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  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
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  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• the invention relates to a series of novel substituted benzyl piperidine compounds that are useful in the treatment of proliferative or inflammatory diseases, such as cancer, fibrosis or athritis in mammals. Also encompassed by the present invention is the use of such compounds in the treatment of proliferative or inflammatory diseases in mammals, especially humans, and pharmaceutical compositions containing such compounds.
• Lysophospholipids are membrane-derived bioactive lipid mediators. Lysophospholipids affect fundamental cellular functions that include proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis. These functions influence many biological processes that include, but are not limited to, neurogenesis, angiogenesis, wound healing, fibrosis, immunity, inflammation, and carcinogenesis.
• Lysophosphatidic acid is a lysophospholipid that has been shown to act through sets of specific G protein-coupled receptors (GPCRs) in an autocrine and paracrine fashion. LPA binding to its cognate GPCRs (LPA,, LPA 2 , LPA 3 , LPA 4 , LPA 5 , LPA 6 ) activates intracellular signaling pathways to produce a variety of biological responses.
• GPCRs G protein-coupled receptors
• Antagonists of the LPA receptors find use in the treatment of diseases, disorders or conditions in which LPA plays a role, especially in proliferative or inflammatory diseases, such as cancer, fibrosis or arthritis.
• LPA LPA receptor antagonist
• LPA primarily exert its biological effects via G protein-coupled receptors, such as EDG- 2/LPA1 , EDG-4/LPA2, EDG-7/LPA3, GPR23/LPA4, GPR93/LPA5, p2y5/LPA6.
• G protein-coupled receptors such as EDG- 2/LPA1 , EDG-4/LPA2, EDG-7/LPA3, GPR23/LPA4, GPR93/LPA5, p2y5/LPA6.
• EDG-4/LPA2 and EDG-7/LPA3 are consistently up-regulated in malignant ovarian epithelial cells contributing to the aberrant response of ovarian cancer cells to LPA.
• These receptors kick off signalling through the Gj, the G q> n, or the G 2 .13 pathways in the cell. Alteration of the signalling through these pathways is common to all drugs targeting GPCRs, which account for more than half of the marketed drugs today in various indications.
• LPA Low levels of LPA are generated during blood coagulation due to the release of phospholipase PLA1 and sPLA2 from platelets that convert phosphatide acid to LPA.
• LPA is considered to be one of the most potent growth factors in serum used for the growth of cells in vitro.
• LPA receptor antagonists useful in the treatment of proliferative or inflammatory diseases, especially those related to the hyperactivity of LPA, such as cancer, fibrosis or arthritis, in mammals, with superior pharmacological properties both with respect to their activities as well as their solubility, metabolic clearance and bioavailability characteristics.
• this invention provides novel substituted benzyl piperidine compounds or their stereoisomers or tautomers, or pharmaceutically acceptable salts, that are LPA antagonists and useful as medicaments, especially in the treatment of the above mentioned diseases.
• R r , R r , R 2 , R 3 , R 4 , R 5> , R 5" are independently H, Hal, OH, CN, N0 2 , NH 2 , A, NH(LA),
• X, Y, Z are independently CH, C(LA), C(Hal) or N,
• Q is NR 2 , O or S
• LA is unbranched or branched alkyl having 1 , 2, 3 or 4 carbon
• R 3 is H or LA
• Ar is is a mono- or bicyclic aromatic homo- or heterocycle having
• Hal is F, CI, Br or I.
• the invention relates, in particular, to the compounds of the Formula (I) in which at least one of the said residues has one of the preferred meanings indicated below.
• Hal denotes fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine.
• LA denotes unbranched or branched, linear alkyl having 1 , 2, 3 or 4 C atoms, wherein 1 , 2 or 3 H atoms may be replaced by Hal, e.g. methyl, ethyl, trifluoromethyl,
• Ar denotes, for example, unsubstituted phenyl, or naphthyl, furthermore preferably, for example, phenyl or naphthyl, each of which is mono-, or disubstituted by methyl, ethyl, isopropyl, fluorine, chlorine, bromine, hydroxy!, methoxy, ethoxy, propoxy, nitro, cyano, formyl, acetyl, propionyl, trifluoromethyl, methanesulfonyl, amino, methylamino, dimethyl- amino, diethylamino, carboxyl, methoxycarbonyl.
• Ar furthermore denotes phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminopheny), o-, m- or p-(N-methyl- amino)phenyl, o-, m- or p-(N-methyiaminocarbonyl)phenyI, o-, m- or p-acetamidophenyl, 0-, m- or p-methoxyphenyl, o-, m- or p-meth
• Ar furthermore preferably denotes 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl,
• 6-pyrazin-1- or 4-yl furthermore preferably 1 ,2,3-triazoM-, -4- or -5-yl, 1 ,2,4-triazoM- , -3- or 5-yl, 1- or 5-tetrazolyl, 1 ,2,3-oxadiazol-4- or -5-yl, 1 ,2,4-oxadiazol-3- or -5-yl, ,3,4-oxadiazol-2-yl, ,3,4-thiadiazol-2- or -5-yl, 1 ,2,4-thiadiazol-3- or -5-yl, 1 ,2,3- thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-
• 6- or 7-indazolyl 2-, 3-, 4- or 5-isoindolyl, 2-, 6, -or 8-purinyl, 1-, 2-, 4- or
• R , R are independently H, methyl, F, CI, Br or S0 2 NH '2, in Subformula 2
• Ar is phenyl, furyl, pyridyl, thiazolyl or indazolyl, in Subformula 5
• R r , R 1" are independently H, methyl, F, CI, Br or S0 2 NH 2 ,
• R 3 is H or methyl
• R 4 is H or methyl
• Ar is phenyl, furyl, pyridyl, thiazolyl or indazolyl,
• R 5 , R 5" are independently H, F, methyl, ethyl, methoxy, trifluoromethyl, hydroxy or nitro, in Subformula 7
• R 3 is H, in Subformula 8
• R 4 is H, in Subformula 9
• Ar is phenyl, in Subformula 10
• R 2 is H, methyl or isopropyl
• R 2 is H, methyl or isopropyl
• Y is CH, C(LA) or C(Hal),
• Y is CH, C(LA) or C(Hal),
• Y is CH, C-CH 3 or C-F
• Y is CH, C-CH 3 or C-F
• Ar is phenyl
• R 5 , R 5" are independently H, F or methyl, in Subformula 19
• R 3 is H
• R 4 is H
• Ar is phenyl
• R 5 , R 5" are independently H, F
• Y is CH, and the remaining residues have the meaning as indicated for Formula (I)
• the compounds of the Formula (I) may have one or more centres of chirality. They may accordingly occur in various enantiomeric forms and be in racemic or optically active form.
• the invention therefore, also relates to the optically active forms, enantiomers, racemates, diastereomers, collectively: stereoisomers, of these compounds.
• diastereomers are formed from the mixture by reaction with an optically active resolving agent.
• suitable resolving agents are optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitably N-protected amino acids (for example N-benzoylproline or N-benzenesulfonylproline), or the various optically active camphorsulfonic acids.
• optically active acids such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitably N-protected amino acids (for example N-benzoylproline or N-benzenesulfonylproline), or the various optically active camphorsulfonic acids.
• eluents for this purpose are aqueous or alcoholic solvent mixtures, such as, for example, hexane/isopropanol/ acetonitrile, for example in the ratio 82:15:3.
• the compounds of the present invention can be in the form of a prodrug compound.
• Prodrug compound means a derivative that is converted into a biologically active compound according to the present invention under physiological conditions in the living body, e.g., by oxidation, reduction, hydrolysis or the like, each of which is carried out enzymatically, or without enzyme involvement.
• prodrugs are compounds, wherein the amino group in a compound of the present invention is acylated, alkylated or phosphorylated, e.g., eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein the hydroxyl group is acylated, alkylated, phosphorylated or converted into the borate, e.g. acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy or wherein the carbox l group is esterified or amidated, or wherein a sulfhydryl group forms a disulfide bridge with a carrier molecule, e.g.
• a peptide that delivers the drug selectively to a target and/or to the cytosol of a cell.
• prodrugs are compounds, wherein the carboxylate in a compound of the present invention is for example converted into an alkyl-, aryl-, choline-, amino,
• tautomerism e.g., keto-enol tautomerism
• the individual forms e.g., the keto or the enol form
• stereoisomers e.g., enantiomers, cis/trans isomers, conformers and the like.
• isomers can be separated by methods well known in the art, e.g. by liquid chromatography. The same applies for enantiomers, e.g., by using chiral stationary phases. Additionally, enantiomers may be isolated by converting them into
• any enantiomer of a compound of the present invention may be obtained from stereoselective synthesis using optically pure starting materials
• the compounds of the present invention can be in the form of a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt.
• the invention also comprises their corresponding pharmaceutically acceptable salts.
• the compounds of the present invention which contain acidic groups can be present in salt form, and can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids.
• Compounds of the present invention which contain one or more basic groups i.e.
• acids which can be protonated, can be present in salt form, and can be used according to the invention in the form of their addition salts with inorganic or organic acids.
• suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art.
• the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions).
• inner salts or betaines can be obtained by customary methods which are known to a person skilled in the art, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.
• the present invention also includes all salts of the compounds of the present invention which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
• solvate formed is a hydrate, e.g. a mono- or dihydrate.
• solvent is alcohol
• the solvate formed is an alcoholate, e.g., a methanolate or ethanolate.
• solvent is an ether
• the solvate formed is an etherate, e.g., diethyl etherate.
• the invention also relates to the use of a compound according to the invention for the preparation of a medicament for the treatment of proliferative or inflammatory diseases related to the hyperactivity of LPA as well as diseases modulated by LPA in mammals, or disorders mediated by aberrant proliferation, such as cancer.
• This invention also relates to a compound or pharmaceutical composition for inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of the present invention, in combination with an amount of another anti-cancer therapeutic, wherein the amounts of the compound, and of the other anti-cancer therapeutic are together effective in inhibiting abnormal cell growth.
• a compound or pharmaceutical composition for inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of the present invention, in combination with an amount of another anti-cancer therapeutic, wherein the amounts of the compound, and of the other anti-cancer therapeutic are together effective in inhibiting abnormal cell growth.
• Many anti-cancer therapeutics are presently known in the art.
• the anti-cancer therapeutic is a compound or pharmaceutical composition for inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of the present invention, in combination with an amount of another anti-cancer therapeutic, wherein the amounts of the compound, and of the other anti-cancer therapeutic are together effective in inhibiting abnormal cell growth.
• chemotherapeutic selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti- hormones, angiogenesis inhibitors, integrin antagonists, such as cilengitide, and anti- androgens.
• the anti-cancer therapeutic is an antibody selected from the group consisting of bevacizumab, CD40-spectfic antibodies, chTNT-1/B, denosumab, zanolimumab, IGF1 R-specific antibodies, lintuzumab, edrecolomab, WX G250, rituximab, ticilimumab, trastuzumab and cetuximab.
• the anti-cancer therapeutic is an inhibitor of a protein kinase, such as Akt, Axl, Aurora A, Aurora B, dyrk2, epha2, fgfr3, igfl r, IKK2, JNK3, Vegfrl , Vegfr2, Vegfr3 (also known as Flt-4), KDR, MEK, MET, Plk1 , RSK1 , Src, TrkA, Zap70, cKit, bRaf, EGFR, Jak2, PI3K, NPM-Alk, c-Abl, BTK, FAK, PDGFR, TAK1 , LimK, Flt-3, PDK1 and Erk.
• a protein kinase such as Akt, Axl, Aurora A, Aurora B, dyrk2, epha2, fgfr3, igfl r, IKK2, JNK3, Vegfrl , Vegfr2,
• This invention further relates to a method for inhibiting abnormal cell growth in a mammal or treating a proliferative disorder that comprises administering to the mammal an amount of a compound of the present invention or pharmaceutical composition, in combination with radiation therapy, wherein the amounts of the compound or
• composition is in combination with the radiation therapy effective in inhibiting abnormal cell growth or treating the proliferative disorder in the mammal.
• this invention further relates to a method for sensitizing abnormal cells in a mammal to treatment with radiation which comprises administering to the mammal an amount of a compound of the present invention or pharmaceutical composition, which amount is effective in sensitizing abnormal cells to treatment with radiation.
• the amount of the compound in this method can be determined according to the means for ascertaining effective amounts of such compounds described herein.
• the compounds of the present invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
• the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
• any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like.
• any of the usual pharmaceutical media may be employed, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
• the composition may take forms such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound.
• the percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit.
• the amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
• the active compounds can also be administered intranasally as, for example, liquid drops or spray.
• the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
• a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
• tablets may be coated with shellac, sugar or both.
• a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
• Compounds of the present invention may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
• the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
• the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of
• the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
• Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention.
• oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
• Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
• compositions of the present invention are administered orally.
• the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
• the compounds of the present invention are administered at a daily dosage of from about 0.01 milligram to about 100 milligram per kilogram of body weight, preferably given as a single daily dose.
• the total daily dosage is from about 0.1 milligrams to about 1000 milligrams, preferably from about 0.2 milligram to about 50 milligrams.
• the total daily dose will generally be from about 0.2 milligrams to about 200 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
• the invention also relates to a set (kit) consisting of separate packs of
• the set comprises suitable containers, such as boxes, individual bottles, bags or ampoules.
• the set may comprise separate ampoules, each containing an effective amount of a compound according to the invention, and an effective amount of a further medicament active ingredient in dissolved or lyophilised form.
• the instant compounds are generally isolated in the form of their pharmaceutically acceptable salts, such as those described above.
• the amine-free bases corresponding to the isolated salts can be generated by neutralization with a suitable base, such as aqueous sodium hydrogencarbonate, sodium carbonate, sodium hydroxide and potassium hydroxide, and extraction of the liberated amine-free base into an organic solvent, followed by evaporation.
• a suitable base such as aqueous sodium hydrogencarbonate, sodium carbonate, sodium hydroxide and potassium hydroxide
• the amine-free base, isolated in this manner can be further converted into another pharmaceutically acceptable salt by dissolution in an organic solvent, followed by addition of the appropriate acid and subsequent evaporation, precipitation or crystallization.
• R 6' is Hal, such as CI or Br.
• R 6' and R 6" together form a leaving group, which is preferably carbonyl oxygen.
• the hydrazone 2 (7.74 g, 36.6 mmol) was mixed with polyphosphoric acid (43.5 g) in a heavy-walled beaker and heated at 110°C for 1.5 h. After cooling, the mixture was basified with 10% NaOH and extracted with dichloromethane. The combined organic extracts were dried over sodium sulphate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel using
• Example compounds were synthesized, as shown in Table 1 : 1-10, 13-25, 42-44, 54-60, 63, 65-71 , 73, 82, 84-86, 107-112, 124, 125, 132, 136-139 and 143.
• Example 72 compound was prepared by reacting the corresponding piperidine derivative with 1-(4-Fluorophenyl)-ethanone in analogy to procedure d.
• Example compound 75 instead of 2-acetylpyridine 1-pyridine-2-yl- propan-1-one was used in procedure a. The following steps were performed according to procedures b-d.
• 2-acetyl-6-methylpyridine 6 (10.0 g, 99%, 73.2 mmol) was dissolved in absolute ethanol (100 mL), 4-Fluoro-phenylhydrazine (25.1 g, 95%, 147 mmol) was added and the solution was refluxed for 30 min. After cooling to room temperature the precipitate obtained was collected by filtration, washed with cold ethanol. The residue was redissolved in saturated sodium carbonate solution and extracted with
• the hydrazone 7 (16.5 g, 67.5 mmol) was mixed with polyphosphoric acid (42.0 g, 99%, 424 mmol) in a heavy-walled beaker and heated at 110°C for 1 ,5 h. After cooling, the mixture was basified with 10% NaOH and extracted with
• Example compounds were synthesized, as shown in Table 1 , starting with 2-acetyl-5-methylpyridine, 2-acetyl-4-methylpyridine and 2-acetyl-3-methylpyridine: Examples 26-41 , 45, 46, 61 , 62, 64, 68, 74, 76, 79-81 , 83, 87.
• Butoxycarbonylpiperidine-2-carboxylic acid (540 mg, 2.36 mmol) was dissolved in Polyphosphoric acid (1.5 mL) and stirred 18 h at 160°C. The mixture was poured on ice and extracted with Ethyl acetate/butanol twice. The combined organic layer was dried with MgS04, filtered and evaporated to dryness. The residue was identified as compound 11 and was used without further purification (462 mg, 1.95 mmol, 95%). j.
• the racemic mixtures can be separated into enantiomeres.
• the following Example compounds were synthesized, as shown in Table 1 : Examples 47, 49, 51 , 88-106, 113-123, 126-131 , 135, 142.
• Biochemical Enzyme Assay for LP A Activity detects intra cellular calcium which is generated by cells upon activation of the LPA2 receptor by its ligand LPA. This transient calcium mobilization can be monitored using a commercial calcium detection kit (e.g. from Molecular Devices).
• the main component of such a kit is a dye, which becomes fluorescent when calcium is present - a transient fluorescence signal after laddition of a ligand to a test well are the result. Readers like the FLIPR (Molecular Devices) can be used to monitor such transient "Ca- flux" signals.
• the signals are calculated according to peak maximum minus base line. Compounds which are antogonists of LPA lead to a decreased mobilisation of intracellular calcium and thus to a lower signal.
• the assay is performed in microplates (384 wells per plate).
• LPA 1-Oleoyl-2-Hydroxy- sn-Glycero-3-Phosphate
• Avanti #857130P probenecid water soluble Invitrogen #P36400
• the assay is run according to the following procedure:
• the cells are seeded in DMEM buffer (DMEM, 10% FCS, 10 mM HEPES, 1%
• Dye loading is done in HBSS/HEPES buffer (100 mL 10x HBSS + 20 mL 1 M HEPES + 880 mL water, pH 7.4)
• the LPA is added in Krebs/BSA buffer (120 mM NaCI, 5 mM KCI, 0,62 mM MgS0 4l 1 ,8 mM CaCI 2) 10 mM HEPES, 6 mM D(+)-Glucose, 0.2% BSA, pH 7.4).
• the compounds are pre-diluted in HEPES buffer (20 mM, pH 7.4), whereby the final DMSO content in the assay is kept at 1%.
• the compounds are pre-diluted in order to generate dose response series on the microplates.
• the dose response series consist of 10 concentrations for each compound from 30 uM final to 1 nM final. From all compound wells the resulting signals are referred to control wells (located on each plate besides the compound wells) in terms of %activity. (readout compoupd - readout b i an k)
• Second read interval 1 ,00 s
• IC 50 -values were determined, as shown in Table 1 below, whereby the following classification is used:
• Solvent B Acetonitril + 0.1 % TFA
• Example numbers 11 , 12, 43, 53, 77, 78, and 80 were omitted intentionally

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