US20110218187A1 - Inhibitors of tyrosine kinases - Google Patents
Inhibitors of tyrosine kinases Download PDFInfo
- Publication number
- US20110218187A1 US20110218187A1 US13/106,582 US201113106582A US2011218187A1 US 20110218187 A1 US20110218187 A1 US 20110218187A1 US 201113106582 A US201113106582 A US 201113106582A US 2011218187 A1 US2011218187 A1 US 2011218187A1
- Authority
- US
- United States
- Prior art keywords
- lower alkyl
- phenyl
- amino
- mono
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 0 [1*]N([2*])C(=O)C1=CC(NC2=NC=CC(C3=CC=CN=C3)=N2)=C([4*])C=C1 Chemical compound [1*]N([2*])C(=O)C1=CC(NC2=NC=CC(C3=CC=CN=C3)=N2)=C([4*])C=C1 0.000 description 7
Classifications
-
- 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
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Definitions
- the invention relates to novel substituted pyrimidinylaminobenzamides, processes for the preparation thereof, pharmaceutical compositions containing same, the use thereof optionally in combination with one or more other pharmaceutically active compounds for the therapy of a disease which responds to an inhibition of protein kinase activity, especially a neoplastic disease, in particular leukaemia, and a method for the treatment of such a disease.
- PKs Protein kinases
- PKs are enzymes which catalyze the phosphorylation of specific serine, threonine or tyrosine residues in cellular proteins. These post-translational modifications of substrate proteins act as molecular switches regulating cell proliferation, activation and/or differentiation. Aberrant or excessive PK activity has been observed in many disease states including benign and malignant proliferative disorders. In a number of cases, it has been possible to treat diseases, such as proliferative disorders, by making use of PK inhibitors in vitro and in vivo.
- the Philadelphia Chromosome is a hallmark for chronic myelogenous leukaemia (CML) and carries a hybrid gene that contains N-terminal exons of the bcr gene and the major C-terminal part (exons 2-11) of the c-abl gene.
- the gene product is a 210 kD protein (p210 Bcr-Abl).
- the Abl-part of the Bcr-Abl protein contains the abl-tyrosine kinase which is tightly regulated in the wild type c-abl, but constitutively activated in the Bcr-Abl fusion protein. This deregulated tyrosine kinase interacts with multiple cellular signalling pathways leading to transformation and deregulated proliferation of the cells (Lugo et al., Science 247, 1079 [1990]).
- the compounds of formula I show inhibition of protein kinase activity.
- the compounds of formula I described below in more detail, especially show inhibition of one or more tyrosine kinases, such as c-Abl, Bcr-Abl, the receptor tyrosine kinases PDGF-R, Flt3, VEGF-R, EGF-R, and c-Kit, as well as combinations of two or more of these; in the case of novel pyrimidinylaminobenzamides according to the invention, the compounds are appropriate for the inhibition of these and/or other protein kinases, especially those mentioned above and/or for the inhibition of mutants of these enzymes, especially of Bcr-Abl, for example the Glu255->Valine mutant. In view of these activities, the compounds can be used for the treatment of diseases related to especially aberrant or excessive activity of such types of kinases, especially those mentioned.
- the invention relates to a compound of formula I,
- R 1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl;
- R 2 represents hydrogen, lower alkyl, optionally substituted by one or more identical or different radicals R 3 , cycloalkyl, benzcycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted;
- R 3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted;
- R 1 and R 2 together represent alkylene with four, five or six carbon atoms optionally mono- or disubstituted by lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or disubstituted amino, oxo, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with four or five carbon atoms; oxaalkylene with one oxygen and three or four carbon atoms; or azaalkylene with one nitrogen and three or four carbon atoms wherein nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl, N-mono- or N,N-disubstituted carbamoyl-lower alkyl, cycloalkyl,
- R 4 represents hydrogen, lower alkyl, or halogen
- the prefix “lower” denotes a radical having up to and including a maximum of 7, especially up to and including a maximum of 4 carbon atoms, the radicals in question being either linear or branched with single or multiple branching.
- 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 isomers or as pure isomers, preferably as enantiomer-pure diastereomers.
- the invention relates also to possible tautomers of the compounds of formula I.
- Lower alkyl is preferably alkyl with from and including 1 up to and including 7, preferably from and including 1 to and including 4, and is linear or branched; preferably, lower alkyl is butyl, such as n-butyl, sec-butyl, isobutyl, tert-butyl, propyl, such as n-propyl or isopropyl, ethyl or methyl.
- Preferably lower alkyl is methyl, propyl or tert-butyl.
- Lower acyl is preferably formyl or lower alkylcarbonyl, in particular acetyl.
- aryl group is an aromatic radical which is bound to the molecule via a bond located at an aromatic ring carbon atom of the radical.
- aryl is an aromatic radical having 6 to 14 carbon atoms, especially phenyl, naphthyl, tetrahydronaphthyl, fluorenyl or phenanthrenyl, and is unsubstituted or substituted by one or more, preferably up to three, especially one or two substituents, especially selected from amino, mono- or disubstituted amino, halogen, lower alkyl, substituted lower alkyl, lower alkenyl, lower alkynyl, phenyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterified carboxy, alkanoyl, benzoyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, amidino, guanidino, urei
- Aryl is more preferably phenyl, naphthyl or tetrahydronaphthyl, which in each case is either unsubstituted or independently substituted by one or two substituents selected from the group comprising halogen, especially fluorine, chlorine, or bromine; hydroxy; hydroxy etherified by lower alkyl, e.g. by methyl, by halogen-lower alkyl, e.g. trifluoromethyl, or by phenyl; lower alkylene dioxy bound to two adjacent C-atoms, e.g. methylenedioxy, lower alkyl, e.g. methyl or propyl; halogen-lower alkyl, e.g.
- hydroxy-lower alkyl e.g. hydroxymethyl or 2-hydroxy-2-propyl
- lower alkoxy-lower alkyl e.g. methoxymethyl or 2-methoxyethyl
- lower alkoxycarbonyl-lower alkyl e.g. methoxy-carbonylmethyl
- lower alkynyl such as 1-propynyl
- esterified carboxy especially lower alkoxycarbonyl, e.g. methoxycarbonyl, n-propoxy carbonyl or iso-propoxy carbonyl
- N-mono-substituted carbamoyl in particular carbamoyl monosubstituted by lower alkyl, e.g.
- lower alkylamino e.g. methylamino
- di-lower alkylamino e.g. dimethylamino or diethylamino
- a cycloalkyl group is preferably cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl, and may be unsubstituted or substituted by one or more, especially one or two, substitutents selected from the group defined above as substitutents for aryl, most preferably by lower alkyl, such as methyl, lower alkoxy, such as methoxy or ethoxy, or hydroxy, and further by oxo or fused to a benzo ring, such as in benzcyclopentyl or benzcyclohexyl.
- Substituted alkyl is alkyl as last defined, especially lower alkyl, preferably methyl; where one or more, especially up to three, substituents may be present, primarily from the group selected from halogen, especially fluorine, amino, N-lower alkylamino, N,N-di-lower alkylamino, N-lower alkanoylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, and phenyl-lower alkoxycarbonyl. Trifluoromethyl is especially preferred.
- Mono- or disubstituted amino is especially amino substituted by one or two radicals selected independently of one another from lower alkyl, such as methyl; hydroxy-lower alkyl, such as 2-hydroxyethyl; lower alkoxy lower alkyl, such as methoxy ethyl; phenyl-lower alkyl, such as benzyl or 2-phenylethyl; lower alkanoyl, such as acetyl; benzoyl; substituted benzoyl, wherein the phenyl radical is especially substituted by one or more, preferably one or two, substituents selected from nitro, amino, halogen, N-lower alkylamino, N,N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, and carbamoyl; and phenyl-lower alkoxycarbonyl, wherein the phenyl radical is unsubstituted or especially
- Disubstituted amino is also lower alkylene-amino, e.g. pyrrolidino, 2-oxopyrrolidino or piperidino; lower oxaalkylene-amino, e.g. morpholino, or lower azaalkylene-amino, e.g. piperazino or N-substituted piperazino, such as N-methylpiperazino or N-methoxycarbonylpiperazino.
- lower alkylene-amino e.g. pyrrolidino, 2-oxopyrrolidino or piperidino
- lower oxaalkylene-amino e.g. morpholino
- lower azaalkylene-amino e.g. piperazino or N-substituted piperazino, such as N-methylpiperazino or N-methoxycarbonylpiperazino.
- Halogen is especially fluorine, chlorine, bromine, or iodine, especially fluorine, chlorine, or bromine.
- Etherified hydroxy is especially C 8 -C 20 alkyloxy, such as n-decyloxy, lower alkoxy (preferred), such as methoxy, ethoxy, isopropyloxy, or tert-butyloxy, phenyl-lower alkoxy, such as benzyloxy, phenyloxy, halogen-lower alkoxy, such as trifluoromethoxy, 2,2,2-trifluoroethoxy or 1,1,2,2-tetrafluoroethoxy, or lower alkoxy which is substituted by mono- or bicyclic hetero-aryl comprising one or two nitrogen atoms, preferably lower alkoxy which is substituted by imidazolyl, such as 1H-imidazol-1-yl, pyrrolyl, benzimidazolyl, such as 1-benzimidazolyl, pyridyl, especially 2-, 3- or 4-pyridyl, pyrimidinyl, especially 2-pyrimidinyl,
- Esterified hydroxy is especially lower alkanoyloxy, benzoyloxy, lower alkoxycarbonyloxy, such as tert-butoxycarbonyloxy, or phenyl-lower alkoxycarbonyloxy, such as benzyloxycarbonyloxy.
- Esterified carboxy is especially lower alkoxycarbonyl, such as tert-butoxycarbonyl, iso-propoxycarbonyl, methoxycarbonyl or ethoxycarbonyl, phenyl-lower alkoxycarbonyl, or phenyloxycarbonyl.
- Alkanoyl is primarily alkylcarbonyl, especially lower alkanoyl, e.g. acetyl.
- N-Mono- or N,N-disubstituted carbamoyl is especially substituted by one or two substituents independently selected from lower alkyl, phenyl-lower alkyl and hydroxy-lower alkyl, or lower alkylene, oxa-lower alkylene or aza-lower alkylene optionally substituted at the terminal nitrogen atom.
- a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted, refers to a heterocyclic moiety that is unsaturated in the ring binding the heteroaryl radical to the rest of the molecule in formula I and is preferably a ring, where in the binding ring, but optionally also in any annealed ring, at least one carbon atom is replaced by a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; where the binding ring preferably has 5 to 12, more preferably 5 or 6 ring atoms; and which may be unsubstituted or substituted by one or more, especially one or two, substitutents selected from the group defined above as substitutents for aryl, most preferably by lower alkyl, such as methyl, lower alkoxy, such as methoxy or ethoxy, or hydroxy.
- the mono- or bicyclic heteroaryl group is selected from 2H-pyrrolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, indazolyl, purinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, quinolinyl, pteridinyl, indolizinyl, 3H-indolyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, furazanyl, benzo[d]pyrazolyl, thienyl and furanyl.
- the mono- or bicyclic heteroaryl group is selected from the group consisting of pyrrolyl, imidazolyl, such as 1H-imidazol-1-yl, benzimidazolyl, such as 1-benzimidazolyl, indazolyl, especially 5-indazolyl, pyridyl, especially 2-, 3- or 4-pyridyl, pyrimidinyl, especially 2-pyrimidinyl, pyrazinyl, isoquinolinyl, especially 3-isoquinolinyl, quinolinyl, especially 4- or 8-quinolinyl, indolyl, especially 3-indolyl, thiazolyl, benzo[d]pyrazolyl, thienyl, and furanyl.
- imidazolyl such as 1H-imidazol-1-yl
- benzimidazolyl such as 1-benzimidazolyl
- indazolyl especially 5-indazolyl
- pyridyl
- the pyridyl radical is substituted by hydroxy in ortho position to the nitrogen atom and hence exists at least partially in the form of the corresponding tautomer which is pyridin-(1H)-2-one.
- the pyrimidinyl radical is substituted by hydroxy both in position 2 and 4 and hence exists in several tautomeric forms, e.g. as pyrimidine-(1H, 3H)2,4-dione.
- Heterocyclyl is especially a five, six or seven-membered heterocyclic system with one or two heteroatoms selected from the group comprising nitrogen, oxygen, and sulfur, which may be unsaturated or wholly or partly saturated, and is unsubstituted or substituted especially by lower alkyl, such as methyl, phenyl-lower alkyl, such as benzyl, oxo, or heteroaryl, such as 2-piperazinyl; heterocyclyl is especially 2- or 3-pyrrolidinyl, 2-oxo-5-pyrrolidinyl, piperidinyl, N-benzyl-4-piperidinyl, N-lower alkyl-4-piperidinyl, N-lower alkyl-piperazinyl, morpholinyl, e.g. 2- or 3-morpholinyl, 2-oxo-1H-azepin-3-yl, 2-tetrahydrofuranyl, or 2-methyl-1,3-dioxolan-2-yl
- Salts are especially the pharmaceutically acceptable salts of compounds of formula I.
- Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of formula I with a basic nitrogen atom, especially the pharmaceutically acceptable salts.
- Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
- Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-dis
- salts may also be formed with bases, e.g. metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or tri(2-hydroxyethyl)amine, or heterocyclic bases, for example N-ethyl-piperidine or N,N′-dimethylpiperazine.
- bases e.g. metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or tri(2-hydroxyethyl)amine, or heterocyclic bases, for example N-ethyl-piperidine or N,N′-dimethylpiperazine.
- a compound of formula I may also form internal salts.
- salts for isolation or purification purposes it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates.
- pharmaceutically acceptable salts or free compounds are employed (where applicable in the form of pharmaceutical preparations), and these are therefore preferred.
- any reference to the free compounds hereinbefore and hereinafter is to be understood as referring also to the corresponding salts, as appropriate and expedient.
- Test for activity against c-Abl protein tyrosine kinase The test is conducted as a filter binding assay as follows: The His-tagged kinase domain of c-Abl is cloned and expressed in the baculovirus/Sf9 system as described by Bhat et al., J Biol Chem. 272, 16170-5 (1997). A protein of 37 kD (c-Abl kinase) is purified by a two-step procedure over a Cobalt metal chelate column followed by an anion exchange column with a yield of 1-2 mg/L of Sf9 cells.
- the purity of the c-Abl kinase is >90% as judged by SDS-PAGE after Coomassie blue staining.
- the assay contains: c-Abl kinase (50 ng), 20 mM Tris.HCl, pH 7.5, 10 mM MgCl 2 , 10 ⁇ M Na 3 VO 4 , 1 mM DTT and 0.06 ⁇ Ci/assay [ ⁇ 33 P]-ATP (5 ⁇ M ATP) using 30 ⁇ g/mL poly-Ala,Glu,Lys,Tyr-6:2:5:1 (Poly-AEKY, Sigma P1152) in the presence of 1% DMSO, total volume of 30 ⁇ L.
- Reactions are terminated by adding 10 ⁇ L of 250 mM EDTA, and 30 ⁇ L of the reaction mixture is transferred onto Immobilon-PVDF membrane (Millipore, Bedford, Mass., USA) previously soaked for 5 min with methanol, rinsed with water, then soaked for 5 min with 0.5% H 3 PO 4 and mounted on vacuum manifold with disconnected vacuum source. After spotting all samples, vacuum is connected and each well rinsed with 200 ⁇ L 0.5% H 3 PO 4 . Membranes are removed and washed on a shaker with 0.5% H 3 PO 4 (4 times) and once with ethanol. Membranes are counted after drying at ambient temperature, mounting in Packard TopCount 96-well frame, and addition of 10 ⁇ L/well of MicroscintTM (Packard).
- the murine myeloid progenitor cell line 32Dcl3 transfected with the p210 Bcr-Abl expression vector pGDp210Bcr/Abl (32D-bcr/abl) was obtained from J. Griffin (Dana Faber Cancer Institute, Boston, Mass., USA).
- the cells express the fusion Bcr-Abl protein with a constitutively active abi kinase and proliferate growth factor independent.
- the cells are expanded in RPMI 1640 (AMIMED), 10% fetal calf serum, 2 mM glutamine (Gibco) (“complete medium”), and a working stock is prepared by freezing aliquots of 2 ⁇ 10 6 cells per vial in freezing medium (95% FCS, 5% DMSO (SIGMA)). After thawing, the cells are used during maximally 10-12 passages for the experiments.
- the compound is incubated together with the cells for 90 min at 37° C., 5% CO 2 , followed by centrifugation of the tissue culture plates at 1300 rpm (Beckmann GPR centrifuge) and removal of the supernatants by careful aspiration taking care not to remove any of the pelleted cells.
- the cell pellets are lysed by addition of 150 ⁇ L lysis buffer (50 mM Tris/HCl, pH 7.4, 150 mM sodium chloride, 5 mM EDTA, 1 mM EGTA, 1% NP-40, 2 mM sodium ortho-vanadate, 1 mM PMSF, 50 ⁇ g/mL aprotinin and 80 ⁇ g/mL leupeptin) and either used immediately for the ELISA or stored frozen in the plates at ⁇ 20° C. until usage.
- Black ELISA plates (Packard HTRF-96 black plates) are precoated over night at 4° C.
- the difference between the ELISA-readout (CPS) obtained for with the lysates of the untreated 32D-Bcr/Abl cells and the readout for the assay-background (all components, but without cell lysate) is calculated and taken as 100% reflecting the constitutively phosphorylated Bcr-Abl protein present in these cells.
- the activity of the compound on the Bcr-Abl kinase activity is expressed as percent reduction of the Bcr-Abl phosphorylation.
- the values for the IC 50 and IC 90 are determined from the dose response curves by graphical extrapolation.
- Test for activity against VEGF-receptor tyrosine kinase The test is conducted using Flt-1 VEGF-receptor tyrosine kinase. The detailed procedure is as follows: 30 ⁇ L kinase solution (10 ng of the kinase domain of Flt-1, Shibuya et al., Oncogene 5, 519-24 [1990]) in 20 mM Tris.HCl pH 7.5, 3 mM manganese dichloride (MnCl 2 ), 3 mM magnesium chloride (MgCl 2 ), 10 ⁇ M sodium vanadate, 0.25 mg/mL polyethylenglycol (PEG) 20000, 1 mM dithiothreitol and 3 ⁇ g/ ⁇ L poly(Glu,Tyr) 4:1 (Sigma, Buchs, Switzerland), 8 ⁇ M [ 33 P]-ATP (0.2 ⁇ Ci), 1% DMSO, and 0 to 100 ⁇ M of the compound to be tested
- the reaction is then terminated by the addition of 10 ⁇ L 0.25 M ethylenediaminetetraacetate (EDTA) pH 7.
- EDTA ethylenediaminetetraacetate
- LAB SYSTEMS LAB SYSTEMS, USA
- IC 50 -values are determined by linear regression analysis of the percentages for the inhibition of each compound in at least four concentrations (as a rule 0.01, 0.1, 1.0 and 10 ⁇ mol).
- the IC 50 -values that can be found with compounds of formula I are in the range of 1 to 10′000 nM, preferably in the range of 1 to 100 nM.
- transfected CHO cells which permanently express human VEGF receptor (KDR)
- KDR human VEGF receptor
- FCS fetal calf serum
- the compounds to be tested are then diluted in culture medium (without FCS, with 0.1% bovine serum albumin) and added to the cells. (Controls comprise medium without test compounds). After two hours of incubation at 37° C., recombinant VEGF is added; the final VEGF concentration is 20 ng/mL).
- the cells are washed twice with ice-cold PBS (phosphate-buffered saline) and immediately lysed in 100 ⁇ L lysis buffer per well.
- the lysates are then centrifuged to remove the cell nuclei, and the protein concentrations of the supernatants are determined using a commercial protein assay (BIORAD).
- BIORAD commercial protein assay
- a sandwich ELISA is carried out to measure the KDR-receptor phosphorylation: a monoclonal antibody to KDR (for example Mab 1495.12.14) is immobilized on black ELISA plates (OptiPlateTM HTRF-96 from Packard). The plates are then washed and the remaining free protein-binding sites are saturated with 1% BSA in PBS. The cell lysates (20 ⁇ g protein per well) are then incubated in these plates overnight at 4° C. together with an anti-phosphotyrosine antibody coupled with alkaline phosphatase (PY20:AP from Transduction Laboratories).
- PY20 alkaline phosphatase
- the plates are washed again and the binding of the antiphosphotyrosine antibody to the captured phosphorylated receptor is then demonstrated using a luminescent AP substrate (CDP-Star, ready to use, with Emerald II; TROPIX).
- the luminescence is measured in a Packard Top Count Microplate Scintillation Counter (Top Count).
- Top Count Packard Top Count Microplate Scintillation Counter
- the activity of the tested substances is calculated as % inhibition of VEGF-induced KDR-receptor phosphorylation, wherein the concentration of substance that induces half the maximum inhibition is defined as the ED50 (effective dose for 50% inhibition).
- Compounds of formula I here preferably show ED50 values in the range of 0.25 nM to 1000 nM, preferably 0.25 to 250 nM.
- a compound of formula I or a N-oxide thereof inhibits to varying degrees also other tyrosine kinases involved in signal transduction which are mediated by trophic factors, for example Bcr-Abl and Abl kinase, Arg, kinases from the Src family, especially c-Src kinase, Lck, and Fyn; also kinases of the EGF family, for example, c-erbB2 kinase (HER-2), c-erbB3 kinase, c-erbB4 kinase; insulin-like growth factor receptor kinase (IGF-1 kinase), especially members of the PDGF-receptor tyrosine kinase family, such as PDGF-receptor kinase, CSF-1-receptor kinase, Kit-receptor kinase and VEGF-receptor kinase; and also serine/
- HER-2 c-erbB2 tyrosine kinase
- a compound of formula I according to the invention shows therapeutic efficacy especially against disorders dependent on protein kinase, especially proliferative diseases.
- the compounds of the formula I primarily inhibit the growth of blood vessels and are thus, for example, effective against a number of diseases associated with deregulated angiogenesis, especially diseases caused by ocular neovascularisation, especially retinopathies, such as diabetic retinopathy or age-related macula degeneration, psoriasis, haemangioblastoma, such as haemangioma, mesangial cell proliferative disorders, such as chronic or acute renal diseases, e.g.
- diabetic nephropathy malignant nephrosclerosis, thrombotic microangiopathy syndromes or transplant rejection, or especially inflammatory renal disease, such as glomerulonephritis, especially mesangioproliferative glomerulonephritis, haemolytic-uraemic syndrome, diabetic nephropathy, hypertensive nephrosclerosis, atheroma, arterial restenosis, autoimmune diseases, diabetes, endometriosis, chronic asthma, and especially neoplastic diseases (solid tumors, but also leukemias and other “liquid tumors”, especially those expressing c-kit, KDR, Flt-1 or Flt-3), such as especially breast cancer, cancer of the colon, lung cancer (especially small-cell lung cancer), cancer of the prostate or Kaposi's sarcoma.
- a compound of formula I (or an N-oxide thereof) inhibits the growth of tumours and is especially suited to preventing the metastatic spread of tumors and the growth of micrometastases.
- a compound of formula I can be administered alone or in combination with one or more other therapeutic agents, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic agents being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic agents.
- a compound of formula I can besides or in addition be administered especially for tumor therapy, such as leukaemia therapy, in combination with chemotherapy, radiotherapy, immunotherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.
- Therapeutic agents for possible combination are especially one or more cytostatic or cytotoxic compounds, for example a chemotherapeutic agent or several selected from the group comprising indarubicin, cytarabine, interferon, hydroxyurea, bisulfan, or an inhibitor of polyamine biosynthesis, an inhibitor of protein kinase, especially of serine/threonine protein kinase, such as protein kinase C, or of tyrosine protein kinase, such as epidermal growth factor receptor tyrosine kinase, a cytokine, a negative growth regulator, such as TGF- ⁇ or IFN- ⁇ , an aromatase inhibitor, a classical cytostatic, and an inhibitor of the interaction of an SH2 domain with a phosphorylated protein.
- cytostatic or cytotoxic compounds for example a chemotherapeutic agent or several selected from the group comprising indarubicin, cytarabine, interferon, hydroxyurea, bisulfan
- a compound according to the invention is not only for the (prophylactic and preferably therapeutic) management of humans, but also for the treatment of other warm-blooded animals, for example of commercially useful animals, for example rodents, such as mice, rabbits or rats, or guinea-pigs. Such a compound may also be used as a reference standard in the test systems described above to permit a comparison with other compounds.
- the invention relates also to the use of a compound of formula I or a N-oxide thereof for the inhibition of tyrosine kinase activity, either in vitro or in vivo.
- R 1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl;
- R 2 represents hydrogen, lower alkyl, optionally substituted by one or two identical or different radicals R 3 , cycloalkyl, benzcycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising one, two or three nitrogen atoms or one sulfur atom, which aryl and heteroaryl groups in each case are unsubstituted or mono- or polysubstituted;
- R 3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, an aryl group, furanoyl, thienoyl, or a mono- or bicyclic heteroaryl group comprising one, two or three ring nitrogen atoms, zero or one ring oxygen atom and zero or one ring sulphur atom, which aryl and heteroaryl groups in each case are unsubstituted or mono- or polysubstituted;
- R 1 and R 2 together represent alkylene with four or five carbon atoms, optionally mono- or disubstituted by lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or disubstituted amino, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with four or five carbon atoms in the alkylene group; oxaalkylene with one oxygen and three or four carbon atoms, or azaalkylene with one nitrogen and three or four carbon atoms wherein nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl, N-mono- or N,N-disubstituted carbamoyl-lower alkyl, cycloalkyl,
- R 4 represents hydrogen, lower alkyl, or halogen
- R 1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl;
- R 2 represents hydrogen, lower alkyl, optionally substituted by one or two identical or different radicals R 3 , cyclopentyl, benzcyclopentyl, cylcohexyl, pyrrolidinyl, oxazolinyl, piperidinyl, N-substituted piperidinyl, morpholinyl, azepinyl, oxo-azepinyl, oxazepinyl, phenyl, naphthalinyl, tetrahydronaphthalinyl or a mono- or bicyclic heteroaryl group comprising one or two nitrogen atoms, which phenyl, naphthalinyl and heteroaryl groups in each case are unsubstituted or mono- or polysubstituted, thienyl, or lower alkoxycarbonyl-lower alkylthienyl;
- R 3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, amino, lower alkylamino, di-lower alkylamino, phenylamino, N-lower alkyl-N-phenylamino, pyrrolidino, oxopyrrolidino, piperidino, morpholino, imidazolino, oxoimidazolino, cycloalkyl, heterocyclyl, furyl, phenyl, naphthalinyl, tetrahydronaphthalinyl, or a mono- or bicyclic heteroaryl group comprising one or two nitrogen atoms, which phenyl, naphthalinyl and heteroaryl group are unsubstituted or mono- or polysubstituted;
- R 1 and R 2 together represent alkylene with four or five carbon atoms, optionally mono- or disubstituted by lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or disubstituted amino, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with four or five carbon atoms in the alkylene group; oxaalkylene with one oxygen and four carbon atoms; or azaalkylene with one nitrogen and four carbon atoms wherein nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl, N-mono- or N,N-disubstituted carbamoyl-lower alkyl, cycloalkyl, lower alkoxy
- R 4 represents hydrogen, lower alkyl, or halogen
- R 1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl;
- R 2 represents hydrogen; lower alkyl, optionally substituted by one radical R 3 , by two phenyl groups, by two lower alkoxycarbonyl groups, by phenyl and lower alkoxycarbonyl, or by hydroxyphenyl and lower alkoxycarbonyl; cyclopentyl; benzcyclopentyl; cylcohexyl; pyrrolidinyl; oxazolinyl; piperidinyl; N-lower alkylpiperidinyl; N-benzylpiperidinyl; N-pyrimidinylpiperidinyl; morpholinyl; azepinyl; oxo-azepinyl; oxazepinyl; phenyl, naphthalinyl, tetrahydronaphthalinyl or a mono- or bicyclic heteroaryl group comprising one or two nitrogen atoms, which phenyl, naphthalinyl and heteroaryl groups in
- R 3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, carbamoyl mono-or disubstituted by lower alkyl, phenyl or lower alkylene, amino, lower alkylamino, di-lower alkylamino, phenylamino, N-lower alkyl-N-phenylamino, pyrrolidino, oxopyrrolidino, piperidino, morpholino, imidazolino, oxoimidazolino, cycloalkyl, heterocyclyl, furyl; phenyl, naphthalinyl, tetrahydronaphthalinyl, or a mono- or bicyclic heteroaryl group comprising one or two nitrogen atoms, which phenyl, naphthalinyl and heteroaryl group is unsubstituted or substituted by one or two substituents selected from the group consisting
- R 1 and R 2 together represent alkylene with four or five carbon atoms, optionally mono- or disubstituted by lower alkyl, cycloalkyl, phenyl, hydroxy, lower alkoxy, amino, benzoylamino, piperidino, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with four or five carbon atoms in the alkylene group; oxaalkylene with one oxygen and four carbon atoms; or azaalkylene with one nitrogen and four carbon atoms wherein nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl, carbamoyl-lower alkyl N-mono- or N,N-disubstituted by lower alkyl, phenyl, lower alkylene or
- R 4 represents hydrogen or lower alkyl
- R 1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, or benzyl
- R 2 represents lower alkyl, optionally substituted by one radical R 3 , by two phenyl groups, by two lower alkoycarbonyl groups, by phenyl and lower alkoxycarbonyl, or by hydroxyphenyl and lower alkoxycarbonyl; cyclopentyl; benzcyclopentyl; cylcohexyl; pyrrolidinyl; piperidinyl; N-lower alkylpiperidinyl; N-benzylpiperidinyl; N-pyrimidinylpiperidinyl; morpholinyl; azepinyl; oxoazepinyl; phenyl; naphthalinyl; tetrahydronaphthalinyl; pyridyl; lower alkyl-pyridyl; quinolinyl; thienyl; lower alkoxycarbonylmethylthienyl; or phenyl substituted by one or two substituents selected from the group
- R 3 represents hydroxy, lower alkoxy, lower alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, amino, lower alkylamino, di-lower alkylamino, phenylamino, N-lower alkyl-N-phenylamino, pyrrolidino, oxopyrrolidino, piperidino, morpholino, imidazolino, oxoimidazolino, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, phenyl, naphthalinyl, tetrahydronaphthalinyl, furyl, a mono- or bicyclic heteroaryl group comprising one or two nitrogen atoms, which heteroaryl group is unsubstituted or mono- or disubstituted by lower alkyl, hydroxy and lower alkoxy, or phenyl substituted
- R 1 and R 2 together represent alkylene with four or five carbon atoms, optionally mono- or disubstituted by phenyl, hydroxy, amino, benzoylamino, or piperidino; benzalkylene with four or five carbon atoms in the alkylene group; oxaalkylene with one oxygen and four carbon atoms; or azaalkylene with one nitrogen and four carbon atoms wherein nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, pyrrolidinocarbonyl-lower alkyl, morpholinocarbonyl-lower alkyl, cyclopentyl, lower alkoxycarbonyl, phenyl, methoxyphenyl, trifluoromethylphenyl, pyridinyl; pyrimidinyl, or pyrazinyl;
- R 4 represents hydrogen or methyl
- a specially preferred group of compounds comprises compounds of formula I wherein
- R 1 represents hydrogen
- R 2 represents phenyl substituted by trifluoromethyl, especially 3-trifluoromethylphenyl, and optionally a further substituent selected from the group consisting of hydroxy-lower alkyl, e.g. 1-hydroxy-1-methylethyl, lower alkylamino, e.g. methyl- or ethylamino, hydroxy-lower alkylamino, e.g. 2-hydroxy-1-propylamino or 2-hydroxy-2-propylamino, di-lower alkylamino, e.g. diethylamino, 1H-imidazolyl, lower alkyl-1H-imidazolyl, e.g.
- 2- or 4-methyl-1H-imidazolyl carbamoyl, lower alkylcarbamoyl, e.g. methylcarbamoyl, pyrrolidino, piperidino, piperazino, lower alkylpiperazino, e.g. 4-methylpiperazino, morpholino, lower alkoxy, e.g. methoxy, fluoro-lower alkoxy, e.g. trifluoromethoxy or 2,2,2-trifluoroethoxy, phenyl, pyridyl, e.g. 2-, 3- or 4-pyridyl, and halogenyl, e.g. chloro or fluoro;
- R 4 represents methyl
- R 1 is hydrogen
- R 2 represents phenyl which is mono- or disubstituted by imidazol-lower alkoxy, lower alkyl amino, trifluoromethyl, hydroxy lower alkyl amino, bis-(lower alkoxy lower alkyl)amino, lower alkyl piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, phenyl, pyridyl, imidazolyl which is unsubstituted or mono- or disubstituted by lower alkyl or N-lower alkyl carbamoyl;
- R 4 is lower alkyl
- the invention relates also to 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid and to 3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid; intermediates for the formation of the preferred amides of the invention.
- the invention relates to the use of a compound of formula I or of a N-oxide or a possible tautomer thereof or of a pharmaceutically acceptable salt of such a compound for the preparation of a pharmaceutical composition for the treatment of a disease which responds to an inhibition of protein kinase activity, wherein the disease is a neoplastic disease.
- the invention relates to the use of a compound of the formula I or of a N-oxide or a possible tautomer thereof; or of a pharmaceutically acceptable salt of such a compound for the preparation of a pharmaceutical composition for the treatment of leukaemia which responds to an inhibition of the Abl tyrosine kinase activity.
- the invention provides a method for the treatment of a disease which responds to an inhibition of protein kinase activity, which comprises administering a compound of formula I or a N-oxide or a pharmaceutically acceptable salt thereof, wherein the radicals and symbols have the meanings as defined above, in a quantity effective against said disease, to a warm-blooded animal requiring such treatment.
- a compound of the invention may be prepared by processes that, though not applied hitherto for the new compounds of the present invention, are known per se, especially a process characterized in that for the synthesis of a compound of the formula I wherein the symbols R 1 , R 2 and R 4 are as defined for a compound of the formula I, a 4-R 4 -3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid of formula II
- R 4 is as defined for a compound of formula I, or a derivative thereof wherein the carboxy group —COOH is in activated form, is reacted with an amine of the formula III
- R 1 and R 2 are as defined for a compound of the formula I, optionally in the presence of a dehydrating agent and an inert base and/or a suitable catalyst, and optionally in the presence of an inert solvent;
- an obtainable compound of formula I is converted into another compound of formula I or a N-oxide thereof, a free compound of formula I is converted into a salt, an obtainable salt of a compound of formula I is converted into the free compound or another salt, and/or a mixture of isomeric compounds of formula I is separated into the individual isomers.
- a derivative of the compound of formula II wherein the carboxy group is in activated form is especially a reactive ester, a reactive anhydride or a reactive cyclic amide.
- Reactive esters of the acid of formula II are especially esters unsaturated at the linking carbon atom of the esterifying radical, for example esters of the vinyl ester type, such as actual vinyl esters (obtainable, for example, by transesterification of a corresponding ester with vinyl acetate; activated vinyl ester method), carbamoylvinyl esters (obtainable, for example, by treatment of the corresponding acid with an isoxazolium reagent; 1,2-oxazolium or Woodward method), or 1-lower alkoxyvinyl esters (obtainable, for example, by treatment of the corresponding acid with a lower alkoxyacetylene; ethoxyacetylene method), or esters of the amidino type, such as N,N′-disubstituted amidino esters (obtainable, for example, by treatment of the corresponding acid with a suitable N,N′-disubstituted carbodiimide, for example N,N′-dicyclohexylcarbodiimi
- Anhydrides of the acid of formula II may be symmetric or preferably mixed anhydrides of that acid, for example anhydrides with inorganic acids, such as acid halides, especially acid chlorides (obtainable, for example, by treatment of the corresponding acid with thionyl chloride, phosphorus pentachloride or oxalyl chloride; acid chloride method), azides (obtainable, for example, from a corresponding acid ester via the corresponding hydrazide and treatment thereof with nitrous acid; azide method), anhydrides with carbonic acid semiderivatives, such as corresponding esters, for example carbonic acid lower alkyl semiesters (obtainable, for example, by treatment of the corresponding acid with haloformic, such as chloroformic, acid lower alkyl esters or with a 1-lower alkoxycarbonyl-2-lower alkoxy-1,2-dihydroquinoline, for example 1-lower alkoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; mixed O-
- Suitable cyclic amides are especially amides with five-membered diazacycles of aromatic character, such as amides with imidazoles, for example imidazole (obtainable, for example, by treatment of the corresponding acid with N,N′-carbonyldiimidazole; imidazolide method), or pyrazoles, for example 3,5-dimethyl-pyrazole (obtainable, for example, by way of the acid hydrazide by treatment with acetylacetone; pyrazolide method).
- imidazoles for example imidazole (obtainable, for example, by treatment of the corresponding acid with N,N′-carbonyldiimidazole; imidazolide method)
- pyrazoles for example 3,5-dimethyl-pyrazole (obtainable, for example, by way of the acid hydrazide by treatment with acetylacetone; pyrazolide method).
- Derivatives of the acid of formula II wherein the carboxy group is in activated form are preferably formed in situ.
- N,N′-disubstituted amidino esters can be formed in situ by reacting a mixture of the acid of formula II and the amine of formula III in the presence of a suitable N,N-disubstituted carbodiimide, for example N,N′-dicyclohexylcarbodiimide.
- Reactive mixed anhydrides of the acid of formula II with an organic phosphonic acid may be formed in situ by reaction with e.g. propylphosphonic anhydride or diethylcyanophosphonate in the presence of suitable base, preferably a tertiary amine, e.g. triethylamine or dimethylaminopyridine.
- the reaction can be carried out in a manner known per se, the reaction conditions being dependent especially on whether, and if so how, the carboxy group of the carboxylic acid of formula II has been activated, usually in the presence of a suitable solvent or diluent or of a mixture thereof and, if necessary, in the presence of a condensation agent, which, for example when the carboxy group participating in the reaction is in the form of an anhydride, may also be an acid-binding agent, with cooling or heating, for example in a temperature range from approximately ⁇ 30° C. to approximately +150° C., especially approximately from 0° C. to +100° C., preferably from room temperature (approx.
- Customary condensation agents are, for example, carbodiimides, for example N,N′-diethyl-, N,N′-dipropyl-, N,N′-dicyclohexyl- or N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole, or 1,2-oxazolium compounds, for example 2-ethyl-5-phenyl-1,2-oxazolium 3′-sulfonate and 2-tert-butyl-5-methyl-isoxazolium perchlorate, or a suitable acylamino compound, for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline.
- carbodiimides for example N,N′-diethyl-, N,N′-dipropyl-, N,N′-dicyclohexyl- or N-ethyl-N′-
- Customary acid-binding condensation agents are, for example, alkali metal carbonates or hydrogen carbonates, for example sodium or potassium carbonate or hydrogen carbonate (customarily together with a sulfate), or organic bases, such as, customarily, pyridine or triethylamine, or sterically hindered tri-lower alkylamines, for example N,N-diisopropyl-N-ethyl-amine.
- the carboxylic acid of formula II is reacted with an amine of formula III in a suitable solvent, such as e.g. N,N-dimethylformamide, in the presence of propyl-phosphonic anhydride or diethylcyanophosphanate and triethylamine, between 1 and 48 hours at between 0° C. and around 50° C., preferably at room temperature.
- a suitable solvent such as e.g. N,N-dimethylformamide
- one or more other functional groups for example carboxy, hydroxy, amino, or mercapto, are or need to be protected in a compound of formula III, because they should not take part in the reaction, these are such groups as are usually used in the synthesis of amides, in particular peptide compounds, and also of cephalosporins and penicillins, as well as nucleic acid derivatives and sugars.
- the protecting groups may already be present in precursors and should protect the functional groups concerned against unwanted secondary reactions, such as acylations, etherifications, esterifications, oxidations, solvolysis, and similar reactions. It is a characteristic of protecting groups that they lend themselves readily, i.e. without undesired secondary reactions, to removal, typically by solvolysis, reduction, photolysis or also by enzyme activity, for example under conditions analogous to physiological conditions, and that they are not present in the end-products.
- the specialist knows, or can easily establish, which protecting groups are suitable with the reactions mentioned hereinabove and hereinafter.
- functional groups of the starting compounds which should not take part in the reaction may be present in unprotected form or may be protected for example by one or more of the protecting groups mentioned hereinabove under “protecting groups”.
- the protecting groups are then wholly or partly removed according to one of the methods described there.
- Salts of a compound of formula I with a salt-forming group may be prepared in a manner known per se. Acid addition salts of compounds of formula I may thus be obtained by treatment with an acid or with a suitable anion exchange reagent.
- Salts can usually be converted to free compounds, e.g. by treating with suitable basic agents, for example with alkali metal carbonates, alkali metal hydrogencarbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.
- suitable basic agents for example with alkali metal carbonates, alkali metal hydrogencarbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.
- Stereoisomeric mixtures e.g. mixtures of diastereomers
- Diastereomeric mixtures for example may be separated into their individual diastereomers by means of fractionated crystallization, chromatography, solvent distribution, and similar procedures. This separation may take place either at the level of a starting compound or in a compound of formula I itself.
- Enantiomers may be separated through the formation of diastereomeric salts, for example by salt formation with an enantiomer-pure chiral acid, or by means of chromatography, for example by HPLC, using chromatographic substrates with chiral ligands.
- a compound of the formula I wherein R 1 is hydrogen can be converted to the respective compound wherein R 1 is lower alkyl by reaction e.g. with a diazo lower alkyl compound, especially diazomethane, in an inert solvent, preferably in the presence of a noble metal catalyst, especially in dispersed form, e.g. copper, or a noble metal salt, e.g. copper(I)-chloride or copper(II)-sulfate. Also reaction with lower alkylhalogenides is possible, or with other leaving group carrying lower alkanes, e.g.
- lower alkyl alcohols esterified by a strong organic sulfonic acid such as a lower alkanesulfonic acid (optionally substituted by halogen, such as fluoro), an aromatic sulfonic acid, for example unsubstituted or substituted benzenesulfonic acid, the substituents preferably being selected from lower alkyl, such as methyl, halogen, such as bromo, and/or nitro, e.g. esterified by methanesulfonic acid, or p-toluene sulfonic acid.
- a strong organic sulfonic acid such as a lower alkanesulfonic acid (optionally substituted by halogen, such as fluoro)
- an aromatic sulfonic acid for example unsubstituted or substituted benzenesulfonic acid, the substituents preferably being selected from lower alkyl, such as methyl, halogen, such as bromo, and/or nitro
- the alkylation takes place under usual conditions for alkylation of amides, especially in aqueous solution and/or in the presence of polar solvents, typically alcohols, for example methanol, ethanol, isopropanol, or ethylene glycol, or dipolar aprotic solvents, e.g. tetrahydrofuran, dioxane, or dimethylformamide, where applicable in the presence of acidic or basic catalysts, generally at temperatures from about 0° C. to the boiling temperature of the corresponding reaction mixture, preferably between 20° C. and reflux temperature, if necessary under increased pressure, e.g. in a sealed tube, and/or under inert gas, typically nitrogen or argon.
- polar solvents typically alcohols, for example methanol, ethanol, isopropanol, or ethylene glycol
- dipolar aprotic solvents e.g. tetrahydrofuran, dioxane, or dimethylformamide
- acidic or basic catalysts generally at
- All process steps described here can be carried out under known reaction conditions, preferably under those specifically mentioned, in the absence of or usually in the presence of solvents or diluents, preferably such as are inert to the reagents used and able to dissolve these, in the absence or presence of catalysts, condensing agents or neutralizing agents, for example ion exchangers, typically cation exchangers, for example in the H + form, depending on the type of reaction and/or reactants at reduced, normal, or elevated temperature, for example in the range from ⁇ 100° C. to about 190° C., preferably from about ⁇ 80° C. to about 150° C., for example at ⁇ 80 to ⁇ 60° C., at room temperature, at ⁇ 20 to 40° C. or at the boiling point of the solvent used, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under argon or nitrogen.
- solvents or diluents preferably such as are inert
- Salts may be present in all starting compounds and transients, if these contain salt-forming groups. Salts may also be present during the reaction of such compounds, provided the reaction is not thereby disturbed.
- isomeric mixtures that occur can be separated into their individual isomers, e.g. diastereomers or enantiomers, or into any mixtures of isomers, e.g. racemates or diastereomeric mixtures.
- the invention relates also to those forms of the process in which one starts from a compound obtainable at any stage as a transient and carries out the missing steps, or breaks off the process at any stage, or forms a starting material under the reaction conditions, or uses said starting material in the form of a reactive derivative or salt, or produces a compound obtainable by means of the process according to the invention and processes the said compound in situ.
- a compound of formula I is prepared according to or in analogy to the processes and process steps defined in the Examples.
- the compounds of formula I are also obtainable in the form of hydrates, or their crystals can include for example the solvent used for crystallization (present as solvates).
- the present invention relates furthermore to a method for the treatment of a neoplastic disease which responds to an inhibition of a protein kinase activity, which comprises administering a compound of formula I or a N-oxide or a pharmaceutically acceptable salt thereof, wherein the radicals and symbols have the meanings as defined above for formula I, in a quantity effective against said disease, to a warm-blooded animal requiring such treatment.
- the invention relates to a method for the treatment of leukaemia which responds to an inhibition of the Abl tyrosine kinase activity, which comprises administering a compound of formula I or a N-oxide or a pharmaceutically acceptable salt thereof, wherein the radicals and symbols have the meanings as defined above for formula I, in a quantity effective against said leukaemia, to a warm-blooded animal requiring such treatment.
- compositions that comprise a compound of formula I or a N-oxide thereof as active ingredient and that can be used especially in the treatment of the diseases mentioned at the beginning.
- Compositions for enteral administration such as nasal, buccal, rectal or, especially, oral administration, and for parenteral administration, such as intravenous, intramuscular or subcutaneous administration, to warm-blooded animals, especially humans, are especially preferred.
- the compositions comprise the active ingredient alone or, preferably, together with a pharmaceutically acceptable carrier.
- the dosage of the active ingredient depends upon the disease to be treated and upon the species, its age, weight, and individual condition, the individual pharmacokinetic data, and the mode of administration.
- the present invention relates especially to pharmaceutical compositions that comprise a compound of formula I, a tautomer, a N-oxide or a pharmaceutically acceptable salt, or a hydrate or solvate thereof, and at least one pharmaceutically acceptable carrier.
- the invention relates also to pharmaceutical compositions for use in a method for the prophylactic or especially therapeutic management of the human or animal body, to a process for the preparation thereof (especially in the form of compositions for the treatment of tumors) and to a method of treating tumor diseases, especially those mentioned hereinabove.
- the invention relates also to processes and to the use of compounds of formula I or N-oxides thereof for the preparation of pharmaceutical preparations which comprise compounds of formula I or N-oxides thereof as active component (active ingredient).
- a pharmaceutical preparation is suitable for administration to a warm-blooded animal, especially humans or commercially useful mammals suffering from a disease responsive to an inhibition of the Abl tyrosine kinase, for example chronic myelogenous leukaemia (CML), and comprises an effective quantity of a compound of formula I or N-oxides thereof for the inhibition of the Bcr-Abl fusion protein, or a pharmaceutically acceptable salt thereof, if salt-forming groups are present, together with at least one pharmaceutically acceptable carrier.
- CML chronic myelogenous leukaemia
- a pharmaceutical composition for the prophylactic or especially therapeutic management of neoplastic and other proliferative diseases of a warm-blooded animal, especially a human or a commercially useful mammal requiring such treatment, especially suffering from such a disease, comprising as active ingredient in a quantity that is prophylactically or especially therapeutically active against the said diseases a novel compound of formula I or N-oxides thereof, is likewise preferred.
- the pharmaceutical compositions comprise from approximately 1% to approximately 95% active ingredient, single-dose administration forms comprising in the preferred embodiment from approximately 20% to approximately 90% active ingredient and forms that are not of single-dose type comprising in the preferred embodiment from approximately 5% to approximately 20% active ingredient.
- Unit dose forms are, for example, coated and uncoated tablets, ampoules, vials, suppositories, or capsules.
- Further dosage forms are, for example, ointments, creams, pastes, foams, tinctures, sprays, etc. Examples are capsules containing from about 0.05 g to about 1.0 g active ingredient.
- compositions of the present invention are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes.
- compositions of the active ingredient Preference is given to the use of solutions of the active ingredient, and also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions which, for example in the case of lyophilized compositions comprising the active ingredient alone or together with a carrier can be made up before use.
- the pharmaceutical compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers and are prepared in a manner known per se, for example by means of conventional dissolving and lyophilizing processes.
- the said solutions or suspensions may comprise viscosity-increasing agents or solubilizers.
- Suspensions in oil comprise as the oil component the vegetable, synthetic, or semi-synthetic oils customary for injection purposes.
- liquid fatty acid esters that contain as the acid component a long-chained fatty acid having from 8 to 22 carbon atoms.
- the alcohol component of these fatty acid esters has a maximum of 6 carbon atoms and is a monovalent or polyvalent, for example a mono-, di- or trivalent, alcohol, especially glycol and glycerol.
- compositions for oral administration can be obtained, for example, by combining the active ingredient with one or more solid carriers, if desired granulating a resulting mixture, and processing the mixture or granules, if desired or necessary, by the inclusion of additional excipients, to form tablets or tablet cores.
- Suitable carriers are especially fillers, such as sugars, cellulose preparations, and/or calcium phosphates, and also binders, such as starches, and/or polyvinylpyrrolidone, and/or, if desired, disintegrators. Additional excipients are especially flow conditioners and lubricants.
- Tablet cores can be provided with suitable, optionally enteric, coatings through the use of, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations.
- suitable, optionally enteric, coatings through the use of, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations.
- compositions for oral administration also include hard capsules consisting of gelatin, and also soft, sealed capsules consisting of gelatin and a plasticizer.
- the hard capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, binders, and/or glidants, and optionally stabilizers.
- the active ingredient is preferably dissolved or suspended in suitable liquid excipients, to which stabilizers and detergents may also be added.
- compositions suitable for rectal administration are, for example, suppositories that consist of a combination of the active ingredient and a suppository base.
- aqueous solutions of an active ingredient in water-soluble form for example of a water-soluble salt, or aqueous injection suspensions that contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilizers, are especially suitable.
- the active ingredient optionally together with excipients, can also be in the form of a lyophilizate and can be made into a solution before parenteral administration by the addition of suitable solvents.
- Solutions such as are used, for example, for parenteral administration can also be employed as infusion solutions.
- Preferred preservatives are, for example, antioxidants, such as ascorbic acid, or microbicides, such as sorbic acid or benzoic acid.
- the invention relates likewise to a process or a method for the treatment of one of the pathological conditions mentioned hereinabove, especially a disease which responds to an inhibition of a tyrosine kinase, especially a corresponding neoplastic disease.
- the compounds of formula I or N-oxides thereof can be administered as such or especially in the form of pharmaceutical compositions, prophylactically or therapeutically, preferably in an amount effective against the said diseases, to a warm-blooded animal, for example a human, requiring such treatment.
- the daily dose administered is from approximately 0.05 g to approximately 5 g, preferably from approximately 0.25 g to approximately 1.5 g, of a compound of the present invention.
- the present invention relates especially also to the use of a compound of formula I or N-oxides thereof, or a pharmaceutically acceptable salt thereof, especially a compound of formula I which is said to be preferred, or a pharmaceutically acceptable salt thereof, as such or in the form of a pharmaceutical formulation with at least one pharmaceutically acceptable carrier for the therapeutic and also prophylactic management of one or more of the diseases mentioned hereinabove, preferably a disease which responds to an inhibition of a protein kinase, especially a neoplastic disease, more especially leukaemia which responds to an inhibition of the Abl tyrosine kinase.
- New starting materials and/or intermediates, as well as processes for the preparation thereof, are likewise the subject of this invention.
- such starting materials are used and reaction conditions so selected as to enable the preferred compounds to be obtained.
- the substituted aminobenzoic acid of formula II for example, can be obtained by reaction of an ester of 3-amino-4-R 4 -benzoic acid, e.g. 3-amino-4-methylbenzoic acid, with cyanamide and condensing the obtainable guanidine with 3-(dimethylamino)-1-(3-pyridinyl)-2-propen-1-one, and finally hydrolyzing the ester function.
- an ester of 3-amino-4-R 4 -benzoic acid e.g. 3-amino-4-methylbenzoic acid
- the starting material is prepared as follows:
- Cyanamide (Fluka, Buchs, Switzerland; 77.4 g, 1.842 mol) is added to a solution of 3-amino-4-methylbenzoic acid ethyl ester (J. Med. Chem. 16, 118-122, 1973; 150 g, 0.837 mol) in 850 mL of ethanol.
- Hydrochloric acid (Fluka, Buchs, Switzerland; 108 mL of 12M, 1.27 mol) is then added dropwise over 15 min and the reaction mixture is then stirred at 90° C. (bath temperature) for 15 hours. The solvent is evaporated off under reduced pressure to give a residue which is treated with water (1000 mL) and stirred with cooling at 5-10° C.
- Aqueous sodium hydroxide 500 mL of 2M is added dropwise to a stirred suspension of the intermediate Example 1b (132.8 g, 0.397 mol) in ethanol (1200 m L) and water (1200 mL).
- the reaction mixture is stirred at 45° C. for 2.5 h and then treated dropwise with aqueous HCl (1000 mL of 1M) over 1.5 hours.
- aqueous HCl 1000 mL of 1M
- the precipitate is filtered off, washed with water (4 ⁇ 500 mL) and dried at room temperature. Residual water present in the air-dried product is removed by azeotropic distillation with toluene under reduced pressure.
- the dried toluene suspension is diluted with diethyl ether and filtered.
- the solid residue is washed with diethyl ether and dried in vacuo at 80° C. to give the title compound, m.p. 277-278° C.
- N-(2-methoxyethyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide utilising 2-methoxyethylamine (Fluke, Buchs, Switzerland).
- N-[4-(Acetylamino)phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide utilising 4-aminoacetanilide (Fluka, Buchs, Switzerland).
- N-(3-Hydroxypropyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide utilising 3-amino-1-propanol (Aldrich, Buchs, Switzerland).
- N-(3-Hydroxypropyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide utilising 3-amino-1-propanol (Aldrich, Buchs, Switzerland).
- N,N-bis(2-Methoxyethyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide utilising bis(2-methoxyethyl)amine (Aldrich, Buchs, Switzerland).
- N-(3-Benzoylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide utilising 3-aminobenzophenone (Aldrich, Buchs, Switzerland).
- Diethylcyanophosphonate (Aldrich, Buchs, Switzerland; 0.33 mL, 2.0 mmol) is added to a stirred mixture of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid (306 mg, 1.0 mmol), 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)benzeneamine (220 mg, 1.0 mmol) and triethylamine (560 ⁇ L, 4.0 mmol) in 5 mL N,N-dimethylformamide at 10° C.
- Diethylcyanophosphonate (Aldrich, Buchs, Switzerland; 0.50 mL, 3.0 mmol) is added to a stirred mixture of 3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid (438 mg, 1.5 mmol), 4-[(4-methyl-1-piperazinyl)methyl]benzeneamine (308 mg, 1.5 mmol) and triethylamine (840 ⁇ L, 3.0 mmol) in 10 mL N,N-dimethylformamide at 10° C. After stirring for 12 hours at 60° C., the mixture is treated with an aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate.
- Example 69a Utilizing the procedure described in Example 1b, but with the intermediate of Example 69a in lieu of 4-methyl-3-[(aminoiminomethyl)amino]-4-methylbenzoic acid ethyl ester mononitrate, afforded the title compound as a crystalline solid, m.p. 195-200° C.
- Example 69b Utilizing the procedure described in Example 1c, but with the intermediate of Example 69b in lieu of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid ethyl ester, afforded the title compound as a crystalline solid, m.p. 285-293° C.
- the aniline is prepared as follows:
- the aniline is prepared as follows:
- Phenyl boronic acid (Aldrich, Buchs, Switzerland; 2.7 g, 22 mmol), Palladium II acetate (0.225 g, 1 mmol), tri-o-tolylphosphine (0.608 g, 2 mmol) and aqueous potassium carbonate solution (50 mL of 1 M) is added to a stirred solution of 2-bromo-5-nitrobenzotrifluoride (Lancaster Synthesis, GmbH; 5.4 g, 20 mmol) in dimethylformamide (200 mL) and heated at 120° C. under an argon atmosphere for 1 h.
- the aniline is prepared as follows:
- the aniline is prepared as follows:
- the aniline is prepared as follows:
- the aniline is prepared as follows:
- the aniline is prepared as follows:
- the aniline is prepared as follows:
- the mixture is then cooled, treated with an aqueous solution of sodium hydroxide (100 mL of 0.1 M) and purged with air for 2 hours.
- the resulting mixture is then diluted with ethylacetate (200 mL) and filtered.
- the organic phase is then sequentially washed with water (2 ⁇ 80 mL) and saturated aqueous sodium chloride (1 ⁇ 80 mL), dried (MgSO 4 ), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography (silica gel, eluent ethyl acetate) to afford the title compound as a brown oil.
- the aniline is prepared as follows:
- Example 90a Utilizing the procedure described in Example 86b but employing [3-bromo-5-(trifluoromethyl)-phenyl]-carbamic acid, 1,1-dimethylethyl ester (Example 90a) in lieu of 3-bromo-5-nitro-benzoic acid, 1,1-dimethylethyl ester, afforded the title compound as a crystalline solid, m.p. 146-148° C.
- [3-(4-morpholinyl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester (Example 90b; 1.7 g, 5 mmol) is treated with a solution of hydrogen chloride in isopropanol (30 mL of 4 M) and heated at 60° C. for 5 h. The solvent is evaporated off under reduced pressure and the residue is treated with aqueous sodium hydrogen carbonate solution (80 mL) and extracted with ethyl acetate (3 ⁇ 80 mL).
- the was aniline is prepared as follows:
- Triethylamine (5.23 mL, 37.5 mmol) is added to a stirred suspension of 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzoic acid (Example 91b; 6.8 g, 25 mmol) in t-butanol (200 mL).
- Diphenylphosphorylazide (7.6 g, 27.5 mmol) is added to the resulting solution and the mixture is heated 80° C. for 16 h. The solvent is evaporated off under reduced pressure and the residue is treated with water (100 mL) and extracted with ethyl acetate (2 ⁇ 100 mL).
- Example 91c Utilizing the procedure described in Example 90c but employing [3-[2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester (Example 91c) in lieu of [3-(4-morpholinyl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester, afforded the title compound as a yellow crystalline solid, m.p. 130-133° C.
- the was aniline is prepared as follows:
- Example 92a Utilizing the procedure described in Example 91b, but employing 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzonitrile (Example 92a) in lieu of 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzonitrile, afforded the title compound as a crystalline solid, m.p. >300° C.
- Example 92b Utilizing the procedure described in Example 91c, but employing 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzoic acid (Example 92b) in lieu of 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzoic acid, afforded the title compound as a crystalline solid, m.p. 186-188° C.
- Example 92c Utilizing the procedure described in Example 91d, but employing [3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester (Example 92c) in lieu of [3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester, afforded the title compound as a colourless crystalline solid, m.p. 127-131° C.
- the aniline is prepared as follows:
- Example 93a Utilizing the procedure described in Example 91b, but employing 3-(5-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzonitrile (Example 93a) in lieu of 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzonitrile, afforded the title compound as a colourless crystalline solid, m.p. 243-245° C.
- Example 93b Utilizing the procedure described in Example 91c, but employing 3-(5-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzoic acid (Example 93b) in lieu of 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzoic acid, afforded the title compound as a crystalline solid, m.p. 169-171° C.
- Example 93c Utilizing the procedure described in Example 91d, but employing [3-(5-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester (Example 93c) in lieu of [3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester, afforded the title compound as a colourless crystalline solid, m.p. 131-133° C.
- the aniline is prepared as follows:
- Example 94a Utilizing the procedure described in Example 90c, but employing [3-(4-methyl-1-piperazinyl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester (Example 94a) in lieu of [3-(4-morpholinyl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester, afforded the title compound as oil.
- 5000 soft gelatin capsules each comprising as active ingredient 0.05 g of one of the compounds of formula I mentioned in the preceding Examples, are prepared as follows: 250 g pulverized active ingredient is suspended in 2 L Lauroglykol® (propylene glycol laurate, Gattefossé S. A., Saint Priest, France) and ground in a wet pulverizer to produce a particle size of about 1 to 3 ⁇ m. 0.419 g portions of the mixture are then introduced into soft gelatin capsules using a capsule-filling machine.
- Lauroglykol® propylene glycol laurate, Gattefossé S. A., Saint Priest, France
- the compound of formula I to be tested is formulated for administration to female OF1 mice from IFACREDO, France, by first dissolving in NMP, and then by diluting with PEG300 to a final concentration of 10% v/v NMP: 90% v/v PEG300, producing a clear solution of the compound. The concentrations were adjusted to deliver a constant volume of 10 ml/kg body weight.
- the compound is prepared immediately before use.
- the formulated compound is administered perorally by gavage to provide dosages of 50 mg/kg.
- mice (4 at each time) are anesthetized with 3% isoflurane in medical oxygen and blood samples are obtained by heart puncture into heparinized tubes (ca. 30 IU/mL). The animals are subsequently killed without recovering from the anesthetic. Plasma is prepared from the blood by centrifugation (10,000 g, 5 min) and either analyzed immediately or stored frozen at ⁇ 70° C.
- the plasma samples (10-250 ⁇ L) are e.g. spiked with 5 ⁇ L of internal standard, mixed with 200 ⁇ L 0.1 M NaOH and 500 ⁇ L chloroform in a 1.5 mL Eppendorf tube and shaken vigorously for 10 minutes on an Eppendorf mixer. Thereafter, the mixture is centrifuged (3 min at 10′000 ⁇ g), the organic phase transferred to a second Eppendorf tube and evaporated to dryness in a vacuum centrifuge (Speedvac 5301). The dry residue e.g. is dissolved in 250 ⁇ L of 10% v/v Acetonitrile in water containing 0.1% formic acid. The subsequent analysis is carried out e.g.
- the column is prepared for the next sample e.g. by re-equilibrating for 3 min with 100 water to the starting conditions.
- the separation is performed e.g. at a column temperature of 40° C.
- the column effluent is introduced e.g.
- the concentration of unknown samples is calculated from a plot of the peak area ratio of the selected daughter ion of the analyte to the product of its internal standard (ordinate) against the nominal concentration (abscissa). Regression analysis is performed using QuanlynxTM, MasslynxTM software 3.5 (Micromass, Manchester, UK).
- Enzymatic (c-Abl, KDR, Flt3) in vitro inhibition data are presented as % inhibition at 10 ⁇ M. The measurements are made as described above in the general description.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Oncology (AREA)
- Pulmonology (AREA)
- Cardiology (AREA)
- Reproductive Health (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Heart & Thoracic Surgery (AREA)
- Gynecology & Obstetrics (AREA)
- Obesity (AREA)
- Pregnancy & Childbirth (AREA)
- Emergency Medicine (AREA)
- Transplantation (AREA)
- Ophthalmology & Optometry (AREA)
- Vascular Medicine (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to compounds of formula
- wherein the substituents R1, R2 and R4 have the meaning as set forth and explained in the description of the invention, to processes for the preparation of these compounds, pharmaceutical compositions containing same, the use thereof optionally in combination with one or more other pharmaceutically active compounds for the therapy of a disease which responds to an inhibition of protein kinase activity, especially a neoplastic disease, in particular leukaemia, and a method for the treatment of such a disease.
Description
- This application is a continuation of U.S. patent application Ser. No. 12/489,049 filed Jun. 22, 2009 which is a continuation of U.S. patent application Ser. No. 12/061,334, filed Apr. 2, 2008, which is a continuation of U.S. patent application Ser. No. 11/607,542, filed Dec. 1, 2006, which is a continuation of U.S. patent application Ser. No. 10/520,359, filed Sep. 12, 2005, which is a 371 of international application No. PCT/EP03/07198, filed Jul. 4, 2003 which claims benefit of Great Britain Application No. 0215676.8 filed Jul. 5, 2002 and Great Britain Application No. 0229893.3 filed Dec. 20, 2002, which in their entirety are herein incorporated by reference.
- The invention relates to novel substituted pyrimidinylaminobenzamides, processes for the preparation thereof, pharmaceutical compositions containing same, the use thereof optionally in combination with one or more other pharmaceutically active compounds for the therapy of a disease which responds to an inhibition of protein kinase activity, especially a neoplastic disease, in particular leukaemia, and a method for the treatment of such a disease.
- Protein kinases (PKs) are enzymes which catalyze the phosphorylation of specific serine, threonine or tyrosine residues in cellular proteins. These post-translational modifications of substrate proteins act as molecular switches regulating cell proliferation, activation and/or differentiation. Aberrant or excessive PK activity has been observed in many disease states including benign and malignant proliferative disorders. In a number of cases, it has been possible to treat diseases, such as proliferative disorders, by making use of PK inhibitors in vitro and in vivo.
- In view of the large number of protein kinase inhibitors and the multitude of proliferative and other PK-related diseases, there is an ever-existing need to provide novel classes of compounds that are useful as PK inhibitors and thus in the treatment of these PTK related diseases. What is required are new classes of pharmaceutically advantageous PK inhibiting compounds.
- The Philadelphia Chromosome is a hallmark for chronic myelogenous leukaemia (CML) and carries a hybrid gene that contains N-terminal exons of the bcr gene and the major C-terminal part (exons 2-11) of the c-abl gene. The gene product is a 210 kD protein (p210 Bcr-Abl). The Abl-part of the Bcr-Abl protein contains the abl-tyrosine kinase which is tightly regulated in the wild type c-abl, but constitutively activated in the Bcr-Abl fusion protein. This deregulated tyrosine kinase interacts with multiple cellular signalling pathways leading to transformation and deregulated proliferation of the cells (Lugo et al., Science 247, 1079 [1990]).
- It has now been found that various compounds of the pyrimidinylaminobenzamide class show inhibition of protein kinase activity. The compounds of formula I, described below in more detail, especially show inhibition of one or more tyrosine kinases, such as c-Abl, Bcr-Abl, the receptor tyrosine kinases PDGF-R, Flt3, VEGF-R, EGF-R, and c-Kit, as well as combinations of two or more of these; in the case of novel pyrimidinylaminobenzamides according to the invention, the compounds are appropriate for the inhibition of these and/or other protein kinases, especially those mentioned above and/or for the inhibition of mutants of these enzymes, especially of Bcr-Abl, for example the Glu255->Valine mutant. In view of these activities, the compounds can be used for the treatment of diseases related to especially aberrant or excessive activity of such types of kinases, especially those mentioned.
- The invention relates to a compound of formula I,
- wherein
- R1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl;
- R2 represents hydrogen, lower alkyl, optionally substituted by one or more identical or different radicals R3, cycloalkyl, benzcycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted;
- and R3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted;
- or wherein R1 and R2 together represent alkylene with four, five or six carbon atoms optionally mono- or disubstituted by lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or disubstituted amino, oxo, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with four or five carbon atoms; oxaalkylene with one oxygen and three or four carbon atoms; or azaalkylene with one nitrogen and three or four carbon atoms wherein nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl, N-mono- or N,N-disubstituted carbamoyl-lower alkyl, cycloalkyl, lower alkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl, pyrimidinyl, or pyrazinyl;
- R4 represents hydrogen, lower alkyl, or halogen;
- and a N-oxide or a pharmaceutically acceptable salt of such a compound.
- The general terms used hereinbefore and hereinafter preferably have within the context of this disclosure the following meanings, unless otherwise indicated:
- The prefix “lower” denotes a radical having up to and including a maximum of 7, especially up to and including a maximum of 4 carbon atoms, the radicals in question being either linear or branched with single or multiple branching.
- 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 isomers or as pure isomers, preferably as enantiomer-pure diastereomers.
- The invention relates also to possible tautomers of the compounds of formula I.
- Lower alkyl is preferably alkyl with from and including 1 up to and including 7, preferably from and including 1 to and including 4, and is linear or branched; preferably, lower alkyl is butyl, such as n-butyl, sec-butyl, isobutyl, tert-butyl, propyl, such as n-propyl or isopropyl, ethyl or methyl. Preferably lower alkyl is methyl, propyl or tert-butyl.
- Lower acyl is preferably formyl or lower alkylcarbonyl, in particular acetyl.
- An aryl group is an aromatic radical which is bound to the molecule via a bond located at an aromatic ring carbon atom of the radical. In a preferred embodiment, aryl is an aromatic radical having 6 to 14 carbon atoms, especially phenyl, naphthyl, tetrahydronaphthyl, fluorenyl or phenanthrenyl, and is unsubstituted or substituted by one or more, preferably up to three, especially one or two substituents, especially selected from amino, mono- or disubstituted amino, halogen, lower alkyl, substituted lower alkyl, lower alkenyl, lower alkynyl, phenyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterified carboxy, alkanoyl, benzoyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, amidino, guanidino, ureido, mercapto, sulfo, lower alkylthio, phenylthio, phenyl-lower alkylthio, lower alkylphenylthio, lower alkylsulfinyl, phenylsulfinyl, phenyl-lower alkylsulfinyl, lower alkylphenylsulfinyl, lower alkylsulfonyl, phenylsulfonyl, phenyl-lower alkylsulfonyl, lower alkylphenylsulfonyl, halogen-lower alkylmercapto, halogen-lower alkylsulfonyl, such as especially trifluoromethanesulfonyl, dihydroxybora (—B(OH)2), heterocyclyl, a mono- or bicyclic heteroaryl group and lower alkylene dioxy bound at adjacent C-atoms of the ring, such as methylene dioxy. Aryl is more preferably phenyl, naphthyl or tetrahydronaphthyl, which in each case is either unsubstituted or independently substituted by one or two substituents selected from the group comprising halogen, especially fluorine, chlorine, or bromine; hydroxy; hydroxy etherified by lower alkyl, e.g. by methyl, by halogen-lower alkyl, e.g. trifluoromethyl, or by phenyl; lower alkylene dioxy bound to two adjacent C-atoms, e.g. methylenedioxy, lower alkyl, e.g. methyl or propyl; halogen-lower alkyl, e.g. trifluoromethyl; hydroxy-lower alkyl, e.g. hydroxymethyl or 2-hydroxy-2-propyl; lower alkoxy-lower alkyl; e.g. methoxymethyl or 2-methoxyethyl; lower alkoxycarbonyl-lower alkyl, e.g. methoxy-carbonylmethyl; lower alkynyl, such as 1-propynyl; esterified carboxy, especially lower alkoxycarbonyl, e.g. methoxycarbonyl, n-propoxy carbonyl or iso-propoxy carbonyl; N-mono-substituted carbamoyl, in particular carbamoyl monosubstituted by lower alkyl, e.g. methyl, n-propyl or iso-propyl; amino; lower alkylamino, e.g. methylamino; di-lower alkylamino, e.g. dimethylamino or diethylamino; lower alkylene-amino, e.g. pyrrolidino or piperidino; lower oxaalkylene-amino, e.g. morpholino, lower azaalkylene-amino, e.g. piperazino, acylamino, e.g. acetylamino or benzoylamino; lower alkylsulfonyl, e.g. methylsulfonyl; sulfamoyl; or phenylsulfonyl.
- A cycloalkyl group is preferably cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl, and may be unsubstituted or substituted by one or more, especially one or two, substitutents selected from the group defined above as substitutents for aryl, most preferably by lower alkyl, such as methyl, lower alkoxy, such as methoxy or ethoxy, or hydroxy, and further by oxo or fused to a benzo ring, such as in benzcyclopentyl or benzcyclohexyl.
- Substituted alkyl is alkyl as last defined, especially lower alkyl, preferably methyl; where one or more, especially up to three, substituents may be present, primarily from the group selected from halogen, especially fluorine, amino, N-lower alkylamino, N,N-di-lower alkylamino, N-lower alkanoylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, and phenyl-lower alkoxycarbonyl. Trifluoromethyl is especially preferred.
- Mono- or disubstituted amino is especially amino substituted by one or two radicals selected independently of one another from lower alkyl, such as methyl; hydroxy-lower alkyl, such as 2-hydroxyethyl; lower alkoxy lower alkyl, such as methoxy ethyl; phenyl-lower alkyl, such as benzyl or 2-phenylethyl; lower alkanoyl, such as acetyl; benzoyl; substituted benzoyl, wherein the phenyl radical is especially substituted by one or more, preferably one or two, substituents selected from nitro, amino, halogen, N-lower alkylamino, N,N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, and carbamoyl; and phenyl-lower alkoxycarbonyl, wherein the phenyl radical is unsubstituted or especially substituted by one or more, preferably one or two, substituents selected from nitro, amino, halogen, N-lower alkylamino, N,N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, and carbamoyl; and is preferably N-lower alkylamino, such as N-methylamino, hydroxy-lower alkylamino, such as 2-hydroxyethylamino or 2-hydroxypropyl, lower alkoxy lower alkyl, such as methoxy ethyl, phenyl-lower alkylamino, such as benzylamino, N,N-di-lower alkylamino, N-phenyl-lower alkyl-N-lower alkylamino, N,N-di-lower alkylphenylamino, lower alkanoylamino, such as acetylamino, or a substituent selected from the group comprising benzoylamino and phenyl-lower alkoxycarbonylamino, wherein the phenyl radical in each case is unsubstituted or especially substituted by nitro or amino, or also by halogen, amino, N-lower alkylamino, N,N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, carbamoyl or aminocarbonylamino. Disubstituted amino is also lower alkylene-amino, e.g. pyrrolidino, 2-oxopyrrolidino or piperidino; lower oxaalkylene-amino, e.g. morpholino, or lower azaalkylene-amino, e.g. piperazino or N-substituted piperazino, such as N-methylpiperazino or N-methoxycarbonylpiperazino.
- Halogen is especially fluorine, chlorine, bromine, or iodine, especially fluorine, chlorine, or bromine.
- Etherified hydroxy is especially C8-C20alkyloxy, such as n-decyloxy, lower alkoxy (preferred), such as methoxy, ethoxy, isopropyloxy, or tert-butyloxy, phenyl-lower alkoxy, such as benzyloxy, phenyloxy, halogen-lower alkoxy, such as trifluoromethoxy, 2,2,2-trifluoroethoxy or 1,1,2,2-tetrafluoroethoxy, or lower alkoxy which is substituted by mono- or bicyclic hetero-aryl comprising one or two nitrogen atoms, preferably lower alkoxy which is substituted by imidazolyl, such as 1H-imidazol-1-yl, pyrrolyl, benzimidazolyl, such as 1-benzimidazolyl, pyridyl, especially 2-, 3- or 4-pyridyl, pyrimidinyl, especially 2-pyrimidinyl, pyrazinyl, isoquinolinyl, especially 3-isoquinolinyl, quinolinyl, indolyl or thiazolyl.
- Esterified hydroxy is especially lower alkanoyloxy, benzoyloxy, lower alkoxycarbonyloxy, such as tert-butoxycarbonyloxy, or phenyl-lower alkoxycarbonyloxy, such as benzyloxycarbonyloxy.
- Esterified carboxy is especially lower alkoxycarbonyl, such as tert-butoxycarbonyl, iso-propoxycarbonyl, methoxycarbonyl or ethoxycarbonyl, phenyl-lower alkoxycarbonyl, or phenyloxycarbonyl.
- Alkanoyl is primarily alkylcarbonyl, especially lower alkanoyl, e.g. acetyl.
- N-Mono- or N,N-disubstituted carbamoyl is especially substituted by one or two substituents independently selected from lower alkyl, phenyl-lower alkyl and hydroxy-lower alkyl, or lower alkylene, oxa-lower alkylene or aza-lower alkylene optionally substituted at the terminal nitrogen atom.
- A mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted, refers to a heterocyclic moiety that is unsaturated in the ring binding the heteroaryl radical to the rest of the molecule in formula I and is preferably a ring, where in the binding ring, but optionally also in any annealed ring, at least one carbon atom is replaced by a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; where the binding ring preferably has 5 to 12, more preferably 5 or 6 ring atoms; and which may be unsubstituted or substituted by one or more, especially one or two, substitutents selected from the group defined above as substitutents for aryl, most preferably by lower alkyl, such as methyl, lower alkoxy, such as methoxy or ethoxy, or hydroxy. Preferably the mono- or bicyclic heteroaryl group is selected from 2H-pyrrolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, indazolyl, purinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, quinolinyl, pteridinyl, indolizinyl, 3H-indolyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, furazanyl, benzo[d]pyrazolyl, thienyl and furanyl. More preferably the mono- or bicyclic heteroaryl group is selected from the group consisting of pyrrolyl, imidazolyl, such as 1H-imidazol-1-yl, benzimidazolyl, such as 1-benzimidazolyl, indazolyl, especially 5-indazolyl, pyridyl, especially 2-, 3- or 4-pyridyl, pyrimidinyl, especially 2-pyrimidinyl, pyrazinyl, isoquinolinyl, especially 3-isoquinolinyl, quinolinyl, especially 4- or 8-quinolinyl, indolyl, especially 3-indolyl, thiazolyl, benzo[d]pyrazolyl, thienyl, and furanyl. In one preferred embodiment of the invention the pyridyl radical is substituted by hydroxy in ortho position to the nitrogen atom and hence exists at least partially in the form of the corresponding tautomer which is pyridin-(1H)-2-one. In another preferred embodiment, the pyrimidinyl radical is substituted by hydroxy both in position 2 and 4 and hence exists in several tautomeric forms, e.g. as pyrimidine-(1H, 3H)2,4-dione.
- Heterocyclyl is especially a five, six or seven-membered heterocyclic system with one or two heteroatoms selected from the group comprising nitrogen, oxygen, and sulfur, which may be unsaturated or wholly or partly saturated, and is unsubstituted or substituted especially by lower alkyl, such as methyl, phenyl-lower alkyl, such as benzyl, oxo, or heteroaryl, such as 2-piperazinyl; heterocyclyl is especially 2- or 3-pyrrolidinyl, 2-oxo-5-pyrrolidinyl, piperidinyl, N-benzyl-4-piperidinyl, N-lower alkyl-4-piperidinyl, N-lower alkyl-piperazinyl, morpholinyl, e.g. 2- or 3-morpholinyl, 2-oxo-1H-azepin-3-yl, 2-tetrahydrofuranyl, or 2-methyl-1,3-dioxolan-2-yl.
- Salts are especially the pharmaceutically acceptable salts of compounds of formula I.
- Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of formula I with a basic nitrogen atom, especially the pharmaceutically acceptable salts. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalene-disulfonic acid, 2-, 3- or 4-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid.
- In the presence of negatively charged radicals, such as carboxy or sulfo, salts may also be formed with bases, e.g. metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or tri(2-hydroxyethyl)amine, or heterocyclic bases, for example N-ethyl-piperidine or N,N′-dimethylpiperazine.
- When a basic group and an acid group are present in the same molecule, a compound of formula I may also form internal salts.
- For isolation or purification purposes it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or free compounds are employed (where applicable in the form of pharmaceutical preparations), and these are therefore preferred.
- In view of the close relationship between the novel compounds in free form and those in the form of their salts, including those salts that can be used as intermediates, for example in the purification or identification of the novel compounds, any reference to the free compounds hereinbefore and hereinafter is to be understood as referring also to the corresponding salts, as appropriate and expedient.
- The compounds of formula I and N-oxides thereof have valuable pharmacological properties, as described hereinbefore and hereinafter.
- The efficacy of the compounds of the invention as inhibitors of c-Abl, Bcr-Abl, and VEGF-receptor tyrosine kinase activity can be demonstrated as follows:
- Test for activity against c-Abl protein tyrosine kinase. The test is conducted as a filter binding assay as follows: The His-tagged kinase domain of c-Abl is cloned and expressed in the baculovirus/Sf9 system as described by Bhat et al., J Biol Chem. 272, 16170-5 (1997). A protein of 37 kD (c-Abl kinase) is purified by a two-step procedure over a Cobalt metal chelate column followed by an anion exchange column with a yield of 1-2 mg/L of Sf9 cells. The purity of the c-Abl kinase is >90% as judged by SDS-PAGE after Coomassie blue staining. The assay contains: c-Abl kinase (50 ng), 20 mM Tris.HCl, pH 7.5, 10 mM MgCl2, 10 μM Na3VO4, 1 mM DTT and 0.06 μCi/assay [γ33 P]-ATP (5 μM ATP) using 30 μg/mL poly-Ala,Glu,Lys,Tyr-6:2:5:1 (Poly-AEKY, Sigma P1152) in the presence of 1% DMSO, total volume of 30 μL. Reactions are terminated by adding 10 μL of 250 mM EDTA, and 30 μL of the reaction mixture is transferred onto Immobilon-PVDF membrane (Millipore, Bedford, Mass., USA) previously soaked for 5 min with methanol, rinsed with water, then soaked for 5 min with 0.5% H3PO4 and mounted on vacuum manifold with disconnected vacuum source. After spotting all samples, vacuum is connected and each well rinsed with 200 μL 0.5% H3PO4. Membranes are removed and washed on a shaker with 0.5% H3PO4 (4 times) and once with ethanol. Membranes are counted after drying at ambient temperature, mounting in Packard TopCount 96-well frame, and addition of 10 μL/well of Microscint™ (Packard).
- Test for activity against Bcr-Abl. The murine myeloid progenitor cell line 32Dcl3 transfected with the p210 Bcr-Abl expression vector pGDp210Bcr/Abl (32D-bcr/abl) was obtained from J. Griffin (Dana Faber Cancer Institute, Boston, Mass., USA). The cells express the fusion Bcr-Abl protein with a constitutively active abi kinase and proliferate growth factor independent. The cells are expanded in RPMI 1640 (AMIMED), 10% fetal calf serum, 2 mM glutamine (Gibco) (“complete medium”), and a working stock is prepared by freezing aliquots of 2×106 cells per vial in freezing medium (95% FCS, 5% DMSO (SIGMA)). After thawing, the cells are used during maximally 10-12 passages for the experiments.
- For cellular assays, compounds are dissolved in DMSO and diluted with complete medium to yield a starting concentration of 10 μM followed by preparation of serial 3-fold dilutions in complete medium. 200′000 32D-Bcr/Abl cells in 50 μL complete medium are seeded per well in 96 well round bottom tissue culture plates. 50 μL per well of serial 3-fold dilutions of the test compound are added to the cells in triplicates. Untreated cells are used as control. The compound is incubated together with the cells for 90 min at 37° C., 5% CO2, followed by centrifugation of the tissue culture plates at 1300 rpm (Beckmann GPR centrifuge) and removal of the supernatants by careful aspiration taking care not to remove any of the pelleted cells. The cell pellets are lysed by addition of 150 μL lysis buffer (50 mM Tris/HCl, pH 7.4, 150 mM sodium chloride, 5 mM EDTA, 1 mM EGTA, 1% NP-40, 2 mM sodium ortho-vanadate, 1 mM PMSF, 50 μg/mL aprotinin and 80 μg/mL leupeptin) and either used immediately for the ELISA or stored frozen in the plates at −20° C. until usage. Black ELISA plates (Packard HTRF-96 black plates) are precoated over night at 4° C. with 50 ng/well of the rabbit polyclonal anti-abl-SH3 domain Ab 06-466 from Upstate in 50 μL PBS. After washing 3 times with 200 μL/well PBS containing 0.05% Tween20 (PBST) and 0.5% TopBlock (Juro), residual protein binding sites are blocked with 200 μL/well PBST, 3% TopBlock for 4 h at room temperature followed by incubation with 50 μL lysates of untreated or compound-treated cells (20 μg total protein per well) for 3-4 h at 4° C. After 3 washings, 50 μL/well anti-phosphotyrosine Ab PY20(AP) labeled with alkaline phosphatase (Zymed) diluted to 0.2 μg/mL in blocking buffer is added and incubated over night (4° C.). For all incubation steps the plates are covered with plate sealers (Costar). Finally, the plates are washed another three times with washing buffer and once with deionized water before addition of 90 μL/well of the AP-substrate CDPStar RTU with Emerald II. The plates, now sealed with Packard TopSear™-A plate sealers, are incubated for 45 min at room temperature in the dark and luminescence is quantified by measuring counts per second (CPS) with a Packard Top Count Microplate Scintillation Counter (Top Count).
- The difference between the ELISA-readout (CPS) obtained for with the lysates of the untreated 32D-Bcr/Abl cells and the readout for the assay-background (all components, but without cell lysate) is calculated and taken as 100% reflecting the constitutively phosphorylated Bcr-Abl protein present in these cells. The activity of the compound on the Bcr-Abl kinase activity is expressed as percent reduction of the Bcr-Abl phosphorylation. The values for the IC50 and IC90 are determined from the dose response curves by graphical extrapolation.
- Test for activity against VEGF-receptor tyrosine kinase. The test is conducted using Flt-1 VEGF-receptor tyrosine kinase. The detailed procedure is as follows: 30 μL kinase solution (10 ng of the kinase domain of Flt-1, Shibuya et al., Oncogene 5, 519-24 [1990]) in 20 mM Tris.HCl pH 7.5, 3 mM manganese dichloride (MnCl2), 3 mM magnesium chloride (MgCl2), 10 μM sodium vanadate, 0.25 mg/mL polyethylenglycol (PEG) 20000, 1 mM dithiothreitol and 3 μg/μL poly(Glu,Tyr) 4:1 (Sigma, Buchs, Switzerland), 8 μM [33P]-ATP (0.2 μCi), 1% DMSO, and 0 to 100 μM of the compound to be tested are incubated together for 10 minutes at room temperature. The reaction is then terminated by the addition of 10 μL 0.25 M ethylenediaminetetraacetate (EDTA) pH 7. Using a multichannel dispenser (LAB SYSTEMS, USA), an aliquot of 20 μL is applied to a PVDF (=polyvinyl difluoride) Immobilon P membrane (Millipore, Bedford, USA), through a Gibco-BRL microtiter filter manifold and connected to a vacuum. Following complete elimination of the liquid, the membrane is washed 4 times successively in a bath containing 0.5% phosphoric acid (H3PO4) and once with ethanol, incubated for 10 minutes each time while shaking, then mounted in a Hewlett Packard TopCount Manifold and the radioactivity measured after the addition of 10 μL Microscint® (β-scintillation counter liquid). IC50-values are determined by linear regression analysis of the percentages for the inhibition of each compound in at least four concentrations (as a rule 0.01, 0.1, 1.0 and 10 μmol). The IC50-values that can be found with compounds of formula I are in the range of 1 to 10′000 nM, preferably in the range of 1 to 100 nM.
- The inhibition of VEGF-induced KDR-receptor autophosphorylation can be confirmed with a further in vitro experiment in cells: transfected CHO cells, which permanently express human VEGF receptor (KDR), are seeded in complete culture medium with 10% fetal calf serum (FCS) in 6-well cell-culture plates and incubated at 37° C. under 5% CO2 until they show about 80% confluency. The compounds to be tested are then diluted in culture medium (without FCS, with 0.1% bovine serum albumin) and added to the cells. (Controls comprise medium without test compounds). After two hours of incubation at 37° C., recombinant VEGF is added; the final VEGF concentration is 20 ng/mL). After a further five minute incubation at 37° C., the cells are washed twice with ice-cold PBS (phosphate-buffered saline) and immediately lysed in 100 μL lysis buffer per well. The lysates are then centrifuged to remove the cell nuclei, and the protein concentrations of the supernatants are determined using a commercial protein assay (BIORAD). The lysates can then either be immediately used or, if necessary, stored at −20° C.
- A sandwich ELISA is carried out to measure the KDR-receptor phosphorylation: a monoclonal antibody to KDR (for example Mab 1495.12.14) is immobilized on black ELISA plates (OptiPlate™ HTRF-96 from Packard). The plates are then washed and the remaining free protein-binding sites are saturated with 1% BSA in PBS. The cell lysates (20 μg protein per well) are then incubated in these plates overnight at 4° C. together with an anti-phosphotyrosine antibody coupled with alkaline phosphatase (PY20:AP from Transduction Laboratories). The plates are washed again and the binding of the antiphosphotyrosine antibody to the captured phosphorylated receptor is then demonstrated using a luminescent AP substrate (CDP-Star, ready to use, with Emerald II; TROPIX). The luminescence is measured in a Packard Top Count Microplate Scintillation Counter (Top Count). The difference between the signal of the positive control (stimulated with VEGF) and that of the negative control (not stimulated with VEGF) corresponds to VEGF-induced KDR-receptor phosphorylation (=100%). The activity of the tested substances is calculated as % inhibition of VEGF-induced KDR-receptor phosphorylation, wherein the concentration of substance that induces half the maximum inhibition is defined as the ED50 (effective dose for 50% inhibition). Compounds of formula I here preferably show ED50 values in the range of 0.25 nM to 1000 nM, preferably 0.25 to 250 nM.
- A compound of formula I or a N-oxide thereof inhibits to varying degrees also other tyrosine kinases involved in signal transduction which are mediated by trophic factors, for example Bcr-Abl and Abl kinase, Arg, kinases from the Src family, especially c-Src kinase, Lck, and Fyn; also kinases of the EGF family, for example, c-erbB2 kinase (HER-2), c-erbB3 kinase, c-erbB4 kinase; insulin-like growth factor receptor kinase (IGF-1 kinase), especially members of the PDGF-receptor tyrosine kinase family, such as PDGF-receptor kinase, CSF-1-receptor kinase, Kit-receptor kinase and VEGF-receptor kinase; and also serine/threonine kinases, all of which play a role in growth regulation and transformation in mammalian cells, including human cells.
- The inhibition of c-erbB2 tyrosine kinase (HER-2) can be measured, for example, in the same way as the inhibition of EGF-R protein kinase, using known procedures.
- On the basis of these studies, a compound of formula I according to the invention shows therapeutic efficacy especially against disorders dependent on protein kinase, especially proliferative diseases.
- On the basis of their efficacy as inhibitors of VEGF-receptor tyrosine kinase activity, the compounds of the formula I primarily inhibit the growth of blood vessels and are thus, for example, effective against a number of diseases associated with deregulated angiogenesis, especially diseases caused by ocular neovascularisation, especially retinopathies, such as diabetic retinopathy or age-related macula degeneration, psoriasis, haemangioblastoma, such as haemangioma, mesangial cell proliferative disorders, such as chronic or acute renal diseases, e.g. diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes or transplant rejection, or especially inflammatory renal disease, such as glomerulonephritis, especially mesangioproliferative glomerulonephritis, haemolytic-uraemic syndrome, diabetic nephropathy, hypertensive nephrosclerosis, atheroma, arterial restenosis, autoimmune diseases, diabetes, endometriosis, chronic asthma, and especially neoplastic diseases (solid tumors, but also leukemias and other “liquid tumors”, especially those expressing c-kit, KDR, Flt-1 or Flt-3), such as especially breast cancer, cancer of the colon, lung cancer (especially small-cell lung cancer), cancer of the prostate or Kaposi's sarcoma. A compound of formula I (or an N-oxide thereof) inhibits the growth of tumours and is especially suited to preventing the metastatic spread of tumors and the growth of micrometastases.
- A compound of formula I can be administered alone or in combination with one or more other therapeutic agents, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic agents being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic agents. A compound of formula I can besides or in addition be administered especially for tumor therapy, such as leukaemia therapy, in combination with chemotherapy, radiotherapy, immunotherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.
- Therapeutic agents for possible combination are especially one or more cytostatic or cytotoxic compounds, for example a chemotherapeutic agent or several selected from the group comprising indarubicin, cytarabine, interferon, hydroxyurea, bisulfan, or an inhibitor of polyamine biosynthesis, an inhibitor of protein kinase, especially of serine/threonine protein kinase, such as protein kinase C, or of tyrosine protein kinase, such as epidermal growth factor receptor tyrosine kinase, a cytokine, a negative growth regulator, such as TGF-β or IFN-β, an aromatase inhibitor, a classical cytostatic, and an inhibitor of the interaction of an SH2 domain with a phosphorylated protein.
- A compound according to the invention is not only for the (prophylactic and preferably therapeutic) management of humans, but also for the treatment of other warm-blooded animals, for example of commercially useful animals, for example rodents, such as mice, rabbits or rats, or guinea-pigs. Such a compound may also be used as a reference standard in the test systems described above to permit a comparison with other compounds.
- In general, the invention relates also to the use of a compound of formula I or a N-oxide thereof for the inhibition of tyrosine kinase activity, either in vitro or in vivo.
- With the groups of preferred compounds of formula I and N-oxides thereof mentioned hereinafter, definitions of substituents from the general definitions mentioned hereinbefore may reasonably be used, for example, to replace more general definitions with more specific definitions or especially with definitions characterized as being preferred.
- In particular, the invention relates to compounds of formula I, wherein
- R1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl;
- R2 represents hydrogen, lower alkyl, optionally substituted by one or two identical or different radicals R3, cycloalkyl, benzcycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising one, two or three nitrogen atoms or one sulfur atom, which aryl and heteroaryl groups in each case are unsubstituted or mono- or polysubstituted;
- and R3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, an aryl group, furanoyl, thienoyl, or a mono- or bicyclic heteroaryl group comprising one, two or three ring nitrogen atoms, zero or one ring oxygen atom and zero or one ring sulphur atom, which aryl and heteroaryl groups in each case are unsubstituted or mono- or polysubstituted;
- or wherein R1 and R2 together represent alkylene with four or five carbon atoms, optionally mono- or disubstituted by lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or disubstituted amino, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with four or five carbon atoms in the alkylene group; oxaalkylene with one oxygen and three or four carbon atoms, or azaalkylene with one nitrogen and three or four carbon atoms wherein nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl, N-mono- or N,N-disubstituted carbamoyl-lower alkyl, cycloalkyl, lower alkoxycarbonyl, phenyl, substituted phenyl, pyridinyl, pyrimidinyl, or pyrazinyl;
- R4 represents hydrogen, lower alkyl, or halogen;
- and a N-oxide or a pharmaceutically acceptable salt of such a compound.
- More particular, the invention relates to compounds of formula I, wherein
- R1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl;
- R2 represents hydrogen, lower alkyl, optionally substituted by one or two identical or different radicals R3, cyclopentyl, benzcyclopentyl, cylcohexyl, pyrrolidinyl, oxazolinyl, piperidinyl, N-substituted piperidinyl, morpholinyl, azepinyl, oxo-azepinyl, oxazepinyl, phenyl, naphthalinyl, tetrahydronaphthalinyl or a mono- or bicyclic heteroaryl group comprising one or two nitrogen atoms, which phenyl, naphthalinyl and heteroaryl groups in each case are unsubstituted or mono- or polysubstituted, thienyl, or lower alkoxycarbonyl-lower alkylthienyl;
- and R3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, amino, lower alkylamino, di-lower alkylamino, phenylamino, N-lower alkyl-N-phenylamino, pyrrolidino, oxopyrrolidino, piperidino, morpholino, imidazolino, oxoimidazolino, cycloalkyl, heterocyclyl, furyl, phenyl, naphthalinyl, tetrahydronaphthalinyl, or a mono- or bicyclic heteroaryl group comprising one or two nitrogen atoms, which phenyl, naphthalinyl and heteroaryl group are unsubstituted or mono- or polysubstituted;
- or wherein R1 and R2 together represent alkylene with four or five carbon atoms, optionally mono- or disubstituted by lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or disubstituted amino, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with four or five carbon atoms in the alkylene group; oxaalkylene with one oxygen and four carbon atoms; or azaalkylene with one nitrogen and four carbon atoms wherein nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl, N-mono- or N,N-disubstituted carbamoyl-lower alkyl, cycloalkyl, lower alkoxycarbonyl, phenyl, substituted phenyl, pyridinyl, pyrimidinyl, or pyrazinyl;
- R4 represents hydrogen, lower alkyl, or halogen;
- and a N-oxide or a pharmaceutically acceptable salt of such a compound.
- More particular, the invention relates to compounds of formula I, wherein
- R1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl;
- R2 represents hydrogen; lower alkyl, optionally substituted by one radical R3, by two phenyl groups, by two lower alkoxycarbonyl groups, by phenyl and lower alkoxycarbonyl, or by hydroxyphenyl and lower alkoxycarbonyl; cyclopentyl; benzcyclopentyl; cylcohexyl; pyrrolidinyl; oxazolinyl; piperidinyl; N-lower alkylpiperidinyl; N-benzylpiperidinyl; N-pyrimidinylpiperidinyl; morpholinyl; azepinyl; oxo-azepinyl; oxazepinyl; phenyl, naphthalinyl, tetrahydronaphthalinyl or a mono- or bicyclic heteroaryl group comprising one or two nitrogen atoms, which phenyl, naphthalinyl and heteroaryl groups in each case are unsubstituted or substituted by one or two substituents selected from the group consisting of lower alkyl, trifluoro-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, N-cyclohexyl-N-lower alkylamino-lower alkyl, lower alkoxycarbonylpiperidino-lower alkyl, N-lower alkylpiperazino-lower alkyl, lower alkoxycarbonyl-lower alkyl, hydroxy, lower alkoxy, trifluoro-lower alkoxy, 1H-imidazolyl-lower alkoxy, lower alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, lower alkyl carbamoyl, amino, lower alkanoylamino, benzoylamino, amino mono- or disubstituted by lower alkyl, by hydroxy-lower alkyl or by lower alkoxy-lower alkyl, 1H-imidazolyl, mono- or di-lower alkyl-1H-imidazolyl, pyrrolidino, piperidino, piperazino, N-lower alkylpiperazino, morpholino, sulfamoyl, lower alkylsulfonyl, phenylsulfonyl, lower alkylsulfinyl, phenylsulfinyl, lower alkylthio, phenylthio, phenyl, pyridyl, halogenyl, or benzoyl; thienyl; or lower alkoxycarbonyl-lower alkylthienyl; and
- R3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, carbamoyl mono-or disubstituted by lower alkyl, phenyl or lower alkylene, amino, lower alkylamino, di-lower alkylamino, phenylamino, N-lower alkyl-N-phenylamino, pyrrolidino, oxopyrrolidino, piperidino, morpholino, imidazolino, oxoimidazolino, cycloalkyl, heterocyclyl, furyl; phenyl, naphthalinyl, tetrahydronaphthalinyl, or a mono- or bicyclic heteroaryl group comprising one or two nitrogen atoms, which phenyl, naphthalinyl and heteroaryl group is unsubstituted or substituted by one or two substituents selected from the group consisting of lower alkyl, trifluoro-lower alkyl, lower alkoxycarbonyl-lower alkyl, hydroxy, lower alkoxy, trifluoro-lower alkoxy, lower alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, amino, lower alkanoylamino, benzoylamino, amino mono- or disubstituted by lower alkyl, by hydroxy-lower alkyl or by loweralkoxy-lower alkyl, pyrrolidino, piperidino, morpholino, piperazino, N-lower alkylpiperazino, N-lower alkoxycarbonylpiperazino, phenyl, pyridyl, 1H-imidazolyl, lower alkyl-1H-imidazolyl, sulfamoyl, lower alkylsulfonyl, phenylsulfonyl, lower alkylsulfinyl, phenylsulfinyl, lower alkylthio, phenylthio, halogenyl, or benzoyl;
- or wherein R1 and R2 together represent alkylene with four or five carbon atoms, optionally mono- or disubstituted by lower alkyl, cycloalkyl, phenyl, hydroxy, lower alkoxy, amino, benzoylamino, piperidino, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with four or five carbon atoms in the alkylene group; oxaalkylene with one oxygen and four carbon atoms; or azaalkylene with one nitrogen and four carbon atoms wherein nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl, carbamoyl-lower alkyl N-mono- or N,N-disubstituted by lower alkyl, phenyl, lower alkylene or oxa-lower alkylene, cycloalkyl, lower alkoxycarbonyl, phenyl, methoxyphenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, pyridinyl, pyrimidinyl, or pyrazinyl;
- R4 represents hydrogen or lower alkyl;
- and a N-oxide or a pharmaceutically acceptable salt of such a compound.
- In a preferred group of compounds of formula I,
- R1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, or benzyl;
- R2 represents lower alkyl, optionally substituted by one radical R3, by two phenyl groups, by two lower alkoycarbonyl groups, by phenyl and lower alkoxycarbonyl, or by hydroxyphenyl and lower alkoxycarbonyl; cyclopentyl; benzcyclopentyl; cylcohexyl; pyrrolidinyl; piperidinyl; N-lower alkylpiperidinyl; N-benzylpiperidinyl; N-pyrimidinylpiperidinyl; morpholinyl; azepinyl; oxoazepinyl; phenyl; naphthalinyl; tetrahydronaphthalinyl; pyridyl; lower alkyl-pyridyl; quinolinyl; thienyl; lower alkoxycarbonylmethylthienyl; or phenyl substituted by one or two substituents selected from the group consisting of lower alkyl, trifluoro-lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, N-cyclohexyl-N-lower alkylamino-lower alkyl, lower alkoxycarbonylpiperidino-lower alkyl, N-lower alkylpiperazino-lower alkyl, lower alkoxycarbonyl-lower alkyl, hydroxy, lower alkoxy, trifluoro-lower alkoxy, 1H-imidazolyl-lower alkoxy, lower alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, amino, lower alkanoylamino, benzoylamino, amino mono- or disubstituted by lower alkyl, by hydroxy-lower alkyl or by loweralkoxy-lower alkyl, 1H-imidazolyl, lower alkyl-1H-imidazolyl, pyrrolidino, piperidino, piperazino, N-lower alkylpiperazino, morpholino, sulfamoyl, lower alkylsulfonyl, phenyl, pyridyl, halogenyl, or benzoyl;
- and R3 represents hydroxy, lower alkoxy, lower alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, amino, lower alkylamino, di-lower alkylamino, phenylamino, N-lower alkyl-N-phenylamino, pyrrolidino, oxopyrrolidino, piperidino, morpholino, imidazolino, oxoimidazolino, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, phenyl, naphthalinyl, tetrahydronaphthalinyl, furyl, a mono- or bicyclic heteroaryl group comprising one or two nitrogen atoms, which heteroaryl group is unsubstituted or mono- or disubstituted by lower alkyl, hydroxy and lower alkoxy, or phenyl substituted by one or two substituents selected from the group consisting of lower alkyl, trifluoro-lower alkyl, lower alkoxycarbonyl-lower alkyl, hydroxy, lower alkoxy, trifluoro-lower alkoxy, lower alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, amino, lower alkanoylamino, benzoylamino, amino mono- or disubstituted by lower alkyl, by hydroxy-lower alkyl or by loweralkoxy-lower alkyl, pyrrolidino, piperidino, morpholino, piperazino, N-lower alkylpiperazino, N-lower alkoxycarbonylpiperazino, phenyl, pyridyl, 1H-imidazolyl, lower alkyl-1H-imidazolyl, sulfamoyl, lower alkylsulfonyl, halogenyl, or benzoyl;
- or wherein R1 and R2 together represent alkylene with four or five carbon atoms, optionally mono- or disubstituted by phenyl, hydroxy, amino, benzoylamino, or piperidino; benzalkylene with four or five carbon atoms in the alkylene group; oxaalkylene with one oxygen and four carbon atoms; or azaalkylene with one nitrogen and four carbon atoms wherein nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, pyrrolidinocarbonyl-lower alkyl, morpholinocarbonyl-lower alkyl, cyclopentyl, lower alkoxycarbonyl, phenyl, methoxyphenyl, trifluoromethylphenyl, pyridinyl; pyrimidinyl, or pyrazinyl;
- R4 represents hydrogen or methyl;
- and a N-oxide or a pharmaceutically acceptable salt of such a compound.
- A specially preferred group of compounds comprises compounds of formula I wherein
- R1 represents hydrogen, and
- R2 represents phenyl substituted by trifluoromethyl, especially 3-trifluoromethylphenyl, and optionally a further substituent selected from the group consisting of hydroxy-lower alkyl, e.g. 1-hydroxy-1-methylethyl, lower alkylamino, e.g. methyl- or ethylamino, hydroxy-lower alkylamino, e.g. 2-hydroxy-1-propylamino or 2-hydroxy-2-propylamino, di-lower alkylamino, e.g. diethylamino, 1H-imidazolyl, lower alkyl-1H-imidazolyl, e.g. 2- or 4-methyl-1H-imidazolyl, carbamoyl, lower alkylcarbamoyl, e.g. methylcarbamoyl, pyrrolidino, piperidino, piperazino, lower alkylpiperazino, e.g. 4-methylpiperazino, morpholino, lower alkoxy, e.g. methoxy, fluoro-lower alkoxy, e.g. trifluoromethoxy or 2,2,2-trifluoroethoxy, phenyl, pyridyl, e.g. 2-, 3- or 4-pyridyl, and halogenyl, e.g. chloro or fluoro;
- R4 represents methyl;
- and a N-oxide or a pharmaceutically acceptable salt of such a compound.
- One preferred embodiment of the invention relates to compounds of formula I wherein
- R1 is hydrogen,
- R2 represents phenyl which is mono- or disubstituted by imidazol-lower alkoxy, lower alkyl amino, trifluoromethyl, hydroxy lower alkyl amino, bis-(lower alkoxy lower alkyl)amino, lower alkyl piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, phenyl, pyridyl, imidazolyl which is unsubstituted or mono- or disubstituted by lower alkyl or N-lower alkyl carbamoyl;
- R4 is lower alkyl;
- and to the N-oxides and pharmaceutically acceptable salts of such compounds.
- Particularly preferred are the compounds of the Examples.
- Other compounds which are particularly preferred are:
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzanilide,
- 4-Methyl-N-(3-pyridinyl)-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,
- N-(4-Chlorophenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,
- 2(R)- and 2(S)-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoylamino]propanoic acid,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(8-quinolinyl)benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-[trifluoromethoxy]phenyl)benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(2-pyrrolidinoethyl)benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-pyrrolidinophenyl)benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(1-[2-pyrimidinyl]-4-piperidinyl)benzamide,
- N-(4-Di-[2-methoxyethyl]amino-3-trifluoromethylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,
- N-(4-[1H-imidazolyl]-3-trifluoromethylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(2-pyrrolidino-5-trifluoromethylphenyl)benzamide,
- N-(3,4-difluorophenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-trifluoromethylbenzyl)benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-trifluoromethylphenyl)benzamide,
- N-(3-Chloro-5-trifluoromethylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,
- N-(4-Dimethylaminobutyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,
- 4-Methyl-N-[4-(4-methyl-1-piperazinyl)-3-trifluoromethylphenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(2,2,2-trifluoroethoxy)-3-trifluoromethylphenyl]benzamide,
- 4-Methyl-N-[4-(2-methyl-1H-imidazolyl)-3-trifluoromethylphenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,
- 4-Methyl-N-(4-phenyl-3-trifluoromethylphenyl)-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,
- 4-Methyl-N-[4-(4-methyl-1H-imidazolyl)-3-trifluoromethylphenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,
- Methyl 2(R)- and 2(S)-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoylamio]-3-[4-hydroxyphenyl]propanoate,
- N-[2-(N-Cyclohexyl-N-methylaminomethyl)phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,
- N-[3-[2-(1H-Imidazolyl)ethoxy]phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,
- 4-Methyl-N-[3-morpholino-5-trifluoromethylphenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(4-pyrrolidino-3-trifluoromethylphenyl)benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(4-piperidino-3-trifluoromethylphenyl)benzamide,
- 4-Methyl-N-[4-morpholino-3-trifluoromethylphenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,
- N-(4-Ethylamino-3-trifluoromethylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-trifluoromethoxyphenyl)benzamide,
- N-[4-(2-Hydroxypropylamino)-3-trifluoromethylphenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,
- N-(4-Diethylamino-3-trifluoromethylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-(3-pyridinyl)-5-trifluorophenyl]benzamide,
- N-[3-[3-(1H-Imidazolyl)propoxy]phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(3-pyridinyl)-3-trifluorophenyl]benzamide,
- 4-Methyl-N-[3-(4-methyl-1-piperazinyl)-5-trifluorophenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,
- 4-Methyl-N-[3-methylcarbamoyl-5-trifluorophenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,
- 4-Methyl-N-[3-methylcarbamoyl-5-morpholino]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide.
- Further compounds which are particularly preferred are:
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[3-(1H-imidazol-1-yl)propoxy]-phenyl]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[2-(1H-imidazol-1-yl)ethoxy]phenyl]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(ethylamino)-3-(trifluoromethyl)phenyl]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(diethylamino)-3-(trifluoromethyl)phenyl]benzamide,
- (±)-4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-[(2-hydroxypropyl)amino]-3-(trifluoromethyl)phenyl]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-[bis(2-methoxyethyl)amino]-3-(trifluoromethyl)phenyl]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(4-methyl-1-piperazinyl)-3-(trifluoromethyl)phenyl]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(1-piperidinyl)-3-(trifluoromethyl)phenyl]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(1-pyrrolidinyl)-3-(trifluoromethyl)phenyl]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(4-morpholinyl)-3-(trifluoromethyl)phenyl]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-phenyl-3-(trifluoromethyl)phenyl]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[4-(3-pyridinyl)-3-(trifluoromethyl)phenyl]methyl]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(2,4-dimethyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(2-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-(4-morpholinyl)-5-[(methylamino)carbonyl]phenyl]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[(methylamino)carbonyl]-5-(trifluoromethyl)phenyl]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(3-pyridinyl)-3-(trifluoromethyl)phenyl]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-morpholinyl)-3-(trifluoromethyl)phenyl]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(2-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(5-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-(4-methyl-1-piperazinyl)-5-(trifluoromethyl)phenyl]benzamide, and
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl]benzamide.
- The invention relates also to 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid and to 3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid; intermediates for the formation of the preferred amides of the invention.
- Especially, the invention relates to the use of a compound of formula I or of a N-oxide or a possible tautomer thereof or of a pharmaceutically acceptable salt of such a compound for the preparation of a pharmaceutical composition for the treatment of a disease which responds to an inhibition of protein kinase activity, wherein the disease is a neoplastic disease.
- More particularly, the invention relates to the use of a compound of the formula I or of a N-oxide or a possible tautomer thereof; or of a pharmaceutically acceptable salt of such a compound for the preparation of a pharmaceutical composition for the treatment of leukaemia which responds to an inhibition of the Abl tyrosine kinase activity.
- Furthermore, the invention provides a method for the treatment of a disease which responds to an inhibition of protein kinase activity, which comprises administering a compound of formula I or a N-oxide or a pharmaceutically acceptable salt thereof, wherein the radicals and symbols have the meanings as defined above, in a quantity effective against said disease, to a warm-blooded animal requiring such treatment.
- A compound of the invention may be prepared by processes that, though not applied hitherto for the new compounds of the present invention, are known per se, especially a process characterized in that for the synthesis of a compound of the formula I wherein the symbols R1, R2 and R4 are as defined for a compound of the formula I, a 4-R4-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid of formula II
- wherein R4 is as defined for a compound of formula I, or a derivative thereof wherein the carboxy group —COOH is in activated form, is reacted with an amine of the formula III
-
R1—NH—R2 (III) - wherein R1 and R2 are as defined for a compound of the formula I, optionally in the presence of a dehydrating agent and an inert base and/or a suitable catalyst, and optionally in the presence of an inert solvent;
- where the above starting compounds II and III may also be present with functional groups in protected form if necessary and/or in the form of salts, provided a salt-forming group is present and the reaction in salt form is possible;
- any protecting groups in a protected derivative of a compound of the formula I are removed;
- and, if so desired, an obtainable compound of formula I is converted into another compound of formula I or a N-oxide thereof, a free compound of formula I is converted into a salt, an obtainable salt of a compound of formula I is converted into the free compound or another salt, and/or a mixture of isomeric compounds of formula I is separated into the individual isomers.
- A derivative of the compound of formula II wherein the carboxy group is in activated form is especially a reactive ester, a reactive anhydride or a reactive cyclic amide.
- Reactive esters of the acid of formula II are especially esters unsaturated at the linking carbon atom of the esterifying radical, for example esters of the vinyl ester type, such as actual vinyl esters (obtainable, for example, by transesterification of a corresponding ester with vinyl acetate; activated vinyl ester method), carbamoylvinyl esters (obtainable, for example, by treatment of the corresponding acid with an isoxazolium reagent; 1,2-oxazolium or Woodward method), or 1-lower alkoxyvinyl esters (obtainable, for example, by treatment of the corresponding acid with a lower alkoxyacetylene; ethoxyacetylene method), or esters of the amidino type, such as N,N′-disubstituted amidino esters (obtainable, for example, by treatment of the corresponding acid with a suitable N,N′-disubstituted carbodiimide, for example N,N′-dicyclohexylcarbodiimide; carbodiimide method), or N,N-disubstituted amidino esters (obtainable, for example, by treatment of the corresponding acid with an N,N-disubstituted cyanamide; cyanamide method), suitable aryl esters, especially phenyl esters suitably substituted by electron-attracting substituents (obtainable, for example, by treatment of the corresponding acid with a suitably substituted phenol, for example 4-nitrophenol, 4-methylsulfonyl-phenol, 2,4,5-trichlorophenol, 2,3,4,5,6-pentachloro-phenol or 4-phenyldiazophenol, in the presence of a condensation agent, such as N,N′-dicyclohexylcarbodiimide; activated aryl esters method), cyanomethyl esters (obtainable, for example, by treatment of the corresponding acid with chloroacetonitrile in the presence of a base; cyanomethyl esters method), thio esters, especially unsubstituted or substituted, for example nitro-substituted, phenylthio esters (obtainable, for example, by treatment of the corresponding acid with unsubstituted or substituted, for example nitro-substituted, thiophenols, inter alia by the anhydride or carbodiimide method; activated thiol esters method), amino or amido esters (obtainable, for example, by treatment of the corresponding acid with an N-hydroxy-amino or N-hydroxy-amido compound, for example N-hydroxy-succinimide, N-hydroxy-piperidine, N-hydroxy-phthalimide or 1-hydroxy-benzotriazole, for example by the anhydride or carbodiimide method; activated N-hydroxy esters method), or silyl esters (which are obtainable, for example, by treatment of the corresponding acid with a silylating agent, for example hexamethyl disilazane, and react readily with hydroxy groups but not with amino groups).
- Anhydrides of the acid of formula II may be symmetric or preferably mixed anhydrides of that acid, for example anhydrides with inorganic acids, such as acid halides, especially acid chlorides (obtainable, for example, by treatment of the corresponding acid with thionyl chloride, phosphorus pentachloride or oxalyl chloride; acid chloride method), azides (obtainable, for example, from a corresponding acid ester via the corresponding hydrazide and treatment thereof with nitrous acid; azide method), anhydrides with carbonic acid semiderivatives, such as corresponding esters, for example carbonic acid lower alkyl semiesters (obtainable, for example, by treatment of the corresponding acid with haloformic, such as chloroformic, acid lower alkyl esters or with a 1-lower alkoxycarbonyl-2-lower alkoxy-1,2-dihydroquinoline, for example 1-lower alkoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; mixed O-alkylcarbonic acid anhydrides method), or anhydrides with dihalogenated, especially dichlorinated, phosphoric acid (obtainable, for example, by treatment of the corresponding acid with phosphorus oxychloride; phosphorus oxychloride method), or anhydrides with organic acids, such as mixed anhydrides with organic carboxylic acids (obtainable, for example, by treatment of the corresponding acid with an unsubstituted or substituted lower alkane- or phenylalkane-carboxylic acid halide, for example phenylacetic acid chloride, pivalic acid chloride or trifluoroacetic acid chloride; mixed carboxylic acid anhydrides method), with organic sulfonic acids (obtainable, for example, by treatment of a salt, such as an alkali metal salt, of the corresponding acid, with a suitable organic sulfonic acid halide, such as lower alkane- or aryl-, for example methane- or p-toluene-sulfonic acid chloride; mixed sulfonic acid anhydrides method), or with organic phosphonic acids (obtainable, for example, by treatment of the corresponding acid with a suitable organic phosphonic anhydride or phosphonic cyanide; mixed phosphonic acid anhydrides methhod), and symmetric anhydrides (obtainable, for example, by condensation of the corresponding acid in the presence of a carbodiimide or of 1-diethylaminopropyne; symmetric anhydrides method).
- Suitable cyclic amides are especially amides with five-membered diazacycles of aromatic character, such as amides with imidazoles, for example imidazole (obtainable, for example, by treatment of the corresponding acid with N,N′-carbonyldiimidazole; imidazolide method), or pyrazoles, for example 3,5-dimethyl-pyrazole (obtainable, for example, by way of the acid hydrazide by treatment with acetylacetone; pyrazolide method).
- Derivatives of the acid of formula II wherein the carboxy group is in activated form are preferably formed in situ. For example, N,N′-disubstituted amidino esters can be formed in situ by reacting a mixture of the acid of formula II and the amine of formula III in the presence of a suitable N,N-disubstituted carbodiimide, for example N,N′-dicyclohexylcarbodiimide. Reactive mixed anhydrides of the acid of formula II with an organic phosphonic acid may be formed in situ by reaction with e.g. propylphosphonic anhydride or diethylcyanophosphonate in the presence of suitable base, preferably a tertiary amine, e.g. triethylamine or dimethylaminopyridine.
- The reaction can be carried out in a manner known per se, the reaction conditions being dependent especially on whether, and if so how, the carboxy group of the carboxylic acid of formula II has been activated, usually in the presence of a suitable solvent or diluent or of a mixture thereof and, if necessary, in the presence of a condensation agent, which, for example when the carboxy group participating in the reaction is in the form of an anhydride, may also be an acid-binding agent, with cooling or heating, for example in a temperature range from approximately −30° C. to approximately +150° C., especially approximately from 0° C. to +100° C., preferably from room temperature (approx. +20° C.) to +70° C., in an open or closed reaction vessel and/or in the atmosphere of an inert gas, for example nitrogen. Customary condensation agents are, for example, carbodiimides, for example N,N′-diethyl-, N,N′-dipropyl-, N,N′-dicyclohexyl- or N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole, or 1,2-oxazolium compounds, for example 2-ethyl-5-phenyl-1,2-oxazolium 3′-sulfonate and 2-tert-butyl-5-methyl-isoxazolium perchlorate, or a suitable acylamino compound, for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. Customary acid-binding condensation agents are, for example, alkali metal carbonates or hydrogen carbonates, for example sodium or potassium carbonate or hydrogen carbonate (customarily together with a sulfate), or organic bases, such as, customarily, pyridine or triethylamine, or sterically hindered tri-lower alkylamines, for example N,N-diisopropyl-N-ethyl-amine.
- In a preferred variant, the carboxylic acid of formula II is reacted with an amine of formula III in a suitable solvent, such as e.g. N,N-dimethylformamide, in the presence of propyl-phosphonic anhydride or diethylcyanophosphanate and triethylamine, between 1 and 48 hours at between 0° C. and around 50° C., preferably at room temperature.
- If one or more other functional groups, for example carboxy, hydroxy, amino, or mercapto, are or need to be protected in a compound of formula III, because they should not take part in the reaction, these are such groups as are usually used in the synthesis of amides, in particular peptide compounds, and also of cephalosporins and penicillins, as well as nucleic acid derivatives and sugars.
- The protecting groups may already be present in precursors and should protect the functional groups concerned against unwanted secondary reactions, such as acylations, etherifications, esterifications, oxidations, solvolysis, and similar reactions. It is a characteristic of protecting groups that they lend themselves readily, i.e. without undesired secondary reactions, to removal, typically by solvolysis, reduction, photolysis or also by enzyme activity, for example under conditions analogous to physiological conditions, and that they are not present in the end-products. The specialist knows, or can easily establish, which protecting groups are suitable with the reactions mentioned hereinabove and hereinafter.
- The protection of such functional groups by such protecting groups, the protecting groups themselves, and their removal reactions are described for example in standard reference books for peptide synthesis as cited hereinbefore, and in special books on protective groups such as J. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973, in “Methoden der organischen Chemie” (Methods of organic chemistry), Houben-Weyl, 4th edition, Volume 15/I, Georg Thieme Verlag, Stuttgart 1974, and in T. W. Greene, “Protective Groups in Organic Synthesis”, Wiley, New York.
- In the additional process steps, carried out as desired, functional groups of the starting compounds which should not take part in the reaction may be present in unprotected form or may be protected for example by one or more of the protecting groups mentioned hereinabove under “protecting groups”. The protecting groups are then wholly or partly removed according to one of the methods described there.
- Salts of a compound of formula I with a salt-forming group may be prepared in a manner known per se. Acid addition salts of compounds of formula I may thus be obtained by treatment with an acid or with a suitable anion exchange reagent.
- Salts can usually be converted to free compounds, e.g. by treating with suitable basic agents, for example with alkali metal carbonates, alkali metal hydrogencarbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.
- Stereoisomeric mixtures, e.g. mixtures of diastereomers, can be separated into their corresponding isomers in a manner known per se by means of suitable separation methods. Diastereomeric mixtures for example may be separated into their individual diastereomers by means of fractionated crystallization, chromatography, solvent distribution, and similar procedures. This separation may take place either at the level of a starting compound or in a compound of formula I itself. Enantiomers may be separated through the formation of diastereomeric salts, for example by salt formation with an enantiomer-pure chiral acid, or by means of chromatography, for example by HPLC, using chromatographic substrates with chiral ligands.
- A compound of the formula I wherein R1 is hydrogen can be converted to the respective compound wherein R1 is lower alkyl by reaction e.g. with a diazo lower alkyl compound, especially diazomethane, in an inert solvent, preferably in the presence of a noble metal catalyst, especially in dispersed form, e.g. copper, or a noble metal salt, e.g. copper(I)-chloride or copper(II)-sulfate. Also reaction with lower alkylhalogenides is possible, or with other leaving group carrying lower alkanes, e.g. lower alkyl alcohols esterified by a strong organic sulfonic acid, such as a lower alkanesulfonic acid (optionally substituted by halogen, such as fluoro), an aromatic sulfonic acid, for example unsubstituted or substituted benzenesulfonic acid, the substituents preferably being selected from lower alkyl, such as methyl, halogen, such as bromo, and/or nitro, e.g. esterified by methanesulfonic acid, or p-toluene sulfonic acid. The alkylation takes place under usual conditions for alkylation of amides, especially in aqueous solution and/or in the presence of polar solvents, typically alcohols, for example methanol, ethanol, isopropanol, or ethylene glycol, or dipolar aprotic solvents, e.g. tetrahydrofuran, dioxane, or dimethylformamide, where applicable in the presence of acidic or basic catalysts, generally at temperatures from about 0° C. to the boiling temperature of the corresponding reaction mixture, preferably between 20° C. and reflux temperature, if necessary under increased pressure, e.g. in a sealed tube, and/or under inert gas, typically nitrogen or argon.
- It should be emphasized that reactions analogous to the conversions mentioned in this chapter may also take place at the level of appropriate intermediates.
- All process steps described here can be carried out under known reaction conditions, preferably under those specifically mentioned, in the absence of or usually in the presence of solvents or diluents, preferably such as are inert to the reagents used and able to dissolve these, in the absence or presence of catalysts, condensing agents or neutralizing agents, for example ion exchangers, typically cation exchangers, for example in the H+ form, depending on the type of reaction and/or reactants at reduced, normal, or elevated temperature, for example in the range from −100° C. to about 190° C., preferably from about −80° C. to about 150° C., for example at −80 to −60° C., at room temperature, at −20 to 40° C. or at the boiling point of the solvent used, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under argon or nitrogen.
- Salts may be present in all starting compounds and transients, if these contain salt-forming groups. Salts may also be present during the reaction of such compounds, provided the reaction is not thereby disturbed.
- At all reaction stages, isomeric mixtures that occur can be separated into their individual isomers, e.g. diastereomers or enantiomers, or into any mixtures of isomers, e.g. racemates or diastereomeric mixtures.
- The invention relates also to those forms of the process in which one starts from a compound obtainable at any stage as a transient and carries out the missing steps, or breaks off the process at any stage, or forms a starting material under the reaction conditions, or uses said starting material in the form of a reactive derivative or salt, or produces a compound obtainable by means of the process according to the invention and processes the said compound in situ. In the preferred embodiment, one starts from those starting materials which lead to the compounds described hereinabove as preferred, particularly as especially preferred, primarily preferred, and/or preferred above all.
- In the preferred embodiment, a compound of formula I is prepared according to or in analogy to the processes and process steps defined in the Examples.
- The compounds of formula I, including their salts, are also obtainable in the form of hydrates, or their crystals can include for example the solvent used for crystallization (present as solvates).
- The present invention relates furthermore to a method for the treatment of a neoplastic disease which responds to an inhibition of a protein kinase activity, which comprises administering a compound of formula I or a N-oxide or a pharmaceutically acceptable salt thereof, wherein the radicals and symbols have the meanings as defined above for formula I, in a quantity effective against said disease, to a warm-blooded animal requiring such treatment.
- In particular the invention relates to a method for the treatment of leukaemia which responds to an inhibition of the Abl tyrosine kinase activity, which comprises administering a compound of formula I or a N-oxide or a pharmaceutically acceptable salt thereof, wherein the radicals and symbols have the meanings as defined above for formula I, in a quantity effective against said leukaemia, to a warm-blooded animal requiring such treatment.
- The present invention relates also to pharmaceutical compositions that comprise a compound of formula I or a N-oxide thereof as active ingredient and that can be used especially in the treatment of the diseases mentioned at the beginning. Compositions for enteral administration, such as nasal, buccal, rectal or, especially, oral administration, and for parenteral administration, such as intravenous, intramuscular or subcutaneous administration, to warm-blooded animals, especially humans, are especially preferred. The compositions comprise the active ingredient alone or, preferably, together with a pharmaceutically acceptable carrier. The dosage of the active ingredient depends upon the disease to be treated and upon the species, its age, weight, and individual condition, the individual pharmacokinetic data, and the mode of administration.
- The present invention relates especially to pharmaceutical compositions that comprise a compound of formula I, a tautomer, a N-oxide or a pharmaceutically acceptable salt, or a hydrate or solvate thereof, and at least one pharmaceutically acceptable carrier.
- The invention relates also to pharmaceutical compositions for use in a method for the prophylactic or especially therapeutic management of the human or animal body, to a process for the preparation thereof (especially in the form of compositions for the treatment of tumors) and to a method of treating tumor diseases, especially those mentioned hereinabove.
- The invention relates also to processes and to the use of compounds of formula I or N-oxides thereof for the preparation of pharmaceutical preparations which comprise compounds of formula I or N-oxides thereof as active component (active ingredient).
- In the preferred embodiment, a pharmaceutical preparation is suitable for administration to a warm-blooded animal, especially humans or commercially useful mammals suffering from a disease responsive to an inhibition of the Abl tyrosine kinase, for example chronic myelogenous leukaemia (CML), and comprises an effective quantity of a compound of formula I or N-oxides thereof for the inhibition of the Bcr-Abl fusion protein, or a pharmaceutically acceptable salt thereof, if salt-forming groups are present, together with at least one pharmaceutically acceptable carrier.
- A pharmaceutical composition for the prophylactic or especially therapeutic management of neoplastic and other proliferative diseases of a warm-blooded animal, especially a human or a commercially useful mammal requiring such treatment, especially suffering from such a disease, comprising as active ingredient in a quantity that is prophylactically or especially therapeutically active against the said diseases a novel compound of formula I or N-oxides thereof, is likewise preferred.
- The pharmaceutical compositions comprise from approximately 1% to approximately 95% active ingredient, single-dose administration forms comprising in the preferred embodiment from approximately 20% to approximately 90% active ingredient and forms that are not of single-dose type comprising in the preferred embodiment from approximately 5% to approximately 20% active ingredient. Unit dose forms are, for example, coated and uncoated tablets, ampoules, vials, suppositories, or capsules. Further dosage forms are, for example, ointments, creams, pastes, foams, tinctures, sprays, etc. Examples are capsules containing from about 0.05 g to about 1.0 g active ingredient.
- The pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes.
- Preference is given to the use of solutions of the active ingredient, and also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions which, for example in the case of lyophilized compositions comprising the active ingredient alone or together with a carrier can be made up before use. The pharmaceutical compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers and are prepared in a manner known per se, for example by means of conventional dissolving and lyophilizing processes. The said solutions or suspensions may comprise viscosity-increasing agents or solubilizers.
- Suspensions in oil comprise as the oil component the vegetable, synthetic, or semi-synthetic oils customary for injection purposes. In respect of such, special mention may be made of liquid fatty acid esters that contain as the acid component a long-chained fatty acid having from 8 to 22 carbon atoms. The alcohol component of these fatty acid esters has a maximum of 6 carbon atoms and is a monovalent or polyvalent, for example a mono-, di- or trivalent, alcohol, especially glycol and glycerol.
- Pharmaceutical compositions for oral administration can be obtained, for example, by combining the active ingredient with one or more solid carriers, if desired granulating a resulting mixture, and processing the mixture or granules, if desired or necessary, by the inclusion of additional excipients, to form tablets or tablet cores.
- Suitable carriers are especially fillers, such as sugars, cellulose preparations, and/or calcium phosphates, and also binders, such as starches, and/or polyvinylpyrrolidone, and/or, if desired, disintegrators. Additional excipients are especially flow conditioners and lubricants.
- Tablet cores can be provided with suitable, optionally enteric, coatings through the use of, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations.
- Pharmaceutical compositions for oral administration also include hard capsules consisting of gelatin, and also soft, sealed capsules consisting of gelatin and a plasticizer. The hard capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, binders, and/or glidants, and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquid excipients, to which stabilizers and detergents may also be added.
- Pharmaceutical compositions suitable for rectal administration are, for example, suppositories that consist of a combination of the active ingredient and a suppository base.
- For parenteral administration, aqueous solutions of an active ingredient in water-soluble form, for example of a water-soluble salt, or aqueous injection suspensions that contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilizers, are especially suitable. The active ingredient, optionally together with excipients, can also be in the form of a lyophilizate and can be made into a solution before parenteral administration by the addition of suitable solvents.
- Solutions such as are used, for example, for parenteral administration can also be employed as infusion solutions.
- Preferred preservatives are, for example, antioxidants, such as ascorbic acid, or microbicides, such as sorbic acid or benzoic acid.
- The invention relates likewise to a process or a method for the treatment of one of the pathological conditions mentioned hereinabove, especially a disease which responds to an inhibition of a tyrosine kinase, especially a corresponding neoplastic disease. The compounds of formula I or N-oxides thereof can be administered as such or especially in the form of pharmaceutical compositions, prophylactically or therapeutically, preferably in an amount effective against the said diseases, to a warm-blooded animal, for example a human, requiring such treatment. In the case of an individual having a bodyweight of about 70 kg the daily dose administered is from approximately 0.05 g to approximately 5 g, preferably from approximately 0.25 g to approximately 1.5 g, of a compound of the present invention.
- The present invention relates especially also to the use of a compound of formula I or N-oxides thereof, or a pharmaceutically acceptable salt thereof, especially a compound of formula I which is said to be preferred, or a pharmaceutically acceptable salt thereof, as such or in the form of a pharmaceutical formulation with at least one pharmaceutically acceptable carrier for the therapeutic and also prophylactic management of one or more of the diseases mentioned hereinabove, preferably a disease which responds to an inhibition of a protein kinase, especially a neoplastic disease, more especially leukaemia which responds to an inhibition of the Abl tyrosine kinase.
- The preferred dose quantity, composition, and preparation of pharmaceutical formulations (medicines) which are to be used in each case are described above.
- New starting materials and/or intermediates, as well as processes for the preparation thereof, are likewise the subject of this invention. In the preferred embodiment, such starting materials are used and reaction conditions so selected as to enable the preferred compounds to be obtained.
- The substituted aminobenzoic acid of formula II, for example, can be obtained by reaction of an ester of 3-amino-4-R4-benzoic acid, e.g. 3-amino-4-methylbenzoic acid, with cyanamide and condensing the obtainable guanidine with 3-(dimethylamino)-1-(3-pyridinyl)-2-propen-1-one, and finally hydrolyzing the ester function.
- Starting materials of the formula III are known, commercially available, or can be synthesized in analogy to or according to methods that are known in the art.
- The following Examples serve to illustrate the invention without limiting the invention in its scope.
- DMSO dimethylsulfoxide
HPLC/MS-MS high-pressure liquid chromatography/tandem mass spectrometry
min minutes
m.p. melting point - NMR nuclear magnetic resonance
PEG polyethylen glycol
THF tetrahydrofuran - A solution containing ˜50% of propylphosphonic anhydride in N,N-dimethylformamide (Fluka, Buchs, Switzerland; 674 μL, ˜1 mmol) is added within 20 minutes to a stirred mixture of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid (214.4 mg, 0.7 mmol), furfurylamine (Aldrich, Buchs, Switzerland; 61.8 μL, 0.7 mmol) and triethylamine (776 μL, 5.6 mmol) in 2 mL N,N-dimethylformamide. After stirring for 24 hours at room temperature, the mixture is treated with a half-saturated aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The solvent is evaporated off under reduced pressure and the residue dried in vacuo. The crude product is crystallised from dichloromethane to give the title compound as a crystalline solid.
- 1H-NMR (400 MHz, DMSO-d6, δ): 2.28 (s, 3H); 4.43 (d, 2H); 6.23 (m, 1H); 6.33-6.37 (m, 1H); 7.30 (d, 1H); 7.42 (d, 1H); 7.49 (ddd, 1H); 7.53 (m, 1H); 7.59 (dd, 1H); 8.11 (d, 1H); 8.38 (m, 1H); 8.49 (d, 1H); 8.66 (dd, 1H); 8.87 (t, 1H); 9.05 (s, 1H); 9.22 (m, 1H).
- The starting material is prepared as follows:
- Cyanamide (Fluka, Buchs, Switzerland; 77.4 g, 1.842 mol) is added to a solution of 3-amino-4-methylbenzoic acid ethyl ester (J. Med. Chem. 16, 118-122, 1973; 150 g, 0.837 mol) in 850 mL of ethanol. Hydrochloric acid (Fluka, Buchs, Switzerland; 108 mL of 12M, 1.27 mol) is then added dropwise over 15 min and the reaction mixture is then stirred at 90° C. (bath temperature) for 15 hours. The solvent is evaporated off under reduced pressure to give a residue which is treated with water (1000 mL) and stirred with cooling at 5-10° C. A solution of ammonium nitrate (Merck, Darmstadt, Germany; 134.8 g, 1.68 mol) in water (400 mL) is added dropwise over 30 min. followed by ice-water (1200 mL). After stirring for an additional 30 min. the product is filtered off, washed with ice-water (3×1000 mL) and air-dried. The residue is washed with diethyl ether (2×2000 m L) and dried in vacuo at 50° to give the title compound as a crystalline solid, m.p. 195-197° C.
- A stirred mixture of the intermediate Example 1a (164 g, 0.577 mol), 3-(dimethylamino)-1-(3-pyridinyl)-2-propen-1-one (113.8 g, 0.646 mol) and powdered NaOH (99%; Merck, Darmstadt, Germany; 26.6 g, 0.658 mol) in ethanol (2200 mL) is heated under reflux for 68 h. The reaction solvent is evaporated off under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer is separated and the aqueous phase extracted twice with ethyl acetate. The combined organic extracts are washed with water and brine, dried (Na2SO4) and the solvent is evaporated off under reduced pressure to give a residue, which is crystallised from diethyl ether to give the title compound as a crystalline solid, m.p. 95-96° C.
- Aqueous sodium hydroxide (500 mL of 2M) is added dropwise to a stirred suspension of the intermediate Example 1b (132.8 g, 0.397 mol) in ethanol (1200 m L) and water (1200 mL). The reaction mixture is stirred at 45° C. for 2.5 h and then treated dropwise with aqueous HCl (1000 mL of 1M) over 1.5 hours. After addition of water (1000 mL) the precipitate is filtered off, washed with water (4×500 mL) and dried at room temperature. Residual water present in the air-dried product is removed by azeotropic distillation with toluene under reduced pressure. The dried toluene suspension is diluted with diethyl ether and filtered. The solid residue is washed with diethyl ether and dried in vacuo at 80° C. to give the title compound, m.p. 277-278° C.
- A solution containing ˜50% of propylphosphonic anhydride in N,N-dimethylformamide (Fluka, Buchs, Switzerland; 875 μL, ˜1.5 mmol) is added within 20 minutes to a stirred mixture of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid (306 mg, 1.0 mmol), 4-[(4-methyl-1-piperazinyl)methyl]benzeneamine (Chem. Abstr. Reg. Number: 70261-82-4; 205 mg, 1.0 mmol) and triethylamine (830 μL, 6.0 mmol) in 8 mL N,N-dimethylformamide. After stirring for 24 hours at room temperature, the mixture is treated with a saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The solvent is evaporated off under reduced pressure and the residue dried in vacuo. The crude product is crystallised from ethanol-ethyl acetate to give the title compound as a crystalline solid, m.p. 153-155° C.
- A solution containing ˜50% of propylphosphonic anhydride in N,N-dimethylformamide (Fluka, Buchs, Switzerland; 674 μL, ˜1 mmol) is added within 20 minutes to a stirred mixture of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid (214.4 mg, 0.7 mmol), 1-(2-pyridyl)piperazine (Aldrich, Buchs, Switzerland; 114.3 mg, 0.7 mmol) and triethylamine (776 μL, 5.6 mmol) in 2 mL N,N-dimethylformamide. After stirring for 24 hours at room temperature, the mixture is treated with a half-saturated aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The solvent is evaporated off under reduced pressure and the residue dried in vacuo. The crude product is purified by column chromatography on silica gel, eluent 5-10% methanol in dichloromethane, to give the title compound as a solid. 1H-NMR (400 MHz, DMSO-d6,δ): 2.31 (s, 3H); 3.35-3.74 (m, 8H); 6.65 (ddd, 1H); 6.79 (d, 1H); 7.13 (dd, 1H); 7.32 (d, 1H); 7.44 (d, 1H); 7.49-7.56 (m, 2H); 7.69 (m, 1H); 8.11 (m, 1H); 8.40 (m, 1H); 8.52 (d, 1H); 8.66 (dd, 1H); 9.06 (s, 1H); 9.24 (m, 1H).
- The following compounds are prepared analogously by utilising the appropriate amine (supplier in parenthesis):
- 4-Methyl-N-[2-(2-pyridinyl)ethyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide utilising 2-(2-aminoethyl)pyridine (Fluka, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, 5): 2.27 (s, 3H); 2.97 (t, 2H); 3.58 (m, 2H); 7.18 (ddd, 1H); 7.25 (m, 1H); 7.29 (d, 1H); 7.42 (d, 1H); 7.47-7.56 (m, 2H); 7.65 (m, 1H); 8.06 (d, 1H); 8.39 (m, 1H); 8.44-8.51 (m, 3H); 8.66 (dd, 1H); 9.04 (s, 1H); 9.22 (m, 1H).
- 4-Methyl-N-[1-(phenylmethyl)-4-piperidinyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]benzamide utilising 4-amino-1-benzylpiperidine (Aldrich, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 1.47-1.63 (m, 2H); 1.69-1.80 (m, 2H); 1.92-2.05 (m, 2H); 2.27 (s, 3H); 2.73-2.83 (m, 2H); 3.43 (s, 2H); 3.68-3.83 (m, 1H); 7.18-7.33 (m, 6H); 7.42 (d, 1H); 7.49 (ddd, 1H); 7.55 (dd, 1H); 8.10 (m, 1H); 8.14 (d, 1H); 8.37 (m, 1H); 8.49 (d, 1H); 8.65 (dd, 1H); 9.04 (s, 1H); 9.21 (m, 1H).
- 4-Methyl-N-(4-pyridinylmethyl)-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide utilising 4-(aminomethyl)pyridine (Aldrich, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 2.30 (s, 3H); 4.46 (d, 2H); 7.26 (m, 2H); 7.33 (d, 1H); 7.43 (d, 1H); 7.47 (ddd, 1H); 7.62 (dd, 1H); 8.16 (d, 1H); 8.38 (m, 1H); 8.45 (m, 2H); 8.50 (d, 1H); 8.66 (dd, 1H); 9.03 (t, 1H); 9.08 (s, 1H); 9.23 (m, 1H).
- 4-Methyl-N-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]benzamide utilising 2-(2-aminoethyl)-1-methylpyrrol [Chem. Abstr. Reg. Number: 83732-75-6]. 1H-NMR (400 MHz, DMSO-d6, δ): 2.28 (s, 3H); 2.75 (t, 2H); 3.42 (m, 2H); 3.51 (s, 3H); 5.76-5.85 (m, 2H); 6.57 (m, 1H); 7.30 (d, 1H); 7.43 (d, 1H); 7.46-7.58 (m, 2H); 8.10 (br. 1H); 8.40 (m, 1H); 8.48-8.55 (m, 2H); 8.64-8.69 (m, 1H); 9.05 (s, 1H); 9.23 (m, 1H).
- N-[(4-Methoxyphenyl)methyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide utilising 4-methoxybenzylamine (Fluka, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 2.28 (s, 3H); 3.69 (s, 3H); 4.37 (d, 2H); 6.80-6.87 (m, 2H); 7.17-7.23 (m, 2H); 7.31 (d, 1H); 7.42 (d, 1H); 7.47 (ddd, 1H); 7.59 (dd, 1H); 8.11 (d, 1H); 8.38 (m, 1H); 8.49 (d, 1H); 8.66 (dd, 1H); 8.87 (t, 1H); 9.05 (s, 1H); 9.23 (m, 1H).
- 4-Methyl-N-(2-methylpropyl)-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide utilising isobutylamine (Fluka, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 0.85 (d, 6H); 1.81 (m, 1H); 2.27 (s, 3H); 3.04 (m, 2H); 7.29 (d, 1H); 7.42 (d, 1H); 7.48 (dd, 1H); 7.55 (dd, 1H); 8.07 (d, 1H); 8.31-8.41 (m, 2H); 8.49 (d, 1H); 8.65 (dd, 1H); 9.05 (s, 1H); 9.22 (m, 1H).
- 4-Methyl-N-(2-morpholinoethyl)-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide utilising 4-(2-aminoethyl)morpholine (Fluka, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 2.28 (s, 3H); 2.33-2.46 (m, 6H); 3.30-3.40 (m, 2H); 3.53 (m, 4H); 7.30 (d, 1H); 7.42 (d, 1H); 7.46-7.57 (m, 2H); 8.06 (d, 1H); 8.30 (m, 1H); 8.38 (m, 1H); 8.49 (d, 1H); 8.66 (dd, 1H); 9.05 (s, 1H); 9.22 (m, 1H).
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[(tetrahydro-2-furanyl)-methyl]benzamide utilising tetrahydrofurfurylamine (Fluka, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 1.49-1.63 (m, 1H); 1.70-1.93 (m, 3H); 2.27 (s, 3H); 3.27 (m, 2H); 3.58 (m, 1H); 3.72 (m, 1H); 3.94 (m, 1H); 7.29 (d, 1H); 7.42 (d, 1H); 7.49 (ddd, 1H); 7.56 (dd, 1H); 8.08 (d, 1H); 8.35-8.45 (m, 2H); 8.49 (d, 1H); 8.66 (dd, 1H); 9.04 (s, 1H); 9.21 (m, 1H).
- N-[2-(2,4-Dihydroxy-5-pyrimidinyl)ethyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide utilising 5-(2-aminoethyl)-2,4(1H,3H)-pyrimidinedione [Chem. Abstr. Reg. Number: 221170-25-8]. 1H-NMR (400 MHz, DMSO-d6, δ): 2.27 (s, 3H); 2.40 (t, 2H); 3.34 (m, 2H); 7.15 (m, 1H); 7.29 (d, 1H); 7.42 (d, 1H); 7.47-7.55 (m, 2H); 8.07 (d, 1H); 8.35-8.42 (m, 2H); 8.49 (d, 1H); 8.66 (dd, 1H); 9.04 (s, 1H); 9.22 (m, 1H); 10.59 (s, 1H); 11.01 (s, 1H).
- N-Cyclohexyl-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide utilising cyclohexylamine (Fluka, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 1.00-1.16 (m, 1H); 1.18-1.36 (m, 4H); 1.52-1.85 (m, 5H); 2.27 (s, 3H); 3.66-3.82 (m, 1H); 7.28 (d, 1H); 7.41 (d, 1H); 7.48 (m, 1H); 7.55 (dd, 1H); 8.06-8.12 (m, 2H); 8.37 (m, 1H); 8.49 (d, 1H); 8.66 (dd, 1H); 9.04 (s, 1H); 9.21 (m, 1H).
- N-[(3S)-Hexahydro-2-oxo-1H-azepin-3-yl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide utilising L(−)-alpha-amino-epsilon-caprolactam [Chem. Abstr. Reg. Number: 21568-87-6]. 1H-NMR (400 MHz, DMSO-d6, δ): 1.11-1.31 (m, 1H); 1.37-1.82 (m, 3H); 1.83-1.96 (m, 2H); 2.28 (s, 3H); 3.00-3.13 (m, 1H); 3.15-3.30 (m, 1H); 4.58 (m, 1H); 7.32 (d, 1H); 7.43 (d, 1H); 7.51 (ddd, 1H); 7.55 (dd, 1H); 7.84 (m, 1H); 8.08 (d, 1H); 8.13 (d, 1H); 8.40 (m, 1H); 8.50 (d, 1H); 8.66 (dd, 1H); 9.06 (s, 1H); 9.22 (m, 1H).
- N-[2-(3,4-Dimethoxyphenyl)ethyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]benzamide utilising 2-(3,4-dimethoxyphenyl)ethylamine (Fluka, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 2.27 (s, 3H); 2.75 (t, 2H); 3.43 (m, 2H); 3.67 (s, 6H); 6.70 (dd, 1H); 6.77-6.83 (m, 2H); 7.30 (d, 1H); 7.42 (d, 1H); 7.46-7.57 (m, 2H); 8.07 (d, 1H); 8.36-8.46 (m, 2H); 8.49 (d, 1H); 8.66 (dd, 1H); 9.05 (s, 1H); 9.22 (m, 1H).
- 2-[[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]amino]-4-thiazole-acetic acid ethyl ester utilising ethyl 2-amino-4-thiazoleacetate (Aldrich, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 1.16 (t, 3H); 2.32 (s, 3H); 3.70 (s, 2H); 4.06 (q, 2H); 7.01 (s, 1H); 7.36 (d, 1H); 7.42-7.54 (m, 2H); 7.82 (d, 1H); 8.34-8.47 (m, 2H); 8.52 (d, 1H); 8.66 (m, 1H); 9.08 (s, 1H); 9.24 (m, 1H); 12.57 (br., 1H).
- N-[3-(1H-Imidazol-1-yl)propyl]-4-methyl-3-[[4-(3-pyridinyl)-2pyrimidinyl]amino]-benzamide utilising 1-(3-aminopropyl)imidazole (Aldrich, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 1.96 (qui, 2H); 2.30 (s, 3H); 3.24 (m, 2H); 4.01 (t, 2H); 6.91 (s, 1H); 7.22 (m, 1H); 7.34 (d, 1H); 7.45 (d, 1H); 7.51 (ddd, 1H); 7.59 (dd, 1H); 7.70 (s, 1H); 8.14 (d, 1H); 8.42 (m, 1H); 8.47 (t, 1H); 8.52 (d, 1H); 8.68 (dd, 1H); 9.10 (s, 1H); 9.25 (m, 1H).
- N-(Cyclopropylmethyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide utilising cyclopropanemethylamine (Fluke, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 0.17-0.22 (m, 2H); 0.36-0.42 (m, 2H); 0.96-1.06 (m, 1H); 2.28 (s, 3H); 3.11 (m, 2H); 7.31 (d, 1H); 7.43 (d, 1H); 7.50 (ddd, 1H); 7.58 (dd, 1H); 8.10 (d, 1H); 8.40 (m, 1H); 8.47 (t, 1H); 8.50 (d, 1H); 8.67 (dd, 1H); 9.07 (s, 1H); 9.23 (m, 1H).
- N-(2-methoxyethyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide utilising 2-methoxyethylamine (Fluke, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 2.28 (s, 3H); 3.23 (s, 3H); 3.36-3.46 (m, 4H); 7.31 (d, 1H); 7.43 (d, 1H); 7.51 (ddd, 1H); 7.57 (dd, 1H); 8.10 (d, 1H); 8.38-8.47 (m, 2H); 8.50 (d, 1H); 8.68 (dd, 1H); 9.07 (s, 1H); 9.23 (m, 1H).
- 4-Methyl-N-[3-(2-oxo-1-pyrrolidinyl)propyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]benzamide utilising 1-(3-aminopropyl)-2-pyrrolidinone (Aldrich, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 1.67 (m, 2H); 1.89 (m, 2H); 2.18 (t, 2H); 2.28 (s, 3H); 3.19 (m, 4H); 3.32 (m, 2H); 7.30 (d, 1H); 7.42 (d, 1H); 7.49 (ddd, 1H); 7.54 (dd, 1H); 8.09 (d, 1H); 8.31-8.42 (m, 2H); 8.49 (d, 1H); 8.66 (dd, 1H); 9.04 (s, 1H); 9.22 (m, 1H).
- N,4-Dimethyl-N-(phenylmethyl)-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide utilising N-benzylmethylamine (Fluke, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 2.28 (s, 3H); 2.86 (s, 3H); 4.51-4.68 (m, 2H); 7.08-7.35 (m, 7H); 7.43 (d, 1H); 7.48 (m, 1H); 7.71 (s, 1H); 8.35-8.54 (m, 2H); 8.67 (m, 1H); 8.97-9.09 (m, 1H); 9.24 (m, 1H).
- N-[4-(Acetylamino)phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide utilising 4-aminoacetanilide (Fluka, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 2.01 (s, 3H); 2.32 (s, 3H); 7.38 (d, 1H); 7.45 (d, 1H); 7.47-7.54 (m, 3H); 7.63-7.71 (m, 3H); 8.22 (m, 1H); 8.43 (m, 1H); 8.52 (d, 1H); 8.67 (dd, 1H); 9.13 (s, 1H); 9.25 (m, 1H); 9.90 (s, 1H); 10.11 (s, 1H).
- N-(4-Methoxy-2-methylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide utilising 4-methoxy-2-methylaniline (Aldrich, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 2.16 (s, 3H); 2.32 (s, 3H); 3.73 (s, 3H); 6.75 (dd, 1H); 6.82 (m, 1H); 7.16 (d, 1H); 7.37 (d, 1H); 7.45 (d, 1H); 7.49 (ddd, 1H); 7.69 (dd, 1H); 8.25 (d, 1H); 8.41 (m, 1H); 8.52 (d, 1H); 8.67 (dd, 1H); 9.12 (s, 1H); 9.25 (m, 1H); 9.69 (s, 1H).
- 4-Methyl-N-[4-(methylsulfonyl)benzyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide utilising 4-methylsulfonylbenzylamine hydrochloride (Acros, Morris Plains, N.J.). 1H-NMR (400 MHz, DMSO-d6, δ): 2.30 (s, 3H); 3.16 (s, 3H); 4.54 (d, 2H); 7.34 (d, 1H); 7.44 (d, 1H); 7.49 (ddd, 1H); 7.55 (m, 2H); 7.63 (dd, 1H); 7.86 (m, 2H); 8.16 (d, 1H); 8.40 (m, 1H); 8.51 (d, 1H); 8.67 (dd, 1H); 9.10 (m, 2H); 9.24 (m, 1H).
- N-[[4-(Dimethylamino)phenyl]methyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]benzamide utilising 4-(dimethylamino)benzylamine dihydrochloride (Aldrich, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 2.28 (s, 3H); 2.82 (s, 6H); 4.32 (d, 2H); 6.64 (m, 2H); 7.11 (m, 2H); 7.31 (d, 1H); 7.43 (d, 1H); 7.48 (ddd, 1H); 7.59 (dd, 1H); 8.12 (d, 1H); 8.39 (m, 1H); 8.50 (d, 1H); 8.68 (dd, 1H); 8.81 (t, 1H); 9.07 (s, 1H); 9.24 (m, 1H).
- N-(2-Amino-2-oxoethyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide utilising glycinamide hydrochloride (Fluka, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 2.29 (s, 3H); 3.78 (d, 2H); 7.02 (s, 1H); 7.30-7.36 (m, 2H); 7.44 (d, 1H); 7.53 (ddd, 1H); 7.61 (dd, 1H); 8.11 (m, 1H); 8.41 (m, 1H); 8.50 (d, 1H); 8.57 (t, 1H); 8.67 (dd, 1H); 9.08 (s, 1H); 9.24 (m, 1H).
- N-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]glycine methyl ester utilising glycine methylester hydrochloride (Fluka, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 2.29 (s, 3H); 3.63 (s, 3H); 3.98 (d, 2H); 7.34 (d, 1H); 7.44 (d, 1H); 7.52 (ddd, 1H); 7.59 (dd, 1H); 8.11 (d, 1H); 8.41 (m, 1H); 8.50 (d, 1H); 8.67 (dd, 1H); 8.87 (t, 1H); 9.09 (s, 1H); 9.23 (m, 1H).
- N-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]beta-alanine methyl ester utilising beta-alanine methylester hydrochloride (Fluka, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 2.27 (s, 3H); 2.57 (t, 2H); 3.46 (m, 2H); 3.57 (s, 3H); 7.31 (d, 1H); 7.43 (d, 1H); 7.50-7.55 (m, 2H); 8.07 (d, 1H); 8.40 (m, 1H); 8.47 (t, 1H); 8.50 (d, 1H); 8.67 (dd, 1H); 9.07 (s, 1H); 9.23 (m, 1H).
- N-[[4-(Aminosulfonyl)phenyl]methyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]benzamide utilising p-(aminomethyl)benzenesulfonamide hydrochloride (Sigma, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 2.29 (s, 3H); 4.51 (d, 2H); 7.30 (s, 2H); 7.34 (d, 1H); 7.43-7.50 (m, 4H); 7.62 (dd, 1H); 7.75 (m, 2H); 8.16 (d, 1H); 8.40 (m, 1H); 8.51 (d, 1H); 8.68 (dd, 1H); 9.06 (t, 1H); 9.09 (s, 1H); 9.24 (m, 1H).
- N-(3-Hydroxypropyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide utilising 3-amino-1-propanol (Aldrich, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 1.65 (qui, 2H); 2.28 (s, 3H); 3.29 (m, 2H); 3.42 (m, 2H); 4.50 (m, 1H); 7.30 (d, 1H); 7.43 (d, 1H); 7.51 (ddd, 1H); 7.56 (dd, 1H); 8.09 (d, 1H); 8.36-8.43 (m, 2H); 8.50 (d, 1H); 8.67 (dd, 1H); 9.07 (s, 1H); 9.23 (m, 1H).
- N,N-Diethyl-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide utilising diethylamine (Fluka, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 1.04 (m, 6H); 2.28 (s, 3H); 3.31 (m, 4H); 7.02 (dd, 1H); 7.27 (d, 1H); 7.44 (d, 1H); 7.51 (ddd, 1H); 7.61 (m, 1H); 8.39 (m, 1H); 8.51 (d, 1H); 8.68 (dd, 1H); 9.01 (s, 1H); 9.23 (m, 1H).
- N-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-(L)-phenylalanine 1,1-dimethylethyl ester utilising L-phenylalanine t-butylester hydrochloride (Novabiochem (Juro), Lucerne, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 1.32 (s, 9H); 2.28 (s, 3H); 3.07 (m, 2H); 4.53 (m, 1H); 7.13-7.29 (m, 5H); 7.32 (d, 1H); 7.44 (d, 1H); 7.50 (ddd, 1H); 7.55 (dd, 1H); 8.05 (m, 1H); 8.39 (m, 1H); 8.49 (d, 1H); 8.63 (d, 1H); 8.67 (dd, 1H); 9.08 (s, 1H); 9.23 (m, 1H). 1H); 7.59 (dd, 1H); 8.11 (d, 1H); 8.41 (m, 1H); 8.50 (d, 1H); 8.67 (dd, 1H); 8.87 (t, 1H); 9.09 (s, 1H); 9.23 (m, 1H).
- N-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]beta-alanine methyl ester utilising beta-alanine methylester hydrochloride (Fluka, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 2.27 (s, 3H); 2.57 (t, 2H); 3.46 (m, 2H); 3.57 (s, 3H); 7.31 (d, 1H); 7.43 (d, 1H); 7.50-7.55 (m, 2H); 8.07 (d, 1H); 8.40 (m, 1H); 8.47 (t, 1H); 8.50 (d, 1H); 8.67 (dd, 1H); 9.07 (s, 1H); 9.23 (m, 1H).
- N-[[4-(Aminosulfonyl)phenyl]methyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]benzamide utilising p-(aminomethyl)benzenesulfonamide hydrochloride (Sigma, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 2.29 (s, 3H); 4.51 (d, 2H); 7.30 (s, 2H); 7.34 (d, 1H); 7.43-7.50 (m, 4H); 7.62 (dd, 1H); 7.75 (m, 2H); 8.16 (d, 1H); 8.40 (m, 1H); 8.51 (d, 1H); 8.68 (dd, 1H); 9.06 (t, 1H); 9.09 (s, 1H); 9.24 (m, 1H).
- N-(3-Hydroxypropyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide utilising 3-amino-1-propanol (Aldrich, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 1.65 (qui, 2H); 2.28 (s, 3H); 3.29 (m, 2H); 3.42 (m, 2H); 4.50 (m, 1H); 7.30 (d, 1H); 7.43 (d, 1H); 7.51 (ddd, 1H); 7.56 (dd, 1H); 8.09 (d, 1H); 8.36-8.43 (m, 2H); 8.50 (d, 1H); 8.67 (dd, 1H); 9.07 (s, 1H); 9.23 (m, 1H).
- N,N-Diethyl-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide utilising diethylamine (Fluka, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 1.04 (m, 6H); 2.28 (s, 3H); 3.31 (m, 4H); 7.02 (dd, 1H); 7.27 (d, 1H); 7.44 (d, 1H); 7.51 (ddd, 1H); 7.61 (m, 1H); 8.39 (m, 1H); 8.51 (d, 1H); 8.68 (dd, 1H); 9.01 (s, 1H); 9.23 (m, 1H).
- N-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-(L)-phenylalanine 1,1-dimethylethyl ester utilising L-phenylalanine t-butylester hydrochloride (Novabiochem (Juro), Lucerne, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 1.32 (s, 9H); 2.28 (s, 3H); 3.07 (m, 2H); 4.53 (m, 1H); 7.13-7.29 (m, 5H); 7.32 (d, 1H); 7.44 (d, 1H); 7.50 (ddd, 1H); 7.55 (dd, 1H); 8.05 (m, 1H); 8.39 (m, 1H); 8.49 (d, 1H); 8.63 (d, 1H); 8.67 (dd, 1H); 9.08 (s, 1H); 9.23 (m, 1H).
- N-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-(D)-alanine 1,1-dimethylethyl ester utilising D-alanine t-butylester hydrochloride (Novabiochem (Juro), Lucerne, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 1.34 (d, 3H); 1.38 (s, 9H); 2.28 (s, 3H); 4.32 (m, 1H); 7.33 (d, 1H); 7.43 (d, 1H); 7.51 (ddd, 1H); 7.61 (dd, 1H); 8.14 (m, 1H); 8.40 (m, 1H); 8.50 (m, 1H); 8.58 (d, 1H); 8.67 (dd, 1H); 9.08 (s, 1H); 9.23 (m, 1H).
- N-[1-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-4-piperidinyl]-benzamide utilising N-4-piperidinyl-benzamide (Maybridge Chemical Co. Ltd). 1H-NMR (400 MHz, DMSO-d6, δ): 1.49 (m, 2H); 1.68-1.94 (m, 2H); 2.30 (s, 3H); 2.92 (m, 1H); 3.16 (m, 1H); 3.79 (m, 1H); 4.05 (m, 1H); 4.42 (m, 1H); 7.08 (dd, 1H); 7.31 (d, 1H); 7.41-7.54 (m, 5H); 7.63 (m, 1H); 7.79-7.84 (m, 2H); 8.28 (d, 1H); 8.40 (m, 1H); 8.51 (d, 1H); 8.66 (dd, 1H); 9.06 (s, 1H); 9.24 (m, 1H).
- 4-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-morpholine utilising morpholine (Fluka, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 2.29 (s, 3H); 3.47 (m, 8H); 7.10 (dd, 1H); 7.30 (d, 1H); 7.44 (m, 1H); 7.52 (ddd, 1H); 7.65 (m, 1H); 8.40 (m, 1H); 8.51 (d, 1H); 8.69 (dd, 1H); 9.05 (s, 1H); 9.23 (m, 1H).
- 1-(4-Methoxyphenyl)-4-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoyl]piperazine utilising 1-(4-methoxyphenyl)-piperazine (Emka Chemie, Neufahrn, Germany). 1H-NMR (400 MHz, DMSO-d6, δ): 2.30 (s, 3H); 2.87-3.08 (m, 4H); 3.50-3.75 (m, 4H); 3.67 (s, 3H); 6.78-6.88 (m, 4H); 7.12 (dd, 1H); 7.31 (d, 1H); 7.44 (m, 1H); 7.51 (ddd, 1H); 7.67 (m, 1H); 8.38 (m, 1H); 8.52 (m, 1H); 8.67 (dd, 1H); 9.06 (s, 1H); 9.23 (m, 1H).
- 1-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-4-(4-pyridinyl)-piperazine utilising 1-(4-pyridyl)-piperazine (Emka Chemie, Neufahrn, Germany). 1H-NMR (400 MHz, DMSO-d6, δ): 2.31 (s, 3H); 3.30 (m, 4H); 3.59 (m, 4H); 6.77 (m, 2H); 7.14 (dd, 1H); 7.32 (d, 1H); 7.45 (d, 1H); 7.52 (ddd, 1H); 7.70 (m, 1H); 8.16 (m, 2H); 8.41 (m, 1H); 8.53 (d, 1H); 8.67 (dd, 1H); 9.07 (s, 1H); 9.24 (m, 1H).
- 1-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-4-(pyrazinyl)-piperazine utilising 1-(2-pyrazinyl)-piperazine (Emka Chemie, Neufahrn, Germany). 1H-NMR (400 MHz, DMSO-d6, δ): 2.31 (s, 3H); 3.57 (m, 8H); 7.14 (dd, 1H); 7.32 (d, 1H); 7.45 (d, 1H); 7.51 (ddd, 1H); 7.72 (m, 1H); 7.85 (d, 1H); 8.08 (d, 1H); 8.29 (d, 1H); 8.40 (m, 1H); 8.53 (d, 1H); 8.65 (dd, 1H); 9.06 (s, 1H); 9.24 (m, 1H).
- 1-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-4-(phenylmethyl)-piperazine utilising 1-benzyl-piperazine (Aldrich, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 2.21-2.42 (m, 4H); 2.28 (s, 3H); 3.34-3.63 (m, 6H); 7.07 (dd, 1H); 7.21-7.34 (m, 6H); 7.43-7.50 (m, 2H); 7.63 (m, 1H); 8.38 (m, 1H); 8.50 (d, 1H); 8.65 (dd, 1H); 9.03 (s, 1H); 9.22 (m, 1H).
- 1-Cyclopentyl-4-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl-piperazine utilising 1-cyclopentyl-piperazine (Emka Chemie, Neufahrn, Germany). 1H-NMR (400 MHz, DMSO-d6, δ): 1.20-1.31 (m, 2H); 1.39-1.62 (m, 4H); 1.65-1.75 (m, 2H); 2.18-2.47 (m, 8H); 3.27-3.62 (m, 4H); 7.08 (dd, 1H); 7.29 (d, 1H); 7.44 (d, 1H); 7.51 (ddd, 1H); 7.62 (m, 1H); 8.38 (m, 1H); 8.51 (d, 1H); 8.68 (dd, 1H); 9.04 (s, 1H); 9.22 (m, 1H).
- 4-{{4-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-1-piperazinyl}-acetyl}morpholine utilising 4-[2-(piperazin-1-yl)-acetyl]-morpholine (Emka Chemie, Neufahrn, Germany). 1H-NMR (400 MHz, DMSO-d6, δ): 2.29 (s, 3H); 2.31-2.49 (m, 4H); 3.16 (s, 2H); 3.37-3.60 (m, 12H); 7.07 (dd, 1H); 7.29 (d, 1H); 7.45 (d, 1H); 7.52 (ddd, 1H); 7.65 (m, 1H); 8.39 (m, 1H); 8.51 (d, 1H); 8.68 (dd, 1H); 9.04 (s, 1H); 9.23 (m, 1H).
- 1-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-4-[2-oxo-2-(1-pyrrolidinyl)ethyl]piperazine utilising 1-[2-(piperazin-1-yl)-acetyl-pyrrolidine (Emka Chemie, Neufahrn, Germany). 1H-NMR (400 MHz, DMSO-d6, δ): 1.73 (m, 2H); 1.83 (m, 2H); 2.29 (s, 3H); 2.43 (m, 4H); 3.09 (s, 2H); 3.25 (m, 2H); 3.34-3.63 (m, 6H); 7.07 (dd, 1H); 7.29 (d, 1H); 7.45 (d, 1H); 7.52 (ddd, 1H); 7.64 (m, 1H); 8.39 (m, 1H); 8.51 (d, 1H); 8.68 (dd, 1H); 9.04 (s, 1H); 9.22 (m, 1H).
- 4-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-1-piperazine-carboxylic acid ethyl ester utilising ethyl 1-piperazinecarboxylate (Aldrich, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 1.16 (t, 3H); 2.29 (s, 3H); 3.19-3.63 (m, 8H); 4.02 (q, 2H); 7.10 (dd, 1H); 7.30 (d, 1H); 7.45 (d, 1H); 7.52 (ddd, 1H); 7.66 (m, 1H); 8.40 (m, 1H); 8.51 (d, 1H); 8.68 (dd, 1H); 9.06 (s, 1H); 9.23 (m, 1H).
- 2-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-1,2,3,4-tetrahydro-isoquinoline utilising 1,2,3,4-tetrahydroisoquinoline (Fluka, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 2.31 (s, 3H); 2.79 (m, 2H); 3.57-3.90 (m, 2H); 4.58-4.79 (m, 2H); 7.08-7.23 (m, 5H); 7.32 (d, 1H); 7.42-7.50 (m, 2H); 7.70 (m, 1H); 8.39 (m, 1H); 8.51 (d, 1H); 8.67 (dd, 1H); 9.05 (s, 1H); 9.24 (m, 1H).
- N,N-bis(2-Methoxyethyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide utilising bis(2-methoxyethyl)amine (Aldrich, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 2.28 (s, 3H); 3.09 (br.s, 3H); 3.23 (br.s, 3H); 3.47 (m, 8H); 7.04 (dd, 1H); 7.27 (d, 1H); 7.44 (d, 1H); 7.51 (ddd, 1H); 7.62 (m, 1H); 8.39 (m, 1H); 8.51 (d, 1H); 8.68 (dd, 1H); 9.01 (s, 1H); 9.23 (m, 1H).
- 1′-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-1,4′-bipiperidine utilising 4-piperidinopiperidine (Aldrich, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 1.21-1.50 (m, 8H); 1.51-1.83 (m, 2H); 2.29 (s, 3H); 2.39 (m, 4H); 2.68 (m, 1H); 2.95 (m, 1H); 3.71 (m, 1H); 4.42 (m, 1H); 7.07 (dd, 1H); 7.28 (d, 1H); 7.45 (d, 1H); 7.52 (ddd, 1H); 7.63 (m, 1H); 8.40 (m, 1H); 8.51 (d, 1H); 8.67 (dd, 1H); 9.03 (s, 1H); 9.23 (m, 1H).
- N-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-N-(phenylmethyl)-glycine ethyl ester utilising N-benzylglycine ethyl ester (Fluka, Buchs, Switzerland). 1H-NMR (300 MHz, DMSO-d6, δ): 0.97-1.20 (m, 3H); 2.27 (s, 3H); 3.90-4.12 (m, 4H); 4.58-4.68 (m, 2H); 7.07 (m, 1H); 7.15-7.34 (m, 6H); 7.38-7.53 (m, 2H); 7.65-7.74 (m, 1H); 8.35-8.51 (m, 2H); 8.66 (dd, 1H); 8.96-9.04 (m, 1H); 9.22 (m, 1H).
- N-(3-Chlorophenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide utilising 3-chlor-aniline (Fluka, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 2.33 (s, 3H); 7.14 (m, 1H); 7.36 (m, 1H); 7.41 (d, 1H); 7.46 (d, 1H); 7.49 (ddd, 1H); 7.68-7.73 (m, 2H); 7.95 (m, 1H); 8.25 (m, 1H); 8.43 (m, 1H); 8.53 (d, 1H); 8.66 (dd, 1H); 9.15 (s, 1H); 9.26 (m, 1H); 10.33 (s, 1H).
- N-(2,2-Diphenylethyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide utilising 2,2-diphenylethylamine (Aldrich, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 2.24 (s, 3H); 3.87 (m, 2H); 4.41 (m, 1H); 7.12-7.17 (m, 2H); 7.23-7.31 (m, 9H); 7.41-7.44 (m, 2H); 7.51 (ddd, 1H); 7.97 (m, 1H); 8.37-8.44 (m, 2H); 8.48 (d, 1H); 8.68 (dd, 1H); 9.05 (s, 1H); 9.23 (m, 1H).
- N-(2,3-Dihydro-1H-inden-1-yl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide utilising 1-Aminoindane (Fluka, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 1.90-2.01 (m, 1H); 2.29 (s, 3H); 2.43 (m, 1H); 2.77-2.86 (m, 1H); 2.91-2.98 (m, 1H); 5.56 (m, 1H); 7.08-7.25 (m, 4H); 7.31 (d, 1H); 7.43 (d, 1H); 7.50 (ddd, 1H); 7.64 (dd, 1H); 8.20 (m, 1H); 8.40 (m, 1H); 8.50 (d, 1H); 8.68-8.72 (m, 2H); 9.08 (s, 1H); 9.24 (m, 1H).
- N-(Diphenylmethyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide utilising alpha-aminodiphenylmethane (Fluka, Buchs, Switzerland)1H-NMR (400 MHz, DMSO-d6, δ): 2.29 (s, 3H); 6.41 (d, 1H); 7.20-7.36 (m, 11 H); 7.43 (d, 1H); 7.46 (ddd, 1H); 7.67 (dd, 1H); 8.18 (m, 1H); 8.38 (m, 1H); 8.50 (d, 1H); 8.68 (dd, 1H); 9.10 (s, 1H); 9.20 (d, 1H); 9.24 (m, 1H).
- 4-Methyl-N-[2-(1-piperidinyl)ethyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide utilising 1-(2-aminoethyl)piperidine (Aldrich, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 1.30-1.38 (m, 2H); 1.41-1.48 (m, 4H); 2.28 (s, 3H); 2.31-2.41 (m, 6H); 3.33 (m, 2H); 7.31 (d, 1H); 7.44 (d, 1H); 7.51 (ddd, 1H); 7.55 (dd, 1H); 8.08 (m, 1H); 8.28 (t, 1H); 8.40 (m, 1H); 8.51 (d, 1H); 8.67 (dd, 1H); 9.07 (s, 1H); 9.24 (m, 1H).
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(5,6,7,8-tetrahydro-1-naphthalenyl)benzamide utilising 5,6,7,8-tetrahydro-1-naphthylamine (Aldrich, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 1.63-1.71 (m, 4H); 2.32 (s, 3H); 2.60 (m, 2H); 2.74 (m, 2H); 6.96 dd, 1H); 7.07-7.14 (m, 2H); 7.37 (d, 1H); 7.45 (d, 1H); 7.49 (ddd, 1H); 7.69 (dd, 1H); 8.25 (m, 1H); 8.41 (m, 1H); 8.52 (d, 1H); 8.67 (dd, 1H); 9.12 (s, 1H); 9.25 (m, 1H); 9.65 (br.s).
- 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[[4-(trifluoromethyl)phenyl]-methyl]benzamide utilising 4-(trifluoromethyl)benzylamine (Aldrich, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 2.30 (s, 3H); 4.53 (d, 2H); 7.34 (d, 1H); 7.44 (d, 1H); 7.46-7.53 (m, 3H); 7.62 (dd, 1H); 7.66 (m, 2H); 8.16 (m, 1H); 8.40 (m, 1H); 8.51 (d, 1H); 8.67 (dd, 1H); 9.08 (t, 1H); 9.10 (s, 1H); 9.24 (m, 1H).
- 4-Methyl-N-[(5-methylpyrazinyl)methyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide utilising 2-(aminomethyl)-5-methylpyrazine (TCI-JP, Distrib. Zurich, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 2.29 (s, 3H); 2.45 (s, 3H); 4.54 (d, 2H); 7.33 (d, 1H); 7.44 (d, 1H); 7.49 (ddd, 1H); 7.62 (dd, 1H); 8.14 (m, 1H); 8.40 (m, 1H); 8.45 (m, 2H); 8.50 (d, 1H); 8.66 (dd, 1H); 9.07 (t, 1H); 9.09 (s, 1H); 9.23 (m, 1H).
- N-(2-Ethoxyethyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide utilising 2-ethoxyethylamine (TCI-JP, Distrib. Zurich, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ) 1.07 (t, 3H); 2.28 (s, 3H); 3.30-3.49 (m, 6H); 7.31 (d, 1H); 7.43 (d, 1H); 7.51 (ddd, 1H); 7.57 (dd, 1H); 8.09 (m, 1H); 8.38-8.45 (m, 2H); 8.50 (d, 1H); 8.67 (dd, 1H); 9.07 (s, 1H); 9.24 (m, 1H).
- 4-Methyl-N-[2-(2-oxo-1-imidazolidinyl)ethyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]benzamide utilising 1-(2-aminoethyl)imidazolidin-2-one [Chem. Abstr. Reg. Number: 6281-42-1]. 1H-NMR (400 MHz, DMSO-d6, δ): 2.27 (s, 3H); 3.13-3.22 (m, 4H); 3.30-3.40 (m, 4H); 6.27 (br.s, 1H); 7.30 (d, 1H); 7.43 (d, 1H); 7.49-7.56 (m, 2H); 8.08 (d, 1H); 8.40 (m, 1H); 8.45 (t, 1H); 8.50 (d, 1H); 8.67 (dd, 1H); 9.06 (s, 1H); 9.23 (m, 1H).
- 4-Methyl-N-(5-methyl-2-pyridinyl)-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide utilising 2-amino-5-picoline (Aldrich, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 2.26 (s, 3H); 2.32 (s, 3H); 7.35 (d, 1H); 7.45 (d, 1H); 7.49 (ddd, 1H); 7.64 (dd, 1H); 7.77 (dd, 1H); 8.07 (d, 1H); 8.18 (m, 1H); 8.31 (d, 1H); 8.43 (m, 1H); 8.52 (d, 1H); 8.66 (dd, 1H); 9.08 (s, 1H); 9.25 (m, 1H); 10.58 (s, 1H).
- 1-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-4-phenyl-4-piperidinol utilising 4-hydroxy-4-phenylpiperidine (Aldrich, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 1.45-1.73 (m, 2H); 1.88 (m, 2H); 2.28 (s, 3H); 3.15 (m, 1H); 3.47 (m, 1H); 3.64 (m, 1H); 4.39 (m, 1H); 5.14 (s, 1H); 7.14 (dd, 1H); 7.19 (m, 1H); 7.26-7.31 (m, 3H); 7.43 (d, 1H); 7.45-7.51 (m, 3H); 7.69 (d, 1H); 8.40 (m, 1H); 8.48 (d, 1H); 8.67 (dd, 1H); 9.03 (s, 1H); 9.24 (m, 1H).
- N-(3-Benzoylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide utilising 3-aminobenzophenone (Aldrich, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 2.32 (s, 3H); 7.39 (d, 1H); 7.43-7.58 (m, 6H); 7.67 (m, 1H); 7.70-7.77 (m, 3H); 8.13 (m, 1H); 8.20 (m, 1H); 8.27 (m, 1H); 8.42 (m, 1H); 8.52 (d, 1H); 8.66 (dd, 1H); 9.14 (s, 1H); 9.25 (m, 1H); 10.41 (s, 1H).
- N-[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]-glycine 1,1-dimethylethyl ester utilising glycine t-butyl ester hydrochloride (Aldrich, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 1.40 (s, 9H); 2.29 (s, 3H); 3.86 (d, 2H); 7.33 (d, 1H); 7.43 (d, 1H); 7.51 (ddd, 1H); 7.58 (dd, 1H); 8.10 (d, 1H); 8.40 (m, 1H); 8.50 (d, 1H); 8.67 (dd, 1H); 8.75 (t, 1H); 9.08 (s, 1H); 9.23 (m, 1H).
- 4-[[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]amino]benzene-acetic acid ethyl ester utilising ethyl 4-aminophenylacetate (Maybridge Chemical Co. Ltd.). 1H-NMR (400 MHz, DMSO-d6, δ): 1.16 (t, 3H); 2.32 (s, 3H); 3.60 (s, 2H); 4.06 (q, 2H); 7.21 (m, 2H); 7.38 (d, 1H); 7.45 (d, 1H); 7.48 (ddd, 1H); 7.70 (m, 3H); 8.23 (m, 1H); 8.41 (m, 1H); 8.52 (d, 1H); 8.66 (dd, 1H); 9.13 (s, 1H); 9.25 (m, 1H); 10.16 (s, 1H).
- 4-Methyl-N-[3-(methylphenylamino)propyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]benzamide utilising N-(3-aminopropyl)-N-methylaniline (TCI-JP, Distrib. Zurich, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 1.73 (qui, 2H); 2.28 (s, 3H); 2.84 (s, 3H); 3.24-3.37 (m, 4H); 6.55 (m, 1H); 6.65 (m, 2H); 7.10 (m, 2H); 7.31 (d, 1H); 7.43 (d, 1H); 7.47 (ddd, 1H); 7.55 (dd, 1H); 8.10 (d, 1H); 8.37-8.44 (m, 2H); 8.50 (d, 1H); 8.65 (dd, 1H); 9.06 (s, 1H); 9.23 (m, 1H).
- 1-[[3-[[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]amino]phenyl]-methyl]-4-piperidinecarboxylic acid ethyl ester utilising ethyl 1-(3-aminobenzyl)piperidine-4-carboxylate (Maybridge Chemical Co. Ltd.). 1H-NMR (400 MHz, DMSO-d6, δ): 1.14 (t, 3H); 1.49-1.61 (m, 2H); 1.72-1.80 (m, 2H); 1.92-2.02 (m, 2H); 2.27 (m, 1H); 2.32 (s, 3H); 2.74 (m, 2H); 3.40 (s, 2H); 4.03 (q, 2H); 6.98 (d, 1H); 7.25 (m, 1H); 7.38 (d, 1H); 7.43-7.51 (m, 2H); 7.66-7.73 (m, 3H); 8.25 (s, 1H); 8.42 (m, 1H); 8.52 (d, 1H); 8.65 (dd, 1H); 9.12 (s, 1H); 9.25 (m, 1H); 10.14 (s, 1H).
- [[4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoyl]amino]propanedioic acid diethyl ester utilising diethyl aminomalonate hydrochloride (Aldrich, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 1.19 (t, 6H); 2.30 (s, 3H); 4.10-4.22 (m, 4H); 5.27 (d, 1H); 7.35 (d, 1H); 7.44 (d, 1H); 7.51 (ddd, 1H); 7.63 (dd, 1H); 8.15 (m, 1H); 8.40 (m, 1H); 8.50 (d, 1H); 8.67 (dd, 1H); 9.11 (s, 1H); 9.21-9.25 (m, 2H).
- N-[2-[bis(1-Methylethyl)amino]ethyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]benzamide utilising 2-diisopropylamino-ethylamine (Fluka, Buchs, Switzerland). 1H-NMR (400 MHz, DMSO-d6, δ): 0.95 (m, 12H); 2.28 (s, 3H); 2.49 (m, 2H); 2.94 (m, 2H); 3.17 (m, 2H); 7.30 (d, 1H); 7.43 (d, 1H); 7.50 (ddd, 1H); 7.54 (dd, 1H); 8.09 (br.s, 1H); 8.27 (m, 1H); 8.40 (m, 1H); 8.50 (d, 1H); 8.67 (dd, 1H); 9.06 (s, 1H); 9.23 (m, 1H).
- N-[3-(Diethylamino)phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide
- A solution containing ˜50% of propylphosphonic anhydride in N,N-dimethylformamide (Fluka, Buchs, Switzerland; 674 μL, ˜1.05 mmol) is added within 20 minutes to a stirred mixture of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid (214.4 mg, 0.7 mmol), N,N-diethyl-1,3-benzenediamine (115 mg, 0.7 mmol) and triethylamine (776 μL, 5.6 mmol) in 2 mL N,N-dimethylformamide. After stirring for 24 hours at room temperature, the mixture is treated with a half-saturated aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The solvent is evaporated off under reduced pressure and the residue dried in vacuo. The crude product is purified by chromatography on silica gel, eluent 2% methanol in dichloromethane and crystallised from acetone to give the title compound as a crystalline solid. 1H-NMR (400 MHz, DMSO-d6, δ): 1.07 (t, 6H); 2.31 (s, 3H); 3.29 (m, 4H); 6.38 (m, 1H); 7.06 (m, 2H); 7.11 (m, 1H); 7.36 (d, 1H); 7.43-7.50 (m, 2H); 7.67 (m, 1H); 8.21 (m, 1H); 8.43 (m, 1H); 8.51 (d, 1H); 8.66 (dd, 1H); 9.12 (s, 1H); 9.24 (m, 1H); 9.90 (s, 1H).
- Diethylcyanophosphonate (Aldrich, Buchs, Switzerland; 0.33 mL, 2.0 mmol) is added to a stirred mixture of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid (306 mg, 1.0 mmol), 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)benzeneamine (220 mg, 1.0 mmol) and triethylamine (560 μL, 4.0 mmol) in 5 mL N,N-dimethylformamide at 10° C. After stirring for 3 hours at 60° C., the mixture is treated with saturated aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The combined extracts are dried (MgSO4), filtered and the solvent is evaporated off under reduced pressure to afford a crude product which is recrystallised from ethylacetate to give the title compound as a crystalline solid, m.p. 253-258° C.
- Diethylcyanophosphonate (Aldrich, Buchs, Switzerland; 0.50 mL, 3.0 mmol) is added to a stirred mixture of 3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid (438 mg, 1.5 mmol), 4-[(4-methyl-1-piperazinyl)methyl]benzeneamine (308 mg, 1.5 mmol) and triethylamine (840 μL, 3.0 mmol) in 10 mL N,N-dimethylformamide at 10° C. After stirring for 12 hours at 60° C., the mixture is treated with an aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The combined extracts are washed with water, and the solvent is evaporated off under reduced pressure to give a residue. The residue is resuspended in water and filtered to afford the crude product which is recrystallised from tetrahydrofuran-ethyl acetate to give N-[3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[(4-methyl-1-piperazinyl)-methyl]benzamide as a crystalline solid, m.p. 220-224° C.
- Utilising the procedure described in Example 1a, but with 3-aminobenzoic acid methyl ester (Fluka, Buchs, Switzerland) in lieu of 3-amino-4-methylbenzoic acid ethyl ester, afforded the title compound as a crystalline solid, m.p. 170-172° C.
- Utilising the procedure described in Example 1b, but with the intermediate of Example 69a in lieu of 4-methyl-3-[(aminoiminomethyl)amino]-4-methylbenzoic acid ethyl ester mononitrate, afforded the title compound as a crystalline solid, m.p. 195-200° C.
- Utilising the procedure described in Example 1c, but with the intermediate of Example 69b in lieu of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid ethyl ester, afforded the title compound as a crystalline solid, m.p. 285-293° C.
- Utilising the procedure described in Example 69, but with 3-(1-hydroxy-1-methylethyl)-5-(1,1,1-trifluoromethyl)benzeneamine in lieu of 4-[(4-methyl-1-piperazinyl)methyl]benzeneamine, afforded 3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[(3-(1-hydroxy-1-methylethyl)-5-(1,1,1-trifluoromethyl)phenyl]benzamide as a crystalline solid, m.p. 213-215° C.
- Utilising the procedure described in Example 3, but employing 343-(1H-imidazol-1-yl)propoxy]-benzenamine (Takao Nishi et al., JP 10182459) in lieu of 1-(2-pyridyl)piperazine, afforded the title compound as a solid. 1H-NMR (400 MHz, DMSO-d6, δ): 2.12-2.21 (m, 2H); 2.33 (s, 3H); 3.87 (t, 2H); 4.13 (t, 2H); 6.66 (dd, 1H); 6.87 (s, 1H); 7.15-7.26 (m, 2H); 7.32-7.42 (m, 2H); 7.44-7.52 (m, 3H); 7.61 (s, 1H); 7.70 (d, 1H); 8.24 (s, 1H); 8.43 (d, 1H); 8.53 (d, 1H); 8.67 (d, 1H); 9.13 (s, 1H); 9.26 (br. s, 1H); 10.13 (s, 1H).
- Utilising the procedure described in Example 3, but employing 3-[2-(1H-imidazol-1-yl)ethoxy]-benzenamine (Rolf Paul et al., Journal of Medicinal Chemistry (1993), 36(19), 2716-25) in lieu of 1-(2-pyridyl)piperazine, afforded the title compound as a crystalline solid. 1H-NMR (400 MHz, DMSO-d6, δ): 2.34 (s, 3H); 4.22 (t, 2H); 4.37 (t, 2H); 6.68 (dd, 1H); 6.90 (s, 1H); 7.21-7.27 (m, 2H); 7.36-7.43 (m, 2H); 7.46-7.53 (m, 3H); 7.67-7.74 (m, 2H); 8.25 (br. s, 1H); 8.44 (dt, 1H); 8.54 (d, 1H); 8.68 (dd, 1H); 9.15 (s, 1H); 9.27 (br. d, 1H); 10.15 (s, 1H).
- Utilising the procedure described in Example 69, but employing N-ethyl-2-(trifluoromethyl)-1,4-benzenediamine in lieu of 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)-benzeneamine, afforded the title compound as a crystalline solid, m.p. 178-180° C.
- The aniline is prepared as follows:
- A mixture of 2-bromo-5-nitrobenzotrifluoride (Lancaster Synthesis, GmbH; 5.4 g, 20 mmol) and a solution of ethylamine in ethanol (50 mL of 2M, 100 mmol) is heated at 80° C. for 18 hours in a steel pressure vessel. The mixture is then cooled and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography (silica gel, eluent 20% ethyl acetate in hexane) to afford N-ethyl-4-nitro-6-(trifluoromethyl)-benzenamine as yellow oil. This product is dissolved in ethanol (180 mL) and hydrogenated at atmospheric pressure over Raney nickel (0.5 g) at 45° C. The calculated amount of hydrogen is taken up in 50 hours. The mixture is then filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography (silica gel; eluent 50% ethyl acetate in hexane) and recrystallised from ether-hexane to give the title compound as a beige crystalline solid. 1H-NMR (400 MHz, DMSO-d6): 1.11 (t, 3H), 3.05 (m, 2H), 4.18 (br t, 1H), 4.66 (br.s, 2H), 6.58-6.64 (m, 1H) and 6.68-6.75 (m, 2H).
- Utilising the procedure described in Example 3, but employing N,N-diethyl-2-(trifluoromethyl)-1,4-benzenediamine (Toshio Niwa, DE 3524519) in lieu of 1-(2-pyridyl)piperazine, afforded the title compound as a crystalline solid, m.p. 128-131° C.
- Utilising the procedure described in Example 3, but employing (±)-1-[[4-amino-2-(trifluoromethyl)phenyl]amino]-2-propanol (Tsutomu Mano, EP 299497) in lieu of 1-(2-pyridyl)piperazine, afforded the title compound as a crystalline solid, m.p. 184-186° C.
- Utilising the procedure described in Example 3, but employing N,N-bis(2-methoxyethyl)-2-(trifluoromethyl)-1,4-benzenediamine (Toshio Niwa, DE 3524519) in lieu of 1-(2-pyridyl)piperazine, afforded the title compound as a crystalline solid, m.p. 156-157° C.
- Utilising the procedure described in Example 3, but employing 4-(4-methyl-1-piperazinyl)-3-(trifluoromethyl)-benzenamine (Anthony David Baxter, WO 0119800) in lieu of 1-(2-pyridyl)piperazine, afforded the title compound as a crystalline solid, m.p. 214-217° C.
- Utilising the procedure described in Example 3, but employing 4-(1-piperidinyl)-3-(trifluoromethyl)-benzenamine (Leping Li, WO 0151456) in lieu of 1-(2-pyridyl)piperazine, afforded the title compound as a crystalline solid, m.p. 201-202° C.
- Utilising the procedure described in Example 3, but employing 4-(1-pyrrolidinyl)-3-(trifluoromethyl)-benzenamine (Steven Lee Bender WO 0153274) in lieu of 1-(2-pyridyl)piperazine afforded the title compound as a crystalline solid, m.p. 129-130° C.
- Utilising the procedure described in Example 69, but employing 4-(4-morpholinyl)-3-(trifluoromethyl)-benzenamine (Steven Lee Bender WO 0153274) in lieu of 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)benzeneamine, afforded the title compound as a crystalline solid, m.p. 216-218° C.
- Utilising the procedure described in Example 3, but employing 4-(phenyl)-3-(trifluoromethyl)-benzenamine in lieu of 1-(2-pyridyl)piperazine afforded the title compound as a crystalline solid, m.p. 172-174° C.
- The aniline is prepared as follows:
- Phenyl boronic acid (Aldrich, Buchs, Switzerland; 2.7 g, 22 mmol), Palladium II acetate (0.225 g, 1 mmol), tri-o-tolylphosphine (0.608 g, 2 mmol) and aqueous potassium carbonate solution (50 mL of 1 M) is added to a stirred solution of 2-bromo-5-nitrobenzotrifluoride (Lancaster Synthesis, GmbH; 5.4 g, 20 mmol) in dimethylformamide (200 mL) and heated at 120° C. under an argon atmosphere for 1 h. The mixture is then evaporated to dryness under reduced pressure and the residue is treated with water (100 mL) and extracted with ethyl acetate (3×80 mL). The combined extracts are washed (brine), dried (MgSO4), filtered and the solvent is evaporated off under reduced pressure to afford 4′-nitro-2′-(trifluoromethyl)-[1,1′-Biphenyl]. The biphenyl is dissolved in ethanol (200 mL) and hydrogenated at atmospheric pressure over Raney nickel (2 g) at 22° C. The calculated amount of hydrogen is taken up in 11 hours. The mixture is then filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography (silica gel; eluent ethyl acetate) to give the title compound as a brown oil. 1H-NMR (400 MHz, DMSO-d6): 5.62 (br.s, 2H), 6.80 (dd, 1H), 6.96 (d, 1H), 6.99 (d, 1H), 7.19-7.23 (m, 2H), and 7.29-7.39 (m, 3H).
- Utilising the procedure described in Example 69, but employing 4-(3-pyridinyl)-3-(trifluoromethyl)-benzenamine in lieu of 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)benzeneamine, afforded the title compound as a crystalline solid, m.p. 276-280° C.
- The aniline is prepared as follows:
- A stirred solution of 2-bromo-5-nitrobenzotrifluoride (Lancaster Synthesis, GmbH; 3.37 g, 12.5 mmol) and 3-(tri-n-butylstannyl)pyridine (Maybridge Chemical Co. Ltd., England; 5.0 g, 13.6 mmol) in xylene (75 mL) was purged with argon for 10 minutes at 20° C. Tetrakis(triphenylphosphine)palladium (0) (1.4 g, 1.25 mmol) is then added and the resulting mixture is heated at 130° C. for 24 hours under an argon atmosphere. The mixture is then cooled, treated with an aqueous solution of sodium hydroxide (150 mL of 0.1 M) and purged with air for 2 hours. The resulting mixture is then diluted with ethylacetate (200 mL) and filtered. The organic phase is then sequentially washed with water (2×80 mL) and saturated aqueous sodium chloride (1×80 mL), dried (MgSO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography (silica gel, eluent 50% ethyl acetate in hexane) to afford 3-[(4-nitro-3-(trifluoromethyl)phenyl]pyridine. This product is dissolved in ethanol (200 mL) and hydrogenated at atmospheric pressure over Raney nickel (0.23 g) at 22° C. The calculated amount of hydrogen is taken up in 24 hours. The mixture is then filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography (silica gel; eluent 50% ethyl acetate in hexane) and recrystallised from ether-hexane to give the title compound as a colourless crystalline solid, m.p. 92-93° C.
- Utilising the procedure described in Example 3, but employing 4-(1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine (Steven Lee Bender WO 0153274) in lieu of 1-(2-pyridyl)piperazine afforded the title compound as a crystalline solid, m.p. 226-229° C.
- Utilising the procedure described in Example 69, but employing 4-(2,4-dimethyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine in lieu of 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)benzeneamine, afforded the title compound as an amorphous solid.
- The aniline is prepared as follows:
- A mixture of 2-bromo-5-nitrobenzotrifluoride (Lancaster Synthesis, GmbH; 6.0 g, 22 mmol) and 2,4-dimethylimidazole (10.6, 110 mmol) is heated at 120° C. for 36 hours under an argon atmosphere. The mixture is then cooled and the residue is treated with water (150 mL) and extracted with ethyl acetate (3×80 mL). The combined extracts are washed (brine), dried (MgSO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography (silica gel, eluent ethyl acetate) to afford 1-[4-nitro-2-(trifluoromethyl)phenyl]-1H-imidazole as yellow crystalline solid. This product is dissolved in ethanol (290 mL) and hydrogenated at atmospheric pressure over Raney nickel (1.15 g) at 25° C. The calculated amount of hydrogen is taken up in 14 hours. The mixture is then filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by recrystallisation from ether-hexane to give the title compound as a crystalline solid, m.p. 163-164° C.
- Utilising the procedure described in Example 69, but employing 4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine in lieu of 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)benzeneamine, afforded the title compound as a crystalline solid, m.p. 154-163° C.
- The aniline is prepared as follows:
- Utilising the procedure described in Example 84a, but employing 4(5)-methyl-1H-imidazole in lieu of 2,4-dimethylimidazole, afforded the title compound as a beige crystalline solid, m.p. 141-143° C.
- Utilising the procedure described in Example 69, but employing 4-(2-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine in lieu of 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoro-methyl)benzeneamine, afforded the title compound as a crystalline solid, m.p. 154-163° C.
- The aniline is prepared as follows:
- Utilising the procedure described in Example 84a, but employing 2-methyl-1H-imidazole in lieu of 2,4-dimethylimidazole, afforded the title compound as a colourless crystalline solid, m.p. 117-119° C.
- Utilising the procedure described in Example 69, but employing 3-amino-5-(4-morpholinyl)-N-(methyl)-benzamide in lieu of 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)-benzeneamine, afforded the title compound as a crystalline solid, m.p. 153-156° C.
- The aniline is prepared as follows:
- A solution of n-butyllithium in hexane (12.8 mL of 2.5 M, 32 mmol) is added with stirring to t-butanol (46 mL) at 25° C. under an argon atmosphere. After 30 min the mixture is treated dropwise with a solution of 3-bromo-5-nitro-benzoyl chloride (J. Mindl, Collect. Czech. Chem. Commun. (1973), 38, 3496-505; 32 mmol) in dry THF (40 mL) and stirred for a further 17 h. The mixture is then treated with ether (250 mL) and washed with brine. The ether solution was dried (MgSO4) and the solvent is evaporated off under reduced pressure to give the crude product which is purified by column chromatography (silica gel, eluent 20% ethyl acetate in hexane) and recrystallised from ether-hexane to afford the title compound as colourless crystalline solid, m.p. 77-78° C.
- A stirred mixture of 3-bromo-5-nitro-benzoic acid, 1,1-dimethylethyl ester (example 86a; 3.02 g, 10 mmol) and morpholine (1.22 mL, 14 mmol) in toluene (50 mL) is treated with sodium t-butylate (1.34 g, 14 mmol), tri-t-butylphosphine (3 mL, 1.5 mmol) and tris-(dibenzylidene-acetone)dipalladium[0] (0.45 g, 0.5 mmol) under an argon atmosphere, and then heated at 60° C. for 18 h. The mixture is diluted with ethyl acetate (150 mL), filtered, washed with brine (2×50 mL), dried (MgSO4) and the solvent is evaporated off under reduced pressure to give the crude product which is purified by column chromatography (silica gel, eluent 15% ethyl acetate in hexane) and recrystallised from ethyl acetate-hexane to afford the title compound as colourless crystalline solid, m.p. 116-118° C.
- A mixture of 3-(4-morpholinyl)-5-nitro-benzoic acid, 1,1-dimethylethyl ester (Example 87b; 0.77 g, 2.5 mmol), 1,8-diazabicyclo[5,4,0]undec-7-ene (0.56 mL, 3.75 mL), and potassium bromide (1.09 g, 12.5 mmol) in methanol (25 mL) is stirred at 90° C. for 250 min. The cooled mixture is then added to hydrochloric acid (50 mL of 0.1 M) and extracted with ethyl acetate (3×100 mL). The combined extracts are washed with saturated aqueous sodium hydro-carbonate (2×25 mL), water (2×25 mL) and brine (2×50 mL), dried (MgSO4) and the solvent is evaporated off under reduced pressure to give the crude product which is purified by recrystallisation from ethyl acetate-hexane to afford the title compound as yellow crystalline solid.
- A stirred solution of 3-(4-morpholinyl)-5-nitro-benzoic acid, methyl ester (Example 86c; 0.53 g, 2 mmol) in toluene (5 mL) under an argon atmosphere, is treated with a mixture of methylamine hydrochloride (0.27 g, 4 mmol), trimethylaluminium (2 mL of a 2 M solution in toluene, 4 mmol) in toluene (5 mL) and heated at 60° C. for 18 h. The cooled mixture is then treated with hydrochloric acid (10 mL of 2 M), stirred for 5 min and then treated with aqueous sodium hydroxide (5 mL of 4 M). The mixture is then treated with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts are washed with brine (2×50 mL), dried (MgSO4) and the solvent is evaporated off under reduced pressure to give the crude product which is purified by recrystallisation from ethyl acetate to afford the title compound as yellow crystalline solid, m.p. 204-207° C.
- A solution of 3-(4-morpholinyl)-5-nitro-N-(methyl)-benzamide (Example 86d; 300 mg, 1.12 mmol) in ethanol (20 mL) is hydrogenated at atmospheric pressure over Raney nickel (0.2 g) at 25° C. The calculated amount of hydrogen is taken up in 19 hours. The mixture is then filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by recrystallisation from ethyl acetate to give the title compound as a beige crystalline solid, m.p. 201-204° C.
- Utilising the procedure described in Example 69, but employing 3-amino-5-(trifluoromethyl)-N-(methyl)-benzamide in lieu of 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)-benzeneamine, afforded the title compound as a crystalline solid, m.p. 245-249° C.
- Utilising the procedure described in Example 86e, but employing α,α,α-trifluoro-N-methyl-5-nitro-m-toluamide (Dean E. Welch, J. Med. Chem. (1969), 12, 299-303) in lieu of 3-(4-morpholinyl)-5-nitro-N-(methyl)-benzamide, afforded the title compound as a beige crystalline solid, m.p. 113-115° C.
- Utilising the procedure described in Example 69, but employing 5-(3-pyridinyl)-3-(trifluoro-methyl)-benzenamine in lieu of 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)-benzeneamine, afforded the title compound as a crystalline solid, m.p. 275-279° C.
- The aniline is prepared as follows:
- A stirred solution of 3-amino-5-bromo-benzotrifuoride (Apollo, England; 1.12 g, 5 mmol) and 3-(tri-n-butylstannyl)pyridine (Maybridge Chemical Co. Ltd., England; 2.0 g, 5.4 mmol) in xylene (30 mL) was purged with argon for 10 minutes at 20° C. Tetrakis(triphenylphosphine)-palladium (0) (1.16 g, 1.0 mmol) is then added and the resulting mixture is heated at 140° C. for 36 hours under an argon atmosphere. The mixture is then cooled, treated with an aqueous solution of sodium hydroxide (100 mL of 0.1 M) and purged with air for 2 hours. The resulting mixture is then diluted with ethylacetate (200 mL) and filtered. The organic phase is then sequentially washed with water (2×80 mL) and saturated aqueous sodium chloride (1×80 mL), dried (MgSO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography (silica gel, eluent ethyl acetate) to afford the title compound as a brown oil. 1H-NMR (400 MHz, DMSO-d6, δ): 5.73 (br s, 2H), 6.83 (dd, 1H), 6.99 (d, 1H), 7.04 (d, 1H), 7.39 (dd, 1H), 7.64 (d, 1H), 8.42 (m, 1H) and 8.53 (dd, 1H).
- Utilising the procedure described in Example 69, but employing 5-(4-morpholinyl)-3-(trifluoromethyl)-benzenamine in lieu of 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoro-methyl)benzeneamine, afforded the title compound as a crystalline solid, m.p. 208-211° C.
- The aniline is prepared as follows:
- A mixture of 3-amino-5-bromo-benzotrifuoride (Apollo, England; 12 g, 50 mmol), di-t-butyl-dicarbonate (12 g, 55 mmol) and 4-dimethylaminopyridine (0.61 g, 5 mmol) in acetonitrile (100 mL) is stirred at 60° C. for 8 h. The solvent is then evaporated off under reduced pressure to yield the crude product which is purified by column chromatography (silica gel, eluent 10% ethyl acetate in hexane) and recrystallised from hexane to afford the title compound as a colourless crystalline solid, m.p. 113-115° C.
- Utilising the procedure described in Example 86b but employing [3-bromo-5-(trifluoromethyl)-phenyl]-carbamic acid, 1,1-dimethylethyl ester (Example 90a) in lieu of 3-bromo-5-nitro-benzoic acid, 1,1-dimethylethyl ester, afforded the title compound as a crystalline solid, m.p. 146-148° C.
- [3-(4-morpholinyl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester (Example 90b; 1.7 g, 5 mmol) is treated with a solution of hydrogen chloride in isopropanol (30 mL of 4 M) and heated at 60° C. for 5 h. The solvent is evaporated off under reduced pressure and the residue is treated with aqueous sodium hydrogen carbonate solution (80 mL) and extracted with ethyl acetate (3×80 mL). The combined extracts are washed with brine (2×50 mL), dried (MgSO4) and the solvent is evaporated off under reduced pressure to give the crude product which is purified by recrystallisation from ether-hexane to afford the title compound as yellow crystalline solid, m.p. 96-97° C.
- Utilising the procedure described in Example 69, but employing 5-(2-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine in lieu of 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoro-methyl)benzeneamine, afforded the title compound as a crystalline solid, m.p. 242-247° C.
- The was aniline is prepared as follows:
- A mixture of 3-fluoro-5-(trifluoromethyl)-benzonitrile (Lancaster Synthesis GmbH; 17 g, 89 mmol) and 2-methylimidazole (Fluka, Buchs, Switzerland; 22.2 g, 270 mmol) in N,N-dimethylacetamide (80 mL) is stirred at 145° C. for 19 h. The solvent is evaporated off under reduced pressure and the residue is dissolved in ethyl acetate (200 mL). The solution is washed with brine (200 mL), dried (Na2SO4) and the solvent is evaporated off under reduced pressure to give the crude product which is purified by recrystallisation from ether-hexane to afford the title compound as yellow crystalline solid, m.p. 132-134° C.
- A solution of 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzonitrile (Example 91a; 16.7 g, 66 mmol) in dioxane (300 mL) is added to an aqueous solution of sodium hydroxide (275 mL of 1 M) and the mixture is heated at 95° C. for 18 h. The solvent is evaporated off under reduced pressure and the residue is neutralised with hydrochloric acid (1 M) and extracted with butanol (2×250 mL). The solvent is evaporated of under reduced pressure to give the title compound. 1H-NMR (400 MHz, DMSO-d6, δ): 7.17 (s, 1H); 8.03 (s, 1H); 8.12 (s, 1H); 8.35 (s, 1H); 8.41 (s, 1H); 8.53 (s, 1H); 13.90 (br., 1H).
- Triethylamine (5.23 mL, 37.5 mmol) is added to a stirred suspension of 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzoic acid (Example 91b; 6.8 g, 25 mmol) in t-butanol (200 mL). Diphenylphosphorylazide (7.6 g, 27.5 mmol) is added to the resulting solution and the mixture is heated 80° C. for 16 h. The solvent is evaporated off under reduced pressure and the residue is treated with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined extracts are washed with brine (100 mL), dried (Na2SO4) and the solvent is evaporated off under reduced pressure to give the crude product which is purified by column chromatography (silica gel, eluent 2% ethanol in ethyl acetate) and recrystallised from ether-hexane to afford the title compound as a colourless crystalline solid, m.p. 203-208° C.
- Utilising the procedure described in Example 90c but employing [3-[2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester (Example 91c) in lieu of [3-(4-morpholinyl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester, afforded the title compound as a yellow crystalline solid, m.p. 130-133° C.
- Utilising the procedure described in Example 69, but employing 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine in lieu of 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoro-methyl)benzeneamine, afforded the title compound as a crystalline solid, m.p. 235-236° C.
- The was aniline is prepared as follows:
- Utilising the procedure described in Example 91a, but employing 4-methyl-1H-imidazole in lieu of 2-methylimidazole, afforded the title compound as a crystalline solid, m.p. 127-128° C.
- Utilising the procedure described in Example 91b, but employing 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzonitrile (Example 92a) in lieu of 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzonitrile, afforded the title compound as a crystalline solid, m.p. >300° C.
- Utilising the procedure described in Example 91c, but employing 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzoic acid (Example 92b) in lieu of 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzoic acid, afforded the title compound as a crystalline solid, m.p. 186-188° C.
- Utilising the procedure described in Example 91d, but employing [3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester (Example 92c) in lieu of [3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester, afforded the title compound as a colourless crystalline solid, m.p. 127-131° C.
- Utilising the procedure described in Example 3, but employing 5-(5-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine in lieu of 1-(2-pyridyl)piperazine, afforded the title compound as a crystalline solid, m.p. 231-233° C.
- The aniline is prepared as follows:
- Utilising the procedure described in Example 91a, but employing 4-methyl-1H-imidazole in lieu of 2-methylimidazole, afforded the title compound as a crystalline solid, m.p. 99-101° C.
- Utilising the procedure described in Example 91b, but employing 3-(5-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzonitrile (Example 93a) in lieu of 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzonitrile, afforded the title compound as a colourless crystalline solid, m.p. 243-245° C.
- Utilising the procedure described in Example 91c, but employing 3-(5-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzoic acid (Example 93b) in lieu of 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzoic acid, afforded the title compound as a crystalline solid, m.p. 169-171° C.
- Utilising the procedure described in Example 91d, but employing [3-(5-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester (Example 93c) in lieu of [3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester, afforded the title compound as a colourless crystalline solid, m.p. 131-133° C.
- Utilising the procedure described in Example 69, but employing 3-(4-methyl-1-piperazinyl)-5-(trifluoromethyl)-benzenamine in lieu of 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoro-methyl)benzeneamine, afforded the title compound as a crystalline solid, m.p. 192-194° C.
- The aniline is prepared as follows:
- Utilising the procedure described in Example 87b, but employing 1-methyl-1-piperazine in lieu of morpholine, afforded the title compound as a crystalline solid, m.p. 225° C.
- Utilising the procedure described in Example 90c, but employing [3-(4-methyl-1-piperazinyl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester (Example 94a) in lieu of [3-(4-morpholinyl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester, afforded the title compound as oil. 1H-NMR (400 MHz, DMSO-d6): 2.20 (s, 3H), 2.42 (m, 4H), 3.07 (m, 4H), 3.32 (br s, 2H), 5.34 (s, 1H) and 6.31 (s, 2H).
- Utilising the procedure described in Example 3, but employing 2-(1-pyrrolidinyl)-5-(trifluoromethyl)-benzenamine (Lancaster Synthesis Ltd.; Yasuhiro Ohtake et al., WO 9965874) in lieu of 1-(2-pyridyl)piperazine, afforded the title compound as a crystalline solid. 1H-NMR (400 MHz, DMSO-d6): 1.77-1.82 (m, 4H); 2.34 (s, 3H); 3.31-3.37 (m, 4H); 6.86 (d, 1H); 7.34-7.44 (m, 2H); 7.47 (d, 1H); 7.49-7.53 (m, 1H); 7.73 (dd, 1H); 8.27 (d, 1H); 8.43 (dt, 1H); 8.53 (d, 1H); 8.69 (dd, 1H); 9.13 (s, 1H); 9.27 (d, 1H); 9.96 (s, 1H).
- Utilising the procedure described in example 1, but employing 3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid in lieu of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid and 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine in lieu of furfurylamine, afforded the title compound as as pale-yellow crystalline solid, m.p. 264-266° C.
- Utilising the procedure described in example 1a but employing 3-amino-benzoic acid ethyl ester (Fluka, Buchs, Switzerland) in lieu of 3-amino-4-methylbenzoic acid ethyl ester, afforded the title compound as a crystalline solid, m.p. 170-172° C.
- Utilising the procedure described in example 1b but employing 3-[(aminoiminomethyl)amino]-benzoic acid ethyl ester mononitrate in lieu of 3-[(aminoiminomethyl)amino]-4-methyl-benzoic acid ethyl ester mononitrate, afforded the title compound as a crystalline solid, m.p. 197-199° C.
- Utilising the procedure described in example 1c but employing 3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid ethyl ester in lieu of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid ethyl ester, afforded the title compound as a crystalline solid, m.p. 291-295° C.
- 5000 soft gelatin capsules, each comprising as active ingredient 0.05 g of one of the compounds of formula I mentioned in the preceding Examples, are prepared as follows: 250 g pulverized active ingredient is suspended in 2 L Lauroglykol® (propylene glycol laurate, Gattefossé S. A., Saint Priest, France) and ground in a wet pulverizer to produce a particle size of about 1 to 3 μm. 0.419 g portions of the mixture are then introduced into soft gelatin capsules using a capsule-filling machine.
- The compound of formula I to be tested is formulated for administration to female OF1 mice from IFACREDO, France, by first dissolving in NMP, and then by diluting with PEG300 to a final concentration of 10% v/v NMP: 90% v/v PEG300, producing a clear solution of the compound. The concentrations were adjusted to deliver a constant volume of 10 ml/kg body weight. The compound is prepared immediately before use. The formulated compound is administered perorally by gavage to provide dosages of 50 mg/kg. At the allotted time points mice (4 at each time) are anesthetized with 3% isoflurane in medical oxygen and blood samples are obtained by heart puncture into heparinized tubes (ca. 30 IU/mL). The animals are subsequently killed without recovering from the anesthetic. Plasma is prepared from the blood by centrifugation (10,000 g, 5 min) and either analyzed immediately or stored frozen at −70° C.
- The plasma samples (10-250 μL) are e.g. spiked with 5 μL of internal standard, mixed with 200 μL 0.1 M NaOH and 500 μL chloroform in a 1.5 mL Eppendorf tube and shaken vigorously for 10 minutes on an Eppendorf mixer. Thereafter, the mixture is centrifuged (3 min at 10′000×g), the organic phase transferred to a second Eppendorf tube and evaporated to dryness in a vacuum centrifuge (Speedvac 5301). The dry residue e.g. is dissolved in 250 μL of 10% v/v Acetonitrile in water containing 0.1% formic acid. The subsequent analysis is carried out e.g. by HPLC/MS-MS using an Agilent 1100 Series (Agilent, Palo Alto, Calif., USA) HPLC system with vacuum degasser, binary pump, and thermostated column compartment combined with a cooled autosampler system (HTS PAL, CTC Analytics, Zwingen, Switzerland). The sample (5-15 μL) is injected e.g. onto an Ultra Phenyl column (particle size 3 μm, 50×1 mm; Restek, Bellefonte, USA) with a guard column (4×2 mm) of the same material (Phenomenex, Torrance, USA). After equilibration e.g. with water and a latency period of 1 min the sample is eluted e.g. by a linear gradient of 0-100% acetonitrile in water containing 0.2% v/v formic acid over a period of 11 min at a flow rate of 60 μL/min. The column is prepared for the next sample e.g. by re-equilibrating for 3 min with 100 water to the starting conditions. The separation is performed e.g. at a column temperature of 40° C. The column effluent is introduced e.g. directly into the ion source of a triple stage quadrupole mass spectrometer (Quattro Ultima™, Micromass, Manchester, UK) controlled by Masslynx™ 3.5 software (Micromass, Manchester, UK) using as ionization technique electrospray ionization positive mode (ESI+). The compound is detected by MS/MS following fragmentation of the parent ions. The limit of quantitation is determined at e.g. 0.002 nmol/L. A calibration curve is constructed with known amounts of compound including a fixed amount of internal standard in plasma which is processed as described above. The concentration of unknown samples is calculated from a plot of the peak area ratio of the selected daughter ion of the analyte to the product of its internal standard (ordinate) against the nominal concentration (abscissa). Regression analysis is performed using Quanlynx™, Masslynx™ software 3.5 (Micromass, Manchester, UK).
- Enzymatic (c-Abl, KDR, Flt3) in vitro inhibition data are presented as % inhibition at 10 μM. The measurements are made as described above in the general description.
-
Example Abl % @10 μM KDR % @10 μM Flt3 % @10 μM 1 51 57 2 97 73 3 66 71 4 77 46 5 71 60 6 51 56 7 72 45 8 70 81 9 44 39 10 57 48 11 53 41 12 22 33 13 78 48 14 49 54 15 60 23 16 42 10 17 54 62 18 56 62 19 41 33 20 56 22 21 30 93 22 59 7 23 90 67 24 80 70 25 44 73 26 55 56 27 54 51 28 73 61 29 78 30 57 37 31 68 83 32 90 37 33 97 51 34 73 89 35 27 47 36 57 77 37 28 82 38 74 91 39 64 74 40 65 78 41 13 52 42 32 56 43 37 63 44 75 97 45 34 61 46 1 43 47 39 74 48 90 50 49 72 37 50 87 83 51 92 52 52 78 37 53 88 79 54 69 74 55 43 54 56 40 44 57 8 42 58 40 26 59 75 83 60 79 36 61 95 65 62 59 44 63 74 82 64 56 59 65 96 60 66 67 23 67 98 88 41 68 99 96
Claims (15)
1-7. (canceled)
8. A compound of formula
wherein
R1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl;
R2 represents hydrogen, lower alkyl, optionally substituted by one or more identical or different radicals R3, cycloalkyl, benzcycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted; and
R3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted; or wherein
R1 and R2 together represent alkylene with four, five or six carbon atoms optionally mono- or disubstituted by lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or disubstituted amino, oxo, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with four or five carbon atoms; oxaalkylene with one oxygen and three or four carbon atoms; or azaalkylene with one nitrogen and three or four carbon atoms wherein nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl, N-mono- or N,N-disubstituted carbamoyl-lower alkyl, cycloalkyl, lower alkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl, pyrimidinyl, or pyrazinyl;
R4 represents hydrogen, lower alkyl, or halogen;
and a N-oxide or a pharmaceutically acceptable salt of such a compound.
9. compound of formula I according to claim 1 wherein
R1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl;
R2 represents hydrogen, lower alkyl, optionally substituted by one or two identical or different radicals R3, cycloalkyl, benzcycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising one, two or three nitrogen atoms or one sulfur atom, which aryl and heteroaryl groups in each case are unsubstituted or mono- or polysubstituted; and
R3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, an aryl group, furanoyl, thienoyl, or a mono- or bicyclic heteroaryl group comprising one, two or three ring nitrogen atoms, zero or one ring oxygen atom and zero or one ring sulphur atom, which aryl and heteroaryl groups in each case are unsubstituted or mono- or polysubstituted; or wherein
R1 and R2 together represent alkylene with four or five carbon atoms, optionally mono- or disubstituted by lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or disubstituted amino, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with four or five carbon atoms in the alkylene group; oxaalkylene with one oxygen and three or four carbon atoms, or azaalkylene with one nitrogen and three or four carbon atoms wherein nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl, N-mono- or N,N-disubstituted carbamoyl-lower alkyl, cycloalkyl, lower alkoxycarbonyl, phenyl, substituted phenyl, pyridinyl, pyrimidinyl, or pyrazinyl;
R4 represents hydrogen, lower alkyl, or halogen;
and a N-oxide or a pharmaceutically acceptable salt of such a compound.
10. A compound of formula I according to claim 1 wherein
R1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl;
R2 represents hydrogen, lower alkyl, optionally substituted by one or two identical or different radicals R3, cyclopentyl, benzcyclopentyl, cylcohexyl, pyrrolidinyl, oxazolinyl, piperidinyl, N-substituted piperidinyl, morpholinyl, azepinyl, oxo-azepinyl, oxazepinyl, phenyl, naphthalinyl, tetrahydronaphthalinyl or a mono- or bicyclic heteroaryl group comprising one or two nitrogen atoms, which phenyl, naphthalinyl and heteroaryl groups in each case are unsubstituted or mono- or polysubstituted, thienyl, or lower alkoxycarbonyl-lower alkylthienyl; and
R3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, amino, lower alkylamino, di-lower alkylamino, phenylamino, N-lower alkyl-N-phenylamino, pyrrolidino, oxopyrrolidino, piperidino, morpholino, imidazolino, oxoimidazolino, cycloalkyl, heterocyclyl, furyl, phenyl, naphthalinyl, tetrahydronaphthalinyl, or a mono- or bicyclic heteroaryl group comprising one or two nitrogen atoms, which phenyl, naphthalinyl and heteroaryl group are unsubstituted or mono- or polysubstituted; or wherein
R1 and R2 together represent alkylene with four or five carbon atoms, optionally mono- or disubstituted by lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or disubstituted amino, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with four or five carbon atoms in the alkylene group; oxaalkylene with one oxygen and four carbon atoms; or azaalkylene with one nitrogen and four carbon atoms wherein nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl, N-mono- or N,N-disubstituted carbamoyl-lower alkyl, cycloalkyl, lower alkoxycarbonyl, phenyl, substituted phenyl, pyridinyl, pyrimidinyl, or pyrazinyl;
R4 represents hydrogen, lower alkyl, or halogen;
and a N-oxide or a pharmaceutically acceptable salt of such a compound.
11. A compound of formula I according to claim 1 wherein
R1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl;
R2 represents hydrogen; lower alkyl, optionally substituted by one radical R3, by two phenyl groups, by two lower alkoycarbonyl groups, by phenyl and lower alkoxycarbonyl, or by hydroxyphenyl and lower alkoxycarbonyl; cyclopentyl; benzcyclopentyl; cylcohexyl; pyrrolidinyl; oxazolinyl; piperidinyl; N-lower alkylpiperidinyl; N-benzylpiperidinyl; N-pyrimidinylpiperidinyl; morpholinyl; azepinyl; oxo-azepinyl; oxazepinyl; phenyl, naphthalinyl, tetrahydronaphthalinyl or a mono- or bicyclic heteroaryl group comprising one or two nitrogen atoms, which phenyl, naphthalinyl and heteroaryl groups in each case are unsubstituted or substituted by one or two substituents selected from the group consisting of lower alkyl, trifluoro-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, N-cyclohexyl-N-lower alkylamino-lower alkyl, lower alkoxycarbonylpiperidino-lower alkyl, N-lower alkylpiperazino-lower alkyl, lower alkoxycarbonyl-lower alkyl, hydroxy, lower alkoxy, trifluoro-lower alkoxy, 1H-imidazolyl-lower alkoxy, lower alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, lower alkyl carbamoyl, amino, lower alkanoylamino, benzoylamino, amino mono- or disubstituted by lower alkyl, by hydroxy-lower alkyl or by lower alkoxy-lower alkyl, 1H-imidazolyl, mono- or di-lower alkyl-1H-imidazolyl, pyrrolidino, piperidino, piperazino, N-lower alkylpiperazino, morpholino, sulfamoyl, lower alkylsulfonyl, phenylsulfonyl, lower alkylsulfinyl, phenylsulfinyl, lower alkylthio, phenylthio, phenyl, pyridyl, halogenyl, or benzoyl; thienyl; or lower alkoxycarbonyl-lower alkylthienyl; and
R3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, carbamoyl mono-or disubstituted by lower alkyl, phenyl or lower alkylene, amino, lower alkylamino, di-lower alkylamino, phenylamino, N-lower alkyl-N-phenylamino, pyrrolidino, oxopyrrolidino, piperidino, morpholino, imidazolino, oxoimidazolino, cycloalkyl, heterocyclyl, furyl; phenyl, naphthalinyl, tetrahydronaphthalinyl, or a mono- or bicyclic heteroaryl group comprising one or two nitrogen atoms, which phenyl, naphthalinyl and heteroaryl group is unsubstituted or substituted by one or two substituents selected from the group consisting of lower alkyl, trifluoro-lower alkyl, lower alkoxycarbonyl-lower alkyl, hydroxy, lower alkoxy, trifluoro-lower alkoxy, lower alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, amino, lower alkanoylamino, benzoylamino, amino mono- or disubstituted by lower alkyl, by hydroxy-lower alkyl or by loweralkoxy-lower alkyl, pyrrolidino, piperidino, morpholino, piperazino, N-lower alkylpiperazino, N-lower alkoxycarbonylpiperazino, phenyl, pyridyl, 1H-imidazolyl, lower alkyl-1H-imidazolyl, sulfamoyl, lower alkylsulfonyl, phenylsulfonyl, lower alkylsulfinyl, phenylsulfinyl, lower alkylthio, phenylthio, halogenyl, or benzoyl; or wherein
R1 and R2 together represent alkylene with four or five carbon atoms, optionally mono- or disubstituted by lower alkyl, cycloalkyl, phenyl, hydroxy, lower alkoxy, amino, benzoylamino, piperidino, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with four or five carbon atoms in the alkylene group; oxaalkylene with one oxygen and four carbon atoms; or azaalkylene with one nitrogen and four carbon atoms wherein nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl, carbamoyl-lower alkyl N-mono- or N,N-disubstituted by lower alkyl, phenyl, lower alkylene or oxa-lower alkylene, cycloalkyl, lower alkoxycarbonyl, phenyl, methoxyphenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, pyridinyl, pyrimidinyl, or pyrazinyl;
R4 represents hydrogen or lower alkyl;
and a N-oxide or a pharmaceutically acceptable salt of such a compound.
12. A compound of formula I according to claim 1 wherein
R1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, or benzyl;
R2 represents lower alkyl, optionally substituted by one radical R3, by two phenyl groups, by two lower alkoycarbonyl groups, by phenyl and lower alkoxycarbonyl, or by hydroxyphenyl and lower alkoxycarbonyl; cyclopentyl; benzcyclopentyl; cylcohexyl; pyrrolidinyl; piperidinyl; N-lower alkylpiperidinyl; N-benzylpiperidinyl; N-pyrimidinylpiperidinyl; morpholinyl; azepinyl; oxoazepinyl; phenyl; naphthalinyl; tetrahydronaphthalinyl; pyridyl; lower alkyl-pyridyl; quinolinyl; thienyl; lower alkoxycarbonylmethylthienyl; or phenyl substituted by one or two substituents selected from the group consisting of lower alkyl, trifluoro-lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, N-cyclohexyl-N-lower alkylamino-lower alkyl, lower alkoxycarbonylpiperidino-lower alkyl, N-lower alkylpiperazino-lower alkyl, lower alkoxycarbonyl-lower alkyl, hydroxy, lower alkoxy, trifluoro-lower alkoxy, 1H-imidazolyl-lower alkoxy, lower alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, amino, lower alkanoylamino, benzoylamino, amino mono- or disubstituted by lower alkyl, by hydroxy-lower alkyl or by loweralkoxy-lower alkyl, 1H-imidazolyl, lower alkyl-1H-imidazolyl, pyrrolidino, piperidino, piperazino, N-lower alkylpiperazino, morpholino, sulfamoyl, lower alkylsulfonyl, phenyl, pyridyl, halogenyl, or benzoyl; and
R3 represents hydroxy, lower alkoxy, lower alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, amino, lower alkylamino, di-lower alkylamino, phenylamino, N-lower alkyl-N-phenylamino, pyrrolidino, oxopyrrolidino, piperidino, morpholino, imidazolino, oxoimidazolino, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, phenyl, naphthalinyl, tetrahydronaphthalinyl, furyl, a mono- or bicyclic heteroaryl group comprising one or two nitrogen atoms, which heteroaryl group is unsubstituted or mono- or disubstituted by lower alkyl, hydroxy and lower alkoxy, or phenyl substituted by one or two substituents selected from the group consisting of lower alkyl, trifluoro-lower alkyl, lower alkoxycarbonyl-lower alkyl, hydroxy, lower alkoxy, trifluoro-lower alkoxy, lower alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, amino, lower alkanoylamino, benzoylamino, amino mono- or disubstituted by lower alkyl, by hydroxy-lower alkyl or by loweralkoxy-lower alkyl, pyrrolidino, piperidino, morpholino, piperazino, N-lower alkylpiperazino, N-lower alkoxycarbonylpiperazino, phenyl, pyridyl, 1H-imidazolyl, lower alkyl-1H-imidazolyl, sulfamoyl, lower alkylsulfonyl, halogenyl, or benzoyl; or wherein
R1 and R2 together represent alkylene with four or five carbon atoms, optionally mono- or disubstituted by phenyl, hydroxy, amino, benzoylamino, or piperidino; benzalkylene with four or five carbon atoms in the alkylene group; oxaalkylene with one oxygen and four carbon atoms; or azaalkylene with one nitrogen and four carbon atoms wherein nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, pyrrolidinocarbonyl-lower alkyl, morpholinocarbonyl-lower alkyl, cyclopentyl, lower alkoxycarbonyl, phenyl, methoxyphenyl, trifluoromethylphenyl, pyridinyl; pyrimidinyl, or pyrazinyl;
R4 represents hydrogen or methyl;
and a N-oxide or a pharmaceutically acceptable salt of such a compound.
13. A compound of formula I according to claim 1 wherein
R1 represents hydrogen;
R2 represents phenyl substituted by trifluoromethyl and optionally a further substituent selected from the group consisting of hydroxy-lower alkyl, lower alkylamino, hydroxy-lower alkylamino, di-lower alkylamino, 1H-imidazolyl, lower alkyl-1H-imidazolyl, carbamoyl, lower alkylcarbamoyl, pyrrolidino, piperidino, piperazino, lower alkylpiperazino, morpholino, lower alkoxy, trifluoro-lower alkoxy, phenyl, pyridyl, and halogenyl;
R4 represents methyl;
and a N-oxide or a pharmaceutically acceptable salt of such a compound.
14. A compound of formula I according to claim 1 wherein
R1 represents hydrogen;
R2 represents phenyl substituted by 3-trifluoromethyl and optionally a further substituent selected from the group consisting of 1-hydroxy-1-methylethyl, methylamino, ethylamino, 2-hydroxy-1-propylamino, 2-hydroxy-2-propylamino, diethylamino, 1H-imidazolyl, 2- and 4-methyl-1H-imidazolyl, carbamoyl, methylcarbamoyl, pyrrolidino, piperidino, piperazino, 4-methylpiperazino, morpholino, methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, phenyl, 2-, 3- and 4-pyridyl, chloro, and fluoro;
R4 represents methyl;
and a N-oxide or a pharmaceutically acceptable salt of such a compound.
15. The compound of formula I according to claim 1 wherein
R1 represents hydrogen;
R2 represents 3-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)phenyl;
R4 represents methyl;
and a N-oxide or a pharmaceutically acceptable salt of such a compound.
16. A compound according to any one of claim 1 wherein
R1 is hydrogen;
R2 represents phenyl which is mono- or disubstituted by imidazol-lower alkoxy, lower alkyl amino, trifluoromethyl, hydroxy lower alkyl amino, bis-(lower alkoxy lower alkyl)amino, lower alkyl piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, phenyl, pyridyl, imidazolyl which is unsubstituted or mono- or disubstituted by lower alkyl or N-lower alkyl carbamoyl;
R4 is lower alkyl;
and a N-oxide or a pharmaceutically acceptable salt of such a compound.
18. A process for the synthesis of a compound of the formula
or an N-oxide or a salt thereof, wherein the symbols R1, R2 and R4 are as defined in claim 1, characterized in that a compound of formula II
wherein R4 is as defined for a compound of formula I, or a derivative thereof wherein the carboxy group —COOH is in activated form, is reacted with an amine of the formula III
R1—NH—R2 (III)
R1—NH—R2 (III)
wherein R1 and R2 are as defined for a compound of the formula I, optionally in the presence of a dehydrating agent and an inert base and/or a suitable catalyst, and optionally in the presence of an inert solvent;
where the above starting compounds II and III may also be present with functional groups in protected form if necessary and/or in the form of salts, provided a salt-forming group is present and the reaction in salt form is possible;
any protecting groups in a protected derivative of a compound of the formula I are removed;
and, if so desired, an obtainable compound of formula I is converted into another compound of formula I or a N-oxide thereof, a free compound of formula I is converted into a salt, an obtainable salt of a compound of formula I is converted into the free compound or another salt, and/or a mixture of isomeric compounds of formula I is separated into the individual isomers.
19. A pharmaceutical composition comprising as an active ingredient a compound of formula I according to claim 1 or a N-oxide or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.
20. A method for the treatment of a disease which responds to an inhibition of protein kinase activity, which comprises administering a compound of formula I according to claim 1 or a N-oxide or a pharmaceutically acceptable salt thereof.
21. The use of a compound of formula I according to claim 1 or a N-oxide or a possible tautomer thereof or of a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment of a disease which responds to an inhibition of protein kinase activity.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13/106,582 US20110218187A1 (en) | 2002-07-05 | 2011-05-12 | Inhibitors of tyrosine kinases |
Applications Claiming Priority (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0215676.8 | 2002-07-05 | ||
GBGB0215676.8A GB0215676D0 (en) | 2002-07-05 | 2002-07-05 | Organic compounds |
GBGB0229893.3A GB0229893D0 (en) | 2002-07-05 | 2002-12-20 | Organic compounds |
GB0229893.3 | 2002-12-20 | ||
US10/520,359 US7169791B2 (en) | 2002-07-05 | 2003-07-04 | Inhibitors of tyrosine kinases |
PCT/EP2003/007198 WO2004005281A1 (en) | 2002-07-05 | 2003-07-04 | Inhibitors of tyrosine kinases |
US11/607,542 US20070093506A1 (en) | 2002-07-05 | 2006-12-01 | Inhibitors of tyrosine kinases |
US12/061,334 US7569566B2 (en) | 2002-07-05 | 2008-04-02 | Inhibitors of tyrosine kinases |
US12/489,049 US7956053B2 (en) | 2002-07-05 | 2009-06-22 | Inhibitors of tyrosine kinases |
US13/106,582 US20110218187A1 (en) | 2002-07-05 | 2011-05-12 | Inhibitors of tyrosine kinases |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/489,049 Continuation US7956053B2 (en) | 2002-07-05 | 2009-06-22 | Inhibitors of tyrosine kinases |
Publications (1)
Publication Number | Publication Date |
---|---|
US20110218187A1 true US20110218187A1 (en) | 2011-09-08 |
Family
ID=32178870
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/520,359 Expired - Lifetime US7169791B2 (en) | 2002-07-05 | 2003-07-04 | Inhibitors of tyrosine kinases |
US11/607,542 Abandoned US20070093506A1 (en) | 2002-07-05 | 2006-12-01 | Inhibitors of tyrosine kinases |
US12/061,334 Expired - Lifetime US7569566B2 (en) | 2002-07-05 | 2008-04-02 | Inhibitors of tyrosine kinases |
US12/489,049 Expired - Lifetime US7956053B2 (en) | 2002-07-05 | 2009-06-22 | Inhibitors of tyrosine kinases |
US13/106,582 Abandoned US20110218187A1 (en) | 2002-07-05 | 2011-05-12 | Inhibitors of tyrosine kinases |
Family Applications Before (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/520,359 Expired - Lifetime US7169791B2 (en) | 2002-07-05 | 2003-07-04 | Inhibitors of tyrosine kinases |
US11/607,542 Abandoned US20070093506A1 (en) | 2002-07-05 | 2006-12-01 | Inhibitors of tyrosine kinases |
US12/061,334 Expired - Lifetime US7569566B2 (en) | 2002-07-05 | 2008-04-02 | Inhibitors of tyrosine kinases |
US12/489,049 Expired - Lifetime US7956053B2 (en) | 2002-07-05 | 2009-06-22 | Inhibitors of tyrosine kinases |
Country Status (31)
Country | Link |
---|---|
US (5) | US7169791B2 (en) |
EP (4) | EP2100891A1 (en) |
JP (4) | JP4110140B2 (en) |
KR (2) | KR100864740B1 (en) |
CN (2) | CN1324022C (en) |
AR (1) | AR040390A1 (en) |
AT (1) | ATE414699T1 (en) |
AU (1) | AU2003249962C9 (en) |
BR (1) | BRPI0312464B8 (en) |
CA (3) | CA2491632C (en) |
CO (1) | CO5680432A2 (en) |
CY (1) | CY1108813T1 (en) |
DE (1) | DE60324805D1 (en) |
DK (1) | DK1532138T3 (en) |
EC (1) | ECSP055525A (en) |
ES (2) | ES2318164T3 (en) |
GB (2) | GB0215676D0 (en) |
HK (2) | HK1077811A1 (en) |
IL (2) | IL165977A (en) |
MX (1) | MXPA05000328A (en) |
MY (1) | MY143466A (en) |
NO (1) | NO331166B1 (en) |
NZ (1) | NZ537396A (en) |
PE (1) | PE20040647A1 (en) |
PL (3) | PL395096A1 (en) |
PT (2) | PT1532138E (en) |
RU (2) | RU2348627C2 (en) |
SI (1) | SI1532138T1 (en) |
TW (1) | TWI313603B (en) |
WO (1) | WO2004005281A1 (en) |
ZA (1) | ZA200410322B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9567317B2 (en) | 2012-10-19 | 2017-02-14 | Basf Se | Multicomponent crystalline system comprising nilotinib and selected co-crystal formers |
Families Citing this family (347)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0215676D0 (en) * | 2002-07-05 | 2002-08-14 | Novartis Ag | Organic compounds |
GB0325031D0 (en) * | 2003-10-27 | 2003-12-03 | Novartis Ag | Organic compounds |
ES2324917T3 (en) * | 2003-11-18 | 2009-08-19 | Novartis Ag | INHIBITORS OF THE MUTANT FORM OF KIT. |
JPWO2005063720A1 (en) * | 2003-12-25 | 2007-07-19 | 日本新薬株式会社 | Amide derivatives and pharmaceuticals |
WO2005089718A2 (en) | 2004-03-23 | 2005-09-29 | Novartis Ag | Pharmaceutical compositions |
WO2005113494A2 (en) * | 2004-05-07 | 2005-12-01 | Amgen Inc. | Nitrogenated heterocyclic derivatives as protein kinase modulators and use for the treatment of angiogenesis and cancer |
RU2007123675A (en) * | 2004-11-24 | 2008-12-27 | Новартис АГ (CH) | JAK INHIBITOR COMBINATIONS |
CN1939910A (en) * | 2004-12-31 | 2007-04-04 | 孙飘扬 | Amino-metadiazine compound and its salt, its preparation and pharmaceutical use |
BRPI0606872A2 (en) * | 2005-01-28 | 2009-07-21 | Novartis Ag | use of pyrimidylaminobenzamides for the treatment of diseases that respond to modulation of tie-2 kinase activity |
EP1863491A1 (en) * | 2005-02-25 | 2007-12-12 | Novartis AG | Pharmaceutical combination of bcr-abl and raf inhibitors |
EP1879584B1 (en) * | 2005-05-02 | 2016-06-22 | Novartis AG | Pyrimidylaminobenzamide derivatives for hypereosinophilic syndrome |
US20080176879A1 (en) * | 2005-05-02 | 2008-07-24 | Leila Alland | Pyrimidylaminobenzamide Derivatives For Sytemic Mastocytosis |
KR101562549B1 (en) | 2005-05-10 | 2015-10-23 | 인사이트 홀딩스 코포레이션 | Modulators of indoleamine 2,3-dioxygenase and methods of using the same |
BRPI0611506A2 (en) * | 2005-06-03 | 2010-09-14 | Novartis Ag | COMBINATION OF PYRIMIDYLAMINOBENZAMIDE AND IMATINIB COMPOUNDS TO TREAT OR PREVENT PROLIFERATIVE DISEASES |
GT200600207A (en) * | 2005-06-09 | 2007-01-15 | Novartis Ag | PROCESS FOR THE SYNTHESIS OF ORGANIC COMPOUNDS |
SA06270147B1 (en) * | 2005-06-09 | 2009-12-22 | نوفارتيس ايه جي | Process for the Synthesis Of 5-(methyl-1h-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine |
AU2013205820B2 (en) * | 2005-06-09 | 2015-11-26 | Novartis Ag | Process for the synthesis of organic compounds |
MY146795A (en) * | 2005-06-09 | 2012-09-28 | Novartis Ag | Process for the synthesis of organic compounds |
ES2356257T3 (en) * | 2005-06-09 | 2011-04-06 | Novartis Ag | PROCESS FOR THE SYNTHESIS OF 5- (METHYL-1H-IMIDAZOL-1-IL) -3- (TRIFLUOROMETIL) -BENCENOAMINE. |
US8071768B2 (en) | 2005-06-10 | 2011-12-06 | Janssen Pharmaceutica, N.V. | Alkylquinoline and alkylquinazoline kinase modulators |
US20060281788A1 (en) | 2005-06-10 | 2006-12-14 | Baumann Christian A | Synergistic modulation of flt3 kinase using a flt3 inhibitor and a farnesyl transferase inhibitor |
US7825244B2 (en) | 2005-06-10 | 2010-11-02 | Janssen Pharmaceutica Nv | Intermediates useful in the synthesis of alkylquinoline and alkylquinazoline kinase modulators, and related methods of synthesis |
JP5118029B2 (en) * | 2005-06-14 | 2013-01-16 | タイゲン バイオテクノロジー カンパニー,リミテッド | Pyrimidine compounds |
US8193206B2 (en) | 2005-06-14 | 2012-06-05 | Taigen Biotechnology Co., Ltd. | Pyrimidine compounds |
GT200600316A (en) * | 2005-07-20 | 2007-04-02 | SALTS OF 4-METHYL-N- (3- (4-METHYL-IMIDAZOL-1-ILO) -5-TRIFLUOROMETILO-PHENYL) -3- (4-PIRIDINA-3-ILO-PIRIMIDINA-2-ILOAMINO) - BENZAMIDA. | |
EP1954278A2 (en) * | 2005-07-20 | 2008-08-13 | Novartis AG | Combination comprising a pyrimidylaminobenzamides and a flt-3 inhibitor for treating proliferative diseases |
GT200600315A (en) * | 2005-07-20 | 2007-03-19 | CRYSTAL FORMS OF 4-METHYL-N- [3- (4-METHYL-IMIDAZOL-1-ILO) -5-TRIFLUOROMETILO-PHENYL] -3- (4-PYRIDINA-3-ILO-PIRIMIDINA-2-ILOAMINO) -BENZAMIDA | |
AU2012203844B2 (en) * | 2005-07-20 | 2014-12-11 | Novartis Ag | Salts of 4-methyl-n-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide |
MX2008000897A (en) * | 2005-07-20 | 2008-03-18 | Novartis Ag | Combination of a pyrimidylaminobenzamide and an mtor kinase inhibitor. |
KR100674813B1 (en) * | 2005-08-05 | 2007-01-29 | 일양약품주식회사 | N-phenyl-2-pyrimidine-amine derivatives and process for the preparation thereof |
US20080200488A1 (en) * | 2005-08-11 | 2008-08-21 | Manley Paul W | Combinations Comprising a Protein Kinase Inhibitor Being a Pyrimidylaminobenzamide Compound and a Hsp90 Inhibitor Such as 17-Aag |
AU2006279781A1 (en) * | 2005-08-11 | 2007-02-22 | Novartis Ag | Combination of organic compounds |
EP1926735A1 (en) | 2005-09-22 | 2008-06-04 | Incyte Corporation | Tetracyclic inhibitors of janus kinases |
JP2009511450A (en) * | 2005-10-07 | 2009-03-19 | ノバルティス アクチエンゲゼルシャフト | Combination of nilotinib and farnesyltransferase inhibitor |
UA94719C2 (en) | 2005-10-18 | 2011-06-10 | Янссен Фармацевтика Н.В. | Use of imidazole-2-carboxylic acid derivative for the treatment or prevention of hematological malignancy |
WO2007051862A1 (en) * | 2005-11-07 | 2007-05-10 | Novartis Ag | Combination of organic compounds |
EP1955073A2 (en) * | 2005-11-15 | 2008-08-13 | Brystol-Myers Squibb Company | Methods of identifying and treating individuals exhibiting mdr-1 overexpression with protein tyrosine kinase inhibitors and combinations thereof |
WO2007065898A1 (en) * | 2005-12-06 | 2007-06-14 | Novartis Ag | Pyrimidylaminobenzamide derivatives for the treatment of neurofibromatosis |
LT2474545T (en) | 2005-12-13 | 2017-02-27 | Incyte Holdings Corporation | Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as Janus kinase inhibitors |
WO2007109527A1 (en) * | 2006-03-17 | 2007-09-27 | Bristol-Myers Squibb Company | Methods of identifying and treating individuals exhibiting mutant bcr/abl kinase polypeptides |
EP2314297A1 (en) * | 2006-04-05 | 2011-04-27 | Novartis AG | Combinations comprising bcr-abl/c-kit/pdgf-r tk inhibitors for treating cancer |
AU2011202833B2 (en) * | 2006-04-07 | 2012-05-24 | Novartis Ag | Combination comprising a) a pyrimidylaminobenzamide compound, and b) a Thr315lle kinase inhibitor |
MX2008012971A (en) | 2006-04-07 | 2008-10-15 | Novartis Ag | Combination comprising a) a pyrimidylaminobenzamide compound, and b) a thr315lle kinase inhibitor. |
BRPI0710548B8 (en) | 2006-04-20 | 2021-05-25 | Janssen Pharmaceutica Nv | c-fms kinase inhibitors, pharmaceutical composition and pharmaceutical dosage form |
US8697716B2 (en) | 2006-04-20 | 2014-04-15 | Janssen Pharmaceutica Nv | Method of inhibiting C-KIT kinase |
ATE510832T1 (en) | 2006-04-20 | 2011-06-15 | Janssen Pharmaceutica Nv | HETEROCYCLIC COMPOUNDS AS C-FMS KINASE INHIBITORS |
PE20110235A1 (en) | 2006-05-04 | 2011-04-14 | Boehringer Ingelheim Int | PHARMACEUTICAL COMBINATIONS INCLUDING LINAGLIPTIN AND METMORPHINE |
JP2009537606A (en) * | 2006-05-25 | 2009-10-29 | ノバルティス アクチエンゲゼルシャフト | Tyrosine kinase inhibitor |
PT2068938E (en) | 2006-09-22 | 2011-03-23 | Novartis Ag | Optimization of the treatment of philadelphia-positive leukemia with abl tyrosine kinase inhibitor imatinib |
EP1923053A1 (en) * | 2006-09-27 | 2008-05-21 | Novartis AG | Pharmaceutical compositions comprising nilotinib or its salt |
WO2008044045A1 (en) | 2006-10-12 | 2008-04-17 | Astex Therapeutics Limited | Pharmaceutical combinations |
EP2073803B1 (en) | 2006-10-12 | 2018-09-19 | Astex Therapeutics Limited | Pharmaceutical combinations |
CN101622244A (en) * | 2006-11-03 | 2010-01-06 | Irm责任有限公司 | Compounds and compositions as protein kinase inhibitors |
WO2008059724A1 (en) * | 2006-11-13 | 2008-05-22 | Toray Fine Chemicals Co., Ltd. | Process for production of 2,2'-bis(trifluoromethyl)- 4,4'-diaminobiphenyl |
CN101568537A (en) * | 2006-12-21 | 2009-10-28 | 安斯泰来制药有限公司 | Method for producing C-glycoside derivative and synthetic intermediate thereof |
WO2008079965A1 (en) | 2006-12-22 | 2008-07-03 | Incyte Corporation | Substituted heterocycles as janus kinase inhibitors |
JP5160636B2 (en) * | 2007-05-04 | 2013-03-13 | アイアールエム・リミテッド・ライアビリティ・カンパニー | Pyrimidine derivatives and compositions as c-kit and PDGFR kinase inhibitors |
MX2009011951A (en) | 2007-05-04 | 2009-12-11 | Irm Llc | Compounds and compositions as c-kit and pdgfr kinase inhibitors. |
CA2689989A1 (en) * | 2007-06-04 | 2008-12-11 | Avila Therapeutics, Inc. | Heterocyclic compounds and uses thereof |
WO2008153959A1 (en) | 2007-06-07 | 2008-12-18 | Intra-Cellular Therapies, Inc. | Novel heterocycle compounds and uses thereof |
EP2166860B1 (en) | 2007-06-07 | 2016-09-21 | Intra-Cellular Therapies, Inc. | Novel heterocycle compounds and uses thereof |
EP2170887A2 (en) | 2007-06-07 | 2010-04-07 | Amgen Inc. | Heterocyclic compounds as raf kinase modulators |
CL2008001709A1 (en) | 2007-06-13 | 2008-11-03 | Incyte Corp | Compounds derived from pyrrolo [2,3-b] pyrimidine, jak kinase modulators; pharmaceutical composition; and use in the treatment of diseases such as cancer, psoriasis, rheumatoid arthritis, among others. |
CA2689663C (en) | 2007-06-13 | 2016-08-09 | Incyte Corporation | Salts of the janus kinase inhibitor (r)-3-(4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropanenitrile |
EP2190825B1 (en) | 2007-08-22 | 2014-04-09 | Irm Llc | 5- (4- (haloalkoxy) phenyl) pyrimidine-2-amine compounds and compositions as kinase inhibitors |
EA017392B1 (en) | 2007-08-22 | 2012-12-28 | Айрм Ллк | 2-heteroarylamino-pyrimidine derivatives as kinase inhibitors |
PT2200436E (en) * | 2007-09-04 | 2015-04-29 | Scripps Research Inst | Substituted pyrimidinyl-amines as protein kinase inhibitors |
JO3240B1 (en) | 2007-10-17 | 2018-03-08 | Janssen Pharmaceutica Nv | Inhibitors of c-fms Kinase |
BRPI0820544A2 (en) | 2007-11-16 | 2015-06-16 | Incyte Corp | 4-pyrazolyl-n-arylpyrimidin-2-amines and pyrazolyl-n-heteroarylpyrimidin-2-amines as janus kinase inhibitors |
PL2240172T3 (en) | 2007-12-21 | 2014-08-29 | Novartis Ag | Combination of nilotinib and chlorambucil for the treatment of chronic lymphocytic leukemia |
RS55263B1 (en) | 2008-03-11 | 2017-02-28 | Incyte Holdings Corp | Azetidine and cyclobutane derivatives as jak inhibitors |
JP2011518836A (en) | 2008-04-24 | 2011-06-30 | インサイト・コーポレイション | Macrocycles and their use as kinase inhibitors |
EA029781B1 (en) | 2008-07-08 | 2018-05-31 | Инсайт Корпорейшн | 1,2,5-oxadiazoles as inhibitors of indoleamine-2,3-dioxygenase |
US20100016590A1 (en) * | 2008-07-17 | 2010-01-21 | Teva Pharmaceutical Industries Ltd. | Nilotinib intermediates and preparation thereof |
UY32030A (en) | 2008-08-06 | 2010-03-26 | Boehringer Ingelheim Int | "TREATMENT FOR DIABETES IN INAPPROPRIATE PATIENTS FOR THERAPY WITH METFORMIN" |
MX2011001668A (en) * | 2008-08-13 | 2011-03-25 | Novartis Ag | Treatment of pulmonary arterial hypertension. |
KR20100021321A (en) * | 2008-08-14 | 2010-02-24 | 일양약품주식회사 | Process for the preparation of n-phenyl-2-pyrimidine-amine derivatives |
US20110190322A1 (en) | 2008-08-14 | 2011-08-04 | Boehringer Ingelheim International Gmbh | Purin derivatives for use in the treatment of fab-related diseases |
CL2009001884A1 (en) | 2008-10-02 | 2010-05-14 | Incyte Holdings Corp | Use of 3-cyclopentyl-3- [4- (7h-pyrrolo [2,3-d] pyrimidin-4-yl) -1h-pyrazol-1-yl) propanonitrile, janus kinase inhibitor, and use of a composition that understands it for the treatment of dry eye. |
PL2262793T3 (en) * | 2008-11-05 | 2013-01-31 | Teva Pharma | Nilotinib hci crystalline forms |
EP2186514B1 (en) | 2008-11-14 | 2016-06-29 | Kinki University | Treatment of Malignant Peripheral Nerve Sheath Tumors |
WO2010060074A1 (en) * | 2008-11-24 | 2010-05-27 | Teva Pharmaceutical Industries Ltd. | Preparation of nilotinib and intermediates thereof |
BRPI0923121A2 (en) | 2008-12-23 | 2015-08-11 | Boehringer Ingelheim Int | Saline forms of organic compounds |
CN101759683B (en) * | 2008-12-25 | 2011-12-28 | 哈尔滨誉衡药业股份有限公司 | Preparation method of hydrindene amide compound, medical composition comprising hydrindene amide compound and application thereof as protein kinase inhibitor |
AR074990A1 (en) | 2009-01-07 | 2011-03-02 | Boehringer Ingelheim Int | TREATMENT OF DIABETES IN PATIENTS WITH AN INAPPROPRIATE GLUCEMIC CONTROL THROUGH METFORMIN THERAPY |
WO2010085597A1 (en) | 2009-01-23 | 2010-07-29 | Incyte Corporation | Macrocyclic compounds and their use as kinase inhibitors |
TWI466672B (en) | 2009-01-29 | 2015-01-01 | Boehringer Ingelheim Int | Treatment for diabetes in paediatric patients |
AU2010212823B2 (en) | 2009-02-13 | 2016-01-28 | Boehringer Ingelheim International Gmbh | Antidiabetic medications comprising a DPP-4 inhibitor (linagliptin) optionally in combination with other antidiabetics |
CN102316738A (en) * | 2009-02-18 | 2012-01-11 | 盛泰萨路申有限公司 | Amides as kinase inhibitors |
US20120015968A1 (en) | 2009-03-06 | 2012-01-19 | Novartis Ag | Use of pyrimidylaminobenzamide derivatives for the treatment of disorders mediated by the leucine zipper-and sterile alpha motif-containing kinase (zak) |
BRPI1012159B1 (en) | 2009-05-22 | 2022-01-25 | Incyte Holdings Corporation | Compounds derived from n-(hetero)aryl-pyrrolidine of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines and pyrrol-3-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors, compositions pharmaceuticals comprising said compounds and uses thereof |
DK2432472T3 (en) | 2009-05-22 | 2019-11-18 | Incyte Holdings Corp | 3- [4- (7H-PYRROLO [2,3-D] PYRIMIDIN-4-YL) -1H-PYRAZOL-1-YL] OCTAN OR HEPTAN NITRIL AS JAK INHIBITORS |
TW201102068A (en) * | 2009-06-02 | 2011-01-16 | Novartis Ag | Treatment of ophthalmologic disorders mediated by alpha-carbonic anhydrase isoforms |
US20110053968A1 (en) * | 2009-06-09 | 2011-03-03 | Auspex Pharmaceuticals, Inc. | Aminopyrimidine inhibitors of tyrosine kinase |
ME01838B (en) | 2009-06-29 | 2014-12-20 | Lncyte Holdings Corp | Pyrimidinones as pi3k inhibitors |
WO2011014520A2 (en) | 2009-07-29 | 2011-02-03 | Irm Llc | Compounds and compositions as modulators of gpr119 activity |
WO2011016861A2 (en) | 2009-08-05 | 2011-02-10 | Intra-Cellular Therapies, Inc. | Novel regulatory proteins and inhibitors |
TW201113285A (en) | 2009-09-01 | 2011-04-16 | Incyte Corp | Heterocyclic derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors |
WO2011033307A1 (en) | 2009-09-17 | 2011-03-24 | Generics [Uk] Limited | Nilotinib dihydrochloride salt |
US20120219623A1 (en) | 2009-10-02 | 2012-08-30 | Boehringer Ingelheim International Gmbh | Pharmaceutical compositions comprising bi-1356 and metformin |
CA2777114C (en) | 2009-10-09 | 2018-10-23 | Incyte Corporation | Hydroxyl, keto, and glucuronide derivatives of 3-(4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropanenitrile |
US8575168B2 (en) | 2009-10-09 | 2013-11-05 | Irm Llc | Compounds and compositions as modulators of GPR119 activity |
RU2012120901A (en) * | 2009-10-23 | 2013-12-10 | Новартис Аг | METHOD FOR TREATING PROLIFERATIVE DISORDERS AND OTHER PATHOLOGICAL CONDITIONS mediated by the action of kinases BCR-ABL, C-KIT, DDR1, DDR2 OR PDGF-R |
JO3634B1 (en) | 2009-11-17 | 2020-08-27 | Novartis Ag | Method of treating proliferative disorders and other pathological conditions mediated by bcr-abl, c-kit, ddr1, ddr2 or pdgf-r kinase activity |
CN102753161A (en) | 2009-11-27 | 2012-10-24 | 贝林格尔.英格海姆国际有限公司 | Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin |
US8394858B2 (en) | 2009-12-03 | 2013-03-12 | Novartis Ag | Cyclohexane derivatives and uses thereof |
AR079529A1 (en) | 2009-12-18 | 2012-02-01 | Incyte Corp | ARILO AND HETEROARILO DERIVATIVES REPLACED AND FOUNDED AS INHIBITORS OF THE PI3K |
US8759359B2 (en) | 2009-12-18 | 2014-06-24 | Incyte Corporation | Substituted heteroaryl fused derivatives as PI3K inhibitors |
US9109227B2 (en) | 2010-01-05 | 2015-08-18 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | FLT3 receptor antagonists for the treatment or the prevention of pain disorders |
JP5734313B2 (en) | 2010-01-12 | 2015-06-17 | アーべー・シオンス | Thiazole and oxazole kinase inhibitors |
IN2010KO00035A (en) | 2010-01-15 | 2016-09-02 | ||
AU2011217961B2 (en) | 2010-02-18 | 2016-05-05 | Incyte Holdings Corporation | Cyclobutane and methylcyclobutane derivatives as Janus kinase inhibitors |
KR20220015492A (en) | 2010-03-10 | 2022-02-08 | 인사이트 홀딩스 코포레이션 | Piperidin-4-yl azetidine derivatives as jak1 inhibitors |
US20130109703A1 (en) | 2010-03-18 | 2013-05-02 | Boehringer Ingelheim International Gmbh | Combination of a GPR119 Agonist and the DPP-IV Inhibitor Linagliptin for Use in the Treatment of Diabetes and Related Conditions |
EP2558463A1 (en) | 2010-04-14 | 2013-02-20 | Incyte Corporation | Fused derivatives as i3 inhibitors |
JP2013525296A (en) * | 2010-04-16 | 2013-06-20 | ノバルティス アーゲー | Treatment of endocrine therapy-resistant breast cancer |
EP2382976A1 (en) | 2010-04-30 | 2011-11-02 | Hiroshima University | Use of pdgf-r inhibitors for the treatment of lymph node metastasis of gastric cancer |
WO2011138421A1 (en) | 2010-05-05 | 2011-11-10 | Boehringer Ingelheim International Gmbh | Combination therapy |
PL2574168T3 (en) | 2010-05-21 | 2016-10-31 | Topical formulation for a jak inhibitor | |
EP2571863B1 (en) | 2010-06-21 | 2015-09-23 | Teva Pharmaceutical Industries Ltd. | Nilotinib salts and crystalline forms thereof |
US9062055B2 (en) | 2010-06-21 | 2015-06-23 | Incyte Corporation | Fused pyrrole derivatives as PI3K inhibitors |
EP3124041A1 (en) | 2010-06-24 | 2017-02-01 | Boehringer Ingelheim International GmbH | Diabetes therapy |
US8697739B2 (en) | 2010-07-29 | 2014-04-15 | Novartis Ag | Bicyclic acetyl-CoA carboxylase inhibitors and uses thereof |
US8426418B2 (en) | 2010-08-27 | 2013-04-23 | CollabRx Inc. | Method to treat melanoma in BRAF inhibitor-resistant subjects |
AR083878A1 (en) | 2010-11-15 | 2013-03-27 | Boehringer Ingelheim Int | VASOPROTECTORA AND CARDIOPROTECTORA ANTIDIABETIC THERAPY, LINAGLIPTINA, TREATMENT METHOD |
CA2818542A1 (en) | 2010-11-19 | 2012-05-24 | Incyte Corporation | Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as jak inhibitors |
ES2536415T3 (en) | 2010-11-19 | 2015-05-25 | Incyte Corporation | Pyrrolopyridines and heterocyclic substituted pyrrolopyrimidines as JAK inhibitors |
US8703788B2 (en) * | 2010-11-26 | 2014-04-22 | Bandi Parthasaradhi Reddy | Polymorph of nilotinib hydrochloride |
EP2655374B1 (en) | 2010-12-20 | 2019-10-23 | Incyte Holdings Corporation | N-(1-(substituted-phenyl)ethyl)-9h-purin-6-amines as pi3k inhibitors |
ES2608829T3 (en) | 2011-01-21 | 2017-04-17 | Sun Pharma Advanced Research Company Limited | Tyrosine kinase inhibitors containing diarylacetylene hydrazide |
ES2547916T3 (en) | 2011-02-18 | 2015-10-09 | Novartis Pharma Ag | MTOR / JAK inhibitor combination therapy |
WO2012118599A1 (en) | 2011-02-28 | 2012-09-07 | Emory University | C-abl tyrosine kinase inhibitors useful for inhibiting filovirus replication |
US9108984B2 (en) | 2011-03-14 | 2015-08-18 | Incyte Corporation | Substituted diamino-pyrimidine and diamino-pyridine derivatives as PI3K inhibitors |
WO2012135009A1 (en) | 2011-03-25 | 2012-10-04 | Incyte Corporation | Pyrimidine-4,6-diamine derivatives as pi3k inhibitors |
SI2717883T1 (en) | 2011-05-02 | 2017-06-30 | Stichting Vumc | Protection against endothelial barrier dysfunction through inhibition of the tyrosine kinase abl-related gene (arg) |
EP2721028B1 (en) | 2011-06-20 | 2015-11-04 | Incyte Corporation | Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as jak inhibitors |
ES2713566T3 (en) | 2011-07-15 | 2019-05-22 | Boehringer Ingelheim Int | Derivative of substituted dinamic quinazoline, its preparation and its use in pharmaceutical compositions for the treatment of type I and II diabetes |
US9358229B2 (en) | 2011-08-10 | 2016-06-07 | Novartis Pharma Ag | JAK PI3K/mTOR combination therapy |
CN102321073A (en) * | 2011-08-12 | 2012-01-18 | 西安交通大学 | Preparation method of nilotinib |
TW201313721A (en) | 2011-08-18 | 2013-04-01 | Incyte Corp | Cyclohexyl azetidine derivatives as JAK inhibitors |
KR102371532B1 (en) | 2011-09-02 | 2022-03-07 | 인사이트 홀딩스 코포레이션 | Heterocyclylamines as pi3k inhibitors |
UA111854C2 (en) | 2011-09-07 | 2016-06-24 | Інсайт Холдінгс Корпорейшн | METHODS AND INTERMEDIATE COMPOUNDS FOR JAK INHIBITORS |
WO2013063003A1 (en) | 2011-10-28 | 2013-05-02 | Novartis Ag | Method of treating gastrointestinal stromal tumors |
WO2013063000A1 (en) | 2011-10-28 | 2013-05-02 | Novartis Ag | Method of treating gastrointestinal stromal tumors |
GB2496135B (en) | 2011-11-01 | 2015-03-18 | Valirx Plc | Inhibitors of the interaction between a Src family kinase and an androgen receptor or estradiol receptor for treatment of endometriosis |
EP2776130A1 (en) | 2011-11-07 | 2014-09-17 | Institut National de la Sante et de la Recherche Medicale (INSERM) | A ddr1 antagonist or an inhibitor of ddr1 gene expression for use in the prevention or treatment of crescentic glomerulonephritis |
EP2779995A1 (en) * | 2011-11-14 | 2014-09-24 | Novartis AG | Immediate release 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-n-[5-(4-methyl- 1h-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide formulation |
CN103172617A (en) * | 2011-12-20 | 2013-06-26 | 天津市国际生物医药联合研究院 | Application of 1,5-2 substituent-1,2,3-triazole trifluoromethyl compound |
US20130172244A1 (en) | 2011-12-29 | 2013-07-04 | Thomas Klein | Subcutaneous therapeutic use of dpp-4 inhibitor |
ES2564969T3 (en) | 2012-02-09 | 2016-03-30 | Natco Pharma Limited | Process for the preparation of nilotinib hydrochloride |
US9061028B2 (en) | 2012-02-15 | 2015-06-23 | Natco Pharma Limited | Process for the preparation of Nilotinib |
RS61500B1 (en) | 2012-03-01 | 2021-03-31 | Array Biopharma Inc | Serine/threonine kinase inhibitors |
AR090548A1 (en) | 2012-04-02 | 2014-11-19 | Incyte Corp | BICYCLIC AZAHETEROCICLOBENCILAMINS AS PI3K INHIBITORS |
TW201348213A (en) | 2012-04-24 | 2013-12-01 | Chugai Pharmaceutical Co Ltd | Quinazolinedione derivative |
JP6177768B2 (en) | 2012-04-24 | 2017-08-09 | 中外製薬株式会社 | Benzamide derivatives |
JP6218811B2 (en) | 2012-05-14 | 2017-10-25 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Xanthine derivatives as DPP-4 inhibitors for use in the treatment of SIRS and / or sepsis |
WO2013171167A1 (en) | 2012-05-14 | 2013-11-21 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in the treatment of podocytes related disorders and/or nephrotic syndrome |
PL2900637T3 (en) | 2012-05-15 | 2018-01-31 | Novartis Ag | Thiazole or imidazole substituted pyrimidine, pyridine and pyrazine amide derivatives and related compounds as abl1, abl2 and bcr-abl1 inhibitors for the treatment of cancer, specific viral infections and specific cns disorders |
BR112014026383B1 (en) * | 2012-05-15 | 2020-11-17 | Novartis Ag | benzamide derivatives, their use, and pharmaceutical composition |
EP2858988B1 (en) * | 2012-05-15 | 2018-02-28 | Novartis AG | Benzamide derivatives for inhibiting the activity of abl1, abl2 and bcr-abl1 |
EA201492007A1 (en) | 2012-05-15 | 2015-03-31 | Новартис Аг | DERIVATIVES OF BENZAMIDE FOR INHIBITION OF ABL1, ABL2 AND BCR-ABL1 ACTIVITY |
WO2013173720A1 (en) | 2012-05-18 | 2013-11-21 | Incyte Corporation | Piperidinylcyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as jak inhibitors |
EP2854812A1 (en) | 2012-05-24 | 2015-04-08 | Boehringer Ingelheim International GmbH | A xanthine derivative as dpp -4 inhibitor for use in the treatment of autoimmune diabetes, particularly lada |
WO2013174767A1 (en) | 2012-05-24 | 2013-11-28 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference |
US9056860B2 (en) * | 2012-06-05 | 2015-06-16 | Gilead Pharmasset Llc | Synthesis of antiviral compound |
ME02651B (en) | 2012-06-13 | 2017-06-20 | Incyte Holdings Corp | Substituted tricyclic compounds as fgfr inhibitors |
JP2015522070A (en) | 2012-07-11 | 2015-08-03 | ノバルティス アーゲー | How to treat gastrointestinal stromal tumors |
BR112015001838B1 (en) | 2012-07-27 | 2022-10-25 | Izumi Technology, Llc | COMPOSITION OF EFLUX INHIBITOR |
JOP20180012A1 (en) | 2012-08-07 | 2019-01-30 | Janssen Pharmaceutica Nv | Sulfonylation process using nonafluorobutanesulfonyl fluoride |
AU2013299922B2 (en) | 2012-08-07 | 2018-06-21 | Janssen Pharmaceutica Nv | Process for the preparation of heterocyclic ester derivatives |
TWI569799B (en) | 2012-09-21 | 2017-02-11 | 安羅格製藥股份有限公司 | Method of inhibiting constitutively active phosphorylated flt3 kinase |
WO2014052619A1 (en) | 2012-09-27 | 2014-04-03 | Irm Llc | Piperidine derivatives and compositions as modulators of gpr119 activity |
NZ707495A (en) | 2012-11-01 | 2019-01-25 | Incyte Holdings Corp | Tricyclic fused thiophene derivatives as jak inhibitors |
PE20200175A1 (en) | 2012-11-15 | 2020-01-24 | Incyte Holdings Corp | SUSTAINED RELEASE RUXOLITINIB DOSAGE FORMS |
BR112015016282A2 (en) | 2013-01-07 | 2017-07-11 | Arog Pharmaceuticals Inc | crenolanib for treatment of mutated flt3 proliferative disorders |
CN103910714A (en) * | 2013-01-09 | 2014-07-09 | 天津泰瑞倍药研科技有限公司 | Fluoro cyclobutyl imidazole compound |
WO2014124860A1 (en) | 2013-02-14 | 2014-08-21 | Boehringer Ingelheim International Gmbh | Specific pde4b-inhibitors for the treatment of diabetes mellitus |
TWI657090B (en) | 2013-03-01 | 2019-04-21 | 英塞特控股公司 | USE OF PYRAZOLOPYRIMIDINE DERIVATIVES FOR THE TREATMENT OF PI3Kδ RELATED DISORDERS |
UA120162C2 (en) | 2013-03-06 | 2019-10-25 | Інсайт Холдінгс Корпорейшн | Processes and intermediates for making a jak inhibitor |
CA2903577C (en) | 2013-03-15 | 2023-10-17 | Boehringer Ingelheim International Gmbh | Use of linagliptin in cardio- and renoprotective antidiabetic therapy |
CA2909207C (en) | 2013-04-19 | 2021-11-02 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
EP2988729A1 (en) | 2013-04-25 | 2016-03-02 | Sun Pharmaceutical Industries Limited | Pharmaceutical gastro-retentive solid oral dosage form of nilotinib |
GB2513615A (en) | 2013-05-01 | 2014-11-05 | Cancer Rec Tech Ltd | Medical use |
HUE033587T2 (en) | 2013-05-17 | 2017-12-28 | Incyte Corp | Bipyrazole derivatives as jak inhibitors |
CN103288804A (en) * | 2013-05-24 | 2013-09-11 | 苏州明锐医药科技有限公司 | Preparation method of nilotinib |
CA3155500A1 (en) | 2013-08-07 | 2015-02-12 | Incyte Corporation | Sustained release dosage forms for a jak1 inhibitor |
CA2921568A1 (en) | 2013-08-20 | 2015-02-25 | Incyte Corporation | Survival benefit in patients with solid tumors with elevated c-reactive protein levels |
EP3757130A1 (en) | 2013-09-26 | 2020-12-30 | Costim Pharmaceuticals Inc. | Methods for treating hematologic cancers |
JP6307088B2 (en) | 2013-10-23 | 2018-04-04 | 中外製薬株式会社 | Quinazolinone and isoquinolinone derivatives |
US10463658B2 (en) | 2013-10-25 | 2019-11-05 | Videra Pharmaceuticals, Llc | Method of inhibiting FLT3 kinase |
WO2015092624A1 (en) | 2013-12-16 | 2015-06-25 | Ranbaxy Laboratories Limited | Nilotinib mono-oxalate and its crystalline form |
JOP20200094A1 (en) | 2014-01-24 | 2017-06-16 | Dana Farber Cancer Inst Inc | Antibody molecules to pd-1 and uses thereof |
JOP20200096A1 (en) | 2014-01-31 | 2017-06-16 | Children’S Medical Center Corp | Antibody molecules to tim-3 and uses thereof |
MX2016011103A (en) | 2014-02-28 | 2017-02-28 | Incyte Corp | Jak1 inhibitors for the treatment of myelodysplastic syndromes. |
AU2015229103C9 (en) | 2014-03-14 | 2020-11-26 | Immutep S.A.S | Antibody molecules to LAG-3 and uses thereof |
CA3158254C (en) | 2014-04-08 | 2024-05-21 | Incyte Corporation | Treatment of b-cell malignancies by a combination jak and pi3k inhibitors |
SG10201809518QA (en) | 2014-04-30 | 2018-11-29 | Incyte Corp | Processes of preparing a jak1 inhibitor and new forms thereto |
US9498467B2 (en) | 2014-05-30 | 2016-11-22 | Incyte Corporation | Treatment of chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) by inhibitors of JAK1 |
US10077277B2 (en) | 2014-06-11 | 2018-09-18 | Incyte Corporation | Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors |
WO2016016370A1 (en) | 2014-07-31 | 2016-02-04 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Flt3 receptor antagonists |
WO2016033304A1 (en) | 2014-08-28 | 2016-03-03 | Codexis, Inc. | Imidazoyl anilide derivatives and methods of use |
WO2016035023A1 (en) | 2014-09-03 | 2016-03-10 | Novartis Ag | Pharmaceutical combinations and their use |
EP3925622A1 (en) | 2014-09-13 | 2021-12-22 | Novartis AG | Combination therapies |
US20170209574A1 (en) | 2014-10-03 | 2017-07-27 | Novartis Ag | Combination therapies |
MA41044A (en) | 2014-10-08 | 2017-08-15 | Novartis Ag | COMPOSITIONS AND METHODS OF USE FOR INCREASED IMMUNE RESPONSE AND CANCER TREATMENT |
TWI716362B (en) | 2014-10-14 | 2021-01-21 | 瑞士商諾華公司 | Antibody molecules to pd-l1 and uses thereof |
WO2016059220A1 (en) | 2014-10-16 | 2016-04-21 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Tcr-activating agents for use in the treatment of t-all |
CN104592122B (en) * | 2014-12-09 | 2018-01-23 | 凯莱英医药集团(天津)股份有限公司 | The preparation method of 3 (base of 4 methyl 1H imidazoles 1) 5 (trifluoromethyl) aniline |
WO2016130501A1 (en) | 2015-02-09 | 2016-08-18 | Incyte Corporation | Aza-heteroaryl compounds as pi3k-gamma inhibitors |
CR20170390A (en) | 2015-02-20 | 2017-10-23 | Incyte Holdings Corp | BICYCLE HETEROCICLES AS FGFR INHIBITORS |
MA41551A (en) | 2015-02-20 | 2017-12-26 | Incyte Corp | BICYCLIC HETEROCYCLES USED AS FGFR4 INHIBITORS |
NZ734993A (en) | 2015-02-27 | 2024-03-22 | Incyte Holdings Corp | Salts of pi3k inhibitor and processes for their preparation |
CN105985293B (en) * | 2015-03-04 | 2018-04-03 | 埃斯特维华义制药有限公司 | The preparation method of AMN107 intermediate |
JP6692826B2 (en) | 2015-03-10 | 2020-05-13 | アドゥロ バイオテック,インク. | Compositions and methods for activation of "interferon gene stimulator" dependent signaling |
EP3271351A1 (en) | 2015-03-20 | 2018-01-24 | Cipla Limited | Novel polymorphic form x of nilotinib dihydrochloride hydrate |
US9988401B2 (en) | 2015-05-11 | 2018-06-05 | Incyte Corporation | Crystalline forms of a PI3K inhibitor |
WO2016183062A1 (en) | 2015-05-11 | 2016-11-17 | Incyte Corporation | Salts of (s)-7-(1-(9h-purin-6-ylamino)ethyl)-6-(3-fluorophenyl)-3-methyl-5h-thiazolo[3,2-a]pyrimidin-5-one |
US9732097B2 (en) | 2015-05-11 | 2017-08-15 | Incyte Corporation | Process for the synthesis of a phosphoinositide 3-kinase inhibitor |
EP3095782A1 (en) | 2015-05-18 | 2016-11-23 | Esteve Química, S.A. | New method for preparing 3-(4-methyl-1h-imidazol-1-yl)-5-(trifluoromethyl)benzenamine |
CN104860929B (en) * | 2015-05-26 | 2017-10-31 | 凯莱英医药集团(天津)股份有限公司 | The preparation method of AMN107 |
US20180222982A1 (en) | 2015-07-29 | 2018-08-09 | Novartis Ag | Combination therapies comprising antibody molecules to pd-1 |
EP3316902A1 (en) | 2015-07-29 | 2018-05-09 | Novartis AG | Combination therapies comprising antibody molecules to tim-3 |
LT3317301T (en) | 2015-07-29 | 2021-07-26 | Novartis Ag | Combination therapies comprising antibody molecules to lag-3 |
JP2019500893A (en) | 2015-11-03 | 2019-01-17 | ヤンセン バイオテツク,インコーポレーテツド | Antibodies that specifically bind to PD-1 and TIM-3 and uses thereof |
MA43169B1 (en) | 2015-11-06 | 2022-05-31 | Incyte Corp | Heterocyclic compounds as pi3k-gamma inhibitors |
US20180371093A1 (en) | 2015-12-17 | 2018-12-27 | Novartis Ag | Antibody molecules to pd-1 and uses thereof |
CN106905298A (en) * | 2015-12-22 | 2017-06-30 | 江苏先声药业有限公司 | The preparation method of hydrochloric acid AMN107 impurity |
ES2833955T3 (en) | 2016-01-05 | 2021-06-16 | Incyte Corp | Pyridines substituted with pyrazole / imidazole as PI3K-Gamma inhibitors |
US11174250B2 (en) | 2016-03-01 | 2021-11-16 | Propellon Therapeutics Inc. | Substituted carboxamides as inhibitors of WDR5 protein-protein binding |
EP3423451B1 (en) | 2016-03-01 | 2022-08-17 | Propellon Therapeutics Inc. | Inhibitors of wdr5 protein-protein binding |
CN105801559B (en) * | 2016-04-28 | 2019-03-01 | 北京化工大学 | The preparation method of 4- methyl -3- [[4- (3- pyridyl group) -2- pyrimidine radicals] amino] ethyl benzoate |
EP3254698A1 (en) | 2016-06-08 | 2017-12-13 | Universite De Montpellier | Flt3 receptor inhibitor at low dosage for the treatment of neuropathic pain |
JP2019517542A (en) | 2016-06-10 | 2019-06-24 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Combination of linagliptin and metformin |
TW201803871A (en) | 2016-06-24 | 2018-02-01 | 英塞特公司 | Heterocyclic compounds as PI3K-[gamma] inhibitors |
WO2018002958A1 (en) | 2016-06-30 | 2018-01-04 | Sun Pharma Advanced Research Company Limited | Novel hydrazide containing compounds as btk inhibitors |
US11098077B2 (en) | 2016-07-05 | 2021-08-24 | Chinook Therapeutics, Inc. | Locked nucleic acid cyclic dinucleotide compounds and uses thereof |
AU2017353925A1 (en) | 2016-11-02 | 2018-09-27 | Arog Pharmaceuticals, Inc. | Crenolanib for treating FLT3 mutated proliferative disorders associated mutations |
WO2018148533A1 (en) | 2017-02-09 | 2018-08-16 | Georgetown University | Compositions and methods for treating lysosomal storage disorders |
WO2018165718A1 (en) | 2017-03-17 | 2018-09-20 | Cardio Therapeutics Pty Ltd | Heterocyclic inhibitors of pcsk9 |
UY37695A (en) | 2017-04-28 | 2018-11-30 | Novartis Ag | BIS 2’-5’-RR- (3’F-A) (3’F-A) CYCLE DINUCLEOTIDE COMPOUND AND USES OF THE SAME |
EP3404025B1 (en) | 2017-05-16 | 2019-12-04 | F.I.S.- Fabbrica Italiana Sintetici S.p.A. | Process for the preparation of pure nilotinib and its salt |
EP3624780A1 (en) | 2017-05-17 | 2020-03-25 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Flt3 inhibitors for improving pain treatments by opioids |
AR111960A1 (en) | 2017-05-26 | 2019-09-04 | Incyte Corp | CRYSTALLINE FORMS OF A FGFR INHIBITOR AND PROCESSES FOR ITS PREPARATION |
CN107188887A (en) * | 2017-06-15 | 2017-09-22 | 苏州立新制药有限公司 | A kind of AMN107 oxidative degradation impurity and preparation method thereof |
EP3642240A1 (en) | 2017-06-22 | 2020-04-29 | Novartis AG | Antibody molecules to cd73 and uses thereof |
WO2019057649A1 (en) | 2017-09-19 | 2019-03-28 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of acute myeloid leukemia |
JOP20200086A1 (en) | 2017-10-18 | 2020-04-30 | Incyte Corp | Condensed imidazole derivatives substituted by tertiary hydroxy groups as pi3k-gamma inhibitors |
US10596161B2 (en) | 2017-12-08 | 2020-03-24 | Incyte Corporation | Low dose combination therapy for treatment of myeloproliferative neoplasms |
CZ2017821A3 (en) | 2017-12-20 | 2019-07-03 | Zentiva, K.S. | Dosing of crystalline nilotinib |
WO2019126505A1 (en) | 2017-12-21 | 2019-06-27 | Incyte Corporation | 3-(5-amino-pyrazin-2-yl)-benzenesulfonamide derivatives and related compounds as pi3k-gamma kinase inhibitors for treating e.g. cancer |
CN112105608B (en) | 2018-01-30 | 2023-07-14 | 因赛特公司 | Process for the preparation of (1- (3-fluoro-2- (trifluoromethyl) isonicotinyl) piperidin-4-one |
PE20212186A1 (en) | 2018-02-16 | 2021-11-11 | Incyte Corp | JAK1 PATHWAY INHIBITORS FOR THE TREATMENT OF CYTOKINE-RELATED DISORDERS |
AU2019227607C1 (en) | 2018-02-27 | 2023-07-20 | Incyte Corporation | Imidazopyrimidines and triazolopyrimidines as A2A / A2B inhibitors |
EP3762368B1 (en) | 2018-03-08 | 2022-01-26 | Incyte Corporation | Aminopyrazine diol compounds as pi3k-y inhibitors |
MX2020010322A (en) | 2018-03-30 | 2022-11-30 | Incyte Corp | Treatment of hidradenitis suppurativa using jak inhibitors. |
US11220510B2 (en) | 2018-04-09 | 2022-01-11 | Incyte Corporation | Pyrrole tricyclic compounds as A2A / A2B inhibitors |
CN108530364B (en) * | 2018-04-10 | 2020-01-21 | 江苏创诺制药有限公司 | Crystal form of 3- (4-methyl-1H-imidazole-1-yl) -5-trifluoromethyl aniline monohydrochloride and application thereof |
BR112020022373A2 (en) | 2018-05-04 | 2021-02-02 | Incyte Corporation | salts of a fgfr inhibitor |
WO2019213544A2 (en) | 2018-05-04 | 2019-11-07 | Incyte Corporation | Solid forms of an fgfr inhibitor and processes for preparing the same |
CA3100731A1 (en) | 2018-05-18 | 2019-11-21 | Incyte Corporation | Fused pyrimidine derivatives as a2a / a2b inhibitors |
EP3802534B1 (en) | 2018-05-25 | 2022-07-13 | Incyte Corporation | Tricyclic heterocyclic compounds as sting activators |
TW202015726A (en) | 2018-05-30 | 2020-05-01 | 瑞士商諾華公司 | Entpd2 antibodies, combination therapies, and methods of using the antibodies and combination therapies |
TWI770624B (en) | 2018-06-15 | 2022-07-11 | 漢達生技醫藥股份有限公司 | Use of nilotinib lauryl sulfate salt dosage form for treating chronic myeloid leukemia |
JP2020002108A (en) * | 2018-06-29 | 2020-01-09 | 住友化学株式会社 | Manufacturing method of benzoic acid compound |
US11046658B2 (en) | 2018-07-02 | 2021-06-29 | Incyte Corporation | Aminopyrazine derivatives as PI3K-γ inhibitors |
JP2020007240A (en) * | 2018-07-04 | 2020-01-16 | 住友化学株式会社 | Method for producing benzamide compound |
WO2020010197A1 (en) | 2018-07-05 | 2020-01-09 | Incyte Corporation | Fused pyrazine derivatives as a2a / a2b inhibitors |
AU2019306036A1 (en) | 2018-07-17 | 2020-12-17 | Boehringer Ingelheim International Gmbh | Cardio- and renosafe antidiabetic therapy |
WO2020016232A1 (en) | 2018-07-17 | 2020-01-23 | Boehringer Ingelheim International Gmbh | Cardiosafe antidiabetic therapy |
WO2020028565A1 (en) | 2018-07-31 | 2020-02-06 | Incyte Corporation | Tricyclic heteraryl compounds as sting activators |
US10875872B2 (en) | 2018-07-31 | 2020-12-29 | Incyte Corporation | Heteroaryl amide compounds as sting activators |
PE20211815A1 (en) | 2018-09-05 | 2021-09-14 | Incyte Corp | CRYSTALLINE FORMS OF A PHOSPHOINOSITIDE 3-KINASE (PI3K) INHIBITOR |
US11066404B2 (en) | 2018-10-11 | 2021-07-20 | Incyte Corporation | Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors |
US11396502B2 (en) | 2018-11-13 | 2022-07-26 | Incyte Corporation | Substituted heterocyclic derivatives as PI3K inhibitors |
US11078204B2 (en) | 2018-11-13 | 2021-08-03 | Incyte Corporation | Heterocyclic derivatives as PI3K inhibitors |
US11161838B2 (en) | 2018-11-13 | 2021-11-02 | Incyte Corporation | Heterocyclic derivatives as PI3K inhibitors |
US11596692B1 (en) | 2018-11-21 | 2023-03-07 | Incyte Corporation | PD-L1/STING conjugates and methods of use |
EP3903828A4 (en) | 2018-12-21 | 2022-10-05 | Daiichi Sankyo Company, Limited | Combination of antibody-drug conjugate and kinase inhibitor |
WO2020146237A1 (en) | 2019-01-07 | 2020-07-16 | Incyte Corporation | Heteroaryl amide compounds as sting activators |
TWI829857B (en) | 2019-01-29 | 2024-01-21 | 美商英塞特公司 | Pyrazolopyridines and triazolopyridines as a2a / a2b inhibitors |
US11384083B2 (en) | 2019-02-15 | 2022-07-12 | Incyte Corporation | Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors |
SG11202108702XA (en) | 2019-02-15 | 2021-09-29 | Incyte Corp | Cyclin-dependent kinase 2 biomarkers and uses thereof |
WO2020180959A1 (en) | 2019-03-05 | 2020-09-10 | Incyte Corporation | Pyrazolyl pyrimidinylamine compounds as cdk2 inhibitors |
WO2020185532A1 (en) | 2019-03-08 | 2020-09-17 | Incyte Corporation | Methods of treating cancer with an fgfr inhibitor |
WO2020205560A1 (en) | 2019-03-29 | 2020-10-08 | Incyte Corporation | Sulfonylamide compounds as cdk2 inhibitors |
WO2020223469A1 (en) | 2019-05-01 | 2020-11-05 | Incyte Corporation | N-(1-(methylsulfonyl)piperidin-4-yl)-4,5-di hydro-1h-imidazo[4,5-h]quinazolin-8-amine derivatives and related compounds as cyclin-dependent kinase 2 (cdk2) inhibitors for treating cancer |
US11447494B2 (en) | 2019-05-01 | 2022-09-20 | Incyte Corporation | Tricyclic amine compounds as CDK2 inhibitors |
US20200405627A1 (en) | 2019-06-10 | 2020-12-31 | Incyte Corporation | Topical treatment of vitiligo by a jak inhibitor |
US11591329B2 (en) | 2019-07-09 | 2023-02-28 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
EP4007602A1 (en) | 2019-08-01 | 2022-06-08 | Incyte Corporation | A dosing regimen for an ido inhibitor |
TW202115024A (en) | 2019-08-14 | 2021-04-16 | 美商英塞特公司 | Imidazolyl pyrimidinylamine compounds as cdk2 inhibitors |
CN114585625A (en) | 2019-08-26 | 2022-06-03 | 因赛特公司 | Triazolopyrimidines as A2A/A2B inhibitors |
JP2022548881A (en) | 2019-09-18 | 2022-11-22 | ノバルティス アーゲー | ENTPD2 Antibodies, Combination Therapy and Methods of Using Antibodies and Combination Therapy |
KR20220099970A (en) | 2019-10-11 | 2022-07-14 | 인사이트 코포레이션 | Bicyclic amines as CDK2 inhibitors |
JOP20220083A1 (en) | 2019-10-14 | 2023-01-30 | Incyte Corp | Bicyclic heterocycles as fgfr inhibitors |
SG10201909596RA (en) * | 2019-10-14 | 2021-05-28 | Esco Aster Pte Ltd | Synthesis of Tyrosine Kinase Inhibitors |
WO2021076124A1 (en) | 2019-10-16 | 2021-04-22 | Incyte Corporation | Use of jak1 inhibitors for the treatment of cutaneous lupus erythematosus and lichen planus (lp) |
US11566028B2 (en) | 2019-10-16 | 2023-01-31 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
US11992490B2 (en) | 2019-10-16 | 2024-05-28 | Incyte Corporation | Use of JAK1 inhibitors for the treatment of cutaneous lupus erythematosus and Lichen planus (LP) |
BR112022010664A2 (en) | 2019-12-04 | 2022-08-16 | Incyte Corp | DERIVATIVES OF A FGFR INHIBITOR |
JP2023505258A (en) | 2019-12-04 | 2023-02-08 | インサイト・コーポレイション | Tricyclic heterocycles as FGFR inhibitors |
WO2021146424A1 (en) | 2020-01-15 | 2021-07-22 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
AU2021212258A1 (en) | 2020-01-31 | 2022-09-29 | Nanocopoeia, Llc | Amorphous nilotinib microparticles and uses thereof |
EP4103560A1 (en) | 2020-02-15 | 2022-12-21 | Cipla Limited | Novel salts of nilotinib and polymorphic forms thereof |
EP4114401A1 (en) | 2020-03-06 | 2023-01-11 | Incyte Corporation | Combination therapy comprising axl/mer and pd-1/pd-l1 inhibitors |
PE20230825A1 (en) | 2020-04-16 | 2023-05-19 | Incyte Corp | FUSIONED TRICYCLIC KRAS INHIBITORS |
EP3904342A1 (en) | 2020-04-28 | 2021-11-03 | Grindeks, A Joint Stock Company | Process for the preparation of 3-(trifluoromethyl)-5-(4-methyl-1h-imidazole-1-yl)-benzeneamine hydrochloride |
EP4142699A1 (en) | 2020-04-30 | 2023-03-08 | Nanocopoeia LLC | Orally disintegrating tablet comprising amorphous solid dispersion of nilotinib |
WO2021228983A1 (en) | 2020-05-13 | 2021-11-18 | INSERM (Institut National de la Santé et de la Recherche Médicale) | A pharmaceutical composition comprising an arsenic compound, an inductor of type-1 ifn and a protein kinase inhibitor for treating cancer |
US11739102B2 (en) | 2020-05-13 | 2023-08-29 | Incyte Corporation | Fused pyrimidine compounds as KRAS inhibitors |
AU2021283271A1 (en) | 2020-06-02 | 2022-12-15 | Incyte Corporation | Processes of preparing a JAK1 inhibitor |
US11833155B2 (en) | 2020-06-03 | 2023-12-05 | Incyte Corporation | Combination therapy for treatment of myeloproliferative neoplasms |
US11713310B2 (en) | 2020-07-20 | 2023-08-01 | Arog Pharmaceuticals, Inc. | Crystal forms of crenolanib and methods of use thereof |
US11999752B2 (en) | 2020-08-28 | 2024-06-04 | Incyte Corporation | Vinyl imidazole compounds as inhibitors of KRAS |
EP4213800A1 (en) | 2020-09-16 | 2023-07-26 | Incyte Corporation | Topical treatment of vitiligo |
WO2022072783A1 (en) | 2020-10-02 | 2022-04-07 | Incyte Corporation | Bicyclic dione compounds as inhibitors of kras |
US11969420B2 (en) | 2020-10-30 | 2024-04-30 | Arog Pharmaceuticals, Inc. | Combination therapy of crenolanib and apoptosis pathway agents for the treatment of proliferative disorders |
MX2023006542A (en) | 2020-12-08 | 2023-08-25 | Incyte Corp | Jak1 pathway inhibitors for the treatment of vitiligo. |
CN112745300A (en) * | 2021-01-21 | 2021-05-04 | 杭州浙中医药科技有限公司 | Method for preparing N- (5-carboxyl-2-methylphenyl) -4- (3-pyridine) -2-pyrimidinamine |
WO2022155941A1 (en) | 2021-01-25 | 2022-07-28 | Qilu Regor Therapeutics Inc. | Cdk2 inhibitors |
WO2022206888A1 (en) | 2021-03-31 | 2022-10-06 | Qilu Regor Therapeutics Inc. | Cdk2 inhibitors and use thereof |
US20220324986A1 (en) | 2021-04-12 | 2022-10-13 | Incyte Corporation | Combination therapy comprising an fgfr inhibitor and a nectin-4 targeting agent |
WO2022261159A1 (en) | 2021-06-09 | 2022-12-15 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
TW202313611A (en) | 2021-06-09 | 2023-04-01 | 美商英塞特公司 | Tricyclic heterocycles as fgfr inhibitors |
US11981671B2 (en) | 2021-06-21 | 2024-05-14 | Incyte Corporation | Bicyclic pyrazolyl amines as CDK2 inhibitors |
PE20241127A1 (en) | 2021-07-07 | 2024-05-24 | Incyte Corp | TRICYCLIC COMPOUNDS AS KRAS INHIBITORS |
CA3224841A1 (en) | 2021-07-14 | 2023-01-19 | Zhenwu Li | Tricyclic compounds as inhibitors of kras |
WO2023034290A1 (en) | 2021-08-31 | 2023-03-09 | Incyte Corporation | Naphthyridine compounds as inhibitors of kras |
CN113717152B (en) * | 2021-09-08 | 2022-06-17 | 上海皓鸿生物医药科技有限公司 | Preparation method of specific MRK small molecule inhibitor |
WO2023049697A1 (en) | 2021-09-21 | 2023-03-30 | Incyte Corporation | Hetero-tricyclic compounds as inhibitors of kras |
US12030884B2 (en) | 2021-10-01 | 2024-07-09 | Incyte Corporation | Pyrazoloquinoline KRAS inhibitors |
IL312114A (en) | 2021-10-14 | 2024-06-01 | Incyte Corp | Quinoline compounds as inhibitors of kras |
WO2023081923A1 (en) | 2021-11-08 | 2023-05-11 | Frequency Therapeutics, Inc. | Platelet-derived growth factor receptor (pdgfr) alpha inhibitors and uses thereof |
IL312886A (en) | 2021-11-22 | 2024-07-01 | Incyte Corp | Combination therapy comprising an fgfr inhibitor and a kras inhibitor |
TW202329937A (en) | 2021-12-03 | 2023-08-01 | 美商英塞特公司 | Bicyclic amine cdk12 inhibitors |
US11976073B2 (en) | 2021-12-10 | 2024-05-07 | Incyte Corporation | Bicyclic amines as CDK2 inhibitors |
US20230183251A1 (en) | 2021-12-10 | 2023-06-15 | Incyte Corporation | Bicyclic amines as cdk12 inhibitors |
US20230192722A1 (en) | 2021-12-22 | 2023-06-22 | Incyte Corporation | Salts and solid forms of an fgfr inhibitor and processes of preparing thereof |
WO2023168686A1 (en) | 2022-03-11 | 2023-09-14 | Qilu Regor Therapeutics Inc. | Substituted cyclopentanes as cdk2 inhibitors |
TW202341982A (en) | 2021-12-24 | 2023-11-01 | 大陸商上海齊魯銳格醫藥研發有限公司 | Cdk2 inhibitors and use thereof |
TW202342023A (en) | 2022-03-07 | 2023-11-01 | 美商英塞特公司 | Solid forms, salts, and processes of preparation of a cdk2 inhibitor |
EP4260848A1 (en) | 2022-04-11 | 2023-10-18 | Lotus Pharmaceutical Co., Ltd. | Pharmaceutical composition for solid dosage form containing nilotinib and process for its preparation |
WO2023245053A1 (en) | 2022-06-14 | 2023-12-21 | Incyte Corporation | Solid forms of a jak inhibitor and process of preparing the same |
WO2023250430A1 (en) | 2022-06-22 | 2023-12-28 | Incyte Corporation | Bicyclic amine cdk12 inhibitors |
WO2024015731A1 (en) | 2022-07-11 | 2024-01-18 | Incyte Corporation | Fused tricyclic compounds as inhibitors of kras g12v mutants |
US20240058343A1 (en) | 2022-08-05 | 2024-02-22 | Incyte Corporation | Treatment of urticaria using jak inhibitors |
WO2024142002A1 (en) | 2022-12-29 | 2024-07-04 | Renata Pharmaceuticals (Ireland) Limited | Pharmaceutical suspension of nilotinib |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4788195A (en) * | 1986-01-13 | 1988-11-29 | American Cyanamid Company | 4,5,6-substituted-N-(substituted-phenyl)-2-pyrimidinamines |
US5516775A (en) * | 1992-08-31 | 1996-05-14 | Ciba-Geigy Corporation | Further use of pyrimidine derivatives |
US5521184A (en) * | 1992-04-03 | 1996-05-28 | Ciba-Geigy Corporation | Pyrimidine derivatives and processes for the preparation thereof |
US20060014742A1 (en) * | 2002-06-28 | 2006-01-19 | Tetsuo Asaki | Amide derivative |
US7163791B2 (en) * | 1993-03-29 | 2007-01-16 | Kyowa Hakko Kogyo Co., Ltd. | α,2,8-sialyltransferase |
US7569566B2 (en) * | 2002-07-05 | 2009-08-04 | Novartis Ag | Inhibitors of tyrosine kinases |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3524519A1 (en) | 1984-07-11 | 1986-01-16 | Mitsubishi Chemical Industries Ltd., Tokio/Tokyo | Dyes for heat-sensitive sublimation transfer recording |
US4871372A (en) | 1987-07-17 | 1989-10-03 | Kao Corporation | Dye composition for keratinous fiber |
TW225528B (en) * | 1992-04-03 | 1994-06-21 | Ciba Geigy Ag | |
KR100330553B1 (en) * | 1993-10-01 | 2002-11-27 | 노파르티스 아게 | Pharmacologically Active Pyridine Derivatives and Processes for the Preparation Thereof |
JPH10182459A (en) | 1996-12-26 | 1998-07-07 | Otsuka Pharmaceut Co Ltd | Cgmp phosphodiesterase inhibitor |
JP2002179651A (en) | 1998-06-19 | 2002-06-26 | Wakamoto Pharmaceut Co Ltd | Benzanilide derivative and medicine composition |
AU779089B2 (en) | 1999-04-15 | 2005-01-06 | Bristol-Myers Squibb Holdings Ireland Unlimited Company | Cyclic protein tyrosine kinase inhibitors |
US6545005B1 (en) | 1999-09-16 | 2003-04-08 | Curtis, Inc. | Mediators of hedgehog signaling pathways, compositions and uses related thereto |
AU2001239725A1 (en) | 2000-01-13 | 2001-07-24 | Tularik, Inc. | Antibacterial agents |
HN2001000008A (en) | 2000-01-21 | 2003-12-11 | Inc Agouron Pharmaceuticals | AMIDA COMPOSITE AND PHARMACEUTICAL COMPOSITIONS TO INHIBIT PROTEINKINASES, AND THE INSTRUCTIONS FOR USE |
US7122544B2 (en) | 2000-12-06 | 2006-10-17 | Signal Pharmaceuticals, Llc | Anilinopyrimidine derivatives as IKK inhibitors and compositions and methods related thereto |
US7129242B2 (en) | 2000-12-06 | 2006-10-31 | Signal Pharmaceuticals, Llc | Anilinopyrimidine derivatives as JNK pathway inhibitors and compositions and methods related thereto |
-
2002
- 2002-07-05 GB GBGB0215676.8A patent/GB0215676D0/en not_active Ceased
- 2002-12-20 GB GBGB0229893.3A patent/GB0229893D0/en not_active Ceased
-
2003
- 2003-07-03 PE PE2003000676A patent/PE20040647A1/en active IP Right Grant
- 2003-07-03 AR ARP030102415A patent/AR040390A1/en active IP Right Grant
- 2003-07-03 TW TW092118223A patent/TWI313603B/en not_active IP Right Cessation
- 2003-07-04 ES ES03762632T patent/ES2318164T3/en not_active Expired - Lifetime
- 2003-07-04 PT PT03762632T patent/PT1532138E/en unknown
- 2003-07-04 EP EP20080161965 patent/EP2100891A1/en not_active Withdrawn
- 2003-07-04 ES ES10174608.9T patent/ES2475066T3/en not_active Expired - Lifetime
- 2003-07-04 CA CA002491632A patent/CA2491632C/en not_active Expired - Lifetime
- 2003-07-04 EP EP10174608.9A patent/EP2357182B1/en not_active Expired - Lifetime
- 2003-07-04 CA CA2677315A patent/CA2677315C/en not_active Expired - Lifetime
- 2003-07-04 RU RU2005102917/04A patent/RU2348627C2/en active
- 2003-07-04 MX MXPA05000328A patent/MXPA05000328A/en active IP Right Grant
- 2003-07-04 CN CNB038187280A patent/CN1324022C/en not_active Expired - Lifetime
- 2003-07-04 AT AT03762632T patent/ATE414699T1/en active
- 2003-07-04 DK DK03762632T patent/DK1532138T3/en active
- 2003-07-04 PL PL395096A patent/PL395096A1/en not_active Application Discontinuation
- 2003-07-04 PL PL374583A patent/PL219723B1/en not_active IP Right Cessation
- 2003-07-04 PL PL406680A patent/PL406680A1/en not_active Application Discontinuation
- 2003-07-04 DE DE60324805T patent/DE60324805D1/en not_active Expired - Lifetime
- 2003-07-04 CN CNA2007101077481A patent/CN101045727A/en active Pending
- 2003-07-04 JP JP2004518718A patent/JP4110140B2/en not_active Expired - Lifetime
- 2003-07-04 CA CA2677313A patent/CA2677313C/en not_active Expired - Lifetime
- 2003-07-04 PT PT101746089T patent/PT2357182E/en unknown
- 2003-07-04 NZ NZ537396A patent/NZ537396A/en not_active IP Right Cessation
- 2003-07-04 KR KR1020067024168A patent/KR100864740B1/en active IP Right Grant
- 2003-07-04 AU AU2003249962A patent/AU2003249962C9/en not_active Expired
- 2003-07-04 US US10/520,359 patent/US7169791B2/en not_active Expired - Lifetime
- 2003-07-04 SI SI200331512T patent/SI1532138T1/en unknown
- 2003-07-04 EP EP10174830A patent/EP2368889A1/en not_active Withdrawn
- 2003-07-04 WO PCT/EP2003/007198 patent/WO2004005281A1/en active Application Filing
- 2003-07-04 BR BRPI0312464A patent/BRPI0312464B8/en active IP Right Grant
- 2003-07-04 KR KR1020057000159A patent/KR100733639B1/en active IP Right Review Request
- 2003-07-04 MY MYPI20032514A patent/MY143466A/en unknown
- 2003-07-04 EP EP03762632A patent/EP1532138B1/en not_active Expired - Lifetime
-
2004
- 2004-12-22 ZA ZA200410322A patent/ZA200410322B/en unknown
- 2004-12-23 IL IL165977A patent/IL165977A/en unknown
-
2005
- 2005-01-05 EC EC2005005525A patent/ECSP055525A/en unknown
- 2005-01-12 CO CO05001801A patent/CO5680432A2/en active IP Right Grant
- 2005-02-04 NO NO20050636A patent/NO331166B1/en not_active IP Right Cessation
- 2005-10-31 HK HK05109671.2A patent/HK1077811A1/en not_active IP Right Cessation
-
2006
- 2006-12-01 US US11/607,542 patent/US20070093506A1/en not_active Abandoned
-
2007
- 2007-10-31 JP JP2007283773A patent/JP4895976B2/en not_active Expired - Lifetime
-
2008
- 2008-04-02 US US12/061,334 patent/US7569566B2/en not_active Expired - Lifetime
- 2008-09-24 RU RU2008137927/04A patent/RU2445309C2/en active
-
2009
- 2009-02-19 CY CY20091100190T patent/CY1108813T1/en unknown
- 2009-05-27 IL IL198996A patent/IL198996A/en active IP Right Grant
- 2009-06-22 US US12/489,049 patent/US7956053B2/en not_active Expired - Lifetime
-
2011
- 2011-05-12 US US13/106,582 patent/US20110218187A1/en not_active Abandoned
- 2011-07-11 JP JP2011153046A patent/JP2011219495A/en active Pending
-
2012
- 2012-02-13 HK HK12101403.5A patent/HK1160859A1/en not_active IP Right Cessation
-
2013
- 2013-08-15 JP JP2013168882A patent/JP2013227358A/en active Pending
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4788195A (en) * | 1986-01-13 | 1988-11-29 | American Cyanamid Company | 4,5,6-substituted-N-(substituted-phenyl)-2-pyrimidinamines |
US5521184A (en) * | 1992-04-03 | 1996-05-28 | Ciba-Geigy Corporation | Pyrimidine derivatives and processes for the preparation thereof |
US5516775A (en) * | 1992-08-31 | 1996-05-14 | Ciba-Geigy Corporation | Further use of pyrimidine derivatives |
US7163791B2 (en) * | 1993-03-29 | 2007-01-16 | Kyowa Hakko Kogyo Co., Ltd. | α,2,8-sialyltransferase |
US20060014742A1 (en) * | 2002-06-28 | 2006-01-19 | Tetsuo Asaki | Amide derivative |
US7569566B2 (en) * | 2002-07-05 | 2009-08-04 | Novartis Ag | Inhibitors of tyrosine kinases |
US7956053B2 (en) * | 2002-07-05 | 2011-06-07 | Novartis Ag | Inhibitors of tyrosine kinases |
Non-Patent Citations (2)
Title |
---|
Gura, Systems for identifying New Drugs Are Often Faulty, Cancer Models, Science, Vol. 278, No. 5340, pp. 1041-1042, November 1997. * |
Johnson et al., Relationships between drug activity in NCl preclinical in vitro and in vivo models and early clinical trials, British Journal of Cancer (2001) 64(10): 1424-1431. * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9567317B2 (en) | 2012-10-19 | 2017-02-14 | Basf Se | Multicomponent crystalline system comprising nilotinib and selected co-crystal formers |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7956053B2 (en) | Inhibitors of tyrosine kinases | |
EP1546127B1 (en) | Novel pyrimidineamide derivatives and the use thereof | |
AU2008202194B2 (en) | Inhibitors of tyrosine kinases |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |