Salt-10--aryloxyalkyl-2,3,4,10-tetrahydropyrimido[1,2-a] benzimidazole with a local anesthetic action

 

The invention relates to new derivatives 10H-2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazole, namely water-soluble salts 10--aryloxyalkyl-2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazole of General formula

where Ar=C6H5With6H4R, where R = alkoxycarbonyl or carboxypropyl in o-, m - and p-positions of the benzene ring, n=1-6, X=C1 or Br, with a local anesthetic action in case of infiltration, wiring and spinal anaesthesia. 1 N. C.p. f-crystals, 4 PL.

The invention relates to new derivatives 10H-2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazole, namely water-soluble salts of 10-with-aryloxyalkyl-2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazole of the formula I

where AG=C6H5C6H4R, where R = alkoxycarbonyl or carboxypropyl in o-, m - and p-positions of the benzene ring, n=1-6, X = CL or Br, with local anesthetic effects at infiltration, wiring and spinal anaesthesia.

One of the most active and long-acting local anesthetics is the drug marcain (bupivacaine). He finds Chi-0,5%) (M. D. Mashkovsky. Medicines, 15th ed., Rev. and more., M.: Medicine, 1998, H. 1, S. 378), spinal, epidural, caudal, intra-articular anesthesia, when conducting paracervical and retro-bulbar analgesia (for example, R. P. Alston. Spinal anaesthisis with 0,5% bupivacaine 3 ml: Comparison of plain and hyperbarric solutions administered to seated patients. Brit. J. Anatsth., 1988, vol. 61, No. 4, p. 385-389; A. R. Wolf, R. D. Valley, D. W. Fear et al. Bupivacaine for caudal analgesia in infants and childrens the optimal effective concentration. Anaesthesiology, 1988, vol. 69, No. 1, p. 101-105). It should be noted that marcain not only highly active but also very toxic anesthetic (N. B. Raciborska. Mestnoanesteziruyuschie properties of some derivatives of piperidine and indole. Abstract. dis. Kida. the honey. Sciences. Rostov-on-don, 1991; J. Kambam, B. Mets, R. Hickman et al. Comparative systemic toxicity ofintravenously infused bupivacaine (B) cocaine (C) and lidocaine (L) in pigs: [Abstr.] Int. Anaesth. Res. S.66thCongr., San Francisco, Calif., March 13-17, 1992; Anaesth. And The Play Mode Display., 1992, vol. 74, No. 25, p. 87), which requires special attention when used in practical medicine. With the proper doses, the drug provides a strong and long-lasting anesthesia. With an increase in their possible convulsions, depression of cardiac activity (until the heart stops) (M. D. Mashkovsky, 1998). In addition, marcain can cause generalized rash, angioedema, laryngeal stridor, bronchospasm (H. GacI, the-2,3,4,10-tetrahydropyrimido[1,2-a]-benzimidazole are not known compounds, with local anesthetic effect.

The most similar structure among the derivatives of 10H-2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazole salts are 10-dialkylaminomethyl-2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazole, exhibiting hypoglycemic and antiplatelet properties (V. A. Anisimova, M. V. Levchenko, T. B. Korochma et al. New derives du benzimidazole, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. Fr.Pat.2691462(1995); Bull., 95/23. EP 0571253).

The technical result of the invention are new compounds in series 1 HE-2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazole, showing unknown for this class connection local anesthetic action, more effective than the known local anesthetics.

The technical result is achieved by the compounds I, the synthesis of which lies in the interaction of N-unsubstituted 1H-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole in neutral conditions with 1--aryloxy-2-haloalkanes in the environment of a solvent or without (method A) and by substitution of the halogen atom in the 10--halogenated-2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazole on alloctype under the action of a reaction of alkali metals (method B).

Example 1. Hydrochloride 10--phenoxyethyl)-2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazole(I, AG = C6H5n=2, X=CL; RU-1151).

Method A. a Mixture of 1.73 g (10 mmol) of 1H-1,2,3,4-tetrahydropyrimido[ 1,2-a]benzimidazole and 2.0 ml (15 mmol) of-phenoxyethylamine in 5 ml of dimethylformamide boiled for 3.5 hours. The next day, the precipitation is filtered off, thoroughly washed with acetone, obtaining 3.2 g (94%) hygroscopic hydrochloride. The latter is crystallized from isopropyl alcohol and dried at 105S. T. pl. 206-207C.

Found, %: C 65,5; 6,2; C1 10,6; N 12,5.

C18H19N30·HCl.

Calculated, %: C,6; N6,1; CL 10,8; N 12,7.

IR-spectrum (vaseline oil), cm-1: 1660 (C= N).

Range PMR (300 MHz, l3),, M. D.: of 2.25 (2H, m, 3-CH2, of 3.75 (2H, m, 4-CH2), 4,06 (2H, m, 2-CH2), 4,50 (2H, t, CH2O), is 4.93 (2H, t, NCH2), is 6.78 (2H, d, 2’- and 6’-H, J=7.9 Hz), make 6.90 (1H, t, 4’-H, J=7,3 Hz), 7,19 (1H, d, 6-H, J=8.5 Hz), 7,20 (2H, t, 3’- and 5’-H), 7,31 (1H, t, 7-H), 7,37 (1H, m, 8-H), EUR 7.57 (1H, d, 9-H,.7 =7,6 Hz), 11,64(1H, N+N).

Method b In the mix a solution of 1.73 g (10 mmol) of 1H-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole in 4 ml of dimethylformamide, obtained by heating, make 1 ml (15 mytablet overnight at low temperature (5-7C). The precipitation of the hydrochloride 10-(-hydroxyethyl)-2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazole is filtered off, thoroughly washed with acetone. The output of 2.16 -2,3 g (85,0-91,0%). So pl. 238 -240C (decomp., from 2-propanol).

Found, %: C 56,7; N6,5; CL 14,1; N 16,6.

C12H15N3O HCl.

Calculated, %: From 56.8; H 6,4; 14,0 Cl; N Is 16.6.

IR-spectrum (vaseline oil), cm-1: 1660 (C=N).

Range PMR (300 MHz, DMSO-d6),memorial plaques: 2,13 (2H, kV, 3-CH2, J = 5.8 Hz), 3,48 of 3.56 (2H, m, 2-CH2), 3,71 (2H, t, CH2Oh, J = 5,1 Hz), 4,11 (2H, t, 4-CH2, J = 5,9 Hz), 4,22 (2H, t, NCH2, 7-5,1 Hz), of 5.05 (1H, broad s, OH), 7,27 -7,34 (2H, m, arene.N), 7,47 -7,59 (2H, m, arene.N), at 9.53 (1H, s, N+N).

Base-10-(-hydroxyethyl)-2,3,4,10-tetrahydropyrimido[1,2-a]-benzimidazole - allocate processing 22% aqueous solution of NH4OH the corresponding hydrochloride, the synthesis of which is described above, and extracted with chloroform. For purification, the extract is passed through a layer of aluminum oxide, elwira the basis of chloroform. The residue after evaporation of the solvent from the eluate is recrystallized from ethanol or acetonitrile. So pl. 155-156C.

Found,%: From 66.5; H 7,0; N 19,1. C12H15N3O.

10--hydroxyethylamino in 10-15 ml of dry chloroform was added 0.7 ml (15 mmol) of chloride tonila, and then boil it for 4-5 hours, controlling the chlorination process using TLC (Al2About3, eluent - l3, Rfinitial 0,1, Rfend - of 0.55). The chloroform is evaporated, the residue is treated with petroleum ether or hexane, waving at the latest together with excess chloride tiomila. Output hydrochloride 10-(-chloroethyl)-2,3,4,10-tetrahydropyrimido [ 1,2-a] benzimidazole quantitative.

So pl. 221-223C.

Found, %: C Of 52.8; H 5,6; C1 25,9; N 15,6.

C12H14ClN3HCl.

Calculated, %: C53,0; H5,6; Cl 26,0; N 15,4.

Salt is introduced to further transformation without further purification or transferred using ammonia solution into the base, which is also used in reactions with different substituted phenols. The output of 95-98%. So pl. 69-70(From acetonitrile).

Found, %: C 61,3; N6,1; Cl 14,7; N 18,1.

C12H14ClN3.

Calculated, %: From 61.2; H 6,0; Cl 14,9; N 17,9.

To a solution of 0.2 g (about 2 mmol) of phenol and 0.12 g of KOH in 7-10 ml of methanol is added 2 mmol of 10-chloroethylamines and boil the mixture until complete reaction (control - TLC: the complete disappearance of the stain is alance-Al2About3, elwira chloroform and collecting the first fraction with Rf0,22. Output 10-(-phenoxyethyl)-2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazole 74,2%. So pl. 98-99With (isooctane).

Found, %: With 73.6; H 6,5; N14,5.

C18H19N3O.

Calculated, %: C,7; N. Of 6.5; N 14,3.

The resulting base can serve as the basis for any of the salts with pharmaceutically acceptable acids.

Hydrochloride, identical to that described in method A, obtained by acidification of a solution of the base in alcohol or acetone saturated solution of Hcl in isopropyl alcohol or ether.

Example 2. The hydrobromide 10-(-phenoxyethyl)-2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazole (I, AG = C6H5, X = Br). A mixture of 1.73 g (10 mmol) of 1H-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole and 2.4 g (20 mmol) of-phenoxyethylamine (M. C. Rubtsov, A. G. Bizikov. Synthetic chemical-pharmaceutical preparations, M.: Medicine, 1971, S. 86) in 5 ml of dimethylformamide or any other solvent boil for 3-5 hours (control reaction - TLC). Cool deposited precipitate is filtered off, washed with acetone, getting a 3.2-3.4 g (85,5 - 90.7 percent) hydrobromide. Cleanse salt per the ri acidification acetone or alcohol solution of 10-(-phenoxyethyl)-2,3,4,10-tetrahydropyrimido[1,2-a]-benzimidazole conc. NVG.

Example 3. The hydrobromide 10-[-(4-methoxycarbonylbenzyl)ethyl]-2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazole (I, AG = C6H4SOON3, X = Br). A mixture of 0.87 g (5 mmol) of 1H-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole and 1.55 g (6 mmol) of methyl ester of 4-(-bromoethoxy)benzoic acid (P. M. Kochergin, R. M. Paley, L. C. Balandin and other Chem.-Pharm.J., 1995, No. 2, S. 56-57), triturated and heated at 150C (bath temperature) for 30 minutes and Then the melt is cooled and treated with acetone, the crystalline precipitate is filtered off, washed with acetone. The output of the chromatographic pure hydrobromide 1.88 g (87.3 per cent). So pl. 222-223(From acetonitrile).

Found, %: C Of 55.5; H 5,2; Bi-18,8; N 9,9.

C20H21N3O3HBr.

Calculated, %: From 55.6; H 5,1; Br 18,5; N 9,7.

IR-spectrum (vaseline.oil), cm-1: 1680 (C=N), 1720 (C=O).

Range PMR (300 MHz, Dl3),, M. D.: 2,28 (2H, m, 3-CH2), of 3.77 (2H, t, 4-CH2), of 3.84 (3H, s, CH2), 4.09 to (2N, t, 2-CH2J-6,1 Hz), 4,55 (2H, t, och2, J = 4,7 Hz), is 4.93 (2H, t, NCH2, J = 4.4 Hz), for 6.81 (2H, d, 2’,6’-H, J = 8,8 Hz), 7.23 percent (1H, d, 6-H, J = 7,3 Hz), 7,31 -7,41 (2H, the D/chr/946.gif">-(4-carboxyphenoxy)ethyl]-2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazole (I, AG = C6H4COOH, X = Br)

obtained by the interaction of equimolar amounts 1H-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole and 4-(p-bromoethoxy)benzoic acid (P. M. Kochergin and others, 1995) in dimethylformamide (yield 78%) or saponification methoxycarbonyl group 4-methoxycarbonylmethylene pyrimido[1,2-a]benzimidazole (see example 3). Saponification carried out as follows: 0,86 g (2 mmol) 4-methoxycarbonylamino, 10 ml glacial acetic acid and 2 ml conc. NVG boil for 3 hours. The resulting solution was cooled and left overnight in the refrigerator. The precipitation is filtered off, washed with acetone. Yield 0.71 g (84,9%). So pl. 260-261C (from ethanol).

Found, %: From 54.6; H 4,9; Br 18,9; N11,1.

With19H19N3About3·HBr.

Calculated, %: 54.6; H 4,8; Br 19,1; N 10,0.

IR-spectrum (vaseline oil), cm-1: 1673 (C=N), 1693 (C=O), 3285-3605 (HE).

Range PMR (300 MHz, DMSO-d6),, M. D.: of 2.15 (2H, m, 3-CH2), of 3.56 (2H, t, 4-CH2, J = 5.3 Hz), 4,10 (2H, m, 2-CH2, J = 5.6 Hz), 4,37 (2H, t, CH2Oh, J = 4,7 Hz), 4,58 (2H, t, NCH2, J = 4,7 Hz) 6,91 (2H, d, 2,6-H, J = 8,80 Hz), 7,34 (2H, m, 7,8-H), 7.51 (1H, d, 6-H, J = 8,8 Hz), 7,66 (1H, d, 9-H, J = 8,80 Hz), to 7.84 (2H, d, 3’,5’-H, on the skin of Guinea pigs (Bulbring E., Wajda J. Biologicak comparison of local anaesthetica //J. Pharmacol. and exp. therap. -1945. -Vol. 85, No. 1. -P. 78-84).

Conduction anesthesia was studied in experiments on the nerves of rats tails (Ignatov Y. D., Vasiliev, Y. N., Beetles C. N. and other Methodological guidelines for experimental study of local anaesthetics. - M.: the USSR Ministry of health, 1990. - 49 S.).

Spinal anesthesia was investigated in experiments on rats (Yu D. Ignatov et al., 1990), catheterized subarachnoid space (Hwang A. A. Analgesic effect of clonidine when injected into the brain ventricles and under the sheath of the spinal cord //Pharmacol. and toxicol. - 1987. No. 2. - S. 26 -29; Yaksh T. L., Rudy T. A. Chronic catheterisation of the spinal subarachnoid space //Physiol. Behav. -1976. - Vol. 17. - P. 1031 -1036).

The analgesic effects of substances in terms of wiring and spinal anaesthesia was assessed in a standard altimetrical test tail-flick (Grossman M. L., Basbaum A. I., Fields, H. L. Afferent and efferent connections of the rat tail flick reflex (a model used to analyze pain control mechanisms) //J. Tech. Neurol. -1982. -Vol. 206. -P. 9 -16; Hahn, E. E. Testing and evaluation of opiate analgesics and antagonists //Meth. Find. Exp. Clin. Pharmacol. -1985. -Vol. 7. -P. 373-381).

Local irritation and damaging effect was studied in experiments on the skin of rats (Yu D. Ignatov et al., 1990).

Acute toxicity was investigated [determined the median lethal (lethal) dose-LD50] in the experiments is the study of curves lethality //Pharmacol. and toxicol. -1962. -So 25, No. 1.-S. 115-119).

As a matter of comparison was taken marcain (bupivacaine).

Statistical processing of data carried in graded form, conducted by M. L. Belenky (Belenky, M. L. elements of a quantitative evaluation of the pharmacological effect. -Leningrad, 1963. -152 C.), in an alternative [define LD50medium effective concentration (EC50), the borders of their confidence interval, therapeutic index, or the breadth of therapeutic action (LD50/EU50)] - Century B. the Prozorovsky (1962) and J. D. Ignatov et al. (1990).

When infiltration anesthesia in experiments on Guinea pigs minimum anesthetic concentration for RU-1151 and marcaine is 0,0156%. However, it should be noted that in this concentration index Bullring and Wade for RU-1151 equal 13,0, whereas for marcaine is 6.4. With increasing concentration of the solutions to 0,0312 and 0.0625% indexes Bullring and Wade for RU-1151 respectively amounted to 26.2 and 36,0, whereas for marcaine - 10,8 and 32.6 (PL. 1).

Mapping EC50showed (table. 2), RU-1151 in 1.70 times more active than marcain. Thus, therapeutic index (the breadth of therapeutic action) RU-1151 at 1.34 exceeds marcain.

In outcome 1, and marcain in 5 min after introducing them to the root of the tail is called a full (100%) anesthesia, whereas the duration of the anesthetic effect of the ROUX-1151 1.89 and 2,60 therefore more important than marcain.

In terms of spinal anaesthesia in experiments on rats it has been shown (PL. 4) that in the 0.25 and 0.5% solutions of RU-1151, like Marciano, induces full (100%) analgesia after 5 min after subarachnoid injection, whereas the duration of anesthetic action is RU-1151 in 3.17 and 2.39 times respectively exceeds marcain.

Connection ROUX-1151 0.5, 1 and 2% solutions of irritating and damaging effect on the skin of rats.

Thus, the substance RU-1151 when infiltration, conduction and methods spinal anesthesia significantly exceeds marcain as local anaesthetic activity and the breadth of therapeutic action.

On the basis of the connection ROUX-1151 possible the creation of local anesthetic drugs for infiltration, wiring and spinal anaesthesia.

Claims

Salt 10--aryloxyalkyl-2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazole observer or carboxypropyl in o, m - and p-positions of the benzene ring;

n=1-6;

X is Cl or Br.

 

Same patents:

-aryloxyalkyl-2,3-dihydroimidazo[1,2-a] benzimidazole with a local anesthetic action" target="_blank">

The invention relates to new derivatives N-2,3-dihydroimidazo[1,2-a]benzimidazole, namely water-soluble salts of 9--aryloxyalkyl-N-2,3-dihydroimidazo[1,2-a]benzimidazole of the formula I

where Ar = C6H5WITH6H4R, where R = alkoxycarbonyl or carboxypropyl in o-, m - and p-positions of the benzene ring, n = 1-6, X=Cl or Br, with local anesthetic effects at the surface (terminal) anesthesia

The invention relates to new triazolo[4,5-d]pyrimidine compounds of General formula (I) or their pharmaceutically acceptable salts, which have the effect of P2T-antagonists, in particular, show inhibitory platelet aggregation activity

The invention relates to new compounds of General formulas I, II, III

< / BR>
or their pharmaceutically acceptable salts, in which the dotted lines indicate optional double bonds; A is-CR7or N; - - NR1R2, -CR1R2R11, -C(= CR2R12R1, -NHCHR1R2, -ОСHR1R2, -SCHR1R2, -CHR2OR12,

-CHR2SR12, -C(S)R2or-C(O)R2N-ethyl-2,2,2-triptorelin; G is oxygen, sulfur, NH, NH3hydrogen, methoxy, ethoxy, triptoreline, methyl, ethyl, dimethoxy, NH2, NHCH3N(CH3)2or trifluoromethyl; Y Is N; Z is NH, O, S, -N(C1-C2alkyl) or-C(R13R14), where R13and R14independently of one another represent hydrogen, trifluoromethyl or methyl, or one of the elements of R13and R14is cyano and the other is hydrogen or stands; R1- C1-C6alkyl which may be optionally substituted by one or two substituents R8independently from each other selected from the group comprising hydroxy, fluorine, chlorine, bromine, iodine, CF3C1-C4alkoxy, -O-CO-(C1-C4alkyl), where (C1-C2- C1-C12alkyl, aryl or -(C1-C4alkylene)aryl, where aryl is phenyl, naphthyl; R3is methyl, ethyl, fluorine, chlorine, bromine, iodine, cyano, methoxy, OCF3, methylthio, methylsulphonyl, CH2HE or CH2OCH3; R4is hydrogen, C1-C4alkyl, fluorine, chlorine, bromine, iodine, C1-C4alkoxy, triptoreline, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CF3, amino, nitro, -NH(C1-C4alkyl), -N(CH3)2, -NHCOCH3, -NHCONHCH3, hydroxy, -CO(C1-C4alkyl), -Cho, COOH, cyano, or-COO(C1-C4alkyl), where C1-C4the alkyl may be substituted by one Deputy chosen from the group comprising hydroxy, amino, -NHCOCH3, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, fluorine, chlorine, cyano, nitro; R5is phenyl, naphthyl, pyridyl, pyrimidyl, where each of the above groups R5substituted with one to three substituents that are independently from each other selected from fluorine, chlorine, C1-C6the alkyl or C1-C6alkoxyl, or one Deputy chosen from the group comprising hydroxy, iodine, bromine, formyl, cyano, nitro, trifluoromethyl, amino, -(C1-C6these groups of R5may be optionally substituted with one hydroxy-group; R6is hydrogen or C1-C6alkyl; R7is hydrogen, methyl; R11is hydrogen, hydroxy, fluorine or methoxy; R12is hydrogen or C1-C4alkyl, and R16and R17independently of one another represent hydrogen, hydroxy, methyl, ethyl, methoxy or ethoxy, except that both R16and R17cannot both be methoxy or ethoxy; or R16and R17together form oxo (=O) group; provided that if G is an atom of oxygen, sulfur, NH or NCH3he is joined by a double bond to a five-membered ring of the formula III, and further provided that R6is absent when the nitrogen atom to which it is linked, is attached by a double bond to an adjacent carbon atom in the ring

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The invention relates to new derivatives pyrazolopyrimidinones General formula (1) or their pharmaceutically acceptable salts that may be used in the treatment of impotence, and method of production thereof

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The invention relates to the field of organic chemistry, namely to new bicyclic derivative

The invention relates to new derivatives of benzothiadiazole, benzoxazoles and benzodiazines formula I in free base form or in the form of a pharmaceutically acceptable acid salt additive that can be used as an anxiolytic drug in the treatment of any condition, which is associated with increased endogenous levels of CRF or in which violated the regulation of the hPa system (hypothalamic - pituitary), or various diseases that are caused by CRF1or the manifestation of which contributes CRF1such as arthritis, asthma, allergies, anxiety, depression, etc

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes a method for preparing compounds of the formula (I):

wherein each R1, R2, R3 means independently of one another (C-C6)-alkyl; R can represent also pyridyl; R4 and R5 in common with nitrogen atoms to which they are joined form unsaturated 5-8-membered heterocyclic ring that can be broken by oxygen atom; G means hydrogen atom. Method involves interaction of compound of the formula (II):

wherein R1, R2 and R3 have above given values; R6 is a group RR9N-; R7 is a group R10R11N-; each among R8, R, R10 and R11 means independently of one another hydrogen atom or (C1-C6)-alkyl in inert organic solvent being optionally with the presence of a base with compound of the formula (IV) ,

(IVa)

or (IVb) ,

wherein R4 and R have above given values; H x Hal means hydrogen halide. The prepared compound of the formula (I) wherein G represents ammonium cation is converted to the corresponding compound of the formula (I) by treatment with Brensted's acid wherein G represents hydrogen atom. Also, invention describes compound of the formula (II) wherein R1, R2, R3, R6 and R7 have above indicated values.

EFFECT: improved preparing method.

9 cl, 12 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

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

20 cl, 6 tbl, 192 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.

SUBSTANCE: invention relates to improved synthesis method of pyrlindone hydrochloride having formula (I) 1. Method features intramolecular cyclization of 6-methyl-1-(2-chloroethyl-imino)-1,2,3,4-tetrahydrocarbazole hydrochloride of formula IV 2 at 80°-140°C with alkali agent in presence of phase transfer catalyst to provide 1,2,5,6-tetrahydro-8-methyl-pyrazine[3,2,1-j,k]-4H-carbazole of formula VI 3 followed by reduction at 80°-120°C. Method of present invention makes in possible to produce compound of formula I with yield nearly 70 % and purity more than 99 %.

EFFECT: method of high yield with reduced amount of alkali agent and phase transfer catalyst.

7 cl, 2 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to novel pyrasolbenzodiazepines of formula I 1 (in formula R1 is hydrogen, -NO2, -CN, halogen, -OR5, -COOR7, -CONR8R9, -NR10R11, NHCOR12, NHSO2R13; each R2 and R4 independently of one another are hydrogen, halogen, -NO2, -CF3; R3 is hydpegen, C3-C8-cycloalkyl, aryl, in particular C6-C10-aromatic group having 1 or 2 rings, 5-10-membered heteroaryl, having 1 or 2 rings and1-3 heteroatoms, selected from N, O, and S, -COOR7, CN, C2-C6-alkenyl, -CONR8R9 or C1-C6-alkyl optionally substituted with OR9-group, F or aryl as mentioned above; R5 is C1-C6-alkyl; R7 is hydrogen or C1-C6-alkyl; each independently of one another are hydrogen or C1-C6-alkyl optionally substituted with hydroxyl or NH2, or alternatively R8 and R9 together form morpholino group; each R10,R11 and R12 independently of one another are hydrogen or C1-C6-alkyl; R13 is C1-C6-alkyl optionally substituted with halogen or -NR14R15; each R14 and R15 independently of one another are hydrogen or C1-C6-alkyl optionally substituted with halogen; or alternatively -NR14R15 is morpholino group) or pharmaceutically acceptable salts thereof, as well as to certain pyrasolbenzodiazepine derivatives, thiolactam intermediates for production of compound (I) and pharmaceutical compositions containing the same. Compound and pharmaceutical composition of present invention are cycline-dependent kinase (CDK2) inhibitors and antiproliferation agents used in treatment or controlling disorders associated with cell proliferation, in particular breast, colon, lung and/or prostate tumors.

EFFECT: new antiproliferation agents.

20 cl, 12 tbl, 8 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, medicine, gastroenterology, pharmacy.

SUBSTANCE: invention relates to a pyrrolopyridazine derivative of the following formula: wherein R1 represents (C3-C7)-cycloalkyl-(C1-C6)-alkyl group that can be substituted optionally with (C1-C6)-alkyl group; R2 represents (C1-C6)-alkyl group; R3 represents hydroxymethyl group, (C2-C6)-aliphatic acyloxymethyl group, (C6-C10)-arylcarbonyloxymethyl group, (C1-C6)-alkoxycarbonyloxymethyl group, formyl group, carboxyl group, (C1-C6)-alkoxycarbonyl group or (C6-C10)-aryloxycarbonyl group; R4 represents (C6-C10)-aryl group that can be substituted optionally with substitutes taken among the group consisting of (C1-C6)-alkyl groups, halogen-(C1-C6)-alkyl groups, (C1-C6)-alkoxy-groups, halogen-(C1-C6)-alkoxy-groups and halogen atoms; A represents imino-group, oxygen or sulfur atom, or its pharmaceutically acceptable salt. Pyrrolopyridazine derivatives elicit inhibitory activity with respect to gastric juice secretion and protective activity with respect to stomach mucosa and can be useful as a curative agent for prophylaxis or treatment of ulcer disease. Except for, invention relates to a pharmaceutical composition based on compounds of the invention and to a method for prophylaxis and treatment of ulcer disease.

EFFECT: valuable medicinal properties of compound.

25 cl, 1 tbl, 11 ex

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention describes bicyclical nitrogen-containing heterocycles of the general formula (I): , wherein R1 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, pyridyl, naphthyl, furyl-(C1-C4)-alkyl, phenyl optionally substituted with di-(C1-C7)-alkylamino-(C1-C7)-group, halogen atom, (C1-C7)-alkoxy-group or hydroxy-(C1-C7)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group, amino-(C1-C7)-alkyl, amino-group or di-(C1-C7)-alkylamino-(C1-C7)-alkoxy-group; R2 means (C1-C7)-alkyl, (C3-C7)-cycloalkyl, furyl-(C1-C4)-alkyl, pyridyl or its N-oxide; phenyl optionally substituted with halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, hydroxy-group or trifluoromethyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group; R3 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, (C3-C7)-cycloalkenyl, pyridyl-(C1-C4)-alkyl, naphthyl, phenyl optionally substituted with phthalimido-(C1-C4)-alkyl, amino-(C1-C7)-alkyl, hydroxy-(C1-C7)-alkyl, (C1-C7)-alkylamino-(C1-C7)-alkyl, di-(C1-C7)-alkylamino-(C1-C7)-alkyl, morpholino-(C1-C4)-alkyl or piperazinyl-(C1-C4)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxycarbonyl or carboxy-group. Also, invention relates to pharmaceutically acceptable salts of compounds of the formula (I) as a base with acids or pharmaceutically acceptable salts of compounds of the formula (I) as acid with bases, and pharmaceutical composition based on thereof. Compounds described above show inhibitory activity with respect to tyrosine kinase and can be used in treatment or prophylaxis of inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular diseases, for treatment of asthma, disorders in the central nervous system or complications associated with diabetes mellitus, or for prophylaxis against transplant rejection after surgery transplantation.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 tbl, 92 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, medicine, pharmacy.

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

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

26 cl, 1 tbl, 119 ex

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