- Discovery of N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays
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A series of substituted 2-(aminopyridyl)- and 2-(aminopyrimidinyl)thiazole- 5-carboxamides was identified as potent Src/Abl kinase inhibitors with excellent antiproliferative activity against hematological and solid tumor cell lines. Compound 13 was orally active in a K562 xenograft model of chronic myelogenous leukemia (CML), demonstrating complete tumor regressions and low toxicity at multiple dose levels. On the basis of its robust in vivo activity and favorable pharmacokinetic profile, 13 was selected for additional characterization for oncology indications.
- Lombardo, Louis J.,Lee, Francis Y.,Chen, Ping,Norris, Derek,Barrish, Joel C.,Behnia, Kamelia,Castaneda, Stephen,Cornelius, Lyndon A. M.,Das, Jagabandhu,Doweyko, Arthur M.,Fairchild, Craig,Hunt, John T.,Inigo, Ivan,Johnston, Kathy,Kamath, Amrita,Kan, David,Klei, Herbert,Marathe, Punit,Pang, Suhong,Peterson, Russell,Pitt, Sidney,Schieven, Gary L.,Schmidt, Robert J.,Tokarski, John,Wen, Mei-Li,Wityak, John,Borzilleri, Robert M.
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Read Online
- Scalable and impurity-free process for dasatinib: Src and BCR-Abl inhibitor
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An efficient, telescopic, impurity-free and scalable process for Bcr-Abl and Src family tyrosine kinase inhibitor for synthesis of Dasatinib with high yield and purity is described.
- Buchappa,Sagar Vijay Kumar,Durga Prasad,Aparna
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- Synthesis and biological evaluation of novel dasatinib analogues as potent DDR1 and DDR2 kinase inhibitors
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Novel dasatinib analogues as DDR1 and DDR2 inhibitors were designed and synthesized. The synthesized compounds were screened for DDR1 and DDR2 kinase inhibitory and cancer cell proliferation inhibitory activities. Some of the compounds showed the potent i
- Liu, Lu,Hussain, Muzammal,Luo, Jinfeng,Duan, Anna,Chen, Chaonan,Tu, Zhengchao,Zhang, Jiancun
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- HALOGENATED-HETEROARYL AND OTHER HETEROCYCLIC KINASE INHIBITORS, AND USES THEREOF
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The invention relates to kinase inhibitors, in particular inhibitors of protein kinases including the SIK-family CSF1R, ABL/BCR-ABL, SRC, HCK, PDGFR, KIT and/or their mutants. Although structurally similar to dasatinib, the kinase inhibitors of the invention are distinctive; possessing a particular class of halogenated heteroaryls. Such kinase inhibitors can display one or more certain properties distinct to dasatinib and other structurally similar kinase inhibitors. The kinase inhibitors of the invention or pharmaceutical compositions comprising them may be used in the treatment of a disorder or condition, such as a proliferative disorder, for example, a leukaemia or solid tumour. In particular, these and other structurally similar kinase inhibitors may be used in the treatment of a proliferative disorder - such as a mixed phenotype acute leukaemia (MPAL) - characterised by (inter-alia) the presence of MEF2C protein, a human chromosomal translocation at 11q23, and/or a KMT2A fusion oncoprotein. The kinase inhibitors or pharmaceutical compositions disclosed herein may be used topically to modulate skin pigmentation in a subject, for example to impart UV protection and reduce skin cancer risk.
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- N-phenyl-2-(pyrimidin-4-ylamino)thiazol-5-carboxamide derivatives, pharmaceutically acceptable salts thereof and a whitening material composition containing the same as an active ingredient
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The present invention relates to a whitening material composition comprising an N-phenyl-2-(pyrimidin-4-ylamino)thiazole-5-carboxamide derivative as an active ingredient. Since the whitening material composition provided in one aspect of the present invention has an excellent effect of inhibiting the promotion of cell melanogenesis even when a small amount thereof is used, a cosmetic product for skin whitening and a product for preventing, alleviating, and treating melanin hyperpigmentation diseases can be usefully used.
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- HETEROCYCLIC KINASE INHIBITORS AND USES THEREOF
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The invention relates to kinase inhibitors, in particular inhibitors of protein kinases including the protein-tyrosine kinases LCK, ABL, SRC, KIT, SIK-family and/or their mutants. Although structurally similar to dasatinib, the kinase inhibitors of the invention can display one or more certain properties distinct to dasatinib. Also, the invention relates to pharmaceutical compositions that comprise one or more of the kinase inhibitors. The kinase inhibitors or pharmaceutical compositions of the invention may be used in the treatment of a disorder or condition, such as a proliferative disorder, for example, a leukaemia or solid tumour. The kinase inhibitors or pharmaceutical compositions may be used in a treatment regimen that corresponds to, is similar to or is distinct from that used with dasatinib for a corresponding disorder, and in particular may be used in a combination treatment regimen together with one or more additional therapeutic agents, such as immune-checkpoint inhibitors.
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- Preparation method of dasatinib hydrate
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The invention provides a preparation method ofdasatinib hydrate. The dasatinib hydrate is prepared by reacting a compound shown asstructural formula I in a compound a and a compound b. According to the technical scheme provided by the invention, the high-quality dasatinib hydrate can be obtained, tedious separation and purification steps are avoided, the operation is simple, the waste of raw materials is also avoided, the production cost is reduced, and the method is more suitable for industrial production.
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Paragraph 0027; 0033-0035
(2020/06/20)
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- Preparation method for dasatinib monohydrate
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The invention provides a preparation method for a dasatinib monohydrate. The dasatinib monohydrate is obtained by a reaction of dasatinib in an ethanol aqueous solution. According to a technical scheme of the invention, the high-quality dasatinib monohydrate can be obtained; tedious separation and purification steps are avoided; operation is simple; the waste of raw materials is also avoided; theproduction cost is reduced; and the preparation method is more applicable to industrial production.
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Paragraph 0040; 0049-0050
(2020/07/13)
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- Method for preparing dasatinib tablets
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The invention relates to a method for preparing dasatinib tablets. The method comprises the following steps: enabling 3-oxo-ethyl propionate to react with 2-chlorine-6-methylaniline under an alkali condition, further adding a solvent in which cupric bromide is dissolved to carry out a reaction, further adding thiourea, and cyclizing with a catalyst so as to obtain 2-amino-N-(2-chlorine-6-methyphenyl)thiazole-5-formamide; further synthesizing dasatinib tablets from 4,6-dichloro-2-methyl pyrimidine, N-ethoxy piperazine and 2-amino-N-(2-chlorine-6-methyphenyl)thiazole-5-formamide according to a one-pot method under the action of an alkali and an ionic liquid 1-butyl-3-methylimidazole glycinate. The method is mild in condition, simple in step, environmentally friendly, high in yield and applicable to industrial production.
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- Preparation process of dasatinib
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The invention relates to a preparation process of dasatinib. The method comprises the following steps: enabling 3-oxopropionic acid ethyl ester to react firstly with 2-chlo-6-methylaniline under an alkaline condition, then adding a solvent dissolved with cupric bromide, and reacting to obtain a compound 3; cyclizing the compound 3 and thiourea in solvent water to obtain 2-amino-N-(2-chlo-6-methylphenyl)thiazole-5-formamide; and then synthesizing dasatinib from 4,6-dichloro-2-methyl pyrimidine, N-ethoxyl piperazine, and 2-amino-N-(2-chlo-6-methyl phenyl)thiazole-5-formamide through a one-pot method under the actions of an alkali K3PO4 and a catalyst 1-butyl-3-methylimidazole glycinate. The conditions are mild, the steps are simple, and the preparation process is environmentally-friendly, high in yield and suitable for industrial production.
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- Preparation process of dasatinib
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The invention relates to a preparation process of dasatinib. The preparation process includes the following steps that 3-ethyl propionate reacts with 2-chlorine-6-methylaniline under an alkaline condition to obtain a compound 3; the compound 3, copper bromide and thiourea react under action of hydroxyethyl-beta-cyclodextrin to obtain 2-amino-N-(2-chlorine-6-methyl phenyl) thiazole-5-formamide through a heating reaction; secondly, 4,6-dichloro-2-methyl pyrimidine reacts with N-hydroxyethyl piperazine, 2-amino-N-(2-chloro-6-methyl phenyl) thiazole-5-formamide sequentially in the presence of alkali, a catalytic system and an organic solvent, and a compound 1, namely dasatinib, is obtained. The conditions are mild, the steps are simple, the process is environmentally friendly, the yield is high, and the process is suitable for industrial production.
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- A reach [...] preparation method
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The invention relates to a preparation method of up to [...], the method comprises the following steps: 3 - ethyl oxo propionic acid under alkaline condition first with 2 - chloro - 6 - methylaniline reaction, then adding [...] copper solution reaction, to obtain compound 3; with the thiourea reaction, from 2 - amino - N - (2 - chloro - 6 - methyl phenyl) thiazole - 5 - carboxamide; after the 4, 6 - dichloro - 2 - methyl pyrimidine in alkali, catalytic system, organic solvents, successively with the N - hydroxyethyl piperazine, 2 - amino - N - (2 - chloro - 6 - methyl phenyl) thiazole - 5 - carboxamide reaction, to obtain compound 1, has reached the [...]. Mild condition of this invention, the step is simple, short reaction time, speed, friendly to the environment and have high yield, is suitable for industrial production.
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- Preparation method of Dasatinib
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The invention provides a preparation method of Dasatinib. 2-Bromothiazole-5-formic acid and 2-methyl-4-amino-6-cloro pyridine are adopted as raw materials, a first-time substitution reaction is performed, the raw materials and 4-(2-acetyl oxyl) Ethylpiperazine are subjected to a second-time substitution reaction to prepare 2-[[6-[4-(2-acetyloxy ethyl)-1-piperazinyl]-2-methl-4-pyrimidyl]amino]-5-Febuxostat; then, the product and an acylating chlorination reagent are subjected to an acylating chlorination reaction and subjected to an amidation reaction with 2-cholo-6-methylaniline, and finally ahydrolysis reaction is performed to remove acetyl to prepare dasatinib. The raw materials are cheap and easy to obtain and low in cost; the technological process is simple, operation is safe and easy, technological wastewater generation amount is small, and the method is environmentally friendly; raw materials and intermediate products stability is suitable, the reaction activity and selectivityare high, reaction conditions are easy to obtain, side reactions are few, the manufactured dasatinib contains few impurities, the purity and yield are high, and industrial production of dasatinib is facilitated.
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- Process for preparing dasatinib
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The invention relates to a process for preparing dasatinib. The process includes steps of carrying out heating reflux on 3-oxo-propionic acid ethyl ester and 2-chlorine-6-methylaniline under alkalineconditions, adding cupric bromide, carrying out temperature-rise reflux, adding thiourea and a catalyst heteropoly acid salt, and carrying out room-temperature stirring reaction to obtain 2-amine-N-(2-chlorine-6-methyl phenyl)thiazole-5-formamide; carrying out 'one-pot reaction' on the 2-amine-N-(2-chlorine-6-methyl phenyl)thiazole-5-formamide, 4, 6-dichloro-2-methylpyrimidine and N-hydroxyethyl piperazine under the effects of catalysts to obtain the dasatinib. The process has the advantages of mild condition, simple step, environmental friendliness, high yield and applicability to industrialproduction.
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Paragraph 0049-58; 065-74
(2019/03/08)
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- POLYMORPHIC FORMS OF DASATINIB
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The present invention provides for the dasatinib- thymine co-crystal and dasatinib-adenine co-crystal. The present invention further provides dasatinib-butanediol solvate. The present invention further provides for crystalline dasatinib-(±) – 1, 2-Butane diol, crystalline dasatinib (R)-1, 2-Butanediol, crystalline dasatinib (S)-1, 2-Butanediol and crystalline dasatinib (±)-2, 3-Butanediol and processes for preparation thereof. The present invention also provides for a process for preparation of amorphous dasatinib using dasatinib- butanediol solvate. The present invention further provides for the preparation of anhydrous dasatinib. The present invention also provides for a process for preparation of dasatinib monohydrate from anhydrous dasatinib
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Page/Page column 69; 70; 77; 78; 79; 80; 81
(2019/01/22)
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- Synthesis method of dasatinib key intermediate
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The invention discloses a synthesis method of a dasatinib key intermediate. The synthesis method comprises the step of carrying out dehydration condensation reaction on a compound 2 and a compound 3 to generate a compound 4, i.e., the dasatinib key intermediate. By adopting the synthesis method of the dasatinib key intermediate, disclosed by the invention, the occurrence of side reaction is greatly reduced, the selectivity of the reaction is improved, and the final yield of dasatinib is improved; the synthesis method is suitable for industrial production. A formula is shown in the description.
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- AN IMPROVED PROCESS FOR THE PREPARATION OF DASATINIB POLYMORPH
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The present invention is related to an improved process for the preparation of dasatinib anhydrous crystalline Neat form N-6 with high purity and high yield. The present invention also relates to purification of dasatinib crystalline Neat form N-6.
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- INTRACELLULAR KINASE ASSOCIATED WITH RESISTANCE AGAINST ANTI-TUMOUR IMMUNE RESPONSES, AND USES THEREOF
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The invention is based on the surprising finding that SIK3 is associated with resistance against anti-tumour immune responses. In particular, the invention provides methods for treating proliferative diseases using inhibitors of SIK3, especially nucleic acid or small molecule inhibitors of SIK3. Also provided are methods of sensitising cells involved with a proliferative disorder against the cytotoxic effect of certain pro-inflammatory signalling pathways, and/or to kill such cells and/or methods for treating proliferative diseases, using a SIK3 inhibitor together with ligands or agonists of such signalling pathways. Other methods provided by the invention include those involving SIK3 inhibitors to enhance or overcome certain side effects associated with treatments that utilise such signalling pathways, as well as diagnostic, prognostic and monitoring methods and kits based on the detection of SIK3 in a sample obtained from a subject, and screening methods useful for identifying or characterising inhibitors of SIK3.
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Page/Page column 447; 461; 462; 463
(2018/11/22)
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- POLYMORPHS OF DASATINIB
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The present invention provides novel polymorphic forms of dasatinib compound of the formula 1 as well as the process for the preparation thereof.
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Page/Page column 19; 20
(2018/05/23)
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- New method for preparing dasatinib and dasatinib intermediates
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The invention discloses a new method for preparing dasatinib and dasatinib intermediates. The method is characterized in that dasatinib (1) is prepared from 2-aminothiazole (2) through substitution, hydroxymethylation, oxidation amidation, fixed site chlorination and amination reactions. The method has the advantages of short synthesis route, high reaction yield, cheap and easily available raw materials, great reduction of the production cost, mild reaction conditions, suitableness for industrial large-scale production, avoiding of use of acyl chloride, and reduction of environmental pollution.
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- CRYSTALLINE FORMS OF N-(2-CHLORO-6-METHY]PHENVN-2-[F6-[4-(2-HVDROXVETHVL)-L- PIPERAZINVIL-2-METHVL-4-PVRIMIDINVLLAMINOL-5-THIAZOLECARBOXAMIDE AND THEIR PROCESS THEREOF
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The present invention relates to crystalline 1,2-Propanediol solvate of N-(2-chloro-6- methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl]ainino]-5- thiazolecarboxamide compound of formula- lb, its process for the preparation and its use in the preparation of anhydrous crystalline form (N-6) and monohydrate of N-(2-chloro-6- methy lphenyl)-2- [ [6- [4-(2 -hydroxy ethyl)- 1 -piperazinyl] -2-methyl-4-pyrimidinyl]amino] -5 - thiazolecarboxamide. [formula] 1,2-Propanediol solvate Formula- lb
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- Preparation method of dasatinib
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The invention discloses a preparation method of dasatinib. The preparation method comprises the following steps: (1) preparing N-(2-chloro-6-methyl-phenyl)-2-[(6-chloro-2-methyl-4-pyrimidyl)amino]-5-thiazole carboxamides; (2) preparing a dasatinib crude product; (3) refining the dasatinib: adding the dasatinib crude product and absolute methanol into a reaction kettle, stirring, performing nitrogen displacement, heating to refluxing while stirring, cooling, adding a seed crystal, stirring materials uniformly, cooling to 5 to 10 DEG in a uniform-speed cooling way, stirring at a constant temperature, filtering the materials, leaching an obtained filter cake with a proper amount of methanol, and drying the filter cake in a gradient heating way to a constant weight to obtain a dasatinib product. The preparation method has the advantages of simple process, high product yield and high product purity; the prepared Dasatinib product of a Form I crystal form has high stability, and the bioavailability of the product is equivalent to an existing T1H1-7 crystal form product.
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Paragraph 0058; 0059
(2018/02/04)
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- Preparation method for Dasatinib compound
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The invention discloses a preparation method for a Dasatinib compound. The synthetic method provided by the invention comprises the following steps: reacting initial raw material N-piperazine with methyl 3-chloro-3-oxopropanoate, thereby acquiring a compound IV; causing the compound IV react with the compound V, thereby acquiring a compound VI; cyclizing the compound VI and acetamidine hydrochloride, thereby acquiring the Dasatinib. According to the invention, the synthetic route is short, the operation is simple, the reaction condition is mild, the purity and yield are high and the method is fit for industrial production.
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Paragraph 0044; 0045; 0046; 0047; 0048; 0049
(2017/06/02)
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- A is suitable for industrial production reaches Sha Tini method for the synthesis of
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The invention discloses a preparation method for dasatinib. The preparation method includes using an intermediate II as a starting raw material; preparing an intermediate III; preparing a thiourea derivative; synthesizing imide; performing cyclization to generate thiophene; performing condensation and the like to prepare the dasatinib. A novel ideal and the novel method are provided for synthesizing the dasatinib, and the preparation method has the advantages of simplicity and convenience in operation, mild reaction condition, convenience in purification and suitability for industrial manufacturing.
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- Synthetic method of medicine namely parecoxib sodium for treating leukaemia
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The invention discloses a synthetic method of a medicine namely parecoxib sodium for treating leukaemia. The method comprises the following steps of (1) stirring and mixing N-(2-chlorine-6-methylphenyl)-3-ethoxy acrylamide with iodine monobromide and 1-butyl-3-methyl bromide imidazolium so as to obtain a mixture, then adding thiourea to the mixture obtained by mixing, and performing a contact reaction so as to obtain 2-amino-N-(2-chlorine-6-methylphenyl) thiazole-5-formylamine; and (2) enabling the 2-amino-N-(2-chlorine-6-methylphenyl) thiazole-5-formylamine obtained in the step (1) and 1-methyl-4-chlorine-6-(4-hydroxyethyl-piperydyl) pyrimidine to be subjected to a reaction in the presence of alkali so as to obtain the parecoxib sodium. The method for preparing the parecoxib sodium disclosed by the invention is simple in steps, mild in conditions and high in yield, and besides, the reaction time is also greatly shortened.
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Paragraph 0051; 0052; 0053
(2017/01/19)
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- A process for the preparation of anticancer drug reaches Sha Tini method (by machine translation)
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The invention discloses a method for preparing anti-cancer drugs reaches Sha Tini method, the method comprises: in the presence of cuprous chloride and bipyridine, the N - (2 - chloro - 6 - methylphenyl) - 2 - [(6 - chloro - 2 - methyl - 4 - pyrimidinyl) amino] - 5 - thiazole carboxamide with 1 - (2 - hydroxyethyl) piperazine in DMF in reaches Sha Tini contact reaction. The preparation of this invention reaches Sha Tini of mild conditions, high yield and good selectivity, and can greatly shorten the reaction time, which is particularly suitable for industrial production. (by machine translation)
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Paragraph 0029
(2017/01/12)
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- A high-purity of the process for the preparation of anhydrous reaches Sha Tini
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The invention relates to the field of dasatinib synthesis, and especially relates to a preparation method of high-purity anhydrous dasatinib. The method comprises the steps that: N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4-pyrimidinyl)amino]-5-thiazolecarboxamide and N-hydroxyethyl piperazine are prepared into a dasatinib crude product under an optimized reaction condition; and the dasatinib crude product is prepared into high-purity anhydrous dasatinib. The technical scheme provided by the invention is simple and feasible, and has the advantages of mild reaction condition, low production cost, environment-friendliness, and suitability for industrialized productions.
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Paragraph 0042 - 0044
(2017/03/08)
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- Process and intermediates for the preparation of dasatinib
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The present invention relates to a process for the synthesis of dasatinib and to intermediates useful for its preparation.
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- METHOD OF PREPARING ANHYDROUS POLYMORPHIC FORM N-6 OF DASATINIB
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A method for the preparation of the crystalline Form N-6 of dasatinib, characterized by the following reflexions in the X-ray powder pattern, measured with the beam radiation CuKα: 6.8; 12.3; 13.2; 13.8; 16.7; 21.0; 24.3, and 24.8 ± 0.2° 2-theta. The method consists in drying a solvate of dasatinib from the group of the ethanol solvate, methanol solvate, and acetonitrile solvate of dasatinib, or their mixtures.
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Page/Page column 3; 5; 6
(2015/07/07)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF DASATINIB
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The present invention relates to a novel synthetic route to N-(2-chloro-6-methylphenyl)- 2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl] -2-methyl-4-pyrimidyl] amino]-5- thiazolformamide of the formula I and also relates to the process for the preparation of novel amorphous forms of dasatinib (formula I).
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Page/Page column 22
(2015/04/22)
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- PROCESS FOR PREPARING DASATINIB MONOHYDRATE
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The present invention provides an improved process for preparing N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate or Dasatinib monohydrate (Formula A).
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Page/Page column 0072; 0073
(2015/03/04)
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- CRYSTALLINE DASATINIB PROCESS
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The present invention relates to a process for preparation of crystalline Form-SDI of Dasatinib (I). Said crystalline Form-SDI of Dasatinib is characterized by X-ray powder diffraction pattern comprising of at least seven 2θ° peaks selected from the XRPD peak set of 5.8, 11.5, 12.7, 13.2, 17.3, 17.5, 18.1, 20.1, 20.5, 22.1, 25.4, 26.6, 26.8 ± 0.20 2θ°; IR spectrum having at least five absorption peaks selected from about 3390 cm-1, 2923 cm-1, 1621 cm-1, 1615 cm-1, 1537 cm-1, 1316 cm-1, 1061 cm-1, 815 cm-1 and 783 cm-1; and DSC isotherm comprising at least two endothermic peaks ranging between- 130 °C to 150 °C, 160 °C to 175 °C or 280 °C to 290 °C. The pharmaceutical compositions of the crystalline Form-SDI of Dasatinib or its hydrate thereof may be useful as an anti-cancer agent.
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Page/Page column 13; 14
(2015/05/26)
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- SYNTHESIS PROCESS OF DASATINIB AND INTERMEDIATE THEREOF
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Synthesis process of dasatinib is disclosed, which includes the step of reacting the compound of formula I with that of formula II to obtain the compound of formula III. Also disclosed is the compound of formula III which is used as an intermediate for synthesizing dasatinib. The substituents of R1, R2, R3 or R4 in formulae I, II or III are defined as in the description.
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Paragraph 0278-0281
(2013/03/26)
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- ANHYDROUS FORM OF DASATINIB, PROCESS FOR ITS PREPARATION AND ITS USE
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The present invention provides a novel anhydrous form of Dasatinib and process for the preparation thereof. The present invention also provides a process for the preparation of Dasatinib monohydrate using novel anhydrous form.
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Page/Page column 13
(2013/05/22)
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- SYNTHESIS PROCESS OF DASATINIB AND INTERMEDIATE THEREOF
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Synthesis process of dasatinib is disclosed, which includes the step of reacting the compound of formula I with that of formula II to obtain the compound of formula III. Also disclosed is the compound of formula III which is used as an intermediate for synthesizing dasatinib. The substituents of R1, R2, R3 or R4 in formulae I, II or III are defined as in the description.
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Page/Page column 16; 26
(2013/02/27)
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- POLYMORPHS OF DASATINIB
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The present invention provides a novel crystalline form I of dasatinib, process for its preparation and to pharmaceutical composition containing it. The present invention also provides dasatinib dimethylformamide solvate, dasatinib dimethyl sulfoxide solvate, dasatinib toluene solvate and dasatinib isopropyl acetate solvate, processes for its preparation. The present invention further provides a process for preparation of crystalline dasatinib monohydrate.
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Page/Page column 6
(2010/07/02)
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- PROCESSES FOR PREPARING CRYSTALLINE FORMS
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The present invention relates to intermediates and their preparation, for use in the manufacture of pure dasatinib, in particularly dasatinib monohydrate and anhydrous dasatinib. The invention also relates to pharmaceutical compositions comprising pure dasatinib and their use in the treatment of cancer.
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Page/Page column 16-17
(2010/12/29)
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- PROCESS FOR PREPARING CRYSTALLINE DASATINIB MONOHYDRATE
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The present invention relates to processes for the preparation of crystalline N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5- thiazolecarboxamide (dasatinib) monohydrate. The invention further relates to pure polymorphs, to pharmaceutical compositions comprising said polymorphs and to uses thereof.
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Page/Page column 13
(2010/12/29)
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- POLYMORPHS OF DASATINIB AND PROCESS FOR PREPARATION THEREOF
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Provided is dasatinib, solvates thereof and their crystalline forms, methods for their preparation, and pharmaceutical compositions thereof.
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Page/Page column 34
(2009/05/28)
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- ORAL ADMINISTRATION OF N-(2-CHLORO-6-METHYLPHENYL)-2-[[6-[4-(2-HYDROXYETHYL)-1-PIPERAZINYL]-2-METHYL-4-PYRIMIDINYL]AMINO]-1,3-THIAZOLE-5-CARBOXAMIDE AND SALTS THEREOF
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Disclosed are a method of treating cancer and/or other proliferative diseases comprising orally administering N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)-1-piperazinyl)-2-methyl-4-pyrimidinyl)amino)-1,3-thiazole-5-carboxamide or a salt thereof, and pharmaceutical compositions comprising N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)-1-piperazinyl)-2-methyl-4-pyrimidinyl)amino)-1,3-thiazole-5-carboxamide or a salt thereof. Also disclosed are N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)-1-piperazinyl)-2-methyl-4-pyrimidinyl)amino)-1,3-thiazole-5-carboxamide salts, as well as crystalline forms thereof.
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Page/Page column 58
(2010/11/26)
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- PROCESS FOR PREPARING N-(2-CHLORO-6-METHYLPHENYL)-2-[[6-[4-(2-HYDROXYETHYL)-1-PIPERAZINYL]-2-METHYL-4-PYRIMIDINYL]AMINO] -5-THIAZOLECARBOXAMIDE AND RELATED METABOLITES THEREOF
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The present invention is directed to process for the preparation of metabolites as well as the parent compound of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl] amino]-5-thiazolecarboxamide, the compound of formula (I).
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Page/Page column 27; 28
(2010/11/28)
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- 2-Aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6- [4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-1, 3-thiazole-5-carboxamide (Dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor
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2-Aminothiazole (1) was discovered as a novel Src family kinase inhibitor template through screening of our internal compound collection. Optimization through successive structure-activity relationship iterations identified analogs 2 (Dasatinib, BMS-354825) and 12m as pan-Src inhibitors with nanomolar to subnanomolar potencies in biochemical and cellular assays. Molecular modeling was used to construct a putative binding model for Lck inhibition by this class of compounds. The framework of key hydrogen-bond interactions proposed by this model was in agreement with the subsequent, published crystal structure of 2 bound to structurally similar Abl kinase. The oral efficacy of this class of inhibitors was demonstrated with 12m in inhibiting the proinflammatory cytokine IL-2 ex vivo in mice (ED50 ～ 5 mg/kg) and in reducing TNF levels in an acute murine model of inflammation (90% inhibition in LPS-induced TNFα production when dosed orally at 60 mg/kg, 2 h prior to LPS administration). The oral efficacy of 12m was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally at 0.3 and 3 mg/kg twice daily. Dasatinib (2) is currently in clinical trials for the treatment of chronic myelogenous leukemia.
- Das, Jagabandhu,Chen, Ping,Norris, Derek,Padmanabha, Ramesh,Lin, James,Moquin, Robert V.,Shen, Zhongqi,Cook, Lynda S.,Doweyko, Arthur M.,Pitt, Sidney,Pang, Suhong,Shen, Ding Ren,Fang, Qiong,De Fex, Henry F.,McIntyre, Kim W.,Shuster, David J.,Gillooly, Kathleen M.,Behnia, Kamelia,Schieven, Gary L.,Wityak, John,Barrish, Joel C.
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p. 6819 - 6832
(2007/10/03)
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- PROCESS FOR PREPARING 2-AMINOTHIAZOLE-5-AROMATIC CARBOXAMIDES AS KINASE INHIBITORS
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The invention relates to processes for preparing compounds having the formula (I) and crystalline forms thereof, wherein Ar is aryl or heteroaryl, L is an optional alkylene linker, and R2, R3, R4, and R5, are as defined in the specification herein, which compounds are useful as kinase inhibitors, in particular, inhibitors of protein tyrosine kinase and p38 kinase.
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Page/Page column 54-55
(2008/06/13)
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- Process for preparing 2-aminothiazole-5-carboxamides useful as kinase inhibitors
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The invention is directed to processes for preparing 2-aminothiazole-5-carboxamides of formula I [image] wherein R1, R2, R3, R4 and R5 are as defined as set forth in the specification herein.
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Page/Page column 15
(2008/06/13)
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- Synergistic methods and compositions for treating cancer
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Combination therapies using IGF1R inhibitors in combination with additional kinase inhibitors are described for the synergistic treatment of cancer.
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- Cyclic protein tyrosine kinase inhibitors
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Novel cyclic compounds and salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds in the treatment of protein tyrosine kinase-associated disorders such as immunologic and oncologic disorders.
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- Cyclic protein tyrosine kinase inhibitors
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Novel cyclic compounds and salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds in the treatment of protein tyrosine kinase-associated disorders such as immunologic and oncologic disorders.
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