The combination of inhibitors of no-synthetase and catchers reactive forms of oxygen

 

(57) Abstract:

The invention can be used in medicine for the treatment of pathological conditions, in the event involving the nitric monoxide and reactive forms of oxygen. The claimed pharmaceutical drug for the above purpose, containing at least one substance inhibiting NO-synthetase, and at least one substance that traps the reactive forms of oxygen. Stated another variant of the drug, made in the form of a separate form for simultaneous or sequential use. One form contains at least one substance inhibiting NO-synthetase, and the other at least one substance that traps the reactive forms of oxygen. Compounds of pharmaceutical drugs act synergistically. This allows lower doses of active substances and thus reduce the manifestation of the unwanted side effects with the use of new drugs. 2 C. and 13 C.p. f-crystals, 5 PL.

The invention relates to pharmaceutical compositions containing as active ingredient at least one substance inhibiting NO-synthetase, and at least one substance, Britanie also applies to the product, containing at least one substance inhibiting NO-sintheta, and at least one substance that traps the reactive forms of oxygen, in the form of a combined product of the individual forms of these active ingredients.

Pharmaceutical composition and preparation of the present invention offer advantages in the treatment of pathological conditions, in the event involving the nitric monoxide and reactive forms of oxygen, in particular:

- cardiovascular and cerebrovascular disorders, including, for example, atherosclerosis, migraine, hypertension, septic shock, cardiac and cerebral infarction ischemic or hemorrhagic nature, ischemia and thrombosis;

- disorders of the Central or peripheral nervous system, such as, for example, neurodegenerative diseases, including, in particular, heart brain, senile dementia, including Alzheimer's disease, horey chorea, Parkinson's disease Creutzfeld-Jakob disease caused by prions, amyotrophic lateral sclerosis, pain, cerebral trauma or spinal cord injury, addiction to opiates, alcohol and other substances, visodate, depression, anxiety, schizophrenia, epilepsy, sleep disorders, eating disorders (anorexia, bulimia);

- proliferative, and inflammatory changes, such as, for example, atherosclerosis, pulmonary hypertension, glomerulonephritis, portal hypertension, psoriasis, osteoarthritis and rheumatoid arthritis, fibrosis, amyloidosis, inflammation of the gastro-intestinal tract (colitis, Crohn's disease) or pulmonary system and pneumatic paths (asthma, sinusitis);

- diarrhea, vomiting, including autacoids nature, radioactive radiation, solar radiation (UV-a, UV-b);

- organ transplantation; autoimmune and viral diseases, such as lupus, AIDS, parasitic and viral infections, diabetes, multiple sclerosis, myopathy;

cancer; and

all pathological condition characterized by the production or dysfunction of nitrogen monoxide and/or reactive forms of oxygen.

With all these pathological conditions experimentally demonstrated the involvement of nitrogen monoxide or reactive forms of oxygen (Kerwin et al. , Nitric oxide: a new paradigm for second messengers, J. Med. Chem. 38, 4343-4362, 1995; Halliwell B., Gutteridge JMC., Free radicals in biology and medicine, 2nd ed., Oxford, Clarendon Press, 1989). The invention is illustrated particularly Yar model of focal ischemia., Br.J. Pharmacol. 106, 766-767, 1992; Nowicki et al., Nitric oxide mediates neuronal cell death after focal cerebral ischemia in the mouse, Eur. J. Pharmacol. 204, 339-340, 1991; Zhao et al. , Delayed treatment with the spin trap-phenyl-N-tent-butyl nitrone (PBN) reduces infarct dementia size following transient middle cerebral artery occlusion in rats, Acta. Physiol. Scando, 1994; Schulz et al., Improved therapeutic window for treatment of histotoxic hypoxia with a free radical spin trap, J. Cereb. Blood Flow Metab. 15, 948-952 (1995)). In this regard, medicinal substances, which are able to inhibit the formation of nitrogen monoxide or reactive forms of oxygen, can have a positive effect. The combination of these two active ingredients, namely, an inhibitor of NO-synthetase and catcher reactive forms of oxygen, still has not been received. As follows from the experimental part, these two active ingredients act synergistically. Indeed, with the introduction of subactive doses (i.e. doses, which themselves do not give a therapeutic effect) of these two active ingredients in combination achieved significant therapeutic effect. The advantage of this combination is to reduce the doses of each active ingredient, thereby significantly decreasing the manifestation of undesirable effects in the achievement of therapeutic efficacy. This invention is particularly well illustrated in patie relates to pharmaceutical compositions, comprising as active ingredient at least one substance inhibiting NO-synthetase, and at least one substance that traps the reactive forms of oxygen, and, optionally, a pharmaceutically acceptable carrier.

More specifically, the invention relates to pharmaceutical compositions comprising as active ingredient a substance inhibiting NO-synthetase, and the substance that traps the reactive forms of oxygen.

The term "inhibitor of NO-synthetase" is used to refer to any specific or non-specific inhibitor of one of its isoforms, regardless of whether it is constitutive (neuronal or endothelial or inducible. (Kerwin et al., Nitric oxide: a new paradigm for second messengers, J. Med. Chem. 38, 4343-4362, 1995).

The term "catcher reactive forms of oxygen" is used to refer to any chemical or enzymatic substances that can counteract or to catch at least one of the reactive forms of oxygen, such as O2o, OH-, RO2o, ROo, ONO2-NOo, NO2oor H2O2(Halliwell B. , Gutteridge JMC., Free radicals in biology and medicine, 2and properties. (Santrucek and Krepelka, Antioxidants - Potential chemotherapeutic agents. Drugs of the Future 13, 975-996, 1988; Jackson et al., Antioxidants: a biological defense mechanism for the prevention of atherosclerosis, Med. Res. Reviews 13, 161 - 182 (1993); Aruoma, Characterization of drugs as antioxidant prophylactics. Free Rad. Biol. Med. 20, 675-705 (1996)).

In accordance with the invention in the pharmaceutical composition, the inhibitor of NO-synthetase and catcher reactive forms of oxygen may be separate or combined, forming a salt. Preferably, the salt is formed from the derived substances, inhibition of NO-synthase and containing at least one basic group, and derived substances, catching reactive forms of oxygen and containing at least one acid group. Thus, the salts can be obtained in accordance with methods known in the art, inhibitors of NO-synthetase, such as, for example, amidine, guanidine, pyridine or piperidine, as defined below, and catchers reactive forms of oxygen, such as, for example, acid phenol, the following, in particular 3,5-di-tert-butyl-4 - hydroxybenzoic acid, caffeic (coffeicola) acid, sinova acid or Gallic acid.

The invention also relates to a product containing at least army oxygen, and used as a combined product of a separate form for simultaneous or sequential injection in the treatment of pathological conditions, the pathogenesis of which involves a nitric monoxide and reactive forms of oxygen, such as cardiovascular and cerebrovascular diseases, disorders of the Central and peripheral nervous system, proliferative and inflammatory diseases, organ transplantation, autoimmune and viral diseases, cancer and all pathological condition characterized by the production or dysfunction of nitrogen monoxide and/or reactive forms of oxygen.

In the pharmaceutical composition or product inhibitor of NO-synthetase and catcher reactive forms of oxygen may be the same or different doses. Dosage is chosen based compounds, mixed with suitable solvents or fillers.

The inhibitor of NO-synthetase and catcher reactive forms of oxygen may be introduced simultaneously or sequentially, the same or different routes of administration, depending on how they are separate or combined. Preferably the drug Volotovo and nominaciones types. Inhibitors of NO-synthetase amino acid type can be a compound described in applications WO 95/00505, WO 94/12163, WO 96/06076 and EP 230037, incorporated into the present application by reference, or a derivative of L-arginine, ornithine or lysine, as described in applications WO 93/24126, WO 95/01972, WO 95/24382, WO 95/09619 and WO 95/22968 included in the present application by reference.

Inhibitors of NO-synthetase nominaciones type can be compounds belonging to the same group of compounds, including guanidine, estimacion, nitro - or tionarily, aminopyridines or aminopyrimidine, amidine, indazole or imidazoles.

Guantinamo inhibitors of NO-synthetase may be compounds described in applications WO 95/28377, WO 91/04023, WO 94/21621, WO 96/18607 and WO 96/18608 included in the present application by reference.

Estimaciones inhibitors of NO-synthetase may be compounds described in applications WO 95/09619, WO 96/09286, WO 94/12165, WO 96/14842, WO 96/18607, WO 96/18608, WO 96/09286, EP 717040 and EP 718294 included in the present application by reference.

Nitro - and cyanazine inhibitors of NO-synthetase may be compounds described in the application WO 94/12163 included in the present application by reference.

Aminopyridinium or aminopyrimidine inhibitors of NO-synthase is I.

Amidinami inhibitors of NO-synthetase may be compounds described in applications WO 95/11014, WO 96/01817, WO 95/05363, WO 95/11231, WO 96/14844 and WO 96/19440 included in the present application by reference, or compounds such as N-phenyl - 2-thiophenecarboxylate.

Indazol inhibitors of NO-synthetase can be compounds of General formula IA

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in which R1represents one or more substituents selected from a hydrogen atom, nitro, halogen, lower alkyl or lower alkoxy.

Imidazole inhibitors of NO-synthetase can be compounds of General formula IIA

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in which R2and R3independently represent a hydrogen atom, halogen, hydroxy, amino, alkyl or alkoxy, or R2and R3combined with the formation of the phenyl radical, condensed with the imidazole ring, where the phenyl radical optionally substituted by one or more substituents selected from hydroxy, trifloromethyl, halogen, carboxy, lower alkyl, lower alkoxy or lower alkenyl; R4represents a hydrogen atom, lower alkyl, amino, lower alkylamino or phenyl; where the phenyl radical optionally substituted by one or more substituents selected from hydroxy, ISSI alkyl, amino, lower alkylamino.

Catchers reactive forms of oxygen may be selected from ascorbic acid, N-acetylcysteine, -carotene (Hao Chen et al., Free Radical Biology and Medicine 18(5), 949-953 (1995)), coenzyme Q10 (S. Tereao et al., J. Org. Chem., 44, 868 (1979)) or captodative compounds (H. G. Viehe et al., Acc. Res. 18, 148-154 (1985)) that are included as references in the present application. Catchers reactive forms of oxygen may also be selected from phenolic compounds, nitroav, indole derivatives, imidazoles or carbazole, or they can be enzymes, capable of neutralizing at least one of the reactive oxygen species such as peroxide dismutase, catalase or glutathione peroxidase and their mimetics.

Catchers reactive forms of oxygen phenolic nature include probucol, ubiquinone, derivatives of tocopherol, namely or-tocopherol or phenolic flavonoids (R. A. et al., Phytochemistry 27(4), 969-978 (1988)), incorporated into the present application by reference. Catchers reactive forms of oxygen phenolic nature can also be selected from compounds of the General formula IB or IIB

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in which R'1represents one or more substituents selected from the atom in kileny, CNS and alkanniny radicals, optionally substituted by hydroxy, halogen, carboxy or amino; R'2represents one or more substituents selected from a hydrogen atom or optionally substituted lower alkyl radicals, lower alkoxy, hydroxy, halogen, amino or carboxy.

Nitrone catchers active forms of oxygen may be compounds described in applications WO 96/15110, WO 88/05044 and in U.S. patent 5310916 included in the present application by reference.

Catchers reactive forms of oxygen, indole derivatives may be compounds corresponding to the General formula IIIB

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in which R'3represents one or more substituents selected from a hydrogen atom, hydroxy, halogen, lower alkyl and lower alkoxy; R'4represents one or more substituents selected from hydrogen atom, halogen, hydroxy, amino, carboxy or alkylcarboxylic.

Catchers reactive forms of oxygen, indole derivatives, may also be a connection, as described in the application WO 96/26941.

Imidazole catchers reactive forms of oxygen include predpoklada may include 4-hydroxycarbazole or carvedilol.

The term "lower" as used here in relation to the alkyl or CNS groups, denotes a saturated, linear or branched aliphatic hydrocarbon group having from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxy, ethoxy. In relation alkenylphenol group, the term "lower" means a group in which there are from 2 to 6 carbon atoms and one or more double or triple links, such as, for example, vinyl group, allyl, propenyl, Isopropenyl, pentenyl, butenyl, hexenyl, propenyl and butadienyl. The term "halogen" denotes chlorine, bromine, iodine or fluorine.

More specifically, the invention relates to a composition or product described above, characterized in that:

- inhibitor, NO-synthetase selected from the group comprising L-nitroarginine (LNA), methyl ester of L-nitroarginine (LNAME), L-N-monomethylarsonic (LNMMA), aminoguanidine, agmatine, 2-amino-1-(methylamino)benzimidazole, 5-nitroindazole, 6-nitroindazole, 7-nitroindazole, 1,2-(triptoreline)imidazole (TRIM), 2-amino-4-methyl-6-(2-amino-ethyl)pyridine, 2-aminopiperidine, 2-iminocoumarin, 2-imino-5,6-dihydro-1,3-thiazin, 2-imino-5,6-dihydro-1,3-oxazin, N-phenyl-2-thiophenecarboxaldehyde, 2-aminotetrahydrofuran forms of oxygen selected from the group including probucol, ubiquinone, or-tocopherol, 3,5-di-tert-butyl-4-hydroxybenzoic acid, 2,3,6-trimethyl-2-hexyloxyphenol, 2,6-di-tert-butyl-4-methoxyphenol, eugenol, trolox, n-propylgallate, tempol, caffeic acid, sinapov acid, Gallic acid, of 2.2.5.5-tetramethyl-3-pyrrolin-1-oxyl-3-carboxylic acid, melatonin, 5-hydroxyindole-2-carboxylic acid, antifungals, cimetidine, ascorbic acid, N-acetylcysteine, -carotene, coferment Q10, captodative connection, 9-[2-(4-morpholinyl)ethyl]-2,4-di-1-pyrrolidinyl - N-pyrimido[4,5-b]indole, 4-hydroxycarbazole or carvedilol.

Compounds that are inhibitors of NO-synthetase and catchers reactive forms of oxygen that are selling products or they can be obtained by methods known in the art (or by analogy with the latter) (P. Hamley et al., Bioorganic and medicinal chemistry letters, vol. 5(15), 1573-1576 (1995); W. M. Moore et al., J. Med. Chem., 39, 662-672 (1996); E. P. Garvey et al. The Journal of Biological Chemistry, vol. 269 (43), 26669-26676 (1994)).

Here are some examples to illustrate these methods, which in no way should be construed as limiting the scope of invention.

Experimental part

Let And be an inhibitor of NO-synthetase, and ulaby combination of active ingredients A and B in the form of a salt, in which A and B are present in equimolar number, where a connection is aminoguanidine, an inhibitor of inducible NO synthetase, and the compound B is 3,5-di-tert-butyl-4-hydroxybenzoic acid, antioxidant catcher of free radicals containing oxygen. Compound a (30 mg/kg) was administered intraperitoneally in physiological serum (10 ml/kg). Compound B (20 mg/kg) was administered intraperitoneally in physiological serum. The combination of AB (A 30 mg/kg + B 20 kg/kg) was administered intraperitoneally in physiological serum.

Example 2.

Compound AB is a combination of active ingredients A and B in separate forms, where the compound is A 7-nitroindazole - inhibitor of constitutive NO-synthetase neuronal type, and compound B is 3,5-di-tert-butyl-4-hydroxybenzoic acid - antioxidant catcher of free radicals containing oxygen.

Compound a (10 mg/kg) was administered intraperitoneally in physiological serum (10 ml/kg of 0.2% montanox 80).

Compound B (20 mg/kg) was administered intraperitoneally in physiological serum (10 mg/kg with 0.2% montanox 80).

The combination of AB (A 10 mg/kg + B 20 mg/kg) was administered intraperitoneally in physiological serum (10 mg/kg with the A and B in separate forms, inserted in different ways, where a connection is NG nitroarginine is a potent inhibitor of constitutive and inducible NO synthetase, and the compound B is 3,5-di-tert-butyl-4-hydroxybenzoic acid - antioxidant catcher of free radicals containing oxygen.

Compound a (0.03 mg/kg) was administered intraperitoneally in physiological serum (2 ml/kg).

Compound B (20 mg/kg) was administered intraperitoneally in physiological serum.

The combination of AB (0.03 mg/kg I.V. + B 20 mg/kg intraperitoneally).

In all cases, the compositions have a common way of mixing the components.

Pharmacological study of the products of the invention

Compounds of the invention were subjected to some biological tests in vitro and in vivo in order to prove their activity when blocking NO synthetase (constitutive and inducible) and the capture of free radicals. Their activity was evaluated in models of focal cerebral ischemia in rats. On this model, which is regarded as a model of severe heart attack, brain, close to the clinical situation in humans, it has been shown excessive release of nitrogen monoxide and reactive is capable of reactive oxygen species. The combined effects of the drug were compared with the effects observed when processing separately inhibitor of nitric monoxide or catcher reactive forms of oxygen. The combination of an inhibitor of NO-synthetase or catcher reactive forms of oxygen has a much stronger protective effect in focal cerebral ischemia, whereas the effect of the inhibitor of NO-synthetase or catcher reactive forms of oxygen that are entered separately in the same doses, was insignificant. This demonstrates the synergies between the inhibitor of NO-synthetase or catcher reactive forms of oxygen.

1) the Effect of constitutive NO-synthetase in the rat cerebellum in vitro

The test consists of determining the conversion of L-arginine to L-citrulline under the action of NO-synthetase. Samples of cerebellum of rats Sprague-doli (300 g Charles Riva) just took, did the slices at 4oC and homogenized in a volume of buffer for extraction (HEPES 50 mm, EDTA 1 mm, pH 7,4, pepstatin A 10 mg/ml, leupeptin 10 mg/ml) was centrifuged at 21000 g for 15 min at 4oC. Analysis was carried out in glass test tubes, which were 100 μl of incubation buffer containing 100 mm HEPES, pH of 7.4, 2 mm Adstore, containing 100 nm arginine, tritium-labeled (specific activity: is 56.4 CI/mmol, Amersham), and 40 μm non-radioactive arginine. The reaction was initiated by adding 50 μl of the homogenized product to achieve a final volume of 200 μl (the other 25 µl were either water or investigational product) " After 15 minutes the reaction was stopped by adding 2 ml of the table-buffer (20 mm HEPES, pH 5.5, 2 mm EDTA) After passing the samples through a column of 1 ml resin DOWEX, radioactivity was quantitatively assessed by liquid scintillation spectrometer. The results were expressed in terms IC50and summarized in the table (the first column of results, entitled "constitutive NO-synthase, education citrulline").

2) Effect on inducible NO-synthase J774A1 macrophages of mice in vitro

J774A1 macrophages mice produce large amounts of nitric monoxide when activated by lipopolysaccharides (LPS) and interfereon- (IFN-). After activation with LPS and IFN-, cells were cultured in the medium of DMEM (modificirovannaja by way of Dulbecco Wednesday Needle), enriched with 10% fetal calf serum at 37oC in an atmosphere of 5% CO2; cells were seeded in the amount of 5000 cells/cm2150-cm2the vessels. Incubi orothy. NO-synthetase was isolated using an extraction buffer (50 mm HEPES, pH of 7.4, 0.5 mm dithiothreitol, pepstatin A 1 mg/ml, leupeptin 1 mg/ml soybean trypsin inhibitor, 1 mg/ml, antipain 1 mg/ml PMSF and 10 mg/ml). After ultrasonic treatment in the extracting buffer at 4oC homogenised products have ultracentrifugal (100.00 g of 3,5-di-tert-butyl-4-hydroxybenzoic acid at 4oC for 1 hour). The subsequent procedure is identical to the procedure described for the NO-synthetase of the cerebellum, with the exception of the composition of the incubation buffer (100 mm HEPES, pH 7,4, dithiothreitol, 2.5 mm CaCl2, 10 M tetrahydrobiopterin, 10 µm FAD, BSA 1 mg/ml, 2 mm restored NADPH). The results are expressed in terms IC50and summarized in table. 1 (second column of results, entitled "inducible NO synthase, education citrulline").

3) Effect of macrophages J774 A1 mice on the formation of nitrite in vitro

This test was performed to measure the inhibitory activity of the products displayed on NO-synthase in cell cultures. Cells are grown in an environment of DMEM (modified by way of Dulbecco Wednesday Needle), enriched with 10% fetal calf serum at 37oC in an atmosphere of 5% CO2. In this experiment, the cells were distributed in 96-Lu is fetal calf serum with LPS (1 µg/ml) and murine IFN- (50 U/ml) in the presence or absence of the investigated products. After 48 hours the concentration of nitrite, the products of decomposition of nitrogen monoxide in culture medium was measured by the colorimetric method according to Green et al., (Analytical Biochemistry, 126, 131-138 (1982)). The results are expressed in terms IC50and summarized in table. 1 (third column of results, entitled "inducible NO synthase, the formation of nitrite").

4) influence on the formation of peroxide anions in vitro

Activation of cells of J774A1 macrophages by phorbolmiristatacetate (PMA) results in a few minutes to the formation of peroxide anions. These peroxy anions can oxidize luminescent substrate, luminal. In this reaction are photons, the formation of which was determined using chemiluminometer. The effect of food on the formation of peroxide anions was investigated by incubation of cells J774AI at 37oC in the presence of PMA, researched products and lyuminola. The results are expressed in terms IC50and are given in table. 2.

5) Impact on focal cerebral ischemia with reperfusion

The experiments were conducted on rats male line Sprague-doli (Charles Riva) weight from 330 to 360, After anesthesia with isoflurane rats temporarily occlusional middle cerebral artery according to the method described Memeza artery. Two hours later the wire was removed, which was restored blood flow in Willisau circle. Monitoring and control of the body temperature of the animals was performed within 6 hours after occlusion. Forty-eight hours after occlusion rats was performed under anesthesia with isoflurane and subjected decapitate. Samples of the brain was rapidly removed and immersed in isopentane at -15oC for 2 minutes. Then did six slices of 2 mm thickness, which was immersed in a solution containing 2% chloride 2,3,5-triphenyltetrazolium (TCC), for 20 minutes and then were fixed with formalin. Area exposed to a heart attack, had a white color and a healthy area was red. The surface area of the infarction area was measured on plots 6 slices using image analyzer. The volume of infarction was determined by integration of these different areas, given that these surfaces are at a distance of 2 mm from each other. The drugs were injected intraperitoneally. The first injection was done 4 hours after occlusion, i.e., two hours after he removed the wire, and then after 24 hours.

Examples 1-3 illustrate table. 3-5.

The results show that 3,5-di-tert-butyl-4-hydroxybenzoic acid is used as the catcher of reakcionnoyj, and that aminoguanidine (an inhibitor of NO-synthetase) has low activity. On the other hand, the mixture of these two compounds provides a high degree of protection of animals from ischemia.

Similarly, 7-nitroindazole used as an inhibitor of constitutive forms of NO-synthetase, is not sufficiently effective in the dosage of 10 mg/kg, but, on the other hand, when it is combined with 3,5-di-tert-4-hydrobenzoic acid has a high protective activity. These two active ingredient detect synergistic protective effect.

Similarly, NG nitroarginine used as an inhibitor of NO-synthetase intravenously at a dose of 0.03 mg/kg, inactive. On the other hand, when it is combined with 3,5-di-tert-4-hydrobenzoic acid, introduced intraperitoneally, there is a high protective activity. This protective effect shows that synergies between the two active ingredients is observed also in the case where the active ingredients have introduced different ways.

1. Pharmaceutical preparation for the treatment of pathological conditions involving the nitric monoxide and reactive form of oxygen, containing at least one substance inhibiting NO-farmacevticheskiy drug under item 1, additionally contains a pharmaceutically acceptable carrier.

3. Pharmaceutical drug under item 1 or 2, wherein the substance inhibiting NO-synthetase, and the substance that traps the reactive forms of oxygen are in the form of salts.

4. Pharmaceutical drug under item 3, in which the salt of the substance that inhibits NO-synthetase, contains at least one basic group, and a salt of a substance that traps the reactive form of oxygen that contains at least one acid group.

5. The pharmaceutical preparation according to any one of the preceding paragraphs, in which the substance, inhibiting NO-synthetase is an amino acid, for example, derivatives of L-arginine, ornithine or lysine, or a compound from the group comprising guanidine, estimacion, nitro - or tionarily, aminopyridines or aminopyrimidine, amidine, indazols or imidazoles, and the substance that traps the reactive form of oxygen, is ascorbic acid, N-acetylcysteine, -carotene, coenzyme Q10, captodative compound or compounds selected from the group comprising phenols, Nitron, indole derivatives, imidazoles, carbazole.

6. The pharmaceutical preparation according to any one of predestroy ester of L-nitroarginine; L-N-monomethylarsonic; aminoguanidine, agmatine; 2-amino-1-(methyl-amino)benzimidazole; 5-nitroindazole; 6-nitroindazole, 7-nitroindazole; 1,2-(triptoreline)imidazole; 2-amino-4-methyl-6-(2-amino-ethyl)-pyridine; 2-aminopiperidin; 2-iminocoumarin; 2-imino-5,6-dihydro-1,3-thiazin; 2-imino-5,6-dihydro-1,3-oxazin; 2-aminomethylpyrimidine; N-phenyl-2-thiophenecarboxylate; S-ethyl-ISO-thiourea; S-methyl-L-thiocitrulline or S-ethyl-L-thiocitrulline, and the substance that traps the reactive forms of oxygen selected from the group comprising probucol; ubiquinone; or-tocopherol; 3,5-di-tertbutyl-4-hydroxybenzoic acid; 2,3,6-trimethyl-2-hexyloxyphenol; 2,6-di-tertbutyl-4-methoxyphenol; eugenol; trolox; N-propylgallate; tempol, caffeic acid; sinapov acid; Gallic acid; of 2.2.5.5-tetramethyl-3-pyrrolin-1-oxyl-3-carboxylic acid; melatonin; 5-hydroxyindole-2-carboxylic acid; imidazole; cimetidine; ascorbic acid; N-acetylcysteine; -carotene; coenzyme Q10; captodative connection; 9-[2-(4-morpholinyl)ethyl]-2,4-di-1-pyrrolidinyl-N-pyrimido[4,5-b]indole; 4-hydroxycarbazole or carvedilol.

7. Pharmaceutical preparation for the treatment of pathological conditions involving the nitric monoxide and reactive podna of which contains at least one substance, inhibition of NO-synthase and the other at least one substance that traps the reactive forms of oxygen.

8. The pharmaceutical preparation according to p. 7 for the treatment of such pathological conditions as cardiovascular and cerebrovascular diseases, disorders of the Central and peripheral nervous system disorders, proliferative and inflammatory diseases, diarrhea, vomiting, radiation exposure, exposure to sunlight, organ transplantation, autoimmune and viral diseases, cancer and all pathological condition characterized by the production or dysfunction of nitrogen monoxide and/or reactive forms of oxygen.

9. The pharmaceutical preparation according to p. 7 for the treatment of cardiovascular and cerebrovascular diseases, such as atherosclerosis, migraine, hypertension, septic shock, cardiac and cerebral infarction ischemic or hemorrhagic nature, ischemia and thrombosis.

10. The pharmaceutical preparation according to p. 7 for the treatment of disorders of the Central or peripheral nervous system, such as neurodegenerative disease, pain, injury, brain and spinal cord, addiction to opiates, alcohol, and other substances of concern used and, encephalopathy, depression, anxiety, schizophrenia, epilepsy, sleep disorder, eating disorders.

11. The pharmaceutical preparation according to p. 7 for the treatment of proliferative and inflammatory diseases such as atherosclerosis, pulmonary hypertension, glomerulonephritis, portal hypertension, psoriasis, osteoarthritis and rheumatoid arthritis, fibrosis, amyloidosis, inflammation of the gastrointestinal system or pulmonary system and pneumatic paths.

12. The pharmaceutical preparation according to p. 7 for the treatment of autoimmune and viral diseases such as lupus, AIDS, parasitic and viral infections, diabetes, multiple sclerosis, myopathy.

13. The pharmaceutical preparation according to any one of paragraphs.7-12, contains a substance inhibiting NO-synthetase, and the substance that traps the reactive forms of oxygen.

14. The pharmaceutical preparation according to any one of paragraphs.7-13, in which the inhibitor of NO-synthetase is an amino acid and, more specifically, derivatives of L-arginine, ornithine or lysine, or a compound from the group comprising guanidine, estimacion, nitro - or tionarily, aminopyridines or aminopyrimidine, amidine, indazols, imidazoles, and catcher reactive forms of oxygen is the dust, including phenols, Nitron, indole derivatives, imidazoles, carbazole, peroxide dismutase, catalase or glutathione peroxidase.

15. The pharmaceutical preparation according to any one of paragraphs.7-14, in which the inhibitor of NO-synthetase selected from the group comprising L-nitroarginine; methyl ester of L-nitroarginine; L-N-monomethylaniline, aminoguanidine; agmatine, 2-amino-1-(methylamino)benzimidazole, 5-nitroindazole; 6-nitroindazole; 7-nitroindazole; 1,2-(triptoreline)imidazole; 2-amino-4-methyl-6-(2-amino-ethyl)pyridine; 2-aminopiperidin; 2-iminocoumarin; 2-imino-5,6-dihydro-1,3-thiazin; 2-imino-5,6-dihydro-1,3-oxazin; 2-aminomethylpyrimidine; N-phenyl-2-thiophenecarboxylate; S-utilizationfocused; S-methyl-L-thiocitrulline or S-ethyl-L-thiocitrulline, and catcher reactive forms of oxygen selected from the group comprising probucol; or-tocopherol; 3,5-di-tertbutyl-4-hydroxybenzoic acid; 2,3,6-trimethyl-2-hexyloxyphenol; 2,6-di-tertbutyl-4-methoxyphenol; eugenol; trolox; N-propylgallate; tempol; caffeic acid; sinapov acid; Gallic acid; of 2.2.5.5-tetramethyl-3-pyrrolin-1-oxyl-3-carboxylic acid; melatonin; 5-hydroxyindole-2-carboxylic acid; antifungals, cimetidine, ascorbic acid, N-acetylcysteine, -carotene, coenzyme Q10; or carvedilol.

 

Same patents:

The invention relates to a method for producing compounds of formula (I) consists in the fact that the compound of formula (IX):

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in which R1' has the abovementioned meaning and M represents a hydrogen atom or the radical R2' which has the values specified above for R2in which the possible reactive functions can be protected by a protective group, is subjected to reaction with the compound of the formula (VIII) defined above, to obtain a product of formula (X):

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in which R1' M and R4' have the above values, the obtained compound of formula (X), if M implies R2' defined above, is subjected to a halogenation reaction, to obtain the product of formula (XI):

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in which R1', R2', R4' and Hal have the above values, which is subjected to the reaction of the exchange of the halogen-metal, then the reaction with the compound of the formula (XII):

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in which R9' matter referred to in paragraph 1 for R9where possible reaction ф�g/rupat4/200110/01/2174513-36t.gif" ALIGN="ABSMIDDLE">< / BR>
in which R1', R2', R4' and R9' have the above meanings and, if necessary, or interact product of formula (I2) with the compound of the formula (XV):

O=C=N-R6' (XV)

in which R6' matter referred to in paragraph 1 for R6in which the possible reactive functions can be protected by a protective group, to obtain a product of formula (I3):

< / BR>
in which R1', R2', R4', R6' and R9' have the above meanings, or the product of formula (I2) is subjected to a saponification reaction with the product of formula (I4):

< / BR>
in which R1', R2', R4' and R9' have the above meanings, is subjected to reaction with COCl2to obtain a product of formula (I5):

< / BR>
in which R1', R2', R4' and R9' have the above meanings, or the product of formula (X), provided that M denotes a hydrogen atom, is subjected to a halogenation reaction to obtain a product of formula (XIV):

< / BR>
in which R1', R4'Hal and R3" have the above values, the compound obtained is subjected to the reaction of the exchange of the halogen-metal, then the processing of the compound of formula (IVa') (IVb'), (IVc'), (IVd') or (IVe') defined above, to obtain a product of formula (I7):

< / BR>
in which R1', R4', R2and R3" have the above meanings; then the above products of formula I2, I3, I4, I5, I6, I7that are a product of the formula I, allocate or subjected, if necessary, one or more reactions of transformation to other products of the formula I, in any order:

a) esterification of the acid function,

(b) saponification functions of ester to acid functions,

C) transforming functions of ester function acyl,

d) transforming Sinopoli in an acid function,

e) conversion of the acid function to an alcohol function,

g) transforming functions alkoxy function hydroxyl or hydroxyl function in the function alkoxy,

h) oxidation of the alcohol function to the aldehyde, acid or keto-function

i) the conversion of the formyl radical in the radical carbarnoyl,

j) turning radical carbarnoyl in the nitrile radical,

k) converting the nitrile radical in tetrazolyl,

l) oxidation of ancilliary or aristocraty to the corresponding sulfoxide or sulfone,

m) the transformation function sulfide, sulfoxide or sulfone function corresponding sulfoximine,

n) the transformation function oxo function of thioxo,

a) transforming radical

< / BR>
in radical

< / BR>
p) conversion of the acid function in function

< / BR>
q) is the transformation function of beta-keto-sulfoxide in the function of alpha-ketotioefir,

r) the conversion of carbamate into urea and, in particular, sulfonylamino in the sulfonylurea,

s) removal of protective groups, which can protect the reaction functions,

t) salt formation using mineral or organic cisisomer, enantiomers and diastereoisomers

The invention relates to compounds of the formula I, in all stereoisomeric forms and mixtures in any ratio, where NV denotes maleic acid, to a method for producing compounds of formula I, which lies in the fact that compounds of the formula II exercise anionic exchange with maleic acid and/or maleate

The invention relates to new substituted 1,2,3,4-tetrahydro-2-naphthalenamine formula I, where R1and R2independently represent hydrogen, C1-4alkyl, C1-4alkoxy, halogen, trifluoromethyl; R3represents hydrogen, hydroxyl, C1-4alkoxyl, cyano, carbarnoyl; R4and R5independently represent hydrogen, C1-4alkyl, hydroxy2-4alkyl, or form together with the nitrogen atom to which they are attached, piperidine; in the form of free bases or salts obtained by attaching acid

The invention relates to medicine, namely to surgery, and can be used for the treatment of diabetic angiopathies of the lower extremities

The invention relates to medicine

The invention relates to new naphtylpropionate F.-ly (I), where R1and R2- N, -HE or-O(C1-C4-alkyl); R3- 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholinyl, dialkylamino - or 1-hexamethylen-aminogroup; n = 2 or 3, or pharmaceutically acceptable salts

The invention relates to a method for producing compounds of formula (I) consists in the fact that the compound of formula (IX):

< / BR>
in which R1' has the abovementioned meaning and M represents a hydrogen atom or the radical R2' which has the values specified above for R2in which the possible reactive functions can be protected by a protective group, is subjected to reaction with the compound of the formula (VIII) defined above, to obtain a product of formula (X):

< / BR>
in which R1' M and R4' have the above values, the obtained compound of formula (X), if M implies R2' defined above, is subjected to a halogenation reaction, to obtain the product of formula (XI):

< / BR>
in which R1', R2', R4' and Hal have the above values, which is subjected to the reaction of the exchange of the halogen-metal, then the reaction with the compound of the formula (XII):

< / BR>
in which R9' matter referred to in paragraph 1 for R9where possible reaction ф�g/rupat4/200110/01/2174513-36t.gif" ALIGN="ABSMIDDLE">< / BR>
in which R1', R2', R4' and R9' have the above meanings and, if necessary, or interact product of formula (I2) with the compound of the formula (XV):

O=C=N-R6' (XV)

in which R6' matter referred to in paragraph 1 for R6in which the possible reactive functions can be protected by a protective group, to obtain a product of formula (I3):

< / BR>
in which R1', R2', R4', R6' and R9' have the above meanings, or the product of formula (I2) is subjected to a saponification reaction with the product of formula (I4):

< / BR>
in which R1', R2', R4' and R9' have the above meanings, is subjected to reaction with COCl2to obtain a product of formula (I5):

< / BR>
in which R1', R2', R4' and R9' have the above meanings, or the product of formula (X), provided that M denotes a hydrogen atom, is subjected to a halogenation reaction to obtain a product of formula (XIV):

< / BR>
in which R1', R4'Hal and R3" have the above values, the compound obtained is subjected to the reaction of the exchange of the halogen-metal, then the processing of the compound of formula (IVa') (IVb'), (IVc'), (IVd') or (IVe') defined above, to obtain a product of formula (I7):

< / BR>
in which R1', R4', R2and R3" have the above meanings; then the above products of formula I2, I3, I4, I5, I6, I7that are a product of the formula I, allocate or subjected, if necessary, one or more reactions of transformation to other products of the formula I, in any order:

a) esterification of the acid function,

(b) saponification functions of ester to acid functions,

C) transforming functions of ester function acyl,

d) transforming Sinopoli in an acid function,

e) conversion of the acid function to an alcohol function,

g) transforming functions alkoxy function hydroxyl or hydroxyl function in the function alkoxy,

h) oxidation of the alcohol function to the aldehyde, acid or keto-function

i) the conversion of the formyl radical in the radical carbarnoyl,

j) turning radical carbarnoyl in the nitrile radical,

k) converting the nitrile radical in tetrazolyl,

l) oxidation of ancilliary or aristocraty to the corresponding sulfoxide or sulfone,

m) the transformation function sulfide, sulfoxide or sulfone function corresponding sulfoximine,

n) the transformation function oxo function of thioxo,

a) transforming radical

< / BR>
in radical

< / BR>
p) conversion of the acid function in function

< / BR>
q) is the transformation function of beta-keto-sulfoxide in the function of alpha-ketotioefir,

r) the conversion of carbamate into urea and, in particular, sulfonylamino in the sulfonylurea,

s) removal of protective groups, which can protect the reaction functions,

t) salt formation using mineral or organic cisisomer, enantiomers and diastereoisomers

The invention relates to compositions intended for parenteral or oral administration

The invention relates to compounds of the formula I, in all stereoisomeric forms and mixtures in any ratio, where NV denotes maleic acid, to a method for producing compounds of formula I, which lies in the fact that compounds of the formula II exercise anionic exchange with maleic acid and/or maleate

The invention relates to compounds of the formula I, in all stereoisomeric forms and mixtures in any ratio, where NV denotes maleic acid, to a method for producing compounds of formula I, which lies in the fact that compounds of the formula II exercise anionic exchange with maleic acid and/or maleate

The invention relates to medicine, namely to anesthesiology

The invention relates to new sulfonamidnuyu derivatives or their pharmaceutically acceptable salts, which have the properties of inhibitor action of endothelin receptors and can find application in the treatment of diseases associated with disorders in the circulatory system, such as hypertension, ischemia, angina, spasms of the blood vessels as well as to pharmaceutical drugs based on them

The invention relates to new heterocyclic derivatives of the formula I, where one of R1, R2, R5are carboxy, C2-C5-alkoxycarbonyl, C1-C8by alkyl, substituted hydroxy, carboxy, C2-C5-alkoxycarbonyl or a group of the formula - NR9R10where R9, R10each independently is C1-C6the alkyl, and the other two are each independently is a hydrogen atom, a C1-C6the alkyl or C1-C6alkoxy; R3or R4group - NHCOR7where R7-C1-C20alkyl, C1-6alkoxy, - C1-C6alkyl, C1-C6alkylthio - C1-C6alkyl, C3-C8- cycloalkyl, C3-C8cycloalkyl-C1-C3alkyl, phenyl, phenyl-C1-C4alkyl group-other8where R8-C1-C20alkyl, and the others are a hydrogen atom, a C1-C6the alkyl or C1-C6alkoxy; R6-C1-C20alkyl, C3-C12alkenyl, C1-C6alkoxy, C1-C6alkyl, C1-C6alkylthio C1-C6alkyl, C3-C8cycloalkyl, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-CLIGN="ABSMIDDLE">and is a bridging group to the nitrogen atom, provided that when one of R1, R2, R5is carboxy or C2-C5alkoxycarbonyl, Z is a group of

The invention relates to new derivatives of arylethanolamine formula I or its pharmaceutically acceptable salts, which have a high affinity for endothelin and can find application in medicine
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