N-triazolyl-2-indocarbocyanine, the retrieval method (variants), containing pharmaceutical composition (options) and 1-substituted 3-aminotriazole

 

(57) Abstract:

Describes N-triazolyl-2-indocarbocyanine General formula I, where R1represents -(C2-C6)alkyl; a group -(CH2)n-G with n ranging from 0 to 5, and G represents a non-aromatic mono - or polycyclic3-C13hydrocarbon group; phenyl(C1-C3)alkyl in which the phenyl group possibly substituted once by halogen or (C1-C3)alkoxy; a group -(CH2)nNR2R3in which n is an integer from 1 to 6, a R2and R3that may be the same or different, represent a (C1-C3)alkyl or form, with the nitrogen atom to which they are attached, a group of morpholino or piperidino; X1, X2, X3and X4each independently represents a hydrogen atom or halogen, (C1-C6)alkyl or (C1-C3)alkoxy, provided that only one of X1, X2, X3and X4possibly represents a hydrogen atom; R4represents hydrogen, a group -(CH2)nCOOR5in which n is as defined above, a R5represents the atom bodoro the/SUB>)nOR2R5in which n, R2, R3and R5are as defined above; a group -(CH2)n-tetrazolyl, in which n is as defined above, or R4represents one of these groups in the form of a salt of an alkali metal; Y1, Y2and Y3independently represent hydrogen, halogen, (C1-C3)alkyl, (C1-C3)alkoxy or carbarnoyl; or one of their salts or solvate; methods for their preparation, pharmaceutical composition containing them, and 1-substituted 3-aminotriazole formula (7) is an intermediate compound in the synthesis of compounds I. the Compounds I have activity a partial or full agonist CCK-A receptor and can be used to treat problems of food intake, obesity, tardive dyskinesia and disorders of the gastrointestinal areas. 9 C. and 4 h.p. f-crystals, 8 PL.

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The invention relates to new derivatives of triazole, method of their production and to their containing medicines.

More specifically the present invention relates to new ones compounds showing affinity to cholecystokinin receptors.

Cholecystokinin (CCK) is a peptide in response to gloth et al., Peptides, 1994, 15 (4), 731-735).

Since CCK was identified in the brain, it is, perhaps, the most common neuropeptide acting as a neuromodulator of cerebral functions by stimulating receptor type CCK-B (Crawley J. N. et al., Peptides, 1994, 15 (4), 731-735). In the Central nervous system of CCK interacts with dopamineproducing neural transmission (Crawley J. N. et al., ISIS Atlas of Sci., Pharmac. 1988, 84-90). It also plays a role in the mechanisms that are involved in acetylcholine, GABA (4-aminobutyric acid), serotonin, opioids, somatostatin and substance P, and ion channels.

Its introduction causes physiological changes: palpebral ptosis, hypothermia, hyperglycemia, catalepsy, and changes in behavior, reducing the ability of movement, decreased ability to research, analgesia, change in ability to learn, as well as changes in sexual behavior and satiety.

CCK exerts its biological activity through at least two types of receptors: CCK-A receptors localized mainly perifericheskie, and CCK-a receptors are present mainly in the cortex. CCK-A receptors peripheral type are minoglou core (Moran T. N. et al., Brain Research, 1986, 362, 175-179; Hill, D. R. et al., J. Neurosci. 1990, 10, 1070-1081); however, specific differences (Hill, D. R. et al., J. Neurosci. 1990, 10, 1070-1081; Mailleux P. et al., Neurosci. lett, 1990, 117, 243-247; Barrett, R. W. et al. , Mol. Pharmacol., 1989, 36, 285-290; Mercer J. G. et al., Neurosci Lett, 1992, 137, 229-231; Moran, T. N. et al., Trends in Pharmacol. Sci., 1991, 12, 232-236).

On the periphery, via CCK-A receptors (Moran T. N. et al., Brain Research, 1986, 362, 175-179), CCK inhibits gastric emptying, modifies intestinal motility, stimulates contraction of the gallbladder, increases bile secretion and control of pancreatic secretion (McHugh, P. R. et al., Fed. Proc. , 1986, 45, 1384-1390; Pendleton, R. G. et al., J. Pharmacol. Exp. Ther., 1987, 241, 110-116).

In some cases, CCK may act on blood pressure and affect the immune system.

The role of CCK in the signal saturation is confirmed by the fact that the concentration of CCK in plasma, which depend on the composition of the food (high concentrations of proteins or lipids), become after eating higher than concentrations observed prior to eating (Izzo R. S. et al., Regul. Pept., 1984, 9, 21-34; Pfeiffer, A. et al., Eur. J. Clin. Invest., 1993, 23, 57-62; Lieverse, R. J. Gut, 1994, 35, 501). Those with bulimia have a decrease in the secretion of CCK-induced eating (Geraciotti T. D. Jr. et al., N. Engl. J. Med., 1988, 319, 683-688; Devlin, M. J. et al., Am. J. CIin. Nutr., 1997, 65, 114-120), and reduced con the camping cell compartment, which may reflect the Central neural secretion, basal concentrations of CCK significantly lower in patients suffering from nervous bulimia (Brambilla F. et al., Psychiatry Research, 1995, 37, 51-56).

Treatment (such as L-phenylalanine or inhibitors of trypsin), which increases the secretion of endogenous CCK causes a decrease in food intake in several species, including humans (Hill A. J. et al., Physiol. Behav. 1990, 48, 241-246; Ballinger A. B. et al., Metabolism, 1994, 735-738). Similarly, the introduction of exogenous CCK reduces food intake in many species, including humans (Crawley J. N. et al., Peptides, 1994, 15, 731-755).

Inhibition of food intake of CCK is mediated by CCK-A receptor. Devazepide antagonist, selective in respect of CCK-A receptors, inhibits anorectic effects of CCK, whereas selective agonists of these receptors inhibit food intake (Asin, K. E. et al., Pharmacol. Biochem. Behav., 1992, 42, 699-704; Elliott R. L. et al., J. Med. Chem., 1994, 37, 1562-1568). In addition, the rat line OLEFT, which does not Express CCK-A receptor is not sensitive to the anorectic effects of CCK (Myasaka K. et al., 1994, 180, 143-146).

Based on this evidence the key role of CCK in the peripheral signal saturation, the use of agonists and antagonists of CCK as medicines when Lemoine also be used therapeutically in the treatment of emotional and sexual behavioral disorders and memory disorders (Itoh S. et al., Drug. Develop. Res., 1990, 21, 257-276), schizophrenia, psychosis (Crawley J. N. et al., Isis Atlas of Sci., Pharmac., 1988, 84-90 and Crawley J. N. Trends in Pharmacol. Sci., 1991, 12, 232-265), Parkinson's disease (Bedhar I. et al., Biogenic amine, 1996, 12 (4), 275-284), tardive dyskinesia (T. Nishikawa et al., Prog. Neuropsychopharmacol. Biol. Psych. , 1988, 12, 803-812; Kampen J. V. et al., Eur. J. Pharmacol., 1996, 298, 7-15) and various disorders of the gastrointestinal areas (Drugs of the Future, 1992, 17 (3), 197-206).

CCK-A receptor agonists of CCK described in the literature. For example, some products having such properties as described in EP 383690 and WO 90/06937, WO 95/28419, WO 96/11701 or WO 96/11940.

Most of the agonists of CCK-And described to date have a peptide nature. So, FPL 14294 derived from CCK-7 is a potent non-selective agonist CCK-And in relation to CCK-Century He has a high inhibitory activity against food intake in rats and dogs after intranasal (Simmons R. D. et al., Pharmacol. Biochem. Behav., 1994, 47 (3), 701-708; Kaiser E. F. et al., Faseb, 1991, 5, A864). Similarly, it was shown that A - 71623, tetrapeptides agonist, selective in respect of CCK-A receptors, is effective in models of anorexia over a period of 11 days and leads to a significant reduction in weight gain compared to control rodents and tobaccogrowing monkeys (baboons and selectivity for CCK receptors, have significant anorectic activity in rats (Elliott R. L. et al., J. Med. Chem., 1994, 37, 309-313; Elliott R. L. et al., J. Med. Chem. , 1994, 37, 1562- 1568). GW-7854 (Hirst G. C. et al. J. Med. Chem. , 1996, 38, 5236-5245), 1,5-benzodiazepine is agonist CCK-A receptor in vitro. This molecule orally active in reducing the gall bladder in mice and food intake in rats.

Now unexpectedly found that a number of triazole derivative has the activity of a partial or full agonist in respect of CCK-A receptors.

Compounds of the present invention were subjected to systematic research in order to characterize:

- their ability to displace [125I]-CCK with their binding sites present on pancreatic membranes of rats (CCK-A receptor) or cells ZTZ, which Express recombinant CCK-A receptor of the person;

their affinity for the CCK-receptor, is expressed on the membranes of the cerebral cortex of the Guinea pig, and some compounds are selective or non-selective ligands of CCK-A receptor;

their property agonist CCK-A receptor through their ability to induce in vitro mobilization of intracellular calcium in cells ZTZ, which Express the mi CCK-A, because they like CCK capable of stimulating partially or fully mobilize intracellular calcium in cell lines that Express recombinant CCK-A receptor human. They are, surprisingly, much more powerful than the thiazole derivatives described in patent applications EP 518731 and EP 611766 than thiadiazole derivatives described in patent application EP 620221, or benzodiazepine derivative, is described in the patent EP 667344.

The reason for this is that these derivatives of thiazole, thiadiazole and benzodiazepine is not able to induce the mobilization of intracellular calcium mediated by CCK-A receptor.

According to the present invention triazole derivatives are more potent than these derivatives of thiazole, thiadiazole or benzazepine, also because of their ability to block in vivo, intraperitoneal, gastric emptying in mice.

Thus, the properties of agonists of CCK-A was investigated in vivo by evaluating their ability to block gastric emptying in mice or cause, again, in vivo, the emptying of the gall bladder in mice.

Some derivatives also possess antagonist activity of CCK-b receptor.

Thus, the present a -(C2-C6)alkyl; a group -(CH2)n-G with n ranging from 0 to 5, and G represents a non-aromatic mono - or polycyclic C3-C13hydrocarbon group; phenyl(C1-C3)alkyl in which the phenyl group possibly substituted once by halogen or (C1-C3)alkoxy; a group -(CH2)nNR2R3in which n is an integer from 1 to 6, and R2and R3that may be the same or different, represent a (C1-C3)alkyl or form, with the nitrogen atom to which they are attached, a group of morpholino or piperidino;

X1X2X3or X4each independently represents a hydrogen atom or halogen, (C1-C6)alkyl or (C1-C3)alkoxy, provided that only one of X1X2X3and X4possibly represents a hydrogen atom;

R4represents hydrogen, a group -(CH2)nCOOR5in which n is as defined above, a R5represents a hydrogen atom or a (C1-C6)alkyl, (C1-C6)alkyl; a group -(CH2)nOR5or a group -(CH2)nNR2R3in which n, R24represents one of these groups in the form of a salt of an alkali metal;

Y1, Y2and Y3independently represent hydrogen, halogen, (C1-C3)alkyl, (C1-C3)alkoxy or carbarnoyl;

or one of their salts or solvate.

The compounds of formula (I) in which R1represents cyclohexyl-(C1-C3)alkyl, are preferred compounds.

Also preferred are the compounds of formula (I), in which the phenyl in position 5 of the triazole is trehzameshchenny preferably a methoxy group at positions 2 and 6 and stands in position 4.

Even more preferred are the compounds of formula (I), in which the phenyl in position 5 of the triazole is trehzameshchenny preferably a methoxy group at positions 2 and 5, and stands or chlorine in position 4.

In particular, the compounds of formula

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where R1, R4X1X2X3and X4are as defined for (I),

their salt or MES are preferred.

Among these compounds, those in which

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represents 2,6-dimethoxy-4-were are is designated for (I),

their salt or MES are the most preferred.

The compounds of formula

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where R1, R4, Y1, Y2and Y3are as defined for (I) and X2represents methyl or chlorine atom, their salts or MES are the most preferred.

1-substituted 3-aminotriazole General formula (7) represent a new key intermediate compounds, which are used to obtain the compounds (I), and they are also part of the present invention.

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where R1X1X2X3and X4are as defined for (I).

The present invention is also a method of obtaining compounds of formula (I), their salts or solvate, characterized in that aminotriazol formula (7)

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where R1X1X2X3and X4are as defined for (I), is subjected to the interaction with the derived indolocarbazoles acid of formula (8)

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where R4, Y1, Y2and Y3are as defined above for (1).

The present invention is also a method of obtaining compounds of formula (I), their salts or solvate, otluca such as defined for (I), is subjected to the interaction with the derived indolocarbazoles acid of formula (8')

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where Y1, Y2and Y3are as defined above for (1), and R'4is a group of the predecessor R4and R4is as defined for (I) obtaining the compounds of formula (I')

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where R1X1X2X3X4, Y1, Y2and Y3are as defined for (I), a R'4is a group of the predecessor R4moreover , the obtained compound of the formula (I') is converted into the compound of formula (I) by conversion of the group R'4in R4.

The present invention also includes pharmaceutical compositions having agonist activity of CCK-A receptors containing as active principle a compound according to the invention or one of its pharmaceutically acceptable salts.

In accordance with the present invention "(C1-C6)alkyl or(C2-C6)alkyl" means a straight or branched alkyl having from 1 to 6 carbon atoms or from 2 to 6 carbon atoms, respectively.

The alkoxy radical refers to a radical of alkyloxy, in which alkyl is the impact saturated or unsaturated, condensed or bridged, mono - or polycyclic radicals which may be a terpene. These radicals are possibly mono - or polyamideimide (C1-C3)alkyl. Monocyclic radicals include cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclododecyl. Polycyclic radicals include, for example, norbornane, adamantane, hexahedronal, norbornene, dehydrogenase, bicyclo[2.2.1] heptane, bicyclo[3.3.1] nonan and tricyclo[5.2.1.02,6]Dean.

In accordance with the present invention, the term halogen means an atom selected from fluorine atoms, chlorine, bromine and iodine, preferably fluorine or chlorine.

The cations of alkali metals are preferably chosen from the cations of sodium or potassium.

When the connection according to the invention has one or more than one asymmetric carbon atom, optical isomers of this compound form an integral part of this invention.

When the connection according to the invention has stereoisomer, for example, axial-Equatorial type, this invention includes all stereoisomers of this compound. Salts of compounds of formula (I) invented the population or crystallization of the compounds of formula (I), such as picric acid, axalingua acid or optically active acid such as tartaric acid, dibenzoyltartaric acid, mandelic acid or camphorsulfonic acid, and acids, which form physiologically acceptable salts such as hydrochloride, hydrobromide, sulphates, hydrosulfate, dihydrofolate, maleate, fumarate, 2-naphthalenesulfonate or para - toluensulfonate.

Salts of compounds of formula (I) also include salts with organic or inorganic bases, for example alkali metal salts, such as salts of sodium or potassium, or a salt with an amine, such as trometamol, or, alternatively, a salt of arginine or lysine or a salt of any physiologically acceptable amine.

Functional groups may be present in the molecule of the compounds of formula (I) and intermediate compounds can be protected either permanent or temporary protective groups, which provide an accurate synthesis of the expected compounds.

The expression of a temporary protective group for amines, alcohols or carboxylic acids means such protective groups described in "Protective Groups in Organic Synthesis", Greene T. W. and Wuts P. G. M., published John Wiley and Sons, 1991, and in Protecting Groups, Kocienski P. J., 1994, Geo are formed sequentially on one or more than one other stage.

The intermediate compound (I') lead to the formation of compounds of formula (I) conversion of the group R'4in R4they have a way known per se, according to the conventional methods of organic chemistry.

Starting materials are commercially available or receive them in accordance with the methods described below.

Scheme 1 illustrates the path of synthesis of compounds of formula 7 (scheme 1-12 listed at the end of the description).

Scheme 2 illustrates the formation of compounds of formula (I) from aminotriazole formula 7.

When R4= -(CH2)nCOOH, the compound (I) is obtained from the corresponding esters, which in turn receive under the scheme 2.

When R4= -(CH2)n-tetrazolyl, compound (I) is obtained from the corresponding NITRILES of the formula

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in which R'4= -(CH2)n-CN,

by the interaction of azeotropically in the presence of dibutylated in accordance with the method described in J.Org. Chem. 1993, 58, 4139 - 4141.

The compounds of formula (I') are obtained according to scheme 2 from compounds 7 and 8' formula

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in which R'4= -(CH2)n-CN.

Substituted benzoic acids are commercially available or get their ways, carboxylterminal litoraneo derived using the CO2according to scheme 3, where Z1= Br or H, depending on the nature and/or position of the substituents X1X2X3and X4in accordance with N. S. Narasimhan et al., Indian J. Chem., 1973, 11, 1192; R. C. Cambie et al., Austr. J. Chem., 1991, 44, 1465; T. de Paulis et al., J. Med. Chem., 1986, 29, 61; or an alternative

2) the regioselective formirovanie disubstituted benzene with subsequent oxidation of the substituted benzaldehyde using KMnO4scheme 4 according to the method described by S. C. Matin et al. in J. Med. Chem., 1974, 17, 877; or an alternative

3) haloform oxidation according to R. Levine et al., J. Am. Chem. Soc., 1959, 72, 1642, aromatic methylketones obtained by acylation Friedel-disubstituted benzene (C. A. Bartram et al., J. Chem. Soc., 1963, 4691) or by the fries rearrangement of substituted acyloxymethyl according to S. E. Cremer et al., J. Org. Chem., 1961, 26, 3653, according to schemes 5 and 6.

Acid, substituted methoxy in position 2, can be derived from a substituted phenol derivative by reacting acetic anhydride in pyridine followed by reaction of Fris in the presence of aluminium chloride with getting hydroxyacetophenone, which is then subjected to interaction with methyliodide in an alkaline medium to obtain, finally, californai reaction R is Idina bicarbonate with benzoyl chloride, derived from benzoic acid 1 by standard methods (SOCl2oxalicacid in an inert solvent), using well-known (Hoggarth, J. Chem. Soc. , 1950, 612). You can also get alternative ways described in the same publication, according to the scheme 7.

Thermal cyclization of benzamidopiperidine 2 in a solvent with a high boiling point, such as diphenyl ether, leads to the production of aryl-5-amino-3-triazole 3 in accordance with the method described by E. Hoggarth in J. Chem. Soc., 1950, 612.

The functional protection of the primary amino group of triazole 3 in the form diphenylamine leads to the production of N-protected triazole 4 in accordance with the method described by M. J. O' Donnell et al. in J.Org. Chem., 1982, 47, 2663.

Compound 4 can also be obtained in an alternative way, which is in the handling of triazole 3, which is previously converted into the hydrochloride of 3', diphenylamino according to scheme 8.

N-alkylation of diphenylimidazole 4 alkylhalogenide R1X in conditions of phase transfer (strong base in a concentrated aqueous solution in the presence of an immiscible organic co-solvent and catalyst based on Quaternary ammonium compounds) priamymi strong bases can be aqueous solutions of NaOH or KOH in a concentration of from 6 M to 12 M The co-solvent may be toluene or benzene, and the Quaternary ammonium compound may be selected from any of the Quaternary ammonium salt and, more specifically, TBAB (tetrabutylammonium bromide).

a) M-Alkylation of diphenylimidazole 4 can be carried out in non-aqueous medium (for example dimethylformamide or tetrahydrofuran) in the presence of a strong base, such as K2CO3or NaH.

b) you Can choose an alternative path, such as described by E. Akerblom in Acta Chem. Scand., 1965, 19, 1142 where the use of an alkylating agent in alcohol, such as ethanol, in the presence of a solid strong base, such as KOH or NaOH.

Triazole 5 very easily separated from its isomer 6 chromatography on a column of silica or flash chromatography depending on the nature of the group R1. Splitting 5 product obtained after separation from the smaller isomer, is carried out in aqueous acid medium, such as 1 N. HCl, according to the method described by J. Yaozhong et al. in Tetrahedron, 1988, 44, 5343, or M. J. O' Donnell et al. in J. Org. Chem., 1982, 47, 2663. This allows to obtain amino-3 - triazole of the formula 7, the N-alkylated in position 1.

Indolocarbazole the compounds of formula 8 receive according to the methods described in patent EP 611766, she ways, presented in figure 9a.

Indoles 11 are commercially available or obtained by the methods described in the literature, for example according to L. Henn et al., J. Chem. Soc. Perkin Trans., 1, 1984, 2189, according to scheme 10, or alternatively, for example, according to the synthesis Fischer (V. Prolog et al. Helv. Chim. Acta., 1948, 31, 1178) according to scheme 11, or according to the synthesis Japp-Klingemann (H. Ishii et al., J. Chem. Soc. Perkin. Trans., 1, 1989, 2407) according to scheme 12.

The above compounds of formula (I) also include compounds in which one or more than one hydrogen, carbon, or halogen, in particular chlorine atoms or fluorine, replaced by their radioactive isotope, for example tritium or carbon-14. Such labeled compounds are suitable for research purposes, the study of metabolism or pharmacokinetics, biochemical tests as ligands of receptors.

The compounds of formula (I) were subjected to in vitro binding of CCK-a and CCK-a receptor using the method described in Europ. J. Pharmacol., 1993, 232, 13-19.

The agonist activity of the compounds in relation to CCK-a receptors was evaluated in vitro on cells ZTZ, expressing the CCK-A receptor human, by measuring the mobilization of intracellular calcium ([Ca++]) in accordance with the method, production is the Finance Fura-2 by the method of dual wavelength excitation. The ratio of fluorescence emitted at two wavelengths, gives after calibration concentration [Ca++]i(Grynkiewiez G. et al., J. Biol. Chem., 1985, 260, 3440-3450).

Compounds according to the invention stimulate [Ca++]ipartially or fully, as well as CCK, and therefore behave as agonists of CCK-A receptor.

The study of agonistic effect of compounds on gastric emptying was carried out as follows. Female mice of Swiss albino CD1 (20-25 g) were placed on a starvation diet for 18 hours. On the day of the experiment, the products (in the form of a suspension in 1% solution of carboxymethyl cellulose or 0.6% solution of methylcellulose) or the corresponding carrier was injected intraperitoneally 30 minutes prior to the introduction of food containing charcoal (0.3 ml of a suspension of 10% carbon powder in water mouse, 5% gum Arabic and 1% carboxymethylcellulose) or orally 1 hour earlier. Mice were killed 5 min after the offset of the cervical vertebrae, and gastric emptying was determined by the presence of charcoal in the intestine before the pyloric sphincter (Europ. J. Pharmacol., 1993, 232, 13-19). The compounds of formula (I) partially or completely block the gastric emptying, as well as himself CCK, and, thus, behave as agonists of CCK-receptor. Some of them is.

The study of agonistic effect of compounds on the reduction of the gallbladder was performed as follows. Female mice of Swiss albino CD1 (20-25 g) were placed on a hunger diet within 24 hours. On the day of the experiment, the products (in the form of a suspension in 1% solution of carboxymethyl cellulose or 0.6% solution of methylcellulose) or the corresponding carrier is administered orally. Mice were killed by cervical vertebrae shift one hour after the introduction of products, and gall bladders were removed and weighed. The results were expressed in mg/kg body weight (Europ. J. Pharmacol., 1993, 232, 13-19).

The compounds of formula (I) partially or completely reduce the gallbladder, as well as himself CCK, and, thus, behave as agonists of CCK. Some of them have ED50(effective dose that induces 50% of the weight of the vesicles observed with CCK) less than 0.1 mg/kg orally.

Therefore, the compounds of formula (I) suitable as agonists of CCK-receptor type A for the preparation of medicines designed to fight disease, the treatment of which requires stimulation of complete or partial agonism of CCK-A receptor cholecystokinin. More specifically, the compounds of formula (I) suitable for the production of medicines, prednaznachen lcna bladder, irritable bowel syndrome), eating disorders and obesity and associated pathologies, such as diabetes and hypertension. The compound (I) induce the saturation state and, thus, they are suitable for the treatment of behavioral disorders in food intake, regulation of appetite and reducing food intake, for the treatment of bulimia nervosa and obesity and for weight loss. Compounds (I) are also useful in disorders of emotional and sexual behavior and memory disorders, psychosis, and particularly in schizophrenia, Parkinson's disease and tardive dyskinesia. They can also be used in the treatment of disorders of appetite, that is, to control the desire to eat, in particular regulation of consumption of sugar, carbohydrates, alcohol or drugs, and generally stimulating the appetite ingredients.

The compounds of formula (I) have low toxicity; their toxicity is compatible with their use as medicaments for treatment of the above diseases and disorders.

No signs of toxicity is not observed when using these compounds in pharmacologically active doses, and their toxicity, therefore, compatible with their medical use as medicines.

In the pharmaceutical compositions of the present invention, intended for oral, sublingual, subcutaneous, intramuscular, intravenous, outdoor, intratracheal, intranasal, transdermal, rectal or intraocular administration, the active principle of formula (I) above or their possible salts can be entered in standard forms of administration, mixed with standard pharmaceutical carriers, to animals and to humans for the prophylaxis or treatment of the above diseases or disorders. The appropriate standard forms for administration include oral forms such as tablets, gelatin capsules, powders, granules and oral suspensions and solutions, sublingual, buccal, intratracheal, intranasal, subcutaneous, intramuscular or intravenous forms of administration and rectal forms of administration. Compounds according to the invention can be used in creams, ointments, lotions or eye drops for topical administration.

To obtain the desired prophylactic or therapeutic effect, the dose of the active agent may be in the range between 0.01 and 50 mg per 1 kg of body weight per day. Each standard dose can contain the LEM. This standard dose can be administered 1 to 5 times a day so that you can enter daily dose of from 0.5 to 5000 mg, preferably from 1 to 2500 mg.

In the preparation of solid compositions in the form of tablets, the main active ingredient is mixed with a pharmaceutical carrier, such as gelatin, starch, lactose, magnesium stearate, talc, gum Arabic or the like. Tablets can be coated with sucrose, a derivative of cellulose, or other suitable substances, or alternatively, they may be treated so that they have a prolonged or delayed activity and so that they would release a predetermined amount of active principle continuously.

The drug is in the form of gelatin capsules is obtained by mixing the active ingredient with a diluent and injecting the resulting mixture into soft or hard gelatin capsules.

The drug is in the form of a syrup or elixir or for administration in the form of drops can contain the active ingredient together with a sweetener, preferably a calorie-free sweetener, methylparaben and propyl paraben as antiseptics, as well as corrigenda and a suitable dye. Dispersible in water powders or granules can soda is their agents, such as polyvinylpyrrolidone, as well as with sweeteners or flavour enhancers and aroma.

For rectal use of suppositories which are prepared with binders which melt at the rectal temperature, for example cocoa butter or polyethylene glycols. Aqueous suspensions, isotonic saline solutions or sterile injectable solutions which contain pharmacologically compatible dispersing agents and/or wetting agents, for example propylene glycol or butyleneglycol, are used for parenteral administration.

The active principle may also be prepared in the form of microcapsules possible in part with one or more than one carrier or additive, or alternative matrix such as a polymer or a cyclodextrin (patch form prolonged release).

The compositions of the present invention can be applied in the treatment or prevention of various diseases in which CCK has therapeutic value.

The compositions of the present invention may contain, along with the above products of formula (I) or their pharmaceutically acceptable salts, other active principle, which can biichi of the present invention contain the product of formula I. 1), (I. 2) or (I. 3) above, or its pharmaceutically acceptable salt, MES or hydrate.

OBTAINING SYNTHETIC INTERMEDIATE COMPOUNDS

A. Receipt of acid 1 (options)

2,5-Dimethoxy-4-methylbenzoic acid (Compound A1)

a) 2,5-Dimethoxy-4-benzaldehyde

After stirring a mixture of 8.5 ml of N-methylformamide (0,068 mol) and 6.3 ml of oxytrichloride phosphorus (0,068 mol) at room temperature for 40 minutes introduce 17.8 g of 2,5-dimethoxytoluene (0,117 mol). The reaction mixture is heated for 6 hours at 50oC, and then, after returning to a temperature of 20oC, its hydrolyzing 100 ml aqueous 10% solution of sodium acetate, extracted twice with diethyl ether and concentrated. The residue is transferred into the water Hydrosulphite solution of sodium and twice extracted with diethyl ether. The aqueous phase is alkalinized (pH = 12) to obtain white crystals; so pl. = 83oC; yield = 67%.

b) 2,5-Dimethoxy-4-methylbenzoic acid

23,86 g (0,132 mol) of 2,5-dimethoxy-4-methylbenzaldehyde dissolved in 500 ml of water, heated to 75oC and type of 29.3 g (0.185 mol) of potassium permanganate dissolved in 500 ml of water. The reaction mixture is left for 2 hours at 75oC, pH adjusted to 10 using 10% of the hot water. The filtrate is cooled, and the precipitate is filtered off and dried under vacuum at 40oC to obtain white crystals; so pl.=120oC; yield=71%.

2,5-Dimethoxy-4-chlorbenzene acid (Compound A2)

a) 2,5-Dimethoxy-4-chlorophenylglycine

162,5 g trichloride aluminum (1.2 mol) are added at room temperature to 2 liters of carbon tetrachloride, followed, at 0oC, by adding dropwise 82 ml acetylchloride (1.2 mol), and then 200 g of 1,4-dimethoxy-2-chlorobenzene (1.2 mol). The reaction mixture is left for 3.5 hours at 0oC, and then hydrolyzing using 700 ml of water. The organic phase is washed with 2 M sodium hydroxide solution, dried over anhydrous sodium sulfate and concentrated. Semi-crystalline residue is transferred in petroleum ether, filtered and dried to obtain white crystals; so pl. = 96oC; yield = 70%.

b) 2,5-dimethoxy-4-chlorbenzene acid

278 g of sodium hydroxide (4,96 mol) are added to 800 ml of water, followed by adding dropwise, at 5oC, 84 ml of bromine (1.6 mol). The reaction mixture is left for 1 hour at room temperature. The resulting aqueous sodium hypobromite solution is added to 107 g of 2,5-dimethoxy-4-chlorophenylglycine (0,494 mol), A temperature reflux distilled. After the reaction injected 100 ml of water Hydrosulphite solution of sodium, and the solvent then evaporated. The residue is acidified with 6 N. hydrochloric acid, and then extracted twice with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is crystallized in diisopropyl ether to obtain white crystals; so pl.=160oC; yield = 91%.

2,6-Dimethoxy-4-methylphenylamine acid (Compound A3)

231,6 g (1.5 mol) of 3,5-dimethoxytoluene dissolved in 1 liter of diethyl ether, followed by adding dropwise in a stream of nitrogen and at room temperature, 1 liter of a 1.6 n solution of utility (1.6 mol) in hexane. The reaction mixture is left for 18 hours at room temperature, and then, after cooling to -30oC add 1 liter of diethyl ether and through this mixture for 1 hour bubbled carbon dioxide, maintaining the temperature -30oC. the Reaction mixture was transferred into 6 liters of 2 M sodium hydroxide solution, the aqueous phase is separated after settling and acidified with 6 N. hydrochloric acid. The precipitate is filtered off, washed with water and dried under vacuum at 40oC to obtain white crystals; so pl.=187oC; yield=88%.

B. Obtaining replacement is B1)

1st method: (Method Japp-Klingemann)

7.2 g (0.104 g mol) of sodium nitrite dissolved in 40 ml of water, add -5oC to a mixture of 10.7 g (0.1 mol) of 4-methylaniline, 74 ml 12 N. hydrochloric acid and 140 ml of water. The reaction mixture is stirred for 15 minutes at -5oC and neutralized by the addition of 8.1 g of sodium acetate. of 12.33 g (of 0.085 mol) of ethyl ether-methylcytosine acid and 80 ml of ethanol is introduced into the three-neck flask and then adding, at 0oC, 4.8 g (of 0.085 mol) of potassium hydroxide dissolved in 20 ml of water and 100 g of ice. Solution, page, obtained above, is added dropwise at 0oC to this reaction mixture, and the mixture is left for 18 hours at 0oC. the Aqueous phase is extracted with 4 times 50 ml of ethyl acetate, and the organic phases are combined and dried over anhydrous sodium sulfate. The residue is transferred in 100 ml of toluene and 16.3 g (of 0.085 mol) of monohydrate para-toluensulfonate acid. The mixture was then slowly heated to 110oC and kept at this temperature for 5 hours. After cooling and then adding a saturated solution of sodium carbonate insoluble substance produce by filtration, and the organic phase is separated after settling, dried over anhydrous sodium sulfate and the con is San, with the receipt of beige crystals; so pl.=94oC; output = 25%.

Obtaining the ethyl ester of 4-methyl-1H-2-indolocarbazoles acid (Compound B2)

2nd way:

Stage 1: Getting azide

9.3 g (0,405 mol) of sodium is added in portions to 200 ml of ethanol. 16.2 g (is 0.135 mol) of ortho-tolualdehyde dissolved of 52.2 g (0,405 mol) of ethylacetoacetate injected dropwise at -20oC in this solution ethylate in ethanol. After 2 hours at -10oC, the reaction mixture pour 400 ml of water, and the precipitate is filtered off. It is dried for 18 hours at 40oC under vacuum to obtain white crystals; so pl. = 55oC; yield = 78%.

Stage 2: the Cyclization of azide

19.5 g (0,0844 mol) azide obtained in stage 1, add portions to 100 ml of xylene, heated to 140oC. Immediately after the addition the reaction mixture is left for 1 hour at 140oC. Xylene concentrated, and the residue is transferred in isopropyl ether, filtered and dried for 18 hours under vacuum at 40oC to obtain white crystals; so pl.=141oC; yield = 62%.

Getting 5-ethyl-1H-2-indolocarbazoles acid (by Fisher) - (Compound B3)

3rd way:

Stage 1: 4-Ethylphenethylamine hydrochloride< dropwise and enter 14 g (0.2 mol) of sodium nitrite, dissolved in 140 ml of water. After 1 hour at 0oC in the reaction mixture was added 112 g (0,496 mol) chloride dihydrate tin, dissolved in 90 ml 12 N. hydrochloric acid at -10oC. After 1 hour at -10oC, the reaction mixture is filtered to obtain a brown solid substance; so pl.=198oC; yield=95%.

Step 2: Ethyl ester of 2-[2-(4-ethylphenyl)-hydrazono]propionic acid

23 ml (0.2 mol) of atilirovanie add to 34,5 g (0.2 mol) of 4-ethylphenethylamine hydrochloride, obtained above, in suspension in 500 ml of ethanol, and the reaction mixture is heated for 3.5 hours at a temperature of reflux distilled. The mixture is then cooled to a temperature of 20oC, and the ethanol is evaporated. The solid residue is washed with pentane and dried at 40oC under vacuum to obtain a colorless liquid; yield = 94%.

Step 3: Ethyl ester 5-ethyl-1H-2-indolocarbazoles acid

19 g (0.1 mol) of monohydrate para-toluensulfonate acids are added in portions within 7 hours at the temperature of reflux distilled to 44 g (0,188 mol) of the hydrazone obtained above, suspended in 300 ml of toluene. The mixture is cooled to a temperature of 20oC, and the insoluble matter is separated by filtration and washed with water. The filtrate is washed with saturated sodium sulfate and concentrated. The residue is purified by chromatography on a column of silica gel using eluent: a mixture 5/5 (about./about.) dichloromethane/cyclohexane, obtaining beige crystals; so pl.=94oC; yield= 51%.

Stage 4: 5-Ethyl-1H-2-indolocarbazole acid

15,8 g (0,073 mol) ethyl ester 5-ethyl-2-indolocarbazoles acid, obtained in stage 3, added to 150 ml of 1,4-dioxane followed by the addition of 45 ml of 2 M sodium hydroxide solution (0.09 mol). The reaction mixture is left for 48 hours at room temperature. After evaporation of 1,4-dioxane, the residue is transferred in 6 n hydrochloric acid, and the precipitate is filtered off and dried under vacuum at 60oC obtaining 5-ethyl-1H-2-indolocarbazoles acid in the form of white crystals; so pl.=184oC; yield = 92%.

Obtaining N-alkyl-1H-2-indolocarbazole acids

5-Ethyl-1-(methoxycarbonylmethyl)-1H-2-indolocarbazole acid: (Compound B4)

Step 1: Benzyl ester 5-ethyl-1H-2-indolocarbazoles acid

12.7 g (0,067 mol) of 5-ethyl-1H-2-indolocarbazoles acid and 10 ml of 1,8 - diazabicyclo[5.4.0] undec-7-ene (0,067 mol) are successively added to 70 ml of dimethylformamide. The reaction mixture is left for 40 minutes at 0oC, followed by dropwise introduced to 10.6 ml benzylbromide the l of water, the precipitate is filtered off, washed with water, and then dried for 18 hours at 50oC under vacuum to obtain yellow crystals; so pl. =99oC; yield=90%.

Step 2: Benzyl ester 5-Ethyl-1-(methoxycarbonylmethyl)-1H-2 - indolocarbazoles acid

75 ml of dimethylformamide is added to 1.5 g (0,031 mol) of sodium hydride as a 50% suspension in oil and then adding portions of 7.9 g (0,0283 mol) of benzyl ester 5-ethyl-1H-2-indolocarbazoles acid, obtained in stage 1. After 40 minutes at 0oC injected dropwise 3.5 ml (0,0315 mol) of methylpropanoate, and the reaction mixture is left for 2 hours at 20oC. Add 300 ml of ethyl acetate, the mixture was washed with 2 x 300 ml of water, the phases are then separated after settling, the organic phase is dried over anhydrous sodium sulfate and concentrated, gaining 9.5 g of colourless oil; yield=95%.

Stage 3: 5-Ethyl-1-(methoxycarbonylmethyl)-1H-2-indolocarbazole acid

2.5 g of 10% Pd/C is added to 9.5 g (0,0269 mol) of benzyl ester 5-ethyl-1-(methoxycarbonylmethyl)-1H-2-indolocarbazoles acid, obtained in stage 2, dissolved in 150 ml of ethanol, followed by addition of 40 ml of cyclohexene (0,395 mol). The reaction mixture is heated for 2 hours at 70oC, and then cooling the E. 18 hours at 40oC under vacuum obtaining beige crystals; so pl.=181oC; yield=90%.

Connections from B5 to 70, described in table. 1, synthesized in accordance with the procedures above, receive, starting from the corresponding synthetic intermediates.

4,5-Dimethyl-1-(3-cyanopropyl)-1H-2-indocarbocyanine acid (Compound V)

Stage 1: Ethyl ester of 4,5-dimethyl-1-(3-cyanopropyl)-1H-2 - indolocarbazoles acid

75 ml of dimethylformamide is added to 1.92 g (0.040 mol) of sodium hydride as a 50% suspension in oil and then adding portions of 7.9 g (0,0363 mol) of ethyl ester of 4,5-dimethyl-1H-2-indolocarbazoles acid. After stirring for 40 minutes at 0oC injected dropwise to 4.0 ml (0.040 mol) of 4-bromobutyronitrile, and the reaction mixture was incubated for 2 hours at 20oC. Add 300 ml of ethyl acetate, the mixture is washed with twice 300 ml of water, the phases are separated after settling, the organic phase is dried over anhydrous sodium sulfate and concentrated. Gain of 9.8 g of a colorless oil; yield=95%.

Stage 2: 4,5-Dimethyl-1-(3-cyanopropyl)-1H-2-indolocarbazole acid

of 9.8 g (0,0345 mol) of ethyl ester of 4,5-dimethyl-1-(3-cyanopropyl)- 1H-2-indolocarbazoles acid is added to 150 the claim within 48 hours at room temperature. After evaporation of 1,4-dioxane, the residue is transferred in 6 M hydrochloric acid, and the precipitate is filtered off and dried under reduced pressure at 60oC obtaining 4,5-dimethyl-1-(3-cyanopropyl)-1H-2-indolocarbazoles acid in the form of white crystals; so pl.=175oC; yield=92%.

Connections from V to V presented in table. Ia obtained in the same way.

C. Obtaining benzimidazolidinone derivatives

Obtaining 2,6-dimethoxy-4-methylbenzenesulfonamide (Compound C1)

1 ml of dimethylformamide is added to 353 g (1.8 mol) of 2,6-dimethoxy-4-methylbenzoic acid, suspended in 1.5 liters of toluene, followed by adding dropwise 190 ml oxalicacid (2,16 mol). The reaction mixture is left for 2 hours at room temperature, and then evaporated to dryness. The crystalline residue is added in portions to a suspension 293,8 g aminoguanidine bicarbonate (2,16 mol) in 2.5 liters of pyridine in 5oC and left for 18 hours at 20oC. the Reaction mixture is evaporated to dryness, and the residue is then transferred into 1 liter of a 2 M solution of sodium hydroxide. The precipitate is filtered off and washed with a minimum amount of water, and then dried under vacuum at 60oC obtaining crystalline osta-were)-1,2,4-triazole (Compound D. 1)

2 liters of diphenyl ether is added to 230 g (of 0.91 mol) of 2,6-dimethoxy-4-methylbenzaldehyde, after which the reaction mixture is heated for 5 minutes at 220oC. the Mixture is cooled to 80oC, and the precipitate is then filtered off, washed with diisopropyl ether and dried under vacuum at 60oC obtaining crystals; so pl.=286oC; yield=93%.

Connections from D2 to D11, described in table. II synthesized in the same way according to the procedure of the obtaining and using the appropriate starting materials.

D. Obtaining diphenylimidazole

Obtaining N-[3-(2,6-dimethoxy-4-were)-1H-1,2,4-triazole-5-yl] -N - diphenylethylamine (Compound E1)

105 g (0.45 mol) of 3-amino-5-(2,6-dimethoxy-4-were)-1,2,4-triazole, suspended in 200 ml of xylene and 150 g (0.9 mol) benzophenone heated at 140oC for 48 hours in a stream of argon. The reaction mixture is cooled to a temperature of 80oC, and then poured into 4 liters of isopropyl ether, and the precipitate is filtered off, washed with diisopropyl ether and dried for 18 hours at 50oC; so pl.=126oC, yield=90%.

Connections from E2 to E11, described in table. III, synthesized in the same way according substituted 3-aminotriazole

Obtain 1-(2-cyclohexylethyl)-5-(2,6-dimethoxy-4-were)-1H - 1,2.4-triazole-3-amine (Compound F1)

a) N-Alkylation of triazole

300 ml of aqueous 6 n sodium hydroxide solution, 24 g (0.06 mol) of N-[3-(2,6-dimethoxy-4-were)-1H-1,2,4-triazole-5-yl]-N - diphenylethylamine and 2.7 g of tetrabutylammonium bromide consistently add to 400 ml of toluene. 17 g (0.09 mol) of 2-prematilleke added dropwise to this reaction mixture, heated to 70oC. Interaction continued for two hours at 80oC. the Organic phase is separated after settling and dried over anhydrous sodium sulfate and evaporated to dryness. The remainder chromatographic on a column of silica gel using as eluent a mixture of 90/10 (vol./about.) toluene/ethyl acetate. Get 21,4 g colourless oil; yield=70%.

b) Hydrolysis diphenylamino functional groups

100 ml of 1 n hydrochloric acid is added to 10.3 g (0.02 mol) of N-[1-(2-cyclohexylethyl)-5-(2,6-dimethoxy-4-were)-1 H - 1,2,4-triazole-3-yl] -N-diphenylethylamine dissolved in 200 ml of methanol. The reaction mixture is left for 18 hours at room temperature, and then evaporated to dryness. Oily residue utverjdayut in diethyl ether, and the precipitate otfit to D37, described in table. IV, synthesized in the same way according to the procedure of the obtaining and using the appropriate starting materials.

1-(2-Cyclohexylethyl)-5-(2,6-dimethoxy-4,5-dimetilfenil)-1H-1,2,4 - triazole-3-amine (Compound F38) get in the same way, since the Connection E10; so pl.=180oC.

J. Obtaining aminotriazole derivatives with non-N-substituted indoles

Synthesis of N-[1-(2-Chlorobenzyl)-5-(2,6-dimethoxy-4-were)-1H-1,2,4 - triazole-3-yl]-5-chloro-1H-2-indocarbocyanine (Compound G1)

0.2 ml of thionyl chloride (0,0028 mol) is added at 0oC to a solution of 1 ml of pyridine (0,013 mol) in 30 ml of methylene chloride. After 15 minutes at 0oC enter 500 mg (0,0025 mol) 5-floridacasino acid, and this reaction mixture is left for 30 minutes atoC. of 0.91 g (0,0028 mol) 1-[(2-chlorophenyl)methyl] -5-(2,6-dimethoxy-4 - were)-1H-1,2,4-triazole-3-amine hydrochloride is added to the formed acylchlorides, and the mixture is left for 18 hours at 20oC.

The reaction mixture was washed with 1 M sodium hydroxide solution. The organic phase is dried over anhydrous sodium sulfate and evaporated to dryness. The remainder chromatographic on silica gel using eluent: 95/5 mixture (about./about. ) dichloromethane/methanol, with testirovany in the same way according to the procedure of the obtaining and using the appropriate starting materials.

H. Obtaining aminotriazole derivatives with N-substituted indoles

Example 1

Methyl ester 2-[2-({ [1-(2-cyclohexylethyl)-5-(2,6-dimethoxy-4 - were)-1H-1,2,4-triazole-3-yl] amino} carbonyl)-5-ethyl-1H-indol-1 - yl]acetic acid

1 ml of pyridine (0,013 mol) and 0.21 ml of thionyl chloride (0,00029 mol) are added successively to a 15 ml dichloromethane. After 15 minutes at 0oC enter 0,627 g of 5-ethyl-1-methoxycarbonylmethyl-1H-2 - indolocarbazoles acid (0,0024 mol) followed by the addition of 0.9 g of 1-(2-cyclohexylethyl)-5-(2,6-dimethoxy-4-were)-1H - 1,2,4-triazole-3-amine hydrochloride. The reaction mixture is left for 18 hours at room temperature, followed by acid washing, and then alkaline leaching. The organic phase is dried over anhydrous sodium sulfate and concentrated. Oily residue chromatographic on silica gel using eluent: a mixture of 98.5/1.5 or less (about./about.) dichloromethane/methanol to obtain a white powder; so pl.=191oC; yield=87%.

Example 2

2-[2-({ [1-(2-Cyclohexylethyl)-5-(2,6-dimethoxy-4-were)-1H - 1,2,4-triazole-3-yl]amino}carbonyl)-5-ethyl-1H-indol-1-yl]acetic acid

1.8 ml (0,0018 mol) of 1 n sodium hydroxide solution is added to 530 mg (0,0009 mol) methyl ester 2-[2-({[1 -(2-cyclohexyl the CSOs according to example 1, dissolved in 50 ml of methanol. After 18 hours at room temperature, the reaction mixture is evaporated to dryness. The residue is transferred into ethyl acetate and 0.5 n hydrochloric acid. The organic phase is separated after settling, dried over anhydrous sodium sulfate and concentrated. The residue is purified by chromatography on a column of silica gel using eluent: a mixture of 92/8 (about./about.) dichloromethane/methanol to obtain white crystals; so pl.=198oC; yield=91%.

Examples 3 to 511, as described in table. VI and VII, obtained in the same way according to the procedure of examples 1 and 2 above, starting from the appropriate intermediates.

Example 512

2-{ N-[5-(4-chloro-2,5-acid)-1-(2-cyclohexylethyl)-1H-1,2,4 - triazole-3-yl]carbarnoyl}-4,5-dimethyl-1-[3-(2H-1,2,3,4-tetrazol-5-yl)- propyl] -1H-indole

Stage 1: 4-[2-({[1-(-(2-Cyclohexylethyl)-5-(2,5-dimethoxy-4-chlorophenyl)- 1H-1,2,4-triazole-3-yl] amino}carbarnoyl)-4,5-dimethyl-1H-1 - indolyl]butyronitrile

1 ml of pyridine (0,013 mol) and 0.21 ml (0,0029 mol) of thionyl chloride are successively added to 15 ml of dichloromethane. After 15 minutes at 0oC enter of 0.615 g of 4,5-dimethyl-1-(3-cyanopropyl)-1H-2-indolocarbazoles acid (0,0024 mol), and then 0.9 g of 1-(2-cyclohexylethyl)-5-(2,5-dimethoxy-4 - chlorophenyl)-1H-1,2,4-trego conduct acid washing and alkaline leaching. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. Oily residue chromatographic on a column of silica gel, elwira mixture of 98.5/1.5 or less (about./vol.), obtaining a white powder; so pl.=178oC; yield=87%.

Stage 2: 2-{ N-[5-(4-chloro-2,5-acid)-1-(2-cyclohexylethyl)- 1H-1,2,4-triazole-3-yl] carbarnoyl} -4,5-dimethyl-1-[3-(2H-1,2,3,4-tetrazol-5 - yl)propyl]-1H-indole

0.5 ml of azeotropically and 0,030 g dibutylated add to determined as 0.720 g (0,0012 mol) 4-{2-({[1-(2-cyclohexylethyl)-5- (2,5-dimethoxy-4-chlorophenyl)-1H-1,2,4-triazole-3-yl] amino}carbonyl)-4,5 - dimethyl-1H-1-indolyl] butyronitrile dissolved in 15 ml of tetrahydrofuran, and the mixture is heated at the temperature of reflux distilled within 18 hours. The reaction mixture is allowed to cool to room temperature, the tetrahydrofuran is removed under reduced pressure and the residue chromatographic on a column of silica gel, elwira mixture 95/5 (about./about.) dichloromethane/methanol. Telling white solid; T. pl.=233oC, yield=78%.

This procedure, described for example 512, is also used for examples 303, 304, 316, 317, 356, 357, 361, 362, 363, 368, 369, 392, 394, 395, 430 431 and 432.

Potassium and sodium salts of these compounds get in acetonitrile dobavleniem pressure, and then drying. TD

1. N-Triazolyl-2-indocarbocyanine General formula

< / BR>
where R1represents -(C2-C6) alkyl; a group -(CH2)n-G with n ranging from 0 to 5, and G represents a non-aromatic mono - or polycyclic3-C13the hydrocarbon group include phenyl (C1-C3) alkyl in which the phenyl group possibly substituted once by halogen or (C1-C3) alkoxy; a group -(CH2)nNR2R3in which n is an integer from 1 to 6, and R2and R3that may be the same or different, represent a (C1-C3) alkyl or form, with the nitrogen atom to which they are attached, a group of morpholino or piperidino;

X1X2, X3or X4each independently represents a hydrogen atom or halogen, (C1-C6) alkyl or (C1-C3) alkoxy, provided that only one of X1X2, X3and X4possibly represents a hydrogen atom:

R4represents hydrogen, a group -(CH2)nCOOR5in which n is as defined above, a R5represents a hydrogen atom or SUB>nNR2R3in which n, R2, R3and R5are as defined above; a group -(CH2)n-tetrazolyl, in which n is as defined above, or R4represents one of these groups in the form of a salt of an alkali metal;

Y1, Y2and Y3independently represent hydrogen, halogen, (C1-C3) alkyl, (C1-C3) alkoxy or carbarnoyl,

or one of their salts or solvate.

2. The compound of formula (I) under item 1, where R1, R4X1, X2, X3and X4are as defined in paragraph 1, a Y1, Y2and Y3represent hydrogen, its salt or MES.

3. The compound of formula (I) under item 1, where R1and R4are as defined in paragraph 1, Y1, Y2and Y3represent hydrogen; and

< / BR>
represents 2,6-dimethoxy-4-were; its salt or MES.

4. The compound of formula (I) under item 1, where R1, R4, Y1, Y2and Y3are as defined in paragraph 1, and

< / BR>
represents 2,6-dimethoxy-4-were; its salt or MES.

5. The compound of formula (I) under item 1, where R1, R4, Y1>represents methyl or a chlorine atom;

its salt or MES.

6. 1-substituted 3-aminotriazole General formula

< / BR>
where R1X1, X2, X3and X4are as defined for (I) in paragraph 1.

7. The method of obtaining compounds of formula (I), their salts or solvate according to any one of paragraphs.1-5, characterized in that aminotriazol formula (7)

< / BR>
where R1X1X2, X3and X4are as defined for (I) in paragraph 1,

subjected to interaction with the derived indolocarbazoles acid of formula (8)

< / BR>
where R4, Y1, Y2and Y3are as defined for (I) in paragraph 1.

8. The method of obtaining compounds of formula (I), their salts or solvate according to any one of paragraphs.1-5, characterized in that aminotriazol formula (7):

< / BR>
where R1X1, X2, X3and X4are as defined for (I) in paragraph 1,

subjected to interaction with the derived indolocarbazoles acid of formula (8')

< / BR>
where Y1, Y2and Y3are as defined for (I) in paragraph 1, a R'4is a group of the predecessor R4and R4is as defined for (I) in paragraph 1,

with the floor and Y3are as defined for (I) in paragraph 1, and R'4is a group of the predecessor R4moreover , the obtained compound of the formula (I') is converted into the compound of formula (I) by conversion of the group R'4in R4.

9. Pharmaceutical composition having agonist activity of CCK-A receptors containing as active principle a compound of formula (I) under item 1 or one of its pharmaceutically acceptable salts.

10. Pharmaceutical composition having agonist activity of CCK-A receptors containing as active principle a connection on p. 2 or one of its pharmaceutically acceptable salts.

11. Pharmaceutical composition having agonist activity of CCK-A receptors containing as active principle a connection on p. 3 or one of its pharmaceutically acceptable salts.

12. Pharmaceutical composition having agonist activity of CCK-A receptors containing as active principle a connection on p. 4 or one of its pharmaceutically acceptable salts.

13. Pharmaceutical composition having agonist activity of CCK-A receptors containing as active principle a connection on p. 5 or one of its pharmaceutical is

 

Same patents:

The invention relates to new derivatives naphthiridine formula I, where R1denotes phenyl, benzyl, 3-nitrophenyl, 3-chlorophenyl, 3-tianfeng, 3-(tetrazolyl)phenyl or benzofuranyl; R2denotes a hydroxy-group, tripterocalyx, allyl, alkyl, alkenyl, quinil, alkoxygroup, phenyl, phenyloxy, carboxyphenyl, carboxymethyl, carbamoylmethyl, phenylamino, diphenylamino-, amino-, elcamino, Alcaidaria, where "ALK" refers to aliphatic fragment having up to 8 carbon atoms and optionally including carboxylate, ether carboxylic acid or a hydroxy-group and/or optionally containing ether and/or ester bond, or its N-oxide in free form or in the form of a pharmaceutically acceptable salt

The invention relates to new compounds of the formula (I), where R1is (C3-C7)cycloalkyl group or a 3-7-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen, oxygen, or sulfur, which may be optionally substituted by oxopropoxy; R2- aryl group, which optionally can be substituted by 1-3 halogen atoms; And a is methylene or carbonyl group; a simple bond; D is oxygen atom or sulfur; G is - (C1-C4)alkylenes group; L is a group of the formula-C(R4)(R5)-, where R4and R5defined in the claims, Z is two hydrogen atoms or an oxygen atom, n = 0 or 1, or its pharmaceutically acceptable salts, esters, Quaternary amines or hydrates

The invention relates to the derivatives of thiophene of the General formula I, in which R1is the formula A1- X1- R3; R2is perhaps the formula A2- X2- R4; ring b is 4-10-membered nitrogen-containing cycloalkyl ring or 5 - or 6-membered nitrogen-containing unsaturated heterocycle; Ar represents an aryl ring or heteroaryl ring; A1, A2and A3may be the same or different and each represents a bond or lower alkylenes group; X1and X2may be the same or different and each represents a bond or a formula-O-, -S-; R3and R4may be the same or different, and each represents a hydrogen atom, cyclic aminogroup or a lower alkyl group, aryl group or aracelio group, or its pharmaceutically acceptable salt

The invention relates to derivatives of 5-phenyl-3-(piperidine-4-yl)-1,3,4-oxadiazol-2(MN)-it General formula I, in which R1is a group (C1-C4)alkyl or the group (C3-C7)cycloalkenyl; X1is a hydrogen atom or halogen or the group (C1-C4)alkoxy or or1and X1together, the group of the formula-och2O-, -O(CH2)2-; -O(CH2)2O - or-O(CH2)3O-; X2is a hydrogen atom or amino group; X3is a hydrogen atom or halogen; R2is a hydrogen atom or a possibly substituted group (C1-C6)alkyl, or a phenyl group(C1-C4)alkyl which may be substituted on the phenyl ring, or a phenyl group(C2-C3)alkenyl, or group of phenoxy(C2-C4)alkyl or cyclo(C3-C7)alkylaryl, or group of 2,3-dihydro-1H-inden-1-yl or 2,3-dihydro-1H-inden-2-yl, or gruppa General formula -(CH2)nFROM a-Z, in which n = 1 to 6, a Z - group piperidine-1-yl or 4-(dimethylamino)piperidine-1-yl

The invention relates to new nitrogen-containing heterocyclic compounds with biological activity, in particular to substituted derivatives of pyrazole and means of having a weed-killing activity
The invention relates to a method for anticancer drug prospidina, which is used in oncological practice, as well as in the treatment of rheumatoid arthritis

The invention relates to new substituted pyrrole General formula I

< / BR>
where R is hydrogen, hydroxyl;

R1and R2- together group of the formula -(CH2)nand R7is hydrogen, or R1and R7- together group of the formula -(CH2)nand R2is hydrogen;

R3is phenyl, naphthyl which may be substituted with halogen, C1-C7- alkoxy, CF3or benzofuranyl, benzo(b)thienyl, indolyl, substituted by 1-3 substituents selected from the group comprising halogen, C1-C7-alkyl, C1-C7-alkoxy; R4, R5and R6is hydrogen, halogen, C1-C4-alkoxy, C1-C7-alkyl,

R8a group of the formula -(CH2)p-R9or -(CH2)q-R100;

R9is hydrogen, C1-C7-alkylsulphonyl, C1-C7-alkylsulfonyl, aminocarbonyl;

R10is hydroxyl, amino, C1-C7-alkylamino, di(C1-C7)-alkylamino, three(C1-C7)-alkylamino, azido, C1-C7-alkoxy-carbylamine, isothiocyanate, C1-C7-alkylcarboxylic, C1-C7-alkylsulfonate, 6-membered nitrogen-containing saturated gets the SUB>2; W is amino; one of X and Y - O-atom, and the other is O or (H,H);

Z - group-CH - or N-atom;

m, p and q is a number from 0 to 5, n is a number from 1 to 5, provided that m and q represent the number from 2 to 5 when Z Is N-atom, and their pharmaceutically acceptable salts

The invention relates to new derivatives of benzimidazole with valuable properties, in particular a derivative of benzimidazole of General formula (I)

< / BR>
where R1is methyl,

R2- benzimidazole-2-yl, unsubstituted or substituted in position 1 by the stands, imidazol-4-yl substituted in position 1 by alkyl with 1 to 3 carbon atoms, substituted in position 2 by morpholinopropan, 5,6,7,8-tetrahydro-imidazo[1,2 - a]pyridine-2-yl or propanesultone-1-Il,

R3- nonbranched alkyl with 2 to 4 carbon atoms,

R4- amino group, sulfonyl substituted by a residue from the group consisting of dimethylaminopropylamine, cycloalkylcarbonyl, benzylaminocarbonyl in which cycloalkyl part contains 5 or 6 carbon atoms and the phenyl portion may be substituted methoxy group, triptorelin, tert
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