The way to obtain 6,8-dimethyl-2-piperidinomethyl-2,3 - dihydrothiazolo-[2,3-f]xanthine
(57) Abstract:The invention relates to an improved process for the preparation of 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo[2,3-f] xanthine of the formula I, causing the induction of microsomal liver enzymes. 8-Romeoville subjected to interaction with 2-(N-piperidinomethyl)Tirana in the environment of dimethylformamide in the presence of sodium hydroxide at the boiling temperature of the reaction mixture. Cooled to room temperature and filtered target product with a yield of 65%, TPL238 - 240oC. the Invention allows to increase the output and to simplify the process. The compound obtained in two intragastric administration to mice-males causes a long, pronounced induction of microsomal liver enzymes, exceeding the number of parameters the effect of the reference inducer of microsomal enzymes of benzonal. 3 table. The invention relates to the field of organic chemistry, namely to a process for the preparation of 6,8-dimethyl-2-piperidinomethyl-2,3 - dihydrothiazolo [2, 3-f] xanthine of the formula I
< / BR>which can find application in medicine.A method of obtaining the compound I (lab code H-68).1. Processing 8-Romeoville caustic receive the imidazole. L III. Synthesis and pharmacological activity of derivatives of imidazo[1,2-f]xanthine / Chem.-Pharm. journal.- 1971.- N 2.- S. 22 - 26. ]. The interaction of the potassium salt of 8-Romeoville with epimyocardium for 10 h are 8-bromo-1,3-dimethyl-7-(2,3-epithiopropyl)-xanthine with the release of 10% [Khaliullin F. A., Kataev C. A., Strokin Y. C. Interaction of halogenated xanthine and benzimidazole with epimyocardium / Dept. In VINITI 22.1 1.88, n 8223.- C. 88.- 5 C.]. Reaction of 8-bromo-1,3-dimethyl-7-(2,3-epithiopropyl)xanthine with piperidine for 3 h get the connection I with the release of 93%, TPL238 - 240oC [Khaliullin F. A., Mironenkov J. C., Gilmanov A. J. and other Synthesis and study of hypoglycemic activity of derivatives of 2,3-dihydrothiazolo[2,3-f]xanthine / Chem.-Pharm. journal.- 1994.- N 9.- S. 33 - 34]. The overall yield of the target compound I is equal to 92% 0.10 0.93 = 8.6%.The disadvantages of the method are: low output (8.6%) of compound I; the complexity of the process: getting comes in three stages, the most common duration (13 h).The purpose of the invention to increase the yield and simplify the process of obtaining 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo[2,3 - f]xanthine.This goal is achieved by obtaining the compounds I by the method lies in the interaction of 8-Romeoville 2-ment of the mixture according to the scheme (see at the end of the description).The following example illustrates how the described method of obtaining.Example. A solution of 1.30 g (5 mmol) of 8-Romeoville, 0.79 g (5 mmol) of 2-(N-piperidinomethyl)Tirana and 0.28 g (5 mmol) of sodium hydroxide in 30 ml of dimethylformamide is boiled for 1 hour. Cooled to room temperature, the precipitation is filtered off, washed with water, dried.Obtain 1.09 g (65%) of compound I with TPL238 - 240oC (isopropanol), which gives no depression of the melting temperature with the sample synthesized by a known method.Found,%: C 53.92, H 6.39, N 20.75;
Calculated,%: C 53.71, H 6.31, N 20.88.An NMR spectrum1H (CDCl3, TMS): 3.31 and 3.49 (3H, s, NCH3); 2.65 (J 8.0 Hz) and 2.70 (J 7.5 Hz) (2H,2J 12.7 Hz, 2-CH2N); 4.21 (J 7.1 Hz) and 4.44 (J 7.6 Hz) (2H,2J 11.3 Hz, NCH2); 4.57 - 4.67 (1H, m, SCH); 1.35 - 1.43 (2H, m, CCH2), 1.47 - 1.61 (4H, m, C(CH2)2); 2.37-2.45 (4H, m, N(CH2)2).An NMR spectrum13With (CDCl3): 27.97 and 29.96 (6 - and 8-CH3); 49.78 (C3), 52.03 (C2), 62.17 (2-CH2); the carbon of the piperidine: 24.16 (CH2); 25.90 (2CH2); 54.86 (N(CH2)2); carbon xanthine 107.11; 151.40; 152.46; 153.72 and 156.91.An NMR spectrum taken on the instrument Bruker AM-300
Thus, the described method is Holocene, reducing the number of stages to one (in terms of the known method three stages) and reducing the processing time to 1 hour (in terms of the known method 13 hours).The effect of compound I (X-68) on the microsomal activity of the liver was studied in experiments on weinbrenner Mature mice-males using conventional test "geksenalovy sleep", which allows to indirectly estimate the functional activity of the mixed oxidase [Kasparov A. A., Sanotski I. C., 1986]. To avoid the Central influences on the duration of sleep (psychoactive and gipnosedativnogo effects) investigated the connection test "baritovogo sleep" [hazura centuries, Saratikov A. C., 1977].As the comparison drug selected benzonal (1-benzoyl-5 - ethyl-5-fenilbarbiturovaya acid), which, along with phenobarbital is the reference inducer of microsomal enzymes, but significantly exceeds its ability to induce microsomal liver enzymes, and has a less pronounced effect gipnosedativny [Mashkovsky M. D., 1997, Navajeevan Etc., 1998].Compounds were diluted in 2% starch suspension was administered intragastrically twice with an interval of 24 hours, a day after the last injection PR is 2">Acute toxicity was determined after intragastric administration according to the method of J. Litchfield and F. Wilcoxon modification Prozorovsky C. B., 1962. Survival of animals was observed during the first day. LD50X-68 = 816 (734-892) mg/kg, which corresponds to 3 hazard class (moderately hazardous). Benzonal belongs to the same class of hazardous chemical substances LD50= 192 (162-223) mg/kgX-68 in a wide range of doses caused a statistically significant reduction in the duration of geksenalovy sleep, a clear effect was observed even at a dose of 0.0005 mg/kg, which is 1/16324000 part from LD50the studied compounds (table. 1). As the table shows, the dependence of the effect of the dose of X-68 was not observed, which is not possible using conventional methods, to calculate the average effective dose and, consequently, therapeutic index of the compound.Shortening geksenalovy sleep observed after double injection X-68, is not associated with effects on the Central nervous system, because the duration baritovogo sleep (barbitala - trudnootdelyaemoy inert compound, almost entirely, to 95%, output by the kidney in unchanged form) when a similar scheme and the doses did not differ from the values of the control group.Introduction equitations the project was more pronounced and was superior to any of benzonal. So, in 1/100 of DL50benzonal had no significant effect, whereas X-68 caused shortening the duration geksenalovy sleep 70%; and in 1/20 from DL50the stimulation index of benzonal was 42%, X-68 - 89% (table.2).We studied the connection, unlike benzonal, has a significantly longer inducing effect (table. 2). Shortening geksenalovy sleep, as the dose of 1/100 DL50(8 mg/kg) and a dose of 1/20 DL50(41 mg/kg) significantly and 8 days after injection, whereas the duration of the effect of benzene (1/20 DL50) no more than 2 days, and the dose of 1/100 DL50without being inducing, at 4-6 days after the last injection causes inhibition of liver microsomal enzymes (table. 3). When using benzonal in the dose that causes a clear induction of microsomal enzymes and, according to literature data, the most frequently used (35 mg/kg) [Navajeevan Etc., 1998], the effect is observed only 4 days (table. 3).Induction of microsomal enzymes under the influence of X-68 confirmed in experiments directly quantify the level of cytochrome P-450 in rat liver by the method of Omura T. and Sato, R., 1962. The level of cytochrome P 450 after 2-fold intragastric administration X-68 (35 mg/kg) was significantly increased by 32% (X-68 - 657.36 dusiruumis effect, significantly superior benzonal therapeutic breadth, duration of action and more favorably low toxicity. The way to obtain 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo [2,3-f]xanthine of the formula
< / BR>including the use of 8-Romeoville, characterized in that the 8-Romeoville subjected to interaction with 2-(N-piperidinomethyl)Tirana in the environment of dimethylformamide in the presence of sodium hydroxide at the boiling temperature of the reaction mixture.
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to a new substance eliciting an antiviral and antibacterial activity that is based on derivatives of 2,8-dithioxo-1H-pyrano[2,3-d;6,5-d']dipyrimidine and their 10-aza-analogues. This substance comprises derivative of indicated group of the general formula: A1*M: wherein X is taken among the group: oxygen atom (O), NH, N-alkyl; R1 is taken among the group: hydrogen atom (H), OH, chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, NH-Ar, N-(alkyl)2, SH, S-alkyl; R2 is taken among the group: unsubstituted or substituted phenyl, naphthyl, thienyl; R3 is taken among the group: hydrogen atom (H), chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, S-dihydroxypyrimidinyl; M is absent or taken among the group: cation Na, K, Li, ammonium or any other pharmacologically acceptable cation; or complex of pharmacologically acceptable cation (see above) with anion of one of derivatives of A1 (variants R1-R3 are given above). Invention provides preparing new compounds eliciting an antiviral and antibacterial activity.
EFFECT: valuable medicinal properties of substance.
17 cl, 7 tbl, 16 ex
FIELD: organic chemistry, pharmacy.
SUBSTANCE: invention relates to a new derivative of bicyclic heteroaromatic compound of the general formula (I) or its pharmaceutically acceptable salt eliciting agonistic activity with respect to luteinizing hormone (LH). Compounds can be used for preparing medicinal agents for control ability for conception. In compounds of the general formula (I) R1 represents R7 wherein R7 represents (C6-C10)-aryl optionally substituted with halogen atom at ortho- and/or meta-position; NHR8, OR8 wherein R8 means (C1-C8)-alkyl that can be substituted with halogen atom, (C1-C8)-alkylcarbonyl, (C1-C8)-alkylcarbonyloxy-group, phenyl, (C6-C10)-arylcarbonylamino-group, 5-methyl-2-phenylimidazol-4-yl, (C6)-heterocycloalkyl wherein 1-2 heteroatoms are taken among nitrogen and oxygen atoms, ethyloxycarbonylmethylthio-(C1-C4)-alkoxy-group, amino-group, (C6-C7)-heteroaryl; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R2 represents (C1-C8)-alkyl or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R3 represents (C1-C8)-alkyl possibly substituted with (C6-C14)-aryl possibly substituted with halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, mono- or tri-(C6-C10)-cycloalkyl, (C6-C10)-aryl, (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; (C5-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; (C3-C8)-cycloalkyl, (C2-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; X represents sulfur atom (S) or N(R4); Y represents nitrogen atom (N); R4 represents (C1-C8)-alkyl, phenyl-(C1-C8)-alkyl; or X represents sulfur atom (S), and Y represents CH; Z represents NH2 or OH; A represents sulfur (S), oxygen atom (O) or a bond. Also, invention relates to a pharmaceutical composition.
EFFECT: valuable properties of compounds and composition.
14 cl, 1 tbl, 119 ex
FIELD: organic chemistry, pharmaceutical composition.
SUBSTANCE: compounds satisfying the formula I 1 are disclosed, wherein each R1 and R2 independently to one another are H, OH, OA or Hal; or R1 and R2 together are -O-CH2-O- or -O-CH2-CH2-O-; R3 and R4 are A-group; X - group monosubstituted with R8, R5 or R7; R5 is linear or branched C1-C10-alkylene, wherein one or two CH2-groups may be substituted with oxygen atom; R7 is phenyl or phenylmethyl; R8 is COOH, COOA, CONH2, CONHA, CON(A)2 or CN; F is C1-C6-alkyl; and Hal is F, Cl, Br, or I, as well as physiologically acceptable salts or solvates thereof. Methods for production of claimed compounds (I) and pharmaceutical composition containing the same also are disclosed. Said compounds and pharmaceutical composition have activity as phosphodiesterase V inhibitors and are useful in treatment of cardiovascular diseases and potency disorders.
EFFECT: pharmaceutically applicable compounds and compositions.
7 cl, 16 ex
FIELD: organic chemistry and medicine.
SUBSTANCE: invention relates to new imidazole derivatives of general formula I useful as adenosine A3-receptor modulators, as well as to method for cancer treatment and detection of tumor cells using claimed derivatives.
EFFECT: compounds for treatment and diagnosis of improved activity.
13 cl, 4 dwg, 19 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new azaheterocycles comprising fragment of piperidin-2-yl- of the general formula (1):
as separate enantiomers or mixture of enantiomers, or their pharmaceutically acceptable salts, oxides or hydrates. In compounds of the formula (1) R1 represents hydrogen atom, inert substitute or NH-protecting substitute; W represents optionally substituted azaheterocycle, such as: pyridin-3-yl, pyrazolo[1,5-a]pyridin-6-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-7-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-9-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-8-yl or [1,8]naphthyridin-3-yl. Compounds elicit activity with respect to nicotine receptors and can be used in pharmaceutical industry. Also, invention relates to the focused library for search of physiologically active compound-leaders, and to pharmaceutical compositions based on new compounds of the formula (1).
EFFECT: valuable medicinal and pharmacological properties of compounds.
9 cl, 1 tbl, 15 sch, 22 ex
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):
. 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: organic chemistry, medicine, biochemistry, pharmacy.
SUBSTANCE: invention relates to 2-aminomethylthieno[2,3-d]pyrimidines of the general formula (I): wherein R1 and R2 in common with C-atoms with which they are bound form 5-7-membered monounsubstituted cycloalkenyl ring; R3 and R4 are similar or different and represent independently of one another (C1-C8)-alkoxy-group or halogen atom; R5 and R6 can be similar or different and represent independently of one another hydrogen atom, linear or branched (C1-C8)-alkyl group that can be substituted with one or more hydroxyl, (C1-C8)-alkoxy-group, amine, mono-(C1-C8-alkyl)-amine or di-(C1-C8-alkyl)-amine groups, or in common with nitrogen atom to which they are bound form a heterocyclic ring that comprises optionally one or more additional nitrogen atoms and substituted with one or more hydroxyl, (C1-C8)-alkoxy- or (C1-C8)-alkylol groups. Compounds elicit the inhibitory effect with respect to activity of phosphodiesterase V and can be used in treatment of cardiovascular system states and in disturbance in the potency injury. Also, invention describes a medicinal preparation based on compounds said, a method for its preparing and a method for preparing compounds.
EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds.
6 cl, 1 tbl, 16 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:
wherein Ag represents (1) group of the formula:
; (2) group represented by the formula:
or ; (3) group represented by the formula:
; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:
; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.
EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.
40 cl, 51 tbl, 741 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to novel substituted 2-aryl-3-(heteroaryl)imidazo[1,2-a]-pyrimidines of the formula (I):
or to their pharmaceutically acceptable salts wherein: (a) R1 is taken among the group consisting of -NH2, C1-5-alkylamino-, di-C1-5-alkylamino-, phenylmethylamino-group; (b) Y is taken among the group consisting of hydrogen atom (H), halogen atom, piperidine, OR4, SR4, -SO2CH3, NHR4 and NR4R5 wherein R4 and R5 are taken independently among hydrogen atom (H), α-alkylphenyl-C1-5-alkyl, linear or branched alkyl substituted optionally with C3-5-carbocycle, phenyl or substituted phenyl wherein indicated phenyl can be substituted with one or some substituted taken among C1-5-alkoxy-group; (c) R2 represents from one to five members taken independently among the group including hydrogen atom (H), halogen atom, trifluoromethyl; (d) R3 represents hydrogen atom (H), or radicals R3 taken in common form aromatic ring; (e) X represents nitrogen atom (N) or -CH. Also, invention relates to methods for preparing indicated compounds and to a method for treatment based on these compounds. Invention provides preparing novel compounds that can be used in relief states by reducing the level of inflammatory cytokines, for example, the indicated state represents proliferative (rheumatic) arthritis.
EFFECT: valuable medicinal properties of compounds and compositions.
40 cl, 1 tbl, 4 ex