Salt 9--aryloxyalkyl-2,3-dihydroimidazo[1,2-a] benzimidazole with a local anesthetic action

 

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. 1 N. p. F.-ly, 3 tables.

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 AG=C6H5With6H4R, where R=alkoxycarbonyl, carboxypropyl in the o-, p - and m-positions of the benzene ring, n=1-6, X=CL or Br, with local anesthetic effects at the surface (terminal) anesthesia.

Wide application in terminal method of pain relief found the drug dikain (tetracaine), which analgesic activity 2-3 times greater than cocaine and 10-12 times novocaine, about. and more. - M.: Medicine, 1998, H. 1, S. 371-382). In addition, side effects (tachycardia, convulsions, loss of consciousness, paralysis of the respiratory center), called (B. M. beavers. Our experience of applying the solution trimekainom for surface anaesthesia for ENT surgery. The honey. sister, 1990, No. 9, S. 14 -17), complicate its application (O. F. Konovaltsev, N. P. Field. The action of aqueous solutions dikaina and piromekaina on the epithelium of the mucous membrane of the oral cavity. Dentistry, 1990, I. 69, No. 3, S. 39-41).

In a series of 9-substituted N-2,3-dihydroimidazo[1,2-a]benzimidazole unknown compounds with a local anesthetic effect.

The closest structure substance among derivatives N-2,3-dihydroimidazo[1,2-a]benzimidazole is the dihydrochloride 9-diethyl-amino-ethyl-2,3-dihydroimidazo[1,2-a]benzimidazole with hypoglycemic and antiplatelet activity (V. A. Anisimova, M. V. Levchenko, T. B. Korochina 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 0 571 253; G. C. Kovalev, A. A. Spasov, C. A. Anisimov and other Means of having antiaggregatory activity. Pat. Of the Russian Federation No. 2061481,1996).

The technical result of the invention are new compounds in the series N-2,3-dihydroimidazo[1,2-a]benzimidazole, manifesting unknown is nustatymuose of the drug.

The technical result is achieved by the compounds I, the synthesis of which lies in the interaction of N-unsubstituted 1H-2,3-dihydroimidazo-[1,2-a]benzimidazole in neutral conditions with 1--aryloxy-2-halogen-alkanes in the environment of a solvent or without it:

where Ar, R, n and X take the values specified above.

Below are examples of methods of synthesis of the proposed compounds. Example 1. The hydrochloride of 9-(-phenoxyethyl)-2,3-dihydroimidazo[1,2-a]-benzimidazole (I, AG=C6H5n=2, X=CL; CH - 1148). Carefully pounded mixture of 1.59 g (10 mmol) of 1H-2,3-dihydroimidazo[1,2-a]-benzimidazole (A. F. Pozharsky, C. A. Anisimov, E. B. Tupac. Practical work in chemistry of heterocyclic compounds, Publishing house of Rostov University, 1988, S. 124-125) and 1.9 g (12 mmol) of-phenoxyethylamine heated 1 h at 150C (bath temperature). The melt is cooled, treated with acetone, the precipitate is filtered and washed with acetone. The output of 3.16 g (quantitative). Salt is purified by recrystallization from acetonitrile or ethanol, dried at 105S. T. pl. 246-247C (decomposition).

Found, %: C 64,6; N 5,8; CL 11,3; N 13,4.

With17H17N3),, M. D.: 4,34 (2H, m, 3-CH2), 4,47-to 4.52 (4H, m, 2-CH2and CH2), 4,91 (2H, m, N2), 6,79 (2H, d, 2', 6'-H, J=7.9 Hz), 6,91 (1H, t, 6-H, J=7,3 Hz), 7,14-7,24 (3H, m, aromatic.), 7,31-7,34 (2H, m, aromatic.), 7,56 (1H, d, 8-H, J=6.5 Hz), 11.87 per (1H, s, N+N).

Example 2. The hydrobromide 9-(-phenoxyethyl)-2,3-dihydroimidazo[1,2-a]benzimidazole (I, AG=C6H5n=2, X=Br). A mixture of 1.59 g (10 mmol) of 1H-2,3-dihydroimidazo[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 and 10 ml of butanol boil for 3-5 h (control reaction - TLC). Cool deposited precipitate is filtered off, washed with acetone, getting 3,15-of 3.32 g (87,5-92,3%) of the hydrobromide. Cleanse salt by recrystallization from isopropyl alcohol. So pl. 223-225C.

Found, %: C 56,5; H5,1; Br 22,0; N 11,9.

C17H17N3O·HBr.

Calculated, %: C Of 56.7; H 5,0; Br 22,2; N 11,7.

The Foundation allocated from the corresponding hydrochloride and hydrobromide in the processing of their 22% ammonia solution, identical and represent white crystals with so pl. 64-65 C (from ethyl acetate).

Found, %: From 72.9; H 6,3; N 15,2.

Withslichnih pharmaceutically acceptable salts.

Example 3. The hydrobromide 9-[-(4-methoxycarbonylbenzyl)ethyl]-2,3-dihydroimidazo[1,2-a]benzimidazole (I, Ar=C6H4COOCH3, X=Br). Carefully pounded mixture of 0.8 g (5 mmol) of 1H-2,3-dihydroimidazo[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), placed in a heat-resistant test tube, heated in a silicone bath to 150C. When 115-120With the formed transparent slightly yellow water, which quickly zakristallizuetsya at 130°C. the Mass is allowed to stand for 1 h at 145-150C. 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 of 1.61 g (77,0%). So pl. 203-204(From acetonitrile).

Found, %: C 54,5; N4,8; VG 19,2; N 10,0.

With19H19H3About3·NVG.

Calculated, %: From 54.6; H 4,8; Br l9,l; N 10,1.

IR-spectrum (vaseline. oil), cm-1: 1667(C=N), 1707 (C=O).

Range PMR (300 MHz, Dl3),: of 3.85 (3H, s CH3), 4,39 (2H, m, 3-CH2), a 4.53 (2H, m, 2-CH2), 4,55 (2H, t, CH2+H).

Example 4. The hydrobromide 9-[-(4-carboxyphenoxy)ethyl]-2,3-dihydro-imidazo[1,2-a]benzimidazole (I, Ar=C6H4COOH, X=Br) can be obtained by the interaction of equimolar amounts 1H-2,3-dihydroimidazo[1,2-a]benzimidazole and 4-(-bromoethoxy)benzoic acid (P. M. Kochergin and others, 1995) in dimethylformamide (yield 78%) or any other solvent or by saponification methoxycarbonyl group 4-methoxycarbonylmethylene imidazo[1,2-a]benzimidazole (see example 3). In the latter case, 0.8 g (2 mmol) 4-methoxy-carbonyldiimidazole, 10 ml glacial acetic acid and 2 ml conc. NVG boiled for 3 hours the resulting solution was cooled and left overnight in the refrigerator. The precipitation (snow-white silky needles) is filtered off, washed with acetone. Yield 0.71 g (87,5%). So pl. 255-256C (from ethanol).

Found, %: C 53, 5; N 4,5; VG 19,7; N 10,4.

With18H17H3About3·NVG.

Calculated, %: From 53.5; H 4,5; Br l9,8; N 10,4.

IR-spectrum (vaseline oil), cm-1: 1680 (C=N), 1693 (C=0), 3452 (wide band).

Range PMR (300 MHz, DMSO-d6),, M. D.:4,29-4,37 (4H, m, 3-CH2and CH2O) to 4.41 (2H, t, 2-CH2, J=4,7 Hz), 4,55 (2H, t, N-CH2/sup>H), 12,38 (1H, broad m, HE).

Surface (terminal) anesthesia were investigated on the cornea of rabbits using the method Rainier-Jack (Ignatov Y. D., Chernyakova, I. C., Vasilyev, Y. N., Galenko-Yaroshevsky A. P., Zhukov Century. N. Guidelines for the study of the local anaesthetic activity of pharmaceutical substances //Guidance on experimental (preclinical) study of new pharmacological substances. - M., 2000. - S. 176-192), while simultaneously studied the possible irritant effects (Setnicar I. Tolerance dosage of some-phenoxyaethylamino derivatives with local anaesthetic properties //Arzneim. - Forsch. - 1966. - Vol. 16, No. 5. - P. 623).

Acute toxicity (LD50) was determined in mice after subcutaneous administration.

As the comparison drug was taken dikain.

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 [determination of the mean effective concentration (EC50), LD50, borders, their confidence intervals, breadth of therapeutic action (LD50/EU50)] - Century B. the Prozorovsky (Prozorovsky Century B. Using the method of least Quadra is DEXA Rainier for RU-1148, taken in 0,125, 0,25, 0,5, 1 and 2% solutions are 584,2, 858,8, 1102,2, 1227,2 and 1300 while dikaina (in the similar solutions) - 436,4, 694,5, 950,0 1149,5 and 1300, respectively; the indices of Diamonds for RU-1148 (relatively dikaina) was equal to 1.6, and 1.6, and 1.8, 1.5, and 1.0 in. It is important to note that RU-1148 none of the investigated solutions had no irritants, while dikain 1% and especially 2% solutions induced irritation of the tissues of the anterior eye (PL. 1).

The time of onset of anesthesia during installation into the conjunctival SAC 0,125, 0,25, 0,5, 1 and 2% solutions of RU-1148 and dikaina was almost comparable and ranged from 1-3 min depending on the concentration of the solution. The end time of full anesthesia and the total duration of anesthesia PN-1148 in the investigated solutions of 1.2-1.8 and 1.2-1.4 times, respectively, exceeded such dikaina (PL. 2).

On the local anaesthetic activity when comparing EU50expressed in mm/l, and therapeutic index - RU-1148 1.68 times more significant and 1.73 times has a great breadth of therapeutic action than dikain (PL. 3).

Thus, the connection ROUX-1148 by local anaesthetic activity (at surface IU predstavljaetsja possible the creation of local anesthetic drugs, designed like dikaina for surface anesthesia.

Claims

Salt 9--aryloxyalkyl-2,3-dihydroimidazo[1,2-a]benzimidazole of the formula

where AG - C6H5With6H4R, where R is alkoxycarbonyl or carboxypropyl in o-, m - and p-positions of the benzene ring;

n = 1-6;

X is Cl or Br.

 

Same patents:

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

The invention relates to 4-hydroxy-3-chinainternational and hydrazides of General formula (I), where a represents a-CH2- or-NH-, a R1, R2, R3and R4such as defined in the claims

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

The invention relates to new derivatives of 1,5-dihydropyrazolo[3,4-d] pyrimidinone General formula (I) having the properties of an inhibitor of phosphodiesterase, which can be used, for example, high blood pressure, angina and heart disease

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

The invention relates to a new one with selective affinity to T6receptors, pyrazolo[1,5-a]pyrimidines and pyrazolo[1,5-a]triazines General formula I, where X denotes a =C(R4)- or =N-, R1denotes phenyl, optionally substituted by one or more radicals of lower alkyl, halogen, lower alkoxygroup, tolyl, pyridyl, naphthyl or thiophenyl, R2denotes hydrogen, (ness.)alkyl, (ness.)thioalkyl or hydroxy(ness.) alkoxygroup, R3denotes amino(ness.)alkylamino, di(ness.)alkylamino, piperazinil, optionally substituted by one or more radicals, lower alkyl, benzyl, phenyl or hydroxy(NISS

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

Up!