Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/32—One oxygen, sulfur or nitrogen atom
  • C07D239/42—One nitrogen atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
  • C07D401/02—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
  • C07D401/12—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 linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • 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
  • C07D403/12—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 linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • 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
  • C07D405/12—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 linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to organic compounds, e.g. substituted amines having pharmaceutical e.g. IgE-synthesis inhibiting, activity.
• the present invention provides a compound of formula wherein
• the present invention provides a compound of formula I, wherein
• the present invention provides a compound of formula I, selected from the group consisting of
• aryl includes phenyl.
• Halogen includes fluoro, chloro, bromo.
• Haloalkyl includes halo(C 1-4 )alkyl, wherein halo is one or more halogen, preferably trifluoromethyl.
• (C 3-8 )cycloalkyl includes e.g. (C 3-6 )cycloalkyl.
• Amino includes amino, (C 1-4 )alkylamino and di(C 1-4 )alkylamino.
• Aminoalkyl includes amino(C 1-6 )alkyl, e.g.
• (C 1-4 )alkylamino(C 1-6 )alkyl di(C 1-4 )alkylamino(C 1-6 )alkyl, preferably disubstituted amino(C 1-4 )alkylamino(C 1-4 )alkyl, e.g. dimethyl- or diethylamino(C 1-4 )alkyl.
• Hydroxyalkylamino includes hydroxy(C 1-6 )alkyl, hydroxy(C 1-4 )alkylamino(C 1-6 )alkyl, preferably hydroxy(C 1-3 )alkyl or hydroxy(C 1-2 )alkylamino(C 1-2 )alkyl.
• Amino acid includes all natural and synthetic amino acids, preferably ⁇ -amino acids, e.g. alanine, phenylalanine, glycine, glutamic acid and lysine.
• Amino acid includes one or more of amino acid, e.g. di- or tripeptides.
• Heterocyclyl includes 5 or 6 membered heterocyclic ring systems having 1 to 4 heteroatoms selected from N, O or S.
• the heterocyclyl is a 5 or 6 membered ring system having 1 or 2 heteroatoms selected from N or O.
• Preferred is pyrrolidine, morpholine and piperazine.
• Any group may be unsubstituted or substituted, e.g. substituted by groups as conventional in organic chemistry, e.g. including groups selected from halogen, haloalkyl, alkylcarbonyloxy, alkoxy, hydroxy, amino, alkylcarbonylamino, aminoalkylcarbonylamino, hydroxyalkylamino, aminoalkylamino, alkylamino, dialkylamino, heterocyclyl having 5 or 6 ring members and 1 to 4 heteroatoms selected from N,O,S; (C 1-4 )alkylheterocyclyl, wherein heterocyclyl having 5 or 6 ring members and 1 to 4 heteroatoms selected from N,O,S; hydroxy(C 1-4 )alkylheterocyclyl, wherein heterocyclyl having 5 or 6 ring members and 1 to 4 heteroatoms selected from N,O,S; carboxyl, (C 1-4 )alkylcarbonyloxy, amino(C 1-4 )
• a compound of the present invention includes a compound in any form, e.g. in free form, in the form of a salt, in the form of a solvate and in the form of a salt and a solvate.
• a salt of a compound of the present invention includes a pharmaceutically acceptable salt, e.g. including a metal salt or an acid addition salt.
• Metal salts include for example alkali or earth alkali salts;
• acid addition salts include salts of a compound of formula I with an acid, e.g. including inorganic and organic acids, e.g. including pharmaceutically acceptable acids, such as hydrochloric acid, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, tartaric acid.
• a compound of the present invention in free form may be converted into a corresponding compound in the form of a salt; and vice versa.
• a compound of the present invention in free form or in the form of a salt and in the form of a solvate may be converted into a corresponding compound in free form or in the form of a salt in unsolvated form; and vice versa.
• a compound of the present invention may exist in the form of isomers and mixtures thereof; e.g. optical isomers, diastereoisomers, cis-trans conformers.
• a compound of the present invention may e.g. contain asymmetric carbon atoms and may thus exist in the form of enantiomeres, diastereoisomeres and mixtures thereof, e.g. racemates.
• a substitutent attached to an asymmetric carbon atom in a compound of the present invention may be in the R— or in the S-configuration, including mixtures thereof.
• the present invention includes a compound of the present invention in any isomeric form and in any isomeric mixture.
• Any compound described herein, e.g. a compound of the present invention, may be prepared as appropriate, e.g. according to a method as conventional, e.g. or as described herein.
• a compound of the present invention wherein the amine group is substituted by phenyl-substituted pyrimidin; and phenyl; and hydrogen may be prepared e.g. according, e.g. analogously, to a method as conventional, preferably according to the following reaction scheme 1: e.g. wherein in a compound of formula I, II and III R 1 , R 2 and R 3 are as defined above, and R 4 is H; and optionally further reacting a compound obtained with an appropriate reagent to obtain a compound of of the present invention, e.g. a compound of formula I, wherein R 4 is as defined above, but other than hydrogen; e.g. reacting a compound of formula I wherein R 4 is H and the other substituents are as defined above
• Reactions of a compound of formula I wherein R 4 is H and the other substituents are as defined above with appropriate reagents to obtain a compound of formula I; wherein R 4 is as defined above, but other than hydrogen, are alkylation or acylation reactions and may be carried out as appropriate, e.g. according, such as analogously, to a method as conventional, e.g. or as described above.
• substiutents e.g. hydroxy or amine groups, may be protected before reaction and deprotected during or after reaction.
• the present invention provides a process for the production of a compound of formula I comprising reacting a compound of formula II wherein R 1 is as defined above and ALK denotes alkyl or cycloalkyl, with a compound of formula III, wherein R 2 and R 3 are as defined above, to obtain a compound of formula I wherein R 1 , R 2 and R 3 are as defined above, and R 4 is hydrogen, and optionally alkylating or acylating a compound obtained, e.g. and deprotecting groups if desired, to obtain a compound of formula I wherein R 1 , R 2 and R 3 are as defined above and R 4 is as defined above, but other than hydrogen, and isolating a compound of formula I obtained from the reaction mixture.
• Any compound described herein, e.g. a compound of the present invention, may be prepared as appropriate, e.g. according to a method as conventional, e.g. or as described herein.
• Compounds of formula II and of formula III are known or may be obtained e.g. according to a method as conventional or as described herein.
• the compounds of the present invention exhibit in vitro and in vivo pharmacological activity and are therefore useful as pharmaceuticals:
• Th2 cells T-helper type 2 cells
• DC dendritic cells
• Th2 cytokine IL-4 Th2 cytokine IL-4
• IL-4 IL-4, IL-5, IL-10 and IL-13
• pro-inflammatory effector cells such as eosinophils, basophils and mast cells which accumulate in the lungs.
• IL-4 and IL-13 induce IgE production by B-cells. Binding of IgE to high affinity IgE receptors (Fc ⁇ Rl) on mast cells and basophils results, following crosslinking by allergen, in the activation of the pro-inflammatory cells and the release of mediators of allergic inflammation.
• the compounds of the present invention may act as modulators of human DC function.
• DC cell surface molecules known to be important for interaction with na ⁇ ve T-cell precursors, such as CD86, CD83, CD25 and HLA class II antigens may be diminished on the surface of human monocyte-derived dendritic cells upon treatment with compounds of the present invention.
• the secretion of IL-6 by mature DC may be inhibited by the compounds of the present invention.
• Compound-treated dendritic cells show impaired ability to stimulate the proliferation and cytokine production of na ⁇ ve CD4-positive autologous T-cells.
• the compounds of the present invention may act as specific inhibitors of IgE synthesis.
• a compound of the present invention may suppress immunoglobulin synthesis, in particular the synthesis of immunoglobulin E in B-lymphocytes, i.e. a compound of the present invention may exhibit isotype specificity.
• a compound of the present invention may not inhibit B-cell proliferation in concentrations below the concentrations needed to block IgE synthesis.
• Mononuclear cells are purified from normal human spleens.
• the resulting cell suspension contains 50-70% Blympbocytes as judged by CD19 expression in a FACS analysis.
• Using 96-well round-bottomed microtiter plates (Costar) 5 ⁇ 10 4 spleenocytes are set up in a final volume of 200 ⁇ l/well in IMDM. After pre-incubation with test compound for one hour the cells are cultured to induce IgE production for 9 days at 37° in air supplied with 5% CO 2 in the presence of 50 ng/ml of IL-4 and 500 ng/ml of anti-CD40 antibody.
• the culture cell supernatants are collected and quantitated for IgE by standard isotype specific sandwich ELISA.
• the cells are cultured with 100 ng/ml IL-10 and 500 ng/ml of anti-CD40 antibody for the same time period before IgG levels are quantitated in the cell supernatants by isotype specific ELISA.
• the compounds of the present invention inhibit IgE production preferentially over IgG (IgG1).
• Normal human B-lymphocytes are purified from tonsils by removing contaminating T-cells with SRBC-rosetting according to M. S. Weiner et al., Blood 42 (1973) 939. The resulting B-cells are more than 95% pure as judged by CD19 expression in a FACS analysis.
• Using 96-well round-bottomed microtiter plates (Costar) 1 ⁇ 10 5 spleenocytes are set up in a final volume of 200 ⁇ l/well in IMDM. After pre-incubation with test compound for one hour, cell proliferation is induced with 50 ng/ml IL-4 and 500 ng/ml anti-CD40 antibody.
• compounds of the present invention inhibit IL-4 and anti-CD40 antibody mediated B-cell proliferation above the concentrations needed to block IgE synthesis.
• Human peripheral blood monocytes are prepared by elutriation or by negative selection of PBMC using a commercially available kit (Miltenyi). The resulting monocyte population is routinely >97% positive for CD14 as checked for purity by FACS staining for CD14.
• Monocytes are seeded in 6-well plates at 3 ⁇ 10 6 cells/well in 5 ml of IMDM medium supplemented with 1% FCS, streptomycin and glutamin.
• Generation of immature Mo-DC is induced by adding 40 ng/ml IL-4 and 15 ng/ml GM-CSF for 6 days in the absence or presence of test compounds. After the first 2 days, half of the volume is replaced with fresh medium, cytokines and compounds where appropriate. On day 6 of culture, cell surface expression levels of CD86 and HLA-DR is measured by FACS staining.
• Maturation of DC is induced by activation of immature DC with 100 ng/ml LPS (Sigma) or by a cocktail containing 20 ng/ml GM-CSF, 100 U/ml IFN- ⁇ , 20 U/ml TNF- ⁇ and 4 ⁇ g/ml crosslinked anti-CD40 monoclonal antibodies for 24 hours. Then, cell surface expression levels of CD83 and CD25 was quantitated by FACS.
• compounds of the present invention inhibit the cell surface expression levels of CD86, HLA-DR, CD83 and CD25.
• Immature Mo-DC are generated in the absence or presence of test compounds. Then, the cells are pulsed with 100 ⁇ g/ml KLH over night and then co-cultured with autologous CD4-positive T-cells for nine days to elicit a primary T-cell response in the absence or presence of test compound. After washing the cells, the primed T-cells are re-stimulated with fresh KLH-pulsed DC in different T/DC ratios for 3 days without adding compound. For the last 16 hours 1 ⁇ Ci of tritiated thymidine is added. The cells are collected on a nitrocellulose filter and the DNA-bound radioactivity is quantitated by liquid scintillation counting.
• compounds of the present invention inhibit DC mediated T-cell proliferation.
• Heparinized blood is obtained from human volunteers and from Balb/c mice. Blood obtained is centrifuged for 4 minutes at 13,000 rpm at room temperature (RT) to obtain plasma. To aliquots of plasma (1 ml) test compounds, i.e. compounds of the present invention, are added (1 ⁇ l of 10 mM stock solutions in DMSO or water). The samples are incubated at 37°. At various time points, aliquots of 100 ⁇ l are taken from said samples. An internal standard (5 ⁇ l of a 100 ⁇ g/ml solution of an internal standard compound in methanol) is added, followed by 300 ⁇ l of methanol (or acetonitrile or acetonitrile/1 M HCl, as required). Samples are centrifuged for 5 minutes at 13,000 rpm.
• test compounds i.e. compounds of the present invention
• HPLC system HP1090
• HP1090 Hypersil BDS C-8 column
• pre-column 10 ⁇ 4.6 mm
• the column is eluted isocratically at 55° C. and at a flow rate of 1.5 ml/min with mixtures of acetonitrile and 10 mM (NH 4 ) 2 SO 4 , pH 2.7; the acetonitrile content of the mixtures used is in the range of 55-65% for various substances.
• UV detection is carried out at 277 nm.
• plasma samples are spiked with a compound of formula I wherein R 4 is hydrogen, or with a compound of formula I wherein R 4 is as defined above, but other than hydrogen; both in the range of 0.5 to 20 ⁇ M, and internal standard. Absolute concentrations are calculated using these calibration sets.
• Compounds of the present invention show a good solubility and good plasma levels after e.g. oral administration.
• the compounds of the present invention are therefore indicated for use as modulators of DC function and inhibitors of immunoglobulin synthesis, especially inhibitors of IgE synthesis, and are useful in the treatment of IgE-mediated diseases, particularly IgE-mediated allergic diseases, e.g. of diseases mediated by IgE expression, such as atopic dermatitis, particularly in children, urticaria, particularly acute urticaria, allergic asthma, allergic rhinitis, food allergies, allergic conjunctivitis, hayfever, bullous pemphigoid and industrial sensitization.
• IgE-mediated allergic diseases e.g. of diseases mediated by IgE expression, such as atopic dermatitis, particularly in children, urticaria, particularly acute urticaria, allergic asthma, allergic rhinitis, food allergies, allergic conjunctivitis, hayfever, bullous pemphigoid and industrial sensitization.
• these compounds are indicated in other diseases in which inflammatory conditions play a major pathological role,
• the present invention provides the use of an amine, which is substituted by
• a third substituent e.g. includes a group R 4 as defined above.
• the present invention provides the use of a compound of formula I wherein the substituents R 1 to R 4 are as defined above in the preparation of a medicament for the treatment of IgE-synthesis-mediated diseases, autoimmune diseases, gastrointestinal diseases and chronic rejection of transplants.
• the dosage to be used will vary, of course, depending e.g. on the particular compound employed, the mode of administration and the treatment desired. However, in general satisfactory results may be obtained when the compounds are administered at a daily dosage of from about 1 mg/kg to about 30 mg/kg animal body weight, suitably given in divided doses two to four times daily. For most larger mammals the total daily dosage is from about 70 mg to about 2000 mg, conveniently administered, for example, in divided doses up to four times a day or in retard form.
• Unit dosage forms comprise, for example, from about 17.5 mg to about 1000 mg of compound in admixture with at least one solid or liquid pharmaceutically acceptable excipient, e.g. carrier or diluent.
• a compound of the present invention may be administered in similar manner to known standards such as glucocorticoids and antihistaminics for use in such indications. It may be admixed with conventional therapeutically acceptable carriers and diluents and, optionally, further excipients, and administered e.g. orally in such forms, e.g. in the form of tablets, capsules; or, alternatively, it may be administered topically, e.g. in conventional forms, such as aerosols, ointments or creams; parenterally or intravenously.
• the concentration of the substance will, of course vary, e.g. depending on the compound administered, the treatment desired and the nature of the form. In general, however, satisfactory results may be obtained in topical application forms at concentrations of from about 0.05% to about 5%, particularly from about 0.1% to about 1% by weight.
• the present invention provides the use of a compound of the present invention in the preparation of a medicament for the therapy of IgE-mediated diseases, e.g. of diseases mediated by IgE expression, autoimmune diseases, gastrointestinal diseases and chronic transplant rejection.
• IgE-mediated diseases e.g. of diseases mediated by IgE expression, autoimmune diseases, gastrointestinal diseases and chronic transplant rejection.
• compositions for use in the therapy of IgE-mediated diseases, autoimmune diseases, gastrointestinal diseases and chronic transplant rejection may be prepared by mixing a compound of the present invention together with at least one pharmaceutically acceptable excipient, e.g. carrier or diluent.
• the present invention provides a method of treatment of IgE-mediated diseases, autoimmune diseases, gastrointestinal diseases and chronic transplant rejection which comprises administering a therapeutically effective amount of a compound of the present invention, e.g. in the form of a pharmaceutical composition, to a subject in need of such treatment.
• a compound of the present invention may be well tolerated, as may be determined according to a method as conventional.
• a compound of the present invention may possess beneficial pharmacogalenical properties, such as good solubility in various solvents.
• the present invention provides a compound of the present invention for use as a pharmaceutical, preferably in indications of IgE mediated diseases, autoimmune diseases, gastrointestinal diseases and chronic transplant rejection.
• the compounds of the present invention may be administered in the form of a pharmaceutically acceptable salt, e.g. an acid addition salt or metal salt; or in free form; optionally in the form of a solvate.
• a pharmaceutically acceptable salt e.g. an acid addition salt or metal salt
• the compounds of the present invention in the form of a salt exhibit the same order of activity as the compounds of the present invention in free form; optionally in the form of a solvate.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of the present invention in association with at least one pharmaceutical excipient, e.g. carrier or diluent.
• Such compositions may be manufactured according to a method as conventional.
• a compound, or more than one compounds, of the present invention may be used for pharmaceutical treatment according to the present invention alone, or in combination with one or more other pharmaceutically active agents, e.g. such as useful in the treatment of IgE-mediated diseases, particularly IgE-mediated allergic diseases, e.g. of diseases mediated by IgE expression, such as atopic dermatitis, particularly in children, urticaria, particularly acute urticarla, allergic asthma, allergic rhinitis, food allergies, allergic conjunctivitis, hayfever, bullous pemphigoid and industrial sensitization.
• IgE-mediated diseases particularly IgE-mediated allergic diseases, e.g. of diseases mediated by IgE expression, such as atopic dermatitis, particularly in children, urticaria, particularly acute urticarla, allergic asthma, allergic rhinitis, food allergies, allergic conjunctivitis, hayfever, bullous pemphigoid and industrial sensitization.
• these compounds are indicated
• Such other pharmaceutically active agents include e.g. steroids, anti-histaminica, ascomycins, ASM981, rapamycins.
• Combinations include fixed combinations, in which two or more pharmaceutically active agents are in the same formulation; kits, in which two or more pharmaceutically active agents in separate formulations are sold in the same package, e.g. with instruction for co-administration; and free combinations in which the pharmaceutically active agents are packaged separately, but instruction for simultaneous or sequential administration are given.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising as an active ingredient a compound of the present invention in combination, e.g. including fixed combinations, kits and free combinations, with one or more other pharmaceutically active agents, e.g. which other pharmaceutically active agents are, e.g. selected from, e.g. the group consisting of, steroids, anti-histaminica, ascomycins, ASM981, rapamycins.
• a mixture of 1.5 g of 1-(3-chloro-phenyl)-3-dimethylamino-propenone, 1.7 g of of N-(4-trifluoromethyl-phenyl)guanidine carbonate and 15 ml of n-butanol is heated at 120° for ca. 24 hours, the mixture obtained is cooled to RT and a solid precipitates. The precipitate is filtrated off and is re-crystallised from n-butanol. 1.0 g of N-[4-(3-chloro-phenyl)-pyrimidin-2-yl]-N-(4-trifluoromethyl-phenyl)-amine in crystalline form are obtained. m.p. 201.5°.
• R 1EX , R 2EX and R 3EX are as defined in TABLE 1 below and R 4EX is H, having a melting point m.p. as defined in TABLE 1 below are obtained: TABLE 1 Example R 1EX R 2EX R 3EX m.p. (°) 2 CF 3 CF 3 F 168.0 3 Cl CF 3 Cl 182.3 4 CF 3 CF 3 Cl 161.8 5 CF 3 H CF 3 185.9
• R 4EX is a Group of Formula —CO—CH 3 N-[-4-(3-Chloro-phenyl)-pyrimidin-2-yl]-N-(4-trifluoromethyl-phenyl)-acetamide
• N-[4-(3-Chloro-phenyl)-pyrimidin-2-yl]-N-(4-trifluoromethyl-phenyl)-acetamide is obtained in solid (crystalline) form from a mixture of toluene and pentane in the form of a powder. m.p. 128.6-129.6°.
• the m.p. or 1 H-NMR data is the data of the compounds of examples 22 to 28, 29a and 30 in the form of hydrochlorides, for example 29b in the form of the besylate and for example 31 in the form of the trifluoroacetate.
• the mixture obtained is treated at RT with 0.675 ml of a solution of 2-[(2-hydroxy-ethyl)-methyl-amino]-ethanol in 5 ml of chlorobenzene and stirred at 130°, cooled to RT and concentrated in vacuum.
• the concentration residue obtained is dissolved in ethyl acetate and washed with aqueous, saturated NaHCO 3 solution and brine.
• the organic layer obtained is treated with acetic acid, the mixture obtained is concentrated in vacuum and the concentrate obtained is subjected to chromatography.
• the m.p. or 1 H-NMR data of examples 33, 37 and 40 is the data of the compounds in free base form
• the m.p. or 1 H-NMR data of examples 34, 35, 36, 38 and 39 is the data of the compounds in the form of hydrochlorides
• the m.p. of example 32b to 32f) are the date for the following salts: 32b) mesylate, 32c) sulfate, 32d) tartrate, 32e) p-toluenesulfonate and 32f) besylate.
• R 4EX is CO—N(CH 3 ) 2
• aqueous NaOH is added dropwise to a solution of 4.5 g N-[4-(3-chloro-phenyl)-pyrimidin-2-yl]-N-(4-trifluoromethyl-phenyl)-amine in a mixture of tetrahydrofuran and water.
• a precipitate formed is filtered off and solvent is evaporated.
• the evaporation residue obtained is filtered and a filtrate obtained is acidified to pH 2 with 0.1 N HCl and extracted with ethylacetate. The organic phase is washed and dried and solvent is stripped off to give a solid. Crystallisation from a mixture dichloromethane and pentane results in the product. m.p.: 138.6° C.

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  • 2003-01-31 IL IL16276603A patent/IL162766A0/xx unknown
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