Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • 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
  • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • 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
• • 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
• • 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
• • 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
  • C07D403/10—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 carbon chain containing aromatic rings
• • 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
  • 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
  • C07D403/14—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 three or more hetero rings

Definitions

• AD Alzheimer's disease
• APP ⁇ -Amyloid Precursor Protein
• a ⁇ peptides are produced from APP through the sequential action of two proteolytic enzymes termed ⁇ - and ⁇ -secretase.
• ⁇ -Secretase cleaves first in the extracellular domain of APP just outside of the trans-membrane domain (TM) to produce a C-terminal fragment of APP containing the TM- and cytoplasmatic domain (CTF ⁇ ).
• CTF ⁇ is the substrate for ⁇ -secretase which cleaves at several adjacent positions within the TM to produce the A ⁇ peptides and the cytoplasmic fragment.
• Various proteolytic cleavages mediated by ⁇ -secretase result in A ⁇ peptides of different chain length, e.g. A ⁇ 38, A ⁇ 40 and A ⁇ 42. The latter one is regarded to be the more pathogenic amyloid peptide because of its strong tendency to form neurotoxic aggregates.
• the ⁇ -secretase is a typical aspartyl protease.
• the ⁇ -secretase is a proteolytic activity consisting of several proteins, its exact composition is incompletely understood. However, the presenilins are essential components of this activity and may represent a new group of atypical aspartyl proteases which cleave within the TM of their substrates and which are themselves polytopic membrane proteins. Other essential components of ⁇ -secretase may be nicastrin and the products of the aph1 and pen-2 genes.
• Proven substrates for ⁇ -secretase are the APP and the proteins of the Notch receptor family, however, ⁇ -secretase has loose substrate specificity and may cleave further membrane proteins unrelated to APP and Notch.
• the ⁇ -secretase activity is absolutely required for the production of A ⁇ peptides. This has been shown both by genetic means, i.e., ablation of the presenilin genes and by low-molecular-weight inhibitory compounds. Since according to the amyloid hypothesis for AD the production and deposition of A ⁇ is the ultimate cause for the disease, it is thought that selective and potent inhibitors of ⁇ -secretase will be useful for the prevention and treatment of AD.
• An alternative mode of treatment is the modulation of the ⁇ -secretase activity which results in a selective reduction of the A ⁇ 42 production. This will result in to an increase of shorter A ⁇ isoforms, such as A ⁇ 38, A ⁇ 37 or others, which have reduced capability for aggregation and plaque formation, and hence less neurotoxic.
• Compounds which show this effect on modulating ⁇ -secretase activity include certain non-steroidal anti-inflammatory drugs (NSAIDs) and related analogues (Weggen et al. Nature, 414 (2001) 212-16).
• the invention provides compounds of formula I
• the invention provides all forms of optically pure enantiomers, racemates, or diastereomeric mixtures of the compounds of the invention.
• the invention also provides pharmaceutical compositions containing compounds of formula I or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.
• the invention further provides methods for the manufacture of the compounds and compositions of the invention.
• Compounds of formula I are modulators for amyloid beta and thus, they are useful for the treatment or prevention of a disease associated with the deposition of ⁇ -amyloid in the brain, in particular Alzheimer's disease, and other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.
• a disease associated with the deposition of ⁇ -amyloid in the brain in particular Alzheimer's disease, and other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.
• lower alkyl denotes a saturated straight- or branched-chain hydrocarbon group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl and the like.
• Preferred alkyl groups are groups with 1-4 carbon atoms.
• halogen denotes a chlorine, fluorine, bromine, or iodine, with fluorine being preferred.
• lower alkyl substituted by halogen denotes a lower alkyl group as defined hereinabove which is substituted by one or more, preferably one, two or three halogen atom(s), i.e. chlorine, iodine, fluorine or bromine.
• lower alkyl substituted by fluoro denotes an alkyl group as defined above, wherein at least one hydrogen atom is replaced by fluoro, for example CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CH 2 CF 3 , CH 2 CF 2 CF 3 , CH 2 CF 2 CF 2 CF 3 , CH 2 CH 2 CF 2 CF 3 and the like.
• lower alkyl substituted by hydroxy denotes a lower alkyl group as defined hereinabove which is substituted by one or more, hydroxy group(s).
• lower alkoxy denotes a lower alkyl group as defined above that is attached via an oxygen atom.
• the term “five-membered heteroaryl group” denotes an aromatic ring having five ring atoms, wherein at least two ring atoms are heteroatoms, selected from the group consisting of N, O and S, for example oxazolyl, [1,2,4]triazolyl, imidazol-1-yl, thiazolyl, isothiazolyl, isoxazolyl, pyrazol-1-yl, [1,2,4]-oxadiazol-5-yl or [1,3,4]-oxadiazol-2-yl.
• Preferred is the imidazolyl group.
• heterocyclic ring denotes a five or six membered non aromatic ring containing a N atom in the 1-position, wherein the remaining ring atoms are selected from N, O and S, for example the groups piperidine-1-yl, morpholinyl, thiomorpholin or piperazine.
• “Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
• pharmaceutically acceptable acid addition salts embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
• “Therapeutically effective amount” means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
• Preferred compounds are those where Ar is oxazolyl, [1,2,4]triazolyl, imidazol-1-yl, thiazolyl, isothiazolyl, isoxazolyl, pyrazol-1-yl, [1,2,4]-oxadiazol-5-yl or [1,3,4]-oxadiazol-2-yl.
• Preferred compounds are those wherein Ar is imidazol-1-yl.
• Preferred compounds from this group are those, wherein one of R 3 or R 4 is NR′′R′′′ and R′′ and R′′′ together with the N-atom to which they are attached form a heterocyclic ring, optionally substituted by one or more lower alkyl, CH 2 C(O)O-lower alkyl or CH 2 C(O)OH, for example the following compounds:
• Preferred compounds are those where one of R 3 and R 4 is halogen.
• Preferred compounds are those where one of R 3 and R 4 is OR′.
• R 3 and R 4 are NR′′R′′′.
• Still other preferred compounds are those where one of R 3 and R 4 is lower alkyl substituted by halogen or hydroxyl.
• preferred compounds are those where one of R 3 and R 4 is phenyl optionally substituted by one or two halogen atoms.
• Preferred compounds are those where one of R 3 and R 4 is benzyl optionally substituted by one or two halogen atoms.
• the compounds of formula I can be prepared in accordance with process variant a), b) or c) and with the following schemes 1, 2 and 3.
• the present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, starting either from cyanuric chloride II (commercial available) or from commercially available dichloro-intermediates by sequential substitution of the chloro-atoms, as shown in the Schemes 1 and 2.
• R 3 or R 4 is hydrogen
• the replacement of the chloro atom can be done by reduction with Pd on charcoal and hydrogen, as described for example in J. Am. Chem. Soc. 78, 2477 (1956).
• R 3 or R 4 is lower alkyl
• the replacement of the chloro atom can be done with alkyl-Grignard reagents, as described for example in Helv. 33, 1365 (1950).
• R 3 or R 4 is OR′
• the nucleophilic substitution of the chloro atom can be done by reaction with the corresponding alcohols or alcoholates, in analogy to J. Am. Chem. Soc. 79, 944 (1957) or the corresponding phenolates, in analogy to J. Am. Chem. Soc. 73, 2990 (1951).
• R 3 or R 4 is NR′′R′′′ then the nucleophilic substitution of the chloro atom can be done with the corresponding amine HNR′′R′′′, as shown for example in Bull. Soc. Chim. Fr. 1973, 2112. Alternatively, for less nucleophilic or sterically hindered amines, the substitution can be done under Buchwald-Hartwig conditions, using Pd-catalysis.
• R 3 is phenyl or substituted phenyl
• the chloro atom can be reacted with arylboronic acids in presence of a base and a palladium catalyst (Suzuki-coupling, as described, for example, in Tetrahedron 57, 2787 (2001)) for other triazine-derivatives.
• R 3 is lower alkyl substituted by hydroxy, for example the group C(CH 3 ) 2 OH
• the chloro atom can be alkoxycarbonylated, as described, for example, in Tetrahedron 55, 405 (1995) for analogous pyrimidine-derivatives.
• the resulting ester is then reacted with methylmagnesium halide, as described, for example, in Tetrahedron 61, 6330 (2005) for analogous pyridine-derivatives. This procedure is shown in Scheme 3.
• Aniline III can be prepared as described in Scheme 4.
• a nitro derivative VIII can be prepared from a suitable precursor, such as a carbonyl derivative IX (R ⁇ H or C 1-4 -alkyl), by applying standard reaction sequences for the formation of the substituent R 1 .
• a nitro compound VIII can be reduced to an aniline III using generally known procedures, e.g. hydrogenation in the presence of a catalyst (like e.g. 10% palladium on carbon) in a solvent (like e.g. ethanol or ethyl acetate) or, by using a metal (like e.g. iron) or a metal salt (like e.g. stannous chloride) in a polar solvent (like e.g. acetic acid or tetrahydrofuran).
• Human neuroglioma H4 cells overexpressing human APP were plated at 30,000 cells/well/200 ⁇ l in 96-well plates in IMDM media containing 10% FCS, 0.2 mg/l Hygromycin B and incubated for 2 h at 37° C., 5% CO 2 prior to adding test compounds.
• 50 ⁇ l assay buffer 50 mM Tris/Cl, pH 7.4, 60 mM NaCl, 0.5% BSA, 1% TWEEN 20
• detection antibody ruthenylated A ⁇ 42-specific antibody BAP15 0.0625 ⁇ g/mL in assay buffer
• 50 ⁇ l of a premix of capture antibody biotinylated 6E10 antibody, 1 ⁇ g/mL
• Steptavidin-coated magnetic beads Dynal M-280, 0.125 mg/mL
• Toxicity of compounds was monitored by a cell viability test of the compound-treated cells using a colorimetric assay (CellTiter 96TM AQ assay, Promega) according to the manufacturer's instructions. Briefly, after removal of 50 ⁇ l cell culture supernatant for detection of A ⁇ 42, 20 ⁇ l of 1 ⁇ MTS/PES solution was added to the cells and incubated for 30 min at 37° C., 5% CO 2 . Optical density was then recorded at 490 nm.
• IC 50 values for inhibition of A ⁇ 42 secretion were calculated by nonlinear regression fit analysis using XLfit 4.0 software (IDBS).
• the preferred compounds show a IC 50 ⁇ 1.0 ( ⁇ M).
• ⁇ M IC 50 ⁇ 1.0
• the present invention also provides pharmaceutical compositions containing compounds of the invention, for example, compounds of formula I or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.
• Such pharmaceutical compositions can be in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions.
• the pharmaceutical compositions also can be in the form of suppositories or injectable solutions.
• compositions of the invention in addition to one or more compounds of the invention, contain a pharmaceutically acceptable carrier.
• suitable pharmaceutically acceptable carriers include pharmaceutically inert, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragées and hard gelatin capsules.
• Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatin capsules.
• Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like.
• Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
• compositions can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
• the present invention also provides a process for the manufacture of pharmaceutical compositions. Such process comprises bringing the compound of formula I and/or pharmaceutically acceptable acid addition salt thereof and, fir desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
• compounds of formula I as well as their pharmaceutically acceptable salts are useful in the control or prevention of illnesses based on the inhibition of the ⁇ -secretase, such as of Alzheimer's disease.
• the dosage at which compounds of the invention can be administered can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case.
• the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof.
• the daily dosage can be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.
• Tablet Formulation mg/tablet Item Ingredients 5 mg 25 mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500 2. Lactose Anhydrous DTG 125 105 30 150 3. Sta-Rx 1500 6 6 6 30 4. Microcrystalline Cellulose 30 30 30 150 5. Magnesium Stearate 1 1 1 1 Total 167 167 167 831
• Capsule Formulation mg/capsule Item Ingredients 5 mg 25 mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500 2. Hydrous Lactose 159 123 148 — 3. Corn Starch 25 35 40 70 4. Talc 10 15 10 25 5. Magnesium Stearate 1 2 2 5 Total 200 200 300 600
• the crude product was purified on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (106 mg, 45%) as a pale-yellow solid.
• the product can be also crystallized from the crude material from diethyl ether.
• Triethylamine (0.23 ml, 1.62 mmol) was added to a solution of 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (300 mg, 1.48 mmol) in 5 ml of methanol. The mixture was cooled in an ice-bath and 2,4-dichloro-6-methoxy-[1,3,5]triazine (266 mg, 1.48 mmol) added portionwise. The mixture was stirred for 1 hour at 0° C. The resulting precipitate was removed by filtration and dried to give the title compound as a slightly brownish solid (317 mg, 62%).
• the title compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 4-fluorophenol in analogy to example 3. It was purified by column chromatography on silica gel using ethyl acetate as eluent to give the title compound as a yellowish solid in 52% yield.
• This compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 4-chloro-N-methylaniline in analogy to example 1c. It was purified by column chromatography on Si—NH2 gel (Isolute) using ethyl acetate as eluent to give the title compound as a colorless solid in 14% yield.
• This compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 3,4,5-trifluorophenol in analogy to example 3. Chromatography on silica gel using ethyl acetate as an eluent gave the title compound as a colorless solid in 25% yield.
• This compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and piperidine in analogy to example 1c. Chromatography on Si—NH2 gel (Isolute) using ethyl acetate as an eluent gave the title compound as a colorless solid in 22% yield.
• This compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 2,4-dichlorophenol in analogy to example 3. Chromatography on silica gel using ethyl acetate as an eluent gave the title compound as a colorless solid in 81% yield.
• This compound was prepared from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2,4-dichloro-1,3,5-triazine in analogy to example 2a.
• the compound precipitated from methanol in 50% yield.
• This compound was prepared from (4-chloro-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 2-hydroxybenzotrifluoride in analogy to example 3. Chromatography on silica gel using ethyl acetate as an eluent gave the title compound as a colorless solid in 33% yield.
• This compound was prepared from(4-chloro-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 4-chloro-N-methylaniline in analogy to example 1c. Chromatography on Si—NH2 gel (Isolute) using ethyl acetate as an eluent gave the title compound as a colorless solid in 23% yield.
• the title compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 3-hydroxypyridine in analogy to example 3. It was purified by column chromatography on Si—NH2 gel (Isolute) using ethyl acetate as eluent to give the title compound as a yellowish solid in 21% yield.
• the title compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 2-chloro-3-hydroxypyridine in analogy to example 3. It was purified by column chromatography on Si—NH2 gel (Isolute) using ethyl acetate as eluent to give the title compound as a yellowish solid in 76% yield.
• the title compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 3-hydroxy-2-methylpyridine in analogy to example 3. It was purified by column chromatography on Si—NH2 gel (Isolute) using ethyl acetate as eluent to give the title compound as a yellowish solid in 34% yield.
• the title compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and cis-2,6-dimethylmorpholine in analogy to example 1c. It was purified by column chromatography on Si—NH2 gel (Isolute) using ethyl acetate as eluent to give the title compound as a yellowish solid in 58% yield.
• the title compound was prepared from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2,4-dichloro-6-isopropoxy-[1,3,5]triazine (Synth. Commun. 24, 2153 (1994)) in analogy to example 2a.
• the compound crystallized from methanol as a slightly brownish solid in 41% yield.
• This compound was prepared from (4-chloro-6-isopropoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 2-hydroxy benzotrifluoride in analogy to example 3. Chromatography on silica gel using ethyl acetate as an eluent gave the title compound as a colorless solid in 99% yield.
• This compound was prepared from (4-chloro-6-isopropoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 4-chloro-N-methyl aniline in analogy to example 1c. Chromatography on Si—NH2 gel (Isolute) using ethyl acetate as an eluent gave the title compound as a colorless solid in 27% yield.
• This compound was prepared from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2-chloro-4-methoxy-6-methyl-[1,3,5]triazine in analogy to example 1c. It was purified by chromatography on Si—NH2 (Isolute) using ethyl acetate as an eluent to give the title compound as a slightly yellowish solid in 32% yield.
• This compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and N-(2-methoxyethyl)methylamine in analogy to example 1c. It was purified by chromatography on Si—NH2 (Isolute) using ethyl acetate as an eluent to give the title compound as a slightly yellowish solid in 51% yield.
• 6-Chloro-N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-N′,N′-dimethyl-[1,3,5]triazine-2,4-diamine (100 mg, 0.28 mmol) was treated with N-methylpiperidine (0.31 ml, 2.78 mmol). The mixture was heated to 50° C. for 30 minutes, diluted with water and extracted with ethyl acetate. Purification by chromatography on silica gel using ethyl acetate as an eluent to gave the title compound (114 mg , 97%) as a yellowish gum.
• [1-(2-Methoxy-4-nitro-phenyl)-1H-imidazol-4-yl]-methanol 500 mg, 2.0 mmol
• stannous chloride dehydrate 2.35 g, 10.4 mmol
• the reaction mixture was refluxed for 1 hour, cooled to room temperature and diluted with aqueous sodium hydrogencarbonate solution. Extraction with ethyl acetate gives the title compound (311 mg, 71%) as a yellowish viscous oil.
• This compound was prepared in analogy to example 3 from ⁇ 1-[4-(4-chloro-6-methoxy-[1,3,5]triazin-2-ylamino)-2-methoxy-phenyl]-1H-imidazol-4-yl ⁇ -methanol and 2-chloro-3-hydroxypyridine.
• the title compound was isolated as a slightly brownish solid in 43% yield.
• This compound was prepared in analogy to example 8 from 4-(imidazol-1-yl)aniline, triethylamine and 2,4-dichloro-6-methoxy-1,3,5-triazine.
• the title compound was isolated as a slightly brownish solid in 84% yield.
• Lithium aluminum hydride (1.84 g, 43 mmol) was suspended in 30 ml of tetrahydrofuran and cooled in an ice-bath.
• a solution of (R)-methylamino-phenyl acetic acid (1.0 g, 6 mmol) in 10 ml of tetrahydrofuran was slowly added over a period of 20 minutes.
• the resulting mixture was stirred for 1 hour at 0°, 4 hours at room temperature and then refluxed overnight.
• the mixture was cooled and carefully hydrolysed by addition of 50 ml 15% aqueous sodium hydroxide.
• This compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and (R)-2-methylamino-2-phenyl-ethanol in analogy to example 1c. Purification by chromatography on Si—NH2 gel (Isolute) using ethyl acetate as an eluent gave the title compound as a colorless solid in 32% yield.
• This compound was prepared from [4-chloro-6-(4-chloro-benzyl)-[1,3,5]triazin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (0.60 g, 1.36 mmol) in analogy to example 30 a.
• the crude product was purified by chromatography on silica gel using heptane/0-80% ethyl acetate as eluent to give the title compound (0.41 g, 64%) as a yellow solid.

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