Isoxazole derivative for treating cancer

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents using 5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide or a pharmaceutically acceptable salt, a hydrate, or a solvate thereof for preparing a pharmaceutical composition used for treating bladder cancer, colon cancer, liver cancer, lung cancer, breast cancer, ovarian cancer, pancreatic cancer, stomach cancer, gastro-intestinal cancer, prostate cancer, head and neck cancer and/or blood cancer.

EFFECT: invention refers to treating the number of cancers using 5-(2,4-dihydroxy-5- isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide.

6 cl, 5 ex

 

The invention relates to the use of ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid or its tautomer, or a pharmaceutically acceptable salt, or hydrate, or MES to obtain pharmaceutical compositions intended for the treatment of cancer, e.g. solid tumors, e.g. sarcomas, e.g. carcinomas of the bladder, colon, liver, lung, e.g. pleural mesothelioma, e.g. non-small cell, e.g. small cell mesothelioma, cancer of the breast, vagina, ovary, pancreas, kidneys, stomach, gastrointestinal tract, e.g. gastrointestinal stromal tumor, e.g. the small intestine, e.g. the esophagus, e.g. the bile duct, prostate cancer, head and neck, abdomen, thyroid, bone, brain, Central nervous system, e.g. glioblastoma, e.g. neuroblastoma, and/or melanoma and/or blood cancer, cancer blood system, e.g. leukemia, e.g. acute myeloid leukemia, e.g. chronic myeloid leukemia, e.g. chronic of leukemia, e.g. acute lymphatic leukemia, e.g. multiple myeloma e.g. lymphomas, and/or myelodysplastic syndrome, systemic mastocytosis syndrome von Hippel-Lindau, m is licentiously disease Castleman and/or psoriasis, to use ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid or its tautomer, or a pharmaceutically acceptable salt, or hydrate, or MES for the treatment of cancer, e.g. solid tumors, e.g. sarcomas, e.g. carcinomas of the bladder, colon, liver, lung, e.g. pleural mesothelioma, e.g. non-small cell, e.g. small cell mesothelioma, cancer of the breast, vagina, ovaries, pancreas, kidneys, stomach, gastrointestinal tract, e.g. gastrointestinal stromal tumor, e.g. the small intestine, e.g. the esophagus, e.g. the bile duct, prostate cancer, head and neck, abdomen, thyroid, bone, brain, Central nervous system, e.g. glioblastoma, e.g. neuroblastoma, and/or melanoma and/or blood cancer, cancer blood system, e.g. leukemia, e.g. acute myeloid leukemia, e.g. chronic myeloid leukemia, e.g. chronic lymphatic leukemia, e.g. acute lymphatic leukemia, for example multiple myeloma e.g. lymphomas, and/or myelodysplastic syndrome, systemic mastocytosis syndrome von Hippel-Lindau, multicenter disease Castleman and/or psoriasis, and to a method of treatment teplokrovnosti, including humans, suffering from cancer, such as solid tumors, e.g. sarcomas, e.g. carcinomas of the bladder, colon, liver, lung, e.g. pleural mesothelioma, e.g. non-small cell, e.g. small cell mesothelioma, cancer of the breast, vagina, ovaries, pancreas, kidneys, stomach, gastrointestinal tract, e.g. gastrointestinal stromal tumor, e.g. the small intestine, e.g. the esophagus, e.g. the bile duct, prostate cancer, head and neck, abdomen, thyroid, bone tissue, brain, Central nervous system, e.g. glioblastoma, e.g. neuroblastoma, and/or melanoma and/or blood cancer, for example cancer of the haematopoietic system, e.g. leukemia, e.g. acute myeloid leukemia, e.g. chronic myeloid leukemia, e.g. chronic lymphatic leukemia, e.g. acute lymphatic leukemia, e.g. multiple myeloma e.g. lymphomas, and/or myelodysplastic syndrome, systemic mastocytes syndrome von Hippel-Lindau, multicenter disease Castleman and/or psoriasis, and this method is the introduction to an animal in need of such treatment, an effective dose of ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid or its tautomer is a, or a pharmaceutically acceptable salt, or hydrate, or MES.

Cancer treatment is a major problem, for example, the treatment of solid tumors, e.g. sarcomas, e.g. carcinomas of the bladder, colon, liver, lung, e.g. pleural mesothelioma, e.g. non-small cell, e.g. small cell mesothelioma, cancer of the breast, vagina, ovaries, pancreas, kidneys, stomach, gastrointestinal tract, e.g. gastrointestinal stromal tumor, e.g. the small intestine, e.g. the esophagus, e.g. the bile duct, prostate cancer, head and neck, abdomen, thyroid, bone, brain, Central nervous system, e.g. glioblastoma, e.g. neuroblastoma, and/or melanoma and/or blood cancer, cancer blood system, e.g. leukemia, e.g. acute myeloid leukemia, e.g. chronic myeloid leukemia, e.g. chronic lymphatic leukemia, e.g. acute lymphatic leukemia, e.g. multiple myeloma e.g. lymphomas, and/or myelodysplastic syndrome, systemic mastocytosis syndrome von Hippel-Lindau, multicenter disease Castleman and/or psoriasis.

Protein thermal shock 90 (Hsp90) is a new anticancer target. Hsp90 is universal, the iroko common (1-2% of total cellular protein), vital protein that functions as a molecular chaperone, providing resistance conformation, form and function of the respective proteins. Inhibition of ATP-aznoe activity of the protein of Hsp90 disrupts the interaction with proteins Hsp90 clients, which leads to their degradation by the ubiquitin-proteosome way. Subfamily proteins of Hsp90 clients, such as Raf, AKT, CDK4 and EGFR family, including ErbB2, is a group of oncogenic signaling molecules, which play a major role in the growth, differentiation and apoptosis, processes that play an important role in cancer cells. It is believed that the simultaneous degradation of many oncoproteins is the reason protivoopujolevoe actions observed in the presence of Hsp90 inhibitors.

The family of chaperones Hsp90 consists of four members: Hsp90a and Hsp90p localized in the cytosol, GRP94 in the endoplasmic reticulum, and TRAP1 in mitochondria (Csermely and others, 1998). Hsp90 is the most abundant cellular chaperone, comprising 1-2% of total protein (Jakob and Buchner, 1994). Among the proteins of Hsp90 stress is unique, because it is not required for the biosynthesis of most polypeptides (Nathan and others, 1997). Its cellular targets, also called protein-clients are conformationally labile transmitters of signals that play an important role in the control of growth and survival of cells, as well as in the development of TC is neither (Pratt, Toft, 2003).

The chaperone Hsp90, which are characterized by conservative ATP-binding site in the N-terminal domain (Chene, 2002), belong to a small subfamily of the ATPase and is known as DNA gyrase, Hsp90, histidinate and subfamily MutL (GHKL) (Dutta and Inouye, 2000). Supernova (formation of secondary structure of proteins) activity of Hsp90 is dependent on its ATPase activity, which is reduced in the purified enzyme. However, it was found that the ATPase activity of Hsp90 increases with its binding proteins, the so-called co-chaperones (Kamal and others, 2003). Thus proteins of Hsp90 function in vivo as subunits of a large, dynamic protein complexes. Hsp90 is important for the survival of eukaryotic cells and sverkhekspressiya in many tumors.

Ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid is an inhibitor of Hsp90, its synthesis is described, for example, in the application WO 2004/072051, example 78, included in the present description by reference.

Unexpectedly, it was found that ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid or its tautomer, or a pharmaceutically acceptable salt, or hydrate, or MES can be used in the treatment of cancer, e.g. solid tumors, e.g. sarcomas, e.g. carcinomas of the bladder, colon, p is Chaney, lung, e.g. pleural mesothelioma, e.g. non-small cell, e.g. small cell mesothelioma, cancer of the breast, vagina, ovaries, pancreas, kidneys, stomach, gastrointestinal tract, e.g. gastrointestinal stromal tumor, e.g. the small intestine, e.g. the esophagus, e.g. the bile duct, prostate cancer, head and neck, abdomen, thyroid, bone, brain, Central nervous system, e.g. glioblastoma, e.g. neuroblastoma, and/or melanoma and/or blood cancer, cancer haematopoietic system, e.g. leukemia, e.g. acute myeloid leukemia, e.g. chronic myeloid leukemia, e.g. chronic lymphatic leukemia, e.g. acute lymphatic leukemia, e.g. multiple myeloma e.g. lymphomas, and/or myelodysplastic syndrome, systemic mastocytosis syndrome von Hippel-Lindau, multicenter disease Castleman and/or psoriasis.

In accordance with the foregoing the present invention features the use of ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid or its tautomer, or a pharmaceutically acceptable salt, or hydrate, or MES to obtain pharmaceutical compositions intended for the treatment of cancer, e.g. the measures solid tumors, e.g. sarcomas, e.g. carcinomas of the bladder, colon, liver, lung, e.g. pleural mesothelioma, e.g. non-small cell, e.g. small cell mesothelioma, cancer of the breast, vagina, ovaries, pancreas, kidneys, stomach, gastrointestinal tract, e.g. gastrointestinal stromal tumor, e.g. the small intestine, e.g. the esophagus, e.g. the bile duct, prostate cancer, head and neck, abdomen, thyroid, bone, brain, Central nervous system, for example, glioblastomas for example, neuroblastoma, and/or melanoma, and/or blood cancer, cancer blood system, e.g. leukemia, e.g. acute myeloid leukemia, e.g. chronic myeloid leukemia, e.g. chronic lymphatic leukemia, e.g. acute lymphatic leukemia, e.g. multiple myeloma e.g. lymphomas, and/or myelodysplastic syndrome, systemic mastocytosis syndrome von Hippel-Lindau, multicenter disease Castleman and/or psoriasis.

Another object of the present invention features the use of ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid or its tautomer, or a pharmaceutically acceptable salt, or hydrate, or MES DL the treatment of cancer, for example, solid tumors, e.g. sarcomas, e.g. carcinomas of the bladder, colon, liver, lung, e.g. pleural mesothelioma, e.g. non-small cell, e.g. small cell mesothelioma, cancer of the breast, vagina, ovaries, pancreas, kidneys, stomach, gastrointestinal tract, e.g. gastrointestinal stromal tumor, e.g. the small intestine, e.g. the esophagus, e.g. the bile duct, prostate cancer, head and neck, abdomen, thyroid, bone, brain, Central nervous system, for example, glioblastoma, e.g. neuroblastoma, and/or melanoma, and/or blood cancer, cancer blood system, e.g. leukemia, e.g. acute myeloid leukemia, e.g. chronic myeloid leukemia, e.g. chronic lymphatic leukemia, e.g. acute lymphatic leukemia, e.g. multiple myeloma e.g. lymphomas, and/or myelodysplastic syndrome, systemic mastocytosis syndrome von Hippel-Lindau, multicenter disease Castleman and/or psoriasis.

Another object of the present invention offers ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid or its tautomer, or pharmaceutically acceptable salt or hydrate, or MES for the changes in the treatment of cancer, for example, solid tumors, e.g. sarcomas, e.g. carcinomas of the bladder, colon, liver, lung, e.g. pleural mesothelioma, e.g. non-small cell, e.g. small cell mesothelioma, cancer of the breast, vagina, ovaries, pancreas, kidneys, stomach, gastrointestinal tract, e.g. gastrointestinal stromal tumor, e.g. the small intestine, e.g. the esophagus, e.g. the bile duct, prostate cancer, head and neck, abdomen, thyroid, bone, brain, Central nervous system, for example, glioblastoma, e.g. neuroblastoma, and/or melanoma, and/or blood cancer, cancer blood system, e.g. leukemia, e.g. acute myeloid leukemia, e.g. chronic myeloid leukemia, e.g. chronic lymphatic leukemia, e.g. acute lymphatic leukemia, e.g. multiple myeloma e.g. lymphomas, and/or myelodysplastic syndrome, systemic mastocytosis syndrome von Hippel-Lindau, multicenter disease Castleman and/or psoriasis.

Another object of the present invention proposes a method of treatment of humans suffering from cancer, e.g. solid tumors, e.g. sarcomas, e.g. carcinomas of the bladder, colon, liver, lung, e.g. pleural mesothelioma, PL is very, for example, non-small cell, e.g. small cell mesothelioma, cancer of the breast, vagina, ovaries, pancreas, kidneys, stomach, gastrointestinal tract, e.g. gastrointestinal stromal tumor, e.g. the small intestine, e.g. the esophagus, e.g. the bile duct, prostate cancer, head and neck, abdomen, thyroid, bone, brain, Central nervous system, e.g. glioblastoma, e.g. neuroblastoma, and/or melanoma, and/or blood cancer, for example cancer of the hematopoietic system, such as leukemia for example, acute myeloid leukemia, e.g. chronic myeloid leukemia, e.g. chronic lymphatic leukemia, e.g. acute lymphatic leukemia, e.g. multiple myeloma e.g. lymphomas, and/or myelodysplastic syndrome, systemic mastocytosis syndrome von Hippel-Lindau, multicenter disease Castleman and/or psoriasis, and this method is the introduction to a person in need of specific treatment, the dose of ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid or his tautomer, or a pharmaceutically acceptable salt, or hydrate, or MES, effective in the treatment of cancer, e.g. solid tumors, e.g. sarcomas, e.g. carcinomas of the bladder, about the colonic ulcers, the liver, the lung, e.g. pleural mesothelioma, e.g. non-small cell, e.g. small cell mesothelioma, cancer of the breast, vagina, ovaries, pancreas, kidneys, stomach, gastrointestinal tract, e.g. gastrointestinal stromal tumor, e.g. the small intestine, e.g. the esophagus, e.g. the bile duct, prostate cancer, head and neck, abdomen, thyroid, bone, brain, Central nervous system, e.g. glioblastoma, e.g. neuroblastoma, and/or melanoma and/or blood cancer, for example cancer of the haematopoietic system, e.g. leukemia, e.g. acute myeloid leukemia, e.g. chronic myeloid leukemia, e.g. chronic lymphatic leukemia, e.g. acute lymphatic leukemia, e.g. multiple myeloma e.g. lymphomas, and/or myelodysplastic syndrome, systemic mastocytosis syndrome von Hippel-Lindau, multicenter disease Castleman and/or psoriasis.

Another object of the present invention features a pharmaceutical composition intended for the treatment of cancer, e.g. solid tumors, e.g. sarcomas, e.g. carcinomas of the bladder, colon, liver, lung, e.g. pleural mesothelioma, e.g. non-small cell, e.g. small cell mesothelioma cancer m is Nochnoi gland, vagina, ovaries, pancreas, kidneys, stomach, gastrointestinal tract, e.g. gastrointestinal stromal tumor, e.g. the small intestine, e.g. the esophagus, e.g. the bile duct, prostate cancer, head and neck, abdomen, thyroid, bone, brain, Central nervous system, e.g. glioblastoma, e.g. neuroblastoma, and/or melanoma, and/or blood cancer, cancer blood system, e.g. leukemia, e.g. acute myeloid leukemia, e.g. chronic myeloid leukemia, for example, chronic lymphatic leukemia, e.g. acute lymphatic leukemia, e.g. multiple myeloma e.g. lymphomas, and/or myelodysplastic syndrome, systemic mastocytosis syndrome von Hippel-Lindau, multicenter disease Castleman and/or psoriasis, the composition includes ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid or its tautomer, or a pharmaceutically acceptable salt, or hydrate, or MES, and at least one pharmaceutically acceptable carrier.

Depending on the species, age, individual condition, mode of administration and the clinical picture of the disease a person can enter the effective dose, for example, from 2 to 300 mg, preferably from 50 to 160 methylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid or its tautomer, or a pharmaceutically acceptable salt, or hydrate, or MES once a week.

In addition, the present invention proposes a method of introducing ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid or its tautomer, or a pharmaceutically acceptable salt, or hydrate, or MES, the person suffering from cancer, for example, from solid tumors, e.g. sarcomas, e.g. carcinomas of the bladder, colon, liver, lung, e.g. pleural mesothelioma, e.g. non-small cell, e.g. small cell mesothelioma, breast cancer, vagina, ovaries, pancreas, kidneys, stomach, gastrointestinal tract, e.g. gastrointestinal stromal tumor, e.g. the small intestine, e.g. the esophagus, e.g. the bile duct, prostate cancer, head and neck, abdomen, thyroid, bone, brain, Central nervous system, e.g. glioblastoma, e.g. neuroblastoma, and/or melanoma and/or blood cancer, cancer blood system, e.g. leukemia, e.g. acute myeloid leukemia, e.g. chronic myeloid leukemia, for example, chronic lymphatic leukemia, e.g. acute lymphatic leukemia, e.g. multiple myeloma e.g. lymphomas, and/or myelodysplastic the th syndrome, system mastocytosis syndrome von Hippel-Lindau, multicenter disease Castleman and/or psoriasis, and this method is the introduction of pharmaceutically effective amount of ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid or its tautomer, or a pharmaceutically acceptable salt, or hydrate, or MES person approximately 1 time per week or more often.

The following describes the present invention as an example. Example 1

The effect of ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid (AUY922) in a panel of tumor cell lines in vitro.

To study the action of ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid was used thirty-seven tumor cell lines (WT, MDA-MB-361, MDA-MB-453, SKBr3, T47D, MCF7, MDA-MB-231, MDA-MB-468, SK-MEL-5, A, MALME-3M, SK-MEL-28, WM266.4, RPMI8226, U266, BE, Colo205, NST, NC, MAWI, RKO, U87MG, HN5, RPMI-8226, U, MV522, NCI-H1299, NCI-N, 41M, A, CHI, NCI-N87, SKOV3, RS, Me, GIST882 and Baf3). Cell lines were obtained from American type culture collection (American Type Culture Collection, ATSS). These cell lines include the following 12 types of cancer or tumor cells: breast cancer, melanoma, multiple melanoma, cancer of the colon, glioblastoma, head and neck cancer, ACOs, lung cancer, ovarian cancer, prostate cancer, stomach cancer, and gastrointestinal stromal tumor (GIST). After cell division and replacement of the environment of the cells in the original culture were sown on tablets for cell culture and prior studies have raised them for about 18 h for the growth and attachment of cells. On the first day of the study ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid was added to the medium at various concentrations up to 10 μm. Cells were cultured up to 72 or 96 h and cell proliferation was estimated using commercial kits for analysis of cell proliferation.

Table 1 shows the concentrations (nm) of ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid, in which there is inhibition of proliferation by 50% (IC50). Cells were subjected to the action of ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid continuously for 72 or 96 h, and cell growth was assessed using commercial kits based on the SRB, Alamar blue, methylene blue or methods WST-1.

Table 1
Tumor typeGlue the full-line IC50(nm)
Breast cancerWT2,8
MDA-MB-3616
MDA-MB-453a 3.9
SKBr32,3
T47D2,6
MCF72,3
MDA-MB-2317,7
MDA-MB-4683,5
MelanomaSK-MEL-53
A3
MALME-3M7,7
SK-MEL-288
WM266.46,2
Multiple melanoma (MM)RPMI822636,7
U26623,3
Cancer of the colonBE 2,8
Colo2056,2
ST16
NT30
MAWI50
RKO3,1
GlioblastomaU87MG6
Head and neck cancerHN58
LeukemiaRPMI-82266,3
Lung cancerA11,7
MV5228,1
NCI-H1299the 5.7
NCI-H46014
Ovarian cancer41M3
A6,1
CH12,8
SKOV33,7
Prostate cancerRS5
Stomach cancerNCI-N870,2
Gastrointestinal stromal tumor (GIST)MoE10,6
GIST8826,2
Baf322,4

Example 2

The influence of ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid (AUY922) on the panel of cells primary human tumors in vitro

Antitumor activity of ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid was evaluated in vitro using 30 xenografts of human tumors method for assessing clonogenicity. In the specified experiment studied the ability of ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid to suppress the formation of three-dimensional colonies of human cells obtained from cancer patients. Colonies consist of tumor cells, characterized by the free growth of cells on semi-solid medium. xenotransplanted tumors, which have never been cultivated in cell culture in plastic cups, was isolated from the tissue of Nude mice. Prepared suspensions of tumor cells and incubated them in a 24-hole tablets with a layer of soft agar. In these conditions in the colony selectively growing a particular subpopulation of cells. Investigated 6 different concentrations up to 10 µm ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid. Tumor test panel contains from 1 to 6 samples of 10 different tumors or cancer of various types, namely, cancer of the bladder, colon, liver, small cell lung cancer (glandular, squamous, and both), small cell lung cancer, breast cancer, ovarian cancer, pancreatic cancer, melanoma and pleuromutilins. Antitumor activity was characterized by the suppression of the formation of colonies in comparison with untreated controls. The concentrations at which there is 50%inhibition of the formation of colonies (IC50), are shown in table 2. More detailed information about the method are given in the articles (Burger and others, 2004, Fiebig and others, 2004, Smith and others, 2005).

Table 2 shows the concentrations (nm) of ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid, in which there is a 50%by submitting a is a group of colony growth (IC 50). Cells were incubated in the presence of ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid and registered education colonies.

Table 2
Tumor typeModel tumorsHistologyIC50 (nM)
Bladder cancerBXF 1218Transitional cell carcinoma27
BXF 1228Transitional cell carcinoma630
Cancer of the colonCXF 1103Adenocarcinoma13
CXF 158Adenocarcinoma369
CXF 1729Carcinoma467
CXF 1784Carcinoma418
CXF 609Aden is carcinoma 55
Liver cancerLIXF 575Hepatic cell carcinoma34
Lung cancer, non-small cell lungLXFA 297Adenocarcinoma28
LXFA 526Adenocarcinoma5
LXFA 629Adenocarcinoma35
LXFA 983Adenocarcinoma126
LXFE 1422Squamous cell carcinoma48
LXFL 1647Both carcinoma of the lung34
Lung cancer, small-cellLXFS 615Small cell carcinoma of the lung30
LXFS 650Small cell carcinoma of the lung2
Mammary glands the MAXF 1162Invasive ductal cancer304
MAXF 1322Papillary adenocarcinoma29
MAXF 1384Adenocarcinoma209
MAXF 401Papillary adenocarcinoma78
MAXF 583Ductal cancer333
MelanomaMEXF 1539Melanoma3
MEXF 462Amalonaticus melanoma24
MEXF 535Amalonaticus melanoma43
MEXF 672Amalonaticus melanoma18
MEXF 989Amalonaticus melanoma2
Ovarian cancerOVXF 1353 Adenocarcinoma26
OVXF 1544Carcinoma53
Cancer pancreas
gland
PAXF 1657Adenocarcinoma39
Mesothelioma of the pleuraPXF 1118Biphasic mesothelioma of the pleura223

Example 3

Antitumor activity of ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid (AUY922) model of breast cancer human BT-474

Cell lines BT-474, positive estrogen receptor, was first isolated from the duct carcinoma of the breast of man, derived from a solid tumor invasive ductal breast cancer women aged 60 years (the number ATSS NTV-20). Cells were grown in DMEM with high glucose (4.5 g/l) containing 10% ETS, 200 mm L-glutamine and 1% sodium pyruvate.

To prepare for the inoculation of the cells of each mouse subcutaneously implanted in the upper part of the back of the pellets 17β-estradiol (25 µg/day, the release within 90 days) with the use of needles for trocar. Cells BT-474 (5×106) was administered at 200 MK is the matrix basement membrane Matrigel/HBSS, 1:1 vol./about. (BD Matrigel™). The injection was carried out in the right flank subcutaneously. Treatment with AUY922 started, when the average tumor volume reached approximately 100 mm tumor Growth was recorded at regular intervals of time. The size of the xenografts tumors were measured manually with calipers, and tumor volume was determined by the formula W×L×H×7t/6, where the width (W)height (H) and length (L) denote the three largest diameter.

The results are presented as mean values ± standard deviation. The results of measurements of tumors were analyzed by ANOVA method according to the criterion Donnetta for a posteriori comparisons of treated (L) group and control (K) group. As a performance indicator at the end of the experiment, the expected value of the L/C in % according to the formula:

(Δ tumortreatment/Δ tumorcounter.)×100,

where Δ tumor denotes the mean value of the tumor volume on the day of assessment of tumor minus the mean value of the tumor volume at the beginning of the experiment.

Antitumor activity AUY922 was evaluated using a xenograft models BT-474. In this study, the treatment period was 21 days. Each group consisted of eight animals with tumor. After completion of the experiment, the sizes of the tumors of the treated groups was compared with tumor size groups, which were injected media, and effective is Yunosti were expressed as the ratio of L/K in %. A statistically signicant decrease in tumor size was observed after introduction of the drug AUY922 once a week in doses of 17-25 mg/kg (table 3).

Table 3
The influence of AUY922 on the growth of xenograft BT-474
ConnectionDose, course of treatment, route of administrationL/K (%)Δ tumor (mm3)
Control media10 ml/kg, once a week, intravenous100528±123
AUY9228,3 mg/kg, once a week, intravenous43229±73
AUY92217 mg/kg, once a week, intravenous946±27*
AUY92225 mg/kg, once a week, intravenous315±23*
*P<0,05, univariate ANOVA analysis on the criterion Donnetta for a posteriori comparisons.

the example 4

Antitumor activity of ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid (AUY922) model of breast cancer rats BN-472

The transplanted tumor of the mammary gland of the rat BN472 consistently instilled in the form of fragments females isogenic rats Brown Norway. The injection was made orthotopic method in the fatty tissue of the breast. Treatment with AUY922 started, when the average tumor volume reached approximately 100 mm3. Tumor growth was measured at regular intervals of time. The size of the xenografts tumors were measured manually with calipers, and tumor volume was determined by the formula W×L2×π/6, where the width (W)height (H) denote the two largest diameter.

The results are presented as mean values ± standard deviation. The results of measurements of tumors were analyzed by ANOVA method according to the criterion Donnetta for a posteriori comparisons of treated (L) group and control (K) group. As a performance indicator at the end of the experiment, the expected value of the L/C in % according to the formula:

(Δ tumortreatment/Δ tumorcounter)×100,

where Δ tumor denotes the mean value of the tumor volume on the day of assessment of tumor minus the mean value of the tumor volume at the beginning of the experiment.

Protivoop olivae action AUY922 was evaluated using a xenograft models BN472. Each group consisted of seven animals with tumor. At the end of the experiment, the sizes of the tumors of the treated group (L) was compared with tumor size groups, which were injected carrier (K), and the efficiency was expressed as the ratio of L/K in %. A statistically signicant decrease in tumor size was observed after introduction of the drug AUY922 once a week at a dose of 50 mg/kg (table 4).

Table 4
The influence of AUY922 on the growth of xenograft BN472
ConnectionDose, course of treatment, route of administrationL/K (%)Δ tumor (mm3)
Control media2 ml/kg, once a week, intravenous1005569±1639
AUY92225 mg/kg, once a week, intravenous784357±1338
AUY92250 mg/kg, once a week, intravenous211148±152*
*P<0,05, onefactor the ANOVA analysis on the criterion Donnetta for a posteriori comparisons.

Example 5

Antitumor activity of ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid (AUY922) model of pancreatic cancer rats SA

The transplanted tumor of the pancreas in rats SO consistently instilled in cell homogenates of male isogenic rats Lewis. Injections were made subcutaneously into the right side. Treatment with AUY922 started, when the average tumor volume reached approximately 100 mm3. Tumor growth was recorded at regular intervals of time. The size of the xenografts was measured manually with calipers, and tumor volume was determined by the formula W×L2π/6, where the width (W)height (H) denote the two largest diameter.

The results are presented as mean values ± standard deviation. The results of measurements of tumors were analyzed by ANOVA method according to the criterion Donnetta for a posteriori comparisons of treated (L) group and control (K) group. As a performance indicator at the end of the experiment, the expected value of the L/C in % according to the formula:

(Δ tumortreatment/Δ tumorcounter)×100,

where Δ tumor denotes the mean value of the tumor volume on the day of assessment of tumor minus the mean value of the tumor volume at the beginning of the experiment.

PR is tivaouane action AUY922 was evaluated using a xenograft models SA. Each group consisted of six animals with tumor. At the end of the experiment, the sizes of the tumors of the treated groups was compared with tumor size groups, which were injected media, and the efficiency was expressed as the ratio of L/K in %. A statistically signicant decrease in tumor size was observed after introduction of the drug AUY922 once a week in doses of 50 and 75 mg/kg (table 5).

Table 5
The influence of AUY922 on the growth of xenograft SA
ConnectionDose, course of treatment, route of administrationL/K (%)Δ tumor (mm )
Control media2 ml/kg, once a week, intravenous10023267±7810
AUY92250 mg/kg, once a week, intravenous307090±2553*
AUY92275 mg/kg, once a week, intravenous214796±1354*
*P<0,05, univariate Ana is from ANOVA on the criterion Donnetta for a posteriori comparisons.

1. The use of ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid or its pharmaceutically acceptable salt, or hydrate, or MES to obtain a pharmaceutical composition intended for the treatment of cancer of the bladder, colon, liver, lung, mammary gland, ovary, pancreas, stomach, gastrointestinal tract, prostate, head and neck and/or blood.

2. The use of ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid or its pharmaceutically acceptable salt, or hydrate, or MES for the treatment of cancer of the bladder, colon, liver, lung, mammary gland, ovary, pancreas, stomach, gastrointestinal tract, prostate, head and neck and/or blood.

3. The method of treatment of humans suffering from cancer of the bladder, colon, liver, lung, mammary gland, ovary, pancreas, stomach, gastrointestinal tract, prostate, head and neck and/or blood, including the introduction of the specified person in need of such treatment, the dose of ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid or its pharmaceutically acceptable salt, or hydrate is, or MES, an effective treatment for cancer of the bladder, colon, liver, lung, mammary gland, ovary, pancreas, stomach, gastrointestinal tract, prostate, head and neck and/or blood.

4. Pharmaceutical composition for treatment of cancer of the bladder, colon, liver, lung, mammary gland, ovary, pancreas, stomach, gastrointestinal tract, prostate, head and neck and/or blood, including ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid or its pharmaceutically acceptable salt, or hydrate, or MES, and at least one pharmaceutically acceptable carrier.

5. The use according to claim 1 or 2, wherein the human is administered once a week dose of from 2 to 300 mg ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid or its pharmaceutically acceptable salt, or hydrate, or MES.

6. The method of introducing the person suffering from cancer of the bladder, colon, liver, lung, mammary gland, ovary, pancreas, stomach, gastrointestinal tract, prostate, head and neck and/or blood, ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid or its Tau is Omer, or a pharmaceutically acceptable salt, or hydrate, or MES, including the introduction of a pharmaceutically effective amount of ethylamide 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholine-4-ylmethylene)isoxazol-3-carboxylic acid or its pharmaceutically acceptable salt, or hydrate, or MES person once a week or more often.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely oncology, and may be used for tumour growth inhibition. That is enabled by using a binary catalyst system containing cobalt octacarboxyphthalocyanine sodium salt and ascorbic acid. Administering the binary catalyst system is preceded by intravenous introduction of 3-amino-1,2,4-triazole in a non-toxic dose.

EFFECT: invention provides the growth inhibition of malignant new growths low-sensitive to the action of the binary catalyst system.

2 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical compositions containing (2-hydroxyethoxy)amide 6-(4-brom-2-chlorophenylamino)-7-fluor-3-methyl-3H-benzoimidazole-5-carboxylic acid hydrosulphate and solvates, crystalline forms and amorphous forms thereof, to using the above compositions as a drug; and to methods for preparing the above compositions.

EFFECT: preparing the new pharmaceutical compositions.

20 cl, 7 tbl, 7 ex, 5 dwg

Nanoemulsion // 2491917

FIELD: medicine.

SUBSTANCE: group of inventions refers to a nanoemulsion for active agent delivery, a method for preparing it, compositions containing it, and to using a nanoemulsion for preparing pharmaceutical compositions for local application and cosmetic compositions for skin application. The declared nanoemulstion contains a water ingredient and a carrier which contains a lipophilic ingredient in the amount of 0.1-15 wt %, a surfactant and isopropyl and/or 1-propyl alcohol. The average emulsified particle diameter makes less than 100 nm. The method for preparing the nanoemulsion involves mixing the water ingredient and carrier containing the lipophilic ingredient, surfactant and isopropyl and/or 1-propyl alcohol, for preparing the nanoemulsion at temperature 50-60°C. The invention also refers to the composition for photodynamic therapy containing the above nanoemulsion and the active agent representing 5-aminolevulinic acid, a derivative, a precursor and/or a metabolite thereof. The above composition is applied to prepare the drug substance for photodynamic therapy and to treat senile keratosis. What is also declared is a diagnostic composition for detecting the dividing cells which contains the nanoemulsion and 5-aminolevulinic acid. The invention also refers to a kit for photodynamic therapy which comprises the composition for photodynamic therapy and one ingredient specified in a photoresist coating, an agent for attaching the above coating or an agent for applying the composition.

EFFECT: invention provides better stability and intensified cell and tissue penetration of the nanoemulsion.

25 cl, 6 dwg, 9 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to immunology. What is presented is a low-immunogenicity anti-CD40 monoclonal antibody prepared of a chimeric 5D12 (ch5D12) antibody. There are also described: a nucleic acid, a cell and a cell culture for preparing the antibody according to the invention, a method for preparing it, a pharmaceutical composition, using the antibody for preparing a drug and a method for administering the antibody according to the invention to an individual for the purpose of relieving the symptoms of an autoimmune disease, an inflammatory disease, for the purpose of suppressing a graft rejection reaction and/or treating CD40-positive cancer.

EFFECT: what is described is a method for selecting the high-expression human anti-CD40 antibodies containing insertion, deletion, inversion and/or replacement of 1 to 5 amino acids as compared to the antibody according to the invention, and the antibody prepared by the above method for selecting.

31 cl, 21 dwg, 14 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to field of biotechnology and immunology. Claimed is antibody, specifically binding with form A FcγRIII (CD16) (FcγRIIIA, CD16A) and not-binding specifically with form B (FcγRIIIB, CD16B), its antigen-binding fragment and multi-specific antibody, which includes antigen-binding fragment of antibody by invention. Compositions, which contain antibody by invention or its antigen-binding fragment, and their application in treatment of autoimmune, inflammatory, inflectious diseases, allergy and cancer, as well as set for detection of FcγRIIIA are described. Polynucleotides, vectors and host cells and method of obtaining antibody by invention or its antigen-binding fragment are described.

EFFECT: claimed invention provides novel antibodies to FcγRIIIA and, in that way, can find further application in therapy of FcγRIIIA-mediated diseases.

51 cl, 24 ex, 8 dwg, 5 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to polymorphous form of compound

,

which is characterised by picture of X-ray diffraction, including discriminatory peaks approximately 7.269, 9.120, 11.038, 13.704, 14.481, 15.483, 15.870, 16.718, 17.087, 17.473, 18.224, 19.248, 19.441, 19.940, 20.441, 21.469, 21.750, 22.111, 23.319, 23.763, 24.120, 24.681, 25.754, 26.777, 28.975, 29.609, 30.073 degree 2Θ. Invention also relates to method of obtaining polymorphous form of compound (IX), which includes processing of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-ylthiazol-2-ylamino)phenyl]benzamide with methanesulfonic acid at temperature from 20 to 80°C in solvent, selected from group, which includes methanol, ethanol, acetone, diethyl ether, dioxane and their mixtures.

EFFECT: obtaining polymorphous form of compound (IX), which remains dry at 80% relative humidity and thermodynamically stable at temperatures lower than 200°C.

7 cl, 3 dwg, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method of treating cancer in a patient, wherein the method involves administering a cancer-inhibiting amount of a compound of formula I into a patient's body. The method of treating cancer in the patient, including a human, wherein the method involves administering the cancer-inhibiting amount of a first compound of formula I or a physiologically acceptable salt thereof into the patient's body, wherein X represents CH or N, each R1 independently represents hydrogen or -CH2COR5; R5 represents hydroxy, optionally hydroxylated alkoxy, amino or alkylamino; each R2 independently represents the group ZYR6; Z represents a bond or the C1-3 alkylene or oxoalkylene group optionally substituted by the group R7; Y represents a bond, an oxygen atom or the group NR6; R6 is a hydrogen atom, the group COOR8, the alkyl, alkenyl, cycloalkyl, aryl or aralalkyl group optionally substituted by one or more groups COOR8, CONR82, NR82, OR8, =NR8, =O, OP(O)(OR8)R7 and OSO3M; R7 is hydroxy, the optionally alkoxylated or aminoalkyl group; R8 is a hydrogen atom or the optionally hydroxylated, optionally alkoxylated alkyl group; M is a hydrogen atom or one equivalent of a physiologically acceptable cation; R3 represents the C1-8 alkylene group, 1,2-cycloalkylene group or 1,2-arylene group, optionally substituted by R7; and each R4 independently represents hydrogen or C1-3 alkyl.

EFFECT: invention refers to a pharmaceutical composition for treating cancer in the patient, containing the compound of formula I, as well as to a kit for treating cancer.

23 cl, 3 ex, 7 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new alkylthiopyrimidines of formula III or pharmaceutically acceptable salts thereof: In the compound III X represents a direct bond; R2 means hydrogen, halogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, -NR8aR8b or the group -SR3; each R3 independently represents (C1-C6)alkyl, optionally mono-, di- or trisubstituted by halogen; or (C3-C7)cycloalkyl; R4a and R4b represent hydrogen; R6 represents aryl; or heteroaryl; wherein aryl and heteroaryl are optionally substituted in a substituted position by one or more substitutes specified in a group consisting of (a) halogen; (b) cyano; (c) nitro; (a) hydroxy; (e) guanidino; (f) heteroaryl; (g) phenyl; (h) phenyloxy; (i) benzyl; (j) benzyloxy (k) -NR8aR8b; (1) -C(O)R9; (m)-C(O)NR8aR8b, (n) - OC(O)NR8aR8b; (o) -C(O)OR9; (p) -NR7C(O)0R9; (q) -NR7C(O)R9; (r) sulphamoyl; (s) (C1-C6) alkylsulphonyl; (t) (C1-C6)alkylaminosulphonyl; (i) di(C1-C6)alkylaminosulphonyl; (v) (C1-C6)alkyl, optionally mono-, di- or trisubstituted by halogen; (w) (C1-C6) alkoxy, optionally mono-, di- or trisubstituted by halogen; and (x)(C1-C6)alkylthio, optionally mono-, di- or trisubstituted by halogen R7 represents hydrogen. The other radical values are specified in the patent claim.

EFFECT: compounds possess CRTH2 (G-protein related chemoattractant receptor expressed on Th2 cells) antagonist activity and are applicable for treating and preventing the diseases related to CRTH2, including treating allergic diseases, eosinophil and basophile related diseases.

14 cl, 6 dwg, 1 tbl

Iap inhibitors // 2491276

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula: U1-M-U2, where U1 and U2 have general formula (I), where: G stands for: IVb IVd ive, and values M, X1, X2, R2, R3, R3', R4, R4', R5, R5', R6, R6', R7, Z7, Z2, Z3, Z4, Q2 are given in item 1 of the formula.

EFFECT: compounds can be applied for induction of apoptosis in cell.

37 cl, 13 dwg, 43 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, and concerns using anti-CD40-antibodies in a combination with CHOP for treating diseases or conditions associated with neoplastic B cell growth, wherein the above disease or condition is resistant to a therapy using (i) CHOP, (ii) a chimeric monoclonal anti-CD20-antibody of rituximab or (iii) CHOP and rituximab in the form of the combination therapy, or a patient has shown recurrence following the therapy using (i) CHOP, (ii) the chimeric monoclonal anti-CD20-antibody of rituximab or (iii) CHOP and rituximab in the form of the combination therapy.

EFFECT: group of inventions provides synergistic therapeutic action ensured by using the combination according to the invention.

26 cl, 4 ex, 6 dwg, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmaceutical engineering, and concerns a combined antituberculous remedy containing isonicotinic acid hydrazide (isoniaside) and 2-benzylbenzimidazole (dibazol), and a polymer carrier that is an interpolymer complex of poly(meth)acrylic acid and polyethylene glycol, as well as a method for preparing it.

EFFECT: antituberculous remedy according to the invention has bacteriostatic and bactericidal action on tuberculosis mycobacteria; it provides the continuous maintainance of the active substance concentration at the therapeutically effective level; it causes no considerable blood variations; it is 2,5 times less toxic than isoniaside, and 10 times more active than isoniaside.

7 cl, 1 dwg, 11 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical compositions containing (2-hydroxyethoxy)amide 6-(4-brom-2-chlorophenylamino)-7-fluor-3-methyl-3H-benzoimidazole-5-carboxylic acid hydrosulphate and solvates, crystalline forms and amorphous forms thereof, to using the above compositions as a drug; and to methods for preparing the above compositions.

EFFECT: preparing the new pharmaceutical compositions.

20 cl, 7 tbl, 7 ex, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical compositions containing (2-hydroxyethoxy)amide 6-(4-brom-2-chlorophenylamino)-7-fluor-3-methyl-3H-benzoimidazole-5-carboxylic acid hydrosulphate and solvates, crystalline forms and amorphous forms thereof, to using the above compositions as a drug; and to methods for preparing the above compositions.

EFFECT: preparing the new pharmaceutical compositions.

20 cl, 7 tbl, 7 ex, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, particularly to methods for preparing finely divided dosage forms of ibuprofen widely used in medicine. What is presented is a method by quick cooling of the solutions by solution spraying into a liquid nitrogen container; the solvents are removed further by heating wherein an original substance is presented by ibuprofen, and the solvent is a 1,4-dioxane-water and acetone-water system, wherein the range of the ibuprofen concentrations in the original substance is 80-95% of ibuprofen solubility in this mixture of solvents at certain temperature; the water content in the 1,4-dioxane-water system shall not exceed 30 wt %, and that in the acetone-water system is 30-50 wt %; the prepared solid mixture is sublimated by progressive rise of temperature within the range of -196°C to +30°C in a vacuum-processed temperature-controlled container.

EFFECT: developing the method for preparing the finely divided dosage forms of ibuprofen widely used in medicine.

3 cl, 3 ex, 8 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, namely to a method for preparing solid pharmaceutical dosage forms containing a quinolone compound. E.g. the method under the invention involves using an extruder, particularly a turn-screw extruder designed for granulation from the quinolone compound mixed with a granulation excipient.

EFFECT: developing the method for preparing the solid pharmaceutical dosage forms containing the quinolone compound.

6 cl, 2 ex

Nanoemulsion // 2491917

FIELD: medicine.

SUBSTANCE: group of inventions refers to a nanoemulsion for active agent delivery, a method for preparing it, compositions containing it, and to using a nanoemulsion for preparing pharmaceutical compositions for local application and cosmetic compositions for skin application. The declared nanoemulstion contains a water ingredient and a carrier which contains a lipophilic ingredient in the amount of 0.1-15 wt %, a surfactant and isopropyl and/or 1-propyl alcohol. The average emulsified particle diameter makes less than 100 nm. The method for preparing the nanoemulsion involves mixing the water ingredient and carrier containing the lipophilic ingredient, surfactant and isopropyl and/or 1-propyl alcohol, for preparing the nanoemulsion at temperature 50-60°C. The invention also refers to the composition for photodynamic therapy containing the above nanoemulsion and the active agent representing 5-aminolevulinic acid, a derivative, a precursor and/or a metabolite thereof. The above composition is applied to prepare the drug substance for photodynamic therapy and to treat senile keratosis. What is also declared is a diagnostic composition for detecting the dividing cells which contains the nanoemulsion and 5-aminolevulinic acid. The invention also refers to a kit for photodynamic therapy which comprises the composition for photodynamic therapy and one ingredient specified in a photoresist coating, an agent for attaching the above coating or an agent for applying the composition.

EFFECT: invention provides better stability and intensified cell and tissue penetration of the nanoemulsion.

25 cl, 6 dwg, 9 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: group of inventions relates to field of biochemistry. Claimed is preparation for preservation of culture of stem and differentiated human and animal cells in cultivation, storage and cryoconservation. Preparation represents gel, which contains emulsion of perfluororganic compounds (PFOC) in their stabilisation in emulsified state with water solution of non-ionogenic surface active compounds (SAS) based on block-copolymer of polyethylene oxide (PEO) and polypropylene oxide (PPO) with ratio PEO/PPO from 9:1 to 7:3. SAS concentration in preparation constitutes from 20 to 90% with average molecular weight of SAS from 5000 Da to 21000 Da. Content of PFOC in emulsion constitutes from 5 to 70 vol.%. Size of PFOC emulsion particles lies in the interval from 15 nm to 2000 nm. Water phase of gel contains osmolytes of organic and/or inorganic nature for supporting in it osmotic pressure from 250 to 350 mOsm. As PFOC emulsion, emulsion of perfluorodecalin, perfluoro methylcyclohexyl piperidine and perfluorotributylamine mixture can be used. Also claimed is method of obtaining said preparation. Extrusion of coarse mixture of water SAS solution and liquid PFOCs or PFOC mixture is performed under pressure 400-700 atm until emulsion is obtained. After that, it is mixed in hot condition with concentrated water solution of inorganic salts or osmolytes are added into it until osmotic pressure equal from 250 to 350 mOsm is obtained. Then obtained composition is cooled. After that, partial freeze-drying or centrifugation of gel with observation of temperature gradient and acceleration from 15000 g to 35000 g is performed. Methods of preservation of culture of stem and differentiated human and animal cells in storage, cryoconservation and cultivation are claimed. In storage of cells preparation with PFOC content from 15 to 59 vol.% is added to culture medium with controlled value pH=7.0-7.4, temperature 37°C in CO2 incubator atmosphere or with low pH<6.0, temperature 20°C in air atmosphere. In cryoconservation resuspended in fresh culture medium cells are placed into medium, which contains preparation with PFOC content 59-70 vol.%. After that, cooling is carried out in two stages: first at rate 1 degree per min to -80°C, then with maximally possibly rate to temperature -196°C. In cultivation of cells as medium component preparation with PFOC content from 15 to 70 vol.% is used.

EFFECT: cell cultures after cryoconservation, storage or cultivation in presence of PFOC-containing gels have on average 90% of viable cells, are easily separated from gel, re-inoculated in standard conditions, divided and fully preserve their functions and ability to differentiate.

16 cl, 23 dwg, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented prolonged release pharmaceutical oral dosage form for preventing or treating an upper gastrointestinal disorder (dyspepsia, epigastric burning, erosive esophagitis, gastrooesophageal reflux disease, peptic ulcer, esophagitis, Barrett's esophagus and esophageal adenocarcinoma), containing a therapeutically effective amount of at least one bile acid sequestrant specified in colesevelam and colesevelam hydrochloride, and a carrier composition providing gastric retention containing one or more hydrogels, wherein the dosage form expands upon contact with gastric juice, respective methods of treating or preventing the upper gastrointestinal disorder and protecting the multilayer squamous epithelium against an attack of any hazardous substances by administering the composition, and a kit for the same application comprising the composition, a label or a package insert with instructions for use. The composition may contains a proton pump inhibitor, and one or more agents specified in antacids, histamine H2-receptor antagonists, γ-aminobutyric acid-b (GABA-B) agonists, and protease inhibitors.

EFFECT: invention aims at retaining the active agent in the stomach for relieving and improving prolonged delivery thereof.

16 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention aims at a composition for treating pulmonary hypertension which contains an active agent consisting of 0.001 mg/ml to 20 mg/ml of an ACE inhibitor and additionally containing at least one humidifier. It is isotonic and has the pH value within 3 to 8. It is acceptable to administer the composition by inhalations into a mammal in need thereof. According to the invention, the compositions can represent a solution or a suspension, and preferentially, it is acceptable to administer them by spraying. The present invention also aims at a kit for treating a mammal suffering pulmonary hypertension. 2 primary claims, 12 secondary claims.

EFFECT: preparing the composition for treating pulmonary hypertension.

1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for outpatient treatment and prevention of the cardiovascular diseases, containing therapeutic amounts of a vasodilator, a renin-angiotensin system inhibitor, a thrombocyte aggregation inhibitor, a cholesterol-lowering agent, and an antihypoxic agent. As a vasodilator, the declared composition contains an agent possessing α-adrenergic receptor antagonist action, and a thrombocyte aggregation inhibitor is presented by an ADP-dependent thrombocyte activation mechanism blocking agent.

EFFECT: invention provides the integrated therapeutic effect on the cardiovascular system after acute administration that improves the compliance with treatment regimen by the patient.

20 cl, 1 tbl, 15 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to novel morpholinopurine derivatives of general formula

,

or a pharmaceutically acceptable salt thereof, where R1 and R2, each independent of each other, denote a C1-C6 alkyl group or a hydrogen atom, R3a and R3b, each independent of each other, denote a C1-C6 alkyl group which can contain three substitutes selected from a group A, or a hydrogen atom, R4 denotes a C1-C6 alkyl group or a hydrogen atom, Ra denotes a group of formula -Y-R , where Y denotes a single bond or a C1-C6 alkylene group, R5 is a C1-C6 alkyl group which can contain one, two or three substitutes selected from group A, a tetrahydrofuranyl group, a pyrrolidinyl group which contains one substitute selected from a group D, and Rb and Rc, each independent of each other, denote a C1-C6 alkyl group which contains one substitute selected from a group E, or a hydrogen atom, or Rb and Rc, together with a nitrogen atom to which they are bonded, for a 5-7-member alicyclic nitrogen-containing heterocyclic group, which is pierazine, morpholine, pyrrolidine, piperidine, homopiperazine, which can contain one, two or three substitutes selected from group E; group A: halogen atom, hydroxy group, C3-C8 cycloalkyl group and oxy group; group D: C1-C6 alkylsulphonyl group; and group E: hydroxy group, formyl group, C1-C6 alkyl group, which can contain one substitute selected from said group A, diC1-C6 alkylamino group, C1-C6 alkylsulphonylamino group, C1-C6alkylsulphonyl C1-C6 alkylamino group, C1-C6 alkylsulphonylamino C1-C6alkyl group, C1-C6alkylcarbonyl group, which can contain one substitute selected from said group A, C1-C6 alkylsulphonyl group, C1-C6 alkylamino C1-C6 alkylcarbonyl group, diC1-C6 alkylamino C1-C6alkylcarbonyl group, which can contain one substitute selected from said group A, diC1-C6 alkylaminocarbonyl group, phenylsulphonyl group and hateroaryl C1-C6 alkylcarbonyl group, where the heteroaryl is imidazolyl. The invention also relates to a pharmaceutical composition, an inhibitor of phosphatidylinositol-3-kinase (PI3K), an inhibitor of mammalian target of rapamycin (mTOR) based on the compound of formula (1a), a method of treating cancer and use of the compound of formula (1a).

EFFECT: obtaining novel morpholinopurine derivatives, having useful biological properties.

42 cl, 19 tbl, 138 ex

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