Phenylsilane guanidine alkenylboronic acid and the drug based on them

 

(57) Abstract:

The present invention relates to phenylselenenyl guanidium formula I, where T denotes the formula II, R(A) denotes hydrogen, halogen, alkyl, R(B) R(C) and R(D) is independently mean values for R(A), x and y are 0 or 1, R(F) means hydrogen, halogen, alkyl, R(E) values of R(F), R(1) values as T, or OkCmH2m+1, halogen, -(C=O)-N=C(NH2)2, -Ou(CH2)vC6H5,

-Ou2-(C1-C9-heteroaryl, k, m, u, u2 denote zero or 1, v is mean zero, R(2), R(3), R(4) and R(5) have the meanings as R(1), or R(2) and R(3) together imply-CH-CH= CH-CH-, -(CH2)w2NR(24)R(25) where R(24) and R(25) mean alkyl, and W2 denotes 1, 2, and the molecule contains at least two balance So the Above compounds possess inhibitory activity against Na+/H+-exchange and therefore can be used as an active substance in the medicinal product for the treatment of various diseases associated with the above properties of these compounds. 2 S. and 9 C. p. F.-ly, 1 PL.

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

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Il, 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) value;

x is zero, 1 or 2;

I mean zero, 1 or 2;

R(F) means hydrogen, fluorine, chlorine, bromine, iodine, 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;

B>3-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 means 1, 2, 3, 4, 5, 6, 7 or 8;

r is zero, 1, 2;

r2 denotes zero, 1, 2;

R(31) R(32) independently of one another denote 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 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

R(24) R(25) R(26) R(27) mean hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

w2 is 1, 2, 3 or 4;

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

and their pharmaceutically acceptable salts.

Preferred compounds of formula (I), in SUB>2)aCbF2b+1, (C3-C8-cycloalkyl or NR(7)R(8);

r denotes zero or 1;

a represents zero, 1 or 2;

b means 1, 2, 3 or 4;

R(6) means (C1-C4)-alkyl, (C1-C4)-perfluoroalkyl, phenyl or benzyl;

and the phenyl nucleus is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, C1, CF3, methyl, metoxygroup and NR(9)R(10);

where R(9) and R(10) independently of one another denote hydrogen, CH3or CF3;

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) value;

x is zero or 1;

the means zero or 1;

R(F) means hydrogen, fluorine, chlorine, CN, OR(12), (C1-C4)-alkyl, Op(CH2)fCgF2g+1, (C3-C8-cycloalkyl or (C1-C9)heteroaryl;

R denotes zero or 1;

f is zero, 1 or 2;

g means 1, 2, 3 or 4;

R(12) means (C1-C4)-alkyl, (C1-C4)-perfluoroalkyl, (C3-C8group, consisting of F, C1, CF3, methyl, metoxygroup and NR(13)R(14); where

R(13) and R(14) independently of one another denote hydrogen, CH3or CF3;

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

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

R(1) means hydrogen, -OkCmH2m+1, -OnCqF2q+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 denotes zero, 1, 2, 3 or 4;

n denotes zero or 1;

q is 1, 2, 3 or 4;

r means 2;

r2 denotes zero, 1, 2;

R(31) R(32) independently of one another denote 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-C4)-alkyl;

u means zero or 1;

u2 means zero or 1;

v means zero, 1 or 2;

and the phenyl nucleus is not substituted or is substituted by 1-3 substituents selected from the group sostojashie

R(18) R(19), R(21) R(22) denote hydrogen, (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, Cl, 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

R(24) R(25) R(26) R(27) denote hydrogen, methyl or CF3;

w2 is 1, 2, 3 or 4;

moreover, in the molecule contains only two residue is T, and their pharmaceutically acceptable salts.

Especially preferred are the compounds of formula (I), in which

T mean

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where x is null;

the means null;

R(F) means hydrogen, fluorine, chlorine, CN, OR(12), (C1-C4)-alkyl, -OpWITHgF2g+1, (C3-C8-cycloalkyl or (C1-C9)heteroaryl;

R denotes zero or 1;

g means 1, 2, 3 or 4;

R(12) means (C1-C4about or 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, methyl or CF3;

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

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

R(1) means hydrogen, -OkCmH2m+1, -OnCqF2q+1, fluorine, chlorine, CN, -(C=O)-N= C(NH2)2, -SO2CH3, -SO2NR(31)R(32), -Ou(CH2)vWITH6H5ABOUTu2-(C1-C9-heteroaryl or-Su2-(C1-C9-heteroaryl;

k is zero or 1;

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

n denotes zero or 1;

q is 1, 2, 3 or 4;

R(31) R(32) independently of one another denote hydrogen, or (C1-C8)-alkyl 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;

u means zero or 1;

u2 means zero or 1;

v means zero or 1;

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) and NR(18)R(19); where R(18) R(19), R(21) R(22) independently of one another mean vegeterians (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

R(24) R(25) R(26) R(27) independently of one another denote hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

w2 is 1, 2, 3 or 4;

moreover, in the molecule contains only two residue is T, and their pharmaceutically acceptable salts.

Particularly preferred are the following compounds:

1,2-bis-[3-(guanidin E-2-methyl-propanolol acid)]benzene-dihydrochloride;

1,3-bis-[3-(guanidin E-2-methyl-propanolol acid)]benzene-dihydrochloride;

1,4-bis-[3-(guanidin E-2-methyl-propanolol acid)]benzene-dihydrochloride;

2,3-bis-[3-(guanidin E-2-methyl-propanolol acid)] naphthalene-dihydrochloride;

1,2-bis-[3-(guanidin Z-2-fluoro-propanolol acid)]benzene-dihydrochloride;

1-[3-(guanidin Z-2-fluoro-propanolol acid)]-2-[3-(guanidyl-dihydrochloride;

guanidin 3-(4-chloro-3-guanidiniocarbonyl-5-phenyl)phenyl-2-methyl-propanolol acid;

1,3-bis-[3-(guanidin E-2-metracal)] -2-methoxy-5-methyl-benzene hydrochloride;

1,2-bis-[3-(guanidin E-2-methyl-propanolol acid)] -4-methylbenzol-dihydrochloride;

1,2-bis-[3-(guanidin E-2-methyl-propanolol acid)]-4,5-dichlorobenzene-dihydrochloride;

1,3-bis-[3-(guanidin E-propanolol acid)]benzene-dihydrochloride;

1,2-bis-[3-(guanidin E-2-methyl-propanolol acid)] -4-Brabanthal-dihydrochloride;

1,2-bis-[3-(guanidin E-2-methyl-propanolol acid)]-4-(4-metatitanate)benzene-dihydrochloride;

1,2-bis-[3-(guanidin E-2-methyl-propanolol acid)] -4-(4-methylphenoxy)benzene-dihydrochloride;

1,3-bis-[3-(guanidin E-2-methyl-propanolol acid)] -5-methoxybenzoyl hydrochloride;

1,3-bis-[3-(guanidin E-2-methyl-propanolol acid)] -5-tert.-butylbenzoyl hydrochloride;

1,4-bis-[3-(guanidin E-2-methyl-propanolol acid)]-2,5-dichlorobenzene-dihydrochloride;

1,2-bis-[3-(guanidin E-2-methyl-propanolol acid)]-4-(phenoxy)benzene-dihydrochloride;

1,2-bis-[3-(guanidin E-2-methyl-propanolol acid)]-4-(methoxy)benzene-dihydrochloride;

1,2-bis-[3-(guanidin E-2-methyl-propanolol acid)]-4-(ethoxy)benzene-dihydrochloride; and

1,2-bis-[3-(guanidin E-2-methyl-p or more centers of asymmetry, they can be both in S-and R-configuration. The compounds may be in the form of optical isomers, diastereomers, racemates or mixtures thereof.

The geometry of the double bonds in compounds of formula (I) can represent both the E and z Connection can be in the form of a mixture of geometric isomers.

These alkyl and performanceline residues may be both linear and branched.

Under (C1-C9-heteroaryl see in particular residues, derivatives of phenyl or naphthyl, in which one or more CH groups replaced by nitrogen and/or in which at least two adjacent CH groups (in the formation of five-membered aromatic ring) is replaced by sulfur, NH or oxygen. Further, one or both of the atom in place of the condensation of a bicyclic residues (as in indolizinyl) may represent nitrogen atoms.

As heteroaryl especially use furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, honokalani, hintline, cinnolines.


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where R(1), R(2), R(3), R(4), R(5), R(A) R(B) R(C) R(D) R(E) R(F), x and y have the above values, a L means easy nucleophile replaced the deleted group, is subjected to the interaction with guanidine.

The activated acid derivatives of the formula (II), where L is alkoxy, preferably a methoxy group, phenoxy group, phenylthio-, methylthio-, 2-pyridylthio, nitrogen-containing heterocycle, preferably imidazol-1-yl, get, preferably by known methods from the corresponding carboxylic acid anhydrides (formula (II), L=C1), which in turn also known methods can be obtained from the corresponding carboxylic acids (formula II, L=OH), for example, using thionyl chloride.

Along with carboxylic acid anhydrides of the formula (II) (L=C1) you can also get other activated acid derivatives of the formula (II) in a known manner directly from the appropriate derivatives alkenylboronic acid (formula (II); L=OH), for example, methyl ester of formula (II) with L=co3- by treating it with gaseous hydrogen chloride in methanol, imidazoline formula (II) by treatment with carbonyldiimidazole (L= imidazole-1-yl; Staab, Angew. Chem. Int. Ed. Eng I., 1, 351-367 (1962)), mixed anger is varicela, as well as activating alkenylboronic acids, can be done by using dicyclohexylcarbodiimide (DCC) or with O-[(cyano(etoxycarbonyl)methylene)amino] -1,1,3,3-tetramethylethylenediamine ("TOTU") (Proceedings of the 21. European Peptide Symposium, Peptides, 1990, ed. E. Giralt and D. Andreu, Escom, Leiden, 1991). A number of suitable ways of getting activated derivatives of carboxylic acids of the formula (II) are known from the literature source, J. March, "Advances in organic chemistry", third edition, (John Wiley and Sons, 1985), S. 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, inert organic solvent. When the interaction of methyl esters alkenylboronic acid (formula (II), L-OSS) with guanidine suitable methanol, isopropanol or tetrahydrofuran at a temperature of 20oC to the boiling point of the solvent. In the case of most interactions of the compounds of the formula (II) with guanidine in the form of a free base without salt are preferably in aprotic inert solvents such as tetrahydrofuran, dimethoxyethane, dioxane. However, when the interaction of the compounds of formula (II) with guanidine is Oia.

When L=C1, it is preferable to add a catcher acid, for example, in the form of excess guanidine, to bind halogen acids.

Of the relevant derivatives alkenylboronic acids of the formula (II) are known and described in the literature. Unknown compounds of the formula (II) can be obtained according to known literature methods. Received alkenylboronic acid in the above-described variants of the method in turn proposed according to the invention the compounds of formula (I).

The introduction of some substituents can be known from the literature how the reaction of cross-linking in the presence of palladium, aryl halides, respectively, aritifical, for example, ORGANOTIN compounds, boron acids, or organoborane or copper, respectively, tsinkorganicheskih connections.

Alkenylamine formula (I) are weak bases and can bind the acid with the formation of salts. As salt use salt in any pharmacologically acceptable acids, for example halides, in particular hydrochloride, lactates, sulfates, citrates, tartratami, acetates, phosphates, methylsulfonate, p-toluensulfonate of acylhalides are guanidin pyrazinecarboxamide acid and guanine benzoic acid of the General formula (V) and (VI):

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Amiloride: R, R'=H

Dimethylaniline: R, R'=CH3< / BR>
Ethylisopropylamine: R=CH(CH3)2; R'=C2H5< / BR>
The compounds of formula (V) in the literature referred to generally as amiloride. The amiloride (R,R'=H) is used in therapy as potassium-sparing diuretics. Numerous other compounds amiloride type are described in the literature, for example dimethylaniline or ethylisopropylamine.

There are studies that indicate antiarrhythmic properties of amiloride. (Circulation, 79, 1257-1263 (1989)). The wide use as an antiarrhythmic agent, however, preclude the fact that this effect is weak and is accompanied by a lowering of blood pressure and salureticheskoe action, and these unwanted side effects in the treatment of cardiac arrhythmias.

Indications for antiarrhythmic properties of amiloride obtained in experiments on isolated hearts of animals (Eur. Heart. J. 9 (Supplement 1), 167 (1988) (abstracts)). For example, in the case of the hearts of rats it was shown that artificially induced flicker of the ventricles of the heart can be completely suppressed by amiloride. Even more potent than amiloride, the formula (VI) are selective inhibitors of the ubiquitous sodium/proton exchange (subtype 1, NHE-1). Known from the literature is represented by NOAH 694 and NOAH 642, which are described as acting antiarrhythmic, and coronary heart conditions as cardiotoxin funds [and). Scholz W, Albus u, Linz W., Martorana, P., Lang, H. J., B. A. Scholkens "Effects of inhibitors of PA+/N+-exchange on ischemia of the heart". J. Mol. Cell Cardiol. , 24, 731-739 (1992); b). Scholz W, Albus u "Pas+/N+-metabolism and its inhibition in ischemia of the heart and re-perfusion". Basic Res. Cardiol., 88, 443-455 (1993); Scholz W, Albus u, Counillon L., Gogelein, H., Lang, H. J. Linz W. , A. Weichert, B. A. Scholkens "Protective effects of NOAH 642, selective inhibitor of sodium-hydrogen exchange subtype 1, ischemia of the heart and re-perfusion". Cardlovasc. Res., 29, 260-268 (1995); g) E. Bugge and Ytrehus K. "Inhibition of the sodium-hydrogen exchange, reducing the volume of infarction in the case of isolated rat heart. Safety Supplement at predications States. Cardiovasc. Res., 29, 269-274 (1995)].

Next, from the literature known guanidine 3-phenyl - and 3-thiophenyl-propanolol acid of the formula (VII) as NHE inhibitors (US 2 734 904; WO 84/00875; DE-OS 44 21 536.3 (NOAH 94/F 168)), but these publications are not described or are not recommended no biguanidine the compounds of formula (I).

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R(I) = phenyl, thiophenyl.

Suddenly, what was still known NHE inhibitors of this subtype little active.

The proposed compounds of formula (I) cause a decrease in blood pressure and thus suitable as pharmaceuticals for the treatment of primary and secondary hypertension. On the basis of their solidarities actions they are suitable as a diuretic funds.

In addition, compounds used individually or in combination with STUMP-inhibitors of another subtype specificity, are antiischemic. They protect in acute or chronically insufficient supply of oxygen to the organs by reducing or preventing ischemia-induced lesions and thus suitable as pharmaceuticals, for example, in the case of thrombosis, spasm of blood vessels, atherosclerosis or with surgical intervention (for example, transplantation of kidney and liver, and the connections can be used to protect the organs in the donor before and during removal, for the protection of removed organs, for example, when processing with physiological fluids or during storage in these fluids, and the transfer to the recipient's organism) or in the case of chronic or acute renal nedostatochnosty.

According to their protective action against ishemic nervous system, in particular, the Central nervous system, and they are suitable, for example, for the treatment of stroke or of cerebral oedema. Moreover, it is proposed according to the invention the compounds of formula (I) are also suitable for the treatment of forms of shock, such as, for example, of allergic, cardiogenic, hypovolemic and bacterial shock.

Further, the compounds cause improvement in breathing and can therefore be used to treat conditions of the respiratory system in the following clinical conditions and diseases: impaired Central impulse of breath (for example, the Central stop breathing during sleep, sudden infant death, postoperative hypoxia) caused by muscle respiratory disorders, respiratory disorders after long-term mechanical ventilation, respiratory disorders during adaptation to high-altitude conditions, obstructive and mixed form stop breathing during sleep, acute and chronic lung disease with hypoxia and hypercapnia.

The combination of the STUMP-inhibitor with a carbonic anhydrase inhibitor (eg, acetazolamide), the latter leads to metabolic acidosis and thus increased respiratory activity, is a favorable combination with rigid is ateneu the compounds of formula (I) have strong inhibitory activity against cell proliferation for example, proliferation fibroblastoid cells and proliferation of smooth muscle cells of blood vessels. Therefore, the compounds of formula (I) can be used as a valuable therapeutic agents for the treatment of diseases in which cell proliferation represents a primary or secondary cause, and can therefore be used as anti-atherosclerosis, anti-late diabetic complications, cancer, fibrocycstic diseases such as pulmonary fibrosis, fibrosis of the liver or kidney fibrosis, endothelial dysfunction, hypertrophy of organs and hyperplasia of the authorities, especially when prostate hyperplasia, respectively, hypertrophy of the prostate. In addition, the compounds cause a decrease in level of cholesterol and because of this suitable as pharmaceuticals for the prevention and treatment of atherosclerosis.

Proposed according to the invention compounds are effective inhibitors of the cellular sodium-proton antiport (Na+/H+-exchange), subtype 1 and 3, which in the case of numerous diseases (essential hypertension, atherosclerosis, diabetes, and so on) also increased in these cells, which are easily accessible to measurements, such as, for example, in erythrocytes, is similar and simple scientific tools, for example, in their use as diagnostic tools to identify and differences in certain forms of hypertension, atherosclerosis, diabetes, proliferative diseases, etc. moreover, the compounds of formula (I) are suitable for prophylaxis to prevent the Genesis of high blood pressure, for example, essential hypertension.

In addition, it is shown that the compounds of formula (I) have a favorable impact on serum lipoproteins. It is recognized that the emergence arteriosclerotic changes of blood vessels, especially coronary heart disease, a significant risk factor are too high in fat components in the blood, the so-called hyperlipoproteinemias. For the prevention and regression of atherosclerotic changes so extreme importance to reduce high levels of lipoproteins in the serum. Along with a decrease in total serum cholesterol of particular importance is the decrease in the proportion of specific atherogenic lipid fractions that total cholesterol, particularly low density lipoprotein (LDL) and very low density lipoproteins (VLDL), as these lipid fractions predstavitev coronary heart disease. Accordingly, lipid-lowering means must be able not only to reduce total cholesterol, but also reduce in particular the fraction of LDL and VLDL cholesterol in serum. Now found that compounds of the formula (I) in respect of the impact on lipid levels in serum have therapeutically suitable effective properties. So, they significantly reduce the increased concentration of serum LDL and VLDL, which, for example, can be detected with the increased use of cholesterol-rich and lipid food or with pathological changes in metabolism, for example, in the case of genetically caused hyperlipidemia. Therefore, for the prevention and regression of atherosclerotic changes, you can use these connections because they exclude a causal risk factor. These diseases rank as not only the primary hyperlipidemia, but also known secondary hyperlipidemia, which are, for example, diabetes. Moreover, the compounds of formula (I) lead to a significant reduction of heart attacks caused by abnormalities of metabolism, and in particular to a significant decrease induced heart attack and its severity. Next, connect the STV. In connection with 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 coronary vascular spasm, atherogenesis and atherosclerosis, left ventricular hypertrophy and dilated cardiomyopathy, and thrombotic diseases.

These compounds therefore are used preferably for obtaining a medicinal product for the treatment of hypercholesterolemia; to obtain drugs for prevention of atherogenesis; to obtain drugs for prevention and treatment of atherosclerosis; to obtain drugs for prevention and treatment of diseases caused by high cholesterol levels; to obtain drugs for prevention and treatment of diseases caused by endothelial dysfunction; to obtain drugs for prevention and treatment of hypertension caused by atherosclerosis; to obtain drugs for prevention and treatment of thrombosis caused by atherosclerosis; to obtain drugs for prevention and treatment caused by hypercholesterolemia and endot the drug products for the prevention and treatment caused by hypercholesterolemia and endothelial dysfunction, cardiac hypertrophy and cardiomyopathy; to obtain drugs for prevention and treatment caused by hypercholesterolemia and endothelial dysfunction of the coronary vascular spasm and myocardial infarction; to obtain drugs for the treatment of these diseases in combination with substances that reduce blood pressure, preferably inhibitors of angiotensin converting enzymes (ACE) and receptor antagonists angiotensin, and the combination of the STUMP inhibitor of formula I with active compounds that decrease the level of fat components in the blood, preferably with inhibitor NMG - COA-reductase inhibitors (eg, lovastatin or pravastatin), the latter has a hypolipidemic effect and because of this increases the hypolipidemic properties of the STUMP inhibitor of formula (I), is a favorable combination with intensified action and a reduced amount of active substance.

The object of the invention is the use of inhibitors of the sodium-proton exchange of the formula (I) as a new kind of medicines in order to reduce the high level of fat components in the blood, as well as combinations of inhibitors of the sodium-proton exchange with drugs which lower cu is a group of formula (I), you can enter orally, parenterally, intravenously, rectally or by inhalation, with the preferred form of administration depends on the appropriate clinical picture of the disease. The compounds of formula (I) can be applied individually or together with galenovye auxiliary substances as in veterinary medicine and for the treatment of humans.

What excipients suitable for the desired pharmaceutical form, the specialist is known on the basis of his expert knowledge. Along with solvents, geleobrazovanie, the basics of suppositories, excipients for tablets and other carriers of active substances can be used, for example, antioxidants, dispersants, emulsifiers, antispyware, improves the taste of the ingredients, preservatives, agents, dissolution or dyes.

For orally applied dosage forms the active compound is mixed with suitable for this purpose additives, as carriers, stabilizers or inert diluents, and conventional methods transferred to suitable forms of applications, such as tablets, pills, capsules with the medicine, aqueous, alcoholic or oily solutions. As inert carriers can be used, for example ukurannya starch. You can cook either dry or moist granules. As carriers or solvents are used, for example, vegetable or animal oils as sunflower oil or cod-liver oil.

For subcutaneous or intravenous administration, the active compound in the desired case, along with the usual for this purpose substances as agents of dissolution, emulsifiers or other auxiliaries, transferred into a solution, suspension or emulsion. As the solvent used, for example, water, physiological sodium chloride solution or alcohols, such as ethanol, propanol, glycerin, along with them also solutions of sugars, as glucose or mannitol, or a mixture of these various solvents.

As the dosage form for use in the form of aerosols or sprays are suitable, for example, solutions, suspensions or emulsions of the active substances of the formula (I) in a pharmaceutically acceptable solvent, in particular ethanol or water, or in mixtures of such solvents.

Dosage form, depending on the needs, can also contain other pharmaceutical excipients, as surface-active agents, emulsifiers and the hundred is from 0.1 to 10, in particular from about 0.3 to 3 wt.%.

Dosage entered active substances of the formula (I) and the frequency of administration depend on the effectiveness and duration of action of the compounds used; additionally also on the nature and intensity of treatable disease, gender, age, weight and individual responsiveness treatable patient. The average daily dose of the compounds of formula (I) in the case of a patient weighing about 75 kg is at least 0.001 mg/kg, preferably 0.01 mg/kg up to 10 mg/kg, preferably 1 mg/kg of body weight. In acute outbreaks may also be necessary even higher and especially more frequent dosing, for example, up to four doses per day. Especially with intravenous administration, for example, in the case of patients with heart attack in the hospital, can require up to 200 mg per day.

List of abbreviations:

Meon - methanol

DMF - N,N-dimethylformamide

PI - electron impact

THE - desorption-chemical ionization

CT room temperature

HER - ethyl acetate (EtOAc)

so pl. - melting point NER - n-heptane

DME - dimethoxyethan

ER - e spray

FAB - bombing b>Deep - diisopropyl ether

Experimental part

General methods of obtaining guanidino alkenylboronic acids of the formula (I)

Option 1A: alkenylboronic acid (formula (II), L=IT)

1,0 EQ. carboxylic acid derivative of the formula (II) is dissolved or suspended in anhydrous THF (5 ml/mmol) and then mixed with 1.1 EQ. carbonyldiimidazole. After stirring for two hours at room temperature the reaction solution make 5,0 EQ. guanidine. After stirring over night THF is distilled off under reduced pressure (rotary evaporator), the residue is mixed with water, set the pH value from 6 to 7 with 2n. hydrochloric acid and filtered appropriate guanidin (formula (I)).

Thus, the obtained guanidine carboxylic acids by treatment with aqueous, methanolic or ethereal hydrochloric acid or other pharmacologically acceptable acids can be converted to the corresponding salt.

Option 1B: alilovic esters alkenylboronic acid (formula (II); L=O-alkyl)

1,0 EQ. Olkiluoto ether carboxylic acids of the formula (II), and 5.0 equiv. guanidine (free base) are dissolved in isopropanol or suspend the Yu thin-layer chromatography) (typical reaction time is from 2 to 5 hours). The solvent is distilled under reduced pressure (rotary evaporator), the residue is dissolved in ethyl acetate and washed three times with a solution of sodium bicarbonate. Dried over sodium sulfate, the solvent is distilled off in vacuum and the residue chromatographic on silica gel using a suitable eluting means, for example a mixture of ethyl acetate with methanol in the ratio of 5:1.

(Salt formation, see option a).

Example 1: 1,2-bis-[3-(guanidin E-2-methyl-propanolol acid)] benzene-dihydrochloride

< / BR>
1A): 1 EQ. teeterboro ether 2-phosphonopropionic acid at 0oWith deprotonated using 1 EQ. n-utility in hexane and then at room temperature is mixed with 0.5 EQ. dialdehyde 1,2-phthalic acid. After dialdehyde fully browseinterval, treated with water and shaken out three times with toluene. After drying the combined organic phases over magnesium sulfate the solvent is removed in vacuo and the remaining crude product chromatographic on silica gel using mixtures of ethyl acetate with heptane as the eluting means. Get 1,2-di-[3-(ethyl ester of S-2-methyl-propanolol acid)]benzene as a colourless oil;

mass spectrum (DHI): 303 (M+1+)

di-[3-(E-2-methyl-Papanova acid)]benzene as a colorless solid; so pl. above 187oC;

mass spectrum (DHI): 246 (M+)

1B): Dicarboxylic acid from stage 1B) for option 1A is transferred to biguanide-dihydrochloride; colourless solid; T. pl. above 200oC;

mass spectrum (DHI): 329 (M+l)+.

Example 2: 1,3-bis-[3-(guanidin E-2-methyl-propanolol acid)] benzene-dihydrochloride

< / BR>
2A): 1 EQ. teeterboro ether 2-phosphonopropionic acid at 0oWith deprotonated using 1 EQ. n-utility in hexane and then at room temperature is mixed with 0.5 EQ. dialdehyde 1,3-isophthalic acid. After dialdehyde fully browseinterval, treated with water and shaken out three times with toluene. After drying the combined organic phases over magnesium sulfate to remove the solvent in vacuo and the remaining crude product chromatography allocate on silica gel using mixtures of ethyl acetate with n-heptane as the eluting means. Obtain 1,3-di-[3-(ethyl ester of S-2-methyl-propanolol acid)]benzene; colorless oil; mass spectrum (DHI): 303 (M+1+).

2B); ester from stage 2A) omelet according to the standard method (sodium hydroxide in methanol). Obtain 1,3-di-[3-(E-2-methyl-Papanova acid)] benzene; bestelauto from stage 2B) under option 1A is transferred to biguanide-dihydrochloride; colorless solid; T. pl. 175oC; mass spectrum (DHI): 329 (M+l)+.

Example 3: 1,4-bis-[3-(guanidin E-2-methyl-Papanova acid)]benzene-dihydrochloride

< / BR>
3A): 1 EQ. teeterboro ether 2-phosphonopropionic acid at 0oWith deprotonated using 1 EQ. n-utility in hexane and then at room temperature is mixed with 0.5 EQ. dialdehyde 1,4-terephthalic acid. After dialdehyde fully browseinterval, treated with water and shaken out three times with toluene. After drying the combined organic phases over magnesium sulfate the solvent is removed in vacuo and the remaining crude product emit chromatography on silica gel using mixtures of ethyl acetate with n-heptane as the eluting means. Receive 1,4-di-[3-(ethyl ester of S-2-methyl-propanolol acid)] benzene; colourless solid; T. pl. 41oC; mass spectrum (DHI): 303 (M+1+).

3b): ester from stage 3A) omelet according to the standard method (sodium hydroxide in methanol). Receive 1,4-di-[3-(E-2-methyl-Papanova acid)]benzene; colourless solid; T. pl. above 190oC;

mass spectrum (DHI): 247 (M+1+).

3b): Dicarboxylic acid from stage 3b) coz the P CLASS="ptx2">

Example 4: 2,3-bis-[3-(guanidin E-2-methyl-propanolol acid)]naphthalene-dihydrochloride

< / BR>
4A): 1 EQ. teeterboro ether 2-phosphonopropionic acid at 0oWith deprotonated using 1 EQ. n-utility in hexane and then at room temperature is mixed with 0.5 EQ. 2,3-naphthalimide. After dialdehyde fully browseinterval, treated with water and shaken out three times with toluene. After drying the combined organic phases over magnesium sulfate the solvent is removed in vacuo and the remaining crude product emit chromatography on silica gel using mixtures of ethyl acetate with n-heptane as the eluting means. Receive 2,3-di-[3-(ethyl ester of S-2-methyl-propanolol acid)]naphthalene; colorless oil; mass spectrum (DHI): 353 (M+1+).

4B): ester from stage 4A) omelet according to the standard method (sodium hydroxide in methanol). Receive 2,3-di-[3-(E-2-methyl-Papanova acid)]naphthalene; colourless solid; T. pl. above 210oC;

mass spectrum (DHI): 295 (M-N)-.

4B): Dicarboxylic acid from stage 4B) under option 1A is transferred to biguanide-dihydrochloride; colourless solid; T. pl. above 200oC; mass spectrum (/BR>< / BR>
5A): the Following are known from the literature method (Cousseau, etc., Tetrahedron Letters, 34, 6903 (1993)) and on the basis of dialdehyde 1,2-phthalic acid, receive 1,2-di-[3-(ethyl ester of Z-2-fluoro-propanolol acid)]benzene, which is purified on silica gel using mixtures of ethyl acetate with n-heptane as the eluting means and produce a colorless solid, amorphous; mass spectrum (DHI): 311 (M+1)+.

5B): Complex fluids from the stage 5A) under option 1B into biguanide and transferred to the dihydrochloride.

So pl. above 235oC;

mass spectrum (DHI): 337 (M+l)+.

Example 6: 1-[3-(guanidin Z-2-fluoro-propanolol acid)]-2-[3-(guanidin E-2-methyl-propanolol acid)]benzene-dihydrochloride

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6A): allocated when the connection is obtained according to example 7a) complex monoether-monoallelic 6A) as specified in example 4A) the method of transfer in complex fluids formula 6b):

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6b): Complex fluids from the stage 6b) under option 1B into biguanide and transferred to the dihydrochloride; so pl. above 200oC; mass spectrum (electron spray (ES)): 333 (M+1)+.

Example 7: 1,3-bis-[3-(guanidin Z-2-fluoro-propanolol acid)]benzene-dihydrochloride

< / BR>
7a): Following known ucaut 1,3-di-[3-(ethyl ester of Z-2-fluoro-propanolol acid)]benzene, which is purified on silica gel using mixtures of ethyl acetate with n-heptane as the eluting means and produce a colorless solid, amorphous; mass spectrum (S1): 311 (M+l)+.

7b): Complex fluids from the stage 7a) under option 1B into biguanide and transferred to the dihydrochloride, painted in orange-yellow solid. So pl. above 180oC; mass spectrum (ES): 337 (M+1)+.

Example 8: Guanidin 3-(4-chloro-3-guanidiniocarbonyl-5-phenyl)phenyl-2-methyl-propanolol acid

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8A): 3-bromo-2-chloro-5-methyl-benzoic acid

25 g of 2-amino-3-bromo-5-methyl-benzoic acid are dissolved in 500 ml of 6 N. of an aqueous solution of hydrogen chloride, mixed at 0oWith from 8.25 g of sodium nitrite and diasterous for 30 minutes at this temperature. This solution of the diazonium salts are then added dropwise to the heated to 40oTo a solution of 22 g of copper chloride (I) in 200 ml of a saturated aqueous solution of hydrogen chloride and optionally stirred for 20 minutes at this temperature. The product is filtered under vacuum, washed with 500 ml of water and dried at 40oWith in high vacuum. Obtain 23.3 g of white crystals; so pl. = 170-172oC; Rf (ethyl acetate with methanol in the ratio 5:1) or=0.51; the p-5-methyl-benzoic acid are dissolved in 150 ml of chlorobenzene and heated to the boiling temperature under reflux. At this temperature, add first, 7.2 g of N-bromosuccinimide and 0.5 g of benzoyl peroxide and refluxed for 30 minutes. Then the second time added 7.2 g of N-bromosuccinimide and 0.5 g of benzoyl peroxide and refluxed 3 hours. After cooling, add 200 ml of ethyl acetate, washed with 50 ml saturated aqueous solution of sodium sulfite and 300 ml of a saturated aqueous solution of potassium dihydrophosphate and the aqueous phase is extracted with twice 200 ml of ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed in vacuum. Obtain 14.1 g of a yellow oil. Rf (DIP/2% acetic acid)=0,32.

8b): 3-bromo-2-chloro-5-formyl-benzoic acid

of 11.7 g of silver nitrate dissolved in 150 ml of water and 150 ml of methanol and added dropwise a solution of 14 g of 3-bromo-2-chloro-5-dibromomethyl-benzoic acid in 100 ml of methanol. Additionally stirred for 30 minutes at room temperature, add 100 ml of a saturated aqueous solution of sodium chloride, filtered off under vacuum of silver salts and the solvents removed in vacuo. The residue is treated with 200 ml of 5% aqueous solution KHS4and extracted with three times 200 ml of ethyl acetate. Dried over sodium sulfate and supplies crystals, so pl. 148oC; Rf (DIP/2% acetic acid)=0,12; mass spectrum (DHI): 263 (M+N)+.

8D): Ethyl ester of 3-bromo-2-chloro-5-formyl-benzoic acid

3.6 g of 3-bromo-2-chloro-5-formyl-benzoic acid are dissolved in 100 ml of ethanol was added dropwise to 2.9 ml of thionyl chloride SOCl2and refluxed for 5 hours. Then in vacuum to remove volatile components and the remainder chromatographic on silica gel using mixtures of ethyl acetate with n-heptane in the ratio of 1:8. Obtain 2.7 g of colorless oil. Rf (ethyl acetate with n-heptane in the ratio 1:8)=0,24; mass spectrum (DHI): 291 (M+N)+.

8E): Ethyl ester of 3-(3-bromo-4-chloro-5-etoxycarbonyl)phenyl-2-methyl-propanolol acid

2.7 g of ethyl ester of 3-bromo-2-chloro-5-formyl-benzoic acid analogously to the method of example 4A) is subjected to reaction the Wittig-Horner and obtain 3.4 g of colorless oil. Rf (ethyl acetate with n-heptane in the ratio 1:8)=0,27; mass spectrum (DHI): 374 (M+N)+.

8E) Ethyl ester of 3-(4-chloro-3-etoxycarbonyl-5-phenyl)phenyl-2-methyl-propanolol acid

3,3 g of ethyl ester of 3-(3-bromo-4-chloro-5-ethoxy-carbonyl)phenyl-2-methyl-propanolol acid, of 1.23 g of phenylboric acid, 2.14 g of sodium carbonate, 576 mg of triphenylphosphine and 227 mg of palladium acetate Pd(OAc)2Raut to room temperature, mixed with 200 ml of ethyl acetate and washed twice with 100 ml of saturated aqueous sodium carbonate solution and with 100 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate and the solvent is removed in vacuum. Chromatography on silica gel using mixtures of ethyl acetate with n-heptane in the ratio of 1:8 gives 800 mg of colorless oil. Rf (ethyl acetate with n-heptane in the ratio 1:8)=0,25;

mass spectrum (DHI): 372 (M+H)+.

G): Guanidin 3-(4-chloro-3-guanidiniocarbonyl-5-phenyl)phenyl-2-methyl-propanolol acid

1.8 g of tert. -butyl potassium dissolved in 100 ml of DMF, add 1,82 g of guanidine hydrochloride and stirred for one hour at room temperature. Then add 700 mg of ethyl ester of 3-(4-chloro-3-etoxycarbonyl-5-phenyl)phenyl-2-methyl-propanolol acid and stirred for 5 hours at 100oC. the Reaction mixture is poured into 200 ml of water and extracted with three times 200 ml of ethyl acetate. The extract is dried over sodium sulfate and the solvent is removed in vacuum. Chromatography on silica gel using a mixture of acetone with water at a ratio of 10:1 gives 170 mg of an amorphous foam. Rf (acetone with water in the ratio 10:1)=0,23;

mass spectrum (fast atom bombardment (FAB))% 399 (M+N)+.

When teeterboro ether 2-phosphonopropionic acid at 0oWith deprotonated using 1 EQ. n-utility in hexane and then at room temperature is mixed with 0.5 EQ. level 2-methoxy-5-methyl-1,3-isophthalic acid. After dialdehyde fully browseinterval, treated with water and shaken out three times with toluene. After drying the combined organic phases over magnesium sulfate to remove the solvent in vacuo and the remaining crude product chromatography allocate on silica gel using mixtures of ethyl acetate with n-heptane as the eluting means. Obtain 1,3-di-[3-(ethyl ester of S-2-methyl-propanolol acid)]-2-methoxy-5-methyl-benzene; colorless oil; mass spectrum (S1): 347 (M+1+).

9b): Complex fluids from the stage 9a) omelet according to the standard method (sodium hydroxide in methanol). Obtain 1,3-di-[3-(E-2-methyl-Papanova acid)] -2-methoxy-5-methyl-benzene; colourless solid; T. pl. 196oC; mass spectrum (DHI): 290 (M+).

9b): Dicarboxylic acid from stage 9b) under option 1A is transferred to biguanide and was isolated as hydrochloride; colourless solid; T. pl. 279oC; mass spectrum (NBA): 373 (M+l)+.

Example 10: 1,2-bis-[3-(guanidin E-2-methyl-propanolol acid)]-4-methyl-benzene-di is making use of sociallyengaged) transferred to diol 10A). Then the alcohol is oxidized under standard conditions to dialdehyde 10B) (e.g., oxidation by Turn).

Diol 10A): colorless oil;

mass spectrum (DHI): 153 (M+1+) and 135 (M+1 - N2O).

Dialdehyde 10B): dark colored oil;

mass spectrum (S1): 149 (M+1+).

10V): 1 EQ. teeterboro ether 2-phosphonopropionic acid at 0oWith deprotonated using 1 EQ. n-utility in hexane and then at room temperature is mixed with 0.5 EQ. dialdehyde 4-methyl-1,2-phthalic acid 10B). After dialdehyde fully browseinterval, treated with water and shaken out three times with toluene. After drying the combined organic phases over magnesium sulfate the solvent is removed in vacuo and the remaining crude product emit chromatography on silica gel using mixtures of ethyl acetate with n-heptane as the eluting means. Get 4-methyl-1,2-di-[3-(ethyl ester of S-2-methyl-propanolol acid)] benzene. Colorless oil; mass spectrum (S1): 317 (M+1+).

10g): ester from stage 10B) omelet according to the standard method (sodium hydroxide in methanol). Get 4-methyl-1,2-di-[3-(E-2-methyl-Papanova acid)]benzene; colourless solid; T. pl. 194-198
so pl. 190oC;

mass spectrum (ES): 342 (M+l)+.

Example 11: 1,2-bis-[3-(guanidin E-2-methyl-propanolol acid)]-4,5-dichlorobenzene-dihydrochloride

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11a, b): Diethyl ether 4,5-dichlorphenol acid according to the standard method (e.g., repair using sociallyengaged) transferred to diol 11a). Then the alcohol is oxidized under standard conditions to dialdehyde 11b) (e.g., oxidation by Turn).

Diol 11a): colourless solid; T. pl. 147oC;

mass spectrum (S1): 207 (M+1+).

Dialdehyde 11b): amorphous solid;

mass spectrum (S1): 203 (M+1+).

11b): 1 EQ. teeterboro ether 2-phosphonopropionic acid at 0oWith deprotonated using 1 EQ. n-utility in hexane and then at room temperature is mixed with 0.5 EQ. dialdehyde 4,5-dichloro-1,2-phthalic acid 11b). After dialdehyde fully browseinterval, treated with water and shaken out three times with toluene. After drying the combined organic phases over magnesium sulfate the solvent is removed in vacuo and the remaining crude product emit chromatography on silica gel using mixtures of ethyl acetate with n-Ansol; colorless solid;

so pl. above 230oC;

mass spectrum (S1): 371 (M+1+).

11g): Complex fluids from the stage 11b) under option 1B is switched to biguanide-dihydrochloride; colourless solid;

so pl. above 220oC;

mass spectrum (ES): 397 (M+1)+.

Example 12: 1,3-bis-[3-(guanidin E-propanolol acid)]benzene-dihydrochloride

< / BR>
12A): 1 EQ. triethylphosphate at 0oWith deprotonated using 1 EQ. n-utility in hexane and then mixed with 0.5 EQ. dialdehyde 1,3-isophthalic acid at room temperature. After dialdehyde fully browseinterval, treated with water and shaken out three times with toluene. After drying the combined organic phases over magnesium sulfate the solvent is removed in vacuo and the remaining crude product emit chromatography on silica gel using mixtures of ethyl acetate with n-heptane as the eluting means. Obtain 1,3-di-[3-(ethyl ester E-propanolol acid)]benzene; colorless oil;

mass spectrum (S1): 275 (M+1+).

12B): Complex fluids from the stage 12A) omelet according to the standard method (sodium hydroxide in methanol). Obtain 1,3-di-[3-(E-Papanova acid)] basarbovo acid from stage 12B) under option 1A is transferred to biguanide-dihydrochloride;

colorless solid; T. pl. 296oC;

mass spectrum (ES): 301 (M+1)+.

Example 13: 1,2-bis-[3-(guanidin E-2-methyl-propanolol acid)] - 4-Brabanthal-dihydrochloride

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13A, b): Dimethyl ester of 4-promptlabel acid according to the standard method (e.g., repair using sociallyengaged) transferred to diol 13A). Then the alcohol is oxidized under standard conditions to dialdehyde 13B) (e.g., oxidation by Turn).

Diol 13A): colorless oil;

mass spectrum (DHI): 217 (M+l+) and 199 (M+1-N2O).

Dialdehyde 13B): amorphous solid;

mass spectrum (S1): 213 (M+l+).

13B): 1 EQ. teeterboro ether 2-phosphonopropionic acid at 0oWith deprotonated using 1 EQ. n-utility in hexane and then at room temperature is mixed with 0.5 EQ. dialdehyde 4-bromo-1,2-phthalic acid 13B). After dialdehyde fully browseinterval, treated with water and shaken out three times with toluene. After drying the combined organic phases over magnesium sulfate the solvent is removed in vacuo and the remaining crude product emit chromatography on silica gel using mixtures of ethyl acetate with n-heptane as a researcher is ing oil;

mass spectrum (S1): 381 (M+1+).

13G): ester from stage 13B) omelet according to the standard method (sodium hydroxide in methanol). Get 4-bromo-1,2-di-[3-(E-2-methyl-Papanova acid)]benzene; colorless amorphous substance;

mass spectrum (ES): 325 (M+1+).

D): Dicarboxylic acid from stage 13G) under option 1A is transferred to biguanide-dihydrochloride; colourless solid;

so pl. 240oC;

mass spectrum (NBA): 407 (M+1)+.

Example 14: 1,2-bis-[3-(guanidin E-2-methyl-propanolol acid)]-4-(4-methoxyphenoxy)-benzene-dihydrochloride

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14a): By analogy with the known from the literature (J. Org.Chem., 42, 21, 3419-3425 (1977)) dimethyl ether 4-nitrophthalic acid in dimethylformamide enter into interaction with 4-methoxypropanol sodium obtaining dimethyl ester of 4-(4-methoxyphenoxy)phthalic acid. After standard processing and chromatography using a mixture of hexane with ethyl acetate receive complex fluids in the form of a brownish oil;

mass spectrum (S1): 316 (M+); 317 (M+l+).

14b, C): Complex fluids from the stage 14a) according to standard method (e.g., repair using sociallyengaged) transferred to diol 14b). Then the alcohol is lo; mass spectrum (S1): 260 (M+).

Dialdehyde 14C): brown oil;

mass spectrum (S1): 257 (M+1+).

14g): 1 EQ. teeterboro ether 2-phosphonopropionic acid at 0oWith deprotonated using 1 EQ. n-utility in hexane and then at room temperature is mixed with 0.5 EQ. dialdehyde 1,2-phthalic acid 14C). After dialdehyde fully browseinterval, treated with water and shaken out three times with toluene. After drying the combined organic phases over magnesium sulfate the solvent is removed in vacuo and the remaining crude product emit chromatography on silica gel using mixtures of ethyl acetate with n-heptane as the eluting means. Get 1,2-di-[3-(ethyl ester of S-2-methyl-propanolol acid)]-4-(4-methoxyphenoxy)benzene; slightly brownish oil; mass spectrum (NBA): 424 (M+).

D): Complex fluids from the stage 14g) omelet according to the standard method (sodium hydroxide in methanol). Get 1,2-di-[3-(E-2-methyl-Papanova acid)]-4-(4-methoxyphenoxy)benzene; solid light yellow color; so pl. 112oC;

mass spectrum (electron spray): 368 (M+).

14): Dicarboxylic acid from stage d) according to the war (ES): 451 (M+1)+.

Example 15: 1,2-bis-[3-(guanidin E-2-methyl-propanolol acid)]-4-(4-methylphenoxy)-benzene-dihydrochloride

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15A): Dimethyl ether 4-nitrophthalic acid by analogy with the known from the literature (J. Org.Chem., 42, 21, 3419-3425 (1977)) in dimethylformamide enter into interaction with 4-metilfenidato sodium obtaining dimethyl ester of 4-(4-methylphenoxy)phthalic acid. After standard processing and chromatography using a mixture of hexane with ethyl acetate receive complex fluids in the form of a yellowish oil.

Mass spectrum (S1): 301 (M+1+).

15B, C); Complex fluids from the stage 15A) according to standard method (e.g., repair using sociallyengaged) transferred to diol 15B). Then the alcohol is oxidized under standard conditions to dialdehyde 15V) (e.g., oxidation by Turn).

Diol 15B): yellowish oil;

mass spectrum (S1): 244 (M+); 245 (M+1+).

Dialdehyde 15V): brown oil;

mass spectrum (S1): 241 (M+1+).

15g): 1 EQ. teeterboro ether 2-phosphonopropionic acid at 0oWith deprotonated using 1 EQ. n-utility in hexane and then at room temperature is mixed with 0.5 EQ. dialdehyde 1,2-phthalic acid 15V). Th is Le drying the combined organic phases over magnesium sulfate the solvent is removed in vacuo and the remaining crude product emit chromatography on silica gel using mixtures of ethyl acetate with n-heptane as the eluting means. Get 1,2-di-[3-(ethyl ester of S-2-methyl-propanolol acid)]-4-(4-methylphenoxy)benzene;

slightly brownish oil;

mass spectrum (NBA): 408 (M+); 409 (M+1+).

D): Complex fluids from the stage 15g) omelet according to the standard method (sodium hydroxide in methanol). Get 1,2-di-[3-(E-2-methyl-Papanova acid)]-4-(4-methylphenoxy)benzene;

colorless solid; T. pl. 185oC;

mass spectrum (NBA): 352 (M+).

15th): Dicarboxylic acid from stage d) under option 1A is transferred to biguanide-dihydrochloride;

colorless solid; T. pl. 186oC;

mass spectrum (ES): 435 (M+1)+.

Example 16: 1,3-Bis-[3-(guanidin E-2-methyl-propanolol acid)]- 5-methoxybenzoyl hydrochloride

< / BR>
16A); 1 EQ. teeterboro ether 2-phosphonopropionic acid at 0oWith deprotonated using 1 EQ. n-utility in hexane and then at room temperature is mixed with 0.5 EQ. dialdehyde 5-methoxy-1,3-isophthalic acid. After dialdehyde fully browseinterval, treated with water and shaken out three times with toluene. After drying the combined organic phases over magnesium sulfate the solvent is removed in vacuo and the remaining crude prego funds. Obtain 1,3-di-[3-(ethyl ester of S-2-methyl-propanolol acid)]-5-methoxybenzoyl;

mass spectrum (S1): 333 (M+l+).

16B): Complex fluids from the stage 16A) omelet according to the standard method (sodium hydroxide in methanol). Obtain 1,3-di-[3-(E-2-methyl-Papanova acid)]-5-methoxybenzoyl;

colorless solid;

so pl. above 200oC;

mass spectrum (DHI): 276 (M+).

16B): Dicarboxylic acid from stage 16B) under option 1A is transferred to biguanide and was isolated as hydrochloride;

colorless solid:

so pl. 124oC.

mass spectrum (NBA): 359 (M+1)+.

Example 17: 1,3-bis-[3-(guanidin E-2-methyl-propanolol acid)]-5-tert. -butylbenzoyl hydrochloride

< / BR>
17A): 1 EQ. teeterboro ether 2-phosphonopropionic acid at 0oWith deprotonated using 1 EQ. n-utility in hexane and then at room temperature is mixed with 0.5 EQ. dialdehyde 5-tert.-butyl-1,3-isophthalic acid. After dialdehyde fully browseinterval, treated with water and shaken out three times with toluene. After drying the combined organic phases over magnesium sulfate the solvent is removed in vacuo and the remaining crude product widely. Obtain 1,3-di-[3-(ethyl ester of S-2-methyl-propanolol acid)] -5-methoxybenzoyl; colorless oil;

mass spectrum (S1): 359 (M+1+).

17B): Complex fluids from the stage 17A) omelet according to the standard method (sodium hydroxide in methanol). Obtain 1,3-di-[3-(E-2-methyl-Papanova acid)]-5-tert.butylbenzoyl; colourless solid;

so pl. above 200oC;

mass spectrum (DHI): 302 (M+).

17B): Dicarboxylic acid from stage 17B) under option 1A is transferred to biguanide and was isolated as hydrochloride; colourless solid;

so pl. 115oC;

mass spectrum (NBA): 385 (M+1)+.

Example 18: 1,4-bis-[3-(guanidin E-2-methyl-propanolol acid)]-2,5-dichloro-benzene-dihydrochloride

< / BR>
18a): 1 EQ. teeterboro ether 2-phosphonopropionic acid at 0oWith deprotonated using 1 EQ. n-utility in hexane and then at room temperature is mixed with 0.5 EQ. dialdehyde 1,4-(2,5-dichloro)terephthalic acid. After dialdehyde fully browseinterval, treated with water and shaken out three times with toluene. After drying the combined organic phases over magnesium sulfate the solvent is removed in vacuo and the remaining crude product videla. Receive 1,4-di-[3-(ethyl ester of S-2-methyl-propanolol acid)3-2,5-dichloro-benzene;

colourless solid, amorphous;

mass spectrum (DHI): 371 (M+l+).

18b): ester from stage 18a) omelet according to the standard method (sodium hydroxide in methanol). Receive 1,4-di-[3-(E-2-methyl-Papanova acid)]-2,5-dichlorobenzene;

colorless solid;

mass spectrum (DHI): 315 (M+1+).

18V): Dicarboxylic acid from stage 18b) under option 1A is transferred to biguanide-dihydrochloride; solid yellow; so pl. above 200oC;

mass spectrum (DHI): 397 (M+1)+.

Example 19: 1,2-bis-[3-(guanidin E-2-methyl-propanolol acid)] -4-(phenoxy)-benzene-dihydrochloride

< / BR>
19a): By analogy with the known from the literature (J. Org.Chem., 42, 21, 3419-3425 (1977)) dimethyl ether 4-nitrophthalic acid in DMF enter into interaction with the sodium phenolate with obtaining dimethyl ether 4-phenoxethanol acid. After standard processing and chromatography using a mixture of hexane with ethyl acetate receive complex fluids in the form of a yellowish oil.

Mass spectrum (S1): 287 (M+1+).

19b, C): Complex fluids from the stage 19a) according to standard method (n the conditions to dialdehyde 19c) (for example, oxidation by Turn).

Diol 19b): yellowish oil;

mass spectrum (S1): 230 (M+), 231 (M+l+).

Dialdehyde 19c): brown oil;

mass spectrum (S1): 227 (M+1+).

19g): 1 EQ. teeterboro ether 2-phosphonopropionic acid at 0oWith deprotonated using 1 EQ. n-utility in hexane and then at room temperature is mixed with 0.5 EQ. dialdehyde 1,2-phthalic acid 19c). After dialdehyde fully browseinterval, treated with water and shaken out three times with toluene. After drying the combined organic phases over magnesium sulfate the solvent is removed in vacuo and the remaining crude product emit chromatography on silica gel using mixtures of ethyl acetate with n-heptane as the eluting means. Get 1,2-di-[3-(ethyl ester of S-2-methyl-propanolol acid) 3-4-(phenoxy)benzene;

slightly brownish oil;

mass spectrum (NBA): 394 (M+), 395 (M+l+).

19D): Complex fluids from the stage 19g) omelet according to the standard method (sodium hydroxide in methanol). Get 1,2-di-[3-(E-2-methyl-Papanova acid)]-4-(phenoxy)benzene;

colorless solid; T. pl. 160oC;

mass spectrum (NBA): 338 (M+).
colorless solid; T. pl. 170oC;

mass spectrum (ES): 421 (M+1)+.

Example 20: 1,2-bis-[3-(guanidin E-2-methyl-propanolol acid)] -4-(methoxy)benzene-dihydrochloride

< / BR>
According to the method of example 19 compound of example 20 is obtained by nucleophilic aromatic substitution, ester 4-nitrophthalic acid using sodium methylate, followed by reaction of the reduction/oxidation/education double bond (referirovanija, saponification and guanidine decollate.

20A): W 4-methoxyflavone acid; mass spectrum (S1): 225 (M+1+).

20B): Diol: brownish-yellow oil; mass spectrum (S1): 169 (M+1+).

20V): Dialdehyde: dark oil; mass spectrum (S1): 165 (M+1+).

20g): Complex fluids: dark oil; mass spectrum (NBA): 333 (M+l+).

D): 1,2-di-[3-(E-2-methyl-Papanova acid)]-4-(methoxy) benzene: colourless solid; T. pl. above 200oC; mass spectrum (NBA): 276 (M+).

20E): Dicarboxylic acid from stage d) under option 1A is transferred to biguanide-dihydrochloride;

colorless solid; T. pl. 170oC;

mass spectrum (ES): 359 (M+1)+.

Example 21: 1,2-bis-[3-(guanidin E-2-methyl-propanolol whom atilirovanie 4-hydroxyphthalic acid with 3,5 EQ. ethyliodide and 3.1 EQ. potassium carbonate in DMF at 70oC. Then by the reaction of reduction/oxidation/education double bond (referirovanija) get complex fluids, which for option 1B is switched to biguanide (21).

21A): Diethyl ether 4-ethoxypropanol acid: dark oil; mass spectrum (S1): 267 (M+1+".

21B): Diol: brownish-yellow oil; mass spectrum (S1): 183 (M+1+).

21B): Dialdehyde: dark oil; mass spectrum (S1): 179 (M+1+).

21G): Complex fluids: yellowish oil; mass spectrum (NBA): 347 (M+l+).

E): Complex fluids from the stage 21 g) under option 1B is switched to biguanide-dihydrochloride;

colorless solid; T. pl. 245oC;

mass spectrum (ES): 373 (M+l)+.

Example 22: 1,2-bis-[3-(guanidin E-2-methyl-propanolol acid)]-4-(3-pyridyloxy)-benzene-dihydrochloride

< / BR>
22A): By analogy with the known from the literature (J. Org.Chem., 42, 21, 3419-3425 (1977)) dimethyl ether 4-nitrophthalic acid in DMF enter into interaction with the sodium salt of 3-hydroxypyridine upon receipt of dimethyl ester of 4-(3-pyridyloxy)phthalic acid. After standard processing and chromatography using a mixture of hexane to ethyl acetate of widely the Hai 22A) according to standard method (e.g., a repair using sociallyengaged) transferred to diol 22b). Then the alcohol is oxidized under standard conditions to dialdehyde 22V) (e.g., oxidation by Turn).

Diol 226): yellowish oil;

mass spectrum: 232 (M+1+).

Dialdehyde 22V): brownish-yellow oil;

mass spectrum: 228 (M+1+).

22g): 1 EQ. teeterboro ether 2-phosphonopropionic acid at 0oWith deprotonated using 1 EQ. n-utility in hexane and then at room temperature is mixed with 0.5 EQ. dialdehyde 1,2-phthalic acid 22V). After dialdehyde fully browseinterval, treated with water and shaken out three times with toluene. After drying the combined organic phases over magnesium sulfate the solvent is removed in vacuo and the remaining crude product emit chromatography on silica gel using mixtures of ethyl acetate with n-heptane as the eluting means. Get 1,2-di-[3-(ethyl ester of S-2-methyl-propanolol acid)]-4-(3-pyridyloxy)benzene in the form of a slightly brownish oil;

mass spectrum: 396 (M+1+).

D): Complex fluids from the stage 22g) omelet according to the standard method (sodium hydroxide in methanol). Get 1,2-di-[3-(E-2-methyl-prop is 9 (M+).

22E): Dicarboxylic acid from stage d) under option 1A is transferred to biguanide-dihydrochloride;

colorless solid; T. pl. 176oC;

mass spectrum: 422 (M+l)+.

Example 23: 1,2-bis-[3-(guanidin E-2-methyl-propanolol acid)]-4-[4-(2-dimethylaminoethyl)phenoxy]-benzene-dihydrochloride

< / BR>
23a): By analogy with the known from the literature (J. Org.Chem., 42, 21, 3419-3425 (1977)) dimethyl ether 4-nitrophthalic acid in DMF enter into interaction with 4-(2-dimethylaminoethyl)phenolate sodium in obtaining dimethyl ester 4-[4-(2-dimethylaminoethyl)phenoxy] phthalic acid. After standard processing and chromatography using a mixture of hexane with ethyl acetate to produce complex fluids.

23B, C): Complex fluids from the stage 23a) according to standard method (e.g., repair using sociallyengaged) transferred to diol 236). Then the alcohol is oxidized by dess-Martin (see oxidation on dess-Martin: JOC, 59, 7549-7552 (1994)) to dialdehyde 23C).

Diol 23B): brown-yellow oil; mass spectrum: 340 (M+1+).

Dialdehyde 23C): yellow oil; mass spectrum: 269 (M+l+).

23gr): 1 EQ. teeterboro ether 2-phosphonopropionic acid at 0oFrom aldehide 1,2-phthalic acid 23C). After dialdehyde fully browseinterval, treated with water and shaken out three times with toluene. After drying the combined organic phases over magnesium sulfate the solvent is removed in vacuo and the remaining crude product emit chromatography on silica gel using mixtures of ethyl acetate with n-heptane as the eluting means. Get 1,2-bis-[3-(ethyl ester of S-2-methyl-propanolol acid)] -4-[4-(2-dimethylaminoethyl)phenoxy]benzene; yellowish oil;

mass spectrum: 466 (M+1+).

D): Complex fluids from the stage 23gr) omelet according to the standard method (sodium hydroxide in methanol). Get 1,2-bis[3-(E-2-methyl-Papanova acid)]-4-[4-(2-dimethylaminoethyl) phenoxy]benzene;

colorless solid; T. pl. above 220oC;

mass spectrum: 409 (M+).

23rd): Dicarboxylic acid from stage d) under option 1A is transferred to biguanide-dihydrochloride;

mass spectrum: 410 (M+1)+.

Examples 24 and 25: 1,2-bis-[3-(guanidin E-2-methyl-propanolol acid)]-4-[methoxybenzyloxy] benzene-dihydrochloride and 1,2-bis-[3-(guanidin E-2-methyl-propanolol acid)]-4-hydroxybenzoyl-dihydrochloride

< / BR>
24A): 1 EQ. dimethyl ether 4-hydroxyphthalic th temperature. After 4 days, the process according to the standard method. Get the dimethyl ester of 4-(4-methoxybenzyloxy)phthalic acid as a colourless oil;

mass spectrum: 331 (M+1+).

24B, C): Complex fluids from the stage 24A) according to standard method (recovery using sociallyengaged) transferred to diol 24B). Then the alcohol is oxidized according to the standard method (oxidation by Turn) to dialdehyde 24V).

Diol 24B): amorphous solid;

mass spectrum: 275 (M+1+).

Dialdehyde 24V): yellowish oil;

mass spectrum: 271 (M+1+).

24g): 1 EQ. teeterboro ether 2-phosphonopropionic acid at 0oWith deprotonated using 1 EQ. n-utility in hexane and then at room temperature is mixed with dialdehyde 1,2-phthalic acid 24V). After dialdehyde fully browseinterval, treated with water and shaken out three times with toluene. After drying the combined organic phases over magnesium sulfate the solvent is removed in vacuo and the remaining crude product emit chromatography on silica gel using mixtures of ethyl acetate with n-heptane as the eluting means. Get 1,2-bis-[3-(methyl ether E-2-methyl

24D): Complex fluids from the stage 24g) omelet according to the standard method (sodium hydroxide in methanol). Get 1,2-bis-[3-(E-2-methyl-Papanova acid)] -4-(4-methoxybenzyloxy)benzene as colorless solids; so pl. 206-220oC;

mass spectrum: 382 (M+).

24th): Dicarboxylic acid from stage 24D) under option 1A is transferred to biguanide-dihydrochloride;

so pl. 210oC; mass spectrum: 465 (M+1)+.

Example 25: 1,2-bis-[3-(guanidin E-2-methyl-propanolol acid)]-4-hydroxybenzoyl-dihydrochloride

Dicarboxylic acid of example 24D) under option 1A is converted into biguanide-dihydrochloride. In addition to the compound of example 24 secrete the product of example 25;

mass spectrum: 345 (M+l)+.

Pharmacological data

Inhibitors of Na+/H+-exchange in erythrocytes of rabbit (subtype 1; NHE-1)

White new Zealand rabbits (Ivanovas) receive standard food with 2% cholesterol for six weeks in order to activate Na+/H+- currency and thus can be determined by flame photometry influx of sodium ions in erythrocytes through PA+/N+-currency. Take away the blood from the ear artery and give it incoagulability with 25m centrifugation. Aliquots, each 100 μl, are used to determine the initial content of sodium ions in the blood.

In order to determine sensitive to amiloride influx of sodium, 100 μl of each blood samples respectively in 5 ml of a hyperosmolar environment salt-sucrose (140 mmol/l NaCl, 3 mmol/l potassium chloride, 150 mmol/l sucrose, 0.1 mmol/l ouabain, 20 mmol/l Tris-hydroxyethylaminomethyl) incubated at pH 7.4 and temperature 37oC. the Erythrocytes then thrice washed with ice with a solution ouabain with magnesium chloride (112 mmol/l magnesium chloride; 0.1 mmol/l ouabain) and hemolyzed in 2.0 ml of distilled water. Intracellular sodium was determined by flame photometry.

The net inflow of sodium ions calculated from the difference between the original amounts of sodium and sodium content of the erythrocytes after incubation. Inhibiting amiloride influx of sodium is obtained from the difference of sodium in erythrocytes after incubation without amiloride and amiloride at a concentration of 10-4mol/L. doing So as in the case of proposed according to the invention compounds.

Results inhibition PA+/H+-exchange (subtype 1; NHE-1):

Example (see ex the method, presented in: "Modern methods in molecular biology" (ed. Ausubel F. M., Brent R., Kingston R. E., Moore D. D., Seldman J. G., Smith J. A., Struhe K.; John Wiley and Sons), respectively, "Molecular cloning: a laboratory manual (Sambrock, J. , Fritsch E. F., Maniatis T.; Cold Spring Harbor Laboratory Press (1989))". In the framework of the authors received consistently transfetsirovannyh cell line, which Express one of the following STUMP-subtypes: NHE-1 person (Sardet and others , Cell 56, 271-280 (1989)); NHE-2 rabbit (Tse and others, J. Biol. Chem., 268, 11917-11924 (1993)), accordingly, NHE-3 rats (Orlowski and others, J. Biol. Chem., 267, 9331-9339 (19992)).

Received Professor Pouyssegur cDNA clones corresponding STUMP-subtypes after attaching a suitable linker sequences thus clone in expressing plasmid rampao (receive, for example, through CLONTECH, Heidelberg), which identified NHE-1 sequence of the plasmid is approximately 20-100 base pairs is before the starting codon of the corresponding NHE-subtype and all the coding sequence is in construction.

With the help of the so-called "calcium phosphate method (described in Chapter 9.1 "Modern methods in molecular biology) cell line with a deficit NHE LAP-1 (Franchi and others, Proc. Natl. Acad. Scl. USA, and NHE-subtypes. After selection of transfected cells after cultivation in containing G418 medium (only cells that are produced by transfection of the Neo gene can survive in these conditions) produce selection for functional STUMP-expression. For this purpose use is described Cardamom method "download acid" (Sardet and others, Cell, 56, 271-280 (1989)). Cells that Express funktsionalnostey NHE-subtypes may also compensate in the absence of CO2and the HCO3-implemented in this test acidification, nitrostilbene LAP-1 cells, in contrast, are unable to perform this compensation. After repeated selection method "download acid" surviving cells were seeded in microtiter tablets so that statistically should meet one cell per well. After about 10 days of using the microscope control, how to grow many colonies per well. The population of cells from individual colonies then use a set of "HTT-proliferation" (Boehringer, Mannheim) are examined in relation to their ability to survive after boot "acid". For subsequent use of the best test cell line and to avoid loss transtitional sequence under the constant influence of selection, the cult, the-subtypes with specific substances easily change developed by S. Faber test (Faber and others, Cell Physiol. Blochem., 6, 39-49 (1996)), which is based on the "download acid". In this test, determine the recovery of intracellular pH (pHiafter acidification, which is used in the case funktsionaalsusega NHE also in the absence of bicarbonate. For this pHidetermined using a sensitive pH fluorescent dye BCECF (Calbiochem use predecessor BCECF-AM). Cells first "load" using BCECF. The fluorescence of BCECF determine the spectrometer to determine fluorescence ("Ratio Fluorescence Spectrometer"; Photon Technology International, South Brunswick, N. I., USA) at excitation wavelengths of 505 and 440 nm and the wavelength of emission of 535 nm and using the calibration curves are converted to pHi. In contrast to the described methods cells already under load using BCECF incubated in NH4C1-buffer (pH 7.4) (NH4C1-buffer: 115 mmol of sodium chloride; 20 mmol of ammonium chloride; 5 mmol potassium chloride; 1 mmol of calcium chloride; 1 mmol of magnesium sulfate; 20 mmol of HEPES; 5 mmol glucose; 1 mg/ml bovine serum albumin; pH value of 7.4, installed using a 1M solution of sodium hydroxide). Intracellular acidification cause by adding 975 µl containing NH4C1-buffer to AN register in the case of NHE-1 - 2 minutes in the case of NHE-2 - 5 minutes in the case of NHE-3 - 3 minutes. To calculate the inhibitory capacity of the tested substances, the cells are first investigated in the buffers, which does not, accordingly, no restore pH. For full recovery of pH (100%) of cells incubated in the containing sodium ions buffer (133,8 mmol of NaCl; 4.7 mm KCl; 1.25 mmol of calcium chloride; 1.25 mmol of magnesium chloride; 0.97 mmol Na2NRA2, 0.23 mmol NaH2RHO4; 5 mmol of HEPES; 5 mmol glucose; pH equal to 7.0, installed using a 1M solution of sodium hydroxide). To determine the zero value (0%) cells incubated in not containing sodium ions buffer (133,8 mmol of holdingarea; 4.7 mmol KCl; 1.25 mmol of calcium chloride; 1.25 mmol of magnesium chloride; 0.97 mmol K2HPO2; 0.23 mmol KN2RHO4; 5 mmol of HEPES, 5 mmol glucose; pH equal to 7.0, installed using a 1M solution of sodium hydroxide). Subjects substances injected into the containing sodium ions buffer. Recovery of intracellular pH in the case of each tested concentration of a substance expressed in percentage of maximum recovery. Of the values in the percent recovery of pH with p the tx2">

1. Phenylsilane guanidine alkenylboronic acid of the formula (I)

< / BR>
where T means

< / BR>
moreover, R(A) denotes hydrogen, fluorine, chlorine, bromine, iodine, (C1-C4)-alkyl;

R(B) R(C) and R(D) independently from each other are specified for R(A) value;

x is zero or 1;

the means zero or 1;

R(F) means hydrogen, fluorine, chlorine, bromine, iodine, (C1-C4)-alkyl;

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

R(1) independently has a specified T value or R(1) means hydrogen, -OkCmH2m+1, fluorine, chlorine, bromine, iodine, -(C= O)-N= C(NH2)2ABOUTu(CH2)vWITH6H5, -Ou2-(C1-C9-heteroaryl, and heteroaryl is a derivative of phenyl in which one CH group is replaced by nitrogen,

k is zero or 1;

m denotes zero or 1;

u means zero or 1;

u2 means zero or 1;

v means zero,

R(2), R(3), R(4) and R(5) independently of one another are specified for R(1) value 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 methyl, metoxygroup, -(CH2)w2NR(24)R(25), R(24) and R(25) independently of one another denote (C

2. The compound of formula (I) under item 1, wherein T means

< / BR>
moreover, R(A) denotes hydrogen, fluorine, chlorine, (C1-C4)-alkyl;

R(B) R(C) and R(D) independently from each other are specified for R(A) value;

x is zero or 1;

the means zero or 1;

R(F) means hydrogen, fluorine, chlorine, (C1-C4)-alkyl;

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

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

R(1) means hydrogen, -OkWITHmH2m+1, fluorine, chlorine, bromine, iodine, -(C= O)-N= C(NH2)2ABOUTu(CH2)vWITH6H5, -Ou2-(C1-C9-heteroaryl, and heteroaryl is a derivative of phenyl in which one CH group is replaced by nitrogen,

k is zero or 1;

m denotes zero or 1;

u means zero or 1;

u2 means zero or 1;

v means null;

R(2), R(3), R(4) and R(5) independently of one another are specified for R(1); 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 methyl, metoxygroup, - (CH2)w2NR(24)R(25), R(24) and R(25) denote methyl, w2 means 1, 2,

moreover, in the molecule contains two balance T is l;

the means null;

R(F) means hydrogen, fluorine, chlorine, (C1-C4)-alkyl;

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

R(1) independently has a specified T value; or R(1) means hydrogen, -OkCmH2m+1, fluorine, chlorine, -(C= O)-N= C(NH2)2ABOUTu(CH2)vC6H5, -Ou2-(C1-C9-heteroaryl; and heteroaryl is a derivative of phenyl in which one CH group is replaced by nitrogen,

k is zero or 1;

m denotes zero or 1;

u means zero or 1;

u2 means zero or 1;

v means null;

R(2), R(3), R(4) and R(5) independently of one another are specified for R(1); 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 methyl, metoxygroup, -(CH2)w2NR(24)R(25), R(24) and R(25) independently of one another denote methyl; w2 is 1, 2,

moreover, in the molecule contains two balance So

4. The compound of formula (I) according to any one of paragraphs. 1-3, characterized in that it is a

1,2-bis-[3-(guanidin E-2-methylpropenoic acid)] benzene-dihydrochloride;

1,3-bis-[3-(guanidin E-2-methylpropenoic acid)] benzene-dihydro thisproposal acid)] naphthalene-dihydrochloride;

1,2-bis-[3-(guanidin Z-2-forproposal acid)] benzene-dihydrochloride;

1-[3-(guanidin Z-2-forproposal acid)] -2-[3-(guanidin E-2-methylpropenoic acid)] benzene-dihydrochloride;

1,3-bis-[3-(guanidin Z-2-forproposal acid)] benzene-dihydrochloride;

guanidin 3-(4-chloro-3-guanidiniocarbonyl-5-phenyl)phenyl-2-methylpropanoic acid;

1,3-bis-[3-(guanidin E-2-methylpropenoic acid)] -5-methyl-benzene hydrochloride;

1,2-bis-[3-(guanidin E-2-methylpropenoic acid)] -4-methylbenzol-dihydrochloride;

1,2-bis-[3-(guanidin E-2-methylpropenoic acid)] -4,5-dichlorobenzene-dihydrochloride;

1,3-bis-[3-(guanidin E-propanolol acid)] benzene-dihydrochloride;

1,2-bis-[3-(guanidin E-2-methylpropenoic acid)] -4-Brabanthal-dihydrochloride;

1,2-bis-[3-(guanidin E-2-methylpropenoic acid)] -4-(4-methoxyphenoxy)benzene-dihydrochloride;

1,2-bis-[3-(guanidin E-2-methylpropenoic acid)] -4-(4-methylphenoxy) benzene-dihydrochloride;

1,3-bis-[3-(guanidin E-2-methylpropenoic acid)] -5-methoxybenzoyl hydrochloride;

1,3-bis-[3-(guanidin E-2-methylpropenoic acid)] -5-tert. -butylbenzoyl hydrochloride;

1,4-bis-[3-(guanidin E-2-methylpropenoic acid)] -2,5-dichlorobenzene-dihydrochloride;

1,2-bis-[3-(guanidin E-2-methylethoxy)benzene-dihydrochloride;

1,2-bis-[3-(guanidin E-2-methylpropenoic acid)] -4-(ethoxy)benzene-dihydrochloride;

1,2-bis-[3-(guanidin E-2-methylpropenoic acid)] -4-(3-pyridyloxy)benzene-dihydrochloride.

5. The compound of formula (I) under item 1, used for getting medicines for the treatment of arrhythmias.

6. The compound of formula (I) under item 1, used for getting medicines for the treatment or prevention of heart attack.

7. The compound of formula (I) under item 1, used for getting medicines for the treatment or prophylaxis of angina.

8. The compound of formula (I) under item 1, used for getting medicines for the treatment or prophylaxis of ischemic conditions of the heart.

9. The compound of formula (I) under item 1, used for getting medicines for use in surgical operations and organ transplants.

10. The compound of formula (I) under item 1, used for getting medicines for the treatment of diseases in which cell proliferation represents a primary or secondary cause.

11. Drug, possess inhibitory activity against Na+/H+-exchange isout compounds of General formula (I) p. 1.

 

Same patents:

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 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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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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The invention relates to an improved method of producing TETRAFLUOROMETHANE used as the low-temperature refrigerant, a reagent for dry etching of semiconductors, fire retardant

The invention relates to the production of nonionic surfactants (nonionic surfactants, in particular ethoxylated monoalkylphenols-based propylene trimer (neonols)

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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