Derivatives pyridazino [4',5':3,4]pyrrolo[2,1-a]isoquinoline and their physiologically tolerated salts with acids and complexing agents

 

(57) Abstract:

Derivatives pyridazino [4',5':3,4]pyrrolo[2,1-a]-isoquinoline General formula I where X is oxygen atom or sulfur, the group NHO, R1- C1-10-alkyl, possibly substituted by tenoxicam or phenyl, which in turn can be single or twofold substituted by halogen, alkyl or alkoxyl, R2, R3- alkoxy, and their physiologically tolerated salts with acids and complexing agents, applicable as cardiotoxin funds, funds for brain protection. 9 C.p. f-crystals, 2 tab.

This invention relates to new derivatives of pyridinedimethanol possessing biological activity, more specifically derivatives pyridazino [4',5':3,4]pyrrolo[2,1-a]isoquinoline and their physiologically-tolerated salts with acids and complexing agents.

Of posted bids Germany N 3500941 and 3525048 known existing cardiotoniceski 9-amino-pyridazino[4,5:3,4]pyrrolo- [2,1-a]isoquinolines. From European application N 252299 it is also known that these compounds possess cardio - and neuroprotective effect and therefore encourage the circulation of blood in the tissue and the supply of oxygen to tissues in the Central nervous system.

The task of the mi biological properties.

The problem is solved proposed derivative pyridazino[4', 5':3,4]pyrrolo[2,1-a]isoquinoline General formula I

< / BR>
where X is an oxygen atom or sulfur, the group NHO,

R1is alkyl with 1 to 10 carbon atoms, possibly substituted by tenoxicam or phenyl, which in turn can be single or twofold substituted with halogen, alkyl with 1 to 4 carbon atoms or alkoxyl with 1 to 2 carbon atoms,

R2and R3- alkoxy with 1 to 4 carbon atoms,

and their physiologically tolerated salts with acids and complexing agents, with the exception of compounds in which X represents a sulfur atom, and R1- alkyl with 1-5 carbon atoms or benzyl, as well as their physiologically tolerated salts with acids and complexing agents.

The new compounds possess valuable therapeutically useful properties. They are applicable as cardiotoxin means, means to protect the brain (in particular, in the treatment of patients who have suffered a stroke or who is threatened), as a means for the treatment of chronic inflammatory processes (for example, bronchial asthma, arthritis). Further, these compounds can be used as tools with antiproliferative and medium spans]pyrrolo- [2,1-a]isoquinoline General formula (I) includes compounds have

X is oxygen atom or sulfur, the group NHO,

R1is alkyl with 1 to 5 carbon atoms, possibly substituted by phenyl which, in turn, can be single or twofold substituted with halogen, alkyl with 1 to 4 carbon atoms or alkoxyl with 1 to 2 carbon atoms,

R2and R3- alkoxy with 1-4 carbon atoms, and their physiologically tolerated salts with acids and complexing agents, with the exception of compounds in which X is a sulfur atom, and R1- alkyl with 1-5 carbon atoms.

The second group preferred derivatives pyridazino[4',5':3,4]pyrrolo-[2,1-a]isoquinoline General formula (I) include compounds in which

X is oxygen atom or sulfur, the group NHO,

R1- alkyl with 1-5 carbon atoms, possibly substituted by phenyl which, in turn, can be single or twofold substituted with halogen, alkyl with 1 to 2 carbon atoms or alkoxyl with 1 to 2 carbon atoms,

R2and R3- alkoxy with 1 to 4 carbon atoms, and their physiologically tolerated salts with acids and complexing agents, with the exception of compounds in which X is a sulfur atom, and R1is alkyl with 1 to 5 carbon atoms.

In a third preferred group of derivatives of p is alkyl with 1 to 4 carbon atoms, substituted by one or two unsubstituted phenyl groups or one phenyl group, substituted with halogen, alkyl with 1 to 4 carbon atoms or alkoxyl with 1 or 2 carbon atoms.

The most preferred compounds, in which

R1means alkyl with 1 to 4 carbon atoms substituted by phenyl, unsubstituted or one - or twofold substituted by fluorine atoms, chlorine or stands.

In a fourth preferred group of derivatives pyridazino[4',5':3,4]pyrrolo[2,1-a]isoquinoline General formula (I) include compounds in which

R1means benzyl.

In the fifth group of preferred derivatives pyridazino[4',5':3,4]pyrrolo-[2,1-a]isoquinoline General formula (I) include compounds in which

R2and R3mean methoxyl.

In a sixth group of preferred derivatives pyridazino[4',5':3,4]pyrrolo-[2,1-a]isoquinoline General formula (I) include compounds in which

X means an oxygen atom or sulfur or a group NHO, R1- 4-methylbenzyl, a R2and R3- methoxyl.

In the seventh group of preferred derivatives pyridazino[4',5':3,4]pyrrolo-[2,1-a]isoquinoline General formula (I) include compounds in which the

In the eighth preferred group of derivatives pyridazino[4',5':3,4]pyrrolo- [2,1-a]isoquinoline General formula (I) include compounds in which

X is a sulfur atom.

The compounds of formula (I) are bases and are known to be translated with inorganic or organic acids, as well as with salt and complexing agents in any physiologically harmless adducts (salt).

For the formation of salts are suitable, for example, such acids as hydrochloric acid, Hydrobromic acid, itestosterone acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, Caproic acid, valeric acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, para-hydroxy-benzoic acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulfonate and the like acids.

New connections can be obtained by known methods.

The new compounds of formula (I) in which X means g is uly III

H2N-OR1(III)

where R1has the above values.

The source compound of General formula II is dissolved in a high boiling inert solvent, for example dimethylformamide, dimethylacetamide, chlorobenzene or triamide hexamethylphosphoric acid and heated with the amine component of the General formula (III) under reflux to complete the reaction. The reaction time is from about 1 to 15 hours, and depends on the starting materials.

In the case of reactive hydroxylamine can also be used as solvent to use alcohols or tetrahydrofuran; in some cases it may be useful to conduct the reaction in the autoclave.

If the original hydroxylamine are liquid and have a sufficiently high boiling point, the reaction can be conducted in an excessive amount of amine without added solvent (for example, in the case of ORT-benzyl-hydroxylamine), if necessary, in an atmosphere of nitrogen.

In some cases you can also apply the reagent, which in the interaction also serves as a solvent.

The target product of the General formula (I) in which X is a sulfur atom or oxygen, can poluchil agent of the formula V

R1- Y (V)

where R1have the above meanings and Y represents the anion tsepliaeva group, for example, chlorine, bromine, iodine, group methansulfonate, the rest of triftoratsetata, para-toluenesulfonic acid, para-nitrobenzenesulfonate or para-bromobenzonitrile. As alkylating funds you can also make use of other reagents suitable for this vector Carbo-cation, for example, "onevia" compounds, such as salts Meerwein, for example triethyloxonium-tetrafluoroborate, -phosphate or - hexachloroantimonate.

The source compound of General formula (IV) interacts in an inert solvent, such as dimethylacetamide, triamide hexamethylphosphoric acid, chlorobenzene or acetone with an alkylating agent of General formula (V). Communication is usually carried out at room temperature, in some cases, and the temperature of the return flow, in each case depending on the reactivity of the alkylating funds. The reaction time is from about 1 to 20 hours and depends on the starting materials.

Obtaining the compounds according to the invention is illustrated by the following examples.

Example 1

Hydro ptx2">

3 g of S-methyl compound, 5 g of the hydrochloride of ORT-benzyl-hydroxylamine and 50 ml of toluene was heated with reverse flow for about 5 hours. At the end of the interaction (controlled methods DK) and the mixture was cooled and the product was pressed on the filter.

2 m-al was washed with toluene and separated between dichloromethane and dilute sodium alkali. The organic phase is repeatedly washed with water, dried over sodium sulfate and evaporated. The remainder, if necessary, after purification on a column of silica gel (eluent is a mixture of dichloroethane with methanol = 100+10 weight. parts), absorbed a small amount of dichloromethane and adding ethanolic hydrochloric acid was transferred into the hydrochloride.

Yield 2.86 g (71.5% of theory).

So pl.: 235oC.

Example 2

5,6-dihydro-2,3-dimethoxy-e-(4-bromobenzyl)-Mercato-pyridazino-[4', 5',: 3,4]-pyrrolo [2,1-a]-isoquinoline

1.28 g of 5,6-dihydro-2,C-dimethoxypyridine-[4',5',3,4]- pyrrolo-[2,1-a] isoquinoline-9-(10H)-thione suspended in 30 ml of dimethylacetamide and then under stirring at room temperature was added 3.50 g of 4-bromobenzylamine. After about 20 minutes formed a clear orange-red solution, from which after further stirring preature for 16 hours, the crystals were pressed on the filter was dissolved in a mixture of methylene chloride and methanol (100 + 20). Washed first with dilute sodium alkali, then with water, dried over water-containing sodium sulfate and concentrated. The residue was led from a mixture of dichloromethane and methanol (100 + 20).

Yield 5.5 g (89,3% of theory).

So pl.: 210oC.

Example 3

5,6-dihydro-2,3,9-trimethoxybenzene-[4', 5', : 3,4]- pyrrolo[2,1-a]-isoquinoline

In suspensions containing 6.3 g of 5,6-dihydro-2,3-dimethoxy-pyridazino-[4', 5': 3,4]-pyrrolo-[2,:1-a]-isoquinoline and 50 ml of dimethylacetamide, worked together at room temperature with 5 ml of freshly under the conditions. After about 1 hour formed transparent, which after further stirring at a temperature of 50oC, the precipitated crystals are excellent yellow color, which was pressed on the filter was dissolved in a mixture of methylene chloride and methanol (100 + 20). Washed first with dilute sodium alkali, then with water. The organic phase was dried over water-containing sodium sulfate and concentrated. The residue was dissolved in a mixture of dichloromethane and methanol (100 + 20) and adding ethyl ether was led.

Yield 4.7 g (75.6% of theory).

So pl.: > 270oC.

Analogously to example 2 get svedennyy for the treatment of brain diseases, associated with degeneration and necrosis. Equally possible prevention of such diseases for patients for whom the potential risk of such diseases. This action of the compounds is not based on the improvement of blood circulation. Thus, the compounds applicable to the treatment of a new type of epilepsy and Alzheimer's disease, especially for patients who have suffered a stroke or possible danger from such a shock. Connections can also be used to generate funds for the treatment of chronic inflammatory processes, Colitis Ulcerosa and Morbus Crohn, as well as funds from the antiproliferative action. The action of the compounds can be explained by their suppression of the non-selective channels cation (SAC).

The basis of the pathophysiology of chronic bronchial asthma are inflammatory processes that contribute to the activation of inflammatory cells (Barnes, 1987; Seifert, Shultz, 1991).

Adjustable receptor activation of inflammatory cells (such as neutrophilic granulocytes and mast cells or ACC. their resistant cell line HL-60 or sensitized, i.e., containing gammaglobulin E cells RBL) regardless of the form of stimulating agonist (such as endothelia blocker selective channels cation (SAC) (rink, 1990). Through these channels extracellular calcium enters the cells, which is necessary for the persistence of what is happening with the participation of receptor activated cells (Putin, 1990). If calcium intake is interrupted, which results in blockade of the activation of inflammatory cells.

Classical calcium antagonists type of dihydropyridines or ACC. phenylalkylamine not inhibit either the IAC or the inflammation of wells and others, 1986). To assess the activation of cells or ACC. to evaluate the inhibition of NCC - blocker is calculated spectral kinetics of cytoplasmic calcium concentration in containing Fura-2 cells according to the method described by Grinkevich and others (1985). In the framework of this invention, this technique proved to be a suitable method of screening for recognition NCC-blockers.

For the specific characteristics of nonselective blockers of calcium channels suitable so-called inhibition "Tapsigarginom". Thapsigargin is described by Tastrup, etc. (WGE. Natl. Acad Sci. (USA), 87, 2466-2470, 1990) promoter tumors, which selectively and irreversibly inhibits sensitive to IP3Ca2+drive intracellular adenosinetriphosphatase Ca2+. This results in bistable a physiological irritation for opening non-selective channel of cations in the cell membrane. The consequence of this is the massive flow of ions into the cell of sodium and calcium. Based on these properties Thapsigargin is suitable as an indirect stimulus-independent agonists and from IP3holes nonselective channel cations.

In the framework of this invention, the stimulation Tapsigarginom selective channels cations in cells HL-60 (leukemia cells human), in hippocampal and cortical neuronal cells, and RBL cells (cells of rat basophilic lymphoma) is successful, which proves the existence of these channels in each cell line.

The cytoplasmic concentration of Ca2+([Ca2+]i) plays an important role in profilerate cells and the tumor growth (see review by L. R. Sucharskiego and others in the "Medical journal", T. 19, pp. 145-177, 1988 1. In particular, the flow of Ca2+stimulated by activation of the receptor for subsequent mediation inositoltrifosfata-(IP3the cage should be crucial in cancer cell proliferation (U. Kikkawa and I. Nishizuka, Ann. Cell. Biol., 2, 149-178, 1986). This mechanism also plays a role in the formation of metastasis and "politicist to drugs" (see the above review L. R. Sucharskiego).

This new (NCC) leads to swarnamalya Ca2+in the cell, and is highly active promoter of the tumor (Century Tåstrup and others "Proceedings of the Natl. Acad. Sci. (USA), 87, 2466-2470, 1990). Blockage of the flow of Ca2+through NCC leads to normalization of intracellular Ca ion concentration and thereby to suppress tumor growth, etc.

Classical calcium antagonists do not inhibit these IRP. Unexpectedly, it was found that the claimed according to the invention compounds inhibit the flow of calcium into the cell through the IAC.

As shown by C. H. merch, etc. (Lancet, 339, 381-385, February 15, 1992), the endothelium 1 plays an important pathophysiological role in inflammatory bowel diseases such as Colitis ulcerosa and Morbus Crohn. Using immunohistochemical methods can be established that patients suffering from M. Crohn in the area of Submucosa, and patients suffering from Colitis ulcerosa in the area of the Lamina propria of the large intestine epithelium, have a significant and highly elevated concentrations of endothelin-1 in comparison with normal people. It is assumed that the local eruption of endothelin causes massive vasospasm and subsequent interstitial ischemia with microinfarcts that is considered to be the actual cause of these diseases. Vasospasmen efficiency endothelin due to overload of Ca2+penichette IP3attached to massive transmembrane flux of Ca2+through intensifitsiruya the dihydropyridines channels (M. S. Simonson and others Clin. Invest. Med. , 14, 499-507, 1991; J. Cardiovasc. Pharmacol., 13, Suppi. 5, S1-S4, 1989; J. Pharmacol., 100, 383-392, 1990). In the case of these channels we are talking about non-selective channels cations, the existence of which in the mucosal cells of the colon has recently been described (Fig. Simar and, Hegelian, Europ. J. Physiol., 420, 319-328, 1992).

As a suitable model of screening for detection of functional endothelin antagonists were stimulated by endothelin ektivirovannye cell human leukemia cells HL-60), containing Fura-2. According to column j. The Grinkevich, and others (J. Biol. Chem., 260, 3440-3450, 1985) can be observed intracellular concentration of Ca2+in the cytoplasm of cells HL-60 (suspension) and measure it to assess the activation of cells by endothelin. Stimulation is carried out by adding 0.1 mm of endothelin, it is possible to inhibit depending on the dose of the compounds according to this invention.

Functional antagonism of endothelin compounds according to the invention contributes to the selective blockade of channels cations. Therefore, it is useful also evidence of functional antagonism of Attica tests:

For the purposes of pre-screening in nestorgames Ca2+the incubation medium stimulated with 0.1 mm Thapsigargin stuck, containing Fura-2 cells RBL-hml. Four minutes later restore extracellular Ca2+to 1.5 mm, and using fluorescence Fura-2 register excessive rise of the cytoplasmic concentration of Ca2+due to massive transmembrane flux of Ca2+through selective channels cations. This stream is then metered to inhibit blocker selective channels cations. Neither classical calcium antagonists, no specific blockers antagonists, which can stimulate the exchange of IP3not inhibit resolved indirectly by Tapsigarginom transmembrane flux of Ca2+. Compounds according to this invention are characterized in that they inhibit NCC. Fluorometric measurement of calcium in the cytoplasm of the individual adhering cells RBL-hml is similar to that described Where and Ogura (1986) method for neural cells. Used fluorescent microscope Axiovert 35 firms the Pace in combination with the Imaging device System of the company Hamamatsu, consisting of an image processing system ICMS, the residual of the camera with the control node and the image intensifier DVS3000.

Comparing the two curves of activated cell cultures in the presence and absence of 10 μm test compound. The area under these curves (area under the curve" = CPD) is integrated and is a measure of activation of the cells. The intensity of the inhibitory effect of the tested antagonists, NCC is estimated by the following relation

< / BR>
where %N = inhibition percentage of the flow of calcium through selective channels cations, which stimulated and ingibirovany 10 μm test substance.

ACCing= area under the curve recorded in the presence of stimulator plus 10 μm inhibition test substance.

ACCcounter= area under the curve, recorded only with the use of the stimulator. Literature to the above explanation:

BARNES P. J. , I. W. RODGER und N. C. THOMSON Pathogenesis of asthma in ASTHMA, basic mechanisms and clinical management, ED by P. J. BARNES; ACADEMIC PRESS, LONDON, 1988.

GRYNKIEWICZ, G., M. POENIE, and R. Y. TSIEN A new generation of Ca2+-indicators with greatly improved fluorescence properties, J. BIOL. CHEW. 260: 3440-3450, 1985.

HIDE, M. und M. A. BEAVEN Calcium influx in a rat mast cell (RBL-2H3) line J. BIOL CHEW. 266 15221-15229, 1991.

KUDO, Y. and A. OGURA Glutamate-induced increase in intracellular Ca2+-concentration in isolated hippocampal neurones BR. J PHARMACOL 89: 191-198, 1986.

PUTNEY, J. W. , jr. Capacitative Calcium entry revised CELL CALCIUM II: 611phagocytes: An enzyme system regulated by multiple mechanism REV. PHYSIOL. BIOCHEM. PHARMACOL, Vol. 117, SPRINGER VERL, 1991.

WELLS, E. , C. G. JACKSON, S. T. HARPER, J. MANN and R. P. EAOY Characterization of primate bronchoalveolar mast cells II, inhibition of histamine, LTC4and PGF2arelease from primate bronchoalveolar mast cells and a comparison with rat peritoneal mast cells

J. IMMUNOL 137: 3941-3945, 1986.

Measurements:

Is expressed as the percentage inhibition of NCC after stimulation Thapsigargin (0.1 ám Telegarden) in cells RBL-hm1. The concentration of the tested substances 10-5mol, preferably 10-6the mole.

The results of the experiment are summarized in table 2 (see end of description).

Functional antibacterially activity can be shown in the following tests.

Apply some stuck to a glass plate RBL-2H3 line of tumor cells fat cells).

Cultivation and adhesion of cells RBL-2H3 carried out according to the method described Khalde and Buena (1991). For sensibilizirovannoy the adhered cells RBL-2H3 their incubated for two hours at room temperature and diluted 1:2000 commercially available solution of gammaglobulin E against complex dinitrophenolates bovine serum (BODICE-FOREST-antigen). The cells are then washed. The addition of 0.1 ml LEAF FOREST (10 µg/ml) carried out a massive immunogenetically measurement of calcium in the cytoplasm of the individual adhering cells RBL-2H3 perform similarly described Where and Ogura (1986) method for neural cells.

The material for comparison is used in these tests chromoglycate (10 μm), which causes about 50% inhibition induced by antigen activated cells.

In this test, the above compounds demonstrate the value of % N, which is comparable with the above values.

When research microculture different cell lines of human cancers through analysis of tetrazolium to establish the antiproliferative effect of the compounds according to the invention it was unexpectedly found that the tested compound has 5-10 times stronger effect than substance for comparison Verapamil.

Antiproliferative effectiveness of the tested substances was determined as described Musmanno (J. Immunol. Meth., 65, 55 to 63, 1983), Deniston and other (Int. J. Immunol. Meth., 89, 271-277, 1986) and J. Aliasone and other (Int. J. Cancer, 46, 113-117, 1990) MTT-test. (MTT = [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium-bromide] company Chemicon Inc. El Segundo, Ca, USA). This indicator is metabolized only in the case of living cells with intact mitochondria to blue formazon product. This test used the following cell lines of human tumors: A 549 (adenocarcinoma lungs), A 431 (epidermization vulva), PC 3 (adenocarcinoma prostate), SK My leukemia).

The test was performed on Microtiterwells plate. Each cell contained 100 μl of cell suspension (0.2 x 106 cells/ml). The incubation medium was RPMI 1640 with 10% activated by heating fetal calf serum and 50 μg/ml gentamicin. The cell suspensions were incubated for 0, 24, 48, or 72 hours at 100% humidity in a mixture of carbon dioxide (5%) and air at a temperature of 37oC in the presence or in the absence of the test antiproliferative substances in various concentrations. The test substances were dissolved in DMSO (final dilution: 0.1 per cent). Then added 10 μl of MTT solution (3 mg/ml) and after three hours, 100 μl of 0.08 n solution of hydrochloric acid in isopropanol. After another hour was measured by the absorption of light with a wavelength of 570 nm (wavelength comparison 630 nm) on the reader microplate. The absorption of light is directly proportional to the number of living cells.

Premaxilla concentration of inhibition of the tested substances was 1 µg/ml.

Vazospasticescoe the effectiveness of the above-described functional antagonists of endothelin or ACC. Thapsigargin was confirmed on a dedicated uncut vessel: kataboliceski perpendicula, spontaneously beating on Longeur firm Hugo Sachs Elektronik, March). With these measurements it was possible to register the scale, duration and shape the course of vasospasm with high reliability. When he perpendicularly with endothelin at a concentration of 100 nm, coronary perfusion current was decreased from 11 to 5 ml/min Reduction in perfusion was possible to raise the compounds according to the invention. The force of action of the substances according to the invention inhibition Thapsigargin in cells RBL-hm1 containing Fura-2, or ACC. the efficiency of inhibition of endothelin in cells HL-60, containing Fura-2, clearly correlated with vazospasticescoy effectiveness of the tested substances proven by drugs Langendorf. From this we can conclude that vazospasticescoy the endothelin antagonism to the tested substances caused by non-selective blockade of channels cations.

Compounds according to the invention can be taken as enterline, and parenteral. For oral administration are available doses from 0.1 to 500 mg of active substance per dose, intravenous offered from 0.05 to 150 mg per dose. The required therapeutic dose depends on the indications and usages, and can be set experimentally.

Suitable applications testwuide tablets can be obtained, for example, by mixing one or more active substances with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrating agents such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and/or means to achieve a depot, such as carboxypolymethylene, carboxymethylcellulose, acetated cellulose or polyvinyl acetate. Tablets can also consist of several layers.

Accordingly, it is possible to obtain tablets by coating on cores obtained similarly to obtain tablets, substances commonly used for membranes coated tablets, for example, kollidon or shellac, gum Arabic, talc, titanium dioxide or sugar. To achieve the effect of the depot or to prevent the incompatibility of the core may consist of several layers. Similarly, and shell bean can to achieve the effect depo consist of several layers, and you can apply the above for tablets excipients.

Juices containing substances according to the invention or the ACC. the combination of such substances, may even further the taste of funds for example, flavorings such as vanillin or orange extract. They can, moreover, contain suspendresume AIDS or thickeners, such as carboxymethylcellulose sodium, wetting, for example, the condensation products of fatty alcohols with ethylene oxide, or protective substances, such as para-hydroxybenzoate.

Solutions for injection get the usual manner, for example, adding preservatives, such as para-hydroxybenzoates, or stabilizers such as alkali metal salts of ethylenediaminetetraacetic acid, and poured into vials for injection or capsules.

Containing one or more active substances of the capsule can be obtained, for example, the fact that the active substance is mixed with an inert carrier and encapsulate in capsules made of gelatin.

Suitable for use drops get, for example, by mixing the active substance with stipulated by the carrier, such as neutral fats or polyethylene glycol or ACC. their derivatives.

1. Derivatives pyridazino[4', 5':3, 4]pyrrolo[2,1-a]isoquinoline General formula I

< / BR>
where X is an oxygen atom or sulfur, the group NHO;

R1is alkyl with 1 to 10 carbon atoms, possibly samkelo 1 4 carbon atoms or alkoxyl with 1 to 2 carbon atoms;

R2and R3- alkoxy with 1 to 4 carbon atoms,

and their physiologically tolerated salts with acids and complexing agents, with the exception of compounds in which X represents a sulfur atom, and R1is alkyl with 1 to 5 carbon atoms or benzyl.

2. Derivatives pyridazino[4', 5':3, 4]pyrrolo[2,1-a]isoquinoline General formula I on p. 1, where X is an oxygen atom or sulfur, the group NHO, R1is alkyl with 1 to 5 carbon atoms, possibly substituted by phenyl which, in turn, can be single or twofold substituted with halogen, alkyl with 1 to 4 carbon atoms or alkoxyl with 1 to 2 carbon atoms, R2and R3- alkoxy with 1 to 4 carbon atoms, and their physiologically tolerated salts with acids and complexing agents, with the exception of compounds in which X represents a sulfur atom, and R1is alkyl with 1 to 5 carbon atoms or benzyl.

3. Derivatives pyridazino[4', 5':3, 4]pyrrolo[2,1-a]isoquinoline General formula I on p. 1, where X is an oxygen atom or sulfur, the group NHO, R1is alkyl with 1 to 5 carbon atoms, possibly substituted by phenyl which, in turn, can be single or twofold substituted with halogen, alkyl with 1 to 2 carbon atoms or alcoke salts with acids and complexing agents, with the exception of compounds in which X represents a sulfur atom, and R1is alkyl with 1 to 5 carbon atoms or benzyl.

4. Derivatives pyridazino[4', 5':3, 4]pyrrolo[2,1-a]isoquinoline General formula I on PP.1, 2 or 3, where R1means alkyl with 1 to 4 carbon atoms, substituted by one or two unsubstituted phenyl groups or one phenyl group, substituted with halogen, alkyl with 1 to 4 carbon atoms or alkoxyl with 1 or 2 carbon atoms.

5. Derivatives pyridazino[4', 5':3, 4]pyrrolo[2,1-a]isoquinoline General formula I on p. 4, where R1means alkyl with 1 to 4 carbon atoms substituted by phenyl, unsubstituted or one - or twofold substituted by a fluorine atom, or chlorine stands.

6. Derivatives pyridazino[4', 5':3, 4]pyrrolo[2,1-a]isoquinoline General formula I on PP.1, 2 or 3, where R1means benzyl.

7. Derivatives pyridazino[4', 5':3, 4]pyrrolo[2,1-a]isoquinoline General formula I on p. 6, where R1and R3means methoxyl.

8. Derivatives pyridazino[4', 5':3, 4]pyrrolo[2,1-a]isoquinoline General formula I under item 1 or 2, where X means an oxygen atom or sulfur or a group NHO, R1- 4-methylbenzyl, and R2and R3- methoxyl.

9. Derivatives pyridazino[4', 5':3, 4]pyrrole is 3 - methoxy, and R1- benzyl, 3-Chlorobenzyl or 4-terbisil.

10. Derivatives pyridazino[4', 5':3, 4]pyrrolo[2,1-a]isoquinoline General formula I on PP.1 to 9, where X is a sulfur atom.

 

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R2hydrogen, lower alkyl, lower foralkyl, lower cycloalkyl, lower cycloalkenyl, lower alkenyl, lower quinil, lower alkoxyalkyl, lower alkylthiomethyl, lower alkanoyl, cyano, phenyl, benzyl, lower alkoxybenzyl, methylsulphonyl;

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R4hydrogen, halogen, lower alkyl, nitro, amino;

R5hydrogen, hydroxyl, halogen, lower alkyl, lower alkoxy, trihalomethyl, lower oxyalkyl, cyano;

R8hydrogen, lower alkyl; and when Z is oxygen or sulfur, R2hydrogen, lower alkyl, lower alkenyl, lower quinil, lower alkoxyalkyl, lower alkylthiomethyl, lower alkanoyl, phenyl, benzyl, lower alkoxybenzyl; R3, R4, R5, R6, R7and R8a hydrogen atom or one of the substituents R3, R4, R5, R6, R7and R8the lower alkyl and the other substituents are hydrogen, or one of the substituents R3, R4, R5and R7the halogen and the other substituents R6and R8hydrogen, or one of the substituents R3, R4and R7nitro, and the remaining substituents R5, R6and R8hydrogen, or one of zamestitelei R3, R5and R6is hydroxyl, and the other substituents R4, R7and R8hydrogen, or one of the substituents R3, R4and R7amino and the other substituents R5, R6and R8hydrogen, or one of the substituents R3and R5alkoxy, and the other substituents R4, R6, R7and R8hydrogen, or R5lowest oxyalkyl or cyano, and R3, R4, R6, R7and R8hydrogen, or R7azido, and R3, R4, R5, R6and R83, R4and R5means butyl, and the other substituents R6, R7and R8mean hydrogen, and R6, R7and R8independently of one another denote hydrogen or lower alkyl, provided that at least one of them means hydrogen, or one of the substituents R6, R7and R8means butyl, and the other substituents R3, R4and R5mean hydrogen, R1does not mean hydrogen, lower alkyl, lower alkenyl, benzyl, lower alkanoyl, lower alkoxyalkyl and lower alkylthiomethyl, and their hydrates and pharmacologically tolerable salts have valuable biological properties, particularly an inhibitory effect on reverse transcriptase of the virus HIV-1, so that they can be used for prevention or treatment of AIDS
The invention relates to chemical-pharmaceutical production

The invention relates to new derivatives of 3(2H)-pyridazinone General formula I, where R1is hydrogen, phenyl, methyl, substituted CH3O or CH3SO2NH, C2-C4-alkyl, substituted R8R9N; C3-C5alkenyl, substituted phenyl, which is optionally substituted by halogen, one of A and B is hydrogen and the other a group of formula II, where R2and R3is independently hydrogen, C1-C4-alkyl or together with the adjacent group-N(CH2)nN - form pieperazinove or homopiperazine ring; R4is hydrogen or C1-C4-alkyl, R5, R6and R7is hydrogen, C1-C4-alkoxy, CH3SO2NH, X is a simple valence bond, an oxygen atom or the group-CH= CH-, m = 0-1, n = 2-3; R8and R9- independently C1-C4-alkyl, or together with the nitrogen atom to which they are attached, form morpholino - or 4-R10- piperazinone, where R10- C1-C4-alkyl, substituted phenoxypropane, or C3-C5alkenyl, substituted phenyl group, or an acid additive salts, which possess antiarrhythmic activity, pharmaceutical compositions containing an effective amount of the compounds in the mixture

The invention relates to a new diisobutylaluminum connection, which has an excellent activity, which increases potassium exchange by opening potassium channels and therapeutic agents for the treatment of hypertension, angina pectoris and asthma, which contain diazabicyclo connection as the active agent

The invention relates to a compound of formula I and pharmaceutically acceptable acid additive salts, where: a Is N or CH; b is-NR1R2-NHCHR1R2, -OCHR1R2
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