 mmol
• triethylaluminum 2.6 ml, 2.64 mmol, 1 M in hexane
• Example 81 l-(5,6-Diphenyl-pyridin-2-yl)-propan-l-one Oxime (Compound 81). Following General Procedure P, l-(5,6-diphenyl-pyridin-2-yl)-propan-l-one (Compound 76, 90 mg, 0.31 mmol), NH 2 OH-HCl (87 mg, 1.25 mmol) and pyridine (272 mg, 0.27 mmol) in EtOH (2 ml) were reacted to give title compound as a white solid.
• Example 82 l-(5,6-Diphenyl-pyridin-2-yl)-ethanone O-Methyloxime (Compound 82).
• General Procedure Q To a suspension of NaH (20 mg, 0.80 mmol) in THF (2 ml) at 0 0 C was added a solution of l-(5,6-diphenyl-pyridin-2-yl)-ethanone oxime (Compound 80, 46 mg, 0.16 mmol) in THF (1 ml). After the mixture was stirred at the same temperature for 1 hour, MeI (140 mg, 0.99 mmol) was added and the solution was stirred overnight at room temperature.
• Example 84 [6-Phenyl-5-(4-trifluoromethyl-phenyl)-pyridin-2-yl] -ethanone O-Methyloxime (Compound 84). Following General Procedure P, l-[6-phenyl-5-(4- trifluoromethyl-phenyl)-pyridin-2-yl]-ethanone (Compound 77, 15 mg, 0.04 mmol), NH 2 OMe-HCl (15 mg, 0.18 mmol) and pyridine (14 mg, 0.18 mmol) in EtOH (2 ml) were reacted to give title compound as a white solid. (12 mg, 75%).
• Example 85 l-[6-Phenyl-5-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-propan-l-one O- Methyloxime (Compound 85).
• l-[6-phenyl-5-(4- trifluoromethyl-phenyl)-pyridin-2-yl]-propan-l-one (Compound 78) (24 mg, 0.07 mmol), NH 2 OMe-HCl (23 mg, 0.25 mmol) and pyridine (21 mg, 0.28 mmol) in EtOH (2 ml) were reacted to give title compound as a white solid.
• Example 92 6-Methoxymethyl-2,3-diphenyl-pyridine (92).
• a solution of 5,6-diphenylpyridin- 2-yl)methanol (Compound 90, 15 mg, 0.06 mmol), MeI (0.1 ml), K 2 CO 3 (50 mg) and KOH (5N, 5 drops) in acetone was heated at 56 0 C over night.
• the mixture was diluted with water and the product was extracted with ethyl acetate. .
• the organic layer was washed with water, and brine, and dried over Na 2 SO 4 .
• the filtered solvent was concentrated in vacuo, and the residue was purified by silica gel chromatography (15 % ethyl acetate in hexane) to give title compound as a solid.
• Methyl S ⁇ -Diphenyl-pyrazine-l-carboxylate (93).
• benzyl 500 mg, 2.38 mmol
• 2,3 -diaminopropionic acid monohydro chloride (334 mg, 2.38 mmol)
• NaOH 380 mg, 9.51 mmol
• H 2 SO 4 1 ml was added dropwise and the whole mixture was stirred under reflux for 3 hours. MeOH was removed and the residue was dissolved in water, extracted with ethyl acetate.
• Example 94 l-(5,6-Diphenyl-pyrazin-2-yl)-ethanone (94).
• methyl 5,6-diphenyl-pyrazine-2-carboxylate Compound 93, 83 mg, 0.29 mmol
• Me 3 Al 0.4 ml, 2M in toluene
• DMEDA 28 mg, 0.32 mmol
• Example 95 l-(5,6-Diphenyl-pyrazin-2-yl)-propan-l-one (95).
• methyl 5,6-diphenyl-pyrazine-2-carboxylate (Compound 93) (92 mg, 0.32 mmol), Et 3 Al (0.9 ml, IM in hexane), DMEDA (38 mg, 0.35 mmol) in toluene was reacted to afford the title compound.
• Example 106 l-Methyl-5,6-diphenyl-lH-pyrimidin-2-one (106).
• Example 96 Methyl 4,5-Diphenyl-pyrimidine-2-carboxylate (96).
• Pd(OAc) 2 (2.1 mg) and DPPF (13 mg) were added and CO (g) was bubbled through the solution.
• the reaction was heated to 110 0 C in a sealed tube for 2 days.
• Example 109 (£)-3-(4-Isopropylphenyl)prop-2-en-l-ol (Compound 109).
• 4-iso-propylcinnamic acid (3 g, 15.8 mmol)
• ethyl chloro formate (1.6 ml, 15.8 mmol)
• triethylamine (2.2 ml, 15.8 mmol) in THF (100ml) were reacted to produce a mixed anhydride, which was then were reacted with NaBH 4 (1.3 g, 34.7 mmol) in H 2 O (30 ml) to produce title compound as a white solid.
• NaBH 4 1.3 g, 34.7 mmol
• Example 110 (£)-3-(4-Isopropylphenyl)acrylaldehyde (Compound 110).
• oxalyl chloride (9.5 ml, 19.0 mmol, 2M in CH 2 Cl 2 ), DMSO (1.8 ml, 25.3 mmol), (£)-3-(4-isopropylphenyl)prop-2-en-l-ol (Compound 109, 2.2g, 12.6 mmol) and triethylamine (7.1 ml, 50.7 mmol) in CH 2 Cl 2 (100 ml) were reacted to obtain the title compound as an oil.
• Example 113 (E)-3-(Dimethylamino)-l-phenyl-2-p-tolylprop-2-en-l-one (Compound 113).
• a solution of l-phenyl-2-/?-tolylethanone (2 g, 9.5 mmol) and dimethylformamide dimethylacetal (4.5 g, 38.1 mmol) in DMF (30 ml) was heated at 75 0 C for 24 hours. Solvents were removed under high vacuum to obtain the title compound as a yellow oil, which was used directly in the next step without purification.
• the present invention contemplates and includes a compound comprising a 6-membered heteroaromatic ring including one, two or three enchained nitrogen atoms at the 1 , or 1 and 3 or 1 , 3 and 4 positions, respectively, and the remaining ring atoms being carbon, an aryl radical directly bonded to said 6-membered heteroaromatic ring at both of the 5 and 6 positions and a side chain at the 2 position of said 6-membered heteroaromatic ring, wherein said side chain terminates with an end group selected from the group consisting of a phosphonic acid, a lower alkyl ester thereof, a carboxylic acid, a lower alkyl ester thereof, a lower alkyl ether and a lower alkylcarboxy and a compound comprising a 6- membered heteroaro

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