Substituted guanidine thiophenemethylamine acid and drug

 

(57) Abstract:

Describes substituted guanidine thiophenemethylamine acid of the formula I where at least one of the substituents R(1), R(2) and R(3) denotes R(31)SOk-, R(31) represents C1-C8-alkyl, k is zero or two, and accordingly the other substituents R(1), R(2) and R(3) independently of one another denote H, F, Cl, Br, I, R(4) and R(5) independently from each other hydrogen or C1-C8-alkyl, and their pharmaceutically acceptable salts. These guanidine are very effective antiarrhythmic funds cardiotoxins component and their use for the prevention and treatment of infarction and for the treatment of angina, and they also inhibit or greatly reduce the pathophysiological processes in the emergence of induced ischemia damage, especially during the occurrence of induced ischemia of cardiac arrhythmias. 2 c. and 1 C.p. f-crystals, 1 PL.

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 Il 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, accordingly, the other substituents R(1), R(2) and R(3) independently of one another H, F, Cl, Br, I, CN,

-Ona-CmaH2ma+1or-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 drucil 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.

Preferred compounds of formula I, in which

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 or 2;

q 1, 2, 3 or 4;

k is zero or 2;

R(40) alkyl with 1, 2, 3 or 4 C-atoms, perfluoroalkyl of 1, 2, 3 or 4 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;

R(31) alkyl with 1, 2, 3 or 4 C-atoms, perfluoroalkyl of 1, 2, 3 or 4 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) P(42);

R(41)and R(42)

independently from each other hydrogen, CH3or CF3;

or

R(41)and R(42)

together 4 or 5 methylene groups, of which CH2-group may be replaced by oxygen, S, NH, N Is N, F, Cl, Br, I, CN,

-Ona-CmaH2ma+1or-OgaWITHraH2raR(10);

PA zero or 1;

mA zero, 1, 2, 3 or 4;

ga zero or 1;

ha zero, 1 or 2;

R(10) 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 and methoxy;

R(4) and R(5) independently of one another hydrogen, F, C1, alkyl with 1, 2, 3 or 4 C-atoms, perfluoroalkyl of 1, 2, 3 or 4 C-atoms, cycloalkyl 5, 6, 7 or 8 - volumes, 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 of one another hydrogen, CH3,CF3< / BR>
and their pharmaceutically tolerated salts.

Especially preferred compounds of formula I, in which mean:

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

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

p is zero or 1;

s zero,

q 1;

k is zero or 2;

R(31) CH3,CF3or 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 is h where CH2-group may be replaced by oxygen, S, NH, N-CH3or N-benzyl;

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

independently from each other H, F, Cl, CN,

-Ona-CmaH2ma+1or OgaCraH2raR(10);

PA zero or 1;

mA zero, 1, 2, 3 or 4;

ga zero or 1;

ha zero or 1;

R(10) phenyl, which 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, CH3, CF3< / BR>
and their pharmaceutically tolerated salts.

Very particularly preferred compounds of formula I, in which mean:

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

R(31)SOk-;

k is zero or 2;

R(31) CH3, CF or phenyl which is not substituted or is substituted by 1-3 substituents from the group consisting of F, Cl, CF3, methyl and methoxy;

or

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

R(41)and R(42)

independently from each other hydrogen, CH3or CF3;

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

mA zero, 1, 2, 3 or 4;

ga zero or 1;

ha zero or 1,

R(10) phenyl, which 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, C1, CH3,CF3< / BR>
and their pharmaceutically tolerated salts.

Specifically and especially prefer compounds:

guanidin E-3-[2-(4-methylsulphonyl-thiophenyl)] propylene acid,

guanidin E-3-[2-(5-methylthio-thiophenyl)]-2-methyl-propylene acid,

guanidin E-3-[2-(5-methylsulphonyl-thiophenyl)] -2-methyl-propylene acid,

guanidin E-3-[2-(3-chloro-4-isopropylphenyl-5-methylthio-thiophenyl)] -2-methyl-propylene acid

guanidin E-3-[2-(3-chloro-4-isopropylphenyl-5-methylsulphonyl-thiophenyl)] 2-methyl-propylene acid

and their pharmaceutically tolerated salts.

If the compounds of formula 1 contain one or more centers of asymmetry, the latter can have both S-and R-configuration. The compounds can exist as optical isomers, diastereomers, racemates or mixtures thereof.

The geometry of the double bond of compounds of formula I can be either E or Z. the Compounds can exist in the form of a mixture and the or branched chain.

Further, the invention relates to a production method of compound I, wherein compound of formula II

< / BR>
interacts with guanidino, with R(1)-R(5) have a specified value, and L denotes lacosamide nucleophilic residual group.

Activated derivatives of the acid of formula II, where L denotes alkoxy, mainly methoxy group, fenoxaprop, phenylthio-, methylthio-, 2-pyridylthio, nitrogen-containing heterocycle, preferably 1-imidazolyl, mostly get by known methods from the anhydrides of carboxylic acids (formula II, L= C1), which can be obtained, in turn, by known methods from carboxylic acids (formula II, L=OH), for example, chloride tiomila.

Along with anhydrides of carboxylic acids of the formula II (L=C1) can be obtained other activated acid derivatives of the formula II in a known manner directly from derivatives of benzoic acid (formula II, L=OH), such as methyl ester of the formula II with L=co3treatment with gaseous Hcl in methanol, imidazoline formula II by treatment carbonyl diimidazol [L= 1-imidazolyl, Staab, Angew. Chem. Int. Ed. England 1,351-367 (1962)] , the mixed anhydrides II processing C1-SOOS2 is acid-dicyclohexylcarbodiimide (DCC) or O-[(cyano (etoxycarbonyl)methylene)amino]- 1,1,3,3 - tetramethyluronium - tetrafluoroborate ("TOTU") [Proceedings of the 21st European Symposium Peptides, Peptides 1990, Editors E. Giralt and D. Andreu, Escom, Leiden, 1991]. A number of suitable methods for obtaining activated derivatives of carboxylic acids of formula II listed in the literature J. March, Advanced Organic Chemistry, 3rd edition (John Wiley & 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 but inert organic solvent. When the interaction of the methyl esters of benzoic acids (II, L=OMe) with guanidine, methanol, isopropanol or tetrahydrofuran are suitable as solvents from the 20oWith up to their boiling point. In most cases, compounds II with salt-free guanidine interact in aprotic inert solvents, such as tetrahydrofuran (THF), dimethoxyethane, dioxane. When using a base, for example NaOH as a solvent, you can use water in the interaction of compound (II) with guanidine.

If L= C1, mainly add cyclocopter, for example, in the form of excess guanidine, to bind halomonadaceae acid.

Part p which can be obtained are known from the literature methods. Received alkenylboronic acid make one of the above options how to compounds I according to the invention.

The introduction of some substituents can implement known from the literature by means of a combination of cross-linking by palladium aryl halides or aritifacts, for example, organic tin salts, organic acids boron or organic boron or medialivecasino or tsinkorganicheskih connections.

Guanidine carboxylic acids I are weak bases and can bind the acid with the formation of salts. As the acid additive salts used salts of all pharmacologically tolerated acids, for example, the halides, especially hydrochloride, lactates, sulfates, citrates, acetates, phosphates, methylsulfonate, n-toluensulfonate.

The compounds I are substituted acylhalides. Significant representative of acylhalides is derived pyrazine amiloride, which finds application in therapy as calyceraceae diuretic. Numerous other compounds of the type amiloride described in the literature, as, for example, dimethylaniline or ethylisopropylamine.

< / BR>
The B>3)2.

In addition, there are studies that indicate antiarrhythmic properties of amiloride (Circulation 79, 1257-63 (1989)). However, its widespread use prevents mild effect, accompanied by a decrease in blood pressure and solidarities action, however, these side effects in the treatment of cardiac arrhythmias undesirable.

An indication of the antiarrhythmic properties of amiloride were obtained in experiments on isolated hearts of animals (Eur. Heart J. 9 (1): 167 (1988) (extract)*. For example, in the hearts of rats found that artificially induced flicker of the ventricles of the heart can be completely suppressed by amiloride. Even stronger than amiloride, was derived above amiloride ethylisopropylamine.

From WO 84/00875 known guanidine cinnamic acid (Raand Rcor Rband R=double bond; R(1)=substituted phenyl); however, thiophene compounds is not described.

From U.S. patent 2734904 known guanidine cinnamic acid (R=substituted phenyl, alkyl= albaniles), but not described by any of the claimed compounds thiophene. However, the known guanidine thiophene-alkenyl-carboxylic acid, however, is not the possession is the description of Germany 4421536.3 (NOAH 94/F 168) described guanidine cinnamic acid, however, not described no connection thiophene.

However, the known and proposed connections do not meet all the desired requirements, so that their solubility in water is poor.

In addition, they do not possess the desired degree of selectivity.

The problem is solved by compounds that do not possess unwanted and negative solidariteitsactie properties, however, have a very good antiarrhythmic properties, which are important for the treatment of diseases caused by hypoxia. These compounds, due to their pharmacological properties, making them ideal as antiarrhythmic drugs with cardiotoxin component for the prophylaxis and treatment of infarction and for the treatment of angina, and they prevent or greatly reduce the pathophysiological processes in the emergence of induced ischemic damage, especially during the occurrence of induced ischemic cardiac arrhythmias. Because of their protective actions against pathological hypoxic and ischemic situations, the compounds of formula I according to the invention, due to inhibition of the cellular mechanism of exchange of Na+

In addition, the compounds of formula I according to the invention have strong inhibitory effects on cell proliferation, such as the proliferation of fibroblasts, CL is enaut as valuable therapeutic agents for diseases, in which cell proliferation represents a primary or secondary cause, and can therefore be used as antiatherosclerotic funds funds against diabetic late complications, cancer, fibromya diseases such as pulmonary fibrosis, fibrosis of the liver or kidney, hypertrophy and hyperplasia of the authorities, especially in prostate hyperplasia or prostate hypertrophy.

Compounds according to the invention are inhibitors of the cellular sodium-proton-antinomies (Na+/H+the ion exchanger), which in numerous diseases (essential hypertension, atherosclerosis, diabetes, and so on) increased in these cells; measurement readily available, for example, in erythrocytes, platelets or leukocytes. Therefore, the compounds according to the invention is suitable as a simple scientific tools, for example, in their application as diagnostic tools for the detection and identification of certain forms of hypertension, but also of atherosclerosis, diabetes, proliferative diseases, etc. in Addition, the compounds of formula I are used for prophylactic therapy to prevent the Genesis of high blood pressure, for example, when the essential Gobert is but intravenously, rectally or via inhalation, and the preferred destination depends on the appropriate clinical picture of the disease. Thus the compounds I can be used alone or together with galenovye drugs, both in veterinary and in human medicine.

What auxiliary substances for the desired recipe medicines suitable specialist known on the basis of his special knowledge. Along with solvents, geleobrazovanie, the basics of candles, excipients of the tablets can be applied to other carriers of active substances, such as antioxidants, dispersants, emulsifiers, defoamers, substances, corrective unpleasant taste of drugs, preservatives, agents, dissolution or dyes.

For oral use, the active compounds are mixed with appropriate additives, such as substances-carriers, stabilizers or inert solvents and conventional methods to prepare suitable forms of administration, as tablets, pills, capsules with a shell, water, alcoholic or oily solutions. As carriers can be used, for example, gum Arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially ku is ve oily substances vehicles or solvents used, for example, plant and animal oil, such as sunflower oil or cod-liver oil.

For subcutaneous or intravenous administration prepare a solution, suspension or emulsion of the active compounds, if necessary with conventional for this purpose substances as agents of dissolution, emulsifiers or other auxiliaries. As the solvent used, for example, water, physiological sodium chloride solution or an alcohol, e.g. ethanol, propanol, glycerin, along with this sugar solutions, glucose or mannitol, or a mixture of various of the aforementioned solvents.

As a pharmaceutical preparation for use in the form of aerosols or sprays are used, for example, solutions, suspensions or emulsions of the active substances of the formula I in a pharmaceutically not calling fears solvent, mainly in ethanol or water, or in mixtures of such solvents.

Medication, as needed, may contain other auxiliary substances, such as surfactants, emulsifiers and stabilizers, as well as a blowing gas. This dosage form contains an active ingredient generally in a concentration of about 0.1 - 10, preferably about 0.3-3 wt.%.

On average, the daily dose of the compounds of formula I in 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, for example, immediately after the transfer of myocardial infarction may be necessary as well as higher and especially more frequent dosing, for example up to 4 single doses per day. In particular, with intravenous administration, for example, in a patient with infarction in the intensive care unit can take up to 200 mg per day.

List of abbreviations:

Meon - methanol

DMF - N, N - dimethylformamide

EI is electron impact

DCI - desorption chemical ionization

RT - room temperature

HER - ethyl acetate (tO)

NER - n-heptane

DME - dimethoxyethan

ES - spray of electrons

FAB - fast bombardment of atoms

CH2CL2- dichloromethane

THF - tetrahydrofuran

The experimental part.

General instructions for obtaining guanidino alkenylamine the aqueous carboxylic acid of the formula II is dissolved or suspended in anhydrous THF (5 ml/mmol) and then mixed with 1.1 EQ of carbonyldiimidazole. After stirring over 2 h at room temperature the reaction solution is injected 5.0 eq. of guanidine. After stirring overnight distilled THF under reduced pressure in a rotary evaporator apparatus, mixed with water, set pH to 6-7 using 2n. HCl and filtered appropriate guanidin (formula I). Obtained in this way guanidine carboxylic acid can be converted to the corresponding salts by treatment of aqueous, methanolic or ethereal hydrochloric acid or other pharmacologically tolerated acids.

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

1,0 EQ. complex Olkiluoto ether carboxylic acids of the formula II and 11.5 EQ. guanidine (free base) are dissolved in isopropanol or suspended in THF and boiled at Flyglobespan to complete metamorphosis (control thin layer) (typical reaction time from 2 to 5 h). The solvent is distilled under reduced pressure (rotary evaporator apparatus), absorb with ethyl acetate and washed 3 times using NaHCO3-solution. Dried over Na2SO4the solvent is distilled off in vacuum and chromatographic on silica gel using a suitable solvent, is)] propylene acid

< / BR>
1 (a) methyl ester of E-3-[2-(4-methylsulphonyl-thiophenyl)] propylene acid.

1 EQ. difficult methyl ester 3-[2-(4-bromothiophene)] propylene acid, 2 EQ. sodium salt methylsulfonate acid, 2 EQ. CuI is heated in the reverse flow in toluene/DMF (2/3; 3 ml/mmol of ester). Standard processing and chromatography on silica gel (solvent: cyclohexane/HER) allocate methyl ester of E-3-[2-(4-methylsulphonyl-thiophenyl)] propylene acid;

melting point: amorphous, MS: 247(M+1)+;

1 b) carboxylic acid release under standard conditions (MeOH/NaOH) of ester 1 (a);

melting point: 203 MS: 233(M+1)+;

1 (C) 1 (b) transferred by the common regulations And the hydrochloride of guanidine;

melting point: 200 MS: 274(M+1)+.

EXAMPLE 2: hounded E-3-[2-(5-methylthio-thiophenyl)]-2-methyl-propylene acid, hydrochloride

< / BR>
2 (a) 1 EQ. complex teeterboro ether 2-phosphoproteomes acid is subjected to deprotonation atoWith 1 EQ. n-utility in hexane and then at room temperature was mixed with 1 EQ. 5-methylthiazolidine. After complete conversion of the aldehyde spend processing water and shaken out three times with toluene. After sushi the SPS separated by chromatography on silica gel mixture through HER/NER as solvent. Produce complex ethyl ester E-3-[2-(5-methylthio-thiophenyl)]-2-methyl-propylene acid.

Colorless oil, MS: 243(M+1)+.

2 b) ester of 2 and translated version In the first guanidin and then in hydrochloride;

melting point: 172oC.

EXAMPLE 3: guanidin E-3-[2-(5-methylsulphonyl-thiophenyl)]-2-methyl-propylene acid, hydrochloride

< / BR>
3 (a) ester of 2) by standard reactions are oxidized using 2,2 EQ. m-chloroperbenzoic acid in methylene chloride to complex ethyl ester E-3-[2-(5-methylsulphonyl-thiophenyl)]-2-methyl-propylene acid.

Colorless oil, MS: 275(M+1)+.

3 b) ester of 3 (a) is transferred first with sodium hydroxide in methanol in a free acid and then with option a in guanidinopropionic.

The acid.

Amphora solid MS: 247(M+1)+.

Guanidinopropionic:

melting point: >210oC MS: 288(M+1)+.

EXAMPLE 4: guanidinopropionic E-3-[2-(3-chloro-4-isopropylphenyl-5-methylthio-thiophenyl)]-2-methyl-propylene acid

< / BR>
4 (a) by analogy with (2) commercially available 3-chloro-4-isopropylphenyl-5-methylthio-thiophenyl-2-carbaldehyde was transferred to with whom b) ester of 4 (a) translated version In guanine and was isolated as hydrochloride.

Melting point: 227-235oMS: 396(M +1)+.

EXAMPLE 5: guanidinopropionic E-3-[2-(3-chloro-4-isopropylphenyl-5-methylsulphonyl-thiophenyl)]-2-methyl-propylene acid.

< / BR>
5 (a) ester of 4) by standard reaction with 2,2 EQ. m-chloroperbenzoic acid in methylene chloride was transferred to complex ethyl ester E-3-[2-(3-chloro-4-isopropylphenyl-5-methylsulphonyl-thiophenyl)] -2-methyl-propylene acid. - MS: 416(M+1)+.

5 b) ester 5 (a) option b is transferred to guanidin and isolated in the form of hydrochloride. - MS: 428(M+1)+.

The method of determining the biological activity proposed according to the invention compounds.

To determine the value IC50determined the influx of sodium in erythrocytes, to this new Zealand white rabbits (Ivanovas) received standard feed with 2% cholesterol for six weeks in order to activate the Na+/H+- currency (with Scholz al., 1990) and the erythrocytes acceptable for measuring the flow of sodium through the Na+/H+exchange by flame photometry. A blood sample was taken from the ear artery of the rabbit and pre-coagulate by 25 IE/ml heparin-potassium. Hematocrite: the project for sodium in the blood.

To determine the flow of sodium in erythrocytes, sensitive, such as amiloride, 100 Ál of each sample of blood was added to 5 ml hyperkalemia Saharsa-salt buffer (amounts in mm: NaCl 140, KCl 3, sucrose 150, oubain 0,1, Tris-hydroxy-methylamino-methane 20, pH 7.4) and incubated for 60 min at a temperature of 37oC. the Erythrocytes washed three times in ice-cold solution of MgCl; and oubain (amounts in mm: gl2112, oubain 0,1) using centrifugeuse. To determine the content vnutrijeluderngo Na+cells demolishable in distilled water, the cell membrane was centrifuged and the concentration of sodium in the hemolysate was measured by flame photometry. Net inflows of sodium in erythrocytes was calculated by the difference between the original sodium content and sodium content after incubation. For example, the influx of sodium, sensitive to amiloride, was calculated by the difference between the sodium content of the erythrocytes after incubation with amiloride 310-4M and without amiloride. Each experiment was performed with erythrocytes from six different animals. In each case, the comparison of the contents of Na+were performed on each animal erythrocytes. Statistical analysis the obtained data, Provody may be considered reliable.

The above method of determining the activity of compounds in the ratio of Na+/H+exchange was published in various publications, in particular in the description of the application DE 4318756 A1.

Comparative inhibition of Na+/H+-exchange compounds related in structure unexpectedly showed that the compounds according to the invention have a much greater biological activity than the compounds known from the prior art.

Compound 1 is a compound known from D3 with unsubstituted thiophene ring, has a high IC50value 7 Ámol/l DZ-US 2734904).

Compound 2 according to the invention on the contrary has SN3S-substituents on the thiophene ring and the IC50-value of 0.05 Ámol/l, and is several times more active than most similar in structure compound 1 of D3.

Comparison of compound 3 (with methyl substituents on the thiophene) and compound 2 (according to the invention with CH3's Deputy) showed opposite unexpectedly stronger influence RSOk-Vice according to the invention, since CH3S-connection 2 with IC50- value equal to 0.05, is substantially more active than the substitution, but without unsaturated group between the thiophene ring and the carbonyl group with IC50- value less or much less 10 Ámol/l, is much less active, opposite the connection 5 with the same substitution in the thiophene ring, but additionally containing olefinic group has IC50is set to 3 Ámol/l and is more active.

This comparison shows high values unexpectedly superior biological activity of the compounds according to the invention in comparison with the compounds of the prior art.

1. Substituted guanidine thiophenemethylamine acid of General formula

< / BR>
where at least one of the substituents R(1), R(2) and R(3) denote R(31)SOk-, R(31) - C1-C8-alkyl, k = 0 or 2, and accordingly the other substituents R(1), R(2) and R(3) independently of one another denote H, F, Cl, Br, I,

R(4) and R(5) independently of one another denote hydrogen or C1-C8-alkyl,

and their pharmaceutically acceptable salts.

2. The compounds of formula I on p. 1, representing a compound selected from the group consisting of: guanidine E-3-[2-(4-methylsulphonyl-thiophenyl)] -propanolol acid, guanidine E-3-[2-(5-methylthio-thiophenyl)] -2-methyl-PR-4-isopropylphenyl-5-methylthiophenyl)] -2-methylpropanoic acid, guanidine E-3-[2-(3-chloro-4-isopropylphenyl-5-methylsulphonyl-thiophenyl)] -2-methylpropanoic acid.

3. The drug, inhibition of Na+/H+-currency, characterized in that it contains an effective amount of the compounds of formula 1 according to one of paragraphs. 1 and 2.

 

Same patents:

The invention relates to new derivatives of tamilcanadian with the General formula (I) wherein R' represents 2-thienyl or 3-thienyl radical, R represents ceanorhaditis or a radical of the formula-C(O) - and R2 is optional saturated or unsaturated cyclic hydrocarbon radical or aryl radical

The invention relates to the derivatives of thiophene of the General formula I, in which R1is the formula A1- X1- R3; R2is perhaps the formula A2- X2- R4; ring b is 4-10-membered nitrogen-containing cycloalkyl ring or 5 - or 6-membered nitrogen-containing unsaturated heterocycle; Ar represents an aryl ring or heteroaryl ring; A1, A2and A3may be the same or different and each represents a bond or lower alkylenes group; X1and X2may be the same or different and each represents a bond or a formula-O-, -S-; R3and R4may be the same or different, and each represents a hydrogen atom, cyclic aminogroup or a lower alkyl group, aryl group or aracelio group, or its pharmaceutically acceptable salt

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 new tricyclic pyrazole derivative or its pharmaceutically acceptable salt

The invention relates to novel 2,5-disubstituted tetrahydrofuran or tetrahydrothiophene formula I

< / BR>
where Ar is phenyl, which is optionally substituted by at least one group selected from halo (including, but not limited to, fluorine), lower alkoxy (including methoxy), lower aryloxy (including phenoxy), cyano, or R3;

m = 1;

W is independently - AN(OM)C(O)N(R3R4, -AN(R3)C(O)N(OM)R4, -AN(OM)C(O)R4AC(O)N(OM)R4, -C(O)N(OM)R4or-C(O)NHA;

A - lower alkyl, lower alkenyl or lower quinil, in which one or more carbons optionally may be replaced by O, N or S;

M is hydrogen, a pharmaceutically acceptable cation;

X IS O,S;

Y is O, S, hydrogen, lower alkyl, lower alkenyl, lower quinil, alkaryl;

R1and R2independently is hydrogen, lower alkyl, halo, or-COOH;

R3and R4independently is hydrogen, alkyl, alkenyl, quinil,1-6alkoxy-C1-C10alkyl or C1-6alkylthio-C1-10alkyl,

which possess anti-inflammatory activity through inhibition of 5-lipoxygenase as PAF receptor antagonists and are dual activity, t
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