Orthotamine benzoylpyridine and medicinal products based on them

 

(57) Abstract:

The invention relates to orthotamine benzoylpyridine formula (1), where R(1) denotes R(13)-SOmm denotes the number 2; R(13) denotes alkyl, one of the substituents R(2) and R(3) represents hydrogen; and the other CHR(30)R(31), R(30) represents-(CH2)g-(CHOH)h-(CH2)I-(CHOH)k-R(32), R(32) denotes hydrogen or methyl, g, h, I is equal to zero, k is 1, R(2) and R(3) represents-C(OH)R(33)R(34), R(31), R(33) R(34) denote hydrogen or alkyl, R(4) denotes alkyl, alkoxy, F, Cl, Br, I. These compounds possess inhibitory activity against Na+/H+-exchange and due to this property can be used as a medicine against various diseases. 2 C. and 8 C.p. f-crystals.

The invention relates to benzoylpyridine formula 1

< / BR>
where mean:

R(1) R(13)-SOmor R(14)R(15)N-SO2-;

m=1 or 2;

R(13) - alkyl with 1,2,3,4,5,6,7 or 8 C-atoms, perfluoroalkyl with 1,2,3,4,5,6,7 or 8 C-atoms, alkenyl with 3,4,5,6,7 or 8 C-atoms or

-CnH2n-R(16), n is zero, 1,2,3 or 4;

R(16) - cycloalkyl with 3,4,5,6,7 or 8 C-atoms, phenyl, biphenylyl or naphthyl, and phenyl, biphenylyl and naphthyl are not substituted or is substituted by 1-3 substituents selected from the group sotoyama the mi or perfluoroalkyl from 1, 2, 3 or 4 C-atoms;

R(14) - hydrogen 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, perfluoroalkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, alkenyl with 3, 4, 5, 6, 7 or 8 C-atoms or-CnH2n-R(27), n is zero, 1, 2, 3 or 4;

R(27) - cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms, phenyl, biphenylyl or naphthyl, and phenyl, biphenylyl and naphthyl are not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(28)R(29);

R(28) R(29) independently from each other hydrogen, alkyl with 1, 2, 3 or 4 C-atoms or perfluoroalkyl of 1, 2, 3 or 4 C-atoms;

R(15) is hydrogen, alkyl with 1, 2, 3 or 4 C-atoms or perfluoroalkyl of 1, 2, 3 or 4 C-atoms;

or R(14) R(15) are together 4 or 5 methylene groups, of which one CH2group can be replaced through oxygen, S, NH, N-CH3or N-benzyl;

one of the substituents R(2) and R(3) hydrogen;

and the other substituent R(2) and R(3) -CHR(30)R(31);

R(30)-(CH2)g-(CHOH)h-(CH2)i-(CHOH)k-R(32) or

-(CH2)g-O-(CH2-OH2O)h-R(24);

R(24) and R(32) independently from each other hydrogen or methyl;

g, h, i, equal or different - zero, 1, 2, 3 or 4;

to 1,2,3 or 4;

or the other substituent R(2) and R(3) -C(OH)R(33)R(34);

R(31), R(33) R(34) - one is 5 or 6 C-atoms;

or

R(33) - CH2OH;

R(4) - alkyl with 1, 2, 3 or 4 C-atoms, alkoxy with 1, 2, 3 or 4 C-atoms, F, Cl, Br, I, CN, -(CH2)n-(CF2)O-CFC;

n is zero or 1;

0 - zero, 1 or 2;

and their pharmaceutically tolerable salts.

Preferred compounds of formula 1, in which mean:

R(1) R(13)-SO2or R(14)R(15)N-SO2-;

R(13) - alkyl with 1, 2, 3 or 4-Otomani, perfluoroalkyl with 1, 2, 3 or 4 C-atoms, alkenyl with 3 or 4 C-atoms or-CnH2n-R(16),

n is zero, 1, 2, 3 or 4;

R(l6) - cycloalkyl with 3, 4, 5 or 6 C-atoms, phenyl, biphenylyl or naphthyl,

and phenyl, biphenylyl and naphthyl are not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl or methoxy;

R(14) is hydrogen, alkyl with 1, 2, 3 or 4 C-atoms, perfluoroalkyl of 1, 2, 3 or 4 C-atoms, alkenyl with 3 or 4-atoman or-CnH2n-R(27) n is zero, 1, 2, 3 or 4;

R(27) - cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms, phenyl, biphenylyl or naphthyl, and phenyl, biphenylyl and naphthyl are not substituted or is substituted by 1-3 substituents selected from the group consisting of F, CL, CF3, methyl or methoxy;

R(15) is hydrogen, alkyl with 1, 2, 3 or 4 C-atoms or perfluoroalkyl of 1, 2, 3 or 4 C-atoms;

or R(14) R(15) together >or N-benzyl;

and one of the substituents R(2) and R(3) hydrogen;

and the other substituent R(2) and R(3) -CHR(30)R(31);

R(30)-(CH2)g-(CHOH)h-(CH2)i-(CHOH)k-R(32)

or

-(CH2)g-O-(CH2-CH2O)h-R(24);

R(24) and R(32) independently of one another is hydrogen or methyl;

g, h, I, equal or different - zero, 1 or 2;

to 1 or 2;

or

the other substituent R(2) and R(3)-C(OH)R(33)R(34);

R(33) R(34) the same or different is hydrogen or alkyl with 1, 2, 3 or 4 C-atoms

or R(33) R(34) together - cycloalkyl with 3, 4, 5 or 6 C-atoms;

or R(33) CH2IT;

R(4) alkyl with 1, 2, 3 or 4 C-atoms, alkoxy with 1, 2, 3 or 4

C-atoms, F, Cl, CN or (CF2)o-CF3;

0 zero, 1 or 2;

and their pharmaceutically tolerated salts.

Especially preferred compounds of formula 1, in which mean: R(1) R(13)-S02;

R(13) - alkyl with 1, 2, 3 or 4 C-atoms;

one of the substituents R(2) and R(3) hydrogen;

and the other substituent R(2) and R(3) -C(OH)(CH3)-CH2HE, -CH(CH3)-CH2HE or(HE)(CH3)2;

R(4) - alkyl with 1, 2, 3 or 4 C-atoms, alkoxy with 1, 2, 3 or 4 C-atoms, F, Cl, CN or-CF3;

and pharmaceuticae are derived from phenyl or naphthyl, in which one or more CH groups are replaced by N and/or in which at least two adjacent CH groups (in the formation of five-membered aromatic ring is replaced by S, NH or O. Then one or both of the atom designated condensation of a bicyclic residues (as in indolizinyl) may also be of N-atoms. As with heteroaryl 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms valid especially furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, honokalani, hintline, cinnolines.

If one of the substituents R(1) - R(4) contain one or more asymmetric centers, they may have both S and R-configuration. The compounds can exist as optical isomers, as diastereoisomers. as racemates or as mixtures.

These alkyl residues can have both direct and branched chain.

The invention relates, furthermore, to a method for producing ortho-substituted benzoylpyridine formula 1, which is characterized in that the compound of formula II

< / BR>
where R(1) - R(4) have a specified value, and L denotes Legge acid derivatives of the formula II, where L denotes an alkoxy, preferably a methoxy group, fenoxaprop, phenylthio-, methylthio-, 2-pyridylthio, nitrogen heterocycle, preferably 1-imidazolyl, it is advantageous to obtain a known manner from the underlying anhydrides of carboxylic acids (formula II, L = CL), which, in turn, can be obtained again in a known manner from the underlying carboxylic acids (formula II, L = OH), for example, chloride tiomila.

Along with anhydrides of carboxylic acids of the formula II (L = CL) can be obtained also other activated carboxylic acid derivatives in a known manner directly from the underlying derivatives of benzoic acid (formula II, L = OH), such as methyl ester of the formula II with L = co3processing gas model HC1 in methanol, imidazoline formula II by treatment carbonyl diimidazol [L = 1-imidazolyl, Staab, Angew. Chem. English edition 1,351 - 367 (1962)], the mixed anhydrides II with CL-SOOS2H5or chloride tosilos in the presence of triethylamine in an inert solvent, as activation of benzoic acids with dicyclohexylcarbodiimide (BCA) or 0-[(cyano(etoxycarbonyl)methylene)amino] -1, 1, 3, 3-tetramethylene-tetrafluoroborate ("TOTU") [Proceedings of the 21. European Peptide-Symposium, Peptide 199 is islote formula 1 are indicated in the literature in J. March, Advanced Organic Chemistry, issue 3 (John Wiley & Sons, 1985), page 350.

The interaction of activated carboxylic acid derivative of the formula II with guanidine carried out in a known manner in proton or aprotic, polar but inert organic solvent. This interaction methyl esters of benzoic acids (II, L = OMe) with guanidine was suitable methanol, isopropanol or tetrahydrofuran with a temperature of 20oC to the boiling point of these solvents. Most interactions of compounds II with salt-free guanidine was advantageous to work in an aprotic inert solvents, such as tetrahydrofuran, dioxane, dimethoxyethane. But in the interaction of compound II with guanidine you can also use water when using a base, such as NaOH as solvent.

If L= CL, it is advantageous to work with the addition of traps acid, for example, in the form of excess guanidine binding halomonadaceae acid.

Part of the underlying derivatives of benzoic acid of the formula II are known and described in the literature. Unknown compounds of formula II can be obtained well-known from the literature methods. Received benzoic acid according to one of videopix is stately 2, 3-, 4 - and 5-position you can implement known from the literature methods using palladium reaction cross combinations of aryl halides or aritifical, for example, organostannic, organoboronic acids or organoboranes or medialivecasino or tsinkorganicheskie connections.

Benzoylpyridine 1 are, in General, weak bases and can bind the acid with the formation of salts. As the acid additive salts take into account salts of all pharmacologically tolerated acids, for example halides, especially hydrochloride, lactates, sulfates, citrates, tartratami, acetates, phosphates, methylsulfonate, p-toluensulfonate.

Compounds 1 are substituted acylhalides.

From European patent application 640588 A1 famous benzoylpyridine similar patterns, which, however, do not have alkylsulfonyl or alkylsulfonate, which always have a connection according to the invention.

European patent application 699 also applies to orthotamine benzylguanine, which, however, does not have a hydroxyl group according to the invention in the substituent R(2) or R(3).

Older German application 19608162.9 (NOAH 96/F 042) pre is.

In contrast to the known compounds, the compounds according to the invention are highly effective in the inhibition PA+/H+-exchange in combination with a very good water-solubility.

They are not as well as known compounds, any unwanted and negative solidarities properties, however, have a very good antiarrhythmic properties, as, for example, they are important for the treatment of diseases that appear with symptoms of lack of oxygen. Connection due to their pharmacological properties suitable as antiarrhythmic drugs with cardiotoxin component for the prophylaxis and treatment of infarction and for the treatment of angina, and they are also helpful inhibit or greatly reduce the pathophysiological processes in the occurrence of ischemia-induced damage, especially during provoking ischemia-induced arrhythmias of the heart. Because of their protective actions against pathological hypoxic and ischemic situations, the compounds according to the invention of formula 1 in connection with the inhibition of the cellular Na+/H+-exchange mechanism can be used as medicines for the treatment of all acute or x the deposits. This applies to their use as pharmaceuticals for surgical interventions, such as organ transplants, and the connections can be used to protect the organs in the donor before the procedure and during the seizure, taken to protect organs, for example, in the treatment or during storage in physiological solutions, and during the transfer to the recipient's organism. The compounds are also valuable medicines with protective action when conducting angioplasticheskih surgical interventions, for example on the heart and peripheral vessels. In accordance with their protective effect against ischemia-induced damage, the compounds are also suitable as pharmaceuticals for the treatment of ischemia of the nervous system, especially the Central nervous system, and they are suitable, for example, for the treatment of stroke or of cerebral oedema. In addition, the compounds according to the invention of formula 1 are also suitable for treatment of various forms of shock, such as, for example, of allergic, cardiogenic, hypovolemic and bacterial shock.

On the other hand, the compounds according to the invention of formula 1 have strong inhibitory action on the proliferation of cells, such as proliferation of fibrinoly 1 is used as a valuable therapeutic agent for diseases in which cell proliferation represents a primary or secondary cause, and can therefore be used as antiatherosclerotic tools, as a means against the late complications of diabetes, anti-cancer, anti fibromya diseases such as pulmonary fibrosis, fibrosis of the liver or fibrosis of the kidney, anti-hypertrophy and hyperplasia of the authorities, especially when hyperplasia or hypertrophy of the prostate.

Compounds according to the invention are valuable inhibitors of the cellular sodium-proton-antinomies (Na+/H+exchanger), which in numerous diseases (essential hypertension, atherosclerosis, diabetes, and so on) also increased in those cells that are easily accessible to measurements, such as, for example, in erythrocytes, platelets or leukocytes. Therefore, the compounds according to the invention are used as an excellent and simple scientific tools, for example, in their application as diagnostic tools for the detection and differentiation of certain forms of hypertension, but also of atherosclerosis, diabetes, proliferative diseases, etc. in Addition, the compounds of formula 1 are suitable for preventive therapy to prevent the Genesis of high level is formula 1 have a favorable effect on serum lipoproteins. As you know, for the emergence of arteriosclerotic changes of blood vessels, especially coronary heart disease, too high fat blood, the so-called hyperlipoproteinemias, represent a significant risk factor. Therefore, for the prevention and regression of atherosclerotic plaques attach exceptional importance to reduce high amounts of serum lipoproteins. Along with the decrease in the total serum cholesterol attach special importance to reduce the number of specific atherogenic lipid fractions that total cholesterol, especially low density lipoprotein (LDL) and very low density lipoproteins (VLDL), as these lipid fractions are atherogenic risk factor. On the contrary, high-density lipoprotein attributed a protective role against coronary heart disease. In accordance with this hypolipidemia should be able to reduce not only the total cholesterol, but especially VLDL - and LDL-fraction of serum cholesterol. Then it was found that the compounds of formula 1 show valuable, used in the treatment of properties regarding the influence on the level of serum lipid. So, they significantly reduce the increased serum of concentration and lipid food or with pathological changes in metabolism, for example, genetically determined hyperlipidemia. Therefore, they can be used for the prevention and regression of atherosclerotic changes, and they exclude a causal risk factor. This referred not only the primary hyperlipidemia, but also some secondary hyperlipidemia, as, for example, occur when diabetes. In addition, the compounds of formula 1 lead to the reduction caused by abnormalities of the metabolism of heart attacks and particularly to a considerable reduction caused by the extent of infarction and its severity. Further, the compounds of formula 1 lead to effective protection against damage to the endothelium caused by abnormalities of metabolism. With this protection of the vessels against the syndrome of endothelial dysfunction of the compounds of formula 1 are valuable medicines to prevent and to treat spasms of the coronary vessels, atherogenesis and atherosclerosis, hypertrophy of the left ventricle and dilated cardiomyopathy, and thrombotic diseases.

These compounds are therefore best used to produce the drug for the treatment of hypercholesterolemia, to get medicine for the prevention of atherogenesis, to get medicine for Poterie caused by elevated cholesterol, to obtain medicine for the prevention and treatment of diseases caused by endothelial dysfunction, to get medicine for the prevention and treatment caused by atherosclerosis, hypertension, to get medicine for the prevention and treatment caused by atherosclerosis of blood clots, to get medicine for the prevention and treatment of hypercholesterolemia and endothelial dysfunction caused by ischemia and postischemic reperfusion damage, to get medicine for the prevention and treatment-induced hypercholesterolemia and endothelial dysfunction of cardiac hypertrophy and cardiomyopathy to get medicine for the prevention and treatment-induced hypercholesterolemia and endothelial dysfunction spasms of the coronary vessels and myocardial infarction, to obtain medication for the treatment of the mentioned diseases, in combination with lower blood pressure substances, preferably with angiotensin converting-enzyme (ACE) inhibitors and angiotensin-receptor antagonists, in combination NHE inhibitor of the formula 1 with a decreasing lipid blood level of the active substance, preferably an inhibitor of HMG-CoA reductase inhibitors (eg, lovastatin or pravastatin), and last you a formula 1, turns out to be a favorable combination with intensified action and reduced use of active substances.

Declared reception of inhibitors of the metabolism of sodium-proton formula 1 as a new type of drug to reduce the fat level in the blood, as well as on the combination of inhibitors of exchange of the sodium-proton together with lower blood pressure and/or gipolipidemiceski existing drugs.

While medicines that contain compound 1, can be applied orally, parenterally, intravenously, rectally or via inhalation, and the preferred application depends on the appropriate clinical picture of the disease. In this connection 1 can be applied alone or together with galenovye drugs, namely both in veterinary and in human medicine.

What excipients suitable for the desired recipe medicines, specialist known on the basis of his knowledge. Along with solvents, geleobrazovanie, the basics of candles, excipients of tablets and other carriers of active substances can be applied, for example, antioxidants, dispersants, emulsifiers, defoamers, is For oral use, the active compounds are mixed with appropriate additives, as a matter-carriers, stabilizers or inert diluents, and conventional methods result in suitable forms of administration, as tablets, coated tablets, capsules, aqueous, alcoholic or oily solutions. As inert carriers can be used such as gum Arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. This form of manufacturing medicines can be as dry granulation and wet granulation. As oily substances carriers or solvents take into account, for example, vegetable and animal oils as sunflower oil or cod-liver oil.

For subcutaneous or intravenous administration, the active compounds, if necessary, with the usual substances as agents of dissolution, emulsifiers or other auxiliaries, lead in the form of a solution, suspension or emulsion. As solvents take, for example, the water, physiological sodium chloride solution or alcohols, for example ethanol, propanol, glycerin, along with them also solutions of sugar, as glucose or mannitol, or a mixture of various of the aforementioned solvents.

In which R, solutions, suspensions or emulsions of the active substances of formula 1 in a pharmaceutically not calling fears solvent, especially ethanol, or water, or in mixtures of such solvents.

The composition as needed may also contain other pharmaceutical auxiliary substances, such as surfactants, emulsifiers and stabilizers, as well as working gas. This dosage form contains an active ingredient generally in a concentration of from about 0.1 to 10, especially from about 0.3 to 3 weight. %.

The prescribed dosage of the active substance of formula 1 and the frequency assignment depend on the effectiveness and duration of the applied compounds; in addition, on the type and severity of the disease, which is treated, sex, age, weight and individual susceptibility of a mammal that is being treated.

On average, the daily dose of the compounds of formula 1 is in a patient weighing 75 kg minimum 0.001 mg/kg, preferably 0.01 mg/kg up to 10 mg/kg, preferably 1 mg/kg of body weight. In acute outbreaks, approximately immediately after the transfer of myocardial infarction, may be necessary also to higher and prcac, for example, in a patient with infarction in the intensive care unit may require the dose of 200 mg per day.

List of abbreviations:

Meon - methanol,

DMF - N,N-dimethylformamide,

RT - room temperature,

HER - ethyl acetate (EtOAc),

Smp - melting point

THF is tetrahydrofuran,

eq. - equivalent.

Experimental part:

General instructions for receiving benzoylpyridine (1)

Option a: from benzoic acid (11, L=IT)

1.0 equivalent of a derivative of benzoic acid of formula II is dissolved or suspended in anhydrous THF (5 ml/mmol) and then stirred with 1.1 equivalent of carbonyldiimidazole. After stirring for 2 hours at RT in the reaction solution is injected 5.0 equivalents of guanidine. After stirring over night distilled THF under reduced pressure (rotary evaporator apparatus), mixed with water, set pH 6-7 using 2 n model HC1 and filtered appropriate benzylguanine (formula 1). Obtained in this way benzoylpyridine can be translated by processing water, methanol or ethereal hydrochloric acid or other pharmacologically barnosky acids into the corresponding salt.

General instructions for obtaining b is valent complex Olkiluoto ester of benzoic acid of formula II and 5.0 equivalents of guanidine (free base) are dissolved in isopropanol or suspended in THF and to complete metamorphosis (monitoring by thin-layer chromatography) is heated to boiling (typical reaction time 2 to 5 hours). The solvent is distilled under reduced pressure (rotary evaporator apparatus), absorb IT and washed 3 times with a solution Manso3. Dried over Na2SO4the solvent is distilled off in vacuum and chromatographic on silica gel with a suitable solvent, such as HER/the Meon 5:1 (formation of salt cf. a).

Example 1: 2-chloro-3-(1'-hydroxy-2' -propyl)-5 - methylsulfonylbenzoyl, colorless crystals, Fp. 2NoC (decomposition).

Method of synthesis:

a) methyl ester of 2-chloro-3-iodide-5-methylsulphonyl-benzoic acid from complex methyl ester 2-chloro-5-methylsulfonylbenzoyl acid ladirovannye on Olahu with 1 equivalent of N-iodine - succinimide 5 equivalents of triftoratsetata at RT for 24 hours, colorless crystals, Fp. 155-58oC.

b) methyl ester of 2-chloro-3-Isopropenyl - 5-methylsulfonylbenzoyl acid from complex methyl ester 2-chloro-3-iodide-5-methylsulfonylbenzoyl acid reaction cross combinations with 1.5 equivalents of chloride Isopropylamine in THF with phlegm in the presence of catalytic amounts of palladium acetate (1) and copper iodide (1), water treatment, extraction with acetic ether and subsequent chromatography on a column of the hydroxy-2'-propyl] -5 - methylsulfonylbenzoyl acid gidroborudovaniya difficult methyl ester 2-chloro-3-Isopropenyl-5 - methylsulfonylbenzoyl acid with a complex of borane-THF in THF with phlegm for 3 hours, colourless crystals, Fp. 175-77oC.

d) methyl ester of 2-chloro-3-[1'-hydroxy-2'-propyl] -5-methylsulphonyl-benzoic acid of (C) esterification of 3 EQ. iodine bromide in the presence of potassium carbonate in DMF at RT for 3 hours, water treatment, colorless oil, M++N=307.

e) 2-chloro-3-[1'-hydroxy - 2'-propyl] -5 - methylsulfonylbenzoyl

d) General instructions version Century.

Example 2: 2-methoxy-3-(1'-hydroxy-2 '-propyl) -5 - methylsulfonylbenzoyl, colorless crystals, Fp. 179-80oC (decomposition).

The method of synthesis:

a) 2-methoxy-5-methylsulfonylbenzoyl acid from complex methyl ester 2-chloro-5-methylsulfonylbenzoyl acid with 10 EQ. methanolate sodium in the presence of copper chloride (II) in methanol with phlegm for 4 hours, yellowish solid, Fp. 190-92oC.

b) 2-methoxy-3-iodide-5-methylsulfonylbenzoyl acid 2-methoxy-5-methylsulfonylbenzoyl acid ladirovannye on Olahu with 1 EQ. N-iodine-succinimide 5 EQ. triftoratsetata at RT for 24 hours, colorless crystals, Fp. 205-07oC.

c) methyl ester of 2-methoxy-3-iodide-5-methylsulfonylbenzoyl acid from b) esterification with an excess of chloride vodarny methyl ether 2-methoxy-3-Isopropenyl-5-methylsulfonylbenzoyl acid from complex methyl ester 2-methoxy-3-iodide-5-methylsulfonylbenzoyl acid analogously to method 1 b), colorless oil, M++N=285.

e) 2-methoxy-3-[1'-hydroxy-2'-propyl]- methylsulfonylbenzoyl acid of (d) is similar to method 1), colourless solid, amorphous, M++ N = 289.

f) methyl ester 2-methoxy-3-[1'-hydroxy-2-propyl]-5-methylsulfonylbenzoyl acid esterification with 3 EQ. of methyl iodide in the presence of potassium carbonate in DMF at RT for 3 hours, water treatment, light yellow oil, M++ N = 303.

g) 2-methoxy-3-[1'-hydroxy-2'-propyl]-5 - methylsulfonylbenzoyl 2 f) General instructions version Century.

Example 3: 2-methyl-3-(1'-hydroxy-2'-propyl)-5 - methylsulfonylbenzoyl, colorless crystals, Fp. 208 - 09oC (decomposition).

The method of synthesis:

a) methyl ester of 2-methyl-5 - methylsulfonylbenzoyl acid

from the complicated methyl ester 2-chloro-5 - methylsulfonylbenzoyl acid reaction mix with 2 EQ. chloride medicine in THF/DMF when the phlegm in the presence of catalytic amounts of palladium (II) acetate, triphenylphosphine and copper iodide (1), water extraction with acetic ether and subsequent chromatography on a column of silica gel with acetic ether/n-heptane (3:7), colorless crystals, Fp. 95 - 96oC.

b) the PSS is resultoriented acid ladirovannye on Olahu I eq. N-iodine-succinimide 5 EQ. triftoratsetata at RT for 24 hours, colorless crystals, Fp. 137-38oC.

c) methyl ester of 2-methyl-3-Isopropenyl-5-methylsulfonylbenzoyl acid from complex methyl ester of 2-methyl-3-iodide-5-methylsulfonylbenzoyl acid reaction mix with 1.5 equivalents of chloride Isopropylamine in THF with phlegm in the presence of catalytic amounts of palladium (II) acetate, triphenylphosphine and copper iodide (1), water treatment, extraction with acetic ether and subsequent chromatography on a column of silica gel with acetic ether/n-heptane (3:7), colorless oil, M++ N = 269.

d) 2-methyl-3-[1'-hydroxy-2'-propyl]-5 - methylsulfonylbenzoyl acid gidroborudovaniya difficult methyl ester of 2-methyl-3-Isopropenyl-5 - methylsulfonylbenzoyl acid with a complex of borane-THF with phlegm for 3 hours, amorphous solid, M++ N = 273.

e) methyl ester of 2-methyl-3-[1'-hydroxy-2'-propyl]-5-methylsulphonyl-benzoic acid esterification with 3 EQ. of methyl iodide in the presence of potassium carbonate in DMF at RT for 3 hours, water treatment, light yellow oil, M++ N = 287.

f) 2-methyl-3-[1'-hydroxy-2' -propyl]-5 - methylsulfonylbenzoyl of ionoobmennika erythrocytes rabbit.

White rabbits of New Zealand (Ivanovas) received a standard diet with 2% cholesterol for six weeks in order to activate the Na+/H+- currency and determined by using flame photometer PA+- influx in erythrocytes through the Na+/H+-currency. Blood was taken from the auricular artery and did it not foldable thanks to 25 international units of potassium heparin. One part of each sample was used for double determination of hematocrit by centrifugation. Aliquot parts respectively of 100 Ál were used for measuring PA+- original content in erythrocytes.

To determine sensitive to amiloride influx of sodium, 100 ml of each blood incubated respectively in 5 ml of a hyperosmolar environment salt-sucrose (mmol/l: 140 NaCl, 3 KC1, 150 sucrose, 0,1 strofantina, 20 Tris-hydroxymethyl-aminomethane) at pH 7.4 and at 37oC. After that, the erythrocytes three times washed very cold solution of MgCl2-strofantina (mmol/l: 112 MgCl2, 0,1 strofantina) and caused hemolysis in 2.0 ml of distilled water. Intracellular sodium content was determined by using flame photometer.

Na+- the net inflow of thought from the differences between the original values of the bottom of the difference between the content of sodium in erythrocytes after incubation with amiloride without amiloride 3 x 10-4mol/L. This method worked well as the compounds according to the invention.

Results

Braking PA+/N+-panel:

Connect all of the examples have 1C50-less than 10 mmol.

Abstract:

Ortho-substituted benzoylpyridine

< / BR>
where R(1)-R(4) are specified in paragraphs values represent a valuable antiarrhythmic drugs with cardiotoxin component used to prevent ischemia-induced damage, especially during provoking ischemia-induced cardiac arrhythmias, the method of production thereof, their use as medicaments or diagnostic agents containing medication. As a result of inhibition of the cellular Na+/H+- exchange mechanism of the compounds of formula 1 are used for the treatment of acute or chronic ischemia-induced damage. In addition, they have strong inhibitory effect on cell proliferation. They are used for preventing the Genesis of high blood pressure.

1. Orthotamine benzoylpyridine formula 1

< / BR>
where R(1) denotes R(13)-SOm, m = 2, R(13) alkyl with 1, 2, 3 or 4 C-atoms;

one of the substituents R(2) and R(3) is hydrogen, the B>k-(R(32), R(32) is hydrogen or methyl, d, h, i = 0, K = 1, or, respectively, the other substituent R(2) and R(3) - C(OH)R(33)R(34), R(31), R(33) R(34) the same or different is hydrogen or alkyl with 1, 2, 3 or 4 C-atoms;

R(4) - alkyl with 1, 2, 3 or 4 C-atoms, alkoxy with 1, 2, 3 or 4 C-atoms, F, Cl, Br, I,

and their pharmaceutically tolerated salts.

2. Orthotamine benzoylpyridine under item 1 of formula 1, where R(1) denote R(13)-SO2R(13) - alkyl with 1, 2, 3 or 4 C-atoms, one of the substituents R(2) and R(3) is hydrogen and the other substituent R(2) and R(3) - -CHR(30)R(31), R(30) -(CH2)g-(CHOH)h-(CH2)i(SNON)k-(R(32), R(32) is hydrogen or methyl, d, h, i = 0, K = 1, or, respectively, the other substituent R(2) and R(3) - C(OH)R(33)R(34), R(31), R(33) R(34) the same or different is hydrogen or alkyl with 1, 2, 3 or 4 C-atoms, R(4) alkyl with 1, 2, 3 or 4 C-atoms, alkoxy with 1, 2, 3 or 4 C-atoms, F, Cl.

3. Orthotamine benzylguanine according to any one of p. 1 or 2 formula 1, where R(1) denotes R(13)-SO2R(13) alkyl with 1, 2, 3 or 4 C-atoms, one of the substituents R(2) and R(3) is hydrogen and the other substituent R(2) and R(3) -- (OH)(CH3)-CH2HE, -CH(CH3)-CH2HE or(HE)(CH3)2; R(4) alkyl with 1, 2, 3 or 4 C - atoms, alkoxy with 1, 2, 3 or 4 C-atoms, F, Cl.

Niya Na+/H+exchange.

5. Orthotamine benzoylpyridine formula 1 according to any one of paragraphs. 1-3, characterized in that suitable for the production of medicaments for the treatment or prevention caused by coronary artery disease States.

6. Orthotamine benzoylpyridine formula 1 according to any one of paragraphs. 1-3, characterized in that suitable for the production of medicaments for the treatment or prevention of myocardial infarction and arrhythmias.

7. Orthotamine benzoylpyridine formula 1 according to any one of paragraphs. 1-3, characterized in that suitable for the production of medicaments for the treatment or prophylaxis of angina.

8. Orthotamine benzoylpyridine formula 1 according to any one of paragraphs. 1-3, characterized in that suitable for the production of medicaments for the treatment or prophylaxis of ischemic conditions of the heart.

9. Orthotamine benzoylpyridine formula 1 according to any one of paragraphs. 1-3, characterized in that suitable for the production of medicaments for the treatment of diseases in which cell proliferation represents a primary or secondary cause, and, consequently, to obtain protivoateroskleroticheskim funds funds against late diabetic complications, cancer, fibromya diseases, what a tool possessing inhibitory activity against PA+/N+exchange, on the basis of activitiesthese substances and specific additives, characterized in that as activitiesthese substances it includes the compound of formula 1 according to any one of paragraphs. 1-3 in an effective amount.

 

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The invention relates to compounds of formula (I), where R1, R3-R8 means XYaWZ or X YaWZ', where X Is O; Y - alkylene with 1 to 4 atoms of CH2= 0 , and W is CH2or, if W does not follow directly behind the heteroatom group HUandalso About; Z is-C(=O)R(15) or, if W does not mean Oh, also NR(16)R(17); R(15) is-N=C(NH2)2R(16) and R(17) is hydrogen or alkyl or R(16) and R(17) imply together 4 or 5 methylene groups, of which one CH2-group may be replaced by oxygen or N-(p-chlorophenyl); X' is-C(=O)NR(30); Z' is-C(= O)R(15), N-containing heterocycle with 1-5 C-atoms, and N-containing heterocycle linked through C; the other of R1, R3-R8, which do not fall under the above values, independently of one another denote VpQqU, where V - O, p=0 or 1, q=0, U is hydrogen, alkyl, and one of the substituents R5-R8 are not hydrogen

The invention relates to andinorganic formula I, a method for obtaining medicinal product based on it

The invention relates to new derivatives of 1-afterheading formula (I)

where R2, R3, R4, R5, R6, R7, R8 denote H, F, CL, Br, I, CF3XaYbZ, X stands for O, a=0,1, Y means alkylene, and one of the CH2 groups may be replaced by O-phenylene, b=zero or 1, Z denotes H, alkyl,/=O/ R/15, NR/16/ R/17/ or phenyl, which may be unsubstituted or substituted, or Z means a nitrogen-containing heterocycle with 1-5 carbon atoms, and their pharmaceutically acceptable salts

The invention relates to the field of polymeric organic chemistry, in particular to the synthesis of disinfectants for veterinary and medicine

The invention relates to compounds of formula (I), where R1, R3-R8 means XYaWZ or X YaWZ', where X Is O; Y - alkylene with 1 to 4 atoms of CH2= 0 , and W is CH2or, if W does not follow directly behind the heteroatom group HUandalso About; Z is-C(=O)R(15) or, if W does not mean Oh, also NR(16)R(17); R(15) is-N=C(NH2)2R(16) and R(17) is hydrogen or alkyl or R(16) and R(17) imply together 4 or 5 methylene groups, of which one CH2-group may be replaced by oxygen or N-(p-chlorophenyl); X' is-C(=O)NR(30); Z' is-C(= O)R(15), N-containing heterocycle with 1-5 C-atoms, and N-containing heterocycle linked through C; the other of R1, R3-R8, which do not fall under the above values, independently of one another denote VpQqU, where V - O, p=0 or 1, q=0, U is hydrogen, alkyl, and one of the substituents R5-R8 are not hydrogen

The invention relates to organic chemistry, namely the synthesis of aliphatic perfluorocarbons WITHnF2n+2where n = 1-8, and cyclic perfluorocarbons, corresponding to the formula CmF2mwhere m = 3-8

The invention relates to new derivatives of 1-afterheading formula (I)

where R2, R3, R4, R5, R6, R7, R8 denote H, F, CL, Br, I, CF3XaYbZ, X stands for O, a=0,1, Y means alkylene, and one of the CH2 groups may be replaced by O-phenylene, b=zero or 1, Z denotes H, alkyl,/=O/ R/15, NR/16/ R/17/ or phenyl, which may be unsubstituted or substituted, or Z means a nitrogen-containing heterocycle with 1-5 carbon atoms, and their pharmaceutically acceptable salts
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