Bromohydrate of 4-methoxy-7,7-dimethyl-9-(5'-carboxyamyl)amino-6-h-7,8-dihydropyrimido(4,5-b)-1,4-benzthiazine and synthesis method thereof

FIELD: chemistry.

SUBSTANCE: described is a bromohydrate of 4-methoxy-7,7-dimethyl-9-(5'-carboxyamyl)amino-6H-7,8-dihydropyrimido-(4,5-b)-1,4-benzthiazine (hereinafter methiazine) and a method for synthesis of the said compound. Methiazine has anti-tumour and anti-reductase activity, which has cytostatic and cytotoxic effect which inhibits synthesis of nucleic acids and can be used in medicine. Bromohydrate of 4-methoxy-7,7-dimethyl-9-(5'-carboxyamyl)amino-6H-7,8-dihydropyrimido-(4,5-b)-1,4-benzthiazine of formula I , is obtained by reacting dimedone with ω-amino caproic acid in a medium of boiling isopropanol to obtain enamine-ketone which is subjected to bromation with bromosuccinimide with further treatment with 4-methoxy-5-amino-6-mercaptopyrimidine in a medium of boiling isopropanol.

EFFECT: improved method.

2 cl, 3 ex

 

The invention relates to the field of organic chemistry and relates to a new, not described in the literature connections, namely bromhidrosis 4-methoxy-7,7-dimethyl-9(5'-carboxylic)amino-6N-7,8-dihydropyrimido(4,5-b)-1,4-benzothiazine (hereinafter mediazine), and method of its production. Mathiasen has antitumor and antiredundancy activity with cytostatic and cytotoxic effect, inhibiting the synthesis of nucleic acids, and can be used in medicine.

The claimed compound belongs to the group of hydrogenated 1,3-diazapentane, the first information of which appeared only in 1980. To date, this group discovered compounds having diverse biological activity (analgesic, anti-inflammatory, hypoxic), and there is evidence that compounds belonging to this class are weak antitumor and antiregulatory activity (Chem. Pharm. J. No. 8, 1985, str-968). Famous 7-amino derivatives of 5H-pyrimido[4,5-b] [1,4] diazinon-6 exhibiting antitumor activity (SU 562982, all-Union scientific research chemical-pharmaceutical Institute. Sergo Ordzhonikidze, 07.07.1982, C07D 513/04).

The objective of the invention is the formation of compounds of group hydrogenated 1,3-fenotiazinas with improved biological properties, in particular the wider is their range of biological actions, including a broader spectrum of antitumor activity and more globalstorage expression.

This object is achieved by obtaining bromhidrosis 4-methoxy-7,7-dimethyl-9(5'-carboxylic)amino-6N-7,8-dihydropyrimido(4,5-b)-Benz,4-thiazin (mediazine)with antitumor and antiredundancy activity with cytostatic and cytotoxic effect, inhibiting the synthesis of nucleic acids.

The method consists in the interaction of dimedone with ω-aminocaproic acid in the medium boiling isopropanol to obtain enaminoketone, which are bromirovanii-bromosuccinimide and further processing with 4-methoxy-5-amino-6-mercaptopyridine in the environment of boiling isopropanol.

Owing to this method, the target connection (mathiasen) was isolated in the form of bromhidrosis, not reason, that is, the reaction mass of 2-brakenmonkey and 4-methoxy-5-amino-6-mercaptopyrimidine not treated with an aqueous solution of NaOH as the base mediazine soluble in water and even better soluble in caustic alkali solution (the presence in the molecule of the COOH group).

It is known that available-aminocaproic acid is antifermentny drug and has regenerative properties. Therefore, the acid and its derivatives are used as krooo tanavlivaetsya means, tools for healing wounds, as well as to accelerate the accretion of bone fractures. These compounds are also used for resorption cosmetic scars in cosmetic surgery. It is also known that derivatives of amino acids, which can be attributed mathiasen, 4-5 times faster penetrate through the membrane of tumor cells compared with normal cells and lead to increased drug concentrations in the tumor cells. It was hoped that the introduction of such substituent in the molecule of the claimed compounds could have a positive impact on its biological properties. The synthesis of the claimed compounds is carried out according to the following scheme: diodon enter into interaction with oligoamenorrhea acid and get the enaminoketone. The latter undergoes bromirovanii-bromosuccinimide, and the resulting 2-bremelanotide is introduced into the reaction with 4-methoxy-5-amino-6-mercaptopyrimidine, which leads to the obtaining of the claimed compounds.

The scheme of synthesis

The following example shows how to get the claimed compounds.

1. Getting enaminoketone

In flask 1 l load 500 ml of isopropyl alcohol and when the stirrer was added a mixture consisting of 35 g of dimedone and 32.8 g of ω-amine is Caproic acid. The reaction mixture is stirred at boiling water bath for 12-13 hours. After about 3-4 hours all solid components of the mixture are dissolved, and forms a yellow coloured solution. By the end of the boiling mixture to the chromatographic plate (Silufol, eluent methanol:chloroform 1/10) remains weak spot dimedone. After received this chromatographic picture, boiling ceased, the flask provide direct fridge and when operating the mixer 450 ml distilled solvent. To the residue in the flask add 200-250 ml of water, the mixture is stirred for 20-30 min and transfer it to the filter, separate the precipitate. It is washed with 200 ml of water and dried in air. The precipitate is recrystallized from aqueous isopropanol (420 ml of boiling isopropanol and 320 ml of water). Filtered and dried. Get 57 g (yield 90%) of light yellow crystalline substance. T square 147-151°C.

2. Getting 2-romanamolona

In a flask with a volume of 1 L. the mixture was charged of 380 ml of methanol and 65 ml of water, the flask sprinkled 28 g finely chopped bromosuccinimide. The contents of the flask cooled to 0°C and when the agitator load of 40 g finely ground enaminoketone, ensuring that the reaction temperature did not rise above +2°C. After loading, the reaction mass is maintained at 0°C for 2 hours and then left in an ice BA is e for 12 hours. After such exposure distilled 250 ml of solvent and the remaining residue in the flask was added 400 ml of water. The mixture is stirred for 30-40 min and filtered loose sediment. It is washed with water and dried in air, and recrystallized from 600 to 700 ml of ethyl acetate, get 28-29 g of pale beige crystalline product (62-64%). T square 114-116°C

3. Getting mediazine

In a flask with a volume of 500 ml upload mixture consisting of 350 ml of isopropanol, 4 g of mercaptopyrimidine and 8 g of romanamolona. To the reaction mass add 5 drops of hydrochloric acid and heated to boiling. In the reaction of all the solid components are dissolved, and formed red color solution. Boiling continues 3-3,5 hours with stirring. Process control chromatography. By the end of the boil on the chromatogram shows an orange spot of the target product and traces of the original substance (Silufol, eluent methanol:chloroform 1/10). The flask provide direct fridge and distilled 300-350 ml of solvent when operating the mixer. To the residue, cooled to 30-40°C, add 250 ml of acetone and stirred for 30-40 minutes the Precipitate mediazine filtered off, washed with 50 ml of pure acetone and air-dried. Get about 9 g mediazine (75% yield) as an orange powder with a T square 176-178°C. is Stored in the air without decomposition. Easily soluble in water and is the ethanol, poorly soluble in isopropanol and insoluble in benzene, toluene, petroleum and sulfuric esters.

The characteristic biological activity mediazine

Metasin - original chemical compound, its structure has no analogues in Russia and abroad. Advanced biological research mediazine conducted in the laboratory of experimental cancer chemotherapy CHLS-UNIFI under the guidance of the doctor of medical Sciences, Professor Vasinova. The study was carried out in three directions.

- Found ability mediazine to inhibit the enzyme folic exchange dihydrotetrazolo (FID) (MOT candles. Biol. Sciences Nagrebcan according to the method described in [Assocrule, Nagrebcan, Waerloga. "Oncology", 1975, 21(11), p.45-50).

- Studied cytostatic and cytotoxic effect in cultures of normal and tumor cells (conducted MTL Waarloos by the above method).

- We studied the ability mediazine to inhibit the growth of transplantable tumors in experimental animals (held SNA, KMN Astacology by the method in [Vasenev, in the book "Methods of experimental chemotherapy, a practical guide edited by Tinbergen, M.: Medicine, 1971, str-382).

Discovered that mathiasen inhibits the enzyme preparation FID allocated from pécs and rats at a concentration of 1·10 -4M 95%, at a concentration of 1·10-5M - 50%. Activity in relation to FID it was also noted at a concentration of 1·10-6M by 30% and maintained at a concentration of 1·10-7M by 19%. It is established that mathiasen inhibits the synthesis of nucleic acids adapted to growth in vitro cell leukemia NK/Ly: the dose that causes 50% inhibition of the synthesis of nucleic acids (ED50)is 250δ.

Mathiasen has a cytostatic effect in cultures of tumor cells (sarcoma 45) and normal cells (heart of a chicken embryo). So, for methionine index of inhibition of growth of culture cells of sarcoma 45 (J) at a concentration of 1·10-3reached 100%, at a concentration of 1·10-4M - 30%. In relation to the culture of the heart cells of chicken embryo braking index (J) in a concentration of 1·10-3M was 90%and at a concentration of 1·10-4M inhibition of normal cells was not observed. These data indicate that mediazine some selectivity of the cytotoxic action against the tumor tissue compared to normal.

High antitumor activity was observed in mediazine in experiments in vivo: inhibits the growth of some strains of transplantable tumors in rats. So, mathiasen inhibits the growth of sarcoma Jensen at 90-95%, sarcoma M-1 to 70%, sarcoma 45 by 30%. This mathiasen shows a moderate cytotoxicity: in re NutriBar the tire introduction rats are well tolerated in doses up to 100 mg/kg

The mouse is more sensitive to the action of mediazine and well tolerated in doses of 25 mg/kg daily infusions within a 7 days mathiasen inhibits the growth of ascitic form of Ehrlich up to 85-90%of NK/Ly - 80-90%, carcinoma 755 - 70-75%, sarcoma AK and sarcoma 37 70%.

Thus, mathiasen on the chemical structure and its biological properties can be considered as a new type of inhibitor of the enzyme folic exchange digidrofolatreduktazy having a high antitumor activity in vitro and in vivo. It differs from known enzyme inhibitors folic exchange - cancer drugs of aminopterin and methotrexate other spectrum of antitumor activity and lower toxicity. So, MTD (instantly portable dose) in mice after a single dose of methotrexate 4 mg/kg, and for mediazine 100 mg/kg

1. Bromohydrin 4-methoxy-7,7-dimethyl-9(5'-carboxylic)amino-6N-7,8-dihydropyrimido(4,5-b)-1,4-benzothiazin formula 1

having antitumor and antiredundancy activity with cytostatic and cytotoxic effect, inhibiting the synthesis of nucleic acids.

2. The method of obtaining bromohydrin 4-methoxy-7,7-dimethyl-9-(5'-carboxylic)amino-6N-7,8-dihydropyrimido-(4,5-b)-1,4-benzothiazine according to claim 1, which consists in the interaction of dimedone with ω-aminocaproic the second acid in the medium boiling isopropanol to obtain enaminoketone, which are bromirovanii-bromosuccinimide and further processing with 4-methoxy-5-amino-6-mercaptopyrimidine in the environment of boiling isopropanol.



 

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13 cl, 37 ex

FIELD: medicine.

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5 cl, 1 tbl, 24 ex

FIELD: chemistry.

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23 cl, 13 dwg, 11 tbl, 26 ex

FIELD: chemistry.

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16 cl, 5 tbl, 5 ex

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33 cl, 17 dwg, 11 tbl, 391 ex

FIELD: chemistry.

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15 cl, 67 ex

FIELD: chemistry.

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41 cl, 8 tbl, 423 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to oxazolo- and thiazolo-[4,5-c]-quinoline-4-amines of the general formula (I)

wherein R1 is taken among group consisting of oxygen and sulfur atoms; R2 is taken among hydrogen atom, alkyl, alkyl-OH (hydroxyalkyl), alkyl-X-alkyl, alkyl-O-C(O)-N(R5)2, morpholinyl, pyrrolidinyl, alkyl-X-aryl radical, alkenyl-X-aryl radical; each substitute R3 and R4 represents hydrogen atom or substitutes R3 and R4 taken in common form the condensed aromatic or [1,5]-naphthiridine system; X represents -O- or a single bond; R5 represents hydrogen atom. Also, invention describes intermediate compounds, pharmaceutical composition and a method for stimulating biosynthesis of cytokinins (cytokines) based on these compounds. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds.

21 cl, 2 tbl, 64 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: improved preparing method, valuable medicinal properties of compounds.

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to methods for treatment of diseases or syndromes associated with metabolism of fatty acids and glucose and to new compounds and their pharmaceutically acceptable salts. Invention relates to applying new compounds and pharmaceutical compositions for treatment of cardiovascular diseases, diabetes mellitus, cancer diseases, acidosis and obesity by inhibition of activity of enzyme malonyl-CoA-decarboxylase. Indicated compounds correspond to formulae (I) and (II) wherein Y, C, R1, R2, R6 and R7 have values given in the invention claim.

EFFECT: valuable medicinal and biochemical properties of azoles.

27 cl, 8 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to applying compounds of the general formula (1):

as inhibitors of caspase-3 that allows their applying as "molecular tools" and as active medicinal substances inhibiting selectively the scheduling cellular death (apoptosis). Also, invention relates to pharmaceutical compositions based on compounds of the formula (1), to a method for their preparing and a method for treatment or prophylaxis of diseases associated with enhanced activation of apoptosis. Also, invention relates to new groups of compounds of the formula 91), in particular, to compounds of the formulae (1.1):

and (1.2):

. In indicated structural formulae R1 represents inert substitute; R2, R3 and R4 represent independently of one another hydrogen atom, fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J). CF3, inert substitute, nitro-group (NO2), CN, COOH, optionally substituted sulfamoyl group, optionally substituted carbamide group, optionally substituted carboxy-(C1-C6)-alkyl group; R5 represents oxygen atom or carbon atom included in optionally condensed, optionally substituted and optionally comprising one or some heteroatoms; R6 represents hydrogen atom or inert substitute; X represents sulfur atom or oxygen atom.

EFFECT: improved preparing and applying methods, valuable medicinal and biochemical properties of compounds.

3 cl, 1 dwg, 2 tbl, 1 sch, 8 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel heterocyclic compounds comprising 2-aminopyridin-3-sulfonic fragment of the general formula (1) or their pharmaceutically acceptable salts, N-oxides or hydrates possessing properties of antagonists of glutamate-induced calcium ions transport, in particular, neuroprotective effect. Also, invention relates to the focused library for the search of biologically active leader-compounds comprising at least one heterocyclic compound of the general formula (1) and to pharmaceutical composition if form of tablets, capsules or injections placed into pharmaceutically acceptable package containing compounds of invention as an active substance. In compound of the general formula (1) R1 represents hydrogen atom; R2 represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; or R1 and R2 in common with nitrogen and sulfur atoms to which they are bound form optionally substituted and optionally condensed with other cycles 1,1-dioxo-4H-pyrido[2,3-e][1,2,4]thiadiazine or optionally substituted and optionally condensed with other cycles 5,5-dioxo-5,6,7,9-tetrahydro-5-thia-1,6,9-triazabenzocyclohepten-8-one. Also, invention discloses methods for preparing different compounds of the general formula (1).

EFFECT: improved preparing methods, valuable medicinal properties of compounds.

10 cl, 4 sch, 4 tbl, 9 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.

12 cl, 2 dwg, 32 ex

FIELD: medicine, pharmacology, organic chemistry.

SUBSTANCE: invention relates to using 2-amino-4-acetylthiazolo[5,4-d]indole for protection of body against effect of hemic and hypercapnic hypoxia. Invention proves high effectiveness of the protection effect.

EFFECT: enhanced effectiveness of agent.

2 tbl

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