Dihydrothiaphenanthrenecarbonyl guanidines and uses thereof as pharmaceutical agent

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: disclosed are compounds of general formula I and pharmaceutically acceptable salts thereof, wherein R1 and R3 are hydrogen or C1-C4-alkyl; R2, R4, R5 are hydrogen; R6, R7, R8, R9 are hydrogen, C1-C4-alkyl, C1-C4-alkoxy, F, Cl, Br, I; or R8 and R9 together with phenyl ring attached thereto form naphthalene fragment; A is -SO2-. Compounds of present invention are useful as anti-arrhythmic drugs with cardioprotective components in prophylaxis and treatment of infarct. Also described is drug based on the compounds of formula I.

EFFECT: new drug for prophylaxis and treatment of infarct.

17 cl, 11 ex

 

This invention relates to dehydrationmorecondition formula I

in which

R(1) and R(3) denote independently from each other hydrogen, alkyl with 1, 2, 3 or 4 C-atoms, alkoxy with 1, 2, 3 or 4 C-atoms, F, Cl, Br, I, CN, NR(10)R(11), -Op-(CH2)n-(CF2)x-CF3or -(SOm)p-(CH2)n-(CF2)x-CF3;

R(10) R(11) denote independently from each other hydrogen, alkyl with 1, 2, 3 or 4 C-atoms or -(CH2)n-(CF2)x-CF3;

m is 0, 1 or 2;

n is 0, 1, 2, 3, 4, 5 or 6;

x and R independently from each other 0 or 1;

R(2) denotes hydrogen, F, Cl, Br, I, CN, alkyl with 1, 2, 3 or 4 C-atoms, methoxy, cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms,

R(4) and R(5) denote independently from each other hydrogen, alkyl with 1, 2, 3 or 4 C-atoms;

R(6)R(7)R(8) R(9) denote independently from each other hydrogen, alkyl with 1, 2, 3 or 4 C-atoms; alkoxy with 1, 2, 3 or 4 C-atoms, F, Cl, Br, I, CN, NR(12)R(13), -Oq-(CH2)r-(CF2)s-CF3or -(SOw)t-(CH2)u-(CF2)v-CF3;

R(12) R(13) denote independently from each other hydrogen, alkyl with 1, 2, 3 or 4 C-atoms;

w is 0, 1 or 2;

r and u are equal 0, 1, 2, 3, 4, 5 or 6;

q, s, t and v independently of each other 0 or 1;

or

R(6) R(7) or R(7) and R(8) or R(8) R(9) together with compounds which tion with them the phenyl ring to form a naphthalene fragment;

And represents-S-, -SO - or-SO2,

and their pharmaceutically tolerated salts.

Preferred are the compounds of formula I in which:

R(1) and R(3) denote independently from each other hydrogen, methyl, ethyl, methoxy, ethoxy, F, Cl, Br, I, CN, NR(10)R(11), -Op-(CH2)n-CF3or -(SOm)p-(CH2)n-CF3;

R(10) R(11) denote independently from each other hydrogen, methyl, ethyl, or-CH2-CF3;

m is 0, 1 or 2;

n is 0, 1, 2 or 3;

R independently from each other 0 or 1;

R(2) denotes hydrogen, F, Cl, CN, alkyl with 1, 2, 3 or 4 C-atoms, methoxy, cycloalkyl with 3, 4, 5 or 6 C-atoms,

R(4) and R(5) denote independently from each other hydrogen, methyl or ethyl;

R(6)R(7)R(8) R(9) denote independently from each other hydrogen, alkyl with 1, 2, 3 or 4 C-atoms; methoxy, ethoxy, F, Cl, Br, I, CN, NR(12)R(13), -Oq-(CH2)r-CF3or -(SOw)t-(CH2)u-CF3;

R(12) R(13) denote independently from each other hydrogen, methyl or ethyl;

w is 0, 1 or 2;

r and u are equal to 0, 1, 2 or 3;

q and t are independently from each other 0 or 1;

or

R(6) R(7) or R(7) and R(8) or R(8) R(9) together with the United with them the phenyl ring to form a naphthalene fragment;

And represents-S-, -SO - or-SO2,

and their pharmaceutically tolerated salts.

Especially preferred is the tsya the compounds of formula I, in which:

R(1) denotes hydrogen, methyl, ethyl, methoxy, ethoxy, F, Cl, NR(10)R(11), -Op-(CH2)n-CF3or -(SOm)p-(CH2)n-CF3;

R(10) R(11) denote independently from each other hydrogen, methyl, ethyl, or-CH2-CF3;

m is 0, 1 or 2;

n, p are equal independently of each other 0 or 1;

R(2) denotes hydrogen, F, Cl, methyl, cycloalkyl with 3, 4, 5 or 6 C-atoms,

R(3), R(4) and R(5) represent hydrogen;

R(6)R(7)R(8) R(9) denote independently from each other hydrogen, methyl, methoxy, ethoxy, F, Cl, NR(12)R(13), -Oq-(CH2)r-CF3or -(SOw)t-(CH2)u-CF3;

R(12) R(13) denote independently from each other hydrogen, methyl or ethyl;

w is 0, 1 or 2;

q, r, t and u are equal independently of each other 0 or 1;

or

R(6) R(7) or R(7) and R(8) or R(8) R(9) together with the United with them the phenyl ring to form a naphthalene fragment;

And represents-S-, -SO - or-SO2,

and their pharmaceutically tolerated salts.

Even more preferred are the compounds of formula I in which:

R(1) denotes hydrogen, methyl, methoxy, ethoxy, Cl, NR(10)R(11), -O-CH2-CF3or -(SOm)p-(CH2)n-CF3;

R(10) R(11) denote independently from each other hydrogen, methyl, ethyl, or-CH2-CF3;

m is 0, 1 or 2;

p is 0 or 1;

R(2) Ref is no hydrogen, F, Cl or methyl,

R(3), R(4) and R(5) represent hydrogen;

R(6)R(7)R(8) R(9) denote independently from each other hydrogen, methyl, methoxy, ethoxy, F, Cl, -O-CH2-CF3or -(SOw)t-(CH2)u-CF3;

w is 0, 1 or 2;

t and u are equal independently of each other 0 or 1;

or

R(6) R(7) or R(7) and R(8) or R(8) R(9) together with the United with them the phenyl ring to form a naphthalene fragment;

And means-SO2,

and their pharmaceutically tolerated salts.

The compounds of formula I may, if appropriate substitution to be in stereoisomeric forms. If the compounds of formula I contain one or more asymmetric centers, they may discover independently of each S-configuration or R-configuration. This invention includes all possible stereoisomers, such as enantiomers or diastereomers, and mixtures of two or more stereoisomeric forms such as enantiomers and/or diastereomers, in all ratios. Enantiomers in enantiomerically pure form, both left-and programada antipodes, as well as in the form of mixtures of both enantiomers in different ratios or in the form of racemates are also included within this invention. Getting the individual stereoisomers can be carried out, if desired, separating a mixture by conventional means or, for example, using stereoselective synthesis. In the presence of mobile atoms, the invention includes all tautomeric forms of compounds of formula I.

These alkyl residues can be straight chain or may be branched.

This invention relates also to a method for production of compound I, wherein compound of formula II

in which R(1)-R(9), and a have the above meaning, and L denotes easily nucleophile substitutable leaving group, is subjected to the interaction with guanidine.

The activated acid derivatives of the formula II, in which L denotes an alkoxy, preferably a methoxy group, fenoxaprop, phenylthio-, methylthio-, 2-pyridylthio containing a nitrogen heterocycle, preferably 1-imidazole, get known by way of the components of the acid chlorides of carboxylic acids (formula II, L=Cl), which, in turn, can be obtained in a known manner from carboxylic acids (formula II, L=OH), for example, with thionyl chloride.

Along with carboxylic acid anhydrides of the formula II (L=Cl) more activated acid derivatives of the formula II can also be obtained in a known manner directly from their constituent base derivatives of benzoic acid (formula II, L=OH), such as methyl esters of the formula II with L=OCH3processing of gaseous Cl in methanol, imidazolidin formula II by treatment carbonyl diimidazol [L=1-imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962)], the mixed anhydrides II with Cl-COOC2H5or mozillateam in the presence of triethylamine in an inert solvent, as well as the activation of benzoic acids dicyclohexylcarbodiimide (DCC) or O-[(cyano(etoxycarbonyl)methylene)amino]-1,1,3,3-tetramethylethylenediamine ("TOTU") [Proceedings of the 21. European Peptide Symposium, Peptides 1990, Editors E. Giralt and D. Andreu, Escom, Leiden, 1991]. A number of suitable ways of getting activated derivatives of the formula II provides additional data in J. March, Advanced Organic Chemistry, Third Edition (John Wiley & Sons, 1985), S.350.

The interaction of derivatives of carboxylic acids of the formula II with guanidine is known in proton or aprotic polar but inert organic solvent. In this case the interaction of the methyl ester of benzoic acids (II, L=OMe) with guanidine, methanol, isopropanol or THF support at a temperature of from 20°C to the boiling point of these solvents. In most cases, the interaction of the compounds II with the free guanidine salts carried out mainly in aprotic inert solvents such as THF, dimethoxyethane, dioxane. But can also be used water when applying base, such as NaOH, in a solvent in the conversion of compound (II) guanidine is m If L denotes Cl, use mainly the addition of the acid acceptor, for example, in the form of excess guanidine to capture halogenation acid.

For the synthesis of the main fragment dihydrotestosterone acid preferably extend from an appropriately substituted benzylaniline, phenylmethanesulfonyl or phenylmethanesulfonyl. They are subjected to intramolecular aryl-aryl-binding, which is in principle known (see Chem. Rev. 95(7), 2457 (1995) or "Metal-catalyzed Cross-coupling Reactions", Diedrich, Francois; Stang, Peter J.; Editors Germany (1988) Publisher: (Wiley-VCH, Weinheim, Germany), 517) or Tetrahedron (1998), 54(3/4), 263). Preferred is a binding Bronevoy acid with a suitable arylalkenes, such as areshared, arilbred, arylated, or a suitable complex allowin ether, such as arylmethyl or aritificially. The group Bronevoy acid can be introduced with a reagent containing a benzyl group, or with benzoic acid. Especially preferred is the use of bis(pinacolato)Debora, as described in Tetrahedron Lett. (1997), 38(22), 3841-3844. In the formula III described this original connection, where R(1)-R(9), and a and L have the specified value, and X and Y in each case represent halogen or-O-SO2CH3or " OH-SO2CF3. A preferred metal catalyst is the tsya palladium, especially preferably in the form of its complex Pd(dppf)2. The reaction is carried out in a dipolar aprotic solvent, are preferred DMF or DMA, at a temperature between 0°and the boiling point of the solvent, preferred are temperatures between 40°120°C.

Derivatives of General formula III preferably receive from derivatives of 3-mercaptobenzoic acids or of derivatives of 3-sulfidebearing acid of General formula IV with activated benzylphosphonate General formula V:

In the case of Z we are talking about easy nucleophile substitutable leaving group, such as, for example, chlorine, bromine, iodine, mesilate, toilet or triftorbyenzola. Derivatives IV and V are interacting in a suitable solvent, such as DMF, THF or acetonitrile, with the use of an auxiliary base such as triethylamine or DIPEA, at temperatures between -20°and the boiling point of the solvent, preferably at temperatures between 0°s and 40°C.

Anorganized I are generally weak bases and can bind the acid with the formation of salts. As the acid additive salts are considered salts of all pharmacologically tolerated acids, for example halides, in particular hydrochloride, lactates, Sul the veil, citrate, tartratami, acetates, phosphates, methylsulfonate, para-toluensulfonate.

The compounds I are replaced by arylguanidines.

In contrast to the known compounds, the compounds of this invention differ extremely high efficiency in the inhibition of Na+/H+exchange.

These compounds as well as known compounds do not have undesirable solidarities properties and shortcomings, but have a very good antiarrhythmic properties, which, for example, are important in the treatment of diseases that occur when the symptoms of oxygen deficiency. These compounds due to their pharmacological properties are surprisingly suitable as antiarrhythmic drugs with a cardioprotective component for the prophylaxis of infarction and treatment of infarction and for the treatment of angina, and they also preventively inhibit or greatly reduce the pathophysiological processes in the emergence of induced ischemia damage, in particular, by provoking ischemia-induced cardiac arrhythmias. Because of their protective actions against pathological hypoxic and ischemic situations, the compounds of formula I, by inhibiting the cellular mechanism of Na+/H+-can be used as a Lek is the only means for the treatment of all acute or chronic provoked by ischemia injury or through this primary or secondary induced diseases. This applies to their use as pharmaceuticals for surgical intervention, for example, transplant organs, and connections can be used to protect the organs in the donor and during their removal, for the protection of removed organs, for example, when manipulating with them or keeping them in physiological fluids and transplantation in the recipient's organism. Compounds are also valuable, protective current medicines when conducting angioplasticheskih surgical interventions, for example on the heart and peripheral vessels. In accordance with their protective effect against induced ischemia damages compounds are also suitable as pharmaceuticals for the treatment of ischemia of the nervous system, particularly the Central nervous system, and they are suitable, for example, for treatment of a stroke or cerebral edema. In addition, the compounds of formula I of this invention is also suitable for the treatment of forms of shock, such as, for example, of allergic, cardiogenic, hypovolemic and bacterial shock.

In addition, the compounds of formula I of this invention have strong inhibitory action on the proliferation of cells, for example, cell proliferation of fibroblasts and cell proliferation of vascular smooth muscles. Therefore, the connection forms of the crystals of I are considered as valuable therapeutic agents for diseases, in which cell proliferation is a primary or secondary cause, and can therefore be used as antiatherosclerotic funds funds against diabetic late complications, cancer, fibrocycstic diseases such as pulmonary fibrosis, fibrosis of the liver or fibrosis of the kidney, hypertrophy and hyperplasia of the authorities, in particular prostate hyperplasia or prostate hypertrophy.

The compounds of this invention are effective inhibitors of the cellular sodium-proton antiporters (Na+/H+-exchange), which increases in many diseases (essential hypertension, atherosclerosis, diabetes etc) also in these cells, which are easily accessible to measurements, such as, for example, erythrocytes, platelets or leukocytes. The compounds of this invention are suitable, therefore, as an excellent and simple experimental means, for example, in their use as diagnostics for the detection and differentiation of certain forms of hypertension, but also of atherosclerosis, diabetes, proliferative diseases, etc. in Addition, the compounds of formula I are suitable for preventive therapy to prevent the Genesis of high blood pressure, for example, essential hypertension.

In addition, it was found that the compounds of formulas which I have a favorable impact on serum lipoproteins. It is recognized that the emergence arteriosclerotic changes of vessels, particularly coronary heart disease, high level of fat in the blood, so-called hyperlipemia represent a significant risk factor. For the prevention and regression of atherosclerotic changes of exceptional importance, therefore, to decrease elevated level of serum lipoproteins. In addition to reducing total serum cholesterol, special importance is attached to reducing the share of specific atherogenic lipid fractions that total cholesterol, in particular low-density lipoprotein (LDL) and very low density lipoproteins (VLDL), as these lipid fractions are atherogenic risk factor. In contrast, high-density lipoprotein attributed a protective role against coronary heart disease. In line with this, hypolipidemic funds should be able to reduce not only the total cholesterol, but, in particular, the fraction of serum cholesterol VLDL and LDL. It was found that the compounds of formula I show a therapeutically useful effect in relation to the impact on the level of serum lipids. For example, they reduced significantly higher concentrations of LDL and VLDL in serum, which, for example, are due to the increased acceptance about kamennoi cholesterol and lipids food or with pathological changes in metabolism, for example, when genetically induced hyperlipidemia. So they can become involved in the prevention and regression of atherosclerotic changes, through the elimination of their causal risk factor. Besides, we are talking not only about primary hyperlipidemia, but also about certain secondary hyperlipidemia, which occur, for example, diabetes. In addition, the compounds of formula I leads to a clear reduction of heart attacks induced abnormalities of metabolism, and, in particular, to a considerable decrease in induced sizes of heart attacks and their severity. In addition, the compounds of formula I result in effective protection of endothelial damage in relation induced abnormalities of metabolism. Due to this protection of the vessels against the syndrome of endothelial dysfunction of the compounds of formula I are valuable drugs for the prevention and treatment of spasms of the coronary vessels, atherogenesis and atherosclerosis, hypertrophy of the left ventricle and bilateral cardiomyopathy and thrombotic diseases.

So the above compounds are used for preparing medicines for the treatment of hypercholesterolemia; for the preparation of a medicinal product for the prevention of atherogenesis; for the preparation of medicines warned the I and treatment of atherosclerosis, for the preparation of medicines for the prevention and treatment of diseases that come from the increased level of cholesterol, for preparing a medicinal product for the prevention and treatment of diseases that are the result of endothelial dysfunction, for preparing a medicinal product for the prevention and treatment-induced atherosclerosis hypertension, for preparing a medicinal product for the prevention and treatment-induced atherosclerosis, thrombosis, for preparing a medicinal product for the prevention and treatment-induced hypercholesterolemia and endothelial dysfunction of ischemic damage and postischemic reperfusion damage, for preparing a medicinal product for the prevention and treatment-induced hypercholesterolemia and endothelial dysfunction, hypertrophy of the heart, cardiomyopathies, and congestive heart failure (CHF), for the preparation of medicines for the prevention and treatment-induced hypercholesterolemia and endothelial dysfunction spasms of the coronary vessels and myocardial infarction, for preparing a medicinal product for the treatment of the aforementioned diseases in combination with lower blood pressure means, preferably inhibitors angiotensin is reverseimage enzyme (ACE), combinations of Na+/N+inhibitors of formula I with a decreasing fat levels in the blood of active substance, preferably an inhibitor of HMG-CoA reductase inhibitors (eg, lovastatin or pravastatin), the latter has a hypolipidemic action and because of this increases the hypolipidemic properties of Na+/N+inhibitor of formula I, is a favorable combination with intensified action and reduced utilization of the active ingredient.

It is claimed the use of inhibitors of the sodium-proton exchange of the formula I as new medicines to lower elevated levels of blood lipids, and combinations of inhibitors of the sodium-proton exchange with lower blood pressure and/or gipolipidemiceski existing drugs.

Moreover, there is the use of inhibitors of the sodium-proton exchange of formula I, as well as combinations of inhibitors of the sodium-proton exchange with lower blood pressure medications, particularly with ACE inhibitors (e.g. ramipril), as well as antagonists of angiotensin receptor (e.g., losartan) as new drugs for the treatment of CHF.

Medicines that contain compound I may be administered orally, parenterally, intravenously, rivers is material or by inhalation, preferably the introduction depends on the picture of the manifestations of the disease. The compounds I can be used alone or together with galenovye additives (excipients), both in veterinary and in human medicine.

The person skilled in the art know, what excipients suitable for the desired preparative forms of the drug. Besides solvents, gel-forming agents, bases for suppositories, additives for tablets and other carriers of active ingredients can be used, for example, antioxidants, dispersing agents, emulsifiers, defoamers, improves the taste of agents, preservatives, solubilizing agents or dyes.

For oral forms of application of active compound is mixed with suitable additives, such as carriers, stabilizers or inert diluents, and using conventional methods prepared in the form of a convenient form of application, such as tablets, pills, detachable capsules, aqueous, alcoholic or oily solutions. As inert carriers may be used, for example, Arabian gum, magnesium oxide, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. This form of cooking can be used either dry or moist granules. As oil but is of Italy or as solvents considered, for example, vegetable or animal oils, such as sunflower oil or cod-liver oil.

For subcutaneous or intravenous administration, the active compounds, if desired, with the usual substances, such as solubilizing agents, emulsifiers or further additives, are prepared in the form of a solution, suspension or emulsion. As the solvent are considered, for example, water, physiological sodium chloride solution or alcohols, for example ethanol, propanol, glycerin, along with them, also solutions of sugars such as glucose or mannitol, or a mixture of these various solvents.

As a pharmaceutical formulation for administration in the form of aerosols or sprays are suitable, for example, solutions, suspensions or emulsions of the active ingredient of the formula I in a pharmaceutically acceptable solvent such as ethanol or water, or mixtures of such solvents. Ready preparative form may also contain, as necessary, and other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, such as carrier gas. This new form usually contains the active substance in a concentration of approximately 0.1 to 10, in particular about 0.3 to 3 wt.%.

The dose of active ingredient of formula I and often is and introduction depend on the strength and duration of the applied compounds; in addition, the type and severity of underlying disease, as well as gender, age, weight and individual response of the treated mammal.

The average daily dose of the compounds of formula I in the case of a patient with a weight of approximately 75 kg is at least the minimum 0,mg/kg, preferably 0,mg/kg and up to 10 mg/kg, preferably up to a maximum of 1 mg/kg of body weight. In acute outbreaks, at least immediately after the occurrence of a heart attack, may also be necessary even higher and, above all, more frequent doses of at least up to 4 individual doses per day, in particular when administered intravenously, for example, in the case of a patient with infarction in the intensive care unit may be necessary doses up to 200 mg per day per kg of body weight.

Lists of abbreviations:

DIPEAdiisopropylethylamine
DMAN,N-dimethylacetamide
DME1,2-dimethoxyethan
DMFN,N-dimethylformamide
EAthe ethyl acetate (EtOAC)
EQ.equivalent to
Meonmethanol
Pd(dppf)2complex (1:1) [1,1'-bis(diphenylphosphino)ferrocene]palladium (II-methylene chloride
Smp (TPL)melting point
THFtetrahydrofuran

Experimental part

General methods of synthesis of dehydrationmorecondition

Stage 1) Methyl ester of 4-bromo-5-chlorosulfonyl-2-methylbenzoic acid 12g 4-bromo-5-chlorosulfonyl-2-methylbenzoic acid (J. Med. Chem. 1997, 40, 2017) was boiled with 20 ml of thionyl chloride for 8 hours under reflux. Excess thionyl chloride was removed under vacuum on a rotary evaporator, the residue was placed in approximately 50 ml of dry toluene and again evaporated. The crude acid chloride acid was dissolved in 25 ml of anhydrous toluene, was added 1.7 ml Meon and was stirred for 2 hours at 50°C. Then was added an additional amount of 1.7 ml Meon and stirred for 4 hours at 50°C. the Reaction mixture was diluted with 200 ml of EA and washed with 100 ml saturated aqueous solution of NaHCO3. Dried over Na2SO4and the solvents were removed in vacuum. Received of 11.0 g of pale yellow oil which was used without further purification.

Stage 2) 2-bromo-5-methoxycarbonyl-4-methylbenzenesulfonate acid

550 mg Na2SO3was dissolved in 2 ml of water and 70°C was added dropwise a solution of 337 mg of methyl ester of 4-bromo-5-chlorosulfonyl-2-methylbenzoic acid in 2 ml of DME. While p is capivari the solution became slightly acidic (pH 5). The solution was stirred for 2.5 hours at 70°C, left to cool and brought in an aqueous solution of HCl to a pH of 1.2. The solution was diluted with 50 ml of EA and washed with 50 ml saturated aqueous NaCl. Dried over Na2SO4and the solvents were removed in vacuum. Received 228 mg of a pale yellow oil which was used without further purification.

Stage 3) Methyl ester of 4-bromo-5-(2-bromophenylacetonitrile)-2-methylbenzoic acid

150mg (0,mol) of 2-bromo-5-methoxycarbonyl-4-methylbenzenesulfonic acid (stage 2) was dissolved in 1.5 ml DMF. To the solution was added mg (0,mol) 2-bromobenzylamine in 0.5 ml of DMF and 0.1 ml (0,56 mmol) DIPEA and left at room temperature for 16 hours while removing moisture. The reaction solution was filtered, diluted with 20 ml of EA, washed with 20 ml of 1N hydrochloric acid and then 20ml of 5%aqueous solution of sodium chloride. The organic phase is extruded through a drying cartridge (anhydrous sodium sulfate), the cartridge was washed 5ml EA. The filtrate was evaporated. The crude product was purified preparative HPLC.

According to the General reaction equation

received likewise the following products:

No.BenzylbromideProduct
21-bromo-2-(methyl bromide)naphthalene methyl ester of 4-bromo-5-(1-does not depend-2-elmersolver)-2-methylbenzoic acid
32-bromo-4-methylbenzylaminemethyl ester of 4-bromo-5-(2-bromo-4-methylphenylsulfonyl)-2-methylbenzoic acid
41-bromo-2-methyl bromide-4-chlorobenzenemethyl ester of 4-bromo-5-(2-bromo-5-chlorophenylsulfonyl)-2-methylbenzoic acid
52-bromo-1-methyl bromide-4-torbensonmethyl ester of 4-bromo-5-(2-bromo-4-PerformanceCounter)-2-methylbenzoic acid
61-bromo-2-methyl bromide-3-torbensonmethyl ester of 4-bromo-5-(2-bromo-6-PerformanceCounter)-2-methylbenzoic acid
72-bromo-1-methyl bromide-4-chlorobenzenemethyl ester of 4-bromo-5-(2-bromo-4-chlorophenylsulfonyl)-2-methylbenzoic acid
81-bromo-2-methyl bromide-4-methoxybenzoylmethyl ester of 4-bromo-5-(2-bromo-5-methoxybenzenesulfonyl)-2-methylbenzoic acid
91-bromo-2-methyl bromide-3-chlorobenzenemethyl ester of 4-bromo-5-(2-bromo-6-chlorophenylsulfonyl)-2-methylbenzoic acid
102-bromo-1-methyl bromide-3-methylbenzomethyl ester of 4-bromo-5-(2-bromo-3-methylphenylene sulfonyl)-2-methylbenzoic acid
111-bromo-2-methyl bromide-4-methylbenzoylmethyl ester of 4-bromo-5-(2-bromo-5-methylphenylsulfonyl)-2-methylbenzoic acid

Applied benzylbromide, because they are not commercially available, received either from the corresponding medicaremedicaid connections radical bromirovanii through N-bromosuccinimide any of benzyl alcohols by reacting with aqueous HBr or a mixture of the acid chloride methanesulfonic acid/triethylamine followed by the addition of tetrabutylammonium.

The crude products were mixed with a mixture of acetonitrile/water = 9:1 (1 ml) in some cases, when you add 0,2 ml DMF, was sucked out through the cartridge and washed with a mixture of acetonitrile/water = 9:1 (0,5ml). Precipitated precipitated solids were dried in a vacuum drying Cabinet at 50°and the purity was >80% according to HPLC/MS. The mother liquor was purified preparative HPLC, as it still contained a large proportion of the product.

Stage 4) Methyl ester 6-methyl-9,9-dioxo-9,10-dihydro-9-thia-phenanthrene-7-carboxylic acid

Mg (0,mol) bis(pinacolato)Debora, mg (0,725 mmol) of potassium acetate and 9 mg (0.012 mmol) Pd(dppf)2placed in 2 ml of DMA. Added 112 mg (0,242 mmol) of methyl ester of 4-bromo-5-(2-bromophenylacetonitrile)-2-methylbenzoic acid (stage 3), dissolved in 4 ml of DMA, and the AC is stirred at 80° With overnight under protective gas. The reaction solution was filtered through silica gel and washed with 20 ml of EA. The organic phase is washed with water and 5%sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuum. The crude product was purified preparative HPLC.

According to the General reaction equation

received likewise the following products:

No.Product
2Methyl ester of 2-methyl-5,5-dioxo-5,6-dihydro-5-tiebens[c]phenanthrene-3-carboxylic acid
3Methyl ester of 3,6-dimethyl-9,9-dioxo-9,10-dihydro-9-tefinance-7-carboxylic acid
4Methyl ester 2-chloro-6-methyl-9,9-dioxo-9,10-dihydro-9-tefinance-7-carboxylic acid
5Methyl ester of 3-fluoro-6-methyl-9,9-dioxo-9,10-dihydro-9-tefinance-7-carboxylic acid
6Methyl ether of 1-fluoro-6-methyl-9,9-dioxo-9,10-dihydro-9-tefinance-7-carboxylic acid
7Methyl ether 3-chloro-6-methyl-9,9-dioxo-9,10-dihydro-9-tefinance-7-carboxylic acid
8Methyl ester 2-methoxy-6-methyl-9,9-dioxo-9,10-

dihydro-9-tefinance the-7-carboxylic acid
9Methyl ester 1-chloro-6-methyl-9,9-dioxo-9,10-dihydro-9-tefinance-7-carboxylic acid
10Methyl ester of 4,6-dimethyl-9,9-dioxo-9,10-dihydro-

9-tefinance-7-carboxylic acid
11Methyl ester of 2,6-dimethyl-9,9-dioxo-9,10-dihydro-9-tefinance-7-carboxylic acid

Stage 5) Dihydrothienothiophenes, the General procedure

53 mg (0.5 mmol) of potassium tert-butylate suspended in 2 ml of dry DMF. To the suspension was added 50 mg (0.55 mmol) of guanidine hydrochloride and stirred the suspension when moisture for 30 minutes at room temperature. After this was added 0.1 mmol of the methyl ester from step 4, dissolved in 1 ml DMF and stirred overnight at room temperature. Precipitated precipitated salt was filtered and the filtrate was purified directly by preparative HPLC (column material Merck Supersphere RP18e, gradient mixture of acetonitrile/water with 0.1% formic acid as a buffer). The obtained products were characterized using analytical HPLC/MS on installing Agilent Serie 1100. Detection of the mass was performed using positive ionization.

Method a:

Column: Merck LiChroCart 55-2

Download: PuroSpher STAR RP18

The flow rate: 0.75 ml/min

Temperature: 40°

Gradient:

Solvent A: Acetonitrile/water (90:10)+0.5% of formic acid

Solvent b: Acetonitrile/water (10:90)to+0.5% formic acid

Time< / br>
[min]
The solvent In< / br>
[%]
0,0095,0
0,5095,0
1,755,0
4,255,0
4,5095,0
5,0095,0
6,20STOP

Method:

Column: YMC J ' Sphere ODS H80

Download: 4 ál

The flow rate: 1.0 ml/min

Temperature: 30°

Gradient:

Solvent A: water + 0.05% of triperoxonane acid

Solvent b: Acetonitrile

Time< / br>
[min]
The solvent In< / br>
[%]
0,0010,0
2,5095,0
3,3095,0
3,3510,0
3,60STOP

According to the General method of synthesis of dehydrationmorecondition synthesized compounds specified in the headers of examples 1-11:

Example:N-(6-methyl-9,9-dioxo-9,0-dihydro-9-tefinance-7-carbonyl)guanidinylation

MS (elektrorazpredelenie): 330 (M+1)+the retention time 2384 min (220 nm, method A)

Example:N-(2-methyl-5,5-dioxo-5,6-dihydro-5-tiebens[c]phenanthrene-3-carbonyl)guanidinylation

MS (elektrorazpredelenie): 380 (M+1)+the retention time of 1793 min (220 nm, the way In)

Example:N-(3,6-dimethyl-9,9-dioxo-9,10-dihydro-9-tefinance-7-carbonyl)guanidinylation

MS (elektrorazpredelenie): 344 (M+1)+the retention time of 2411 min (220 nm, method A)

Example: N-(2-chloro-6-methyl-9,9-dioxo-9,10-dihydro-9-tefinance-7-carbonyl)guanidinylation

MS (elektrorazpredelenie): 364 (M+1)+the retention time 2390 min (220 nm, method A)

Example: N-(3-fluoro-6-methyl-9,9-dioxo-9,10-dihydro-9-tefinance-7-carbonyl)guanidinylation

MS (elektrorazpredelenie): 348 (M+1)+the retention time of 2215 min (220 nm, method A)

Example:N-(1-fluoro-6-methyl-9,9-dioxo-9,10-dihydro-9-tefinance-7-carbonyl)guanidinylation

MS (elektrorazpredelenie): 348 (M+1)+the retention time of 2218 min (220 nm, method A)

Example 7: N-(3-chloro-6-methyl)-9,9-dioxo-9,10-dihydro-9-tefinance-7-carbonyl)guanidinylation

MS (electroaspect the e): 364 (M+1) +the retention time 2394 min (220 nm, method A)

Example 8: N-(2-methoxy-6-methyl-9,9-dioxo-9,10-dihydro-9-tefinance-7-carbonyl)guanidinylation

MS (elektrorazpredelenie): 360 (M+1)+the retention time 2271 min (220 nm, method A)

Example:N-(1-chloro-6-methyl)-9,9-dioxo-9,10-dihydro-9-tefinance-7-carbonyl)guanidinylation

MS (elektrorazpredelenie): 364 (M+1)+the retention time 2358 min (220 nm, method A)

Example:N-(4,6-dimethyl-9,9-dioxo-9,10-dihydro-9-tefinance-7-carbonyl)guanidinylation

MS (elektrorazpredelenie): 344 (M+1)+the retention time of 2302 min (220 nm, method A)

Example:N-(2,6-dimethyl-9,9-dioxo-9,10-dihydro-9-tefinance-7-carbonyl)guanidinylation

MS (elektrorazpredelenie): 344 (M+1)+the retention time 2671 min (220 nm, method A)

The way NHE-inhibiting Jansen

IC50[nm] inhibition of NHE-1 (Na+/H+currency 1) was defined as follows:

FLIPR-test to identify inhibitors of NHE-1 by measuring pHi-recovery in transfected cell lines, which expressed NHE-1 person

This test was performed in a FLIPR (tablet reader fluorescent images) with black wall 96-well microtiter plate PL is Hatami with a transparent bottom. Transfetsirovannyh cell line that expressed different subtypes NHE (the original cell line LAP-1 [received from Professor Pouyssegur, Nizza] due to mutagenesis and subsequent selection does not detect NHE activity), placed before the test at a density of ˜25,000 cells per well.

[The culture medium of transfected cells (Claims + 10% fetal calf serum) contains additional G418 as an antibiotic for selection for the exact determination of the presence of the transfected sequences].

The actual test begins with the removal of media for growing and adding 10 µl per well of the boot buffer (5 μm BCECF-AM [acetoxymethyl ester of 2',7'-bis(carboxyethyl)-5-(and-6)-carboxyfluorescein] in 20 mm NH4Cl 115 mm choline chloride, 1 mm MgCl2, 1 mm CaCl2, 5 mm KCl, 20 mm HEPES, 5 mm glucose; pH 7.4 [with bringing through CON]). Cells are then incubated for 20 minutes at 37°C. Incubation leads to the download of cells fluorescent dye, the fluorescence intensity of which depends on pHiand NH4Cl, which leads to weak alkalinization of the cell.

[Effluorescence predecessor dye BCECF-AM able in the form of ester to penetrate through the membrane. Inside the cells under the action of esterases released the actual dye BCECF, which is not pron what appears through the membrane].

After 20-minute incubation boot buffer that contains NH4Cl and free predecessor BCECF-AM, remove triple rinsing device for rinsing cells (Tecan Columbus) in each case, 400 µl of wash buffer (133,8 mm choline chloride, a 4.7 mm KCl, 1.25 mm MgCl2, 1.25 mm CaCl2, 0,97 mm To2NRA4, 0.23 mm KH2PO4, 5 mm HEPES, 5 mm glucose; pH 7.4 [with bringing through CON]). The remaining holes in the residual volume is 90 ál (volume 50-125 ml). Stage washing removes free BCECF-AM and leads due to the removal of external ions NH4+to intracellular acidification (˜pHi6,3-6,4).

Because the balance of intracellular NH4+with NH3disturbed by the removal of extracellular NH4+and next instantly beginning with the passage of NH3through the cell membrane, the washing process leads to intracellular N+remains and causes intracellular acidification, which can eventually lead to cell death if enough time is saved. At this point it is important to wash buffer did not contain sodium (<1 mm), as extracellular sodium ions could lead to immediate restoration of pHidue to the activity of the cloned NHE-isoforms.

It is also important that the CoE used buffers (boot buffer wash buffer, the buffer for recovery) did not contain the HCO3-ions, because the presence of bicarbonate would lead to activation of the interfering bicarbonate-dependent regulation systems pHicontained within the original cell line LAP-1.

Microtiter tablets with acidified cells transferred after that (within 20 minutes after acidification) in the tablet reader FLIPR. In FLIPR intracellular fluorescent dye excite light with a wavelength of nm, which is the argon laser, and measured parameters (laser power, lighting time and aperture (lens) built-in FLIPR CCD camera) is chosen so that the average signal of fluorescence per well was between 30000 and 35000 relative fluorescence units.

The actual measurement in the FLIPR begins with processing software will do one shot CCD-camera every 2 points. Ten seconds to carry out the restoration of intracellular pH by adding 90 ál of buffer for recovery (133,8 mm NaCl, of 4.7 mm KCl, 1.25 mm MgCl2, 1.25 mm CaCl2, 0,97 mm To2NRA4, 0.23 mm KH2PO4, 10 mm HEPES, 5 mm glucose; pH 7.4 [with bringing through CON]) using the built-in FLIPR 96-well device for pipetting.

As a positive control (100% NHE activity) are Lu the key, in that add pure buffer for recovery, negative controls (0% NHE activity) containing wash buffer. All other wells add buffer to restore with a concentrated 2 times the test compound. Measurement in the FLIPR finish in 60 measuring points (two minutes).

The raw data entered in the program ActivityBase. With the help of this program at first expect NHE activity for each test concentration of the compound and from the IC50the indicators for these compounds. Because the recovery progress pHinot during the whole experiment is linear, but decreases in the end result in decreasing NHE activity, it is important to choose for the evaluation of the measurement portion in which the increase in fluorescence of the positive controls is linear.

ExampleIC50inhibition of NHE-1
1the 15.6
224,2
38,6
410,8
5the 15.6
616,5
711,7
810,2
913,9
1067,7
111,5

1. Dihydrothienothiophenes formula I

in which R(1) and R(3) denote independently from each other hydrogen, alkyl with 1, 2, 3 or 4 C-atoms;

R(2) denotes hydrogen;

R(4) and R(5) represent hydrogen;

R(6)R(7)R(8) R(9) denote independently from each other hydrogen, alkyl with 1, 2, 3 or 4 C-atoms; alkoxy with 1, 2, 3 or 4 C-atoms, F, Cl, Br, I; or

R(8) R(9) together with the United with them the phenyl ring to form a naphthalene fragment;

And means-SO2-,

and their pharmaceutically tolerated salts.

2. The compounds of formula I according to claim 1, in which

R(1) and R(3) denote independently from each other hydrogen, methyl, ethyl;

R(6)R(7)R(8) R(9) denote independently from each other hydrogen, alkyl with 1, 2, 3 or 4 C-atoms; methoxy, ethoxy, F, C1; or

R(8) R(9) together with the United with them the phenyl ring to form a naphthalene fragment;

and their pharmaceutically tolerated salts.

3. The compounds of formula I according to claim 1 or 2, in which

R(1) denotes hydrogen, methyl, ethyl;

R(6)R(7)R(8) R(9) denote independently from each other hydrogen, methyl, methoxy, ethoxy, F, C1; or

R(8) R(9) together with the United with them the phenyl ring to form a naphthalene fragment;

and their pharmaceutical is tolerated salt.

4. The compounds of formula I according to claim 1 or 2, in which

R(1) denotes hydrogen, methyl;

R(6)R(7)R(8) R(9) denote independently from each other hydrogen, methyl, methoxy, ethoxy, F, C1; or

R(8) R(9) together with the United with them the phenyl ring to form a naphthalene fragment;

and their pharmaceutically tolerated salts.

5. The use of the compounds I according to claim 1 for the preparation of medicines, inhibition of Na+/H+-currency.

6. The use according to claim 5 for the preparation of drugs for treatment or prevention caused by coronary artery disease States.

7. The use according to claim 5 for the preparation of drugs for treatment or prevention of myocardial infarction and arrhythmias.

8. The use according to claim 5 for the preparation of drugs for treatment or prophylaxis of angina.

9. The use according to claim 5 for the preparation of drugs for treatment or prophylaxis of ischemic conditions of the heart.

10. The use according to claim 5 for the preparation of drugs for treatment or prophylaxis of ischemic conditions of the peripheral and Central nervous system and stroke.

11. The use according to claim 5 for the preparation of drugs for treatment or prophylaxis of ischemic conditions of peripheral organs and konechno the th.

12. The use according to claim 5 for the preparation of drugs for the treatment of States of shock.

13. The use according to claim 5 for preparing a medicinal product for use in surgical operations and organ transplants.

14. The use according to claim 5 for the preparation of medicines for the preservation and storage of transplants for surgical events.

15. The use according to claim 5 for the preparation of drugs for the treatment of diseases, primary or secondary cause of which is the proliferation of the cells.

16. The use according to claim 5 for the preparation of drugs for treatment or prevention of disorders of lipid metabolism.

17. The drug, inhibition of Na+/N+-currency and containing an effective amount of a compound I according to one or more of claims 1 to 4.



 

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SUBSTANCE: invention relates to D-proline derivatives of formula I or IA wherein R1 and R2 are independently lower alcoxy, lower alkenyloxy, hydroxy, -OCH(CH3)OC(O)-lower alkyl or -OCH2C(O)N(R3)N(R4), with the proviso, that only one from R1 and R2 represent hydroxy; R3 and R4 are independently hydrogen, lower alkyl? Lower alkenyl, or cycloalkyl; or R1 and R2 together with carbon atom to which they are attached form linkage group X, wherein X represents -O(CH2)nCH=CH(CH2)nO- or -O(CH2)mO-; n = 1, 2 or 3; m = 4-8.

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42 cl, 8 tbl, 8 ex

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wherein R3 means (C1-C7)-alkyl and others; Y means -O-, -S- or a bond; Z means -O- or -S-; or B means 5-membered heterocyclic group of formulae: (a) , (b) , (c) or (d) . Also, invention relates to methods for preparing compounds and to a medicinal agent based on thereof.

EFFECT: improved preparing methods, valuable medicinal properties of compounds.

22 cl, 1 tbl, 2 sch, 78 ex

The invention relates to medicine, namely to section narcology, and can be used for the treatment of tobacco

The invention relates to new derivatives aminomethylpropanol acid formula 1

< / BR>
where Z represents (CH2)n, O or S; n is 0, 1 or 2; X represents 1-3 substituent, independently selected from hydrogen, halogen, (C1-6)alkyloxy,(C3-6)cycloalkane, (C6-12)aryloxy, (C6-12)aryl, teinila, CN, СООR6and (C1-4)alkyl, optionally substituted with halogen, or 2 substituent in adjacent positions together represent a condensed (C5-6)aryl group, or O-(CH2)m-O, where m is 1 or 2; Y is 1-3 selected from hydrogen, halogen, (C1-4)alkyloxy and (C1-4)alkyl, optionally substituted with halogen; R1represents COOR7; R2and R6are (C1-4)alkyl; R3, R4and R5independently represent hydrogen; R7, R8and R9independently represent hydrogen or (C1-4)alkyl; or pharmaceutically acceptable salts, and pharmaceutical compositions on their basis, with effect on the Central nervous system

The invention relates to new N-phenylamine and N-pyridylamine derivative of the formula I

< / BR>
in which X denotes O or S;

R1and R2which may be identical or different, denote hydrogen, (C1-C6)alkyl or (C3-C8)cycloalkyl or R1and R2together with the carbon atom to which they are attached, form a (C3-C8)cycloalkyl;

R3means (C6-C12)aryl, optionally substituted by one or more radicals Y, which may be the same or different;

Y represents halogen;

R4and R5represent hydrogen;

Ar denotes one of the following groups or WITH:

< / BR>
T represents hydrogen or (C1-C6)alkyl;

T3and T4which may be identical or different, denote (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)allylthiourea;

R6and R7each denotes hydrogen or R6and R7together represent a bond;

Z denotes either (I) the divalent group-CHR9- in which the R11-, in which R10and R11together they form a bond that Z represents the group-CH=CH-, or R10and R11that may be the same or different, have the meanings indicated above for R9or (III) a divalent group-CHR12-CHR13-CH2-, in which R12and R13together they form a bond, Z represents-CH=CH-CH2-, or R12and R13that may be the same or different, have the meanings indicated above for R9,

as well as their additive salts with pharmaceutically acceptable acids or bases, and method of production thereof, pharmaceutical compositions and drug manifesting gipolipedimecescoe and antiatherosclerotic action based on them

The invention relates to new derivatives (tetrahydro-1-oxido-thiopyran-4-yl)phenyloxazolidine General formula I, in which R1means methyl, ethyl, cyclopropyl, dichloromethyl, R2and R3are identical or different and denote hydrogen or fluorine, or their pharmaceutically acceptable salts, and the new derived (tetrahydro-1,1-oxido-thiopyran-4-yl)phenyloxazolidine General formula II in which R2and R3are identical or different and denote hydrogen or fluorine, R4means ethyl or dichloromethyl, or their pharmaceutically acceptable salts

The invention relates to novim retinoid compounds of General formula I, II, III, IV with retinoid negative hormone biological activity and/or activity of antagonist retinoids, compositions based on them, a method of determining the retinoid antagonists hormones,the method of treating a pathological state in a mammal, vospriimchivosti to treatment with retinoid antagonist or negative hormone by injection of compound I or II

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to new derivatives of carbamic acid esters of the general formula (I):

and their pharmaceutically acceptable salts eliciting activity with respect to metabotropic glutamate receptors mGlu of group I that can be used for treatment of acute and/or chronic neurological disorders. In the general formula (I) R1 means hydrogen atom or (C1-C7)-alkyl; R2 and R2' mean independently of one another hydrogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom or trifluoromethyl; X means oxygen (O), sulfur (S) atom or two hydrogen atoms not forming a bridge; A1/A2 mean independently of one another phenyl or 6-membered heterocycle comprising 1 or 2 nitrogen atom; B represents group of the formula:

wherein R3 means (C1-C7)-alkyl and others; Y means -O-, -S- or a bond; Z means -O- or -S-; or B means 5-membered heterocyclic group of formulae: (a) , (b) , (c) or (d) . Also, invention relates to methods for preparing compounds and to a medicinal agent based on thereof.

EFFECT: improved preparing methods, valuable medicinal properties of compounds.

22 cl, 1 tbl, 2 sch, 78 ex

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