The method of obtaining 1,2,3,9 - tetrahydro-9-methyl-3- [(2-methyl - 1h - imidazol-1-yl) methyl]-4h - carbazole-4-or its salts or their hydrates, and intermediates for their synthesis
(57) Abstract:Usage: as substances, which is an antagonist of serotonin receptors 5-HT3. The inventive product 1,2,3,9-tetrahydro -9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H - carbazole-4-one of formula I, or salts thereof, or hydrates. Reagent: 3-[(N-dialkylamino)methyl]- 1,2,3,9-tetrahydro-9-methyl-4H - carbazole-4-one of formula II. Reagent 2: 2-Mei. Reaction conditions: solvent when heated in the presence of catalytic amounts of iodine. The structure of formulas I and II: where NAlk2represents N(C2H5)2or N(CH2)5. 3 C.p. f-crystals. The invention relates to the field of organic chemistry, specifically to an improved method of obtaining 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl] 4H-carbazole-4-or its salts or their hydrates, as well as intermediates for their synthesis, which can find application in pharmaceutical industry.A method of obtaining 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl] 4H-carbazole-4-or its salts, or hydrates of the formula I, namely, that the hydrochloride or iodimetric 3-[(N-dimethylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4H-to the AI. The target product is isolated in the form of a base or salt
N(CH3)2__< / BR>The disadvantage of this method is the duration of the process.The aim of the invention is the intensification of the process.This goal is achieved by the proposed method of obtaining 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl] 4H-carbazole-4-or its salts or their hydrates, namely, that 3-[(N-dialkylamino)methyl] -1,2,3,9-then it is carbonated - draw-9-methyl-4H-carbazole-4-one or its hydrochloride is subjected to interaction with 2-methylimidazole in the aquatic environment when heated in the presence of catalytic amounts of iodine.NAlk2__< / BR>An additional advantage of the proposed method is the use of new intermediate products of General formula II
where NAlk2represents N(C2H5)2or N(CH2)5or their salts with acids, which are intermediate products of the synthesis of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazole-4-or its salts. Especially note 3-[(N-diethylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4H-carbazole-4-one, which can easily be returned to the process, -4-ones of General formula II is based on the well-known in the literature, the reaction of manniche.It should be noted that in the proposed method as a starting compound can be used according to manniche in the form of hydrochloride (similar to the method), and in the form of free base. The advantage of this method is the possibility to use the basis of manniche directly after receiving it without transferring it in salt with acids or Quaternary base.Significant is also the fact that when using the proposed method as Mannich bases can be used not only dimethylaminopropane, but heavier Mannich bases, such as diethylaminomethyl or piperidinedione, the synthesis of which is somewhat simpler and, in addition, they can return to the process used Amin.Distinctive features of the proposed method is the use of a catalytic amount of iodine.The advantages of the preferred variants of the process are the ability to control the process and return for future use secondary amine, as well as the possibility of using the Mannich bases in the form of free base.P R I m e R 1. A mixture of 28.4 g (0.1 mol) of 3-[(N-diethylamino)methyl]-1,2,3,9-tetrahed - ro-9-methyl-4H-carbazole-4-it, 25,0 g (0.3 mol) of 2-methylimidazole, 250 ml of water and 0.05 g (is 0.0002 mol) of iodine in intensive stirring and boiled for 5 hours First dissolving the precipitate, then blurred, and then begins to fall precipitate. The reaction mass is then cooled, the precipitate is filtered off, thoroughly washed with water, dried and receive 27.9 g of a technical product with so pl. 207-210aboutWith (yield 95%). The resulting product (3 g) was transferred by the action of hydrochloric acid into the hydrochloride, which after crystallization and drying is obtained in form of white crystalline powder (1.7 g), so pl. 177,5 178,5aboutC. [literature data: so pl. 178,5-179,5aboutS]
Analysis. Found, Cl 9,70, water 9,92. C18H19N3HCl2H2O. Calculated Cl RS 9.69, water 9,85.P R I m m e R 2. Suspension of 28.4 g (0.1 mol) of 3-[(N-diethylamino)methyl]-1,2,3,9-tetrahed - ro-9-methyl-4H-carbazole-4-it, 12.5 g (0.15 mol) of 2-methylimidazole and 0.05 g of iodine in 250 ml of water is stirred at boiling for 5 hours, cooled, the precipitate filtered off, washed with water, dried and get to 26.9 g (90% ) technical product so pl. 207-Ino)methyl]-1,2,3,9-tetrahed - ro-9-methyl-4H-carbazole-4-it, 184,8 g (2.25 mol) of 2-methylimidazole, 0.5 g of iodine in 1860 ml of water is boiled under stirring with simultaneous distillation of the water and diethylamine. After 6 h of boiling was autogyros 240 ml of water diethylamine. After conventional treatment get 217 g (98%) of a technical product with so pl. 207-209aboutC.P R I m e R 4. Boil a solution of 6.3 g (0,0215 mol) of the hydrochloride of 3-[(N-dimethylamino)methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazole-4-it and 6.0 g (0,064 mol) of 2-methylimidazole in 65 ml of water in the presence of catalytic amounts of iodine for 2.5 h, cooled to 4aboutC, the precipitate is filtered off, washed with water, dried, yielding 5.6 g (89%) of the desired product in the form of a Foundation. To a hot solution of the base in isopropyl alcohol, add the alcohol, saturated with hydrogen chloride until acidic reaction, cooled to 0aboutC, the precipitate is filtered off and dried, yielding 4.9 g of the hydrochloride of the desired product with so pl. 175,5-176,5aboutC.P R I m e R 5. To a solution of 11.6 g (0,039 mol) of Mannich bases in 90 ml of 3% hydrochloric acid solution was added 10 g (0,121 mol) of 2-methylimidazole and catalytic amounts of iodine, refluxed for 3 h, after cooling, the precipitate is filtered off, washed with water, dried, yielding 10.4 g of the base of the target product with so gorodom, to acid reaction. Adding ether falls hydrochloride of the desired product with so pl. 180-182aboutC.Analysis. Found, C 62,10; N 6,18; N 12,10; Cl 9,96. WITH18H19N3OHClH2O. Calculated With 62,15; N 6,37; N 12,07; Cl 10,19.P R I m e R 6. To a suspension of 36 g (0.18 mol) of N-methyl-1,2-dihydro-3H-carbazole-4-it 380 ml of acetic acid under stirring add 18 g of paraform, then added dropwise 25 ml (17.5 g; 0.24 mol) of diethylamine. The reaction mass is stirred at 80aboutC for 5 h, cooled, poured onto 1 l of ice water and alkalinized 48% sodium hydroxide solution to pH 6-7. The precipitation is not included in the initial reaction carbazole (8,2 g) is filtered off. To the filtrate add alkali to a pH of 10, the suspension is filtered, the precipitate washed with water and dried. Get with 37.4 g of 3-[(N-diethylamino)methyl]-1,2,3,9-tetrahed - ro-9-methyl-4H-carbazole-4-it (73% taken or 94% reacted on carbazole). After crystallization from isopropyl alcohol so pl. 134-136aboutC.Analysis. Found, C 76,34; H Cent To 8.85; N There Is A 10.03. C18H24N2O. Calculated With 76,02; N 8,54; N 9,86.Hydrochloride, T. pl. 174-175aboutC (isopropanol).Analysis. Found, 67,46; N. Of 8.04; N 8,73; Cl 11,20. C18H24N2OHCl. Calculated With 67,38; N A 7.85; N is lots with stirring, add 2.0 g of paraform, then added dropwise 2.4 ml (2.1 g; 0,025 mol) of piperidine. The reaction mass is stirred at 80aboutC for 4 h, cooled, poured into ice water, alkalinized 48% sodium hydroxide solution to strongly alkaline and extracted with chloroform. After parki obtain 4.8 g of 3-[(N-piperidino)methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazole-4-it (81%). After crystallization from isopropyl alcohol so pl. 137-138aboutC.Analysis. Found, With 77,10; N. Of 8.37; N 9,66. C19H24N2O. Calculated With 76,99; N 8,16; N 9,45.Hydrochloride, T. pl. 177-178aboutC (isopropanol).Analysis. Found, 68,61; N. Of 7.90; N 8,51; Cl 10,53. C19H24N2OHCl. Calculated With 68,56; N EUR 7.57; N To 8.41; Cl 10,65. 1. The method of obtaining 1,2,3,9-tetrahydro-9-methyl-3-[ (2-methyl-1H-imidazol-1-yl) methyl]-4H-carbazole-4-it formula I
< / BR>or its salts or their hydrates, the interaction of 3-[(N-dialkylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4H-carbazole-4-one with 2-methylimidazole in a solvent under heating, wherein the process is conducted in the presence of catalytic amounts of iodine.2. 3-[(N-dialkylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4H-carbazole-4-ones of General formula II
< / BR>where NAlk2N(C2H5)2or N(CH2)<3-[(2-methyl-1H-imidazol-1-yl) methyl]-4H-carbazole-4-or its salts, or their hydrates.3. The method according to p. 1, characterized in that as 3-[(N-dialkylamino) methyl] -1,2,3, 9 tetrahydro-9-methyl -4 H-carbazole-4-it uses compounds of General formula II, where NAlk2NMe2NEt2N(CH2)5or their salts.4. The method according to PP.1 and 3, characterized in that as 3-[(N-dialkylamino) methyl] -1,2,3,9 tetrahydro-9 methyl-4H-carbazole 4-she used compounds of General formula II, where NAlk2NEt2in the form of free base.
where R1is a hydrogen atom or chlorine;
R2is a hydrogen atom or a C1-C2-alkyl;
R3- C1-C2-alkyl or cyclohexyl, or R2and R3together with the nitrogen atom can be morpholinyl or N-methylpiperazine balance; provided that, if R2is a hydrogen atom, R3can be1-C3-alkyl or cyclohexyl,
m = 0-1; X=Cl or Br
(1) where R1the atom of hydrogen, fluorine, chlorine or bromine, alkyl-, aralkyl-, aryl-, heteroaryl-, R3O-, (R3)2N-, R4CO - NR3-, alkylsulfonyl - NR3-, arylsulfonyl - NR3-, R3S-, R3SO, R3S2O-, or R5group, and R3is a hydrogen atom, an alkyl group containing from 1 to 6 carbon atoms, aryl, heteroaryl, kalkilya, carboxialkilnuyu or alkoxycarbonylmethyl group;
R4a hydrogen atom, alkyl or CNS group containing 1-6 carbon atoms, aryl, heteroaryl or kalkilya group containing 1-6 carbon atoms in the alkyl part;
R5azetidinone, pyrolidine, hexamethyleneimino or heptamethylnonane or piperidino group in which the methylene group in the fourth position may be substituted with oxygen, sulfenyl, sulfinil or sulfonylureas or aminogroups, which can be substituted for R3, R4CO4, alkylsulfonyl - or aryl is
RR6(I) in which groups are represented as follows: R1, R2, R3independently represent a hydrogen atom, hydroxy group, lower alkyl group, which optionally can be substituted by halogen atom, lower alkoxy group, a lower alkylthio group, aralkylated group, aryloxy group, lower alkanoyloxy group, carboxy group, lower alkoxycarbonyl group or nitro group;
R4, R5, R6represent a hydrogen atom or a lower alkyl group;
X represents an oxygen atom or a sulfur atom
(I) or pharmaceutically acceptable salt accession acids him or stereoisomeric form of the compound, where
-A1= AND2- A3= AND4- bivalent radical having the formula
-CH=CH-CH=N (a-5) or
n=1 or 2
IN - NR4or CH2< / BR>R4is hydrogen or C1-C6alkyl
L is hydrogen, C1-C6alkyl, C1-C6allyloxycarbonyl, or a radical of the formula
-Alk - R5(b-1),
-Alk - Y - R6(b - 2),
-Alk - Z1- C(=X) - Z2- R7(b-3), or
-CH2- SNON - CH2- O - R8(b-4), where R5is cyano, phenyl optionally substituted C1-C6alkyloxy; pyridinyl; 4,5-dihydro-5-oxo-1-N-tetrazolyl; 2-oxo-3-oxazolidinyl; 2,3-dihydro-2-oxo-1-N-benzimidazolyl; or bicycling radical of formula (C-4-a)
Gwhere G2- CH=CH-CH=CH-, -S-(CH2)3,- -S-(CH2)/2-, -S-CH=CH - or-CH=C(CH3)-O-;
R6- C1-C6-alkyl, pyridinyl optionally substituted by nitro; pyrimidinyl; feast R7- C1-C6-alkyl; halophenol; 1-methyl-1H-pyrrolyl; furanyl, thienyl, or aminopyrazine;
Y is O or NH;
Z1or Z2each independently NH or a direct link X-O
each Аlk independently - C1-C6alcander
(I)< / BR>(II),whereR is the residue of carboxylic acids, which are used as intermediates in obtaining antibiotics cephalosporin and penicillin ranks as the number of individual substances and mixtures
where I X = 2HCl;
II X = 0,5 (CH2COOH)2that have anti-ischemic, hypoxic and anti-arrhythmic activity and can find application in medicine for the treatment of ischemic heart disease, as well as to the intermediate product to obtain
FIELD: medicine, oncology.
SUBSTANCE: the present innovation deals with treating patients with uterine cervix cancer with relapses in parametral fiber and in case of no possibility for radical operative interference and effect of previous radiation therapy. During the 1st d of therapy one should intravenously inject 30 mg platidiam incubated for 1 h at 37 C with 150 ml autoblood, during the next 3 d comes external irradiation per 2.6 G-r. During the 5th d of therapy one should introduce the following composition into presacral space: 60 ml 0.5%-novocaine solution, 1 ml hydrocortisone suspension, 2 ml 50%-analgin solution, 1 ml 0.01%-vitamin B12 solution, 1.6 g gentamycine, 800 mg cyclophosphan, 10 mg metothrexate. These curative impacts should be repeated at mentioned sequence four times. The method enables to decrease radiation loading and toxic manifestations of anti-tumor therapy at achieving increased percent of tumor regression.
EFFECT: higher efficiency of therapy.
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):
wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.
EFFECT: valuable medicinal properties of compounds.
16 cl, 9 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new 1-(p-thienylbenzyl)-imidazoles of the formula (I): , wherein indicated residues represent the following values: R(1) means halogen atom, (C1-C4)-alkoxyl, (C1-C8)-alkoxyl wherein one carbon atom can be replaced with heteroatom oxygen atom (O); R(2) means CHO; R(3) means aryl; R(4) means hydrogen halogen atom; X means oxygen atom; Y means oxygen atom or -NH-; R(5) means (C1-C6)-alkyl; R(6) means (C1-C5)-alkyl in their any stereoisomeric forms and their mixtures taken in any ratios, and their physiologically acceptable salts. Compounds are strong agonists of angiotensin-(1-7) receptors and therefore they can be used as a drug for treatment and prophylaxis of arterial hypertension, heart hypertrophy, cardiac insufficiency, coronary diseases such as stenocardia, heart infarction, vascular restenosis after angioplasty, cardiomyopathy, endothelial dysfunction or endothelial injures, for example, as result of atherosclerosis processes, or in diabetes mellitus, and arterial and venous thrombosis also. Invention describes a pharmaceutical composition based on above said compounds and a method for their applying also.
EFFECT: valuable medicinal properties of compounds and composition.
10 cl, 19 ex
FIELD: organic chemistry and pharmaceutical compositions.
SUBSTANCE: invention relates to new 3-(5)-heteroaryl-substituted pyrazoles of formula I , tautomers or pharmaceutically acceptable salt of compounds and tautomers. In formula R1 is hydride, piperidinyl substituted with methyl, lower alkyl optionally substituted with halogen, hydroxyl, lower alkylanimo or morpholino; R2 is hydride, lower alkyl, amino, aminocarbonylamino, lower alkylaminocarbonylamino, lower alkylsulfonylamino, aminosulfonylamino, lower alkylaminosulfonylamino; Ar1 is phenyl optionally substituted with one or more independently selected halogen; HetAr2 is pyridinyl with the proviso that R2 is not amino or n-propyl when HetAr2 is pyridinyl; and HetAr2 is not 2-pyriridinyl when R2 is hydrogen or lower alkyl. Compounds of formula I have kinase p38 inhibitor activity and are useful in pharmaceutical compositions for treatment of various diseases.
EFFECT: new effective kinase p38 inhibitors.
23 cl, 6 dwg, 1 tbl, 1 ex
FIELD: veterinary science.
SUBSTANCE: a dog should be introduced with 4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole-1-il]benzene sulfonamide or its pharmaceutically acceptable salt at daily dosage ranged about 0.1-10 mg/kg body weight.
EFFECT: higher efficiency of therapy.
4 cl,262 ex, 12 tbl
FIELD: medicine, gynecology, anesthesiology.
SUBSTANCE: invention concerns to a method for carrying out the anesthesiology assistance for woman in childbirth with accompanying bronchial asthma. Method involves administration of atropine, dimedrol, analgin and clophelin. Method involves additional intravenous administration of transamine for 5-7 min. Transamine is administrated in doses 12-14 and 15-17 mg/kg in woman in childbirth with body mass 75 kg and above and 74 kg and less, respectively. Method provides enhancing quality and safety of anesthesia in this class of woman in childbirth.
EFFECT: improved assistance method.
7 tbl, 4 ex
FIELD: medicine, dermatology, chemical-pharmaceutical industry, pharmacy.
SUBSTANCE: invention relates to an antifungal gel pharmaceutical composition based on ketoconazole and clotrimazole that are derivatives of imidazole. The composition comprises ketoconazole or clotrimazole as an active component, polyethylene glycol-400 (PEG-400) as a solvent, carboxyvinyl polymer as a gel-forming agent, polyethylene glycol as a gel stabilizing agent, organic amine or inorganic bas as a regulator of pH and water taken in the definite ratio of components. The composition is prepared by dissolving active component in PEG-400, dispersing carboxyvinyl polymer in water, successive addition to dispersion propylene glycol as a stabilizing agent and regulator of pH and combination of prepared solution and gel followed by stirring the mixture up to preparing the gel composition with pH 5-7. Invention provides preparing antifungal composition with reduced adverse effect.
EFFECT: improved preparing method, valuable medicinal properties of composition.
2 cl, 1 tbl, 11 ex