An improved synthesis of a class of inhibitor of Focal Adhesion Kinase (FAK) is provided, wherein use of an expensive palladium-based catalyst is reduced and reaction yields and product purities are improved. Two key reactions of coupling of aryl halides with anilines are optimized with the surprising discovery that the palladium-based catalyst can be dispensed with entirely in one of the reactions. The invention also provides the use of the FAK-inhibitory compounds in the treatment of inflammatory and immune disorders and of arthritis.
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
A61K 31/535 - 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
The invention is directed to formulations of bioactive compounds of limited water solubility, inhibitors of focal adhesion kinase (FAK) of the 2,4-diaminopyridine class, adapted for oral administration to patients. The formulations are self-emulsifying in the gastrointestinal tract of the patients, providing enhanced absorption and bioavailability of the bioactive compounds as dispersions or emulsions in an oil base. For example, esters of PEG-ylated glycerol can be used as the oil, in conjunction with surfactants such as lecithin and TEPG succinate and solubilizers such as PEG 400 to provide useful oral formulations for administration to patients having a malcondition wherein inhibition of FAK is medically indicated, such as cancer or arthritis.
A61K 9/127 - Vecteurs à bicouches synthétiques, p. ex. liposomes ou liposomes comportant du cholestérol en tant qu’unique agent tensioactif non phosphatidylique
A method for treatment of small cell lung cancer that does not respond to first-line treatment or that progresses following cessation of first-line organoplatinum chemotherapy is provided that includes the administration of picoplatin and paclitaxel, optionally in conjunction with a regimen of best supportive care. Multiple doses of picoplatin and paclitaxel can be co-administered.
A01N 55/02 - Biocides, produits repoussant ou attirant les animaux nuisibles ou régulateurs de croissance des végétaux, contenant des composés organiques comportant des éléments autres que le carbone, l'hydrogène, les halogènes, l'oxygène, l'azote et le soufre contenant des atomes de métal
5.
METHOD OF PROMOTING APOPTOSIS AND INHIBITING METASTASIS
The invention provides a method of promoting apoptosis in tumor cells, which can result in inhibiting tumor growth, or inhibiting tumor metastasis, or promoting tumor apoptosis, or any combination thereof, by administration of an effective amount of a focal adhesion kinase (FAK) inhibitor. The inhibitor is a small molecule organic compound. Accordingly, the focal adhesion kinase inhibitor can be used in the treatment of tumors, such as malignant cancer. For example, administration of effective amounts of the FAK inhibitor PND-1186 has been found to inhibit tumor cells in murine models for breast and ovarian cancer.
C07D 413/02 - Composés hétérocycliques contenant plusieurs hétérocycles, au moins un cycle comportant des atomes d'azote et d'oxygène comme uniques hétéro-atomes du cycle contenant deux hétérocycles
C07D 413/04 - Composés hétérocycliques contenant plusieurs hétérocycles, au moins un cycle comportant des atomes d'azote et d'oxygène comme uniques hétéro-atomes du cycle contenant deux hétérocycles liés par une liaison directe de chaînon cyclique à chaînon cyclique
An improved method for the synthesis of the anticancer drug picoplatin is provided. Condensation of a tetrachloroplatinate salt (TCP), such as potassium tetrachloroplatinate, and 2-picoline, in a solvent, is catalyzed by the presence of oxygen, such as in air, and additionally catalyzed by the presence of a Pt+4 complex, such as potassium hexachloroplatinate. The oxygen can be introduced into the reaction mixture by sparging, optionally with high shear mixing and under an inert gas headspace. The product trichloropicolineplatinate salt (TCPP) is a key intermediate in the synthesis of picoplatin, to which it can be converted by reaction of the TCPP with ammonia.
A01N 55/02 - Biocides, produits repoussant ou attirant les animaux nuisibles ou régulateurs de croissance des végétaux, contenant des composés organiques comportant des éléments autres que le carbone, l'hydrogène, les halogènes, l'oxygène, l'azote et le soufre contenant des atomes de métal
A61K 31/555 - Composés hétérocycliques contenant des métaux lourds, p. ex. hémine, hématine, mélarsoprol
The invention provides a method of treatment of metastatic hormone-refractory prostate cancer involving substantially concurrent administration of picoplatin and docetaxel. Prednisone may also be administered. Dosages and dosing regimens are provided.
A01N 55/02 - Biocides, produits repoussant ou attirant les animaux nuisibles ou régulateurs de croissance des végétaux, contenant des composés organiques comportant des éléments autres que le carbone, l'hydrogène, les halogènes, l'oxygène, l'azote et le soufre contenant des atomes de métal
A61K 31/555 - Composés hétérocycliques contenant des métaux lourds, p. ex. hémine, hématine, mélarsoprol
The invention provides a method of treatment of colorectal cancer by administration of the anti-cancer platinum drug picoplatin in conjunction with 5-FU and leucovorin in a variety of treatment regimens.
A01N 55/02 - Biocides, produits repoussant ou attirant les animaux nuisibles ou régulateurs de croissance des végétaux, contenant des composés organiques comportant des éléments autres que le carbone, l'hydrogène, les halogènes, l'oxygène, l'azote et le soufre contenant des atomes de métal
A61K 31/555 - Composés hétérocycliques contenant des métaux lourds, p. ex. hémine, hématine, mélarsoprol
9.
HIGH BIOAVAILABILITY ORAL PICOPLATIN ANTI-CANCER THERAPY
The invention provides a method of treatment of cancer, wherein a individual doses of picoplatin, each of less than about 200 mg picoplatin content, the individual doses having high oral bioavailability, are administered to a patient in need thereof. The oral bioavailability can be greater than about 50%, or greater than about 75%, or greater than about 90%, depending upon the particular dosage form and dosing regimen used. The invention provides a quasi-metronomic dosing schedule including drug dosing intervals and drug intermission intervals, optionally including fasting periods prior to and following administration of each individual dose of picoplatin.
A01N 55/02 - Biocides, produits repoussant ou attirant les animaux nuisibles ou régulateurs de croissance des végétaux, contenant des composés organiques comportant des éléments autres que le carbone, l'hydrogène, les halogènes, l'oxygène, l'azote et le soufre contenant des atomes de métal
A61K 31/555 - Composés hétérocycliques contenant des métaux lourds, p. ex. hémine, hématine, mélarsoprol
10.
BIOACTIVE COMPOUNDS FOR TREATMENT OF CANCER AND NEURODEGENERATIVE DISEASES
The invention provides bioactive compounds for the treatment of various malconditions such as cancer and neurodegenerative diseases including Alzheimer's disease. The chemical compounds as disclosed herein are found to show bioactivity in bioassays related to these conditions. Pharmaceutical compositions, combinations and methods of synthesis are provided, as are methods of using the compound, compositions and combinations in the treatment of the diseases.
A01N 43/64 - Biocides, produits repoussant ou attirant les animaux nuisibles, ou régulateurs de croissance des végétaux, contenant des composés hétérocycliques comportant des cycles avec trois atomes d'azote comme uniques hétéro-atomes du cycle
A61K 31/41 - Composés hétérocycliques ayant l'azote comme hétéro-atome d'un cycle, p. ex. guanéthidine ou rifamycines ayant des cycles à cinq chaînons avec plusieurs hétéro-atomes cycliques, l'un au moins étant l'azote, p. ex. tétrazole
Analogs and derivatives of rapamycin are provided, wherein the analogs and derivatives can bind to FK-506 binding protein (FKBP), or inhibit the mTOR function of an FKBP, or both. The analogs and derivatives are rapamycin include the rapamycin skeleton substituted at the 42-hydroxyl group with certain specified chemically feasible groups. Methods of using the rapamycin analogs and derivatives in treatment of malconditions such as cancer, and methods of synthesizing the rapamycin analogs and derivatives, are provided.
A01N 43/42 - Biocides, produits repoussant ou attirant les animaux nuisibles, ou régulateurs de croissance des végétaux, contenant des composés hétérocycliques comportant des cycles avec un atome d'azote comme unique hétéro-atome du cycle des cycles à six chaînons condensés avec des carbocycles
12.
USE OF PICOPLATIN AND BEVACIZUMAB TO TREAT COLORECTAL CANCER
The invention provides a method of treatment of metastatic colorectal cancer by administration of the anti-cancer platinum drug picoplatin in conjunction with bevacizumab (Avastin®) and optionally, with 5-FU and leucovorin in a variety of treatment regimens. The invention also provides a use of picoplatin in conjunction with bevacizumab and, optionally, 5-FU and leucovorin, for the treatment of metastatic colorectal cancer.
A method for treatment of lung cancer comprising administration of picoplatin and amrubicin, or comprising radiation therapy and picoplatin is provided. A use of picoplatin in conjunction with amrubicin for treatment of lung cancer is provided. The lung cancer can be SCLC or NSCLC. The cancer can be resistant or refractory to treatment or that progresses following cessation of first-line organoplatinum chemotherapy. The treatment can include the administration of picoplatin and amrubicin, optionally in conjunction with a regimen of best supportive care. Multiple doses of the drug or drug combination can be administered.
A01N 43/04 - Biocides, produits repoussant ou attirant les animaux nuisibles, ou régulateurs de croissance des végétaux, contenant des composés hétérocycliques comportant des cycles avec un ou plusieurs atomes d'oxygène ou de soufre comme uniques hétéro-atomes du cycle avec un hétéro-atome
A61K 31/70 - Hydrates de carboneSucresLeurs dérivés
14.
USE OF PICOPLATIN AND CETUXIMAB TO TREAT COLORECTAL CANCER
The invention provides a method of treatment of metastatic colorectal cancer by administration of the anti-cancer platinum drug picoplatin in conjunction with cetuximab, 5-FU, and leucovorin in a variety of treatment regimens. The invention also provides a use of picoplatin in conjunction with cetuximab, 5-FU, and leucovorin for treatment of metastatic colorectal cancer. The invention further provides kits adapted for administration of picoplatin in conjunction with cetuximab. Also, methods for determining dosage regimens for patients afflicted with a cancer comprising EGFR are provided.
Methods for stabilizing aqueous solutions of picoplatin are provided. Such solutions are particularly useful for preparing unit dosages of picoplatin for oral or intravenous administration.
A01N 55/02 - Biocides, produits repoussant ou attirant les animaux nuisibles ou régulateurs de croissance des végétaux, contenant des composés organiques comportant des éléments autres que le carbone, l'hydrogène, les halogènes, l'oxygène, l'azote et le soufre contenant des atomes de métal
The invention provides formulations for the organoplatinum anticancer drug picoplatin. Self emulsifying compositions, stabilized nanoparticulate compositions, solid dispersions, and nanoparticulate suspensions in oils are provided, along with methods for preparation of the formulations. The formulations can provide improved oral availability of picoplatin relative a to a simple solution of picoplatin such as in water or normal saline solution and can be used in combination therapy.
The invention provides an encapsulated unit dosage form for picoplatin that is adapted for oral administration of the picoplatin containing a substantially dry powder with about 20 to 55 wt% picoplatin in the physical form of a picoplatin particulate wherein an average picoplatin particle diameter is less than about 10 microns. The picoplatin particles are dispersed within the powder of the formulation which includes a substantially water-soluble, water-dispersible, or water-absorbing carbohydrate and an effective amount of up to about 5 wt% of a lubricant.
A01N 55/02 - Biocides, produits repoussant ou attirant les animaux nuisibles ou régulateurs de croissance des végétaux, contenant des composés organiques comportant des éléments autres que le carbone, l'hydrogène, les halogènes, l'oxygène, l'azote et le soufre contenant des atomes de métal
The invention provides an oral dosage form for the anti-cancer drug picoplatin comprising a core and a coating, the dosage form being free of redox-active metal salts. The core of the tablet is a substantially dry powder comprising about 10 to 60 wt% picoplatin wherein the picoplatin is a particulate of less than about 10 microns average particle diameter, about 40-80 wt% of a filler comprising a substantially water-soluble, water-dispersible, or water-absorbing carbohydrate, and an effective amount of up to about 5 wt% of a lubricant. The dosage form can further include a dispersant.
A01N 55/02 - Biocides, produits repoussant ou attirant les animaux nuisibles ou régulateurs de croissance des végétaux, contenant des composés organiques comportant des éléments autres que le carbone, l'hydrogène, les halogènes, l'oxygène, l'azote et le soufre contenant des atomes de métal
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