5-oxymethyl-5-[3-(2-chloroethyl)-3-nitrosourea]-2 - cyclohexyl-1,3-dioxane with antitumor activity
(57) Abstract:The invention relates to medicine, namely to biologically active compounds with antitumor activity against tumors in rats and mice. Describes a new connection 5-oxymethyl-5-[3-(2-chloroethyl)-3-nitrosourea] -2-cyclohexyl-1,3-dioxane of the formula I with antitumor activity. Compound I is highly active cytotoxic agent with a pronounced therapeutic effect on all 3 strains investigated transplantable tumors. Comparison of antitumor activity of the claimed compounds and TELEMETRY in mice with leukemia P-388 showed an advantage of the claimed compounds. 3 table.The invention relates to medicine, namely to the field of biologically active compounds with antitumor activity against tumors in rats and mice.Object of the invention is the creation of new, more effective anti-cancer agents. The task is achieved by the synthesis of the compounds of formula
< / BR>This connection can be used as anticancer drugs. The proposed compound synthesized is - -cyclohexyl-3-(2-chloroethyl)-3-nitrosoanatabine used in medical practice and synthesized in the United States. The disadvantage of the prototype is its low solubility in water, which prevents the establishment of an injectable dosage form. (Perevozchikova N. I. Chemotherapy of neoplastic diseases. M , 2000, 384 S. ).The synthesis of this compound is carried out as follows.The interaction of 2-cyclohexyl-5-amino-1,3-dioxane with pentachlorphenol ether N-nitroso-N-(2-chloroethyl)carbamino acid in anhydrous dimethylformamide obtained 5-[3-(2-chloroethyl)-3-nitrosourea] -2-cyclohexyl-1,3-dioxane.< / BR>The proposed connection is a low-melting substance is light yellow in color. This connection proved elemental analysis, individuality TLC, the structure of the IR and NMR spectra.Receipt of the proposed compound and its biological properties are illustrated by the following examples.The original 2-cyclohexyl-5-amino-oxymethyl-1,3-dioxane obtained by the method described in the work: Kris B. O. , Schoenberg N. N. , Ivin A. B. VI. Compounds with electrophilic reactivity. Synthesis and properties of new 2,2-dimethyl-5-[2,4-bis(1-aziridinyl)-1,3,5-triazine-6-yl] amino-1,3-dioxaborinane ether N-nitroso-N-(2-chloro-ethyl) - carbamino acid synthesized by the method, described in: J. Martinez, J. Oiry, Imbach J., F. Winternitz. Activated N-Nitrosocarbamates for Regioselective Synthesis of N-Nitrosoureas. - J. Med. Chem. 1982, v. 25, p. 178-182.Example 1. Synthesis of 5-oxymethyl-5-[3-(2-chloroethyl)-3-nitrosourea] -2-cyclohexyl-1,3-dioxane.A solution of 0.01 mole of 2-cyclohexyl-5-amino-5-oxymethyl-1,3-dioxane and 0.01 mole pentachlorphenol ether N-nitroso-N-(2-chloroethyl)carbamino acid in 10 ml of anhydrous DMF was stirred 4 h at 0-5oC. Then the reaction mass was poured into 50 ml ice water, the precipitated yellow precipitate was filtered, washed with water (310 ml), the residue was purified by presidenial from acetone five times by volume the amount of hexane. The output of 2.23 g (75%). So pl. 66-70oC (with decomp. ), TLC on plates of Silufol UV-254, Rf= 062 (eluent acetone: hexane 1: 2).Found, %: CL 11.87 Per. Calculated, %: CL 11,70.PMR spectrum (in CDCl3), M. D.: 1.3 to 1.85 m (10H, 2-C6H10), 3,98 D. (2H, 4,6-CH2-Equatorial), 4,10 D. (2H, 4,6-CH2-axial), 3,45 t (2N, l2), 4,11 t (2H, CH2N), 4,84 (2H, CH2IT), with a 7.62 (1H, NH).NMR13(In CDCl3), M. D.: 38,5 (l2), AND 39.7 (CH2N), 152,8 (C= O), 62,4 (4WITH6), 55,1 (5), 79,8, 62,9 (CH2IT), 98,8 (5), 22,2, 25,2, 29,4, 34,6 (2-WITH6H10).The IR spectrum suspect proposed connection.Acute toxicity of the compounds was studied in mice SHR. A portion of the substance was dissolved in alcohol, the resulting alcoholic solution is diluted with isotonic sodium chloride solution and was injected into mice intraperitoneally. LD50in mice with a single intraperitoneal injection was 49 mg/kg Maximum tolerated dose for a single intraperitoneal injection was 20 mg/kgExample 3. The impact of the proposed connection to the leukemia P-388.Leukemia P-388 transplanted intraperitoneally to mice TWO2the introduction of the 106tumor cells. After a single intraperitoneal administration proposed connection at a dose of 20 mg/kg on day 3 after inoculation the lifespan of mice increased by 451% compared to control, while under the influence of CCNU entered in the maximum tolerated dose of 40 mg/kg, the lifespan of mice increased by 298% (table. 1).Example 4. The impact of the proposed connection on the growth of squamous cell carcinoma, Lewis lung.The Lewis lung carcinoma was inoculated subcutaneously to mice WITH57L the introduction of 0.2 ml of 10% suspension of tumor cells in physiological solution. The proposed connection was introduced intraperitoneally in a dose of 20 mg/kg / day 3 Example 5. The impact of the proposed connection on the growth of carcinosarcoma Walker in rats.Carcinosarcoma Walker was inoculated rats subcutaneously introduction to 0.4 ml of 10% suspension of minced tumor tissue in physiological solution. The proposed connection was introduced once on day 6 after inoculation, at a dose of 20 mg/kg intraperitoneally. The inhibition of tumor growth in different periods after the introduction of the proposed connection was 92-98% (table. 3).Thus, the proposed connection is highly active cytotoxic agent with a pronounced therapeutic effect on all 3 strains investigated transplantable tumors. Comparison of antitumor activity of the proposed connection and CCNU in mice with leukemia P-388 showed the advantage of the proposed connection. 5-Oxymethyl-5-[3-(2-chloroethyl-3-nitrosourea] -2-cyclohexyl-1,3-dioxane of the formula I
< / BR>with antitumor activity.
H2Nhave a weed-killing activity
FIELD: organic synthesis.
SUBSTANCE: invention provides compounds of general formula I:
, where R1 represents -CO-Ra, -SO2-Rb, or aryl optionally substituted by lower alkoxy, wherein Ra represents cycloalkyl, cycloalkyl(lower)alkyl, cycloalkyloxy, aryl, aryloxy, aryl(lower)alkyl, aryl(lower)alkoxy, aryloxy(lower)alkyl, aryl-S-(lower)alkyl, aryl(lower)alkenyl, provided that aryl group can be optionally substituted by halogen, lower alkyl, hydroxy, nitro, cyano, lower alkoxy, phenyl, CF3, cyano(lower)alkyl, lower alkyl-C(O)NH, lower alkyl-CO, and lower alkyl-S; heteroaryl, heteroaryl(lower)alkyl, or heteroaryl(lower)alkoxy, provided that heteroaryl group is 5- or 6-membered ring or bicyclic aromatic group constituted by two 5- or 6-membered rings including 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur and that heteroaryl group can be optionally substituted by lower alkoxy; Rb represents aryl, aryl(lower)alkyl, or heteroaryl, aryl group optionally substituted by halogen, cyano, or lower alkyl-C(O)NH; R2 and R3 represent hydrogen atoms; R4 representshydrogen or lower alkyl; R5 represents hydrogen, lower alkyl, cycloalkyl, benzodioxyl, or aryl optionally substituted by lower alkyl, halogen, lower alkoxy, hydroxy, or (lower)alkyl-C(O)O; n is 1 or 2; and pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable esters thereof. Invention also provides a pharmaceutical composition exhibiting inhibitory activity with regard to cysteine proteases of the cathepsin family, which composition comprises compound of formula I, pharmaceutically acceptable recipient, and/or adjuvant.
EFFECT: increased choice of cysteine protease inhibitors.
34 cl, 1 tbl, 13 ex
FIELD: medicine, veterinary science.
SUBSTANCE: a new group of compounds, such as: 1) 1.3-benzodixole-5-β-nitroethylene
, 2) 1.3-benzodioxole-5-β-nitropropylene
, 4) 2-methylbenzimidazole-5-β-nitroethylene
, 5) benzoxazole-5-β-nitroethylene
, 6) 2-methylbenzoxazole-5-β-nitropropylene
has been suggested to protect against the agents of bacterial, protozoan and fungoid nature. Compounds are being the derivatives of heteronitroalkenes (dioxoles, oxazoles, imidazoles) with below-mentioned structural formulas being efficient to gram-positive bacteria and gram-negative aerobes, fungi of Candida, Trichophyton and other types, trichomonads. They could be applied at treating wound infections, fungoid lesions, septic states, pneumonia, trachoma, ornithosis, salmonellosis.
EFFECT: higher efficiency of protection.
5 cl, 5 tbl
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new derivatives of carboxylic acids of the formula: wherein Y is taken independently in each case among the group comprising C(O), N, CR1, C(R2)(R3), NR5, CH; q means a whole number from 3 to 10; A is taken among the group comprising NR6; E is taken among the group comprising NR7; J is taken among the group comprising O; T is taken among the group comprising (CH2)b wherein b = 0; M is taken among the group comprising C(R9)(R10), (CH2)u wherein u means a whole number from 0 to 3; L is taken among the group comprising NR11 and (CH2)n wherein n means 0; X is taken among the group comprising CO2H, tetrazolyl; W is taken among the group comprising C, CR15 and N; R1, R2, R3 and R15 are taken independently among th group comprising hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy-group, -CF3, amino-group, -NHC(O)N(C1-C3-alkyl)-C(O)NH-(C1-C3-alkyl), -NHC(O)NH-(C1-C6-alkyl), alkylamino-, alkoxyalkoxy-group, aryl, aryloxy-, arylamino-group, heterocyclyl, heterocyclylalkyl, heterocyclylamino-group wherein heteroatom is taken among N atom or O atom, -NHSO2-(C1-C3-alkyl), aryloxyalkyl; R4 is taken among the group comprising hydrogen atom, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindenyl, alkyl, benzodioxolyl, dihydrobenzodioxynyl, furyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl. Other values of radicals are given in the claimed invention. Also, invention relates to pharmaceutical composition used for inhibition binding α4β1-integrin in mammal based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for treatment or prophylaxis of diseases associated with α4β1-integrin.
EFFECT: improved method for inhibition, valuable medicinal properties of compounds.
33 cl, 7 tbl, 42 ex
FIELD: organic chemistry, medicine.
SUBSTANCE: invention relates to 6-(4'-chlorobenzoyl)-7-(N-4''-nitrobenzoyl)amino-1,4-benzodioxane and its analogs of the general formula (I) possessing with an anticonvulsant activity wherein R' represents (C3-C4)-alkyl; Ar-X wherein X means hydrogen atom (H), p-CH3, ortho-, p-Hal; R'' represents -CH2Cl, Ar-X wherein X means p-CH3, meta-, p-OCH, p-NO2, 2-thiophenyl, 6-benzo-1,4-dioxanyl. Invention provides preparing new compounds that can be used in pharmacology.
EFFECT: valuable medicinal properties of compounds.
1 cl, 3 tbl, 2 ex
FIELD: veterinary science.
SUBSTANCE: method involves 5-fold administration of immunoparasitan by intramuscular route with break for 4 days in the dose 0.02-0.1 ml/kg of body mass, riboxin by oral route in the dose 15-20 mg/kg of body mass, 3-4 times per a day for 25-30 days, panangin or asparcam by oral route in the dose 1 lozenge per 25-30 kg of body mass, 3 times per 24 h for 21 days, carsil or essentiale by oral route in the dose 0.035 g (1 lozenge) per 20-30 kg of body mass, 3 times per a day for 30-40 days, avermectin preparations - in 4 days after last injection of immunoparasitan by subcutaneous route, 3-fold with break for 7 days in the dose 0.8-1.0 ml per 50 kg of body mass. Invention promotes to decreasing the dose and unfavorable effect of chemopreparations and toxic substrate formed after death of parasites on the background of enhancing immunity and activation of antitoxic function of liver. Invention can be used in prophylaxis and treatment of dirofilariasis in dogs.
EFFECT: improved method in prophylaxis and treatment.