51 results about "Ribociclib" patented technology

The invention discloses preparation of a ribociclib key intermediate A; propiolic acid ester or amide 2 is directly used as a Sonogashira coupling side chain, coupling conditions are optimized, an intermediate 3 is obtained with relatively high yield, the intermediate 3 is directly subjected to ring closing under simple conditions to complete construction of a mother ring molecule, to obtain a structural formula A or a precursor ester 4 of the structural formula A, and the precursor ester 4 is subjected to hydrolysis and condensation to obtain the structural formula A. The route has simple operation, reaction steps are shorted, the yield is relatively high, and the purity of the obtained product is relatively high, and the method is suitable for enlarged production, wherein the reaction route is described in the specification.

The invention discloses a synthesis technology of ribociclib. The synthesis technology comprises the following steps: 1) in the presence of cesium carbonate, 2-chloro-4-cyclopentylaminopyrimidine and 3-bromo-2-oxo-N,N-dimethylpropionamide react under the co-catalysis of cuprous iodide and L-proline to obtain 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrole[2,3-d]pyrimindine-6-methanamide; and 2) a product obtained in the step 1) and 4-(6-aminopyridine-3-yl)piperazine-1-carboxylic acid tert-butyl ester are subjected to a nucleophilic reaction, and then formic acid-tert-butyl ester is removed under the acidic condition so as to obtain ribociclib. The synthesis technology of the medicine ribociclib for treating breast cancer has advantages of less reaction steps, mild condition and high yield, and is suitable for industrial production.

The invention discloses a ribociclib synthesizing method which comprises the following steps: (1) performing coupling reaction between compound in a formula III and compound in a formula IV under theaction of a first metal catalyst to obtain compound in a formula V; (2) performing self cyclization reaction on the compound in the formula V to obtain compound in a formula VI; (3) performing oxidization amidation between the compound in the formula VI and dimethylamine under the action of a second metal catalyst to obtain compound in a formula VII; (4) performing substitution reaction between the compound in the formula VII and compound in a formula VIII to obtain compound in a formula IX; (5) removing protection groups of the compound in the formula IX under the acid condition to obtain compound in a formula X, namely ribociclib. Compared with the prior art, the method disclosed by the invention avoids using noble metal catalysts, poisonous sodium cyanide reagents or the like; reactionconditions are moderate, synthesizing steps are small, reaction selectivity is good, total yield is higher, product liquid phase purity is high, production cost is greatly reduced, and the method is more suitable for industrial production. The formulas are shown in the description.

The invention provides a proteolytic targeting chimeric body, a prodrug molecule for improving oral bioavailability of the proteolytic targeting chimeric body and application thereof. According to thetechnical scheme, a novel PROTAC degradation agent compound is developed on the basis of a ribociclib derivative and a CRBN ligand. Small molecules can effectively degrade CDK2/4/6 and compounds thereof in malignant melanoma at the same time; the cell cycle can be quickly reset, and apoptosis of various cancer cells, especially melanoma cells, can be induced. A mechanism should be explained as that CDK 2/4/6 deficiency may lead to synthetic lethal effects of malignant melanoma in the presence of a compound. The results show that the combination of CDK2/4/6 is expected to become a kinase target for treating solid tumors. In addition, the invention also develops a prodrug with high oral bioavailability for the first time, and is convenient for oral administration in animal tests. A universal solution is provided for oral administration of PROTAC molecules with CRBN ligands.

The invention discloses an intermediate N-cyclopentyl-2-methoxy-5-(N,N-dimethyl-formamido)-3-pyrrylformonitrile (II) for preparing ribociclib and a preparation method thereof. The preparation method comprises the following steps: carrying out halogenating reaction on N,N-dimethyl-2-carbonyl-propanamide (IV) to obtain N,N-dimethyl-1-halo-2-carbonyl-propanamide (V); carrying out substitution reaction on the intermediate (V) and malononitrile to obtain N,N-dimethyl-1,1-dicyano-3-carbonyl-butyramide (VI); carrying out cyclization reaction on the intermediate (VI) to obtain 2-methoxy-5-(N,N-dimethyl-formamido)-3-pyrrylformonitrile (VII); and carrying out coupling reaction on the intermediate (VII) and bromocyclopentane to obtain the ribociclib intermediate N-cyclopentyl-2-methoxy-5-(N,N-dimethyl-formamido)-3-pyrrylformonitrile (II). The intermediate (II) and N-[5-(1-piperazino)-2-piperidyl]guanidine (III) are subjected to condensation reaction to obtain the ribociclib. The preparation method has the advantages of accessible raw materials, simple technique, high economy and environment friendliness, and is suitable for industrial production.

The invention discloses a preparation method of an intermediate of Ribociclib, wherein the preparation method comprises the following steps: 1) in the presence of manganese salt, making 2-chloro-4-cyclopentyl aminopyrimidine and 2-bromoacetaldehyde in a contact reaction to obtain 2-chloro-7-cyclopentyl-7H-pyrrole[2,3-d]pyrimindine; 2) making the product obtained in the step 1) react with formaldehyde and dimethylamine in an ammonium chloride aqueous solution to obtain 2-chloro-7-cyclopentyl-6-(N,N-dimethyl-aminomethyl)-7H-pyrrole[2,3-d] pyrimindine; 3) oxidizing the product obtained in the step 2) to obtain the Ribociclib intermediate, namely 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrole[2,3-d]pyrimindine-6-formamide. The method is readily available in raw materials, and does not use precious metal catalysts and the like, and is further greatly improved in yield and suitable for industrial production, and ensures the supply of the raw materials for Ribociclib preparation and has great application prospects.

The invention provides a solid dispersion of amorphous ribociclib or a pharmaceutically acceptable salt thereof and a pharmaceutical adjuvant, and a preparation method thereof. The solid dispersion contains ribociclib or the pharmaceutically acceptable salt thereof and the pharmaceutical adjuvant, wherein a weight ratio of ribociclib or the pharmaceutically acceptable salt thereof to the pharmaceutical adjuvant is 1: (0.1-100), ribociclib or the pharmaceutically acceptable salt thereof is amorphous, and the X-ray powder diffraction spectrum of the solid dispersion does not contain the characteristic peaks of crystals of ribociclib or the pharmaceutically acceptable salt thereof after deduction of the background peaks of the pharmaceutical adjuvant. The solid dispersion of ribociclib or thepharmaceutically acceptable salt thereof and the pharmaceutical adjuvant has good stability and dispersibility; the dissolution rate of ribociclib or the pharmaceutically acceptable salt thereof is improved; the bioavailability of the solid dispersion and body absorption of ribociclib are improved; and under accelerated test conditions, the solid dispersion can maintain good physical stability and chemical stability. The preparation method for the amorphous solid dispersion of the invention has the advantages of simple operation, low cost, good reproducibility, easy realization and suitability for industrial production.

A preparation method of ribociclib comprises the following steps: 1) utilizing 4-(6-aminopyridine-3-yl)piperazine-1-carboxylic acid tert-butyl ester and 2-chloro-4-cyclopentyl-N,N-dimethyl-7H-pyrrole[2,3-d]pyrimidine-6-formamide as raw materials and conducting reaction in a protective atmosphere with palladium acetate/ BINAP as a catalyst, cesium carbonate as an acid absorber and 4-methyl-2-pentanone as a solvent to obtain 4-(6-(7-cyclopentyl-6-(dimethylaminoformyl)-7H-pyrrolo[2,3-d]pyrimidine-2-yl)aminopyridine-3-yl)piperazine-1-carboxylic acid tert-butyl ester); 2) dissolving the4-(6-(7-cyclopentyl-6-(dimethylaminoformyl)-7H-pyrrolo[2,3-d]pyrimidine-2-yl)aminopyridine-3-yl)piperazine-1-carboxylic acid tert-butyl ester) obtained in step 1) in an organic solvent, adding acid dropwise at the room temperature to remove tert-butyl formate, conducting liquid separation, adding a water-soluble organic solvent to an aqueous layer, separating solids and filtering to obtain ribociclib acid salt; 3) adding water to the ribociclib acid salt for dissolving, adding an adsorbent, filtering and adding alkali to the filtrate to obtain the ribociclib.

The present invention provides processes for the preparation of Ribociclib, as well as intermediates useful in the preparation thereof. In particular, processes are provided for the preparation of a compound of Formula (4), and its conversion to Ribociclib (1).

The invention relates to a process for the preparation of ribociclib of formula V or its salts. The invention provides novel crystalline forms of ribociclib succinate and ribociclib trifluoroacetate. The present invention also relates to pharmaceutical compositions comprising a crystalline form of ribociclib succinate and at least a pharmaceutically acceptable carrier. It further relates to the use of such compositions in the treatment of cancer.

The invention discloses a synthesis method of a ribociclib intermediate product, which comprises the following steps: by using barbituric acid as a starting material, carrying out chlorination and formylation to obtain a compound 2; and performing condensation, cyclization, dechlorination, elimination and other reactions to obtain the rebociclib intermediate 2-chloro-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2, 3-d] pyrimidine-6-formamide. In addition, the intermediate compound is also disclosed. The synthesis method can avoid the use of noble metal catalysis, has the advantages of simple process route, accessible raw materials and mild conditions, effectively lowers the production cost, and is suitable for large-scale production.

The invention discloses a compound and application thereof in synthesis of ribociclib, and relates to a preparation method and application of a pharmaceutical ribociclib intermediate compound I (6- fluoro - 5,7 - diazindole derivative). The F-substituted compound I avoids the use of a noble metal catalyst in the production process of synthesizing the ribociclib, so that the operation of removing heavy metal residues in the experiment operation is reduced, compared with the substitution reaction of A chlorine element, the method disclosed by the invention is more thorough, efficient and mild, has an important value for the production and purification and quality control of a medicine.

The present invention relates to a pharmaceutical combination comprising LSZ102 and ribociclib; pharmaceutical compositions comprising the same; and methods of using such combinations and compositions in the treatment or prevention of conditions in which degradation of estrogen receptors combined with CDK4/6 inhibition is beneficial in, for example, the treatment of cancers.

This invention relates to the treatment of breast cancer in a subject, for example a female subject. Including methods of: treating metastatic breast cancer; refractory breast cancer; AR-positive breast cancer; AR-positive refractory breast cancer; AR-positive metastatic breast cancer; AR-positive and ER-positive breast cancer; triple negative breast cancer; advanced breast cancer; breast cancer that has failed selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonist (goserelin), aromatase inhibitor (AI) (letrozole, anastrozole, exemestane), cyclin-dependent kinase 4/6 (CDK 4/6) inhibitor (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio)), mTOR inhibitor (everolimus), trastuzumab (Herceptin, ado-trastuzumab emtansine), pertuzumab (Perjeta), lapatinib, neratinib (Nerlynx), olaparib (Lynparza) (an inhibitor of the enzyme poly ADP ribose polymerase (PARP)), bevacizumab (Avastin), and/or fulvestrant treatments; metastasis in a subject suffering from breast cancer; HER2-positive; and/or treating a subject suffering from ER mutant expressing breast cancer, comprising administering to the subject a therapeutically effective amount of a selective androgen receptor modulator (SARM) compound.

The invention relates to a crystal form of hemisuccinic acid Ribociclib, a preparation method and application thereof, a pharmaceutical composition containing the crystal form, and application of the crystal form in preparation of a cyclin-dependent kinase 4/6 inhibitor and a pharmaceutical preparation for treating breast cancer. Compared with the prior art, the Ribociclib crystal form CSI provided by the invention has one or more improved properties, and has important value for optimization and development of the medicine in the future.

The invention relates to a crystal form of ribociclib succinate as well as a preparation method and application thereof. Specifically, the invention provides a plurality of new crystal forms of ribociclib succinate and a preparation method thereof, and the new crystal forms have excellent solubility and other properties.

Drug combinations of a heteroarotinoid (e.g., SHetA2), and an Azabicyclooctan-3-one derivative (e.g., PRIMA-1 or PRIMA^MET) and/or, a CDK4/6 inhibitor (e.g., Palbociclib, Abemaciclib, or Ribociclib), which are synergistically-effective as anti-cancer treatments, and kits and methods of use of such drug combinations.

The present invention relates to an improved process for the preparation of 7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide succinate (1/1) compound of formula-1a and its novel crystalline forms. The said compound of formula-1a is represented by the following structural formula: Formula-1a