Aminoguanidine, the method of production thereof and pharmaceutical composition based on them

 

(57) Abstract:

The invention relates to compounds of the formula

A-X--Y-NH-B

where A is derived from the possibly substituted benzothiophene, indole, 4-Aza - 7-Aza-benzothiophene or-indole; A bear in its 5th position hydrogen, halogen, possibly substituted alkyl, hydroxy, nitro, amino, alkylamino, acylamino, alkoxycarbonyl, sulfamoyl, cyano, trimethylsilyl, carboxy, carbarnoyl, phosphate, oxycarbonyl, heterocyclic radical or a group of simple or complex ester; X--Y - -CR8-N= or-CH(R8)-NH, where R8Is H or alkyl and is attached to A at position 3, and B is a heterocyclic radical or a residue of the formula

< / BR>
where R10- H, possibly substituted alkyl, cycloalkyl, aryl, substituted, acyl or carbarnoyl, and X - alkylthio or NR3R10where R3Is H or alkyl, or R3and R10together with the nitrogen atom to which they are attached, form a heterocyclic radical in free form or in the form of salts, which exhibit pharmaceutical activity, such as to treat disorders of the gastrointestinal tract. 3 S. and 7 C.p. f-crystals, 5 PL.

The invention concerns aminoguanidine used in pharmacology, methods for their production, including their formats the present invention relates to new compounds of the formula (I)

< / BR>
where W is S or NR1which R1hydrogen, C1-C6alkyl or acyl;

R2hydrogen, halogen or C1-C6alkyl;

R5hydrogen, halogen, C1-C6alkyl, hydroxy, nitro, amino, C1-C4alkylamino, acylamino, C2-C6alkoxycarbonyl, SO2NRaRb, in which each Raand Rbindependently hydrogen or C1-C6alkyl; cyano or trimethylsilyl;

or, if A-CR7= R5also C1-C6alkyl, substituted-SO2-C1-C6by alkyl, -SO2NRaRb, -CONRaRb, -NH-SO2-C1-C6by alkyl, -N(C1-C6alkyl)-SO2-(C1-C6alkyl),

-NRaR'bwhich R'bhydrogen, C1-C6alkyl, C3-C7cycloalkyl, C3-C6alkenyl, phenyl or phenyl-C1-C3alkyl, in which phenyl ring may substituted C2-C6alkoxycarbonyl, -PO(C1-C4alkyl)2or heterocyclic radical; carboxy; CONRaRb; -PO(C1-C4alkyl)2; OCONRcRd, in which each of Rcand Rdindependently are C1-C6by alkyl; or heterocyclization R4hydrogen, halogen, hydroxy or C1-C6alkyl or, if R5hydrogen or hydroxy, Z is - also-N=

A-N= or-CR7= in which R7hydrogen, halogen, C1-C6alkyl and C1-C6alkoxy,

or R1and R7together represent -(CH2)mor-X3(CH2)p- where m is 2, 3 or 4, p is 2 or 3 and X3is oxygen, S or-N(C1-C6alkyl)-, and X3attached to 6-membered ring;

X--Y-CR8=N or-CH(R8)-NH-, in which R8is hydrogen or C1-C6alkyl; and

B is a radical of formula (a) or (b)

< / BR>
where n is 1 or 2;

A1C=0 or CH2;

X1S, NR11or CR12R13which R11hydrogen or acyl, and each of R12and R13independently hydrogen, C1-C4alkyl or C5-C7cycloalkyl;

R10hydrogen, C1-C12alkyl, C1-C6alkyl, substituted hydroxy, aryl, aryloxy, adamantium, heterocyclic radical, -NR15-CO-R16or-NH-SO2-aryl; C5-C7cycloalkyl; aryl; substituted; acyl or-CONHR14in which R14C1-C10alkyl, C5-C7cycloalkyl, C5-C7cycloalkyl, C5-C15is hydrogen or C1-C4alkyl, and R16C1-C6alkyl, C5-C7cycloalkyl, C5-C7cycloalkyl-C1-C4alkyl, aryl or aryl-C1-C4alkyl, and

X2-SR20or-NR3R'10which R20C1-C6alkyl, R3hydrogen or C1-C6alkyl, and R'10has one of the values given above for R10or R3and R'10together with the nitrogen atom to which they are attached, form a 5-, 6 - or 7-membered saturated or non-aromatic unsaturated heterocycle, which may include further heteroatom selected from N, S and O and which may be further folded into a benzene ring,

provided that:

I) if B is a radical of formula (b), only one of R10and R'10may be other than hydrogen, and X2maybe-SR20only if R10hydrogen, and

II) R5not hydrogen when B is a radical of the formula

< / BR>
in which R'104-were in the form of aryl, each of Z and A is-CH= W--NH-, R2and R6each hydrogen, and X --Y is CH=N-,

and its physiologically hydrolyzable or acceptable complex or simple the ether, if R5hydroxy, in free form or in salt form.

5hydroxy, means ethers in which R5esterified and which can be either hydrolyzed under physiological conditions to receive alcohol or acids, which are physiologically acceptable, i.e. non-toxic at the desired levels of dosage.

Examples of the ether group as R5include, for example, C1-C6alkoxy, C1-C6alkoxy, substituted hydroxy, C1-C4alkoxy, acyloxy, NRaR'b, CONRaRbwhich Ra, Rband R'bsuch as defined above; C2-C6alkenylacyl, Z can be N-if R5the ether group.

Examples of ester as R5include, for example, acyloxy and pyridyl-carbonyloxy. If R5ester, it is preferably pyridyl-carbonyloxy. If A CR7= R5as the ether group is preferably acyloxy or pyridyl-carbonyloxy.

The compounds of formula I, the alkyl chain can be branched or straight. If R5, R10or R'10substituted by alkyl, Deputy preferably placed at the end of the alkyl chain.

Under the halogen preferably panicacci, polyamidine hydroxy, for example, 2,3-dihydroxy-propoxy.

Aryl is preferably phenyl or naphthyl, preferably phenyl, and may be substituted. Aryl-C1-C4alkyl, preferably phenyl-C1-C4alkyl, for example benzyl or phenethyl, and can be substituted on the phenyl ring.

Aryloxy preferably phenoxy, and may be substituted. Aryl-C1-C6alkoxy is, for example, benzyloxy, and can be substituted on the phenyl ring. If aryl or aryl groups are substituted, they may be mono - or polyamidine, for example, halogen, C1-C4the alkyl or C1-C6alkoxy. Examples are, for example, phenyl or phenyl groups, mono - or polyamidine chlorine, stands or methoxy.

Acyl group or atilov within acyloxy are preferably RCO, where R is a C1-C10alkyl, C2-C10alkenyl, C5-C7cycloalkyl or aryl, preferably C1-C10alkyl.

If each of R1and R11independently are acyl, it is preferably R CO where R' C1-C6alkyl, phenyl or phenyl-C1-C4alkyl, in particular C1-C6alkyl. If R10acyl, it 1-C10alkyl. If R5acyloxy, it is preferably R'-CO-o

Heterocyclic radical as R5is, for example, a radical deriving from oxazole, thiazole, isoxazol, oxadiazole or thiadiazole. If R5is a heterocyclic radical or includes such a radical, preferably a radical of formula (a)

< / BR>
where t is 0, 1, 2 or 3;

hydrogen or C1-C6alkyl;

X' is N or CH;

Y O; and

Z' n

Heterocyclic radical as R10or formed together R3and the nitrogen atom to which they are attached, is preferably a radical derived from a 5 - or 6-membered saturated, aromatic or unsaturated heterocycle, preferably condensed with a benzene ring, for example pyridine, imidazole, benzimidazole, pyrrolidine, pyrrolidone, piperidine, pyrazin or palikonda,

or a radical of formula (c), (d) or (e)

< / BR>
in which R22hydrogen or C1-C4alkyl;

B-CH2CH2-, -COCH2- or -(CH2)3- in which one or two H can be replaced by C1-C4the alkyl or 1,2-phenylene;

E-CH2CH2-, -CH2N(R17)- or -(CH2B> CO or CH2;

R17hydrogen or CC1-C4alkyl;

G CO-CHCOOR18, -CHCOR19, 5,5-dimethyl-1,3-dioxane-2-ilidene - or 1,3-dioxolane-2-ilidene, where R18is hydrogen or C1-C6-alkyl, and R19C1-C6alkyl; and n' is 0 or 1.

This heterocyclic radical may be further substituted, e.g. by halogen.

Examples of alkyl, substituted heterocyclic radical, are, for example, 2-(2-pyrrolidone-1-yl)-ethyl, 3-benzimidazolyl-propyl.

If B is a radical (b), in which R10hydrogen, and X2preferably R3and both are not hydrogen.

The compounds of formula I are the following values are preferred individually or in any combination or sub-combination:

1. W S, -NH-, -NCH3or NC2H5-. More preferably W is NH.

2. R2H, CH3C1or Br. More preferably, R2H.

3. Z CR4=

4. R4H or C1-C4alkyl, preferably H or methyl.

5. Z-N= R5is hydroxy or C1-C4alkoxy, and A is CR7=

6. R5H; -OH; or C1-C6alkoxy; or, if A - -CR7= R5also C1-C2-C1-C6by alkyl, -N(C1-C6alkyl)-SO2-C1-C6the alkyl or PO(C1-C4alkyl)2; acyloxy; carboxy; CONRaRb; -PO(C1-C4alkyl)2; or OCONRcRd.

7. A-CR7=

8. R7H or CH3.

9. X -- Y-CR8=N-.

10. R8H or CH3.

11. B is a radical of formula (a), preferably a radical of formula (a), in which X1Is-NH-.

12. B is a radical of formula (b).

13. R10H.

14. X .

15. R3hydrogen or C1-C4alkyl.

16. hydrogen, C1-C10alkyl, R"CO, CONHR14, -(CH2)1-5-NH-CO-R16or C1-C6-alkyl, substituted in the aryl, a radical of formula (d) or benzimidazolium. More preferably C1-C12alkyl.

17. R3and together with the nitrogen atom to which they are attached, form a 5-, 6 - or 7-membered, saturated or unsaturated non-aromatic heterocyclic group, which may include further heteroatom selected from N, S and O, and which may be further condensed with a benzene ring. More preferably R3and together with the nitrogen atom to which they join the group of compounds according to the invention is the group of compounds of formula I, in which W, R2, A, X -- Y and B such as defined above, Z is CR4= as defined above, and R5hydrogen, C1-C6alkyl, hydroxy, C1-C6alkoxy, C1-C6alkoxy, substituted hydroxy, C1-C4alkoxy, acyloxy, , CONRaR'bor CSNRaRbwhere each of Raand Rbindependently are hydrogen or C1-C6the alkyl and hydrogen, C1-C6alkyl, C3-C7cycloalkyl, C3-C6alkenyl, phenyl or phenyl-C1-C3alkyl, where the phenolic ring, possibly substituted; C2-C6alkenylamine; pyridyl-carbonyloxy; nitro; amino; C1-C4alkylamino; acylamino; C2-C6alkoxycarbonyl; SO2NRaRb; cyano, or trimethylsilyl;

or, if A-CR7= R5also is C1-C6by alkyl, substituted-SO2-C1-C6the alkyl, SO2NRaRb, CONRaRb, -NH-SO2-C1-C6by alkyl, -N (C1-C6alkyl)-SO2-(C1-C6alkyl), C2-C6alkoxycarbonyl or-PO(C1-C4alkyl)2; acyloxy; carboxy; CONRaRb; -PO(C1-C4alkyl)2; or OCONRcRdwhere Kagami compounds of formula I are compounds such in which W is NH, R2H, Z is-CH= or-CCH3= A is-CH= or-CCH3= R5hydrogen, hydroxy, C1-C6alkoxy, C1-C6alkyl, substituted-SO2-C1-C6the alkyl, SO2NRaRb-CONRaRb, -NH-SO2-C1-C6the alkyl, N (C1-C6alkyl)-SO2-C1-C6the alkyl, or-PO(C1-C4alkyl)2acyloxy, carboxy, CONRaRb, -PO(C1-C4alkyl)2or OCONRcRd.

Also especially preferred are compounds of formula I, in which W NR1; R2H; Z-N= A-CH= or-CCH3; R-OH or C1-C6alkoxy.

Even more preferred compounds of formula I are those in which W, R2, Z, A and R5have one of the values given above, and B is a radical or a radical of formula (b).

The compounds of formula I may exist in free form, in salt form, as well as MES or hydrate. Salts may include acid additive salts and salts that can be obtained when R5carboxy. Suitable pharmaceutically acceptable acid salt additive for use in accordance with the present invention, as described above, include the hydroxy, the suitable salts are, for example, salts of alkali metals such as sodium or potassium, or salts of substituted or unsubstituted ammonium.

It should be borne in mind that the compounds of formula I, in which X -- Y is-CR8=N and B is a radical of formula (b')

< / BR>
may exist as tautomers

< / BR>
where R2, R5, R6, R8, A, W, Z, and such as described above.

The compounds of formula I in which Z is-N= and R5hydroxy, can also exist as tautomers

< / BR>
where W, A, R2, B and X -- Y are such as defined above.

Note that when there are tautomeric forms, the invention covers all tautomeric forms and mixtures thereof, that is, although the compounds of formula I are defined for convenience with reference to only one guanidine and one-oxo-shape, it should be understood that the invention is in no way limited to a particular item and used a graphic image. The same applies to raw materials exhibiting guanidine-tautomerism, as described above.

In addition, the present invention also relates to a method for producing compounds of formula I, including:

a) to obtain the compounds of formula I, in koterayama, as defined above with a compound of formula III: H2N-NHB, where B is as defined above, or

b) to obtain the compounds of formula I, in which X -- Y is-CHR8=NH-, gidrogenizirovanii the compounds of formula I in which Y -- X is-CR8=N;

c) to obtain the compounds of formula I in which B is a radical of formula (b'), alkylation, acylation or carbamylcholine the compounds of formula Ia

< / BR>
where A, W, Z, R2, R5, R6and X -- Y are such as defined above,

d) to obtain the compounds of formula I in which R5hydroxy, splitting on essential communication of compounds of formula Ib,

< / BR>
where A, W, Z, R2, R6X -- Y and B such as defined above, and R5asplit the ether group; or

e) to obtain physiologically hydrolyzable and physiologically acceptable simple or complex ester compounds of the formula I, in which R5hydroxy, tarifitsirovana or acylation of compounds of formula I, where R5hydroxy, and the allocation of compounds of the formula I or their physiologically hydrolyzable and physiologically acceptable esters thus obtained in free form or in the form of MES or hydrate.

In the method, step a) can be carried out analogously to known what, bromatologia acid, or organic acids, such as acetic acid, p-toluene-sulfonic or pyridine-p-toluensulfonate acid. The reaction can be conveniently carried out in the presence of proton solvent, for example methanol, ethanol or isopropanol. The reaction is mostly carried out at a temperature between room temperature and boiling.

Stage b) can be carried out according to known methods gidrogenizirovanii. If R5benzyloxy, it can be simultaneously attached to the hydroxy group.

Stage c) can be carried out by means known in the field of methods. Alkylation or acylation of compounds of formula Ia can be conveniently carried out by reaction with alkyl, cycloalkyl or aryl-halide or acyl-halogenide or anhydride, respectively, preferably in the presence of a base, such as triethylamine or cause Hunya (Hunig). Carbamylcholine can be conveniently carried out by reaction with isocyanate, such as R14NCO, preferably in the presence of a solvent, such as dimethylformamide.

Stage d) of the method can be carried out analogously known in the field methods of the ether cleavage. If R5abenzyloxy, it (stage d) can Vesna coal. This reaction can be carried out in a solvent, for example ethanol, at a temperature from about room temperature up to 60oC.

R5acan be alkoxy, substituted alkoxy, alkenylacyl or benzyloxy.

Stage e) of the method may, for example, be carried out by reaction of compounds of formula I in which R5hydroxy, allelochemical, preferably with an acyl-chloride. The compounds of formula I in which R5- pyridyl-carbonyloxy, can be prepared by reaction of compounds of formula I in which R5hydroxy, halide nicotinic acid. This reaction can be conveniently carried out in a solvent such as triperoxonane acid or triptorelin-sulfonic acid.

Starting materials of formula II or III are either already known or can be obtained analogously to the methods known and used in the field.

For example, the compounds of formula II in which W is-NR1- can be obtained according to the following reaction scheme

< / BR>
Compounds of the above formula IV can be conveniently obtained by reaction of compounds of formula V with a reagent of Bredereck, for example, (CH3)2NCH(OCH3)2in the absence of solvent or in the presence of avago catalyst or with hydrazine in the presence of Raney Nickel (Raney).

The compounds of formula II in which W is-NR1- can be conveniently obtained by exposure to the compounds of formula IV modified reaction Vilsmaier, and then alkylation or acylation.

A modified reaction Vilsmeier can be carried out using dimethyl-alkylamine in the presence of POCl3according to known in the field methods. Alkylation or acylation can be carried out in a known manner, for example, in the presence of a base, for example, K2CO3or C2H5MgBr, in solution, such as dimethylformamide or tetrahydrofuran.

The compounds of formula III in which B is a radical of formula (b), in which X2not SR20can be conveniently obtained by reaction of compounds of formula VI

< / BR>
in which R10such as defined above, and

R21or NHNH2or with hydrazine, if R21it , or with the amine of formula if R21this is-NHNH2.

The reaction can mainly be made by heating at boiling point. It can be conveniently carried out in a solvent such as alcohol, such as methanol or ethanol, water or dimethylformamide, in the absence or in the presence of alkali with what dikala formula (b), in which X2this-SR20can be conveniently prepared by alkylation of compounds of formula VII

< / BR>
with R20-Affairs of the connection, in accordance with known methods.

Since the starting materials is not described in detail, it should be used known compounds or compounds that can be obtained analogously to known and used in the field methods, or as disclosed in the following examples.

These examples illustrate the invention but do not restrict it, and all temperatures indicated in them, are given in degrees Celsius.

Used the following abbreviations: THF tetrahydrofuran, DMF is dimethylformamide, Eton ethanol, MeOH methyl alcohol, Acoet - ethyl acetate, (II) foam, (III) the formation of slag.

Example 1. 5-Hydroxy-indole-3-carboxaldehyde [3-(2'-pyrrolidino-1'-yl)-propylamino] metilgidrat.

To a solution of 0.9 g of 5-hydroxy-indole-3-carboxaldehyde of diaminopyrimidine (4.1 mmol) in 10 ml of THF containing 2 ml of DMF and 0.9 ml of O3N (6.2 mmol) at room temperature add 1.3 g of 3-(2'-pyrrolidino-1-yl)-1-bromopropane (6.2 mmol). The mixture is stirred until the morning when 50oC. the mixture is about is: toluene (Eton) NH3in the ratio of 70:30: 2,5) to obtain the above title compound in crystalline form. So pl. 158oC (II). Mass spectral analysis (relative intensity): 343,3 (MH+, 100); 217,2 (20); 168,2 (20); 143,2 (23).

Example 2. 5-Hydroxy-indole-3-carboxaldehyde amino (N-methyl-N-heptylamine)metilgidrata.

To a solution of 0.48 g of 5-benzyloxy-indol-3-carboxaldehyde amino (N-methyl-N-heptylamine)-methylene-hydrazone (1.1 mmol) in Eton add 0.25 g of 10% Pd/C. the Suspension gidrogenit until morning at 45oC. Then the suspension is filtered through silica gel, the solvent is evaporated and the residue chromatographic on silica gel (eluent: toluene (Eton) NH3in the ratio of 85:15:1) to obtain the target compound. Clean material is crystallized from CH2Cl2(hexane in the ratio 2:8). So pl. 110o(III). Mass spectrum: m/z: 329 (M+, 40); 128 (40); 111 (60); 73 (50).

Source materials can be obtained in the following way:

a) To a solution of 3.2 g of 5-benzyloxy-indol-3-carboxaldehyde (12.7 mmol) and 5.0 g of 1-(N-methyl-N-heptyl)-3-N'-aminoguanidine, hydroiodide (16.0 mmol) in 100 ml MeOH was added when 5othe solution of MeOH/HCl to pH 3. After 2 h, the solvent is evaporated and the residue is placed in Acoet. The solution is washed with a solution of Na2CO3in the ratio of 85:15:0.5 in) to obtain the target compound. Mass spectrum m/z (relative intensity): 420 (MH+, 100); 330 (7); 249 (4); 172 (16).

b) 1-(N-methyl-N-heptyl)-3-N'-aminoguanidine hydroiodide.

The solution containing 4.7 g of 3-methyl-isotopologues of hydroiodide (20 mmol) and 3.7 ml of N-methyl-N-heptylamine (22 mmol) in 30 ml of methanol is subjected to reflux for 6 hours the Solution was then cooled to room temperature and the solvent is evaporated to obtain 1-(N-methyl-N-heptyl)-3-N'-aminoguanidine of hydroiodide. The resulting crude material is used for the next step without additional purification.

Example 3. 5-Hydroxy-indole-3-carboxaldehyde amino (N-cyclohexylurea)metilgidrata

To a solution of 0.8 g of 5-hydroxy-indole-3-carboxaldehyde of diaminopyrimidine (3.7 mmol) in 20 ml DMF added dropwise within 5 minutes at 0oto a solution of 0.5 ml of cyclohexyl-isocyanate (4.0 mmol) in 5 ml of DMF. The solution is stirred for 4 hours the Solvent is then evaporated and the residue chromatographic (eluent: toluene (Eton) NH385:15:0.5 in) to obtain the target compound in the form of crystals. So pl. 135o(II). Mass spectrum: m/z (relative intensity): 343 (MH+, 100); 244 (50); 218 (85); 159 (33).

Example 4. 5-Hydrox is according to example 2. So pl. 125o(II).

5-Benzyloxy-6-fluoro-indol-3-carboxaldehyde used as starting material may be obtained as follows:

a) 2-nitro-4-fluoro-5-benzyloxy-toluene.

To a solution for 85.6 g of 2-nitro-4-fluoro-5-hydroxy-toluene (0.5 mol) in 1300 ml of acetone is added at room temperature 138 g K2CO3(1.0 mol). 72 ml of benzyl bromide (0.6 mol) then add dropwise within 1 h and the resulting mixture is stirred until the morning at 60o. The solvent is evaporated and the residue is placed in Acoet. The precipitate is removed by filtration, and the solution washed with water. The organic layer is dried over sodium sulfate, the solvent is evaporated, and the residue will recrystallized from hexane to obtain 2-nitro-4-fluoro-5-benzyloxy-toluene. So pl. 95o. Mass spectrum: m/z 261 (M+).

b) 2-[1'-(N, N-dimethylamino)-ethen-2'-yl] -4-benzyloxy-5-fluoro-nitrobenzene.

A solution of 126 g of 2-nitro-4-fluoro-5-benzyloxy-toluene (0.48 mol) in 200 g of bis-dimethylamino-t-butoxy-methane (1.15 mol) is stirred until the morning when the 90o. Then the solvent is evaporated and the residue crystallized from MeOH to obtain (b) target compound as red crystals. So pl. 146o. Mass spectrum: m/z 316 (M+).

c) 5-Benzyloxy-6 - hydrogenizing at room temperature. After 4 h, the suspension is filtered through "Ryflo, and the solvent is evaporated. The remainder chromatographic average pressure (eluent: toluene) to obtain the target compound, which crystallized from hexane. So pl. 126o. Mass. spectrum: m/z 241 (M+).

d) 5-Benzyloxy-6-fluoro-indol-3-carboxaldehyde.

3,3 ml POCl3(36,0 mmol) is added dropwise at 0oto 14 ml of DMF (180 mmol). After 15 min dropwise within 10 min add 7.30 g of compound c) (30 mmol) in 14 ml of DMF. The mixture is stirred for 1 h at room temperature, then diluted with cold water, and then added dropwise 7.2 g of NaOH in 50 ml water. The residue is filtered and washed with water. The obtained solid substance chromatographic on SiO2(eluent: CH2Cl2) and crystallized from ether to obtain the target (d) connection. So pl. 190o. Mass. spectrum: m/z (relative intensity): 269 (M+, 72); 178 (20); 150 (15); 91 (100); 65 (38).

Example 5. 5-Hydroxy-indole-3-carboxaldehyde amino (butyramide) metilgidrata.

To a solution of 0.5 g of 5-hydroxy-indole-3-carboxaldehyde of diaminopyrimidine (2.3 mmol) in 5 ml of DMF is added dropwise a solution of 0.4 ml of butane-anhydride (2.5 mmol) in 5 ml of DMF. After 7 h at room temperature will rastvoriteleyj target connection, which precipitated from hexane. So pl. 90o(II). Mass. spectrum: m/z (relative intensity): 287 (M+, 16); 217 (8); 200 (4); 158 (30); 98 (100); 70 (46).

Example 6. 5-Hydroxy-indole-3-carboxaldehyde amino (pentyl-amino)-metilgidrata triptorelin.

Melting point 138o.

Example 7. 5-Hydroxy-indole-3-carboxaldehyde amino (pentylamine)-metilgidrata triptorelin.

To a solution of 1.0 g of 5-hydroxy-indole-3-carboxaldehyde-amino (pentylamine) metilgidrata (3.5 mmol) in 10 ml of CF3CO2H add to 0.72 ml hexanolactone (5.2 mmol) at 0o. After 3 h the reaction is quenched with a 2N solution of Na2CO3and the mixture is stirred for 20 minutes Add Acoet, and the separated organic layer was washed with brine and dried over sodium sulfate. The solvent is then evaporated, and the residue is washed with ether to obtain the crystal of the target compounds. So pl. 205o. Mass. spectrum: m/z 385 (M, 20); 160 (30); 158 (25); 69 (100).

By the above the following procedure can be obtained the compounds of formula IA

< / BR>
in which R5, R6and such, as defined in the table.I.

By the above procedure, can be obtained the following compounds fo'-2'-imidazolin-4'-IMT-hidradenitis]-indole.

Melting point 110o(II).

Example 88.

< / BR>
So pl. 239o.

Following the procedure as disclosed above, can be obtained the compounds of formula IC, in which R1, R3, R4, R5, R7and R'10such as defined in the table.III below.

< / BR>
By following the procedure disclosed above, can be obtained the compounds of formula ID, in which R5and such as in table. IV, below.

By following the procedure as disclosed above, can be obtained the following compounds of formula IE

< / BR>
in which R7and such, as defined in the table.V below.

Example 113. (7-Azaindole)-3-carboxaldehyde amino(pentylamine) methylene-hydrazine.

So pl. 78o(III).

Example 114. 5-Hydroxy-6-fluoro-indol-3-carboxaldehyde of amidinopropane.

So pl. 168o(II).

5-(Dimethylphosphino)-indole-3-carboxaldehyde used as the starting material to obtain the compound from example 52, may be prepared according to example 4 (d) of indole-5-dimethylphosphine oxide.

Indole-5-dimethylphosphine oxide can be prepared thus:

Example 115. Indole-5-(dimethylphosphine oxide).

Races 30 ml of ether. After 10 min, to the mixture add a solution ClPO(Me)2(10 mmol) in 10 ml of THF. The reaction mixture was left to warm to room temperature for 6 hours, water is Added and Acoet, the organic layer is separated, and the aqueous phase extracted with Acoet. The organic phases are combined and washed with brine, dried, and the solvent is evaporated. The remainder chromatographic on SiO2(eluent: CH2Cl2/MeOH 95:5) to give the target a) connection. So pl. 180o.

b) Indolin-5-(dimethylphosphine oxide).

A solution of compound a) (1.5 mmol) in 20 ml of MeOH containing 0.2 g of Pd/C hydrogenizing within 2 hours the Solution is filtered over Hyflo and the solvent is evaporated to obtain the target b) connection.

c) Indole-5-(dimethylphosphine oxide).

A solution of compound b) (1.5 mmol) in 25 ml of xylene containing 100 mg of Pd/C are heated to boiling for 3 hours the Solution is filtered over Hyflo, and the catalyst was washed with CH2Cl2. The solvent is evaporated to obtain the target compound (c). So pl. 195o.

5-Hydroxy-benzothiophen-3-carboxaldehyde and 5-methoxybenzamide-3-carboxaldehyde used as starting compounds for preparing compounds according to examples 104-107; can be prepared slide sulfide.

0,165 mol of sodium hydride is added at the parts at 0oto a solution of 4-methoxy-thiophenol (0.15 mol) in 300 ml THF. After 1 h, add chlorate. The mixture is stirred until the morning when the room temperature. Then the solvent is evaporated, and the mixture was dissolved in CH2Cl2and washed with 2N Na2CO3. The organic phase is dried, and the solvent is evaporated to obtain the target compound a), which is used without further purification.

b) 3-Methyl-5-methoxy-benzothiophen.

0.15 mol of compound (a) added for 1 h at boiling to a solution of polyphosphoric acid (to 0.17 mol) in 1 l of chlorobenzene. This solution is stirred while boiling until the morning. The mixture is filtered and the filtrate is evaporated. The crude product chromatografic on SiO2(eluent: hexane to obtain the target b) connection.

c) 5-Methoxy-3-methyl bromide-benzothiophen.

0.01 mol NBS and crystal dibenzoylperoxide added to a solution of compound b) (0.01 mol) in 60 ml of tetrachlorophenol. The mixture is stirred at boiling for 1.5 hours, the Suspension is filtered and the filtrate is evaporated. The oil obtained crystallizes when cooled and further used without additional purification.

d) 5-Methoxy-benzothiophen-3-carbox the form. The mixture is stirred at boiling for 6 hours After cooling, the suspension was added to it ether; and the solid is separated by filtration. The residue is dissolved in 100 ml of 50% CH3COOH and the mixture is heated at boiling for 3 hours Then add 130 ml of water and 25 ml conc. HCl and the mixture is boiled for another 5 minutes the Mixture is cooled on ice. Crystallized target compound d) is separated by filtration and washed with water. So pl. 50o.

Example 117. 5-Hydroxy-benzothiophen-3-carboxaldehyde.

A solution of BBr3(0.07 mol) in 15 ml of CH2Cl2add at 0oto a solution of 0.014 mol 5-methoxy-benzothiophen-3-carboxaldehyde in 80 ml of CH2Cl2. After 4 hours of standing add 2N Na2CO3to pH 7. The organic solvent is evaporated and the suspension filtered. The solid is washed with water to obtain a crude product in the name of the example, which will recrystallized from a mixture of CH3OH/H2O. T. pl. 200o.

The compounds of formula I and their pharmaceutically acceptable salts (hereinafter referred to as compounds according to the invention) exhibit pharmaceutical activity and are therefore useful in pharmacology.

In particular, the compounds according to the invention have stimuleringen test models for example.

Unipolar electrodes implanted into the serosal side of the intestine (small intestine) dog (Beagle). Of these electrodes, the signals in the amplifier and filtered to register potential low and high frequencies to separate slow cuts from sharp. The number of peaks (sharp reductions) is determined over a period of 2 minutes on this Basis, get the following results: duration of phases I-III, the interval between two consecutive blocks of phase III, the speed of propagation. One or two cycles of the record before the introduction of drugs, which is performed by subcutaneously in 10-15 min after phase III, the last the most distal electrode. Control experiments carried out usually through the introduction of a solvent. We fed the dogs a number of sharp contractions for 30 min was determined additionally. In this experiment, the compounds according to the invention stimulate myoelectrically activity in doses of the order of from about 0.001 to 10 mg/kg s. C. (subcutaneously).

Next, stimulatory effect on the activity of the gastrointestinal tract of the compounds according to the invention demonstrates, for example, their effect on the peristaltic reflex in the colon separated moogo plot colon 4-5 cm in length were removed and suspended, as described by Trendelenburg in "Arch. Exp. Path. Pharmacol." 81, 55-129 (1917), in 20 ml of bath during initial start up 1, the Tissue is incubated at 37oin a modified Krebs solution (NaCl 118,6; CaCl22,7; KCl 4,7; KH2PO41,2; MgSO40,1; NaHCO325,0; glucose 5.6 mm), and blew 5% CO in the oxygen. Peristalsis caused 30 by increasing the pressure in the lumen from zero to 1-4 cm with water. The measurements were carried out at the reaction of the longitudinal (smooth) muscles using a displacement sensor isotonic strength and activity of the circular muscle by using a pressure sensor. The area under the curve (abbreviated AUC) peristaltic contractions and determine curves of the reaction depending on the concentration set by defining AUC, representing the activity of longitudinal and circular muscles. Each drug is used as its own control, taking over 100% of peristaltic activity prior to the introduction of the test compounds. Test compounds are added to the serosal side and left in contact with it for 15 minutes In this experiment, the compounds according to the invention had a stimulating effect on peristaltic activity at concentrations of the order of about 10-10up to 10-7lubochna-intestinal tract, for example, to normalize or to improve gastric evacuation and intestinal permeability in patients with a disorder such activity, for example a disease characterized by gastro-esophageal reflux, decreased peristalsis of the esophagus and/or stomach and/or fine and/or intestine, or to treat inflammation of the esophagus, gastroparesis, dyspepsia, nedeljni dyspepsia of pseudoprobability (pseudotumoral intestines), obstruction of the colon, jejunum, the syndrome of acute abdomen, bloating, pain in the stomach, postoperative atony intestines, recurrent nausea and vomiting, nervous exhaustion or dyskinesia of the biliary system.

Further, the compounds according to the invention are also indicated for use in the treatment of psoriasis bladder control allocation cotisol/aldosterone, or to improve memory and memorization.

For the above-mentioned applications, the required dosage will of course depend largely on the route of administration, the particular condition to be treated and the desired effect. Shows daily doses are in the range of about from 0.01 to 3 mg, for example from about 0.01 to 1 mg for parenteral use, or from about 0.1 is Ni, or in forms with delayed release of drugs. Accordingly, unit dosage forms for oral administration include approximately 0,0025-1.5 mg of the active ingredient (i.e. connection according to the invention or its pharmaceutically acceptable salt), mixed with a suitable solid or liquid, pharmaceutically acceptable diluent or carrier.

In accordance with the above, the present invention also provides:

I) a Method of treatment of disorders of the activity of the gastrointestinal tract, for example, by stimulating the motility of the gastro-intestinal tract, bladder dyskinesia, regulation, allocation cortisol/aldosterone or improve memory and remember the person in need of such treatment, introducing a specified person an effective amount of the compounds according to the invention or its pharmaceutically acceptable salt.

Further, it was found that the compounds according to the invention have antiserotoninergic activity, acting on specific receptors 5-HT4as has been demonstrated in standard animal models, for example, as follows: isolated from the body of the Guinea pig longitudinal muscle of the colon is th study of the mechanism of action of neurotransmitters (neurotransmitters).

Method. Guinea pigs (males weighing 200-400 g) were scored by a blow on the head and was driven away. Length removed the small intestine is approximately 2 cm from ileo-ceilinga valve. A piece of the colon stretches over a glass rod and carefully remove mesentery. A layer of longitudinal muscles are separated and removed from the underlying layer of circular muscles tangential motion away from mesenteric connection (i.e. from the mesentery). Plots of the longitudinal muscles of 4-5 cm in length placed in a 10 ml bath for bodies containing Tyrode solution at 37oand rinsed with 5% carbon dioxide in oxygen. The Tyrode solution contains the following substances concentration, mol/l: NaCl 137,0; CaCl21,8; KCl 2.7; The MgCl 1,05; NaHCO311,9; NaHPO4of 0.4; glucose 5,6; and methysergide of 0.1 M. the Sections of intestine were maintained under constant tension efforts to 500 mg. Reduction was recorded using isotonic swinging arm. After equilibration for 30 min was applied specified concentration carbachol in 10-minute intervals until it reached a constant reaction.

Obtaining a curve of concentration and reaction.

Curve response to non-cumulative concentration for 5-HT stipulated in the previous experiments have shown, these intervals were long enough to avoid tachyphylaxis. Each concentration left in contact with the tissue for 1 min Every part of the intestine is used only once to record two curves of reaction on concentration: the first for only one 5-HT, and the second for 5-HT in the presence of prescribed concentration of antagonist, and each plot served as thus your own control. Antagonists allow pre-balanced for at least 10 min before addition of 5-HT. The concentration, expressed in percent of the maximal response to 5-HT, which were obtained from several drugs celebrated as the average values to obtain the logarithmic curves of reaction from concentration. The inhibition constants expressed as values pA2that determine graphically by conventional methods (Arunlakshana and other 159, McRay, 1978).

In this experiment, 5-HT exerts dependent on the concentration contractile action. 5-HT causes this is the basic contractile activity in muscle longitudinal muscle area of the colon of the Guinea pig by the release of substance P from nerve endings in the tissue. This action passes on the release of substance P. Released substance P activates neural receptors substance P, and this causes the release of acetylcholine, which then activates muscarinic receptors, located on the smooth muscle cells, and causes them to fall. At higher concentrations of 5-HT activates the second neural receptor, which leads to the release of substance P to activate receptors substance P in the cells of smooth muscles, crying out at the same time.

Compounds according to the invention is mainly act on the blocking receptors high affinity to 5-HT4by inhibiting this caused by 5-HT reduction, for example, at concentrations of approximately 10-8up to 10-6mol/L. These compounds exhibit less antagonistic activity to the receptor sites of low affinity to 5-HT3.

Compounds according to the invention are therefore useful for the treatment of motility disorders of the gastrointestinal tract, such as tachygastria, difficulties with evacuation of the stomach due to tachygastria syndrome acute abdomen, intestinal spasms, cramps, constipation due to increased tone of the colon, disease, gastro-esophageal reflex and dyskinesia of the biliary system. Prov.forming agents, as demonstrated by the standard experiments, for example, using rats with induced ethanol lesions of the stomach.

These experiments were performed on male animals rats weighing 200-250 g, which were not fed for the night, but had free access to water. The test substance was administered subcutaneously or orally through a metal gastric tube. Absolute alcohol were asked orally within 30 minutes after administration of the test substance and animals scored an hour later. The stomach was opened by incision along the greater curvature and pinned flat. Hemorrhagic erosion was assessed in two ways: by area and length of erosions.

After subcutaneous administration of the compounds according to the invention as the test substance at a dose of from about 0.1 g/kg to 10 mg/kg, there is significant inhibition of gastric damage induced by ethanol, compared with the results obtained with a control group that received placebo instead of the test substance.

Compounds according to the invention, respectively, is shown for use in the treatment or prevention of gastrointestinal disorders such as gastric ulcer and duodenal ulcer.

Connection seita, duodenitis, including inflammatory bowel disease, nausea and vomiting. Further, they also indicated for the treatment of arrhythmia, tachycardia, dyskinesia of the bladder, such as incontinence of urine, to reduce the frequency of attacks or to reduce stress reactions.

For the above-mentioned applications the required dosage will of course vary depending on route of administration, the particular condition to be treated and the desired effect. As shown, the dose is in the range from about 5 g to 5 mg for parenteral use and the order of about 0.1 to 100 mg for oral administration, preferably injected once or in divided doses 2-4 times a day, or in the form of a delayed release of the drug. The unit dose for oral administration respectively include approximately 0.025-50 mg of the compounds according to the invention is mixed with an appropriate solid or liquid pharmaceutically acceptable diluent or carrier of the active ingredient.

In accordance with the foregoing the present invention also provides:

II) a Method of treating any of the above disorders or conditions in persons, which need such treatment, introducing a SS="ptx2">

Further, it was found that the compounds according to the invention have an antagonistic effect on the Central 5HT-1C receptors.

Compounds according to the invention have the potential binding affinity to the Central 5HT-1C receptors, as for example was measured according to the method disclosed by Hoyer and others (Hoyer, Eur. J. Pharmacol. 118, 13-23 (1985)).

Compounds according to the invention are antagonists of lower activity (hypolocomotion), which is caused in rats by the introduction of m-chlorophenyl-piperazine (msrr), according to the method of Kenneth and Curzon (Kennet and Curson Br. J. Pharmacol. 94, 137-147 (1988)). In this experiment, the compounds according to the invention resisted called MSR effect after their introduction in doses of from about 0.1 to 30 mg/kg of live weight.

Compounds according to the invention is therefore useful in the prophylactic treatment of migraine or for the treatment of psychiatric diseases, such as excitation, obsessions, anxiety, depression, bulimia (eating disorder), schizophrenia, situations with increased intracranial pressure and priapism.

For the above mentioned applications the required dose will, of course, differ depending on the route of administration, the particular condition of the patient and the desired effect. Shown dnevna 2-4 servings per day dosage, or in the form of a slow release of the drug.

In accordance with the foregoing, the present invention also provides:

III) a Method of prophylactic treatment of migraine or in the treatment of psychiatric disorders in individuals in need of such treatment, introducing a specified person an effective amount of the compounds according to the invention or its pharmaceutically acceptable salt.

Compounds according to the invention also have agonistic effects on 5HT-1D receptors. Their binding affinity to 5HT-1D receptors was determined, for example, by the method of Weber and others (Waeber, Naunynschmiedeburg''s Arch. Pharmacol, 337, 595-601 (1988)).

Agonistic effect is further demonstrated by the following experiment.

Anterior cerebral artery cut of pork brains obtained from the local slaughterhouse. All sections of 3-4 mm length is placed between the two I-shaped metal prongs and placed in the bath for bodies with controlled (37oC) temperature, filled with Krebs solution, which is continuously rinsed with 5% CO2in the oxygen. Agonistically induced vascular contraction measured isometrically. In order to measure only the effect on 5HT-1D the 5HT-2 receptors. Compounds according to the invention cause vascular contraction at a concentration of from 10-10up to 10-5M, in particular 10-910-7M

Compounds according to the invention is therefore useful for the treatment of conditions associated with headache, in particular for the treatment of migraine, the concentrated headache, chronic paroxysmal cranial pain and headache associated with vascular disorders, as well as to mitigate the symptoms associated with these diseases.

For the above mentioned applications, the dosage will of course vary depending on route of administration, the particular condition of the patient and the desired effect. Shows daily dose is in the range of about 0.5 to 300 mg, preferably typed one-way or divided doses for 2-4 servings per day, or in the form of sustained-release drugs.

In accordance with the foregoing, the present invention also provides:

IV) a Method of treating conditions associated with pain brain, such as described above, providing for the introduction to the patient an effective amount of the compounds according to the invention or its pharmaceutically acceptable salt.

Connection is to be prepared in a traditional manner and exhibit the same level of activity, that and the free connection. Suitable pharmaceutically acceptable salts of the compounds according to the invention include, for example, hydrochloride.

Further, the present invention also provides:

V) the Compound according to the invention or its pharmaceutically acceptable salt, for use as a pharmaceutical, e.g. in any of the above methods.

VI) a Pharmaceutical composition comprising the compound according to the invention, as described above, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable diluent or carrier for him. This composition can be produced in a traditional way, for example by mixing the ingredients.

The compounds of formula I in which R1H, A-N= or-CH=, and Z is-CH= or where R1H, A-CH= Z-N= or-CH= and R5is hydroxy or C1-C6alkoxy, possess, for example, stimulatory effect on the motility of the gastrointestinal tract and therefore can be used in the method according to the invention, for the treatment of disorders of motility, for example, by stimulating peristalsis of the gastrointestinal tract, as indicated above, for the treatment of psoriasis bladder, modulate the release of Corti is 13 and 108.

The compounds of formula I in which R1in W and/or R7in A are not hydrogen, are, in particular, antiserotoninergic the effect of the specific 5-HT4receptors, and inhibit erosion of the stomach caused by necroticism agents, and therefore can be used as antiulcer or improving the mobility agent in the method according to the invention, for the treatment of gastrointestinal disorders and for the prevention or for the treatment of gastric ulcer and duodenal ulcer. They also indicated for the treatment of diarrhea, inflammation of the stomach or intestines, such as gastritis, duodenitis, including inflammatory bowel disease, nausea and vomiting, arrhythmia, tachycardia, dyskinesia of the bladder, such as incontinence, to reduce the frequency of attacks, reduce the likelihood of an attack or to mitigate stress reactions. Preferred are compounds according to examples 89, 90 and 97.

The compounds of formula I in which R5H, -OH, C1-C6alkoxy or nitro; R2H, Cl, Br or C1-C6alkyl; Z is CR4= where R4H, C1-C6alkyl, Cl or Br; A is-CR7= where R7H or C1-C6alkyl; preferably those in which B is radicula, have an antagonistic effect on the Central 5HT-1C receptors and can therefore be used for the prevention of migraines and to treat psychiatric disorders, such as agitation, delusions, anxiety, depression or bulimia. It is preferable compound 38.

The compounds of formula I in which R5H, -OH, C1-C6alkoxy, carboxy, C2-C6alkoxycarbonyl, CONRaRb, SONH (C1-C6alkyl), C1-C6alkyl, substituted SO2C1-C6the alkyl, or PO(C1-C4alkyl), W is NH, A is CH= Z-CH= and R2and R6each are H, especially those in which B is a radical or a radical (b), in which X2- C1-C12alkyl or CONH-C6H11have, in particular, agonistic effect on 5HT-1D receptors, and can therefore be used for treating conditions associated with pain brain, for example, as described above. Particularly preferred compounds according to example 63.

1. Aminoguanidine General formula

< / BR>
where W is S or NR1where R1hydrogen, C1- C6-alkyl or acyl;

R2hydrogen or C1C6-alkyl;

R5hydrogen, halogen, C1aRb, -NH-SO2-C1- C6-alkyl or N-RaRb1where each Ra, Rband R1independently hydrogen or C1C6-alkyl, and NO2, NH2CN, trimethylsilyl,2- C6-alkoxycarbonyl, SO2NRaRb, -COOH, OCONRcRdwhere each Rcand Rdindependently - C1C6-alkyl, C1C6-alkoxy, C2- C6-alkenylamine, benzyloxy; C1C6-alkoxy, HE substituted C1C4-alkoxy, acyloxy, -NRaRb1, -CONRaRbor-CSNRaRbacyloxy, pyridylcarbonyl, CONRaRbor RO(C1- C4-alkyl)2;

R6hydrogen or when R5HE, R6halogen;

Z-CR4= where R4hydrogen, hydroxy or C1- C6-alkyl or, if R5hydrogen or hydroxy, Z N

A-CR7where R7hydrogen, C1C6-alkyl or C1C6-alkoxy;

B is a radical of formula (a)

< / BR>
or formula (b)

< / BR>
where n is 1 or 2;

A1C=O or CH2;

X1S, CH2, NR11where R11is hydrogen or acyl;

X2NR3R'10where R'1SUB>-alkyl, C1- C6-alkyl, substituted hydroxy, phenyl, phenyl mono - or disubstituted by fluorine, chlorine, stands or metaxylem, phenoxy or phenoxy-substituted by halogen, pyridium, imidazolium, benzimidazolium, pyrrolidinium, pyrrolidinium, piperidinemethanol, pergidrolya, or a radical of the form (d)

< / BR>
where E is CH2N(R17), where R17hydrogen or C1C4-alkyl and one or two of hydrogen, which can be substituted C1C6-alkyl;

E1CO or CH2;

R20C1C6-alkyl;

R3hydrogen or C1C6-alkyl or C1C6-alkyl, substituted-NR15-CO-R16or NH-SO2-aryl, where R15hydrogen or C1- C6-alkyl, R16WITH1C6-alkyl, phenyl or phenyl-C1C4-alkyl, or CONHR14where R14C1C10-alkyl, C5- C7-cycloalkyl, phenyl or phenyl-C1C4-alkyl, or

R3and R'10together with the nitrogen atom to which they are attached, form piperidinyl or peritoneally radical;

R2C1C6-alkyl;

X-Y is-CR8=N - or-CH(R1
0and R'10may be other than hydrogen, and X2maybe-SR20if R10hydrogen, and (II) R5not hydrogen when B is a radical of the formula

< / BR>
in which R'10phenyl or phenyl mono - or disubstituted by fluorine, chlorine, CH3or CH3O;

Z and A are each-CH= W= -NH-;

R2and R6each hydrogen;

"X Y is CH=N-,

in free form or in salt form.

2. The compound of the formula I

< / BR>
where W, R2, A, "X Y" and B, Z have the above meanings;

R5hydrogen, hydroxy, C1C6-alkyl, C1- C6-alkyl, substituted-SO2-C1C6-alkyl, -SO2NRaRb, -NH-SO2-C1C6-alkyl or NRaR'bwhere each of Raand R'bindependently is hydrogen or C1C6-alkyl, NO2, NH2CN, trimethylsilyl,2C6-alkoxycarbonyl, -SO2NRaRb, -COOH, -OCONRcRdwhere each Rcand Rdindependently C1C6-alkyl, C1- C6-alkoxy, C2C6-alkenylamine, benzyloxy, C1- C6-alkoxy, HE substituted C1C4-alkoxy, acyloxy, -NRaR'b, -CONRaRbor-CSNRaR< 3. Connection on p. 1, in which W is NH, A is-CH= Z-N= R5H or OH.

4. Connection under item 1 or 2, in which W is-NR1and/or A - CR7= where R1and/or R7different from the other.

5. Connection under item 1 or 2, in which R5hydrogen, OH, C1C6-alkoxy, carboxy, C2C6-alkoxycarbonyl, CONRaRb, SO2NH(C1C6alkyl, C1- C6-alkyl, substituted SO2C1C6-alkyl, or RO(C1C6)2, W is NH, A is-CH= Z-CH= and R2and R6the hydrogen.

6. Connection on p. 1 which is 5-methoxy-indol-3-carboxyaldehyde amino(pentylamine)metilgidrata in free form or in salt form.

7. Connection on p. 1, which is 5-methoxy-indol-3-carboxyaldehyde(pentylamine)metilgidrat, 5-hydroxy-indole-3-carboxaldehyde-(-cyclohexylurea)-metilgidrat, 5-hydroxy-indole-3-carboxaldehyde(3-benzimidazole-2-yl-propylamino)metilgidrat, 5-carbamimidoyl-3-carboxaldehyde(phentolamine)metilgidrat, 5-hydroxy-7-methylindol-3-carboxaldehyde(pentylamine)metilgidrat, 1-ethyl-5-hydroxyindole-3-carboxaldehyde(pentylamine)metilgidrat-5-hydroxy-7-metering the laminitis)metilgidrat in free form or in salt form.

8. The method of obtaining compounds of General formula I on p. 1, characterized in that conduct the interaction of the compounds of formula II

< / BR>
where A, W, Z, R2, R5, R6and R8defined in paragraph 1,

with the compound of the formula III:

H2N-NHB,

where B is specified in paragraph 1,

and, where required, carry out the hydrogenation of the obtained compound of formula I, where X-Y is-CR8=N,

and produce the compounds of formula I in free form or in the form of a salt, solvate or hydrate form.

9. Connection PP.1 7, has a stimulating effect on the gastrointestinal motility, antiserotoninergic effect on 5 - HT4receptor antagonistic action on Central 5-HT - 1C-receptor agonistic action of 5 HT 1D receptors.

10. Pharmaceutical composition having a stimulating effect on the gastrointestinal motility, antiserotoninergic effect on 5 - HT4receptor antagonistic action on Central 5-HT - 1C-receptor agonistic action of 5 HT-preceptory containing an effective amount of the compounds of formula I on PP.1 7 or its pharmaceutically acceptable salts and additives target.

 

Same patents:

The invention relates to certain new derivative thimerisol, provides a way of obtaining them and relates to methods and compositions for use as antibacterial agents

The invention relates to complex compounds of iron, used in medicine, namely to search for new treatments for cancer
The invention relates to medicine, namely to dermatology, and can be used for the treatment of psoriasis
The invention relates to medicine, namely to psychiatry
The invention relates to medicine, namely to psychiatry
The invention relates to medicine, namely to the pathology and can be used for the treatment of patients with vibration disease (WB)
The invention relates to medicine, namely to psychiatry

The invention relates to medicine, namely to the production of medicines on the basis of [N-methyl-N-(D-glyukopiranozil)ammonium-2(acridin-9-one-10-yl)acetate]cycloferon, and can be used for the treatment of atherosclerosis and its complications

FIELD: organic chemistry, natural compounds, medicine, oncology.

SUBSTANCE: invention represents new saponin mixtures used for inhibition of initiation and activation of mammalian epithelial cell in pre-malignant or malignant state, for stimulation of apoptosis of mammalian malignant cell, prophylaxis of anomalous proliferation of mammalian epithelial cell, for treatment of inflammatory and regulation of angiogenesis in mammal. These mixtures are isolated form plants of species Acacia victoriae. Also, invention relates to methods for their applying. These compounds can comprise triterpene component, such as acacic or oleanolic acid to which oligosaccharides and monoterpenoid components are joined. Mixtures and compounds elicit properties associated with regulation of apoptosis and cytotoxicity of cells and strong anti-tumor effect with respect to different tumor cells.

EFFECT: valuable medicinal properties of compositions.

43 cl, 53 tbl, 50 dwg, 44 ex

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

SUBSTANCE: invention relates to new derivative of taxane of the formula (I):

that elicits strong antitumor effect. Also, invention relates to intermediates substances, a method for preparing compound of the formula (I), a method for preparing 1,14-β-hydroxy-1,14-carbonate-baccatin III-derivatives substituted with isoserine residue at position 3 and to pharmaceutical composition based on compounds of the formula (I). Invention provides preparing new derivative of taxane that elicits higher activity and reduced toxicity as compared with paclitaxel.

EFFECT: improved preparing method, enhanced and valuable medicinal properties of compound.

10 cl, 7 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of borrelidin of the general formula (I)

wherein R represents the group of the general formulae -COOR1, -CONR2R3, -CONR4CONR2R5 or -CH2OR6 wherein R1 represents (C2-C6)-alkyl group, (C1-C6)-alkyl group substituted with hydroxyl group or 5-8-membered saturated nitrogen-containing heterocyclic group (it can comprise oxygen atom in addition to nitrogen atom) or 5-6-membered nitrogen-containing aromatic heterocyclic group or (C3-C6)-cycloalkyl group; R2 and R3 are similar or different and represent independently hydrogen atom or (C1-C6)-alkyl group that can be substituted optionally with hydroxyl, (C2-C5)-alkoxycarbonyl or 5-8-membered saturated nitrogen-containing heterocyclic group (it can comprises oxygen atom in addition to nitrogen atom) or 5-6-membered aromatic homocyclic group or aromatic heterocyclic group comprising oxygen and/or nitrogen atom, 5-6-membered cycloalkyl or heteroaryl group; R4 and R5 are similar or different and represent independently hydrogen atom or (C3-C6)-cycloalkyl group; R6 represents hydrogen atom; also, invention relates to tautomers, solvates of these compounds, their mixtures and acid-additive salts. Also, invention relates to pharmaceutical compositions comprising compounds of the general formula (I) as an active component. Angiogenesis inhibitors of the present invention inhibit formation of new vessels in tissues of live organisms and can be used for prophylaxis and inhibition of the angiogenesis process arising in the tumor proliferation, and for prophylaxis of formation of tumor metastasis. Invention provides preparing new derivatives of borrelidin eliciting the value physiological effect.

EFFECT: valuable medicinal properties of compounds.

8 cl, 15 ex

FIELD: medicine, hepatology.

SUBSTANCE: at achieving alkaline phosphatase of 580 U and more one should introduce ursodesoxycholic acid at the dosage of 15-20 mg/kg and orlistate at the dosage of 90-100 mg twice or thrice daily for patients with steatohepatitis. According to normalization of clinical and biochemical values of blood analyses it is possible to conclude upon successfulness of therapy performed. The method provides clinic-laboratory remission of the disease.

EFFECT: higher efficiency of therapy.

3 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to new acid-additive nitrate salts of compounds taken among salbutamol, cetirizine, loratidine, terfenadine, emedastine, ketotifen, nedocromil, ambroxol, dextrometorphan, dextrorphan, isoniazide, erythromycin and pyrazinamide. Indicated salts can be used for treatment of pathology of respiratory system and elicit an anti-allergic, anti-asthmatic effect and can be used in ophthalmology also. Indicated salts have less adverse effect on cardiovascular and/or gastroenteric systems as compared with their non-salt analogues. Also, invention proposes pharmaceutical compositions for preparing medicinal agents for treatment of pathology of respiratory system and comprising above indicated salts or nitrate salts of metronidazol or aciclovir.

EFFECT: improved and valuable properties of compounds.

6 cl, 5 tbl, 19 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to a new pentacyclic compound derivative of taxane represented by the formula:

wherein R1 represents dimethylaminomethyl group or morpholinomethyl group; R2 represents halogen atom or alkoxy-group comprising from 1 to 6 carbon atoms, or its salt eliciting an antitumor effect, and to a medicine agent based on its. Invention provides preparing new derivatives of taxane eliciting the valuable biological effect.

EFFECT: valuable medicinal properties of compound.

13 cl, 1 dwg, 4 tbl, 16 ex

FIELD: woodworking industry.

SUBSTANCE: invention relates to methods for recovering and purifying native bioflavonoids: dihydroquercitine and dihydrokaempferol from larch wood extracts. Method of recovering bioflavonoids from larch wood extracts is characterized by that freeze-dried extract is dissolved in ethylacetone/water mixture composed in specified proportion, specified amount of resulting solution is introduced into column filled with urea (sorbent) preliminarily equilibrated with ethylacetate, and column is then eluted with an ester and/or ketone having boiling point below 120°C, or with ethylacetate/acetone mixture at specified ratio. Eluate is collected and evaporated until crystallization is observed and then cooled. Separated crystals are rinsed and dried.

EFFECT: enabled single-step process for separating dihydroquercitine and dihydrokaempferol from resinous impurities and other polymeric compounds, reduced process expenses, and reduced environmental impact.

4 cl, 1 dwg

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new semi-synthetic taxanes of the formula (1):

wherein R and R1 can be similar or different and represent hydrogen atom (H), (C1-C18)-acyl group, benzoyl group; R2 and R3 represent hydrogen atom (H) or R2 and R3 in common form carbonate or thiocarbonate residue; R4 represents benzoyl group optionally substituted at meta-position; R' represents hydrogen atom (H) or (C1-C4)-alkyl; R'' represents (C1-C4)-alkyl or phenyl; R''' represents tert.-butoxy-group under condition that R and R1 both can't represent hydrogen atom (H). Also, invention relates to a pharmaceutical composition based on compounds of the formula (1) eliciting an anti-tumor, anti-angiogenic and anti-arthrosis effect. Invention provides preparing new compounds eliciting cytotoxicity comparable with cytotoxicity of other taxanes but showing reduced systemic toxicity that can be administrated by intravenous and oral routes.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

6 cl, 1 tbl, 7 ex

Up!