Abrégé

Substituted hexitol derivatives such as dianhydrogalactitol are useful in the treatment of various neoplastic pathologies. Said pathologies include glioblastoma multiforme, non-small-cell lung carcinoma (NSCLC), ovarian cancer, and leptomeningeal carcinomatosis. The anti-neoplastic activity of dianhydrogalactitol is demonstrated to be due to its activity as an alkylating agent that creates N7 methylation and inter-strand DNA crosslinks. The hexitol derivatives may be used alone or in combination with other anti-neoplastic agents.

Classes IPC  ?

• A61K 31/336 - Composés hétérocycliques ayant l'oxygène comme seul hétéro-atome d'un cycle, p. ex. fungichromine ayant des cycles à trois chaînons, p. ex. oxirane, fumagilline
• A61K 47/54 - Préparations médicinales caractérisées par les ingrédients non actifs utilisés, p. ex. les supports ou les additifs inertesAgents de ciblage ou de modification chimiquement liés à l’ingrédient actif l’ingrédient non actif étant chimiquement lié à l’ingrédient actif, p. ex. conjugués polymère-médicament l’ingrédient non actif étant un agent de modification l’agent de modification étant un composé organique
• A61K 47/64 - Conjugués médicament-peptide, médicament-protéine ou médicament-acide polyaminé, c.-à-d. l’agent de modification étant un peptide, une protéine ou un acide polyaminé lié par covalence ou complexé à un agent thérapeutiquement actif
• A61P 35/00 - Agents anticancéreux
• C07D 303/14 - Composés contenant des cycles oxirane avec des radicaux hydrocarbonés, substitués par des atomes d'oxygène liés par des liaisons simples ou doubles par des radicaux hydroxyle libres
• C07D 303/16 - Composés contenant des cycles oxirane avec des radicaux hydrocarbonés, substitués par des atomes d'oxygène liés par des liaisons simples ou doubles par des radicaux hydroxyle estérifiés

Abrégé

The use of dianhydrogalactitol provides a novel therapeutic modality for the treatment of non-small-cell lung carcinoma (NSCLC) and for the treatment of glioblastoma multiforme (GBM). Dianhydrogalactitol acts as an alkylating agent on DNA that creates N7 methylation. Dianhydrogalactitol is effective in suppressing the growth of cancer stem cells and is active against tumors that are refractory to temozolomide; the drug acts independently of the MGMT repair mechanism.

Classes IPC  ?

• A61K 31/336 - Composés hétérocycliques ayant l'oxygène comme seul hétéro-atome d'un cycle, p. ex. fungichromine ayant des cycles à trois chaînons, p. ex. oxirane, fumagilline
• A61K 35/00 - Préparations médicinales contenant des substances ou leurs produits de réaction de constitution non déterminée
• C07D 303/02 - Composés contenant des cycles oxirane

Abrégé

The use of dianhydrogalactitol provides a novel therapeutic modality for the treatment of non-small-cell lung carcinoma (NSCLC) and ovarian cancer. Dianhydrogalactitol acts as an alkylating agent on DNA that creates N7 methylation. Dianhydrogalactitol is effective in suppressing the growth of cancer stem cells and is active against tumors that are refractory to temozolomide, cisplatin, and thymidine kinase inhibitors; the drug acts independently of the MGMT repair mechanism. Dianhydrogalactitol can be used together with other anti-neoplastic agents and can possess additive or super-additive effects.

Classes IPC  ?

• A61K 38/12 - Peptides cycliques

Abrégé

An improved analytical method for analysis of dianhydrogalactitol preparations provides a method for determining the purity of dianhydrogalactitol and detecting impurities in preparations of dianhydrogalactitol, as well as identifying any such impurities. The method employs high performance liquid chromatography (HPLC), in particular, HPLC with evaporative light scattering detection (ELSD); the HPLC can be followed by tandem mass spectroscopy. The method can further comprise the step of performing preparative HPLC collection of at least one specific substance peak present in a preparation of dianhydrogalactitol.

Classes IPC  ?

• C07D 301/02 - Synthèse du cycle de l'oxirane
• C07D 303/14 - Composés contenant des cycles oxirane avec des radicaux hydrocarbonés, substitués par des atomes d'oxygène liés par des liaisons simples ou doubles par des radicaux hydroxyle libres
• G01N 30/22 - Injection dans des systèmes liquides à haute pression
• G01N 30/74 - Détecteurs optiques

Abrégé

Methods and compositions suitable for the treatment of malignancies such as recurrent glioma and progressive secondary brain tumor are disclosed. These methods employ a hexitol derivative such as dianhydrogalactitol, a derivative or analog of dianhydrogalactitol, diacetyldianhydrogalactitol, or a derivative or analog of diacetyldianhydrogalactitol. The compositions can include such hexitol derivatives.

Classes IPC  ?

• A61K 31/7024 - Esters de saccharides

Abrégé

An improved analytical method for analysis of dianhydrogalactitol preparations provides a method for determining the purity of dianhydrogalactitol and detecting impurities in preparations of dianhydrogalactitol, as well as identifying any such impurities. The method employs high performance liquid chromatography (HPLC), in particular, HPLC with evaporative light scattering detection (ELSD); the HPLC can be followed by tandem mass spectroscopy. The method can further comprise the step of performing preparative HPLC collection of at least one specific substance peak present in a preparation of dianhydrogalactitol.

Classes IPC  ?

• G01N 33/15 - Préparations médicinales
• G01N 21/49 - Dispersion, c.-à-d. réflexion diffuse dans un corps ou dans un fluide
• G01N 30/88 - Systèmes intégrés d'analyse, spécialement adaptés à cet effet, non couverts par un seul des groupes

Abrégé

N2 reaction. Other methods for the synthesis of dianhydrogalactitol from dulcitol are described.

Classes IPC  ?

• C07D 303/14 - Composés contenant des cycles oxirane avec des radicaux hydrocarbonés, substitués par des atomes d'oxygène liés par des liaisons simples ou doubles par des radicaux hydroxyle libres
• C07D 301/24 - Synthèse du cycle de l'oxirane par élimination de Hal-Y de composés contenant le radical Hal—C—C—OY
• C07D 301/26 - Y étant de l'hydrogène
• C07D 301/03 - Synthèse du cycle de l'oxirane par oxydation de composés non saturés, ou de mélanges de composés non saturés et de composés saturés
• C07D 301/02 - Synthèse du cycle de l'oxirane

Abrégé

N2 reaction. Other methods for the synthesis of dianhydrogalactitol from dulcitol are described.

Classes IPC  ?

• C07D 301/19 - Synthèse du cycle de l'oxirane par oxydation de composés non saturés, ou de mélanges de composés non saturés et de composés saturés par des hydroperoxydes organiques
• C07D 303/14 - Composés contenant des cycles oxirane avec des radicaux hydrocarbonés, substitués par des atomes d'oxygène liés par des liaisons simples ou doubles par des radicaux hydroxyle libres

Abrégé

An improved analytical method for analysis of dianhydrogalactitol preparations provides a method for determining the purity of dianhydrogalactitol and detecting impurities in preparations of dianhydrogalactitol, as well as identifying any such impurities. The method employs high performance liquid chromatography (HPLC), in particular, HPLC with evaporative light scattering detection (ELSD); the HPLC can be followed by tandem mass spectroscopy. The method can further comprise the step of performing preparative HPLC collection of at least one specific substance peak present in a preparation of dianhydrogalactitol.

Classes IPC  ?

• G01N 21/49 - Dispersion, c.-à-d. réflexion diffuse dans un corps ou dans un fluide
• G01N 30/88 - Systèmes intégrés d'analyse, spécialement adaptés à cet effet, non couverts par un seul des groupes
• G01N 33/15 - Préparations médicinales
• G01N 30/06 - Préparation
• G01N 30/72 - Spectromètres de masse
• G01N 21/00 - Recherche ou analyse des matériaux par l'utilisation de moyens optiques, c.-à-d. en utilisant des ondes submillimétriques, de la lumière infrarouge, visible ou ultraviolette
• G01N 30/74 - Détecteurs optiques
• G01N 30/02 - Chromatographie sur colonne

Abrégé

Methods and compositions suitable for the treatment of malignancies in subjects with a germline deletion polymorphism that blocks the activity of thymidine kinase inhibitors in triggering apoptosis in tumor cells or in subjects having a mutation in or a dysregulation of the AHI1 gene are disclosed. These methods employ an alkylating hexitol derivative such as dianhydrogalactitol, a derivative or analog of dianhydrogalactitol, diacetyldianhydrogalactitol, a derivative or analog of diacetyldianhydrogalactitol, dibromodulcitol, and a derivative or analog of dibromodulcitol. The compositions can include such alkylating hexitol derivatives. The methods can further include administration of a BH3 mimetic, and the compositions can further include a BH3 mimetic. In subjects having a dysregulation of the AHI1 gene, the methods can further include the administration of an agent modulating the expression or activity of the AHI1 gene or AHI1 protein, and the compositions can further include such an agent.

Classes IPC  ?

• A61K 38/12 - Peptides cycliques

Abrégé

An improved analytical method for analysis of dianhydrogalactitol preparations provides a method for determining the purity of dianhydrogalactitol and detecting impurities in preparations of dianhydrogalactitol, as well as identifying any such impurities. The method employs high performance liquid chromatography (HPLC), in particular, HPLC with refractive index (Rl) detection; the HPLC can be followed by tandem mass spectroscopy. The method can further comprise the step of performing preparative HPLC collection of at least one specific substance peak present in a preparation of dianhydrogalactitol.

Classes IPC  ?

• G01N 30/28 - Contrôle des paramètres physiques du fluide vecteur
• G01N 33/15 - Préparations médicinales

Abrégé

The present invention provides an efficient method of synthesizing and purifying dianhydrohexitols such as dianhydrogalactitol. In general, as applied to dianhydrogalactitol, the method comprises: (1) reacting dulcitol with a concentrated solution of hydrobromic acid at a temperature of about 80° C. to produce dibromogalactitol; (2) reacting the dibromogalactitol with potassium carbonate in t-butanol to produce dianhydrogalactitol; and (3) purifying the dianhydrogalactitol using a slurry of ethyl ether to produce purified dianhydrogalactitol.

Classes IPC  ?

• C07D 301/26 - Y étant de l'hydrogène
• C07D 303/14 - Composés contenant des cycles oxirane avec des radicaux hydrocarbonés, substitués par des atomes d'oxygène liés par des liaisons simples ou doubles par des radicaux hydroxyle libres

Abrégé

The present invention describes methods and compositions for improving the therapeutic efficacy of therapeutic agents previously limited by suboptimal therapeutic performance by either improving efficacy as monotherapy or reducing side effects. Such methods and compositions are particularly applicable to substituted hexitols such as dianhydrogalactitol and diacetyldianhydrogalactitol.

Classes IPC  ?

• A01N 31/00 - Biocides, produits repoussant ou attirant les animaux nuisibles, ou régulateurs de croissance des végétaux, contenant des composés organiques de l'oxygène ou du soufre

Abrégé

The present invention provides an efficient method of synthesizing and purifying dianhydrohexitols such as dianhydrogalactitol. In general, as applied to dianhydrogalactitol, the method comprises: (1) reacting dulcitol with a concentrated solution of hydrobromic acid at a temperature of about 80° C to produce dibromogalactitol; (2) reacting the dibromogalactitol with potassium carbonate in t- butanol to produce dianhydrogalactitol; and (3) purifying the dianhydrogalactitol using a slurry of ethyl ether to produce purified dianhydrogalactitol.

Classes IPC  ?

• C07D 413/00 - Composés hétérocycliques contenant plusieurs hétérocycles, au moins un cycle comportant des atomes d'azote et d'oxygène comme uniques hétéro-atomes du cycle