Ortho-substituted benzoylpyridine and medicines containing them

 

(57) Abstract:

The invention relates to novel ortho-substituted benzoylpyridine formula (1), where R(1) denotes H, halogen, Xand-(CH2)b-(CF2)with-CF3, a, b, C denote the zero, one of the two substituents R(2) and R(3) denotes hydroxyl, and the other of the substituents R(2) and R(3) is R(1), R(4) denotes a1-C4-alkyl, halogen, (CH2)n-(CF2)o-CF3n, mean zero, and their pharmaceutically acceptable salts. Drug, possess inhibitory activity against Na+/H+exchange-containing compound of the formula (1) and pharmaceutical additives. The compounds of formula (1) are used to receive medication for the treatment or prevention of heart attacks, strokes. The technical result is to provide new compounds having inhibitory activity against Na+/N+-exchange. 2 C. and 12 C.p. f-crystals.

The invention relates to benzoylpyridine formula I

< / BR>
where mean:

R(1) - H, F, Cl, Br, I, CN, NO2WITH1-C8-alkyl, C1-C8-alkoxy, C3-C8-cycloalkyl,3-C8-cycloalkane or Xa-(SS - zero, 1, 2 or 3;

R(5) - H, C1-C4-alkyl or CdH2dR(6);

d is zero, 1, 2, 3 or 4

R(6) - C3-C8-cycloalkyl, phenyl, biphenylyl or naphthyl,

and phenyl, biphenylyl or naphthyl are not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(7)R(8);

R(7) and R(8) independently of one another N or C1-C4-alkyl

or

R(1) - SR(10), -OR(10) or-CR(10)R(11)R(12);

R(10) - -CfH2f-C3-C8-cycloalkyl or phenyl, unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3CH3, methoxy, hydroxy, amino, methylamino and dimethylamino,

f - zero, 1 or 2;

R(11) R(12) independently of one another R(10), hydrogen or C1-C4-alkyl;

or

R(1) is phenyl, naphthyl, biphenylyl or C1-C9-heteroaryl, the latter is connected through the C - or N-atom rings, which accordingly is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, CL, CF3, methoxy, hydroxy, amino, methylamino and dimethylamino,

or

R(1) - SR(13), -OR(13), -OTHER(13), -NR(13)R(14), -CHR(13)R(15), -C[R(15)R(16)OH] , -CCR(18), -C[R(19)] = CHR(18), -C[R(20)R(21)]to-(CO)-[CR(22)R(23)]I-R(24).

to zero, 1, 2, 3 or 4;
(SNON)j-R(17) or -(CH2)g-O-(CH2-CH2O)h-R(24);

R(17) is hydrogen or methyl, g, h and i are the same or different are zero, 1, 2, 3, or 4

j - 1, 2, 3 or 4;

R(15) R(16) the same or different hydrogen, C1-C6-alkyl or together with the linking carbon atom form a3-C8-cycloalkyl;

R(18) - phenyl, unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(25)R(26);

R(25) R(26) -

N or1-C4-alkyl;

or

R(18) - C1-C9-heteroaryl unsubstituted or substituted as phenyl;

or

R(18) - C1-C6-alkyl unsubstituted or substituted by 1-3 HE group,

or

R(18) - C3-C8-cycloalkyl;

R(19) R(20) R(21) R(22) R(23) are the same or different hydrogen or methyl;

R(24) - C1-C6-alkyl, C3-C8-cycloalkyl or-CmH2m-R(18);

m - 1, 2, 3 or 4;

one of the two substituents R(2) and R(3) hydroxyl;

and

accordingly, the other substituents R(2) and R(3) is R(1);

R(4) - C1-C4-alkyl, C1-C4-alkoxy, F, CL, Br, I or -(CH2)n-(CF2)o-CF3;

n is zero or 1;

of zero or 1;

R(1) - H, F, Cl, Br, I, CN, NO2WITH1-C8-alkyl, C1-C8-alkoxy, C3-C8-cycloalkyl,3-C8-cycloalkane or Xa-(CF2)c-CF3;

X is oxygen;

and zero or 1;

with zero, 1, 2 or 3;

or

R(1) - SR(10) or(10);

R(10) - -CfH2f-C3-C8-cycloalkyl or phenyl, unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF2CH3, methoxy, hydroxy, amino, methylamino and dimethylamino;

f - zero or 1;

or

R(1) - phenyl, biphenylyl or1-C9-heteroaryl, the latter is connected through the C - or N-atom of the ring which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3CH3, methoxy, hydroxy, amino, methylamino and dimethylamino,

or

R(1) - SR(13), -OR(13), -other(13), -NR(13)R(14), -CCR(18) or-C[R(19)] =CHR(18);

R(13) and R(14) the same or different -(CH2)g(SNON)h-(CH2)i(SNON)j-R(17) or -(CH2)g-O-(CH2-CH2O)h-R(24);

R(17) is hydrogen or methyl, g, h and i are the same or different are zero, 1 or 2;

j is 1 or 2;

R(18) - phenyl, unsubstituted or substituted by 1-3 substituents selected from the group>/BR>R(18) - C1-C9-heteroaryl unsubstituted or substituted as phenyl;

or

R(18) - C1-C6-alkyl unsubstituted or substituted by 1-3 HE group,

or

R(18) - C3-C8-cycloalkyl;

R(19) is hydrogen or methyl;

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

and

accordingly, the other substituents R(2) and R(3) is

R(1);

R(4) - C1-C2-alkyl, methoxy, F, Cl, Br, CN or -(CH2)n-(CF2)o-CF3;

n is zero or 1;

of zero or 1;

and their pharmaceutically acceptable salts.

Especially preferred compounds of formula I, in which mean:

R(1) - H, F, Cl1-C4-alkyl, C1-C4-alkoxy, C5-C6-cycloalkyl,5-C6-cycloalkane or-Xa-(CF2)c-CF3;

X is oxygen;

and zero or 1;

with zero, 1, 2 or 3;

or

R(1) - SR(10) or(10);

R(10) - C4-C6-cycloalkyl or phenyl, unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3CH3, methoxy, hydroxy, amino, methylamino and dimethylamino;

or

R(1) - chinolin, ethanolic, pyridyl, which are linked through the C - or N-atom of the ring;
UB>3, methoxy, hydroxy, amino, methylamino and dimethylamino,

or

R(1) - phenyl, unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3CH3, methoxy, hydroxy, amino, methylamino and dimethylamino,

or

R(1) - -CCR(18);

R(18) - phenyl or5-C6-cycloalkyl;

one of the two substituents R(2) and R(3) hydroxyl;

and the other of the substituents R(2) and R(3) is R(1);

R(4) - methyl, methoxy, F, Cl or CF3;

and their pharmaceutically acceptable salts.

Especially preferred compounds of formula I, in which mean:

R(1) - H, F, Cl1-C4-alkyl, C1-C4-alkoxy, C5-C6-cycloalkyl,5-C6-cycloalkane or CF3;

one of the substituents R(2) and R(3) hydroxyl,

and

accordingly, the other substituents R(2) and R(3) is R(1);

R(4) - methyl, methoxy, F, Cl or CF3;

and their pharmaceutically acceptable salts.

Especially preferred compounds of formula I, selected from the group consisting of 2,6-dichloro-benzylguanine-hydrochloride, 3-chloro-2,6-dimethoxy-benzylguanine-hydrochloride, 4-hydroxy-2,3,5,6-titrator-benzylguanine-hydrochloride, 4-hydroxy-2,.

Under the C1-C9-heteroaryl mean radicals formed 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) replaced by S, NH or O. One or both of the atom in place of the condensation of a bicyclic residues (as in indolizinyl) can also be N-atoms. As WITH1-C9-heteroaryl especially suitable furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, honokalani, hintline, cinnoline; especially furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, triazolyl, pyridyl, indolyl, chinosol and ethanolic.

If one of the substituents R(1)-R(4) contains one or more centers of asymmetry, they can have both S-and R-configuration. The compounds can exist as optical isomers, diastereomers, racemates or mixtures thereof.

The mentioned alkyl residues may be linear or branched chain.

Further, the invention relates to sposo with guanidine, where R(1)-R(4) has a specified value, and L denotes easily replaced nucleophile residual group.

Activated derivatives of the acid of formula II, where L denotes an alkoxy, preferably a methoxy group, fenoxaprop, phenylthio-, methylthio-, 2-pyridylthio, nitrogen heterocycle, preferably 1-imidazolyl, get in a known manner from the acid chlorides of carboxylic acids (formula II, L= CL), which, in turn, receive a known manner from carboxylic acids (formula II, L=OH), for example, and chloride tiomila.

Along with anhydrides of carboxylic acids of the formula II (L=Cl) can be obtained also other activated acid derivatives of the formula II in a known manner directly from derivatives of benzoic acid (formula II, L= OH), - methyl ester of the formula II with L=co3treated with gaseous Hcl in methanol, imidazoline formula II is treated with carbonyl diimidazol [L= 1-imidazolyl, Staab, Angew. Chem. Int. Ed. England 1,351 367 (1962)], the mixed anhydrides II process S1-SOOS2H5or chloride tosilos in the presence of triethylamine in an inert solvent, as well as the activation of benzoic acids dicyclohexylcarbodiimide (DCC) or O-[(cyano(etoxycarbonyl)methylene)Appalachee activated derivatives of carboxylic acids of the formula II is specified in the literary source J. March, Advanced Organic Chemistry, Third edition (John Wiley & Sons, 1985), page 350.

The interaction of activated carboxylic acid derivative of the formula II with guanidine occurs in proton or aprotic, polar but inert organic solvent. When the interaction of the methyl esters of benzoic acids (II, L=OMe) with guanidine proven methanol, isopropanol or THF from 20oC to the boiling temperature of these solvents. In most reactions of compounds II with salt-free guanidine profitable to work in aprotic inert solvents, such as THF, dimethoxyethane, dioxane. When using a base, for example NaOH, the solvent in the interaction of II with guanidine you can also use the water.

If L=Cl, it is advantageous to add cyclotouriste, for example, in the form of excess guanidine binding halomonadaceae acid.

Of the derivative 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 any of the above options how to make the compounds I according to the invention.

Introduction some same palladium aryl halides or aritifacts, for example, organosilane, boron acids, or organoborane or medialivecasino or tsinkorganicheskih connections.

Benzoylpyridine I represent, in General, weak bases and can bind the acid with the formation of salts. As the acid additive salts used salts of all pharmacologically acceptable acids, for example halides, especially hydrochloride, lactates, sulfates, citrates, tartratami, acetates, phosphates, methylsulfonate, p-toluensulfonate.

The compounds I are substituted acylhalides.

Compounds similar to the compounds I are known from European application 612 723 A I (HOE 93/F 054). They contain hydroxyl groups as substituents in the phenyl nucleus, however, the substituents in the ortho-position no.

In contrast to the known compounds, the compounds according to the invention distinguish themselves by a high efficiency in the inhibition of Na+/H+-sharing and improved solubility in water.

They have no known connection, no unwanted and negative diuretic properties, but very good antiarrhythmic properties that are important for the treatment of diseases, costoriented as antiarrhythmic drugs with cardiotoxin component for the prevention and treatment of heart attack, and also 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 when 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 I as a result of inhibition of the cellular Na+/N+-exchange mechanism can be used as a drug for the treatment of all acute or chronic damage caused by ischemia or caused by this primary or secondary disease. This applies to their use as pharmaceuticals for surgical interventions, for example, transplant organs, and these compounds can be used to protect the organs in the donor before or during capture, 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 other means 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 I is also used for treatment of various forms of shock, for example, of allergic, cardiogenic, hypovolemic and bacterial shock.

The compounds of formula I according to the invention have strong inhibitory effect on cell proliferation, such as the proliferation of fibroblast cells and on cell proliferation muscles. Therefore, the compounds of formula I used as a valuable therapeutic agent for diseases in which cell proliferation represents a primary or secondary cause, and can therefore be used as protivoateroskleroticheskim funds funds against diabetic late complications, cancer, fibromya diseases such as pulmonary fibrosis, fibrosis of the liver or fibrosis of the kidney, against hypertrophy and hyperplasia of the authorities, especially when hyperplasia or hypertrophy of the prostate.

Compounds according to the invention are effektivnye inhibitors of cellular antinomies sodium-proton (Na+/H+-exchange), which for many diseases (essential for example, in erythrocytes, platelets or leukocytes. Therefore, the compounds according to the invention are used as a simple scientific tools, when used as diagnostic tools for the detection and identification of certain forms of hypertension, 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 of essential hypertension.

Drugs, which contain the compounds I can be assigned orally, parenterally, intravenously, rectally or in the form of inhalation, and the purpose it is preferable depends on the appropriate clinical picture of the disease. Thus the compounds I can be used alone or together with galenovye auxiliary preparations both in veterinary and in human medicine.

What are excipients used for the formulation of the medicinal product, the specialist is known on the basis of his special knowledge. Along with solvents, geleobrazovanie, the basics of candles, excipients of tablets and other carriers of active substances can be applied, for example, antioxidants, dispersing agents, Amul and dyes.

For oral use, the active compounds are mixed with suitable for this purpose additives, as matter-carriers, stabilizers or inert solvents, and conventional methods receive suitable forms of administration, as tablets, coated tablets, capsules shell, aqueous, alcoholic or oily solutions. As inert carriers can be used, for example, gum Arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. This dosage form can be thought of as dry or moist granules. As oily substances vehicles or solvents used, for example, vegetable or animal oils as sunflower oil or cod-liver oil.

For subcutaneous or intravenous set the active compound is dissolved, if necessary with conventional for this purpose substances as agents of dissolution, emulsifiers or other auxiliaries, receive a suspension or emulsion. As the solvent used, for example, water, physiological sodium chloride solution or alcohols, e.g. ethanol, propanol, glycerin, sugar solutions, glucose or mannitol, or a mixture of raslich, suspension or emulsion of the active substance of the formula I in a pharmaceutically not calling fears solvent, especially ethanol or water, or mixtures of such solvents.

The recipe depending on use can also contain other pharmaceutical auxiliary substances, such as surfactants, emulsifiers and stabilizers, as well as evaporative 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 the formula I and frequency assignments depend on the effectiveness and duration of action of the compounds used; the type and severity of the disease, as well as gender, age, weight and individual susceptibility of a mammal, which is being treated.

On average, the daily dose of the compounds of formula I is for a patient weighing about 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, for example directly after transferring myocardial infarction, may require higher and more frequent dosing, is the internal medicine intensive care required up to 200 mg per day.

List of abbreviations:

Meon methanol

DMF N,N-dimethylformamide

ITS ethyl acetate (EtOAc)

THF tetrahydrofuran

The experimental part.

A General method of obtaining benzoyl-guanidine (I).

Option a: from benzoic acids (II, L=OH).

1,0 EQ. a derivative of benzoic acid of formula II is dissolved or suspended in anhydrous THF (5 ml/mmol) and then mixed with 1.1 EQ. carbonyldiimidazole. After stirring for 2 hours at room temperature the reaction solution make 5,0 EQ. guanidine. After stirring overnight distilled THF under reduced pressure (rotary evaporator apparatus), mixed with water, set pH to 6-7 using 2 n Hcl and filtered appropriate benzylguanine (formula I). Received benzoylpyridine processing water, methanol or ethereal hydrochloric acid or other pharmacologically tolerated acids can be converted to the corresponding salt.

A General method of obtaining benzoyl-guanidine (I).

Option b: from complex alilovic esters of benzoic acids (II, L=O-alkyl).

1,0 EQ. complex Olkiluoto ester of benzoic acid of formula II and 5.0 equiv. guanidine (free base of the Ute to a boil (typical reaction time from 2 to 5 hours). The solvent is distilled under reduced pressure (rotary evaporator apparatus), absorb IT and washed 3 times with a solution of NaHCO3. 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.

(Salt formation cf. a).

EXAMPLE 1: 2-chloro-4-hydroxy-benzylguanine hydrochloride. Colorless crystals.

The melting point of 247oWITH

from 2-chloro-4-hydroxy-benzoic acid for option A.

EXAMPLE 2: 2-chloro-4-hydroxy-5-iodine-benzylguanine hydrochloride. Colorless crystals.

The melting point 246-247oC.

The method of synthesis:

a) methyl ester of 2-chloro-4-hydroxy-benzoic acid is obtained from 2-chloro-4-hydroxy-benzoic acid esterification with methanol (excess) in the presence of 10 equivalents of acetyl chloride for 24 hours at RT. After water treatment is the crystallization of simple ether/cyclohexane.

Colorless crystals.

The melting point of 128-130oWITH

b) methyl ester of 2-chloro-4-hydroxy-5-iodine-benzoic acid get (a) reaction with a mixture of 1.1 equivalent of N-chlorosuccinimide and 2.1 ssnoi acid at RT for 1.5 hours. Water treatment and chromatography on a column with cyclohexane/ acetic ether 9:1 to give the desired product as a colourless solid.

The melting point 191-192oC.

And methyl ester of 2-chloro-4-hydroxy-3,5-di-iodine-benzoic acid.

Colorless solid.

The melting point 131-132oC.

C) 2-chloro-4-hydroxy-5-iodine-benzylguanine-hydrochloride complicated methyl ester 2-chloro-4-hydroxy-5-iodine-benzoic acid (see 2B) for option C.

EXAMPLE 3: 2-chloro-4-hydroxy-3,5-di-iodine-benzylguanine hydrochloride.

Colorless solid.

The melting point 205-210oC (decomposition), from the complicated methyl ester 2-chloro-4-hydroxy-3,5-di-iodine-benzoic acid (see 2 b) according to method C.

EXAMPLE 4: 2-chloro-4-hydroxy-5-trifluoromethyl-benzylguanine hydrochloride. Colourless solid, amorphous (M+H)+282

The method of synthesis:

a) methyl ester of 2-chloro-4-benzyloxy-5-iodine-benzoic acid from complex methyl ester 2-chloro-4-hydroxy-5-iodine-benzoic acid by reaction with 1.1 equivalent of benzylbromide in the presence of potassium carbonate in DMF at 80oC for 3 hours.

After the waters of the 8oC.

b) methyl ester of 2-chloro-4-benzyloxy-5-trifluoromethyl-benzoic acid 4 (a) by heating to 160oC with 2 equivalents of triptoreline potassium N-methylpyrrole-2-Ohe in the presence of copper iodide (I) within 5 hours. Water treatment and chromatography on a column with cyclohexane/acetic ether 9: 1 gives colorless crystals,

the melting point of 126-127oC.

C) 2-chloro-4-benzyloxy-5-trifluoromethyl-benzylguanine of 4 b) the way In without salt.

Colourless crystals,

the melting point 180oC.

d) 2-chloro-4-hydroxy-5-trifluoromethyl-benzylguanine hydrochloride of 4) by hydrogenation using palladium/charcoal and subsequent formation of a hydrochloride, a colorless solid, amorphous, (M+N)+282.

EXAMPLE 5: 4-hydroxy-2,5-trifluoromethyl-benzylguanine hydrochloride:

colourless crystals,

the melting point of 211oC.

The method of synthesis:

a) methyl ester of 4-benzyloxy-2,5-trifluoromethyl-benzoic acid 4 b) similar triptoreline, but at elevated temperatures (180oC) and reaction time 5 hours,

colourless crystals,

the melting point 116oC.


the melting point of 221oC.

C) 4-hydroxy-2,5-trifluoromethyl-benzylguanine-hydrochloride 5 b) by hydrogenation with 10% palladium/charcoal in methanol at RT.

EXAMPLE 6: 4-hydroxy-2-methyl-5-trifluoromethyl-benzylguanine hydrochloride:

Amorphous solid.

The method of synthesis:

a) methyl ester of 2-methyl-4-benzyloxy-5-trifluoromethyl-benzoic acid from complex methyl ester 2-chloro-4-benzyloxy-5-trifluoromethyl-benzoic acid (4 b) are cross-combinations with 1.2 equivalent of chloride medicine (from chloride Metalmania transmetallation with a complex of zinc chloride (II) (THF) is stirred at 80oWith in DMF in the presence of catalytic amounts of palladium (II) acetate and copper iodide (I), colorless crystals,

the melting point 105oC.

b) 4-benzyloxy-2-methyl-5-trifluoromethyl-benzylguanine hydrochloride of 6 (a) for General instructions, colorless crystals,

the melting point of 255oC.

C) 4-hydroxy-2-methyl-5-trifluoromethyl-benzylguanine hydrochloride of 6 b) by analogy with the 5 C).

Farmakologicheskie data:

Inhibition of Na+/H+-exchange in erythrocytes of rabbit.

White rabbits from the UP>+-exchange and determination by flame photometer Na+-influx in erythrocytes using Na+/H+-exchange. Blood was taken from the auricular artery and did not foldable with 25 international units of potassium heparin. Part of each sample was used for double determination of hematocrit by centrifugation. Aliquots respectively 100 ml was used for the measurement of Na+-original content of erythrocytes.

To determine very sensitive to amiloride influx of sodium, 100 μl of each blood incubated respectively in 5 ml hyperkalemia salt-sucrose-environment (mmol/1: 140 Nad, 3 KCl, 150 sucrose, 0.1 to ubaida, 20 Tris-hydroxymethyl-aminomethane) at pH 7.4 and 37oC. After that, the erythrocytes were washed 3 times as cold as ice, a solution of MgCl2-oubain (mmol/1:112 MgCl2, 0,1 ubaida) and caused hemolysis in 2.0 ml of distilled water. Intracellular sodium content was determined by using flame photometer.

Na+net inflow was calculated from the difference between the original values of sodium and sodium content of the erythrocytes after incubation. Inhibiting amiloride influx of sodium was obtained from the difference between the content of sodium in erythrocytes after incubation with whom obreteniyu.

Results: inhibition of Na+/N+-exchange

Example - IC50(mol/1)

1: - 4010-6< / BR>
2: - 0,2410-6< / BR>
3: - 0,10l0-6< / BR>
4: - 0,1410-6e

1. Ortho-substituted benzoylpyridine formulas (1)

< / BR>
where R(1) denotes H, halogen, Xand-(CH2)b-(CF2)with-CF3, a, b, C denote null;

one of the two substituents R(2) and R(3) denotes hydroxyl, and the other of the substituents R(2) and R(3) is R(1);

R(4) denotes a1-C4-alkyl, halogen, (CH2)n-(CF2)o-CF3, n, denote zero,

and their pharmaceutically acceptable salts.

2. Benzoylpyridine formula (1) under item 1, where R(1) represents H, fluorine, chlorine or CF3; one of the two substituents R(2) and R(3) denotes hydroxyl, and the other of the substituents R(2) and R(3) is R(1); R(4) denotes methyl, fluorine, chlorine or CF3.

3. Benzoylpyridine formula (1) under item 1, selected from the group consisting of 4-hydroxy-2,5-trifluoromethyl-benzylguanine-hydrochloride and 4-hydroxy-2-methyl-5-trifluoromethyl-benzylguanine-hydrochloride.

4. Benzoylpyridine formula (1) under item 1 for receiving medication for treatment or prevention is the value of a drug for treatment or prevention of myocardial infarction.

6. Benzoylpyridine formula (1) under item 1 for receiving medication for treatment or prevention of angina.

7. Benzoylpyridine formula (1) under item 1 for receiving medication for the treatment or prophylaxis of ischemic conditions of the heart.

8. Benzoylpyridine formula (1) under item 1 for receiving medication for the treatment or prophylaxis of ischemic conditions of the peripheral and Central nervous system and stroke.

9. Benzoylpyridine formula (1) under item 1 for receiving medication for the treatment or prophylaxis of ischemic conditions of peripheral organs and limbs.

10. Benzoylpyridine formula (1) under item 1 for receiving medication for the treatment of States of shock.

11. Benzoylpyridine formula (1) p. 1 to obtain the drug for use in surgical operations and transplant organs.

12. Benzoylpyridine formula (1) under item 1 for receiving medication for preservation and storage of transplants for surgical purposes.

13. Benzoylpyridine formula (1) under item 1 for receiving medication for the treatment of diseases in which cell proliferation represents a primary or secondary cause, and, therefore, their prima, cancer, fibromya diseases such as pulmonary fibrosis, fibrosis of the liver or fibrosis of the kidney, prostate hyperplasia.

14. Drug, possess inhibitory activity against Na+/H+exchange containing the active substance and pharmaceutical additives, characterized in that the active substance is used as a compound of formula (1) under item 1.

 

Same patents:

The invention relates to substituted guanidines thiophenemethylamine acid of the formula I

< / BR>
where mean:

at least one of the substituents R(1), R(2) and R(3)

- Op-(CH2)s-CqF2q+1, R(40)CO - or R(31)SOk-;

p is zero or 1;

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

q 1,2, 3,4, 5, 6, 7 or 8;

k is zero, 1 or 2;

R(40) 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,

cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms or phenyl which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF, methyl or methoxy;

R(31) 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, cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms, or phenyl which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl or methoxy;

or

R(31) NR(41)R(42);

R(41)and R(42)

independently from each other hydrogen, alkyl with 1, 2, 3 or 4 C-atoms,

perfluoroalkyl with 1, 2, 3 or 4 C-atoms,

or

R(41)and R(42)

together 4 or 5 methylene groups, of which CH2-group may be replaced by oxygen, S, NH, N-CH3or N-benzyl;

and sootwetstwii-OgaWITHraH2raR(10);

PA zero or 1;

mA zero, 1, 2, 3, 4, 5, 6, 7 or 8;

ga zero or 1;

ha zero, 1, 2, 3 or 4;

R(10) cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms or phenyl, where the phenyl is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl and methoxy;

R(4) and R(5)

independently from each other hydrogen, F, Cl, Br, I, CN, 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, cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms or phenyl which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(14)R(15);

R(14)R(15)

independently from each other H, alkyl with 1, 2, 3 or 4 C-atoms or perfluoroalkyl of 1, 2, 3 or 4 C-atoms

and their pharmaceutically tolerable salts

The invention relates to phenylselenenyl guanidium alkenylboronic acid of the formula (I)

< / BR>
where T means

< / BR>
moreover, R(A) denotes hydrogen, fluorine, chlorine, bromine, iodine, CN, IT, OR(6), (C1-C4)-alkyl, Or(CH2)aCbF2b+l, (C3-C8-cycloalkyl or NR(7)R(8); where

r denotes zero or 1;

a represents zero, 1, 2, 3 or 4;

b means 1, 2, 3 or 4;

R(6) means (C1-C4)-alkyl, (C1-C4)-perfluoroalkyl, (C3-C6)-alkenyl, (C3-C8-cycloalkyl, phenyl or benzyl;

and the phenyl nucleus is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, metoxygroup and NR(9)R(10);

where

R(9) and R(10) mean hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

R(7) and R(8) independently of one another are specified for R(6) the value, or

R(7) and R(8) together mean 4 or 5 methylene groups, of which one CH2group can be replaced by oxygen, sulfur, NH, N-CH3or N-benzyl;

R(B) R(C) and R(D) independently from each other are specified for R(A) mn is od CN, OR(12), (C1-C8)-alkyl, Op(CH2)fCgF2g+l, (C3-C8-cycloalkyl or (C1-C9)heteroaryl;

R denotes zero or 1;

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

g means 1, 2, 3, 4, 5, 6, 7 or 8;

R(12) means (C1-C8)-alkyl, (C1-C4)-perfluoroalkyl, (C3-C8)-alkenyl, (C3-C8-cycloalkyl, phenyl or benzyl,

and the phenyl nucleus is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, metoxygroup and NR(13)R(14); where

R(13) and R(14) denote hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

R(E) has independently specified for R(F) value;

R(1) independently has a specified T value; or

R(1) means hydrogen, -OkCmH2m+l, -On(CH2)pCqF2q+1, fluorine, chlorine, bromine, iodine, CN, -(C= O)-N=C(NH2)2, -SOrR(17), -SOr2NR(31)R(32), -Ou(CH2)vWITH6H5, -Ou2-(C1-C9-heteroaryl or-Su2-(C1-C9-heteroaryl;

k is zero or 1;

m means zero, 1, 2, 3, 4, 5, 6, 7 or 8;

n denotes zero or 1;

p denotes zero, 1, 2, 3 or 4;

q is 1, 2,with hydrogen, (C1-C8)-alkyl or (C1-C8)-perfluoroalkyl or

R(31) R(32) together form a 4 or 5 methylene groups, of which one CH2group can be replaced by oxygen, sulfur, NH, N-CH3or N-benzyl;

R(17) implies (C1-C8)-alkyl;

u means zero or 1;

u2 means zero or 1;

v means zero, 1, 2, 3 or 4;

and the phenyl nucleus is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, metoxygroup, -(CH2)wNR(21)R(22), NR(18)R(19) and (C1-C9)-heteroaryl;

where

R(18) R(19), R(21) R(22) independently of one another denote (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

w is 1, 2, 3 or 4;

moreover, a heterocycle (C1-C9)-heteroaryl not substituted or is substituted by 1-3 substituents selected from the group consisting of F, C1, CF3, methyl or metoxygroup;

R(2), R(3), R(4) and R(5) independently of one another are specified for R(1); or

R(1) and R(2) or R(2) and R(3) together mean a group-CH-CH=CH-CH-, which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, C1, CF3, methyl, metoxygroup, -(CH2)w2NR(24)R(25) and NR(26)R(27);

where
is 1, 2, 3, or 4;

and the molecule contains at least two residue is T, at most three;

and their pharmaceutically acceptable salts

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

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 medicines, in particular to a mixture of isomers (9)-tetradecanoate

The invention relates to the production of TETRAFLUOROMETHANE used as a solvent, a foaming agent, in the manufacture of foams, as dry provide the Etchant electronic circuits

The invention relates to non-ionic surface-active compositions containing certain combinations of spermatocele, especially useful in detergents
The invention relates to the preparation of polyfluorinated ethers of the formula ROCF2CF2H, where R = CH3or HCF2CF2CH2-

The invention relates to compounds of the formula a-b-D-E-F-G, where the values of the radicals presented in the description in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts

The invention relates to the application of certain hydroxylamine derivatives of General formula I and II to prepare for the treatment and prevention of diseases resulting from damage to endothelial cells

The invention relates to phenylselenenyl guanidium alkenylboronic acid of the formula (I)

< / BR>
where T means

< / BR>
moreover, R(A) denotes hydrogen, fluorine, chlorine, bromine, iodine, CN, IT, OR(6), (C1-C4)-alkyl, Or(CH2)aCbF2b+l, (C3-C8-cycloalkyl or NR(7)R(8); where

r denotes zero or 1;

a represents zero, 1, 2, 3 or 4;

b means 1, 2, 3 or 4;

R(6) means (C1-C4)-alkyl, (C1-C4)-perfluoroalkyl, (C3-C6)-alkenyl, (C3-C8-cycloalkyl, phenyl or benzyl;

and the phenyl nucleus is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, metoxygroup and NR(9)R(10);

where

R(9) and R(10) mean hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

R(7) and R(8) independently of one another are specified for R(6) the value, or

R(7) and R(8) together mean 4 or 5 methylene groups, of which one CH2group can be replaced by oxygen, sulfur, NH, N-CH3or N-benzyl;

R(B) R(C) and R(D) independently from each other are specified for R(A) mn is od CN, OR(12), (C1-C8)-alkyl, Op(CH2)fCgF2g+l, (C3-C8-cycloalkyl or (C1-C9)heteroaryl;

R denotes zero or 1;

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

g means 1, 2, 3, 4, 5, 6, 7 or 8;

R(12) means (C1-C8)-alkyl, (C1-C4)-perfluoroalkyl, (C3-C8)-alkenyl, (C3-C8-cycloalkyl, phenyl or benzyl,

and the phenyl nucleus is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, metoxygroup and NR(13)R(14); where

R(13) and R(14) denote hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

R(E) has independently specified for R(F) value;

R(1) independently has a specified T value; or

R(1) means hydrogen, -OkCmH2m+l, -On(CH2)pCqF2q+1, fluorine, chlorine, bromine, iodine, CN, -(C= O)-N=C(NH2)2, -SOrR(17), -SOr2NR(31)R(32), -Ou(CH2)vWITH6H5, -Ou2-(C1-C9-heteroaryl or-Su2-(C1-C9-heteroaryl;

k is zero or 1;

m means zero, 1, 2, 3, 4, 5, 6, 7 or 8;

n denotes zero or 1;

p denotes zero, 1, 2, 3 or 4;

q is 1, 2,with hydrogen, (C1-C8)-alkyl or (C1-C8)-perfluoroalkyl or

R(31) R(32) together form a 4 or 5 methylene groups, of which one CH2group can be replaced by oxygen, sulfur, NH, N-CH3or N-benzyl;

R(17) implies (C1-C8)-alkyl;

u means zero or 1;

u2 means zero or 1;

v means zero, 1, 2, 3 or 4;

and the phenyl nucleus is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, metoxygroup, -(CH2)wNR(21)R(22), NR(18)R(19) and (C1-C9)-heteroaryl;

where

R(18) R(19), R(21) R(22) independently of one another denote (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

w is 1, 2, 3 or 4;

moreover, a heterocycle (C1-C9)-heteroaryl not substituted or is substituted by 1-3 substituents selected from the group consisting of F, C1, CF3, methyl or metoxygroup;

R(2), R(3), R(4) and R(5) independently of one another are specified for R(1); or

R(1) and R(2) or R(2) and R(3) together mean a group-CH-CH=CH-CH-, which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, C1, CF3, methyl, metoxygroup, -(CH2)w2NR(24)R(25) and NR(26)R(27);

where
is 1, 2, 3, or 4;

and the molecule contains at least two residue is T, at most three;

and their pharmaceutically acceptable salts

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

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 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
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