WO2003040141A1 - Composes d'oxazolyl-phenyl-2,4-diamino-pyrimidine, et methodes de traitement de troubles hyperproliferatifs - Google Patents

Composes d'oxazolyl-phenyl-2,4-diamino-pyrimidine, et methodes de traitement de troubles hyperproliferatifs Download PDF

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WO2003040141A1
WO2003040141A1 PCT/US2002/030633 US0230633W WO03040141A1 WO 2003040141 A1 WO2003040141 A1 WO 2003040141A1 US 0230633 W US0230633 W US 0230633W WO 03040141 A1 WO03040141 A1 WO 03040141A1
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group
amino
phenyl
methyl
pyrimidinyl
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PCT/US2002/030633
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English (en)
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Jacques Dumas
Harold C. E. Kluender
Chengzhi Zhang
Yuanwei Chen
Zhenqiu Hong
Holia Hatoum-Mokdad
Wendy Lee
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Bayer Pharmaceuticals Corporation
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    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic 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

Definitions

  • Oxazolyl-Phenyl-2,4-Diamino-Pyrimidine Compounds and Methods for Treating Hyperproliferative Disorders
  • the present invention relates to:
  • compositions comprising one or more of the compounds or purified stereoisomers of the invention, or their salts or prodrugs forms thereof, with a pharmaceutically acceptable ingredient;
  • A is oxazolyl, which is optionally substituted by:
  • Ri and R 2 are independently selected from: (a) hydrogen; (b) linear or branched C ⁇ -C 5 alkyl;
  • R 3 and R are independently selected from:
  • n is an integer from 0 - 2;
  • R 3 and R> form, together with the nitrogen to which they are attached, a saturated or unsaturated, 4- to 8-membered ring structure, containing zero to four additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring structure contains at least two carbon atoms;
  • R 5 , R_, R 7 and R 8 are independently selected from the group consisting of: (a) hydrogen; (b) linear or branched C i -C 5 alkyl ;
  • R 9 is hydrogen, or a linear or branched C1-C 5 alkyl
  • oxazoyl-phenyl-2,4-diamino-pyrimidine compounds or purified stereoisomers of said compounds and their salts or prodrug forms thereof which have structural formulae (I) or (II):
  • A is oxazolyl, which is optionally substituted by: (a) halogen; or (b) linear or branched C 1 -C 5 alkyl
  • Ri and R 2 are independently selected from: (a) hydrogen; (b) linear or branched C 2 -C 5 alkyl;
  • R 3 and R are independently selected from: (a) hydrogen;
  • X is phenyl, optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, perhaloalkyl, C ⁇ -C 3 alkoxy, hydroxy, amino, C ⁇ -C 3 alkylamino, C ⁇ -C dialkylamino, cyano, and nitro; and n is an integer from 1 -2;
  • a saturated or unsaturated heterocycle consisting of a 4-7 membered ring containing one to three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur;
  • R 5 , R ⁇ , R and R 8 are independently selected from the group consisting of:
  • R is hydrogen, or a linear or branched C 1 -C 5 alkyl
  • the invention relates to a compound of the following formula
  • R 10 represents halogen, C ⁇ -C 3 alkyl, or C ⁇ -C 3 alkoxy; r represents an integer 0-2;
  • R u represents H or C ⁇ -C 3 alkyl
  • R 12 represents C r C 3 alkyl or CH 2 -E wherein E represents phenyl, optionally bearing up to two substituents independently selected from the group consisting of halogen; C ⁇ -C 3 alkyl, halogenated C ⁇ -C 3 alkyl provided that if said halogenated C ⁇ -C alkyl is perhalogenated then R 2 is other than methyl; and C ⁇ -C 3 alkoxy; pyridinyl; furyl; thienyl; or benzimidazolyl; or R 1 ' and R 12 may be joined, and taken together with the N to which they are attached, constitute a morpholinyl moiety;
  • R 13 represents H or C ⁇ -C 3 alkyl;
  • R 14 represents halogen, C ⁇ -C 3 alkyl, or C ⁇ -C 3 alkoxy;
  • s represents an integer 0-2; and
  • R 15 represents an oxazolyl group attached
  • Compound is intended to be inclusive of the compound, purified stereoisomers thereof and salt and prodrug forms of said compound and purified isomers. Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.
  • Any asymmetric carbon atoms may be present in the (R)-, (S)- or (R,S)-configuration, preferably in the (R)- or (S)-configuration.
  • the compounds may thus be present as mixtures of stereoisomers or as pure stereoisomers, preferably as enantiomer-pure diastereomers.
  • Linear or branched C ⁇ -C alkyl means a saturated hydrocarbon radical having up to a maximum of five carbon atoms, which may be linear or branched with single or multiple branching.
  • Halogenoalkyl means a saturated hydrocarbon radical having up to a maximum of five carbon atoms which may be linear or branched with single or multiple branching and is substituted with halogen, up to perhalo. This halogen is preferably chlorine and/or fluorine. Examples of such halogenated alkyl substituents include but are not limited to chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and 1 , 1 ,2,2-tetrafluoroethyl. "Halogen” means fluorine, chlorine, bromine, or iodine but is especially fluorine, chlorine, or bromine.
  • the two R 3 and R groups, together with the nitrogen atom they are attached to, can be combined into a saturated or unsaturated heterocycle of 4-8 atoms which contain zero to four additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur wherein said ring structure contains at least two carbon atoms.
  • nitrogen containing heterocycles include but are not limited to pyrrolidinyl, dioxanyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, azetyl, diazepinyl, azepinyl, pyranyl, furyl, thiophenyl, thiazepinyl and oxazepinyl.
  • “Mono- or bicyclic-heteroaryl” means a monocyclic or fused bicyclic aromatic system with between 5 and 10 atoms in total of which 1-4 are heteroatoms selected from the group comprising nitrogen, oxygen, and sulfur and with the remainder being carbon. Heteroaryl is preferably a monocyclic or bicyclic system with 5, 6, 8, 9, or 10 atoms in total, of which 1-3 are heteroatoms.
  • Examples of monocyclic heteroaryl rings include but are not limited to pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, pyridine, pyrimidine, pyridazinyl, and triazinyl.
  • Examples of bicyclic heteroaryl rings include 5-5, 5-6, and 6-6 fused bicycles, where one of the rings is one of the above heteroaryl rings and the second ring is either benzene or another heteroaryl ring.
  • the moiety Y can be a saturated or unsaturated heterocycle, consisting of a 4-7 membered ring containing one to three heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur.
  • heterocycles include but are not limited to pyrrolidinyl, dioxanyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, azetyl, diazepinyl, azepinyl, pyranyl, furyl, thiophenyl, thiazepinyl and oxazepinyl.
  • Salts are especially the pharmaceutically acceptable salts of compounds of formulae (I) or (II) such as, for example, organic or inorganic acid addition salts of compounds of formulae (I) or (II).
  • Suitable inorganic acids include but are not limited to halogen acids (such as hydrochloric acid), sulfuric acid, or phosphoric acid.
  • Suitable organic acids include but are not limited to carboxylic, phosphonic, sulfonic, or sulfamic acids, with examples including acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, 2- or 3-hydroxybutyric acid, ⁇ -aminobutyric acid (GAB A), gluconic acid, glucosemonocarboxylic acid, furnaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azeiaic acid, malic acid, tartaric acid, citric acid, glucaric acid, galactaric acid, amino acids (such as glutamic acid, aspartic acid, N-methylglycine, acetytaminoacetic acid, N- acetylasparagine or N-acetylcysteine), pyruvic acid, acetoacetic acid, phosphoserine, and 2- or
  • prodrugs are well known in the art in order to enhance the properties of the parent compound; such properties include solubility, abso ⁇ tion, biostability and release time (see “Pharmaceutical Dosage Form and Drug Delivery Systems” (Sixth Edition), edited by Ansel et al., publ. by Williams & Wilkins, pgs. 27-29, (1995) which is hereby inco ⁇ orated by reference).
  • prodrugs of the disclosed oxazolyl-phenyl-2,4- diamino-pyrimidine compounds are designed to take advantage of the major drug biotransformation reactions and are also to be considered within the scope of the invention.
  • Major drug biotransformation reactions include N-dealkylation, O-dealkylation, aliphatic hydroxylation, aromatic hydroxylation, N-oxidation, S-oxidation, deamination, hydrolysis reactions, glucuronidation, sulfation and acetylation (see Goodman and Gilman's The
  • the invention also includes pharmaceutical compositions comprising one or more of the compounds of the invention, or their salts or prodrugs forms thereof, with a pharmaceutically acceptable ingredient.
  • compositions are prepared so that they may be administered orally, dermally, parenterally, nasally, ophthalmically, otically, sublingually, rectally or vaginally.
  • Dermal administration includes topical application or transdermal administration.
  • Parenteral administration includes intravenous, intraarticular, intramuscular, and subcutaneous injections, as well as use of infusion techniques.
  • One or more compounds of the invention may be present in association with one or more non-toxic pharmaceutically acceptable ingredients and optionally, other active anti-proliferative agents, to form the pharmaceutical composition.
  • These compositions can be prepared by applying known techniques in the art such as those taught in Remington's Pharmaceutical Sciences (Fourteenth Edition), Managing Editor, John E.
  • compositions for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine); adsorbents (examples include but are not limited to powdered cellulose and activated charcoal); aerosol propellants (examples include but are not limited to carbon dioxide, CC1 2 F 2 ,
  • air displacement agents examples include but are not limited to nitrogen and argon
  • antifungal preservatives examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate
  • antimicrobial preservatives examples include but are not limited to benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal
  • antioxidants examples include but are not limited to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium
  • compositions can take the form of aerosols, capsules, creams, elixirs, emulsions, foams, gels, granules, inhalants, lotions, magmas, ointments, peroral solids, powders, sprays, syrups, suppositories, suspensions, tablets and tinctures.
  • Optional anti-proliferative agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11 th Edition of the Merck Index, (1996), which is hereby inco ⁇ orated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone
  • anti-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowldeged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ.
  • anti-proliferative agents suitable for use with the composition of the invention include but are not limited to other anti-cancer agents such as epothilone, irinotecan, raloxifen and topotecan.
  • the daily oral dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily dosage for administration by injection including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight. It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be understood, however, that the specific dose level for any given patient will depend upon a variety of factors, including, but not limited to the activity of the specific compound employed, the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, time of administration, route of administration, rate of excretion, drug combinations, and the severity of the condition undergoing therapy.
  • the optimal course of treatment i.e., the mode of treatment and the daily number of doses of a compound of formulae (I) or (II) or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.
  • the compounds of the invention may be prepared by use of known chemical reactions and procedures. Nevertheless, the following general preparative methods are presented to aid the reader in synthesizing the compounds of the present invention, with more detailed particular examples being presented below in the experimental section describing the working examples.
  • variable groups of these methods are as described in the generic description if they are not specifically defined below.
  • R , t a variable group or substituent with a given symbol
  • each of these groups or substituents may be independently varied within the range of definitions for that symbol.
  • compounds of the invention with each claimed optional functional group cannot be prepared with each of the below-listed methods.
  • optional substituents are used which are stable to the reaction conditions, or the functional groups which may participate in the reactions are present in protected form where necessary, and the removal of such protective groups is completed at appropriate stages by methods well known to those skilled in the art.
  • the compounds of formulae (I) or (II) can be made according to conventional chemical methods, and/or as disclosed below, from starting materials which are either commercially available or producible according to routine, conventional chemical methods. General methods for the preparation of the compounds are given below, and the preparation of representative compounds is specifically illustrated in Examples 1-27.
  • the two successive addition reactions (a) and (b) can proceed either in the absence of a solvent (in this case, the amines R 3 NH or (V) resp. (VI) would be used as a solvent) at elevated temperatures, or in a suitable solvent.
  • solvents include ketones (acetone, butanone), alcohols (methanol, ethanol, isopropanol, butanol), amides (dimethylformamide, dimethylacetamide, N-methylpyrrolidinone), ethers (diethyl ether, tetrahydrofuran, dioxane), or hydrocarbons (toluene, xylene).
  • the reaction can be carried out in the presence of an organic base, such as triethylamine, potassium tert-butoxide or pyridine, an inorganic base such as potassium carbonate or sodium hydroxide, or an acid such as hydrochloric, sulfuric, acetic or formic acid.
  • This reaction is carried out a temperature ranging from 0 °C to 150 °C, preferably between room temperature and reflux.
  • An alternative method to carry out reactions (a) and / or (b), especially when lower temperatures are required, is the use of a palladium catalyzed process already described in the art (Wolfe et al., J. Org. Chem. 1997, 62, 6066, and references cited therein).
  • the chlorinating agent can be used in excess as a solvent, at temperatures ranging from 0 °C to reflux, preferably reflux, or in a stoichiometric amount in the presence of an inert solvent such as toluene, tetrahydrofuran, xylene, or dichloromethane.
  • an inert solvent such as toluene, tetrahydrofuran, xylene, or dichloromethane.
  • halogen atoms other than chlorine, especially bromine is also possible. This can be achieved with the appropriate halogenating agents.
  • Uracils are either commercially available, or easily obtained by the condensation of beta- ketoesters and alpha-formylesters with urea in the presence of a base such as sodium methoxide in methanol, at elevated temperatures.
  • Aminophenyl-oxazole intermediates (V) and (VI), where R 5 -R 9 and A are defined as above, can be prepared using a variety of methods known in the art.
  • General approaches to 2-, 4- and 5-substituted 1,3-oxazoles have been reviewed in the literature (Katritzky et al. in “Comprehensive Heterocyclic Chemistry II", Elsevier Science Inc., 1996). The most prominent method is the cyclodehydration of ⁇ -acylaminoketones in the presence of sulfuric or phosphoric acid, according to Robinson and Gabriel (see Eicher et al., in “The Chemistry of Heterocycles", Georg Thieme Verlag, Stuttgart, 1995).
  • the nitro group of (VIII) is then reduced into an amine (LX) using a variety of conditions known in the art. Those conditions include hydrogenation in the presence of a transition metal catalyst such as palladium on carbon, platinum, or platinum dioxide in methanol, ethanol, ethylacetate or acetic acid, treatment with iron or zinc powder in methanol, ethanol, or acetic acid, or treatment with tin dichloride in dimethylformamide. If R 9 is not H, amines (IX) can be converted into 4-(3-aminophenyl)-l,3-oxazoles (Va) via alkylation or reductive amination.
  • a transition metal catalyst such as palladium on carbon, platinum, or platinum dioxide in methanol, ethanol, ethylacetate or acetic acid
  • iron or zinc powder in methanol, ethanol, or acetic acid
  • tin dichloride in dimethylformamide.
  • the amines (IX) are reacted with halogenides, tosylates, mesylates, or triflates in the presence of a base such as potassium hydride, potassium carbonate, or triethylamine in order to introduce the appropriate R 9 residue.
  • a base such as potassium hydride, potassium carbonate, or triethylamine
  • the R 9 residue can be introduced by reductive amination of aldehydes and ketones using a reducing agent such as an alkaline cyanoborohydride.
  • Alkyl substituents can be added either on the formamide or the haloketone / hydroxyketone reagent in order to prepare alkylated 4- (3-aminophenyl)- 1 ,3-oxazoles.
  • the isomeric 4-(4-aminophenyl)-l,3-oxazoles (Via) can be prepared by the method depicted in Scheme 3, using appropriate starting materials (use of 4-nitrophenyl-haloketones or hydroxyketones instead of 3-nitrophenyl-haloketones or hydroxyketones).
  • Those conditions include potassium carbonate in refluxing methanol (Van Leusen et al., Tetrahedron Lett. 1972, 23, 2369-2372), sodium methoxide in methanol (Anderson et al., J. Org. Chem. 1997, 62, 8634-8639), or a basic ion-exchange resin in 1 ,2-dimethoxyethane / methanol (Kulkami et al., Tetrahedron Lett. 1999, 40, 5637-5638, and references cited therein).
  • TosMIC can be replaced by benzotriazolylmethyl isocyanide (Katrizky et al., Tetrahedron Lett.
  • the isomeric 5-(4-aminophenyl)-l,3-oxazoles (VIb) can be prepared by the same method, using appropriate starting materials (use of 4-nitro-benzaldehydes instead of 3- nitrobenzaldehydes).
  • ⁇ -aminoketones of formula (XII) can be prepared according to known literature methods, for example Clemo et al., J Chem. Soc. 1938, 753.
  • the isomeric 2-(4-aminophenyl)-l,3-oxazoles (Vic) can be prepared by the same method, using appropriate starting materials (use of 4-nitro-benzamides instead of 3- nitrobenzamides).
  • Proton (1H) nuclear magnetic resonance (NMR) spectra were measured with a Varian (300 MHz) spectrometer with residual protonated solvent (CHC1 3 ⁇ 7.26; MeOH ⁇ 3.30; DMSO ⁇ 2.49) as standard.
  • MS mass spectra
  • MS were either obtained as electron impact (El) mass spectra, as electrospray (ES) mass spectra, or as fast atom bombardment (FAB) mass spectra.
  • This compound was prepared by the same process as used for Example 2, except that intermediate 2-chloro-5-fluoro-N-(2-furylmethyl)-4-pyrimidinamine (Example 27J, 65 mg, 0.28 mmol) and 3-(l,3-oxazol-4-yl)phenylamine (Example 26F, 55 mg, 0.35 mmol) were used. HPLC purification yielded 26 mg of title compound (0.074 mmol, yield 26%).
  • This compound was prepared by the same process as used for Example 2, except that intermediate 2-chloro-5-methyl-N-(2-thienylmethyl)-4-pyrimidinamine (Example 27B, 60 mg, 0.25 mmol) and 3-(l,3-oxazol-4-yl)phenylamine (Example 26F, 48 mg, 0.30 mmol) were used.
  • Preparative HPLC purification yields 22 mg of title compound (0.06 mmol, yield 24%).
  • This compound was prepared by the same process as used for Example 2, except that intermediate 2-chloro-5-methyl-N-(2-thienylmethyl)-4-pyrimidinamine (Example 27B, 60 mg, 0.25 mmol) and 4-(l,3-oxazol-5-yl)phenylamine (Example 26A, 48 mg, 0.3 mmol) were used.
  • Preparative HPLC purification yields 22 mg of title compound (0.06 mmol, yield 24%).
  • This compound was prepared by the same process as used for Example 2, except that intermediate 2-chloro-N-(2-furylmethyl)-N,5-dimethyl-4-pyrimidinamine (Example 271, 40 mg, 0.16 mmol) and 5-(3-aminophenyl)-oxazole (Example 26B, 32 mg, 0.20 mmol) were used.
  • Preparative HPLC purification yields 22 mg of title compound (0.03 mmol, yield 21%).
  • This compound was prepared by the same process as used for Example 2, except that intermediate 2-chloro-N-(2-furylmethyl)-N,5-dimethyl-4-pyrimidinamine (Example 271, 40 mg, 0.16 mmol) and 5-(4-aminophenyl)-oxazole (Example 26A, 32 mg, 0.20 mmol) were used.
  • Preparative HPLC purification yields 10 mg of title compound (0.015 mmol, yield 12%).
  • This compound was prepared by the same process as used for Example 2, except that intermediate N-benzyl-2-chloro-5-methyl-4-pyrimidinamine (Example 27K, 60 mg, 0.25 mmol) and 4-(l,3-oxazol-5-yl)phenylamine (Example 26A, 48 mg, 0.3 mmol) were used. Preparative HPLC purification yields 60 mg of title compound (0.16 mmol, yield 67%).
  • Example 2 To a solution of Example 2 (104 mg, 0.28 mmol) in MeOH (25 mL) was added a 2.0 M solution of hydrogen chloride in ethyl ether (3 mL). The reaction mixture was stirred at room temperature for 4 hours, then concentrated to yield 92 mg of the title compound.
  • This compound was prepared by the same process as used for Example 2, except that intermediate 2-chloro-N-(2-furylmethyl)-5-methyl-4-pyrimidinamine (Example 27H, 50 mg, 0.21 mmol) and 3-(l,3-oxazol-4-yl)phenylamine (Example 26F, 40 mg, 0.25 mmol) were used.
  • Preparative HPLC purification water-CH CN with 0.1% TFA
  • Example 27D N-(2-chloro-5-methyl-4-pyrimidinyl)-N-(2- pyridinylmethyl)amine
  • Example 26B 5-(3-aminophenyl)-l,3-oxazole
  • Example 27D N-(2-chloro-5-methyl-4-pyrimidinyl)-N-(2-pyridinyl methyl)amine
  • Example 26C 5-(3-amino-6-methoxyphenyl)-l,3-oxazole
  • Step 1 To a stirred solution of 4-nitrobenzaldehyde (10.0 g, 66.2 mmol) in anhydrous methanol (100 mL) was added drop wise a solution of 25% sodium methoxide in methanol (30 mL, 2.0 eq) at 0°C. The resultant yellow reaction mixture was stirred at 0°C for 1 hour, and tosylmethyl isocyanide (13.57 g, 69.51 mmol, 1.05 eq) was added over 15 minutes. The reaction was stirred at 70°C for 3 hours and then poured into water (500 mL).
  • Step 2 To a dry flask containing 10%Pd/C in absolute ethanol (150 mL) and anhydrous methanol (75 mL) was added a solution of 5-(4-nitrophenyl)-l,3-oxazole (7.0 g, 36.8 mmol) in anhydrous ethyl acetate (150 mL). The reaction mixture was stirred under a hydrogen balloon for 16 hours and then filtered through a pad of celite. The filtrate was evaporated under reduced pressure to give a yellow solid.
  • Step 1 A mixture of 2-chloro-5-nitrobenzaldehyde (5.0 g, 26.9 mmol), tosylmethyl isocyanide (5.52 g, 28.3 mmol, 1.05 eq), and potassium carbonate (7.45 g, 53.9 mmol, 2.0 eq) in anhydrous ethylene glycol dimethyl ether (54 mL) was stirred at reflux under argon for 17 hours. The reaction mixture was cooled and poured into ethyl acetate. The organic layer was washed with water (2 x 150 mL) and brine (150 mL), dried (MgSO 4 ), filtered, and evaporated under reduced pressure.
  • Step 2 To a mixture of 5-(2-chloro-5-nitrophenyl)-l,3-oxazole (500 mg, 2.23 mmol) in acetic acid (4.5 mL) and anhydrous tetrahydrofuran (10 mL) was added iron powder (312 mg, 5.58 mmol, 2.5 eq). The reaction mixture was stirred at 50°C for 5 hours. The reaction was quenched with saturated aqueous sodium carbonate (50 mL), and the aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried (MgSO 4 ), filtered, and evaporated under reduced pressure.
  • Step 1 2-Bromo-3'-nitroacetophone (5 g, 19.9 mmol) was dissolved in an excess of formamide (15 mL) and was heated at 60 °C for 6 hours until all the starting material was converted to products. The reaction was cooled to room temperature and was diluted with 60 mL ethyl acetate. The solution was washed with water (3x), dried and concentrated. The resultant crude mixture was purified by column chromatography (3:7 v/v ethyl acetate- hexane) to afford 1.12 g of 4-(3-nitrophenyl)-l,3-oxazole as a solid.
  • Step 2 A flask was charged with 10% Pd/C (100 mg) and flushed with argon. Methanol (60 mL) and a solution of intermediate 4-(3-nitrophenyl)-l,3-oxazole (1 g, 5.25 mmol) in methanol (10 mL) were added. The reaction mixture was stirred under H 2 (1 atm). After 24 hours, the reaction mixture was filtered, the organic solution was collected and concentrated to yield 700 mg of the desired compound 3-(l,3-oxazol-4-yl)phenylamine (4.3 mmol, yield 83%) as a solid.
  • 2,4-Dichloro-5-fluoropyrimidine was prepared as follows: 5-fluoro-uracil (16.192 g, 124 mmol.) and phosphorous pentachloride (51.8 g, 248 mmol) were dissolved in phosphorous oxychloride (46 mL, 496 mmol.) and stirred at reflux for 4 hours. The solvent was removed in vacuo to yield 2,4-dichloro-5-fluoropyrimidine as a yellow solid (17.5 g, 84.5%). LC/MS [M+l] + : 168.
  • the present invention also relates to a method for using oxazolyl-phenyl-2,4-diamino- pyrimidine compounds (including salts and prodrug forms thereof) and compositions to treat hyper-proliferative disorders in mammals.
  • This method comprises administering to the mammal an amount of a compound of the invention, or a salt or prodrug thereof, which is effective to treat the disorder.
  • Hyper-proliferative disorders include but are not limited to solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukemias.
  • hyper-proliferative disorders which can be treated by the disclosed oxazolyl-phenyl- 2,4-diamino-pyridine compounds, salts, prodrugs and compositions thereof include, but are not limited to solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases.
  • Those disorders also include, but are not limited to lymphomas, sarcomas, and leukemias.
  • breast cancer examples include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
  • cancers of the respiratory tract include, but are not limited to small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
  • brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
  • Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer.
  • Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
  • Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallblader, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
  • Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, and urethral cancers.
  • Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
  • liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
  • Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • Head-and-neck cancers include, but are not limited to laryngeal / hypopharyngeal / nasopharyngeal / oropharyngeal cancer, and lip and oral cavity cancer.
  • Lymphomas include, but are not limited to AIDS -related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
  • Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
  • S-Phase elevated kinase or "SPEK” in this disclosure
  • the S-phase marks the start of the cell cycle wherein DNA is synthesized/replicated.
  • the cell After DNA synthesis/replication, the cell enters a premitotic phase (G 2 -phase) before proceeding to mitosis (M-phase). After mitotic division into two daughter cells is complete, the cell enters a pre-DNA synthesis phase (Gi- phase) until the replicative process is to begin again.
  • G 2 -phase premitotic phase
  • M-phase mitosis
  • Si- phase pre-DNA synthesis phase
  • Many known anti-proliferative agents act on specific phases of the cell cycle; examples of S-phase specific inhibitors include cytosine arabinoside, hydroxyurea, 6-mercaptopurine and methotrexate.
  • Example 28 below uses SPEK as an example of a protein kinase to show the in vitro inhibitory protein kinase activity in a biochemical assay with the disclosed oxazolyl- phenyl-2,4-diamino-pyridine compounds, salts, prodrugs and compositions thereof.
  • Isolated nucleic acid molecules, isolated nucleic acid sequences, and the corresponding amino acid sequences for SPEK have been described in U.S. Ser. No. 09/345,473 and 09/562,480, which are hereby inco ⁇ orated by reference.
  • a highly homologous protein kinase was reported in PCT Int. Appl. 2000, WO 00/73469 (U.S. Prov. Appl. 60/136,503) to be useful for modulating cellular growth and/or cellular metabolic pathways particularly for regulating one or more proteins required for growth, cell cycle progression, malignant transformation, signal transduction, metabolism or apoptosis.
  • a SPEK-GST fusion protein ( ⁇ 124kDa, PCT Int. Appl. 2001, WO 01/00879) was produced using a baculovirus overexpression system and purified by GST affinity chromatography.
  • FC 96-well plates that were prewet and filtered with 25 ⁇ L assay buffer (25 mM HEPES pH
  • LDH lactate dehydrogenase
  • the protocol for LDH assay is as follows: tumor cell lines such as HCT-116 (human colon carcinoma) were plated at a density of 3,000 cells per well in a 96-well plate. Tumor cells were allowed to adhere to plastic overnight and subsequently treated with inhibitor at varying concentrations (0.033 ⁇ M - 10 ⁇ M) for a 72 hour period at 37°C. Culture supernatant was removed and LDH activity was spectrophotometrically quantitated (formazan formation @ 490 nm) to determine cytotoxicity of compounds.
  • HCT-116 human colon carcinoma
  • tumor cells were lysed (1 % Triton X-100 in phosphate-buffered saline) and cellular LDH was spectrophotometrically quantitated (formazan formation @ 490 nm) in cellular lysates to determine percent inhibition of cellular proliferation compared to untreated control cultures, and IC 5 o determinations were made for respective compounds.
  • Compounds of examples 2, 3, 4, 5, 7, and 8 show an IC 5 o of less than 15 ⁇ M in this assay.
  • Compound of example 5 shows an IC 50 of less than 15 ⁇ M in this assay, using any of the following cell lines: MDA-MB231 (breast), ZR-75 (breast), A459 (lung), H460 (lung), DU145 (prostate).

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Abstract

L'invention concerne des composés d'oxazolyl-phényl-2,4-diamino-pyrimidine et des dérivés de ces derniers, représentés par la formule (I) ou (II), où A représente oxazolyl, lequel est éventuellement substitué par un halogène ou un alkyle en C1-C5 linéaire ou ramifié, et R1, R2, R3, R4, R5, R6, R7, R8 et R9 sont tels que définis dans le descriptif de l'invention. L'invention a également trait à des procédés de production des composés d'oxazolyl-phényl-2,4-diamino-pyrimidine. Lesdits composés sont des inhibiteurs de la kinase élevée à la phase S (SPEK), et sont utiles dans le traitement de maladies hyperprolifératives.
PCT/US2002/030633 2001-09-28 2002-09-27 Composes d'oxazolyl-phenyl-2,4-diamino-pyrimidine, et methodes de traitement de troubles hyperproliferatifs WO2003040141A1 (fr)

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KR20190092542A (ko) * 2016-12-19 2019-08-07 에피자임, 인코포레이티드 Ehmt2 저해제로서의 아민-치환된 헤테로사이클릭 화합물 및 이의 사용 방법
JP2020504715A (ja) * 2016-12-19 2020-02-13 エピザイム，インコーポレイティド Ｅｈｍｔ２阻害剤としてのアミン置換複素環化合物およびその使用方法
JP2022110080A (ja) * 2016-12-19 2022-07-28 エピザイム，インコーポレイティド Ｅｈｍｔ２阻害剤としてのアミン置換複素環化合物およびその使用方法
KR102693367B1 (ko) * 2016-12-19 2024-08-12 에피자임, 인코포레이티드 Ehmt2 저해제로서의 아민-치환된 헤테로사이클릭 화합물 및 이의 사용 방법
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JP2020537645A (ja) * 2017-10-17 2020-12-24 エピザイム，インコーポレイティド Ｅｈｍｔ２阻害剤としてのアミン置換複素環化合物及びその誘導体
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JP7425724B2 (ja) 2017-10-17 2024-01-31 エピザイム，インコーポレイティド Ｅｈｍｔ２阻害剤としてのアミン置換複素環化合物及びその誘導体

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