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Definitions

• the present invention relates to substituted aryl-benzylamine compounds, to processes for their production, to their use as pharmaceuticals and to pharmaceutical compositions comprising them.
• the compounds of formula (I) in free form or in pharmaceutically acceptable salt form exhibit valuable pharmacological properties, for example for preventing or treating diseases or disorders which are mediated by lymphocyte interactions, or for example as S1P receptor modulators, e.g. S1P1 receptor antagonists and hence are useful for therapy susceptible thereto.
• the present invention provides a compound of formula (I) or a salt thereof;
• R1 is hydrogen, halogen or Ci-C 6 alkyl optionally substituted by halogen;
• R2 is halogen, C C 6 alkyl optionally substituted by halogen, cyano, or Ci-C e alkoxy optionally substituted by halogen;
• R1 and R2 together with the C-atoms to which they are attached form an aryl ring with 6-10 carbon atoms, which may optionally be substituted by 1-4 substituents selected from cyano, d-C 4 -alkyl optionally substituted by halogen, C C 4 -alkoxy optionally substituted by halogen, halogen;
• R3 is hydrogen, halogen or d-C 6 alkyl optionally substituted by halogen
• R4 is hydrogen, C 3 -C 6 cycloalkyl or C C 6 alkyl optionally substituted by halogen;
• R5 is hydrogen or Ci-C 6 alkyl
• R6 and R7 are independently selected from H and C C 6 alkyl or they may form together with the carbon atom to which they are attached a 3 - 7 membered saturated carbocyclic ring;
• R8 and R9 are independently selected from H and C Ce alkyl, or they may form together with the atoms to which they are attached a 4 - 7 membered heterocyclic ring optionally substituted one or more times by C C 6 -alkyl optionally substituted by halogen, trifluoro methyl, hydroxy, C C 6 alkoxy, amino;
• n 1 , 2, 3 or 4 ;
• R10 is hydrogen, C ⁇ -C 6 alkyl, amino, hydroxy, or C C 6 alkoxy;
• R is selected from H ; phenyl being optionally substituted by Ci-C 6 alkyl, d-C 6 alkoxy, halogen or hydroxy ; and C C 6 alkyl optionally substituted by C r C 6 alkoxy, halogen, hydroxy, or phenyl optionally substituted by C r C 6 alkyl, C C 6 alkoxy, halogen or hydroxy,
• i, 2, 3 and X4 are each independently selected from N or CR11 ,
• R11 in each case being independently selected from H, halo, cyano, Ci-C 6 alkoxy, Ci-C 6 alkyl optionally substituted by halo; or -S0 2 -C C 6 alkyl; and
• Y stands in each occurrence independently for CR12R13 wherein R12 and R13 are independently selected from H and d-C 6 alkyl.
• the invention provides a compound of formula (II) or a salt thereof,
• R1 is hydrogen, halogen or C C 6 alkyl optionally substituted by halogen
• R2 is halogen, C C 6 alkyl optionally substituted by halogen, cyano, or C C 6 alkoxy optionally substituted by halogen;
• R1 and R2 together with the C-atoms to which they are attached form an aryl ring with 6-10 carbon atoms, which may optionally be substituted by 1-4 substituents selected from cyano, C ⁇ C ⁇ alkyl optionally substituted by halogen, (VC ⁇ alkoxy optionally substituted by halogen, and halogen;
• R3 is hydrogen, halogen or C C 6 a Iky I optionally substituted by halogen;
• R4 is hydrogen, C 3 -C 6 cycloalkyl or Ci-C 6 alkyl optionally substituted by halogen;
• R5 is hydrogen or C ⁇ Ce alkyl
• R6 and R7 are independently selected from H and C -C 6 alkyl, or they may form together with the carbon atom to which they are attached a 3 - 7 membered saturated carbocyclic ring;
• n 1, 2, 3 or 4 ;
• R10 is hydrogen, C C 6 alkyl, amino, hydroxy, or C,-C 6 alkoxy
• R is selected from H; phenyl being optionally substituted by C C 6 alkyl, CpCe alkoxy, halogen or hydroxy; and C ⁇ Ce alkyl optionally substituted by Ci-C 6 alkoxy, halogen, hydroxy, or phenyl, said phenyl being optionally substituted by C C 6 alkyl, C C 6 alkoxy, halogen or hydroxy;
• Xi, X 2 , X 3 and X4 are each independently selected from N or CR11 ,
• R11 in each case being independently selected from H, halo, cyano, C ⁇ -C 3 alkoxy, C C 6 alkyl optionally substituted by halo; or -SOz-C C 6 alkyl;
• Y stands in each occurrence independently for CR12R13 wherein R12 and R13 are independently selected from H and C C e alkyl optionally substituted by halogen.
• R1 is H or methyl
• R2 is chloro
• R1 and R3 are both methyl
• R3 is methyl
• R4 is methyl or C C 6 alkyl optionally substituted by halogen, or R4 is in particular trifluoromethyl;
• R5 is H;
• R6 is H
• R7 is H
• R8 is H or methyl; in particular H;
• R8 and R9 form together with the atoms to which they are attached a 5 membered heterocyclic ring
• R10 is H, methyl or ethyl
• R10 is hydrogen
• R11 is H
• R11 is methyl
• R11 is chloro or cyano
• R12 is H
• R13 is H
• X 3 and X4 are each CR11 and R11 stands for methyl;
• X 3 stands for N
• Y stands for CH 2 ;
• R is H
• n stands for 1 or 2, especially 2;
• X 3 is CR11 and R11 stands for methyl
• R2 is chloro and R3 is methyl
• R2 is chloro, R3 is methyl and R4 is trifluoromethyl;
• Xi, X 2 , X3 and X are each independently CR11
• R1 and R2 together with the C-atoms to which they are attached form an aryl ring with 6-10 carbon atoms, especially phenyl, naphthyl or tetrahydronaphthyl, which may optionally be substituted by 1-4 substituents selected from cyano, C r C -alkyl optionally substituted by halogen, C C -alkoxy optionally substituted by halogen, and halogen;
• the invention provides compounds in accordance to formula (I) and or formula (II) or a salt thereof wherein R1 and R stand for hydrogen, wherein the other variables are as defined above.
• the invention provides compounds in accordance to formula (I) and or formula (II) or a salt thereof wherein n is 2, and wherein the other variables are as defined above.
• the invention provides compounds in accordance to formula (I) and or formula ⁇ II) or a salt thereof wherein any of X 3 and X are each CR11 and wherein R11 stands for methyl, wherein the other variables are as defined above.
• the invention provides compounds in accordance to formula (I) and or formula ⁇ II) or a salt thereof wherein X 3 is CR11 and wherein R11 stands for methyl, wherein the other variables are as defined above.
• the invention provides compounds in accordance to formula ⁇ I) and or formula ⁇ II) or a salt thereof wherein R4 is trifluoromethyl and R5 is hydrogen, wherein the other variables are as defined above.
• the invention provides compounds in accordance to formula ⁇ I) and or formula (II) or a salt thereof wherein R2 is chloro, R3 is methyl, R4 is trifluoromethyl and R is hydrogen, wherein the other variables are as defined above.
• the invention provides compounds in accordance to formula (I) and or formula ⁇ II) or a salt thereof wherein X t , X 2 , X 3 and X4, are each independently CR11 , R11 is hydrogen, R2 is chloro, R3 is methyl, R4 is trifluoromethyl and R is hydrogen, wherein the other variables are as defined above.
• the invention provides any one of compounds in accordance to the working examples 1 - 87 as described in the experimental section or a
• the invention provides any one of compounds in accordance to the working examples 1 - 87 as described in the experimental section or a
• the invention provides a compound of the formula (I), which is selected from:
• alkyl may be a linear or branched hydrocarbon moiety having 1 to 20 carbon atoms. Unless otherwise provided, alkyl refers to hydrocarbon moieties having 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
• C Ce alkyl represents, for example: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tertiary butyl, 2,2-dimethylpropyl, n-pentyl, neo-pentyl, n-hexyl, iso-hexyl and the like.
• cyc!oa!kyl represents a cyclic hydrocarbon containing from 3 to 12 ring atoms preferably from 3 to 6 ring atoms. Cyc!oalkyl represents, for example:
• a cycloalkyl may optionally be substituted by C C 6 alkyl, trifluoromethyl, C 3 -C e cycloalkyl, halogen, hydroxy, C ⁇ -C 6 alkoxy, acyl, Ci-C 6 aikyl-C(0)-0-, aryl-O-, heteroaryl-O-, amino, thiol, Ci-C 6 alkyl-S-, aryl-S-, nitro, cyano, carboxy, C C 6 alkyl-O-C(O)-, carbamoyl, C C e alkyl-S(O)-, sulfonyl, sulfonamide, or phenyl.
• acyl is a radical R d CO wherein R d is H, C 1-6 alkyl, C ⁇ cycloalkyl,
• acyl is C 1-6 alkyl-CO, C 1-6 alkoxy-CO, benzyloxy-CO or benzyl-CO; especially acyl is C 1-6 alkyl- CO or t-butoxycarbonyl or acetyl (CH 3 CO).
• alkoxy refers to alkyl-O-, wherein alkyl is defined herein above.
• An alkoxy group may be branched or unbranched.
• C C 6 alkoxy represents, for example: methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy or tertiary butoxy.
• Alkoxy includes C 3 -C 6 cycloalkyloxy and C 3 -C 6 cycloalkyl - C C 6 alkyloxy.
• Halo or halogen represents chloro, fluoro, bromo or iodo.
• halo or halogen represents chloro or fluoro.
• Alkyl as defined herein may be substituted by one or more halo groups as defined herein and may also be named haloalkyl.
• the haloalkyl can be monoha!oalkyl, dihaloalkyl or polyhaloalkyi including perhaloalkyl.
• a monohaloalkyl can have one iodo, bromo, chloro or fluoro within the alkyl group.
• Dihaloalkyl and polyhaloalkyi groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl.
• Alkyl is for example C r C 6 alkyl, and halo is for example fluoro and/or chloro.
• Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichioromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyi,
• Alkoxy as defined herein may be substituted by one or more halo groups as defined herein.
• Alkoxy substituted by halo may be monohaloalkoxy, dihaloalkoxy, trihaloalkoxy or pdyhaioalkoxy.
• a monohaloalkoxy may have one iodo, bromo, chloro or fluoro within the alkoxy group.
• Dihaloalkoxy and pdyhaioalkoxy groups can have two or more of the same halo atoms or a combination of different halo groups within the alkoxy.
• Alkoxy is for example C C 6 alkoxy
• halo is for example fluoro and/or chloro.
• Non-limiting examples of haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, pentafluoroethoxy,
• aryl refers to an aromatic hydrocarbon group having 5-20 carbon atoms in the ring portion. Typically, aryl is monocyclic, bicyclic or tricyclic aryl having 5- 20 carbon atoms, also monocyclic or bicyclic having from 6 - 10 carbon atoms.
• aryl refers to an aromatic substituent which can be a single aromatic ring, or multiple aromatic rings that are fused together.
• the term “aryl” further refers to an aromatic ring as defined herein substituted with 1 to 5 substituents independently selected from the groups consisting of hydroxy I, thiol, cyano, nitro, C C 4 -alkyl, C r C 4 -alkenyl, C C 4 -alkynyl, C r C 4 -alkoxy, C C 4 -thioalkyl, C C 4 - alkenyloxy, (-VC ⁇ -alkynyloxy, halogen, trifluoromethyl, CVCValkylcarbonyl, carboxy, C C 4 -alkoxycarbonyl, amino, (VC -alkylamino, di- C C 4 -alkylamino, C C 4 - alkylaminocarbonyl, di- (VC -alkylaminocarbonyl
• Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl, each of which may optionally be substituted by 1-4 substituents, such as hydroxy I, cyano, C C 4 - alkyl, trifluoromethyl, ( CValkoxy, halogen, C C 4 - al ky I carbon yl, carboxy, C C 4 -alkoxycarbonyl, carbamoyl, sulfonyl, sulfamoyl, alkylsulfamoyl, C C -alkylaminosulfonyl.
• substituents such as hydroxy I, cyano, C C 4 - alkyl, trifluoromethyl, ( CValkoxy, halogen, C C 4 - al ky I carbon yl, carboxy, C C 4 -alkoxycarbonyl, carbamoyl, sulfonyl, sulfamoyl, alkyls
• Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl, which may optionally be substituted by 1-4 substituents selected from cyano, C C 4 - alkyl, CrCValkoxy, and halogen.
• heterocyclyl or “heterocyclo” or “heterocyclic ring” refers to a saturated or unsaturated non-aromatic ring or ring system, e.g., which is a 4-, 5-, 6-, or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic or 10-, 1 1-, 12-, 13-, 14- or 15-membered tricyclic ring system and contains at least one heteroatom selected from O, S and N, where the N and S can also optionally be oxidized to various oxidation states.
• the heterocyclic group can be attached at a heteroatom or a carbon atom.
• the heterocyclyl may include fused or bridged rings as well as spirocyclic rings.
• heterocycles include tetrahydrofuran (THF), dihydrofuran, 1 , 4- dioxane, morpholine, 1 ,4-dithiane, piperazine, piperidine, 1 ,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1 ,3-dioxane, 1 ,3-dithiane, oxathiane, thiomorpholine, and the like.
• heterocyclyl further refers to heterocyclic groups as defined herein substituted with 1 to 5 substituents independently selected from the groups consisting of d-Ce-alkyl, trifluoromethyl, C 3 -C 6 cycloalkyl, halogen, hydroxy, C C 6 alkoxy, acyl, C C 6 alkyl-C(0)-0-, aryl-O-, heteroaryl-O-, amino, thiol, C C 6 alkyl-S-, aryl-S-, nitro, cyano, carboxy, C C 6 alkyl-O-C(O)-, carbamoyl, C ⁇ Ce alkyl-S(O)-, sulfonyl, sulfonamido, and phenyl.
• Heterocyclyl may be optionally substituted one or more times by C C 6 -alkyl, trifluoromethyl, C 3 -C 6 cycloalkyl, halogen, hydroxy, C -C 6 alkoxy, acyl, C C 6 alkyl-C(O)- 0-, aryl-O-, heteroaryl-O-, amino, thiol, C r C 6 alkyl-S-, aryl-S-, nitro, cyano, carboxy, C C 6 alkyl-O-C(O)- or carbamoyl, especially optionally substituted one or more times by (VCe-alkyl, trifluoromethyl, C 3 -C 6 cycloalkyl, halogen, hydroxy, C C 6 alkoxy, or acyl.
• heteroaryl refers to a 5-14 tnembered monocyclic- or bicyclic- or tricyclic-aromatic ring system, having 1 to 8 heteroatoms selected from N, O or S.
• the heteroaryl is a 5-10 tnembered ring system (e.g., 5-7 membered monocycle or an 8-10 membered bicycle) or a 5-7 membered ring system.
• heteroaryl may further refer to heteroaryl groups as defined herein substituted with 1 to 5 substituents independently selected from the groups consisting of hydroxyl, thiol, cyano, nitro, Ci-C 4 -alkyl, Ci-C 4 -alkenyl, CrC 4 -alkynyl, C1-C4- alkoxy, Ci-C 4 -thioalkyl, CrC 4 -alkenyloxy, CrC 4 -alkynyloxy, halogen, C r C 4 - alkylcarbonyl, carboxy, CrC 4 -alkoxycarbonyl, amino, Ci-C 4 -alkylamino, dr- Ci- C 4 -alkylamino, C C -alkylaminocarbonyl, di- C C -alkylaminocarbonyl, C1-C4- alkylcarbonylamino, Ci-C 4 -alkylcarbonyl(Ci-C 4
• Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5- imidazolyl, 3-, 4-, or 5- pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5- oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2, 3-triazolyl, tetrazolyl, 2- , 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyi, and 2-, 4-, or 5- pyrimidinyl, which may be optionally substituted by 1 to 4 substituents selected from hydroxyl, cyano, C r C 4 -alkyl, C r C 4 -alkenyl, C C 4 -alkynyl, (VC
• aryloxy refers to an -O-aryl wherein aryl is defined herein.
• heteroaryloxy refers to an -O-heteroaryl group, wherein heteroaryl is defined herein.
• the term “isomers” refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms.
• an optical isomer or “a stereoisomer” refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of for example a carbon atom. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound. "Enantiomers” are a pair of stereoisomers that are non- superimposable mirror images of each other.
• a 1 :1 mixture of a pair of enantiomers is a "racemic" mixture.
• the term is used to designate a racemic mixture where appropriate.
• "Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
• the absolute stereochemistry is specified according to the Cahn- Ingold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S.
• Resolved compounds whose absolute configuration is unknown can be designated ⁇ +) or ⁇ -) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
• Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as ( )- or (S).
• the present invention is meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures.
• Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.
• salt refers to an acid addition or base addition salt of a compound of the invention.
• Salts include in particular “pharmaceutical acceptable salts”.
• pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable effective.
• the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
• Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen, phosphate/dihydr
• Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
• Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
• Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
• Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
• the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
• Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
• Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
• the pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound, a basic or acidic moiety, by conventional chemical methods.
• such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
• a stoichiometric amount of the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like
• Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
• use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable.
• any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
• Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
• isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, i i c 13 C 14 C 15 N 18 F 3i p 32 p 35g se ⁇ 125, respective
• the invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3 H, 13 C, and 4 C , are present.
• Such isotopically labelled compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
• PET positron emission tomography
• SPECT single-photon emission computed tomography
• an 18 F or labeled compound may be particularly desirable for PET or SPECT studies.
• Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
• isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
• a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
• Isotopically-labeied compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeied reagents in place of the non-labeled reagent previously employed.
• solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, de- acetone, d 6 -DMSO.
• Compounds of the invention i.e. compounds of formula (I) that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co- crystals with suitable co-crystal formers.
• These co-crystals may be prepared from compounds of formula (I) by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of formula (I) with the co-crystal former under crystallization conditions and isolating co- crystals thereby formed.
• Suitable co-crystal formers include those described in WO 2004/078163.
• the invention further provides co-crystals comprising a compound of formula (I).
• the term "pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excjpients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
• a therapeutically effective amount of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
• a therapeutically effective amount refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviating, inhibiting, preventing and/or ameliorating a condition, or a disorder or a disease (i) mediated by lymphocytes interactions or sphingosine-1 -phosphate receptors, or (ii) associated with lymphocytes interactions or sphingosine-1 -phosphate receptors activity, or (iii) characterized by activity (normal or abnormal) of lymphocytes interactions or sphingosine-1 -phosphate receptors; or (2) reducing or inhibiting the activity of lymphocytes interactions or sphingosine-1-phosphate receptors.
• a therapeutically effective amount refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of lymphocytes interactions or sphingosine-1 -phosphate receptors.
• the term "subject" refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
• primates e.g., humans, male or female
• the subject is a primate.
• the subject is a human.
• the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
• the term “treat”, “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
• “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
• “treat ", "treating” or “treatment” refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
• “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
• treatment refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
• “treat”, “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
• a subject is "in need of a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
• any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)- configuration.
• each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 %
• a compound of the present invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (c/s or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
• Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
• any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
• a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-0,0'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid.
• Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
• HPLC high pressure liquid chromatography
• the compounds of the present invention may also form internal salts, e.g., zwitterionic molecules.
• the present invention also provides pro-drugs of the compounds of the present invention that converts in vivo to the compounds of the present invention.
• a pro-drug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a subject.
• the suitability and techniques involved in making and using pro-drugs are well known by those skilled in the art.
• Prodrugs can be conceptually divided into two non-exclusive categories, bioprecursor prodrugs and carrier prodrugs. See The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic Press, San Diego, Calif., 2001).
• bioprecursor prodrugs are compounds, which are inactive or have low activity compared to the corresponding active drug compound, that contain one or more protective groups and are converted to an active form by metabolism or solvolysis. Both the active drug form and any released metabolic products should have acceptably low toxicity.
• Carrier prodrugs are drug compounds that contain a transport moiety, e.g., that improve uptake and/or localized delivery to a site(s) of action.
• a transport moiety e.g., that improve uptake and/or localized delivery to a site(s) of action.
• the linkage between the drug moiety and the transport moiety is a covalent bond
• the prodrug is inactive or less active than the drug compound
• any released transport moiety is acceptably non-toxic.
• the transport moiety is intended to enhance uptake
• the release of the transport moiety should be rapid.
• it is desirable to utilize a moiety that provides slow release e.g., certain polymers or other moieties, such as cyclodextrins.
• Carrier prodrugs can, for example, be used to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological effects, increased site-specificity, decreased toxicity and adverse reactions, and/or improvement in drug formulation (e.g., stability, water solubility, suppression of an undesirable organoleptic or physiochemical property).
• lipophilicity can be increased by esterification of (a) hydroxyl groups with lipophilic carboxylic acids (e.g., a carboxylic acid having at least one lipophilic moiety), or (b) carboxylic acid groups with lipophilic alcohols (e.g., an alcohol having at least one lipophilic moiety, for example aliphatic alcohols).
• prodrugs are, e.g., esters of free carboxylic acids and S-acyl derivatives of thiols and O-acyl derivatives of alcohols or phenols, wherein acyl has a meaning as defined herein.
• Suitable prodrugs are often pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid, e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters, such as the co-(amino, mono- or di- lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters, the a-(lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, such as the pi valoyloxy methyl ester and the like conventionally used
• amines have been masked as ary I carbonyloxy methyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bundgaard, J. Med. Chem. 2503 (1989)).
• drugs containing an acidic NH group such as imidazole, imide, indole and the like, have been masked with N- acyloxymethyl groups (Bundgaard, Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.
• EP 039,051 (Sloan and Little) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
• the compounds of the present invention can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
• the compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the invention embrace both solvated and unsolvated forms.
• solvate refers to a molecular complex of a compound of the present invention
• solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like.
• solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like.
• hydrate refers to the complex where the solvent molecule is water.
• the compounds of the present invention including salts, hydrates and solvates thereof, may inherently or by design form polymorphs.
• compounds of the invention may be prepared by a reaction sequence involving reductive amination of an appropriate ketone with an appropriate aniline followed by halogen metal exchange with an appropriate organolithium reagent and subsequent quenching with DMF, and either reductive amination with an appropriate amino ester or amino acid followed by an optional deprotection step or alkyl addition using an appropriate Grignard reagent, oxidation of the alcohol with an appropriate oxidizing agent, and reductive amination with an appropriate amino ester or amino acid followed by an optional deprotection step as shown in Scheme 2 below:
• compounds of the invention may be prepared by a reaction sequence involving Buchwald coupling of an appropriate amine with an appropriate protected halobenzaldehyde or halo-pyridyl-carbaldehyde, deprotection, reductive amination with an appropriate amino ester or amino acid followed by an optional deprotection step as shown in Scheme 3 below:
• compounds of the invention may be prepared by a reaction sequence involving either reductive amination of an appropriate halo-benzaldehyde or halo-pyridyl- carbaldehyde with an appropriate amino ester or Lewis acid catalyzed Michael addition of an appropriate benzylamine with an appropriate ⁇ , ⁇ -unsaturated ester followed by Buchwald coupling with an appropriate amine and an optional deprotection step as shown in Scheme 4 below:
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier.
• the pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc.
• the pharmaceutical compositions of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions).
• compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifers and buffers, etc.
• the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.
• diluents e.g., lactose, dextrose, sucrose
• Tablets may be either film coated or enteric coated according to methods known in the art.
• compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
• Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
• excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
• the tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
• a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
• Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
• an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
• water or an oil medium for example, peanut oil, liquid paraffin or olive oil.
• compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
• Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
• Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.
• compositions for transdermal application include an effective amount of a compound of the invention with a suitable carrier.
• Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
• transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
• compositions for topical application include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g. , for delivery by aerosol or the like.
• topical delivery systems will in particular be appropriate for dermal application, e.g. , for the treatment of skin cancer, e.g. , for prophylactic use in sun creams, lotions, sprays and the like. They are thus particularly suited for use in topical, including cosmetic, formulations well-known in the art.
• Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and
• a topical application may also pertain to an inhalation or to an intranasal application. They may be conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable pro pel la nt.
• a dry powder either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids
• Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
• the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propeliants that may be desirable.
• the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
• excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
• Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
• Sprays can additionally contain customary propeliants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
• Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
• dosage forms can be made by dissolving or dispersing the compound in the proper medium.
• Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active compound in a polymer matrix or gel.
• Ophthalmic formulations are also contemplated as being within the scope of this invention.
• the present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water may facilitate the degradation of certain compounds.
• Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
• An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e. g., vials), blister packs, and strip packs.
• compositions and dosage forms that comprise one or more agents that reduce the rate by which the compound of the present invention as an active ingredient will decompose.
• agents which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc.
• BINAP 2,2'-Bis(diphenylphosphino)-1 , 1 '-binaphthalene
• DIPEA Ethyl-diisopropyl-amine, Hunig's base, DIEA
• PEPPSI-IPr (1 ,3-Bis(2,6-diisopropylphenyl)imidazolidene) ⁇ 3-chloropyridyl) palladium(ll) di chloride
• PS-CNBH 3 Polymer supported cyanoborohydride
• Xphos 2-Dicycl ohexyl phosphi no-2', 6'-trii sopropy I bi phenyl H-NMR spectra were recorded on a Bruker 400 MHz or a Bruker 500 MHz NMR spectrometer. Significant peaks are tabulated in the order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; v, very) and number of protons.
• Electron Spray Ionization (ESI) mass spectra were recorded on an Agilent 1100 Series mass spectrometer. Mass spectrometry results are reported as the ratio of mass over charge.
• Solvent A Water containing 3 mM ammonium acetate and 0.05% formic acid.
• Solvent B Acetonitrile containing 0.04% formic acid.
• Solvent A Water containing 3 mM ammonium acetate and 0.05% formic acid.
• Solvent B Acetonitrile containing 0.04% formic acid.
• LC/MS Method 3 HP1100 Agilent HPLC instrument equipped with PDA UV detector, Waters ZQ2000 mass spectrometer and Waters XBridge C18 (2.5 pm) 3 x 30mm column. Peak detection is reported at 210 nm wavelength.
• Solvent A Water containing 5 % (acetonitrile with 0.05% formic acid).
• Solvent B Acetonitrile containing 0.05% formic acid.
• Solvent A Water containing 3.75 mM ammonium acetate and 0.05% formic acid.
• Solvent B Acetonitrile containing 0.04% formic acid.
• Solvent A water (1800 mL), acetonitrile (200 mL), tetramethylammonium hydroxide (40 mL, 10% in water), phosphoric acid (4 mL)
• Solvent B water (500 mL), acetonitrile (1500 mL), tetramethylammonium hydroxide (40 mL, 10% in water), phosphoric acid (4 mL)
• Method A Separation was performed using a Chiralcel OJ 10 x 50 cm (20 ⁇ ) and n-heptane/EtOH as mobile phase with a flow of 100 mUmin and UV detection (220 nm).
• Method B Analysis was performed using a Chiralcel O J 250 x 4.6 mm (5 ⁇ ) and n-heptane/EtOH/MeOH as mobile phase with a flow of 0.9 mL/min and UV detection (220 nm).
• compounds of the invention may be prepared by a reaction sequence involving reductive amination of an appropriate ketone with an appropriate aniline followed by halogen metal exchange with an appropriate organolithium reagent and subsequent quenching with DMF, and either reductive amination with an appropriate amino ester or amino acid followed by an optional deprotection step or alkyl addition using an appropriate Grignard reagent, oxidation of the alcohol with an appropriate oxidizing agent, and reductive amination with an appropriate amino ester or amino acid followed by an optional deprotection step as shown in Scheme 2 below:
• Trichlorosilane (302 g, 2.233 mol) was added dropwise within 20 minutes and the resulting mixture was stirred overnight keeping the temperature between -25 °C and -22 °C.
• the mixture was poured onto saturated aqueous NaHC0 3 (7 L) and extracted with EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (cyclohexane/EtOAc). The resulting product was further purified by formation of the HCI salt and washing it with Et 2 0.
• the resulting solid was dissolved in hot EtOH and cooled to room temperature while stirring. The resulting solid was filtered off and dried in vacuum.
• Methyl 4-chloro-3-methylbenzoate (12 g, 65 mmol) was dissolved in THF (250 mL) and cooled in an ice-bath. A solution of methyl magnesium bromide (3 M Et 2 0, 87 mL, 260 mmol) was added slowly, then the ice bath was removed and the mixture was stirred at room temperature for 2 hours. To complete the reaction, the Et 2 0 was distilled off and the mixture was heated under reflux for 14 hours. The reaction was then cooled and quenched with MeOH and water, acidified with 2 M HCI and extracted twice with Et 2 0. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The crude was purified by chromatography on silica gel (cyclohexane/EtOAc).
• the chloroform layer was separated and the aqueous layer was extracted once more with chloroform.
• the combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated.
• the crude was purified by chromatography on silica gel (cyclohexane CH 2 CI 2 ).
• INT 25 (10.0 g, 62.8 mmol) in dichoromethane (450 ml.) was added triethylamine (7.98 g, 79 mmol), followed by dropwise addition of trichloroacetyl chloride (14.42 g, 79 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was washed with saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated to give INT 26 which was used in the next step without further purification.
• agents of the invention may be prepared by a reaction sequence involving Buchwald coupling of an appropriate amine with an appropriate protected
• TMS-CF 3 (0.737 mL, 4.99 mmol) in THF (15 mL) was added to a solution of TBAT (2.469 g, 4.57 mmol) and INT 36 (1.13 g, 4.16 mmol) in THF (60.0 mL) at -65 °C. Stirring was continued for 3 hours. Another portion of TBAT (200 mg, 0.37 mmol) was added. After 2 more hours, more TMS-CF 3 (0.369 ml, 2.50 mmol) was added. The suspension became a clear solution which was quenched with saturated ammonium chloride solution, diluted with EtOAc and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude was purified by
• the title compound was prepared by a procedure analogous to Example 57 using 3-amino-propionic acid fert-butyl ester hydrochloride in step 4 and with an additional HCi-induced deprotection step.
• Oxalyl chloride (0.232 mL, 2.70 mmol) was dissolved in CH 2 CI 2 (15 mL) and the solution was cooled to -78 °C. A solution of DMSO (0.383 mL, 5.40 mmol) in CH 2 CI 2 (3 mL) was added dropwise and the mixture was stirred for 10 minutes at this temperature. Then, a solution of INT 55 (329 mg, 1.079 mmol) in CH 2 CI 2 (3 mL) was added dropwise and the mixture was stirred for 1 hour at this temperature. NEt 3 (0.932 mL, 6.69 mmol) was added and the mixture was stirred further at -78 °C for 1 hour and the mixture was quenched with water.
• agents of the invention may be prepared by a reaction sequence involving either reductive amination of an appropriate halo-benzaldehyde or halo-pyridyl- carbaldehyde with an appropriate amino ester or Lewis acid catalyzed Michael addition of an appropriate benzylamine with an appropriate ⁇ , ⁇ - unsaturated ester followed by Buchwald coupling with an appropriate amine and an optional deprotection step as shown in Scheme 4 below:
• the crude was purified by chromatography on silica gel (cyclohexane/EtOAc).
• Example 57 The title compound (single stereoisomer A) was obtained by preparative chiral separation of Example 57. Separation was performed using a Chiralpak AD-i 5 x 20 cm (20 ⁇ ) column and heptane/ CH 2 CI 2 /EtOH TFA (75:22:3:0.05) as mobile phase with a flow of 40 ml/min and UV detection (254 nM).
• Example 57 The title compound (single stereoisomer B) was obtained by preparative chiral separation of Example 57. Separation was performed using a Chiralpak AD-i 5 x 20 cm (20 ⁇ ) column and heptane/ CH 2 Cl z /EtOH/TFA (75:22:3:0.05) as mobile phase with a flow of 40 ml/min and UV detection (254 nM).
• the compounds of formula (I) and/or formula (II) in free form or in salt form exhibit valuable pharmacological properties, e.g. properties susceptible to lymphocytes interactions or sphingosine-1 -phosphate receptor (S1 P) modulating properties, in particular S I P-antagonistic efficacy, especially S1 P1 -antagonistic efficacy, e.g. as indicated in in vitro and in vivo tests as provided in the next sections and are therefore indicated for therapy.
• valuable pharmacological properties e.g. properties susceptible to lymphocytes interactions or sphingosine-1 -phosphate receptor (S1 P) modulating properties, in particular S I P-antagonistic efficacy, especially S1 P1 -antagonistic efficacy, e.g. as indicated in in vitro and in vivo tests as provided in the next sections and are therefore indicated for therapy.
• the assay measures intracellular changes of Ca 2+ mediated by the synthetic probing agonist 3- ⁇ [2-(2-Trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophen-5-ylmethyl]-amino ⁇ - propionic acid (GNF-AC-1 ) in the Hel_a-S1 P1/Ga16 cell clone 1 : HeLa (human cervix carcinoma, ATCC CCL2) cells stably expressing N-terminally myc-tagged human S1 P.1 receptors (GenBankTM accession No.
• NM_001400; UNIPROT P21453) and promiscuous G 16 protein are cultured at 37°C, 5 % C02, and 95 % relative humidity.
• the cells are plated in 384 well black plates (10 ⁇ 00 cells per well). After 24 hours the cells are loaded with Fluo4- AM (1.6 ⁇ in HBSS and 2.5 mM probenicid) for 1 hour at 37°C. After washing, the cells are transferred to the FLIPR.
• the test compounds are added at different concentrations ( ⁇ 100 ⁇ ) in HBSS in the presence of 0.1 % BSA and changes in fluorescence are recorded (indication of agonism).
• the probing agonist is added 20-30 minutes afterwards to the wells at a concentration giving 80% of the maximal activity (EC 80 ). After each addition, time points are collected as follows: 20 time points (2 seconds) before the addition of the agonist (Fmin) and 60 time points (1 or 2 seconds) after the addition of the probing agonist. This allows the determination of the maximal fluorescence (Fmax). The ratio (Fmax-Fmin)/Fmin is plotted against the log of the concentration of the test compounds and the IC 50 (relative antagonism) is calculated using the XLfit-4 software. Compounds with an inhibition ⁇ 20% are usually considered "inactive". A concentration- response curve of the probing agonist is determined on each plate in parallel. The IC 50 values of compounds of formula (I) in the above described Human S1P Receptor Calcium FLIPR Antagonist Assay are displayed in Table 1.
• the compounds of the invention e.g. compounds of formula (I) typically induce the depletion of blood lymphocyte as may be determined in the assay described below.
• compounds of the invention e.g. compounds of formula (I) are typically efficacious in the said assay also when administered via the per oral route of administration.
• test compounds or salts thereof are dissolved in a vehicle such as water, saline, PEG (polyethylene glycol) 200, or PBS (phosphate buffered saline).
• a vehicle such as water, saline, PEG (polyethylene glycol) 200, or PBS (phosphate buffered saline).
• mice C57B 6NCrl strain, female, 18-20 g
• rats Lewis strain, male, 6-12 weeks old
• the vehicle or a reference salt and FTY720 0.3 mg kg are used as negative and positive controls, respectively.
• Blood is collected from the sublingual vein at single time points, e.g. 14 or 24 hours after the test compound administration, under short isoflurane anesthesia. Two to three animals are used in each group. Whole blood samples are subjected to hematology analysis. Peripheral lymphocyte counts are determined using an automated analyzer. The Haemathology System uses a combination of light scatter, cytochemical staining and nuclear density on two independent channels to measure the total and differential white cell counts. The reduction of lymphocytes provoked by each test compound is calculated by comparing the lymphocyte counts measured after each treatment to the mean lymphocyte counts measured in five to eight untreated mice or rats, respectively. The data are presented as mean ⁇ STDEV.
• Table 2 shows the effect on lymphocyte counts at the indicated time points in hours after oral administration of a given dose in mg/kg of some compounds of formula (I) to the indicated species, as compared to the mean lymphocyte counts of untreated animals.
• the compounds of the invention e.g. compounds of formula (I) in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, e.g. as S1P1 receptor antagonists, e.g. as indicated in the above in vitro and in vivo tests and are therefore indicated for therapy.
• Compounds of the invention may be useful in the treatment of an indication selected from:
• lymphocytes interactions e.g. in transplantation, such as acute or chronic rejection of cell, tissue or organ alio- or xenografts or delayed graft function, graft versus host disease, autoimmune diseases, e.g.
• rheumatoid arthritis systemic lupus erythematosus, hashimoto's thyroidis, multiple sclerosis, myasthenia gravis, neuropathic pain, Behcet's disease, Wegener's granulamatosis, ankylosing spondylitis, polymyositis, CIDP (Chronic Idiopathic Demyelinating Polyneuropathy), diabetes type I or II and the disorders associated therewith, vasculitis, pernicious anemia, Sjoegren syndrome, uveitis, psoriasis, Graves ophthalmopathy, alopecia areata and others, allergic diseases, e.g. allergic asthma, atopic dermatitis, allergic
• rhinitis/conjunctivitis allergic contact dermatitis
• inflammatory diseases optionally with underlying aberrant reactions, e.g. inflammatory bowel disease, Crohn's disease or ulcerative colitis, intrinsic asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthritis, irritant contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis, cutaneous manifestations of immunological!y-mediated disorders, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis, ischemia/reperfusion injury, e.g.
• infectious diseases e.g. toxic shock (e.g. superantigen induced), septic shock, adult respiratory distress syndrome or viral infections, e.g. AIDS, viral hepatitis, e.g. hepatitis B or C, chronic bacterial infection, or neurodegenerative diseases, e.g. Alzheimer disease, amyotrophic lateral sclerosis or senile dementia.
• pancreatic islets stem cells, bone marrow, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus.
• the compounds of the invention are useful in the treatment and/or prevention of diseases or disorders associated with deregulated angiogenesis for example diseases caused by ocular neovascularisation, especially retinopathies (diabetic retinopathy, age-related macular degeneration); psoriasis;
• inflammatory diseases such as arthritis, especially rheumatoid arthritis, arterial atherosclerosis and atherosclerosis occurring after transplants, endometriosis or chronic asthma; and, especially, tumor diseases (solid tumors, but also leukemias and other liquid tumors).
• the present invention provides the use of a compound of the invention, e.g. a compound of formula (I) or a salt thereof in therapy.
• the therapy is selected from a disease which may be treated by an antagonist of sphingosine-1-phosphate.
• the disease is selected from the afore-mentioned list, suitably diseases or disorders mediated by lymphocytes interactions, e.g. in transplantation, such as acute or chronic rejection of cell, tissue or organ alio- or xenografts or delayed graft function, graft versus host disease, autoimmune diseases, e.g.
• rheumatoid arthritis systemic lupus erythematosus, hashimoto's thyroidis, multiple sclerosis, myasthenia gravis, neuropathic pain, Behcet's disease, Wegener's granulamatosis, ankylosing spondylitis, polymyositis, CIDP (Chronic Idiopathic Demyelinating Polyneuropathy), diabetes type I or II and the disorders associated therewith, vasculitis, pernicious anemia, Sjoegren syndrome, uveitis, psoriasis, Graves ophthalmopathy, alopecia areata and others, allergic diseases, e.g. allergic asthma, atopic dermatitis, allergic
• rhinitis conjunctivitis allergic contact dermatitis
• inflammatory diseases optionally with underlying aberrant reactions, e.g. inflammatory bowel disease, Crohn's disease or ulcerative colitis, intrinsic asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthritis, irritant contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis, cutaneous manifestations of immunologically-mediated disorders, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis, ischemia/reperfusion injury, e.g.
• infectious diseases e.g. toxic shock (e.g. superantigen induced), septic shock, adult respiratory distress syndrome or viral infections, e.g. AIDS, viral hepatitis, e.g. hepatitis B or C, chronic bacterial infection, or neurodegenerative diseases, e.g. Alzheimer disease, amyotrophic lateral sclerosis or senile dementia.
• pancreatic islets stem cells, bone marrow, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus; also suitably in the treatment and/or prevention of diseases or disorders associated with deregulated angiogenesis for example diseases caused by ocular neovascularisation, especially retinopathies (diabetic retinopathy, age-related macular degeneration);
• various inflammatory diseases such as arthritis, especially rheumatoid arthritis, arterial atherosclerosis and atherosclerosis occurring after transplants, endometriosis or chronic asthma; and, especially, tumor diseases (solid tumors, but also leukemias and other liquid tumors).
• the invention provides a method of treating a disease which is treated by the modulation of the S1 P receptor comprising administration of a

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