1- and 7-[ ω -(benzhydryl-4-piperazinyl-1)alkyl]-3-alkylxantine derivatives with antihistaminic and antiallergenic effect

FIELD: chemistry.

SUBSTANCE: invention concerns new derivatives of 1- and 7-[ω-(benzhydryl-4-piperazinyl-1)alkyl]-3-alkyloxantines of the general formulae I and II, including their pharmaceutically acceptable salts and/or salt hydrates, the derivatives showing antihistaminic and antiallergenic effect. In the general formulae I and II : R = H, Me, CH2Ph; R1 = Me, "н" - C4H9; n = 0-3; X = H, OH, OCOCH2CH2COOH; Y = Y1 = H, Cl, F; on the condition that R and R1 are not both methyl. Compounds of the invention feature high antihistaminic and antiallergenic activity. E.g., 7-[4-(benzhydryl-4-piperazinyl-1)butyl]-3-methyloxantine dihydrochloride surpasses most efficient antihistaminic and antiallergenic medications, such as cetirizine, loratadine and azelastine, in activity and lasting effect.

EFFECT: obtaining a compound with high antihistaminic and antiallergenic activity.

2 cl, 3 tbl, 8 ex

 

Despite the relatively large range of anti-histamine drugs used in medical practice as anti funds, search for new blocker H-1 histamine receptors remains a challenge due to the fact that most of the existing drugs in this class are not without drawbacks, such as short duration of action, side effects from the Central nervous system and other (Medmaravis, Medicines, Moscow, "New wave", 2005, 15th edition, s.285-297). In this regard, of particular interest is the search for the original anti-histamine (anti-allergic) drugs with new chemical structure and, in particular, in a series of xanthine derivatives, among which there are a number of highly active natural compounds (theophylline, theobromine, caffeine), possessing valuable pharmacological properties.

The aim of the invention is the expansion of the range of anti-histamine (anti-allergic) medicines.

This goal is achieved by the synthesis and evaluation of biological activity of the original chemical compounds based on the structure of xanthine, in particular derivatives of 1 - and 7-[ω-(benzhydryl-4-piperazinil-1)alkyl]-3-alkylresorcinol, as well as their pharmaceutically acceptable salts and/or hydrates, the overall shape of the I and II:

where R=H, Me, CH2Ph; R1=Me, n - C4H9; n=0-3

X=H, HE, OSON2CH2COOH; Y=Y1=H, Cl, F;

provided that R and R1at the same time do not mean Me

which have anti-histamine and anti-allergic activity and can be used in medicine for production on their basis of new high-level and low-toxic anti-allergic medicines.

The claimed compounds are synthesized by the following methods:

Method A.

Xantina derivatives of General formulas III and IV, where R=H, Me, CH2Ph; R1=Me, n-C4H9;

obtaining the classical method Traub (Cuvature, Glashenko, Name reactions in organic chemistry, Moscow, in "Chemistry", 1976, s.400; Pmmotion al., CHC, 1995, No. 9, s), alkylate in the form of a salt with alkali metal (Na, K) α,ω-dibromononane General formula V:

Br(CH2)nBr (V, where n=2-5).

Generated ω-romancelatina General formulas VI and VII, where R=H, Me, CH2Ph; R1=CH3the h4H9; n=2-5,

process in the presence of iodotope potassium substituted benzhydrylpiperazine General formula VIII:

where Y and Y1=H, Cl, f

p and get the claimed compounds I and II, where X=N (table 1).

Method B.

According to this method, xanthine derivatives III and IV, where R=H, Me, CH2Ph; R1=Me, n-C4H9; treated with epichlorohydrin. However, depending on the reaction conditions (anhydrous or aqueous medium) are formed of substituted 1 - or 7-(2,3-epoxypropyl)xantina (IX and X, whereor 1 - and 7- (3-chloro-2-oksipropil)-xantina (IX and X, where Z=-CH(OH)-CH2Cl)

(H.J.Roth, Reaction of theophylline and theobromine with 1,2-epoxides, Arch. Pharm., 1959, 292, 234-238; J.Med. Chem., 1985, 28, №5, 652).

When interacting IX and X with benzhydrylpiperazine and its derivatives get the claimed compounds I and II, where X=OH; n=1 (table 1).

The biological activity of derivatives of 1 - and 7-[ω-(benzhydryl-4-piperazinil-1)alkyl]-3-alkylresorcinol (I and II)

The study of the antihistaminic activity of the claimed compounds was performed according to known methods (Manual on experimental study of new pharmacological substances, Moscow, 2005, s) on the isolated ileum of Guinea pigs (suppression spasmogenic effect of histamine) and anesthetized Guinea pigs (antagonism against bronchoconstricting effect of histamine). In experiments on whole animals substances were injected intravenously (5 minutes before the injection of histamine) and inside (2 hours before the start of the study).

When assessing what littelest anti-histamine activity of a compound was injected inside for 24 to 72 hours prior to the study.

The most active compound I (where R=H; R1=CH3; n=2; X=H; Y=Y1=H) were studied in awake Guinea pigs using the model itching caused by instillation into the eyes of an animal of a solution of histamine (anti-histamine action), and in rats in a model of passive cutaneous anaphylaxis (allergic effect); (a Guide for experimental study of new pharmacological substances, Moscow, 2005, s)

The claimed compounds I and II was studied in comparison with similar pharmacological action and is widely used in medical practice drugs: cetirizine, loratadine and azelastine (Mashkovsky PPM, Drugs, "New Wave", 2005, 15th edition, s.285-297)

The results of the study anti-histamine activity and toxicity of the inventive compounds I and II are presented in table 2.

As follows from the presented data, the majority of the claimed compounds in vitro and in vivo by anti-histamine activity (indicators IR50and ED50respectively) are not inferior to cetirizine and loratadine, but less active in comparison with azelastina. The exception is the connection I that on the isolated ileum of Guinea pigs is substantially outweighed by the activity of cetirizine and loratadine, although somewhat inferior AZ is Latino. However, in vivo intravenous connection G more all of the above Comparators; entering into (2 hours before the start of the study) connection G potency surpasses cetirizine and loratadine and similar azelastina.

It should be emphasized that the duration of the anti-histamine action connection G superior to all Comparators, including azelastin. So, on the model of histamine-induced bronchospasm, the connection J, cetirizine, loratadine, azelastin after oral administration at a dose of 3 mg/kg provide effective blockade of H1-histamine receptors of the bronchi within 72, 48, 18, and 48 hours, respectively. On the model of itch induced by histamine, the protective effect of the compounds G dose of 3 mg/kg inside remains stable for 2 days and decreased after 72 hours, whereas a similar effect of cetirizine and azelastina in the same dose after 48 hours significantly reduced, and in 72 hours it disappears completely. On the model of passive cutaneous anaphylaxis connection G and cetirizine at doses of 1 and 3 mg/kg, respectively, have a modest and similar anti-allergic action.

A very important factor is the fact that the connection I less toxic than azelastin and cetirizine. Connection G thermally stable, easily soluble in water is unlike loratidine can be used to prepare solid dosage forms, and eye drops.

The obtained results allow to conclude that found and examined a number of derivatives of 1 - and 7-[ω-(benzhydryl-4-piperazinil-1)alkyl]-3-alkylresorcinol (I and II), among which the detected substances with high antihistaminic and antiallergic activity opens new perspectives in the treatment of allergic diseases (table 2).

Example 1.

Obtaining 1-(4-bromobutyl)-3-methyl-7-benzylcyanide (VI, R=CH2Ph; R1=CH3, n=4).

To 60 ml of abs. CH3HE contains and 2.79 g (0,0517 mol) of sodium methylate is added 10.0 g (0,039 mol) 3-methyl-7-benzylcyanide (III. R=CH2Ph, R1=CH3).

The suspension is boiled under stirring for 30 minutes; the reaction mass is evaporated to dryness; at the end of the process remains the methanol is removed by distillation of the toluene, get 10,86 g 1 sodium salt of 3-methyl-7-benzylcyanide.

To a solution of 42.3 g (24,4 ml; 0,196 mol) of 1,4-dibromobutane in 100 ml of dimethylformamide (DMF) was added 10,86 g (0,039 mol) of 1-sodium salt of 3-methyl-7-benzylcyanide and boil (-150°) when peremeshivanii 3.5 hours. The mass evaporated in vacuo, to the residue water is added and the benzene is stirred, the benzene layer separated, washed with water, dried over sodium sulfate and filtered through a layer of aluminum oxide. The filtrate is evaporated to a volume of ˜30 ml) and add an equal amount of hexane. The precipitation is Hotfile revival and dried. Get 12,16 g (79,6%), 1-(4-bromobutyl)-3-methyl-7-benzylcyanide, TPL 90-92° (from methanol), M+.91.

Example 2.

Obtaining 3-methyl-7-(4-bromobutyl)xanthine (VII, R=H, R1=CH3, n=4).

To a solution of 42.3 g (0,196 mol; and 23.4 ml) of 1,4-dibromobutane in 100 ml of acetonitrile was added 10.0 g (0,049 mol) 7-potassium salt of 3-methylxanthines. The suspension is boiled under stirring for 28 hours, cooled, precipitated precipitate is filtered off, washed until neutral with water, then with methanol and dried. Get 9,0 (61%) technical 3-methyl-7-(4-bromobutyl)xanthine (VII, R=H, R1=CH3, n=4), after two cleaning technical sample crystallization from a mixture of benzene and methanol, and then dimethysulfoxide, TPL 218-220°, M+.301.

Similarly synthesize other VI and VII (see table 3).

Example 3.

Obtaining 1-(2,3-epoxypropyl)was 3.7-dimethylxanthine (IX, whereR=R1=CH3). A suspension of 3 g (0,148 mol) of sodium salt of 3,7-dimethylxanthine (III, 1-Na salt; R=R1=CH3) and 20 ml of epichlorohydrin is heated under stirring at 65-70° for 20 hours. After cooling the precipitate is filtered off and washed with methylene chloride. The resulting solution IX in methylene chloride evaporated, the oily residue is triturated with absolute ether, 2,7 get (77%) of 1-(2,3-epoxypropyl)was 3.7-dimethylxanthine, TPL 115-119°, M+.236 (J-C. Pasal et al, J. Med. Chem., 1985, №28, №5, 647-652, TPL 116-117°).

Likewise, a Na-salt of 3-methyl-7-benzylcyanide (III, 1-Na-salt, R=CH2Ph; R1=CH3) synthesize 1-(2,3-epoxypropyl)-3-methyl-7-benzilate (IX, whereR=CH2Ph; R1=CH3), yield 80%, TPL 90-95°, M+.312.

Example 4.

Obtaining 3-methyl-7-[4-(benzhydryl-4-piperazinil-1)butyl]xanthine dihydrochloride (II, where R=H, R1=CH3X=H, n=2, Y=Y1=H).

A mixture of 2.0 g (0,006 mol) of 90%3-methyl-7-(4-bromobutyl)xanthine (VII, where R=H, R1=Me, n=4), 1.5 g (0,006 mol) benzhydrylpiperazine VIII (where Y=Y1=H) and 0.05 g of potassium iodide in 40 ml of acetonitrile is boiled under stirring for 30 hours. The reaction mass is evaporated, to the residue add 25 ml of 5%hydrochloric acid;

nerastvorim precipitate is filtered off and the solution is extracted with chloroform. Obtained after extraction of hydrochloric acid solution is alkalinized to pH 8 with solid sodium bicarbonate and extracted with chloroform. The extract was washed with a saturated solution of sodium chloride and dried with magnesium sulfate. To the dried chloroform solution was added until pH˜2 saturated solution of hydrogen chloride in methanol, the mass evaporated and the residue crystallized from ethanol with the addition of water, get 1,95 g (56,7%) of 3-methyl-7-[4-(benzhydryl-4-piperazinil-1)butyl]xanthine dihydrochloride (II, where R=H, R1=The h 3X=H, n=2, Y=Y1=H), TPL 216-217°.

Found %: C,47; N6,75; N 14,63; H20 4,70.

C27H32N6O2·2 HCl·1,5H20

Calculated %: C,47; N 6,50; N 14,63; N2O 4,93.

Succinate 3-methyl-7-[4-benzhydryl-4-piperazinil-1)butyl]xanthine, TPL 187,5-189°. Found%: 62,95; N 7,06; N of 14.28; C31H38N6O6;

Calculated %: 63,04; N 6,48; N 14,23.

In similar conditions 3-butyl-7-(4-bromobutyl)xanthine (VII, where R=N R1=n-Bu; n=4) and benzhydrylpiperazine (VIII, where Y=Y1=H) synthesize 3-butyl-7-[4-(benzhydryl-4-piperazinil-1)butyl]the xanthine dihydrochloride (II, where R=H, R1=n-C4H9X=H, n=2, Y=Y1=H), the yield of 49.4%, TPL 240-242°; M+.514.

Found %: C,07; N 6,98; N14,21.

C30H38N6O2·2 HCl

Calculated %: 61,32; N 6,86; N14,30.

Example 5.

Obtaining 1-[4-(benzhydryl-4-piperazinil-1)butyl]-3-methylxanthines dihydrochloride (I, where R=H, R1=CH3X=H, n=2, Y=Y1=H) of 7-benzyl-1-(4-bromobutyl)-3-methylxanthines (VI, where R=benzyl, R1=Me).

A solution of 2.1 g (0,005 mol) 95%7-benzyl-1-(4-bromobutyl)-3-methylxanthines in 50 ml of methanol and 0.21 g of 20%palladium hydroxide on coal hydronaut at 40° to the cessation of hydrogen absorption (˜1.5 hours). The catalyst is filtered off, washed with hot methanol, the filtrate evaporated, to obtain 1.35 g of 1-(4-bromobutyl)-3-methylxanthines (VI, where R=H, R1=Me, n=4).

a Mixture of 1.35 g of the latter, 1.13 g (0.045 mol) benzhydrylpiperazine (VIII, where Y=Y1=H), being 0.036 (0,00022 mol) iodotope potassium and 30 ml of acetonitrile is boiled under stirring for 15 hours. The reaction mass is evaporated, the residue is dissolved in 25 ml of 5%hydrochloric acid, the solution was washed with chloroform and hydrochloric acid solution is alkalinized with solid sodium bicarbonate to pH˜8. The resulting mass is extracted with chloroform, the extract washed with saturated aqueous sodium chloride and dried with magnesium sulfate. The chloroform solution is evaporated, the residue is dissolved in 5 ml of isopropanol, the solution was added a saturated solution of hydrogen chloride in isopropanol to a pH of 2. After cooling (5-7°, 16 hours the precipitate is filtered off and crystallized from methanol-isopropanol, get 1, 38 g (50,7%) 1-[4-(benzhydryl-4-piperazinil-1)butyl]-3-methylxanthines dihydrochloride, TPL 198-198°.

Found %: C,41; N6,54; N15,06.

C27H32N6O2·2 HCl

Calculated %: C59,45; H6,28; N15,40.

Similarly from 1-(4-bromobutyl)-3-butyl-7-benzylcyanide (VI, where R=CH2Ph; R1=n-Bu; n=4) and benzhydrylpiperazine (VIII, where Y=Y1=H) are obtained 1-[4-(benzhydryl-4-piperazinil-1)butyl]-3-butylxanthine the dihydrochloride (I, where R=H, R1=n-Bu, X=H, n=2, Y=Y1=H), the output 42,2%, TPL 215-217°; M+.514.

Found %: C60,29; H7,44; N13,93; N2O 2,55.

C30H38N6O2·2HCl·0,75 H2 O

Calculated %: C,94; H7,04; N13,98; N2O 2,25.

Example 6.

Obtain 1,3-dimethyl-7-[2-hydroxy-3-(benzhydryl-4-piperazinil-1)propyl]xanthine dihydrochloride (II, where R=R1=CH3n=1, X=HE, Y=Y1=H).

A mixture of 2.45 g (0,009 mol) of 1,3-dimethyl-7-(2-hydroxy-3-chlorpropyl)xanthine (X, where Z=-CH(OH)-CH2Cl) (see H.J.Roth, Arch. Pharm., 1959, 292, 234-238), and 2.27 g (0,009 mol) benzhydrylpiperazine (VIII, where Y=Y1=H), 1,38, potash, 0.08 g (0,00005 mol) iodotope potassium and 50 ml of acetonitrile is boiled under stirring for 20 hours. The mass evaporated, the residue is dissolved in chloroform, the solution washed with water, dried with magnesium sulfate. After distillation of the chloroform, the residue is crystallized from ethyl acetate, get 2, 61, base II (where R=R1=CH3; n=1, X=HE, Y=Y1=H), which is dissolved in 70 ml of isopropanol. To the resulting solution was added a solution of hydrogen chloride in isopropanol to pH ˜2 deposited precipitate is filtered off and dried. Get 3,34 (66%) of 1,3-dimethyl-7-[2-hydroxy-3-(benzhydryl-4-piperazinil-1)propyl]candidateguaranteed, TPL 224-226°.

Found %: C,32; N6,10; N14,86.

With27H32N6About3·2 HCl

Calculated %: C,75; N6,10; N14,97.

Example 7.

Obtain 1,3-dimethyl-7-[2-carboxyethylgermanium-3-(benzhydryl-4-piperazinil-1)propyl]xanthine (II, where R=Rl=CH3; n=1; X=ASON2CH2COOH; Y=Y1=H).

A mixture of 2.0 g (0,004 mol) of 1,3-dimethyl-7-[2-ACS is -3(benzhydryl-4-piperazinil-1)propyl]xanthine (II, where R=R1=CH3; n=1; X=OH; Y=Y1=H), 0.5 g (0,005 mol) of succinic acid anhydride and 20 ml of dichloroethane is boiled for 4 hours and evaporated to dryness. The residue is crystallized from absolute ethanol, receive 2,04 g (86,7%) of 1,3-dimethyl-7-[2-carboxyethylgermanium)-3-(benzhydryl-4-piperazinil-1)propyl]xanthine, TPL 183-185°.

Found %: C,28; N6,53; N14,32.

C31H36N6O2.

Calculated %: C,25; N6,16; 14,28.

Example 8

Obtaining 1-[2-hydroxy-3-(benzhydryl-4-piperazinil-1)propyl]was 3.7-dimethylxanthine dihydrochloride I (where R=R1=CH3; n=1; X=OH; Y=Y1=H).

A mixture of 1 g (0,0042 mol) of 1-(2,3-epoxypropyl)was 3.7-dimethylxanthine, 1.26 g (0,0044 mol) benzhydrylpiperazine and 30 ml of isopropanol is boiled under stirring for 30 hours. After cooling the precipitate is filtered off, washed with ether and dried. Get a 1.96 g (95%) of 1-[2-hydroxy-3-(benzhydryl-4-piperazinil-1)propyl]was 3.7-dimethylxanthine:

- base TPL 120-122°, M+.488;

- dihydrochloride, TPL 196-198°; M+.488.

Similarly synthesize:

- 1-[2-hydroxy-3-(41-chlorobenzhydryl-4-piperazinil-1)propyl]was 3.7-dimethylxanthine (I, where R=Rl=CH3; n=1; X=OH; Y=Cl; Y1=H):

- the base, the yield 67%, TPL 152-155°;

- dihydrochloride, TPL 192-194°.

1-[2-hydroxy-3-(benzhydryl-4-piperazinil-1)-propyl]-3-methyl-7-benzilate (I, where R=CH2Ph, R1=Me; n=1; X=OH; Y=Y1=H), the yield is 50%, TPL 98-100°.

p> 1-[2-hydroxy-3-(41-chlorobenzhydryl-4-piperazinil-1)propyl]-3-methyl-7-benzilate (I, where R=CH2Ph, R1=Me; n=1; X=OH; Y=Cl; Y1=H), the yield is 50%, TPL 170-172°.

Table 3.
ConnectionnRR1Output %So pl., °Mass spectrum, PI, m/z; M+.
1234567
VIa2CH2PhCH36577-79363
VI3CH2PhCH37081-83377
VI34-FC6H4CH2CH366123-125395
VI44-FC6H4CH2CH36792-94409
VI5CH2PhCH35996-98405
VI4CH3CH360120-122315
VI4CH2PhN-C4H97588-90433
VIIa2CH3CH370143-145287
VII3CH3CH360131-133301
VII3NCH360126-128287
VII4CH3CH365123-125315
VII4NN-C4H95986-88343

1. Derivatives of 1 - and 7-[ω-(benzhydryl-4-piperazinil-1)alkyl]-3-alkylresorcinol General formulas I and II:

where R=H, Me, CH2Ph; R1=Me, n - C4H9; n=0-3; X=H, HE, OSON2CH2COOH; Y=Y1=H, Cl, F, provided that R and R1at the same time does not mean methyl, including their pharmacy is automatic acceptable salts and/or hydrates.

2. The compound according to claim 1, namely 7-[4-(benzhydrylpiperazine-1)butyl]-3-methylxanthines the dihydrochloride (IIWwhere R=H; R1=Me; n=2; X=H; Y=Y1=N), which has anti-histamine and anti-allergic action.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to compound of the formula (I): or (II): wherein R1 and R2 are chosen independently from hydrogen, optionally substituted alkyl or the group: -D-E wherein R represents a covalent bond or alkylene; E represents optionally substituted alkoxy-group, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkenyl or optionally substituted alkynyl under condition that if D represents a covalent bond then E can't represents alkoxy-group; R3 represents hydrogen atom, optionally substituted alkyl or optionally substituted cycloalkyl; X represents optionally substituted arylene or heteroarylene; Y represents a covalent bond or alkylene wherein one carbon atom can be substituted optionally for -O-, -S- or -NH-, and optionally substituted hydroxy-, alkoxy-, optionally substituted amino-group or -COR wherein R represents hydroxy-, alkoxy- or amino-group under condition that if an optional substitute represents hydroxy- or amino-group then it can't be adjacent with a heteroatom; Z represents hydrogen atom, optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl under condition that Z represents hydrogen atom only under condition that Y represents a covalent bond, and X represents optionally substituted 1,4-pyrazolene, and under condition that if X represents optionally substituted arylene then Z represents optionally substituted monocyclic heteroaryl. Also, invention describes a method for treatment of the morbid state by inhibition of adenosine receptors describes as A2B based on compounds of the formula (I) or the formula (II). Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds.

32 cl, 35 ex

FIELD: organic chemistry, pharmaceutical chemistry, pharmacology, medicine.

SUBSTANCE: invention relates to novel derivatives of 3-methyl-7-(thietanyl-3)-xanthine of formulae (Ia, b, c, d): wherein R means C2H5, R1 means , n = 1 (Ia); R means n-C3H7, R1 means Br, n = 1 (Ib); R means hydrogen atom (H), R1 means -SCH2CONHNH2, n = 0 (Ic); R means H, R1 means -SCH2CONHNH2, n = 2 (Id). Proposed compounds possess the greater hemorheological activity as compared with that of pentoxyphylline and lower toxicity. Invention provides synthesis of novel and not described previously derivatives of 3-methyl-7-(thietanyl-3)-xanthine of formulae (Ia, b, c, d) possessing hemorheological activity.

EFFECT: improved method of synthesis, valuable medicinal property of compounds.

2 tbl, 4 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention proposes compound of the formula (1) in free form or as a salt wherein R1, R2, R3, R4 and R5 have values given in the invention claim. The claimed compounds are selective inhibitors of enzyme PDE-5 and show the high selectivity in inhibition of activity of 3',5'-cycloguanosine monophosphate phosphodiesterase being activity of PDE-5 first of all.

EFFECT: valuable biochemical properties of derivatives.

6 cl, 3 tbl, 87 ex

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

SUBSTANCE: invention describes derivatives of 8-phenyl-6,9-dihydro[1,2,4]-triazolo[3,4-I]purine-5-one of the general formula:

wherein R1 means hydrogen atom, group -CH2-R6 wherein R6 means phenyl; R2 means (C1-C5)-alkyl or group -(CH2)n-R6 wherein n= 1 or 2; R6 means (C1-C4)-alkoxy-group or pyridyl group; R3 means (C1-C6)-alkyl; R4 means hydrogen atom or (C1-C4)-alkyl; R5 means -(CH2)n-R7 wherein n = 0-4; R7 means 3-7-membered ring comprising 1-3 heteroatoms taken among nitrogen atom (N) and oxygen atom (O), (C3-C7)-cycloalkyl or phenyl wherein indicated groups can be substituted with different substitutes; or R4 and R5 mean independently hydrogen atom (H), (C2-C6)-alkynyl or (C1-C6)-alkyl that can be substituted possibly; or R4 and R5 in common with nitrogen atom (N) form 4-7-membered ring comprising 1-2 heteroatoms taken among N and O and substituted possibly. Also, invention relates to their pharmaceutically acceptable salts, methods for preparing these compounds, intermediate substances, pharmaceutical composition and a to a method for treatment of different diseases mediated by activity of phosphodiesterase-5 (PDE-5). Described compounds of the formula (I) are inhibitor of PDE-5.

EFFECT: improved preparing method and treatment, valuable properties of compounds.

20 cl, 5 tbl, 149 ex

The invention relates to a method for producing 3,7-dialkylamino, representing compounds of formula I

< / BR>
Unsubstituted or substituted in position 1 with 3.7-dealkylation are the main four and intermediate products to obtain drugs

FIELD: chemistry.

SUBSTANCE: invention concerns new N,N'-substituted 3,7-diazabicyclo[3.3.1]nonanes of the general formula 1: (HY), where HY is hereinafter a pharmacologically acceptable acid; E is , R1 is H, low-grade alkyl, C1-C10alkoxy; R2 is generally represented by the general formulae (1.1a) , (1.2a) , (1.3a) , (1.4a) , where L is CHR11, ; R11 is H, NH2; R15 is H, low-grade alkyl, C1-C10alkoxy; R19, R19', R20 and R20' can be equal or different, and each is independently H, low-grade alkyl, C1- C10alkoxy; R24 and R25 can be equal or different, and each is independently H, low-grade alkyl, C1- C10alkoxy; R3 and R3' can be equal or different, and each is independently H, low-grade alkyl, C1- C10alkoxy; R4 and R4' can be equal or different, and each is independently H, low-grade alkyl, C1- C10alkoxy; X is a group of the general formula: (CH2)m-Z, where m=0, while Z is acetyl, or X is a valence link. Compounds I are capable of AMPA receptor activity modulation and hence can be applied in pharmaceutical compositions.

EFFECT: obtaining compound capable of AMPA receptor activity modulation.

12 cl, 2 dgw, 2 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention concerns malonamide derivatives of the formulae (IA) or (IB) , and pharmaceutically acceptable acid additive salts of them, where R1, R1',(R2)1,2,3, R3, R4, R14, L, and are such as described in this invention. Also the invention concerns a medicine with inhibition effect on γ-secretase, which can be applied in treatment of Alzheimer's disease.

EFFECT: obtaining new malonamide derivatives with beneficial biological properties.

17 cl, 188 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 1,4-diazabicycloalkane of the formula (IV): or its pharmaceutically acceptable addition salt wherein Ar represents carbocyclic aromatic (aryl) group or heterocyclic aromatic (heteroaryl) group that represents 5-6-membered ring comprising one nitrogen, sulfur or oxygen atom as a heteroatom and wherein aromatic group can be substituted with one substitute chosen from group consisting of (C1-C6)-alkoxy, halogen atom, -CF3, phenyl and benzyl. Also, invention relates to a pharmaceutical composition possessing inhibitory effect on nicotine acetylcholine receptors and containing the effective amount of compound of the formula (IV) or its pharmaceutically acceptable addition salt in combination with at least one pharmaceutically acceptable carrier or diluting agent. Invention provides derivatives of 1,4-diazabicycloalkane possessing inhibitory activity with respect to nicotine acetylcholine receptors.

EFFECT: valuable medicinal and pharmacological properties of compounds.

10 cl, 3 ex

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

SUBSTANCE: invention relates to novel 3-phenyl-3,7-diazabicyclo[3,3,1]nonane compounds of the formula (I): wherein R1 means (C1-C6)-alkyl, (C4-C7)-cycloalkyl; R2 means (lower)-alkyl; R3 means (lower)-alkyl, or R2 and R3 form in common (C3-C6)-alkylene chain; R4 means phenyl monosubstituted at ortho- or para-position with nitro-, cyano-group or (lower)-alkanoyl, or disubstituted at ortho- and para-position with nitro-group, and their physiologically acceptable acid-additive salts. Compounds of the formula (I) possess anti-arrhythmic activity and therefore they can be used in pharmaceutical composition used in treatment and/or prophylaxis of cardiac rhythm disorders. Also, invention describes a method for synthesis of these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

8 cl, 6 tbl, 2 ex

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to condensed heterocyclic succinamide compounds of the formula (I): , their pharmaceutically acceptable salts, solvates or isomers wherein G represents mono- or polycyclic aryl or heterocyclic group substituted possibly at one or more positions; L represents a bond, -(CR7R7')n (wherein n = 1; R7 and R7' represents independently hydrogen atom (H), alkyl or substituted alkyl) or -CH2-NH-; Z1 represents oxygen atom (O); Z2 represents O; A1 and A2 represent -CR7 or in common with R7 from group W is a heterocyclic ring wherein oxygen represents a heteroatom; Y represents -O-, -SO-, -N(V2)-, -CH2-N(V2)-, -CO-N-(alkyl)-, -CH2-S-, -CH2-SO2-; V2 represents hydrogen atom, alkyl, arylalkyl, -CO-alkyl, -CO-O-aryl, -CO-O-arylalkyl; W represents -CR7R7'-CR7R7'-, -CR7R7'-C=O, -NR9-, -CR7R7'-, -N=CR8-, -N=N, -NR9-NR9'-, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo- or substituted heterocyclo-group, aryl or substituted aryl wherein if W doesn't mean -NR9-CR7R7'-, -N=CR8-, -N=N, -NR9-NR9'- or heterocyclo- or substituted heterocyclo-group then Y must mean -O-, -CH2-S-, -SO-, -CH2-SO2-, -N-(V2)- or -CH2-N-(V2)-; Q1 and Q2 represent hydrogen atom (H). Also, invention describes a method for synthesis of intermediate compounds in synthesis of compounds of the formula (I), using the latter for preparing agents modeling function of the nuclear hormone receptors. Compounds of the formula (I) can be used in treatment of prostate cancer.

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

8 cl, 11 tbl, 463 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to a novel chemical compound, namely, to biologically active compound of the formula (I): possessing anti-arrhythmic activity and representing 5'-bromolappaconitine hydrobromide. Toxicity of this compound is by 4.8-fold less toxic as compared with analog used in medicinal practice and representing lappaconitine hydrobromide. Proposed compound possesses the expressed anti-arrhythmic activity in models with calcium chloride and adrenaline arrhythmia and provides the complete blocking both types of arrhythmia after administration of the dose that is 10-fold less of the therapeutic dose of lappaconitine hydrobromide.

EFFECT: improved and valuable medicinal properties of compound.

2 cl, 2 tbl, 4 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a whitening composition comprising: (a) monomeric ligand or catalyst with transient metal of ligand of the formula (I): wherein R represents hydrogen atom; R1 and R2 are chosen independently from (C1-C4)-alkyl, pyridine-2-yl-methyl and (C2-C4)-alkylmethyl; X represents -C=O; R3 and R4 are similar and represent -(CH2)nC(O)O-(C1-C4)-alkyl; n = 0-4, and (b) equilibrating carriers and additional components. This composition is useful for catalytic whitening substrates with atmosphere oxygen. Also, invention describes a method for whitening the substrate involving applying step of the whitening composition on substrate in aqueous medium.

EFFECT: valuable properties of substances, improved whitening method.

11 cl, 2 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: compounds of formula I are disclosed, wherein R1, R2, R3, R4, R5, R6, R7, R41, R42, R43, R44, R45, R46, A, and B are as described in description.

EFFECT: new compounds with increased electrophysiological activity useful in treatment of cardiac arrhythmias.

132 cl, 1 tbl, 37 ex

The invention relates to metallogenica derivative containing four nitrogen atom of the macrocycle, fused with the pyridine cycle, methods for their preparation and their use in medicine to obtain an image

FIELD: chemistry.

SUBSTANCE: invention concerns new tricyclic derivatives of the formula (I) and their pharmaceutically acceptable salts, where: 1 to 3 of A1, A2, A3 and A4 are nitrogen atoms, while the rest are -CH- groups; G1 is a group selected out of -CH2-O-, -CH2-CH2-, - CH=CH-; -N(C1-C4alkyl)-CH2; G2 is a group selected out of -O-CH2-, -CH=CH-, -CH2- CH2-; R4 can be identical or different and are selected out of a group including hydrogen or halogen atoms; p are independently equal to 0, 1 or 2; Y is and optionally substituted residuum selected out of the group of alkyl, cycloalkyl, alkylaryl, alkylcycloalkylalkyl; Z is a tetrazolyl, -COOR5, -CONR5R5, NHSO2R5 or -CONHSO2R5 group, where R5 is hydrogen or optionally substituted alkyl or aryl. The invention also concerns a method of obtaining the claimed compounds.

EFFECT: possible application in treatment and prophylactics of inflammation and allergy diseases.

20 cl, 2 tbl, 46 ex

FIELD: medicine.

SUBSTANCE: present invention refers to medicine and concerns microparticles containing sphere mainly consisting of cross-linked agarose carbohydrate and allergen covalently bonded with sphere, applied for immune system disturbance treatment. Used allergen is produced of plant pollen, specifically of timothy grass pollen. Application of specified microparticles provides effective treatment for patients suffering from allergy, as well as reduces by-effects of parenteral introduction.

EFFECT: development of effective method of allergy treatment and prevention.

9 cl, 4 dwg, 1 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to derivatives of phtalazine with general formula (I) , in which R represents a methyl or difluromethyl group; R1 represents phenyl or oxazolyl or thiophenyl, chemically bonded to a phtalazine ring through a carbon-carbon bond. Both phenyl and the above mentioned heterocycle are substituted with a carboxylic group, and optionally with a second functional group, chosen from methoxy-, nitro-, N-acetylamino-, N-metanesulphonylamino- group. The invention also relates to pharmaceutical salts of such derivatives. The given compounds with general formula (I) are inhibitors of phosphodiesterase.

EFFECT: objective of the invention is also the method of obtaining compounds with general formula (I) and pharmaceutical compositions for treating allergies and antiphlogistic diseases based on the given compounds.

9 cl, 9 tbl, 24 ex

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