34 results about "Trifluridine" patented technology

The present invention relates to a method for treating a cancer comprising orally administering a composition containing α,α,α-trifluorothymidine (FTD) and 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride in a molar ratio of 1:0.5 at a dose of 20 to 80 mg / m2 / day in terms of FTD in 2 to 4 divided portions per to patients in need of the treatment.

The invention provides a preparation method of a trifluridine intermediate. Under the action of an acidic resin catalyst, 1-chloro-2-deoxy-3,5-di-O-p-chlorobenzoyl-D-ribose and 5-trifluoromethyl-2,4-bis(trimethylsilaneoxy)pyrimidine undergo a condensation reaction so as to obtain the trifluridine intermediate. According to the invention, a heterogeneous catalysis technology is utilized, acidic resin is used as a catalyst, and a traditional Lewis acid catalyst is replaced. Under the precondition of guaranteeing that product quality is controllable, a production technology is greatly improved. Catalytic efficiency is high, and conditions are mild. Purity of the prepared 1-(2'-deoxy-3,5-di-O-p-chlorobenzoyl-beta-D-furanose)-5-trifluoromethyluracil is greatly raised, and the problem that the use of the Lewis acid catalyst leads to severe post-treatment emulsification and environmental pollution and is not beneficial to industrial production is also effectively solved.

The present invention relates to a method for treating a cancer comprising orally administering a composition containing α,α,α-trifluorothymidine (FTD) and 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride in a molar ratio of 1:0.5 at a dose of 20 to 80 mg / m2 / day in terms of FTD in 2 to 4 divided portions per to patients in need of the treatment.

The invention belongs to the technical field of pharmaceutical chemical engineering, and particularly discloses a novel crystal form Trifluridine compound, a preparation method and medicine composition thereof. The Trifluridine novel crystal form is good in stability and solubility; the preparation method is relatively good in reproducibility, the operation is simple and convenient, the period is short, the cost is low, damage to the environment and staff is little, and the preparation method is suitable for industrial large-scale production, and has quite important application value in medicine preparation.

The invention provides a preparation method of high purity trifluridine. The method is as below: reacting a raw material of a compound 2 with HMDS under the action of trimethylchlorosilane to obtain a compound 3; subjecting the compound 3 and a compound 4 to condensation in the presence of a catalyst copper difluoride; conducting ethanol recrystallization to obtain a compound 5; and finally conducting deprotection on the compound 5 under the effect of sodium methylate; and recrystallizing by a mixed solvent of ethanol and acetone (1:1) to obtain the high purity object compound 1. The method has the advantages of high purity of the product, simpleness, easy purification and less industrial pollution.

The invention discloses a flufenacet preparation method, which comprises synthesis of 2-methylsulfonyl-5-trifluoromethyl-1,3,4-thiadiazole, synthesis of 2-hydroxy-N-(4-fluoroaniline)-N-(1-methylethyl)acetamide and synthesis of 4'-fluoro-N-isopropyl-2-[5-(trifluridine)-1,3,4-thiadiazole-2-imide]acetamide. The optimal flufenacet preparation method is screened by a large number of experiments, the whole process is reasonable in design, particularly the steps of screening optimal reaction conditions and the optimal amount ratio, reaction temperature, reaction time and the like of reaction raw materials, the reaction yield (capable of reaching 90 percent or more) can be greatly increased, side reaction can be reduced, the reaction rate can be increased, the reaction raw materials can be recycled, the production cost is greatly reduced, and a broad application prospect is achieved.

This invention provides a method for predicting a therapeutic effect of chemotherapy that uses an antitumor agent comprising α,α,α-trifluorothymidine and 5-chloro-6-(1-(2-iminopyrrolidinyl) methyl)uracil hydrochloride at a molar ratio of 1:0.5 on a colorectal cancer patient,the method comprising:(1) detecting the presence or absence of KRAS gene mutation in a biological sample obtained from the patient; and(2) predicting that the patient is likely to sufficiently respond to the chemotherapy, when KRAS gene mutation is detected in Step (1).

The present invention provides an FTD and TPI-containing orally administrable pharmaceutical composition which can be orally administered and is stable even under high-humidity conditions.An orally administrable pharmaceutical composition which comprises α,α,α-trifluorothymidine and 5-chloro-6-(2-iminopyrrolidine-1-yl)methyl-2,4(1H,3H)-pyrimidine dione hydrochloride as active ingredients and additives having a critical relative humidity of 85% or more at 25° C. as an excipient.

The invention discloses a preparation method of trifluridine. The method comprises the specific steps of: adding 2'-deoxyuridine and trifluoromethyl sulfinate sodium to a reaction solvent, stirring and cooling to - 5 to - 3 DEG C, introducing of nitrogen for protection, stirring to dissolve, dropwise adding tert-butyl hydroperoxide, controlling the temperature at less than 5 DEG C, heating to 60-65 DEG C for reaction, and conducting posttreatment after the reaction to obtain a finished product. The method provided by the invention has mild reaction conditions, simple operation, little side reaction, short reaction time, great reduction of feeding amount of tert-butyl hydroperoxide, great saving of the production cost, and high yield and high purity of the product, and is especially applicable to industrial production, and has significance to the quality control of medicine and clinical curative effect.

The present invention provides:an anti-HIV composition comprising at least one member selected from the group consisting of trifluridine and derivatives thereof, and a pharmaceutically acceptable carrier;an anti-HIV composition comprising (a) at least one member selected from the group consisting of trifluridine and derivatives thereof, (b) a thymidine phosphorylase inhibitor, and a pharmaceutically acceptable carrier; anda composition for potentiating the anti-HIV activity of trifluridine and derivatives thereof, comprising a thymidine phosphorylase inhibitor and a pharmaceutically acceptable carrier.

The present invention provides an FTD and TPI-containing oral pharmaceutical composition which can be orally administered and is stable even under high humidity conditions.An oral pharmaceutical composition comprising α,α,α-trifluorothymidine and 5-chloro-6-(2-iminopyrrolidine-1-yl)methyl-2,4(1H,3H)-pyrimidine dione hydrochloride as an active ingredient; and being substantially free of an additive comprising a metal salt.

The present invention provides a novel method that is capable of detecting a trifluridine-related substance from a sample containing trifluridine or a salt thereof by high-performance liquid chromatography comprising two steps that are performed under gradient conditions. More specifically, the method is for detecting a trifluridine-related substance, the method comprising the step of subjecting a sample containing trifluridine or a salt thereof to high-performance liquid chromatography using a mobile phase composed of an organic phase and an aqueous phase, wherein the step of high-performance liquid chromatography comprises steps 1 and 2 that satisfy the following requirements: Step 1: the percentage of the organic phase in the entire mobile phase is 1 to 14% by volume; and Step 2: after step 1, elution is performed by applying a gradient of increasing the percentage of the organic phase in the entire mobile phase.

This invention provides a method for predicting a therapeutic effect of chemotherapy that uses an antitumor agent comprising α,α,α-trifluorothymidine and 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride at a molar ratio of 1:0.5 on a colorectal cancer patient,the method comprising:(1) detecting the presence or absence of KRAS gene mutation in a biological sample obtained from the patient; and(2) predicting that the patient is likely to sufficiently respond to the chemotherapy, when KRAS gene mutation is detected in Step (1).

The invention discloses a method for synthesizing a trifluridine impurity 1-((2S,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione, and belongs tothe technical field of chemical pharmacy. The method comprises the following steps: condensing starting raw materials 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)uracil (2) and 1-chloro-2-deoxy-3,5-di-4-chlorobenzoyl-D-ribose (3) to prepare 3',5'-di(4-chlorobenzoyl)-2'-deoxy-alpha-D-ribose-5-trifluoromethyluracil (4); and hydrolyzing the compound (4) to generate 1-((2S,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione (1). The highly-pure trifluridine impurity synthesized in the invention can be used as an impurity standard product in the detection and analysis of finished trifluridine, so the accurate localization and qualitative diagnosis of the impurity in the detection and analysis of the finished trifluridine are improved, and theenhancement of the control of the impurity is benefited, thereby the quality of the finished trifluridine is improved. The method has the advantages of cheap and easily available raw materials, and simplicity in operation, and allows the yield of the obtained product to be (40 + / - 5)% and the HPLC purity of the product to be equal to or more than 98%.

The invention relates to a method for preparing trifluridine (Viroptic). The method comprises the following main steps: by using uridine (a compound shown in a formula II) as a starting raw material,sequentially carrying out the steps such as esterification and halogenating reaction of hydroxyl, reduction reaction, trifluoromethylation reaction and protective group removal reaction so as to obtain a target. The method provided by the invention has the advantages that the use of expensive raw materials and the use of reagents with high toxicity and capability of polluting an environment are avoided and reaction conditions required in all steps are mild; therefore, the invention provides a preparation method of trifluridine with environmental protection property, security property and a commercial preparation value.

The present invention provides a novel method that is capable of detecting a trifluridine-related substance from a sample containing trifluridine or a salt thereof by high-performance liquid chromatography comprising two steps that are performed under gradient conditions. More specifically, the method is for detecting a trifluridine-related substance, the method comprising the step of subjecting a sample containing trifluridine or a salt thereof to high-performance liquid chromatography using a mobile phase composed of an organic phase and an aqueous phase, wherein the step of high-performance liquid chromatography comprises steps 1 and 2 that satisfy the following requirements: Step 1: the percentage of the organic phase in the entire mobile phase is 1 to 14% by volume; and Step 2: after step 1, elution is performed by applying a gradient of increasing the percentage of the organic phase in the entire mobile phase.

The present invention discloses a new crystal form of trifluridine, and a preparation method thereof, and particularly relates to a new 5-trifluoromethyl-2'-deoxyuridine crystal form represented by a formula (I), and a preparation method thereof, wherein the characteristic peaks of the crystal form in the X-ray powder diffraction spectrum are positioned at (a) 7.3 DEG, (b) 10.0 DEG, (c) 14.5 DEG and (d) 23.4 DEG C by adopting 2[theta] (2[theta]+ / -0.2 DEG) to represent. According to the present invention, the crystal form has characteristics of stable characteristics and good repeatability, and is suitable for drug development. The formula I is defined in the specification.

The invention relates to a novel trifluridine crystal form and a preparation method thereof. The trifluridine crystal form II shown in the formula (I) is characterized in that a CuKa ray is used as the feature X-ray for powder determination, and characteristic peaks are shown when the 2Q diffraction angle is located at the following positions such as 7.405, 9.933, 10.602, 14.865, 17.428, 18.675, 19.027, 20.274 and 23.911. The preparation method of the trifluridine crystal form II shown in the formula (II) comprises the step that trifluridine is crystallized in a supersaturated solution with protic solvent or aprotic solvent at the temperature of 0-30 DEG C, so that the crystal form II is obtained. The property of the crystal form is stable, and the crystal form meets the development requirement for pharmaceutical preparations (please see the specification for the formula).

The present invention relates to a method for detecting a similar substance derived from trefluuridine. The present invention provides a novel method that is capable of detecting a trifluridine-related substance from a sample containing trifluridine or a salt thereof by high-performance liquid chromatography comprising two steps that are performed under gradient conditions. The solution of the invention is the method for detecting the similar substance derived from the trefluuridine, and the method comprises the step of subjecting a sample containing trifluridine or a salt thereof to high-performance liquid chromatography using a mobile phase composed of an organic phase and an aqueous phase, wherein the step of high-performance liquid chromatography comprises steps 1 and 2 that satisfy the following requirements: the step 1: the percentage of the organic phase in the entire mobile phase is 1 to 14% by volume; and the step 2: after step 1, a gradient is set to increase the percentage of the organic phase relative to the entire mobile phase.

Nucleosides and nucleotides (nucleos(t)ides) have been in clinical use for almost 50 years and have become cornerstones of treatment for patients with viral infections or cancer. The approval of several additional drugs over the past decade demonstrates that this family still possesses strong potential. Therefore nucleos(t)ide are of great interest as promising chemotherapeutic agents, including: 2′-deoxy-L-uridine (CAS 31501-19-6), 2′-deoxy-D-uridine (CAS 951-78-0), telbivudine (CAS 3424-98-4), zidovudine (AZT, CAS 30516-87-1), trifluridine (CAS 70-00-8), clevudine (CAS 163252-36-6), PSI-6206 (CAS 863329-66-2), 2′-(S)-2′-chloro-2′-deoxy-2′-fluorouridine (CAS 1673560-41-2), ND06954 (CAS 114248-23-6), stavudine (CAS 3056-17-5), 5-ethynyltavudine (Festinavir, CAS 634907-30-5), torcitabine (CAS 40093-94-5), (−)-beta-D-(2R,4R)-dioxolane-thymine (DOT, 1-((2R,4R)-2-(hydroxymethyl)-1,3-dioxolan-4-yl)-5-methyl-2,4(1H,3H)-pyrimidinedione, CAS No. 127658-07-5), 2-(6-amino-purin-9-yl)-ethanol (CAS 707-99-3), 2′-C-methylcytidine (CAS 20724-73-6), PSI-6130 (CAS 817204-33-4), gemcitabine (CAS 95058-81-4), 2′-chloro-2′-deoxy-2′-fluorocytidine (CAS 1786426-19-4), 2′,2′-dichloro-2′-deoxycytidine (CAS 1703785-65-2), 2′-C-methylcytidine (CAS 20724-73-6), PSI-6130 (CAS 817204-33-4), lamivudine (3TC, CAS 134678-17-4), emtricitabine (CAS 143491-57-0), 2′-deoxyadenosine (CAS 958-09-8), 2′-deoxy-β-L-adenosine (CAS 14365-45-8), 2′-deoxy-4′-C-ethynyl-2-fluoroadenosine (CAS 865363-93-5), didanosine (CAS 69655-05-6), entecavir (CAS 209216-23-9), FMCA (CAS 1307273-70-6), dioxolane-G (DOG, CAS 145514-01-8), β-D-2′-deoxy-2′-(R)-fluoro-2′-β-C-methylguanosine (CAS No 817204-45-8), abacavir (ABC, CAS 136470-78-5), dioxolane-A (DOA, CAS #145514-02-9), [(2R,4R)-4-(6-cyclopropylamino-purin-9-yl)-[1,3]dioxolan-2-yl]-methanol (CAS 1446751-04-7), amdoxovir (AMDX, CAS 145514-04-1), (R)-1-(6-amino-purin-9-yl)-propan-2-ol (CAS 14047-28-0), and [(2S,5R)-5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yl]-methanol.Macroheterocyclic nucleoside derivative and its analog of the general formula 1 or general formula 2, a stereoisomer, isotope-enriched analog, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof,wherein:Ar is aryl or hetaryl;R1 and R2 are not necessarily the same substituents selected from H, F, Cl, CH3, OH;R3 is H or CH3;X is oxygen or ethanediyl-1,1 (C═CH2);Y is CH(R4)(CH2)k, CH(R4)(CH2)mC(O)O(CH2)n;R4 is H or CH3;k has a value from zero to six;m has a value from zero to two;n has a value of one to four;Q is a radical selected from Q1-Q4;wherein: R5 is the substituent selected from H, F, Cl, CH3, OH;the arrow (→) indicates the location, joined by Q1-Q4.

Nucleosides and nucleotides (nucleos(t)ides) have been in clinical use for almost 50 years and have become cornerstones of treatment for patients with viral infections or cancer. The approval of several additional drugs over the past decade demonstrates that this family still possesses strong potential. Therefore nucleos(t)ide are of great interest as promising chemotherapeutic agents, including: 2′-deoxy-L-uridine (CAS No 31501-19-6), 2′-deoxy-D-uridine (CAS No 951-78-0), telbivudine (CAS No 3424-98-4), zidovudine (AZT, CAS No 30516-87-1), trifluridine (CAS No 70-00-8), clevudine (CAS No 163252-36-6), PSI-6206 (CAS No 863329-66-2), 2′-(5)-2′-chloro-2′-deoxy-2′-fluorouridine (CAS No 1673560-41-2), ND06954 (CAS No 114248-23-6), stavudine (CAS No 3056-17-5), 5-ethynyltavudine (Festinavir, CAS No 634907-30-5), torcitabine (CAS No 40093-94-5), (−)-beta-D-(2R,4R)-dioxolane-thymine (DOT, 1-((2R,4R)-2-(hydroxymethyl)-1,3-dioxolan-4-yl)-5-methyl-2,4 (1H,3H)-pyrimidinedione, CAS No. 127658-07-5), 2-(6-amino-purin-9-yl)-ethanol (CAS No 707-99-3), 2′-C-methylcytidine (CAS No 20724-73-6), PSI-6130 (CAS No 817204-33-4), gemcitabine (CAS No 95058-81-4), 2′-chloro-2′-deoxy-2′-fluorocytidine (CAS No 1786426-19-4), 2′,2′-dichloro-2′-deoxycytidine (CAS No 1703785-65-2), 2′-C-methylcytidine (CAS No 20724-73-6), PSI-6130 (CAS No 817204-33-4), lamivudine (3TC, CAS No 134678-17-4), emtricitabine (CAS No 143491-57-0), 2′-deoxyadenosine (CAS No 958-09-8), 2′-deoxy-β-L-adenosine (CAS No 14365-45-8), 2′-deoxy-4′-C-ethynyl-2-fluoroadenosine (CAS No 865363-93-5), didanosine (CAS No 69655-05-6), entecavir (CAS No 209216-23-9), FMCA (CAS No 1307273-70-6), dioxolane-G (DOG, CAS No 145514-01-8), β-D-2′-deoxy-2′-(R)-fluoro-2′-β-C-methylguanosine (CAS No 817204-45-8), abacavir (ABC, CAS No 136470-78-5), dioxolane-A (DOA, CAS #145514-02-9), [(2R,4R)-4-(6-cyclopropylamino-purin-9-yl)-[1,3]dioxolan-2-yl]-methanol (CAS No 1446751-04-7), amdoxovir (AMDX, CAS No 145514-04-1), (R)-1-(6-amino-purin-9-yl)-propan-2-ol (CAS No 14047-28-0), and [(2S,5R)-5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yl]-methanol.Macroheterocyclic nucleoside derivative and its analogue of the general formula 1 or general formula 2, a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof,wherein:Ar is aryl or hetaryl;R1 and R2 are not necessarily the same substituents selected from H, F, Cl, CH3, OH;R3 is H or CH3;X is oxygen or ethanediyl-1,1 (C═CH2);Y is CH(R4)(CH2)k, CH(R4)(CH2)mC(O)O(CH2)n;R4 is H or CH3;k has a value from zero to six;m has a value from zero to two;n has a value of one to four;Q is a radical selected from Q1-Q4;wherein: R5 is the substituent selected from H, F, Cl, CH3, OH;the arrow (→) indicates the location, joined by Q1-Q4.

The invention discloses an application of trifluridine in preparation of an HIV-1 drug, and provides a new application of trifluridine as an HIV-1 latent infection activator, and the trifluridine hasa very good activation effect on HIV-1 latent infection. As trifluridine is a clinically used drug, trifluridine is low in toxicity and good in safety, but the related application of trifluridine serving as an HIV-1 latent infection activator is not reported yet at present. Trifluridine has important research and development value and development significance in the aspect of activation of HIV-1 latent infection.

The present invention discloses a new crystal form of trifluridine, and a preparation method thereof, and particularly relates to a new 5-trifluoromethyl-2'-deoxyuridine crystal form represented by a formula (I), and a preparation method thereof, wherein the characteristic peaks of the crystal form in the X-ray powder diffraction spectrum are positioned at (a) 7.3 DEG, (b) 10.0 DEG, (c) 14.5 DEG and (d) 23.4 DEG C by adopting 2[theta] (2[theta]+ / -0.2 DEG) to represent. According to the present invention, the crystal form has characteristics of stable characteristics and good repeatability, and is suitable for drug development. The formula I is defined in the specification.

The invention provides a preparation method of a trifluridine intermediate. Under the action of an acidic resin catalyst, 1-chloro-2-deoxy-3,5-di-O-p-chlorobenzoyl-D-ribose and 5-trifluoromethyl-2,4-bis(trimethylsilaneoxy)pyrimidine undergo a condensation reaction so as to obtain the trifluridine intermediate. According to the invention, a heterogeneous catalysis technology is utilized, acidic resin is used as a catalyst, and a traditional Lewis acid catalyst is replaced. Under the precondition of guaranteeing that product quality is controllable, a production technology is greatly improved. Catalytic efficiency is high, and conditions are mild. Purity of the prepared 1-(2'-deoxy-3,5-di-O-p-chlorobenzoyl-beta-D-furanose)-5-trifluoromethyluracil is greatly raised, and the problem that the use of the Lewis acid catalyst leads to severe post-treatment emulsification and environmental pollution and is not beneficial to industrial production is also effectively solved.

The invention discloses a preparation method of trifluridine. The method comprises the specific steps of: adding 2'-deoxyuridine and trifluoromethyl sulfinate sodium to a reaction solvent, stirring and cooling to - 5 to - 3 DEG C, introducing of nitrogen for protection, stirring to dissolve, dropwise adding tert-butyl hydroperoxide, controlling the temperature at less than 5 DEG C, heating to 60-65 DEG C for reaction, and conducting posttreatment after the reaction to obtain a finished product. The method provided by the invention has mild reaction conditions, simple operation, little side reaction, short reaction time, great reduction of feeding amount of tert-butyl hydroperoxide, great saving of the production cost, and high yield and high purity of the product, and is especially applicable to industrial production, and has significance to the quality control of medicine and clinical curative effect.

The present invention relates to a method for treating a cancer comprising orally administering a composition containing α,α,α-trifluorothymidine (FTD) and 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride in a molar ratio of 1:0.5 at a dose of 20 to 80 mg / m2 / day in terms of FTD in 2 to 4 divided portions per to patients in need of the treatment.

The invention relates to new application of known compounds, in particular to an application of six small molecule drugs in inhibition of canine parvovirus. The invention provides the application of closantel, Closantel Sodium, gemcitabine HCl, Trifluridine, Gemcitabine and Cladribine in preparation of drugs for inhibiting replication of canine parvovirus, t active components of the medicine comprise Closantel, Closantel Sodium, Gemcitabine HCl, Trifluridine, Gemcitabine and / or Cladribine, and the structural formula of the medicine is shown in the specification. The data prove that the six small molecule drugs have very excellent inhibition effects on CPV replication, and can inhibit expression of different genotypes of CPV virus VP2 proteins.

The invention belongs to the technical field of medicine synthesis, and particularly relates to a trifluridine impurity compound and a preparation method thereof. The preparation method comprises the following steps: esterifying 1-((2S, 4S, 5R)-4-acetoxy-5-(acetoxymethyl) tetrahydrofuran-2-yl)-2, 4-dioxo-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylic acid serving as a raw material and hydroxyl at the 5-position of a glycosyl group of trifluridine under the action of Novozyme 435, and then removing a hydroxyl protecting group on the glycosyl group to prepare the trifluridine impurity compound. The synthesis method provided by the invention is simple, and the trifluridine impurity compound obtained by the method is high in purity and high in yield after recrystallization precipitation, and can be used as an impurity reference substance in a trifluridine finished product detection standard.