Provided in the present application are an aromatic amine compound, and a pharmaceutical composition and the use thereof. The aromatic amine compound comprises a compound as represented by formula (I) or an enantiomer, diastereoisomer, pharmaceutically acceptable salt, prodrug, isotope derivative, solvate, stereoisomer and tritiated compound: (I). The aromatic amine compound of the present application can inhibit the activity of YES1 protein, inhibit the transcription of related genes, and inhibit cell growth by means of binding to the YES1 protein, so that the compound can be used for treating YES1 protein-related diseases or conditions, such as cancer.
C07D 253/08 - Composés hétérocycliques contenant des cycles à six chaînons comportant trois atomes d'azote comme uniques hétéro-atomes du cycle, non prévus par le groupe condensés avec des carbocycles ou avec des systèmes carbocycliques
C07D 471/02 - Composés hétérocycliques contenant des atomes d'azote comme uniques hétéro-atomes du système condensé, au moins un cycle étant un cycle à six chaînons avec un atome d'azote, non prévus dans les groupes dans lesquels le système condensé contient deux hétérocycles
A61K 31/519 - PyrimidinesPyrimidines hydrogénées, p. ex. triméthoprime condensées en ortho ou en péri avec des hétérocycles
A61K 31/53 - Composés hétérocycliques ayant l'azote comme hétéro-atome d'un cycle, p. ex. guanéthidine ou rifamycines ayant des cycles à six chaînons avec trois azote comme seuls hétéro-atomes d'un cycle, p. ex. chlorazanil, mélamine
A61P 35/02 - Agents anticancéreux spécifiques pour le traitement de la leucémie
2.
SULFONAMIDE COMPOUND, PHARMACEUTICAL COMPOSITION THEREOF AND USE THEREOF
The present disclosure relates to a sulfonyl compound, and a pharmaceutical composition thereof and a use thereof. The sulfonamide compound comprises a compound as shown in formula I. The sulfonamide compound competitively binds to KAT6A/KAT6B with the substrate at the binding pocket of the substrate acetyl coenzyme of KAT6A/KAT6B, inhibits acetyl coenzyme from binding to KAT6A/KAT6B to catalyze histone related sites, prevents gene expression that induces cancer cell growth, and is further used to treat tumor diseases related to KAT6A/KAT6B gene amplification or KAT6A/KAT6B protein overexpression.
C07D 493/00 - Composés hétérocycliques contenant des atomes d'oxygène comme uniques hétéro-atomes dans le système condensé
C07D 487/00 - Composés hétérocycliques contenant des atomes d'azote comme uniques hétéro-atomes dans le système condensé, non prévus par les groupes
A61K 31/5365 - Composés hétérocycliques ayant l'azote comme hétéro-atome d'un cycle, p. ex. guanéthidine ou rifamycines ayant des cycles à six chaînons avec au moins un azote et au moins un oxygène comme hétéro-atomes d'un cycle, p. ex. 1,2-oxazines condensées en ortho ou en péri avec des systèmes hétérocycliques
The present disclosure relates to the field of pharmaceutical technology, providing three crystalline forms, i.e., a crystalline form AB, a crystalline form M and a crystalline form F, of the compound 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)aminoformyl]cyclopropanecarbonyl]-amino]phenoxy]-6-methoxy-7-quinolyl]oxy]hexanoic acid for treatment of diseases related to protein kinases AXL and/or VEGFR2. The present disclosure also provides methods for preparing these three crystalline forms and pharmaceutical compositions comprising these three crystalline forms. The crystalline form AB, the crystalline form M and the crystalline form F of the present disclosure all have good chemical stability, and the preparation processes of the three crystalline forms of the present disclosure are simple for implementation with high product yield and purity, allowing stable and mass production that facilitates promotion and application.
The present invention falls within the field of medical technology, and discloses a compound as shown by formula I or a pharmaceutically acceptable salt, cis- or trans-isomer, prodrug, metabolite, isotope derivative and solvate thereof. The compound of the present invention is a cyclobutyl-containing compound used as a tyrosine kinase inhibitor, and can be used for treating tumor diseases related to tyrosine kinase, especially VEGFR. Due to the presence of the cyclobutyl group, the substituents at 1- and 3-position have cis and trans configurations. The rigidity of a branched chain molecule and the directivity of the molecule can be enhanced, and the compound can easily be better bound to a target, so that the dosage of a drug can be reduced, and side effects of the drug is reduced. The present invention also provides a preparation method, the kinase activity, pharmacokinetic data, and pharmacodynamic data of the compound, and the results show that the compound of the present invention has a wide range of application in the treatment of tumor diseases caused by abnormal activity of tyrosine kinases such as VEGFR.
C07D 403/12 - Composés hétérocycliques contenant plusieurs hétérocycles, comportant des atomes d'azote comme uniques hétéro-atomes du cycle, non prévus par le groupe contenant deux hétérocycles liés par une chaîne contenant des hétéro-atomes comme chaînons
A61K 31/517 - PyrimidinesPyrimidines hydrogénées, p. ex. triméthoprime condensées en ortho ou en péri avec des systèmes carbocycliques, p. ex. quinazoline, périmidine
A quinoline anti-tumor pharmaceutical composition containing a phosphorus substituent and a method for increasing the solubility of a pharmaceutical active ingredient in said pharmaceutical composition, the pharmaceutical composition comprising a pharmaceutical active ingredient and a pharmaceutically acceptable acid. By adding an acid compound to a pharmaceutical active ingredient, acid may be released after a drug has entered the gastric juice, thereby increasing the acidity of the gastric juice and lowering the pH value of the gastric juice. The decrease in the pH value of the gastric juice provides a favorable environment for the dissolution of the drug, thus facilitating the dissolution and absorption of the pharmaceutical active ingredient within the stomach, and improving the bioavailability of the drug within the body. Also provided is a method for increasing the solubility in water of a quinoline anti-tumor drug containing a phosphorus substituent.
Provided by the present invention are three crystal forms of a compound 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolinyl]oxy]hexanoic acid used in the treatment of diseases related to protein kinase AXL and/or VEGFR2, the crystal forms comprising: crystal form AB, crystal form M and crystal form F. Further provided by the present invention is a method used for preparing the three crystal forms and a pharmaceutical composition containing the three crystal forms. The crystal form AB, crystal form M and crystal form F of the present invention all have good chemical stability. In addition, the preparation method for the three crystal forms of the present invention is simple and easy to implement, the yield and purity of the products are high, and said products can be produced stably in batches, which is beneficial for promotion and application. The crystal form AB, crystal form M and crystal form F of the present invention are also relatively stable under high temperature, high humidity, and oxidation conditions, which is beneficial both for storage and transportation, and which is beneficial for industrial production. In addition, the crystal form AB, crystal form M and crystal form F of the present invention have high bioavailability, and meet the requirements of clinical medication.
The present application provides a quinolyl-substituted carboxylic acid compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, as well as a method for preparing the compound, a use of the compound, and a formulation containing the quinolyl-substituted carboxylic acid compound or the pharmaceutically acceptable salt thereof. This type of compounds are inhibitors for AXL and/or VEGFR2 protein kinase, and can be used to treat diseases caused by abnormality of the two protein kinases, such as, tumor, etc.
A61K 31/4709 - Quinoléines non condensées contenant d'autres hétérocycles
A61P 1/16 - Médicaments pour le traitement des troubles du tractus alimentaire ou de l'appareil digestif des troubles de la vésicule biliaire ou du foie, p. ex. protecteurs hépatiques, cholagogues, cholélitholytiques
C07D 401/12 - Composés hétérocycliques contenant plusieurs hétérocycles comportant des atomes d'azote comme uniques hétéro-atomes du cycle, au moins un cycle étant un cycle à six chaînons avec un unique atome d'azote contenant deux hétérocycles liés par une chaîne contenant des hétéro-atomes comme chaînons
A61P 25/00 - Médicaments pour le traitement des troubles du système nerveux
Provided in the present invention is a quinolinyl-substituted carboxylic acid compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, and also disclosed are a preparation method and the use of the compound and a preparation comprising the quinolinyl-substituted carboxylic acid compound or a pharmaceutically acceptable salt thereof. The compound is an inhibitor of the protein kinase AXL and/or VEGFR2 and can be used for treating diseases caused by aberrant activity of both kinases, such as tumours, etc.
C07D 401/12 - Composés hétérocycliques contenant plusieurs hétérocycles comportant des atomes d'azote comme uniques hétéro-atomes du cycle, au moins un cycle étant un cycle à six chaînons avec un unique atome d'azote contenant deux hétérocycles liés par une chaîne contenant des hétéro-atomes comme chaînons
C07D 215/233 - Atomes d'oxygène liés en position 2 ou 4 un seul atome d'oxygène qui est lié en position 4
A61K 31/4709 - Quinoléines non condensées contenant d'autres hétérocycles
A61P 1/16 - Médicaments pour le traitement des troubles du tractus alimentaire ou de l'appareil digestif des troubles de la vésicule biliaire ou du foie, p. ex. protecteurs hépatiques, cholagogues, cholélitholytiques
A61P 3/10 - Médicaments pour le traitement des troubles du métabolisme de l'homéostase du glucose de l'hyperglycémie, p. ex. antidiabétiques
The present invention provides agkistrodon acutus hemocoagulase-B. The agkistrodon acutus hemocoagulase-B is high-activity hemocoagulase separated from agkistrodon acutus venom. The hemocoagulase is a single-stranded glycoprotein comprising 236 amino acids, and has an amino acid sequence shown as SEQ ID No. 1. The strand comprises 6 pairs of disulfide bonds; the molecular weight of SDS-PAGE is approximately 35kD; the molecular weight after deglycosylation is 26116.7Da; and an isoelectric point (pI) is 6.0. A hemocoagulase molecule is modified by heterozygotic polysaccharides at an Asn 77, 100, 229 site. The hemocoagulase is serine proteinase. The present invention further provides a separation and purification method of the hemocoagulase. The method comprise: removing undissolved substances by using pretreatment; performing anion-exchange column chromatography for two times and Sephdex-G75 molecular sieve chromatography for one time; obtaining an active elution peak; performing dialysis and lyophilization, so as to obtain the high-purity agkistrodon acutus venom hemocoagulase. The activity of the agkistrodon acutus venom hemocoagulase is not less than 2000U/mg; the purity in the HPLC analysis can exceed 95%; and the yield is 0.25% to 0.30% calculated according to the weight of an agkistrodon acutus venom raw material.
Phosphorus-containing group-substituted quinolines of formula (I) are provided in the present invention. The preparation process and application of the compound, and formulation comprising phosphorus-containing group-substituted quinolines are also disclosed. The compounds are protein kinase inhibitor and can be used for treating protein kinase abnormal activity-associated diseases, such as tumor, etc.
C07F 9/60 - Systèmes cycliques quinoléiniques ou quinoléiniques hydrogénés
A61K 31/675 - Composés du phosphore ayant l'azote comme hétéro-atome d'un cycle, p. ex. phosphate de pyridoxal
C07F 9/6558 - Composés hétérocycliques, p. ex. contenant du phosphore comme hétéro-atome du cycle contenant au moins deux hétérocycles différents ou différemment substitués ni condensés entre eux ni condensés avec un carbocycle commun ou un système carbocyclique commun
11.
HYDROXAMIC ACID COMPOUND CONTAINING QUINOLYL AND PREPARATION METHOD THEREOF, AND PHARMACEUTICAL COMPOSITION CONTAINING THIS COMPOUND AND USE THEREOF
Provided in the present invention is a hydroxamic acid compound containing quinolyl as shown in formula (I), at the same time also disclosed is the preparation method of the compound and the use thereof, and a drug containing the hydroxamic acid compound containing quinolyl. Such compounds are inhibitors of protein kinases and/or histone deacetylases, and can be used in the treatment of diseases caused by the abnormal activity of protein kinases and/or histone deacetylases, for example tumours, etc.
C07D 401/12 - Composés hétérocycliques contenant plusieurs hétérocycles comportant des atomes d'azote comme uniques hétéro-atomes du cycle, au moins un cycle étant un cycle à six chaînons avec un unique atome d'azote contenant deux hétérocycles liés par une chaîne contenant des hétéro-atomes comme chaînons
C07D 215/233 - Atomes d'oxygène liés en position 2 ou 4 un seul atome d'oxygène qui est lié en position 4
A61K 31/4709 - Quinoléines non condensées contenant d'autres hétérocycles
A61P 1/16 - Médicaments pour le traitement des troubles du tractus alimentaire ou de l'appareil digestif des troubles de la vésicule biliaire ou du foie, p. ex. protecteurs hépatiques, cholagogues, cholélitholytiques
A61P 3/10 - Médicaments pour le traitement des troubles du métabolisme de l'homéostase du glucose de l'hyperglycémie, p. ex. antidiabétiques
A61P 25/28 - Médicaments pour le traitement des troubles du système nerveux des troubles dégénératifs du système nerveux central, p. ex. agents nootropes, activateurs de la cognition, médicaments pour traiter la maladie d'Alzheimer ou d'autres formes de démence
A61P 25/14 - Médicaments pour le traitement des troubles du système nerveux pour traiter les mouvements anormaux, p. ex. chorée, dyskinésie
Phosphorus substituted group-containing quinoline-like compound of formula (I) are provided in the present invention. The preparation process and application of the compound, and pharmaceutical formulation comprising phosphorus substituted group-containing quinoline-like compound are also disclosed. The compounds are protein kinase inhibitor and can be used for treating protein kinase abnormal activity-associated diseases, such as neoplasm, etc.
C07F 9/6558 - Composés hétérocycliques, p. ex. contenant du phosphore comme hétéro-atome du cycle contenant au moins deux hétérocycles différents ou différemment substitués ni condensés entre eux ni condensés avec un carbocycle commun ou un système carbocyclique commun
C07F 9/60 - Systèmes cycliques quinoléiniques ou quinoléiniques hydrogénés
A61K 31/675 - Composés du phosphore ayant l'azote comme hétéro-atome d'un cycle, p. ex. phosphate de pyridoxal
A61K 9/00 - Préparations médicinales caractérisées par un aspect particulier
Agkistrodon acutus in the present invention is a serine proteinase having a molecular weight of 29.3-29.5 kD and an isoelectric point of 5.5, and is able to hydrolyze the alpha chain of human fibrinogen. The invention also provides methods of purifying the thrombin-like enzyme from snake venom, which comprise removing insoluble substance by pretreatment, conducting twice of anion-exchange column chromatography, collecting active eluting peak, dialyzing, ultra-filtrating and desalinating so as to obtain a snake venom thrombin-like enzyme.
brevets
